Profiles in Pulmonary Hypertension and Pulmonary Embolism

Profiles in Pulmonary Hypertension and Pulmonary Embolism

Scott H. Visovatti

Vallerie V. Mclaughlin

Some of the material in this chapter was contributed by Samuel Z. Goldhaber, Nils Kucher, and Michael J. Landzberg in previous editions.


Pulmonary hypertension (PH) is a broad term used to describe an elevation of pressure in the pulmonary arteries as a consequence of one or more disease processes (Table 42.1). The diagnosis requires a mean pulmonary artery pressure (mPAP) of >25 mmHg by right heart catheterization (RHC), and is suggested by a Doppler transthoracic echocardiogram (TTE) revealing a tricuspid regurgitation velocity of >2.3 m/second or a right ventricular systolic pressure (RVSP) of >40 mmHg. Pulmonary arterial hypertension (PAH) is a subset of PH, and results from restricted flow through the pulmonary arterial system. The diagnosis of PAH requires an RHC and fulfillment of a specific set of hemodynamic criteria: mPAP of >25 mmHg, pulmonary capillary wedge of ≤15 mmHg, and pulmonary vascular resistance (PVR) of >3 Wood units. Pulmonary venous hypertension (PVH) refers to the subset of PH resulting from processes affecting the left side of the heart, resulting in an increased pressure in the pulmonary veins, which is transmitted back to the right side of the heart. Left heart disease is by far the most common etiology of PH identified by Doppler echocardiography; in one study, pulmonary arterial hypertension was identified in only 2.7% of patients found to have PH by TTE (Table 42.2). The distinction between PAH and PVH is an important one, as it has a large impact upon prognosis, the need for referral to an expert, and treatment options.


The pulmonary vasculature is a low-pressure system with a normal systolic pulmonary artery pressure (sPAP) range of 15 to 30 mmHg and mPAP of 9 to 18 mmHg. The pulmonary circulatory system functions with one-twelfth the resistance to flow observed in the systemic vascular bed, in part due to the large cross-sectional area of the pulmonary circulation.3 Moreover, a typical right ventricular systolic pressure of 25 mmHg is one-fifth the typical left ventricular systolic pressure. Increases in pulmonary vascular resistance are not well tolerated by this low-pressure system, and adaptive responses, including right ventricular hypertrophy (RVH), begin to develop within 96 hours of induced pulmonary hypertension in animal models.4 RVH is often followed by contractile dysfunction and/or RV dilatation as further compensatory responses. Continued remodeling leads to an alteration in RV shape from crescent to concentric, and the septum flattens due to the increased RV pressures. As a result of these processes, RV-LV interventricular dependence is affected, leading to LV diastolic dysfunction, a decrease in LV end-diastolic volume, and a resultant decrease in stroke volume and cardiac output.5 Progressive right-sided heart failure is both the final common pathway and the primary cause of death in patients with PH.

For non-Group I PH, the mechanism by which a disease process results in an elevated PA pressure is often apparent. For example, occlusion of the pulmonary vasculature owing to pulmonary thromboembolic disease results in elevated right-sided pressures as blood is impeded from flowing freely toward the left atrium. A similar process occurs in patients with obstructive lung disease or sleep disordered breathing owing to hypoxic pulmonary vasoconstriction. Left ventricular systolic or diastolic dysfunction or mitral regurgitation results in PH as an inefficient pump hampers antegrade flow.

Table 42.1 Dana Point Clinical Classification of Pulmonary Hypertension (2008)1


Pulmonary Arterial Hypertension (PAH)

1.1 Idiopathic PAH

1.2 Heritable

1.2.1 BMPR2

1.2.2 ALK1, endoglin (with or without hereditary hemorrhagic telangiectasia)

1.2.3 Unknown

1.3 Drug- and toxin-induced

1.4 Associated with

1.4.1 Connective tissue diseases

1.4.2 HIV infection

1.4.3 Portal hypertension

1.4.4 Congenital heart disease

1.4.5 Schistosomiasis

1.4.6 Chronic hemolytic anemia

1.5 Persistent pulmonary hypertension of the newborn

1′. Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH)

2. Pulmonary hypertension owing to left heart disease

2.1 Systolic dysfunction

2.2 Diastolic dysfunction

2.3 Valvular disease

3. Pulmonary hypertension owing to lung diseases and/or hypoxia

3.1 Chronic obstructive pulmonary disease

3.2 Interstitial lung disease

3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern

3.4 Sleep disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic exposure to high altitude

3.7 Developmental disorders

4. Chronic thromboembolic pulmonary hypertension (CTEPH)

5. Pulmonary hypertension with unclear multifactorial mechanisms

5.1 Hematologic disorders: myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis

5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders

5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure on dialysis

(Reproduced with permission from: Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-S54.)

Table 42.2 Prevalence of PH Groups


Prevalence (%)

PAH (Group 1)


Left heart disease


Lung disease and hypoxemia (Group 3)


CTEPH (Group 4)


Miscellanea/Unclear diagnosis (Group 5)


CTEPH, thromboembolic pulmonary hypertension; PAH, Pulmonary arterial hypertension; PH, pulmonary hypertension.

(Data from: Strange G, Playford D, Stewart S, et al. Pulmonary hypertension: prevalence and mortality in the Armadale echocardiography cohort. Heart 2012;98:1805-1811.)

In PAH, more complex structural changes occur in the pulmonary vascular bed, resulting in pulmonary arterial obstruction owing to vascular proliferation and remodeling. This process involves all layers of the vessel wall and is characterized by intimal hyperplasia, medial hypertrophy, adventitial proliferation, and in situ thrombosis.


The vasculopathy that results in PAH is likely triggered by the accumulation of multiple “hits” that may include a genetic predisposition, systemic disorder, or environmental factors.6,7 Once triggered, the pathobiology of PAH is dependent upon contributions from prostanoids, endothelin-1 (ET-1), and nitric oxide (NO), as shown in Figure 42.1. Additional research has implicated the serotonin,9 vasoactive intestinal peptide (VIP),10 and BMPR211,12 pathways in various forms of PAH.


Prostacyclin (PGI2) is a potent vasodilator and a strong inhibitor of platelet aggregation and smooth muscle cell proliferation. Thromboxane A2 is a potent vasoconstrictor and promotes platelet activation. In PAH, a decrease in prostacyclin and an increase in thromboxane A2 levels contribute to the phenotype.13


ET-1 is a potent vasoconstrictor and smooth-muscle mitogen that exerts its effects through the receptors ETA (located on smooth muscle cells) and ETB (located on vascular endothelial cells and smooth muscle cells).14 Activation of the ETA and ETB receptors on smooth muscle cells induces vasoconstriction, cellular proliferation, and hypertrophy, whereas stimulation of ETB receptors on endothelial cells results in production of vasodilators (NO and PGI2). Plasma ET-1 levels increase in PAH, and correlate to severity of disease and prognosis.15 Endothelin receptor antagonists (ERAs) function by selectively (ETA) or nonselectively (ETA and ETB) blocking ET-1 receptors.

Nitric Oxide Pathway

NO is a potent vasodilator and inhibitor of both smooth muscle cell proliferation and platelet activation. NO exerts its effects through cyclic guanosine monophosphate (cGMP), which is ultimately degraded by phosphodiesterase-5 (PDE-5).

PDE-5 inhibitors act by selectively blocking this enzyme, thus promoting the accumulation of intracellular cGMP and enhancing NO-mediated effects.


Serotonin is a vasoconstrictor that promotes smooth muscle cell hypertrophy and hyperplasia. Elevated total plasma serotonin and reduced platelet serotonin have been reported in PAH associated with ingestion of the anorexic agent dexfenfluramine, which increases the release of serotonin from platelets and inhibits its reuptake.16 Mutations in the serotonin transporter (5-HTT) and its receptor 5-HT2B have been described in PAH patients.17 Of note, selective serotonin-reuptake inhibitors (SSRI) are not associated with an increased incidence of pulmonary hypertension, and may be protective against hypoxic PH.18


The earliest classification system (1972) described two categories of PH: primary pulmonary hypertension and secondary pulmonary hypertension, depending upon the presence or absence of an identifiable cause. Groupings in the most recent classification system (Table 42.1) are based upon similar pathophysiological, clinical, and therapeutic characteristics. Familiarity with the system facilitates the generation of a differential diagnosis when considering the etiology of PH. Specialists use the classification when considering treatment options, as the majority of clinical trials involving PH medications have focused on Group 1 diagnoses.

Figure 42.1 Three major mechanistic pathways are known to be perturbed in patients with PAH. (1) The NO pathway: NO is created in endothelial cells by type III NO synthase (eNOS), which in turn induces guanylate cyclase (GC) to convert guanosine triphosphate (GTP) to cGMP, a second messenger that constitutively maintains pulmonary artery smooth muscle cell (PASMC) relaxation and inhibition of PASMC proliferation. (2) The endothelin (ET) pathway: Big-ET (or pro-ET) is converted in endothelial cells to ET-1 (21 amino acids) by endothelin-converting enzyme (ECE). ET-1 binds to PASMC ETA and ETB receptors, which ultimately leads to PASMC contraction, proliferation, and hypertrophy. ET-1 also binds to endothelial cell ETB receptors. (3) The prostacyclin pathway: The production of PGI2 (prostacyclin) is catalyzed by prostacyclin synthase (PS) in endothelial cells. In PASMCs, PGI2 stimulates adenylate cyclase (AC), thus increasing production of cAMP from ATP, another second messenger that maintains PASMC relaxation and inhibition of PASMC proliferation. Importantly, the pathways interact as illustrated, modulating the effect of any single pathway. They also are impacted by transmitters and stimuli that act at cell membrane receptors (Rec). Examples of these include but are not limited to thrombin, bradykinin, arginine vasopressin (AVP), vessel-wall shear stress, angiotensin II (Ang II), cytokines, and reactive oxygen species (ROS). In addition, the effect of a transmitter depends on its specific site of action (such as PASMC ETA or ETB receptors versus endothelial cell ETB receptor). The large white arrows depict aberrations observed in these pathways among patients with PAH. The orange boxes represent agents with reported clinically beneficial effects in patients with PAH. PDE5-inh indicates PDE-5 inhibitor, e.g., sildenafil; ETRA, endothelin receptor antagonist, e.g., bosentan (dual), ambrisentan, and sitaxsentan (receptor A selective). Prostanoids, e.g., epoprostenol, treprostinil, and iloprost, supplement exogenously deficient levels of PGI2. Red stop signs signify an inhibitory effect of the depicted agents. Dotted arrows depict pathways with known and unknown intervening steps that are not shown.8 (Reproduced with permission from: McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation 2006;114:1417-1431.)


A right heart catheterization is required to establish the diagnosis of PAH and is necessary prior to the initiation of PAH-specific medications. Repeat studies may be indicated to assess response to therapy, especially in patients who experience a progression of symptoms. A complete hemodynamic assessment includes the following components:

Right Atrial Pressure

Accurate assessment of right atrial pressure is essential, as it has prognostic implications and can help guide therapy. The most common right atrial manifestations of PAH are an attenuated x descent, prominent c-v wave, and deep and rapid y descent caused by tricuspid regurgitation (TR). In cases with severe TR, the RA waveform may be indistinguishable from that of the RV. Presence of RV hypertrophy and/or pressure overload may produce a prominent a wave owing to RV noncompliance.

Pulmonary Artery and Pulmonary Capillary Wedge Pressures

PAH is diagnosed by an mPAP of >25 mmHg and a pulmonary capillary wedge pressure of ≤15 mmHg. Careful assessment of the PA and PCWP waveforms is essential, as measurements made using an improperly placed catheter can lead to misdiagnosis. For example, an underwedged catheter can produce a hybrid waveform with a morphology intermediate between PA and PCWP tracings (Figure 42.3). Underwedging results in a falsely elevated PCWP that may lead to a diagnosis of PVH instead of PAH. Overwedging is less common and may result in inaccurate pressure measurements and pulmonary artery rupture. If the accuracy of a PCWP is in doubt, it is recommended that a left heart catheterization be performed to measure left ventricular end-diastolic pressure.

Cardiac Output and Pulmonary Vascular Resistance

An accurate cardiac output (CO) is essential, as cardiac index (CI), along with mRAP and mPAP, has been shown to be an important predictor of survival. It should be emphasized that mPAP may actually decrease with advancing PAH as right ventricular function fails.19 CO is also necessary for the computation of pulmonary vascular resistance [(mPAP − PCWP)/CO]. Patients with PAH generally have a transpulmonary gradient (mPAP − PCWP) >12 mmHg and a PVR >3 Wood units.

Vasodilator Testing

Acute vasodilator testing with inhaled NO (most common), intravenous epoprostenol, or intravenous adenosine is useful for identifying patients with a better prognosis who may experience a prolonged and beneficial response to calcium channel blocker (CCB) therapy. Responders exhibit at least a 10-mmHg decrease in mPAP to an absolute mPAP of <40 mmHg without a decrease in cardiac output.20,21 Patients who do not meet these criteria should not be treated
with CCBs. Acute vasodilator testing should be avoided in patients with significantly elevated left heart filling pressures or low cardiac output. Veno-occlusive disease and pulmonary capillary hemangiomatosis should be considered in patients who experience pulmonary edema during vasodilator testing.22

Figure 42.3 Pressure tracings depicting a PA waveform (A), underwedged PCWP with morphology intermediate between PCWP and PA waveforms (B), and a true PCWP waveform (C).

Other Considerations

A careful oximetry run to localize step-ups in the right heart should be performed if an intracardiac shunt is suspected. Dynamic exercise during right heart catheterization is used by some centers to unmask exercise-induced PAH (ePAH) in at-risk populations, such as patients with the scleroderma spectrum of diseases.23

Jun 26, 2016 | Posted by in CARDIOLOGY | Comments Off on Profiles in Pulmonary Hypertension and Pulmonary Embolism

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