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

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.

PATHOLOGY OF PULMONARY HYPERTENSION

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

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

Etiology	Prevalence (%)
PAH (Group 1)	2.7%
Left heart disease	67.9%
Lung disease and hypoxemia (Group 3)	9.3%
CTEPH (Group 4)	2%
Miscellanea/Unclear diagnosis (Group 5)	18.1%
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.

MOLECULAR AND CELLULAR MECHANISM OF PAH

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.

Prostanoids

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

Endothelin-1

ET-1 is a potent vasoconstrictor and smooth-muscle mitogen that exerts its effects through the receptors ET_A (located on smooth muscle cells) and ET_B (located on vascular endothelial cells and smooth muscle cells).¹⁴ Activation of the ET_A and ET_B receptors on smooth muscle cells induces vasoconstriction, cellular proliferation, and hypertrophy, whereas stimulation of ET_B 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 (ET_A) or nonselectively (ET_A and ET_B) 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

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

ETIOLOGIES

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.)

DIAGNOSIS

At the time of diagnosis, patients with PH typically have experienced progressive dyspnea-on-exertion (DOE) over the course of months to years. Fatigue, light-headedness, chest pain, palpitations, orthopnea, edema, paroxysmal nocturnal dyspnea, and cough are other common presenting symptoms. Syncope in a patient with PH is suggestive of advanced disease with RV failure.

Examination findings suspicious for the presence of PH include a prominent P2, a parasternal lift, a right ventricular S4, a systolic murmur of tricuspid regurgitation, an early systolic click, and a diastolic murmur of pulmonary regurgitation. Clues to the etiology of PH include central cyanosis, which may be the result of an intracardiac shunt or Eisenmenger syndrome; clubbing of the fingers owing to congenital heart disease; sclerodactyly or Raynaud’s phenomenon as a result of connective tissue disease; splenomegaly, scleral icterus, and caput medusae from portal hypertension; a left ventricular S3, or mitral and/or aortic valve murmurs as a result of left heart disease; and wheezing or protracted expiration secondary to hypoxic lung disease. Findings in advanced PH with right heart failure may include jugular venous distention, a right ventricular S3, edema, ascites, and hepatomegaly.

Figure 42.2 Diagnostic approach for suspected PAH. Pivotal tests are essential to establishing the definitive diagnosis of PAH.¹⁹ (Reproduced with permission from: McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. Circulation 2009;119:2250-2294.)

The initial evaluation of any patient with suspected PH should begin with a 12-lead ECG and two-view chest X-ray. PH is supported by ECG findings of right axis deviation, right ventricular hypertrophy, right atrial enlargement, and ST and T wave abnormalities in the precordial leads consistent with right ventricular strain. The chest radiograph may show prominent central pulmonary arteries and peripheral hypovascularity or “pruning.” The lateral view may demonstrate RV obliteration of the retrosternal space owing to RV enlargement.

If the history, physical examination, ECG, and CXR are suggestive of PH, a carefully selected systematic series of diagnostic studies is indicated. Experts endorse the approach presented in Figure 42.2. Doppler TTE is
generally obtained early in the evaluation of patients with suspected PH. The tricuspid regurgitant jet is used to estimate the RVSP, and pressures >40 mmHg are consistent with PH. However, TTE can both under- and overestimate pulmonary artery pressures, as compared to the gold standard of RHC. In addition to the pressure measurements, TTE is useful in identifying elevated right-sided pressures by showing evidence of right atrial or ventricular enlargement, flattening of the interventricular septum, or an underfilled LV.

The following points should be kept in mind when ordering and evaluating tests for PH:

Ventilation/perfusion (V/Q) scan: the test of choice for the initial evaluation of chronic, surgically accessible thromboembolic disease. A PE protocol CT is excellent for identifying acute PE; however, is not sensitive for chronic thromboembolic disease. If indicated, pulmonary angiography can often be scheduled immediately following RHC if chronic thromboembolic disease is highly suspected.
Pulmonary function tests (PFTs): may show only mild restrictive disease and a mildly decreased diffusing capacity for carbon monoxide (DLCO); scleroderma patients may have a more marked decrease in DLCO.
Polysomnogram: should be performed if a patient endorses symptoms of sleep disordered breathing.
Blood tests: given the association between PH and both connective tissue disorders and chronic liver disease, antinuclear antibody (ANA) tests and liver function tests (LFTs) are routinely performed. HIV testing should be performed if a patient endorses risk factors. A complete blood count is helpful in identifying anemia as a cause of high-output heart failure. Thyroid function studies should be performed in all patients.
Six minute hall walk (6MWT): commonly used to objectively assess functional capacity; this test is often performed at baseline and repeated periodically to assess response to treatment; it is frequently used as an endpoint in clinical PAH trials.

RIGHT HEART CATHETERIZATION IN PAH

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

TREATMENT

General treatment recommendations for PH include sodium restriction, graded aerobic exercise, limited isometric exercise, and consideration of birth control for women. Non-PAH PH is further treated by addressing the underlying cause and by adding supplemental oxygen and diuretics, as needed. As the vast majority of patients with PH have either diastolic or systolic heart failure, treatment of volume status can often alleviate the PH, thus resulting in increased functional capacity. PAH-specific therapies should be utilized under the direction of a PAH specialist. These therapies may include warfarin, diuretics, calcium channel blockers (for those with a positive vasodilator response during RHC), prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors (Table 42.3).

More invasive strategies may be indicated in select patients. Pulmonary thromboendarterectomy is the treatment of choice for surgically accessible chronic thromboembolic pulmonary hypertension, and should be performed at high-volume centers. Creation of a right-to-left interatrial shunt via percutaneous atrial septostomy improves right heart function and left heart filling by decreasing right heart filling pressures. Though the shunt decreases systemic arterial oxygen saturation, the improved cardiac output results in an overall improvement in systemic oxygen delivery. The mortality associated with atrial septostomy is high (15%), and it is reserved for patients with advanced right heart failure despite maximal medical therapy. Lung and heart-lung transplantation are options for patients with intractable disease.

Table 42.3 PAH-Specific Therapies

Medications		Comments
Supplemental oxygen		As needed to treat symptoms (may be needed for air travel)
Anticoagulation		Improved survival in observational studies involving patients with IPAH
	warfarin	Also recommended in advanced associated PAH
		INR 1.5 to 2.5
Diuretics		As needed to treat symptoms
	furosemide
Calcium channel blockers		Indicated only in patients with positive vasodilator response during RHC; empiric administration without hemodynamic guidance may result in rapid deterioration
	diltiazem
	nifedipine
	amlodipine	Avoid verapamil (decreased inotropy)
IV Epoprostenol		Mechanism: replenishes PGI_2, resulting in vasodilation, inhibition of platelet aggregation and inhibition of vascular SMCs
	Flolan
	Veletri	Indication: WHO class III to IV symptoms (IPAH or scleroderma spectrum of PAH)
		Administration: continuous infusion requires a central venous catheter
		Overdose can result in high-output heart failure
Treprostinil		Mechanism: same as epoprostenol
	Remodulin	Indication: WHO class II to IV symptoms (PAH)
	Tyvaso	Administration: continuous infusion via central venous catheter or subcutaneous sites (Remodulin), intermittent inhalation (Tyvaso)
Iloprost		Mechanism: same as epoprostenol
	Ventavis	Indication: WHO class III to IV symptoms (PAH)
Endothelin receptor antagonist		Mechanism: nonselectively blocks vasoconstrictive and SMC mitogenic effects of endothelin-1 (ET_A and ET_B)
	bosentan (Tracleer)
		Indication: WHO class II to IV symptoms (PAH)
		Administration: oral, 125 mg po BID
		Considerations: must monitor LFTs and hemoglobin; potential teratogen; may reduce sperm count
Endothelin receptor antagonist		Mechanism: blocks vasoconstrictive and SMC mitogenic effects of endothelin-1 by selectively antagonizing ETA receptor (allows NO production via ETB receptor activation)
	ambrisentan (Letairis)
		Indication: WHO class II to III symptoms (PAH)
		Administration: oral, 5 or 10 mg once-daily
		Considerations: must monitor LFTs and hemoglobin, potential teratogen, may reduce sperm count
Phosphodiesterase-5 inhibitor		Mechanism: prevents degradation of cGMP, resulting in vasorelaxation
	sildenafil (Revatio)	Indication: WHO group I symptoms (PAH)
		Administration: oral, 20 mg po TID
		Considerations: contraindicated in patients taking nitrates, may be used in conjunction with IV epoprostenol
Phosphodiesterase-5 inhibitor		Mechanism: prevents degradation of cGMP, resulting in vasorelaxation
	Tadalafil (Adcirca)	Indication: WHO group I symptoms (PAH)
		Administration: oral, 40 mg po daily
		Considerations: contraindicated in patients taking nitrates, may be used in conjunction with IV epoprostenol
cGMP, Cyclic guanosine monophosphate; INR, International normalized ratio; IPAH, Idiopathic pulmonary arterial hypertension; PAH, Pulmonary arterial hypertension; RHC, Right heart catheterization; SMC, Smooth muscle cell.