Ebook Textbook of clinical hemodynamics (2/E): Part 2

(BQ) Part 2 book “Textbook of clinical hemodynamics” has contents: Right-sided heart disorders, pulmonary hypertension and related disorders, pericardial disease and restrictive myocardial diseases, left-ventricular hemodynamics, heart failure, and shock, congenital heart disease,… and other contents.

After Werner Forssmann boldly inserted a urological catheter into his own right atrium, the right heart became accessible to clinical investigation, allowing the study of right-heart physiology in both normal and diseased states.1 The right heart is affected by many cardiac disease states Recall that the primary cause of right-heart failure is left-heart failure; therefore, the myriad cardiac disorders associated with left-heart failure syndromes often impact right-heart hemodynamics In addition, numerous congenital heart conditions as well as disorders of the pericardium affect right-heart hemodynamics The influences these conditions have on right-heart hemodynamics are discussed in their respective chapters This chapter will focus on disorders unique to the right heart, including tricuspid and pulmonic valvular diseases and the hemodynamics of right-ventricular failure with a focus on right-ventricular infarction

TRICUSPID VALVE STENOSIS

This rare valvular lesion is most often due to rheumatic heart disease and is almost always associated with mitral stenosis; isolated rheumatic tricuspid stenosis is very rare.2 Only occasionally is tricuspid stenosis caused by other conditions, including carcinoid syndrome, endomyocardial fibrosis, congenital tricuspid valve stenosis, endocarditis, pacemaker lead–related leaflet fibrosis, or atrial myxoma In the cur-rent era, perhaps the most commonly observed cause of tricuspid stenosis is dysfunction of a prosthetic tricuspid valve

Tricuspid stenosis impairs right-atrial emptying and elevates right-atrial pressure Diminished filling of the right ventricle reduces cardiac output In cases of rheumatic heart disease, the combination of tricuspid and mitral stenosis reduces the cardiac output to levels lower than expected on the basis of either valvular lesion alone Clinical consequences of severe tricuspid stenosis include fatigue caused by low cardiac out-put, elevated jugular veins, peripheral edema, hepatic congestion, and ascites due to elevated right-atrial pressure If unsuspected, the diagnosis may prove challenging because these symptoms occur in other conditions such as pericardial disease, cirrhosis of the liver, and pulmonary hypertension; the latter may, in fact, be present due to associated mitral stenosis

The hemodynamic abnormalities observed in tricuspid stenosis have been well described.3–6

Right-atrial pressure is elevated The a wave reaches giant proportions in patients in normal sinus rhythm and may exceed 20 mmHg However, an enlarged a wave is not specific for tricuspid stenosis because it may

be seen in the presence of pulmonary hypertension and right-ventricular hypertrophy; although, in the

absence of pulmonary hypertension, a prominent a wave supports a diagnosis of tricuspid stenosis.

Similar to mitral stenosis, the presence of a pressure gradient observed while simultaneously measuring pressure in the right atrium and right ventricle during diastole characterizes tricuspid valve stenosis (Fig 7.1) Because of the lower right-sided pressures, the relatively lower cardiac output, and the greater size of the tricuspid orifice when compared with the mitral valve, the observed gradients are correspondingly relatively small, ranging from 2–12 mmHg, with 90% of gradients less than 7 mmHg.6

A mean diastolic gradient greater than 2 mmHg is diagnostic of tricuspid stenosis Small gradients

(2–3 mmHg) that exist only in early diastole may be observed in patients with predominantly tricuspid regurgitation without significant stenosis.3,6 In patients with tricuspid stenosis and normal sinus rhythm,

a small pressure gradient early in diastole increases at end-diastole because of the rise in atrial sure from atrial contraction For patients with atrial fibrillation, right-atrial pressure remains uniformly elevated throughout the cardiac cycle, and the pressure gradient is greatest in early diastole when the right-ventricular diastolic pressure is lowest The transtricuspid valve pressure gradient increases with inspiration, predominantly caused by a fall in the ventricular diastolic pressure with inspiration The gra-dient increases with exercise because of an increase in the right-atrial pressure An increase in volume will also increase the gradient

RIGHT-SIDED HEART

DISORDERS

Michael Ragosta

Calculation of the tricuspid valve orifice area has been estimated using the Gorlin formula (see Chapter

4) Similar to mitral stenosis, the mean pressure gradient across the valve, the diastolic filling period, the

heart rate, and the cardiac output are the important measured variables entered into the formula; however,

unlike the mitral valve, the coefficient has not been determined and has been arbitrarily set at 1.0 (similar

to the aortic valve area) The formula has not been well validated in tricuspid stenosis, although small series

have correlated the calculated valve area with the area determined at surgery.6 Similar to mitral stenosis

with associated mitral regurgitation, if there is associated tricuspid regurgitation, the Gorlin formula will

underestimate the valve area because the true transvalvular flow is not known The value of this

determina-tion is not clear, and today most assessments of the severity of tricuspid stenosis are made based upon the

extent of the transvalvular gradient and its effect on right-atrial pressure

Until recently stenosis of a prosthetic tricuspid valve could only be treated surgically with another

valve replacement In the current era less invasive alternatives are available and transcatheter valve

systems, initially designed for the aortic valve, have been employed to treat bioprosthetic tricuspid stenosis

using a “valve-in-valve” approach Case reports and small series demonstrate the feasibility of this

approach with an improvement in hemodynamics.7–9Fig 7.2 is an example of the hemodynamics obtained

in a patient with bioprosthetic tricuspid stenosis treated with a SAPIEN valve (Edwards Lifesciences, Irving,

CA) In this case, the gradient was reduced from a mean of 7.1 mmHg (Fig 7.2A) to 0 mmHg at

end-diastole postvalve deployment (Fig 7.2B) While no post-implant gradient was seen in this case, residual

gradients after valve-in-valve procedures for bioprosthetic tricuspid stenosis are common and may limit

this approach except in patients at prohibitive risk for reoperation. 

TRICUSPID VALVE REGURGITATION

Tricuspid regurgitation represents the most commonly encountered right-sided valvular heart lesion

Mild-to-moderate degrees of tricuspid regurgitation are very commonly detected on 2D echocardiography and

are of little to no significance Severe tricuspid regurgitation, however, is an important valvular lesion that

causes progressive right-heart failure and increased mortality.10 Among the numerous possible etiologies

(Box 7.1), functional tricuspid regurgitation from right-ventricular pressure or volume overload accounts for

most cases; primary regurgitation caused by organic tricuspid valve pathology is much less prevalent.11

In patients with rheumatic heart disease, tricuspid regurgitation is common, with a prevalence of nearly

40% in patients with mitral stenosis Tricuspid regurgitation is due to several potential mechanisms in

these patients, including rheumatic involvement of the tricuspid valve (i.e., primary tricuspid regurgitation)

or functional regurgitation as a consequence of pressure or volume overload of the right ventricle (often

caused by associated pulmonary hypertension).12 Elucidation of the mechanism of tricuspid regurgitation

seen in association with rheumatic mitral stenosis is important for proper treatment Observation of normal

pulmonary pressures suggests primary valve disease In patients with pulmonary hypertension,

echocar-diography can help distinguish functional regurgitation from organic tricuspid valve disease

Tricuspid regurgitation causes volume overload of the right ventricle and atrium Over time, the right

ventricle dilates further, worsening the degree of regurgitation In the presence of pulmonary hypertension,

Fig 7.1 These hemodynamic waveforms were obtained from a 46-year-old male with a history of congenital ventricular

septal defect repair at age 8 and subsequent tricuspid valve replacement for severe tricuspid valve regurgitation at age

17, who then developed severe stenosis of the bioprosthetic tricuspid valve Simultaneous right-atrial and right-ventricular

pressure waveforms are shown The right-atrial pressure is markedly elevated and there is a large diastolic pressure

e e

d

e

d e

Fig 7.2 The tracings shown here were obtained in a 50-year-old male with a history of traumatic tricuspid valve injury who

had a bioprosthetic tricuspid valve replacement 19 years earlier (A) Simultaneous right-atrial and right-ventricular pressure waveforms confirmed severe tricuspid stenosis He then underwent a percutaneous valve-in-valve procedure using a 26-mm SAPIEN 3 valve (Edwards Lifesciences, Irving, CA) (B) Postvalve implantation, there is no significant end-diastolic gradient pres-

ent The white shaded area represents the pressure gradient during diastole a, a wave; d, diastole; e, end diastole; v, v wave.

Chapter 7 RIGHT-SIDED HEART DISORDERS 145

severe tricuspid regurgitation causes both volume and pressure overload and is less well tolerated, leading

to earlier onset of symptoms Signs of severe tricuspid regurgitation reflect right-heart failure and include lower extremity edema, ascites, distended neck veins, and cachexia Symptoms include dyspnea, anorexia, abdominal distension, and profound fatigue from decreased cardiac output

The observed hemodynamic abnormalities of severe tricuspid regurgitation are preload and afterload dependent and include elevation of right-atrial pressure, decreased cardiac output, and abnormalities of the right-atrial pressure waveform.13 Because the jugular veins mirror the abnormalities present in the right atrium, it is no surprise that the characteristic atrial waveform abnormalities attributed to tricuspid

A

B

d e

e e

d

e

d e

Fig 7.2 The tracings shown here were obtained in a 50-year-old male with a history of traumatic tricuspid valve injury who

had a bioprosthetic tricuspid valve replacement 19 years earlier (A) Simultaneous right-atrial and right-ventricular pressure waveforms confirmed severe tricuspid stenosis He then underwent a percutaneous valve-in-valve procedure using a 26-mm SAPIEN 3 valve (Edwards Lifesciences, Irving, CA) (B) Postvalve implantation, there is no significant end-diastolic gradient pres-

ent The white shaded area represents the pressure gradient during diastole a, a wave; d, diastole; e, end diastole; v, v wave.

Box 7.1 Causes of Tricuspid Regurgitation

Structurally Normal Tricuspid Valve (Functional Tricuspid Regurgitation)

Chronic atrial fibrillation

Annular dilatation from volume or pressure overload

Atrial septal defect

Right-ventricular infarction

Congestive heart failure

Pulmonary hypertension

Post–heart transplantation

Structurally Abnormal Tricuspid Valve

Rheumatic heart disease

regurgitation were first observed on analysis of jugular venous pressure waveforms (Fig 7.3).14 Normally,

an x descent exists on the right-atrial waveform, reflecting descent of the base of the heart during systole Classically, in tricuspid regurgitation, the x descent is attenuated (Fig 7.4) The x descent ultimately disap- pears and is replaced by a systolic wave with a peak-dome contour often termed the c-v wave.1,15–17 The v wave is classically prominent, and the y descent is very rapid (Fig 7.5) Ventricularization of the right-atrial pressure waveform may occur (Fig 7.6) In some cases, the right-atrial pressure wave is nearly indistin-guishable from the right-ventricular pressure contour (Fig 7.7) The v wave may increase further during

with absence of the x descent (because no atrial contraction is present) causing the c-v wave to appear

prominent.17,18 Finding a normal right-atrial pressure, normal x descent, and absence of prominent v

waves does not necessarily exclude significant tricuspid regurgitation.18–20 Ventricularization of right-atrial pressure is very specific for severe tricuspid regurgitation but is seen in only 40% of patients.20 Similar to

mitral regurgitation, the size of the v wave in tricuspid regurgitation depends upon the volume status and

compliance of the right atrium and does not necessarily correlate with the presence or severity of tricuspid regurgitation.21 A subtle hemodynamic finding is perhaps more sensitive for tricuspid regurgitation Instead

SMTR

c1st

2nd

y

Fig 7.3 Venous pressure waveform in severe tricuspid regurgitation demonstrating a large c-v wave (From Messer AL,

Hurst JW, Rappaport MB, Sprague HB A study of the venous pulse in tricuspid valve disease Circulation 1950;1:388–393.)

c, c wave; y, y descent.

a

c-v

Fig 7.4 Right-atrial waveform from a patient with secondary tricuspid regurgitation from associated severe left-sided

heart failure and right-sided heart failure Attenuation of the x descent is present, seen after the a wave (left arrow), ing to a prominent c-v wave (right arrow) a, a wave; RA, right-atrial.

lead-Chapter 7 RIGHT-SIDED HEART DISORDERS 147

of the normal fall in right-atrial pressure with inspiration, one study found that all patients with tricuspid regurgitation demonstrated either a rise or no change in right-atrial pressure during deep inspiration.20 This finding was very sensitive for tricuspid regurgitation but was also apparent in several patients with severe (>90 mmHg) pulmonary hypertension; thus in the absence of severe pulmonary hypertension, this sign may help diagnose tricuspid regurgitation In contrast to mitral regurgitation, angiographic assessment of tricuspid regurgitation is problematic and rarely used, because the presence of a catheter across the tricus-pid valve in order to perform right ventriculography may interfere with tricuspid valve function and cause regurgitation; however, this method is useful for proving the absence of tricuspid regurgitation

Some of the clinical and hemodynamic aspects of severe tricuspid regurgitation may be confused with constrictive pericarditis.22 The predominant symptoms of both conditions (edema, ascites, prominent neck veins, and fatigue) are very similar In addition, the right-atrial pressure waveform may appear similar

with a prominent y descent, particularly if the patient’s rhythm is atrial fibrillation The finding of ventricular

interdependence is an important clue that may distinguish these two conditions (see Chapter 9).23Cardiac output determination using the thermodilution method may be problematic in patients with tricuspid regurgitation because severe degrees of regurgitation underestimate the cardiac output.24 The Fick methodology is more accurate in this setting. 

PULMONIC VALVE STENOSIS

Pulmonic stenosis is the most common abnormality of the pulmonary valve and nearly always has a tal cause It may be seen in association with other congenital heart defects or exist in isolation Often detected

congeni-in childhood, pulmonic stenosis rarely presents congeni-in adults In the majority of cases, the valve leaflets are fused and amenable to balloon or surgical valvotomy The 10%–15% of pulmonic valves stenosed from dysplastic conditions (as seen in association with Noonan syndrome) are often not treatable by valvotomy

Obstruction causes a pressure gradient across the pulmonic valve, with right-ventricle systolic sure exceeding pulmonary artery systolic pressure (Fig 7.8).25 Pressure overload and subsequent hypertro-phy of the right ventricle ensues The hemodynamic abnormalities depend upon the severity of stenosis and the cardiac output In mild cases, the pressure gradient across the pulmonic valve is less than 20 mmHg and the cardiac output increases normally with exercise.25,26 With severe pulmonic stenosis, the pressure gradient exceeds 40 mmHg and may reach very high levels (>100 mmHg), causing the right-ventricular pressure to equal systemic arterial pressures The right-ventricular stroke volume is fixed and unable to augment with exercise.26 In addition, because of diminished right-ventricular compliance from concen-tric hypertrophy of the right ventricle, severe pulmonic stenosis elevates right-ventricular end-diastolic pressure, both at rest and with exercise An elevated right-ventricular end-diastolic pressure may raise right-atrial pressure and cause right-to-left shunting if there is a patent foramen ovale leading to cyanosis

pres-Fig 7.5 Right-atrial waveform in severe tricuspid regurgitation demonstrating absence of the x descent and a large c-v

wave with a prominent y descent RA, Right-atrial.

or paradoxical embolism Furthermore, right-ventricular diastolic pressure rises have been associated with elevations in left-ventricular end-diastolic pressures, likely from interactions via the septum.27 Interest-ingly, many individuals are asymptomatic even with severe stenosis Symptoms of severe stenosis include dyspnea, fatigue, syncope, and exercise intolerance.

Valve area can be calculated using the Gorlin formula, as described in Chapter 4, and adapted to the pulmonic valve.28 However, most clinicians classify the severity of pulmonic stenosis and base treatment decisions upon the extent of the transvalvular gradient alone Current guidelines recommend either surgical

or balloon valvuloplasty for asymptomatic patients with a peak instantaneous gradient greater than 60 mmHg or mean gradient greater than 40 mmHg and for symptomatic patients with a peak instantaneous gradient greater than 50 mmHg and mean gradient greater than 30 mmHg.29 Outcomes with balloon valvuloplasty are excellent with little chance of recurrence (Fig 7.9)

A

B

Fig 7.6 These tracings were obtained from a patient with severe tricuspid regurgitation due to profound biventricular

heart failure (A) The right-atrial waveform shows ventricularization Compare this with (B), the right-ventricular waveform

from the same patient RA, Right-atrial; RV, right-ventricular.

Chapter 7 RIGHT-SIDED HEART DISORDERS 149

Related conditions that cause similar physiologic and hemodynamic effects on the right heart include peripheral pulmonary artery stenosis (discussed in Chapter 11) and right-ventricular infundibular stenosis Infundibular stenosis is commonly associated with severe pulmonic stenosis because compensatory right-ventricular hypertrophy narrows and obstructs the outflow tract With relief of valvular obstruction, hypertrophy regresses and the extent of infundibular stenosis regresses.30 

PULMONIC VALVE REGURGITATION

Pulmonary insufficiency is uncommon It is most often seen in association with congenital heart disease, typically because of either surgical or balloon valvotomy for pulmonic stenosis or from repair of tetralogy

of Fallot Other causes include rheumatic heart disease, endocarditis, dilatation of the pulmonary artery (either idiopathic or from pulmonary hypertension), traumatic disruption of the pulmonic valve, syphilis, or

an isolated congenital defect.31,32 The low-pressure circuit of the right heart causes pulmonary tion to behave differently than aortic regurgitation.33 Right-atrial contraction can maintain forward pulmo-nary blood flow despite severe regurgitation, and the pulmonary resistance is typically very low, allowing blood to easily pass through the lungs and preventing significant backward flow during diastole Thus the volume overload on the right ventricle is substantially less than that seen in severe aortic regurgita-tion and allows this lesion to be tolerated for longer periods Conditions that increase pulmonary vascular resistance, however, will increase the regurgitant volume and may lead to detrimental effects Eventually, the right ventricle dilates and becomes dysfunctional, leading to reduced exercise capacity and right-heart failure

regurgita-A

B

Fig 7.7 Severe tricuspid regurgitation may result in complete ventricularization of the atrial waveform (A) The

right-ventricular pressure wave (B) Note the nearly indistinguishable appearance of the right-atrial waveform RA, Right-atrial;

RV, right-ventricular.

d d

s s s s s s s s

d d d d d d d

s s s s s

s s s

Fig 7.8 Right-heart pressures obtained in an infant with severe, congenital pulmonic stenosis (A) The systolic pulmonary

artery pressure measured 15 mmHg (B) Right-ventricular pressure reached systemic levels at nearly 80 mmHg d, Diastole;

PA, pulmonary artery; RV, right-ventricular; s, systole.

Chapter 7 RIGHT-SIDED HEART DISORDERS 151

A

B

s s

Fig 7.9 Balloon valvuloplasty performed in the patient shown in Fig 7.8 resulted in elimination of the pressure gradient

between (A) the pulmonary artery and (B) the right ventricle d, Diastole; e, end diastole; PA, pulmonary artery; r, R wave;

RV, right-ventricular; s, systole.

The hemodynamic abnormalities reflect the severity of pulmonic regurgitation Patients with severe pulmonary regurgitation demonstrate an increased pulmonary arterial pulse pressure, a rapid dicrotic col-lapse, and early equilibration of the diastolic pressures between the pulmonary artery and right ventricle or

“diastasis”31,32,34 (Figs 7.10–7.11) The pulmonary artery pressure becomes “ventricularized” (Fig 7.12).35Milder forms of pulmonary regurgitation affect the pulse pressure to a lesser degree, and equilibration of the pressure between the right ventricle and pulmonary artery occurs only at end-diastole. 

RIGHT-VENTRICULAR FAILURE

The right ventricle is subject to failure, most commonly from associated left-heart failure Isolated right-heart failure can occur in a variety of settings including severe pulmonary hypertension, chronic severe pulmonic insufficiency, right-ventricular infarction, chronic, severe lung disease, acute massive pulmonary embolism, myocardial contusion from trauma, focal myocarditis, or inadequate cardiopreservation during heart surgery

or from acute rejection after cardiac transplantation (Fig 7.13) Several of these conditions are discussed where in this text, and the remaining discussion will focus on the hemodynamics of right-ventricular infarction. 

Fig 7.10 Diastasis of pressure between the right-ventricular and pulmonary artery pressure is a hemodynamic finding

of severe pulmonic insufficiency (From Nemickas R, Roberts J, Gunnar RM, Tobin JR Isolated congenital pulmonic ficiency Differentiation of mild from severe regurgitation Am J Cardiol 1964;14:456–463.) PA, Pulmonary artery; RV, right-ventricular.

Fig 7.11 This is an example of severe pulmonic valve regurgitation in a 10-year-old with a history of tetralogy of Fallot

with pulmonary atresia and multiple complex surgeries in the past Shown here is diastasis between right-ventricular

and pulmonary artery pressures; there is also a modest gradient consistent with stenosis d, Diastole; e, end diastole;

PA, pulmonary artery; RV, right-ventricular; s, systole.

Chapter 7 RIGHT-SIDED HEART DISORDERS 153

Fig 7.12 These tracings were obtained from a patient with severe pulmonic insufficiency after surgical correction of

tetralogy of Fallot (A) The right-ventricular pressure d, Diastole; c, end diastolic pressure; r, R wave; s, systole.

distinct clinical entity in 1974, it usually occurs in association with between one-third and one-half of all inferior wall myocardial infarctions.36,37 Occlusion of the right coronary artery proximal to the right- ventricular marginal branches is the most common cause, but right-ventricular infarction may also occur with occlusion of the left circumflex or even the left anterior descending in a minority of patients.37,38Rarely, it may occur in isolation (i.e., without associated left-ventricular infarction) from occlusion of a nondominant right coronary artery or occlusion of a right-ventricular marginal branch This may occur as

an iatrogenic event from percutaneous coronary intervention of a right coronary artery if there is loss of a right-ventricular marginal branch

Interestingly, not all cases of proximal right-coronary occlusion cause right-ventricular tion This may be explained by several mechanisms Oxygen demand is much lower in the right ven-tricle given its smaller muscle mass Accordingly, the susceptibility of the right ventricle to infarction and ischemia is increased in patients with right-ventricular hypertrophy Other protective mecha-nisms include collateral supply of the right ventricle and, possibly, perfusion of the right-ventricular myocardium directly from the blood in the ventricular cavity via the Thebesian veins Each of these factors is felt to also explain the high likelihood of recovery of right-ventricular function following infarction Early recognition of right-ventricular infarction remains important, because although the long-term prognosis of right-ventricular infarction is good, the in-hospital morbidity and mortality is high.39–41

infarc-Even if there is a right-ventricular infarction, the clinical consequences of this vary greatly, from no apparent hemodynamic abnormality to profound shock and cardiovascular collapse This wide spectrum

of clinical presentations is because the pathophysiology of right-ventricular infarction depends on many

PA50

25

0

dd

Fig 7.12, cont’d (B) The pulmonary artery pressure Note the wide pulse pressure on the pulmonary artery tracing with

equilibration of diastolic pressures PA, Pulmonary artery; RV, right-ventricular.

Chapter 7 RIGHT-SIDED HEART DISORDERS 155

complex factors (Box 7.2) Each factor plays varying roles in any given patient, explaining the variety of hemodynamic findings observed in this condition

The pathophysiology of right-ventricular infarction is complex Acute ischemia of the right ventricle

results in profound systolic dysfunction, which decreases right-ventricular stroke volume and peak systolic

pressure and thus reduces left-ventricular preload This causes a drop in cardiac output and

hypoten-sion The right ventricle acutely dilates Acute ischemia also results in diastolic dysfunction This elevates

right-sided filling pressures during diastole and increases resistance to early filling The pericardial space becomes filled with the acutely dilated right ventricle, which increases intrapericardial pressure, further

impairing right-ventricular and left-ventricular filling Furthermore, the effect of pericardial constraint also facilitates systolic ventricular interactions mediated by the septum by shifting the interventricular

septum toward the preload-deprived left ventricle, further decreasing left-ventricular filling and cardiac output However, left-ventricular contraction may cause septal bulging to the right, which may be sufficient

A

B

Fig 7.13 These hemodynamics were obtained in a patient with a prior heart transplant who presented with acute, severe

rejection (A) The right-atrial pressure is markedly increased with a mean pressure of 24 mmHg (B) There is “atrialization”

of the right-ventricular waveform from severe right-ventricular failure.

to generate or augment right-ventricular systolic force and enhance pulmonary blood flow Thus if an associated large left-ventricular infarction is present, this force may be lost and cause further worsen-

ing of hemodynamics Finally, the right atrium plays an extremely important role in maintaining adequate

right-ventricular preload If an extensive associated right-atrial infarction is present, or if there is loss of atrioventricular (AV) synchrony from the development of heart block or atrial fibrillation, significant hemody-namic deterioration may ensue The location of the coronary occlusion leading to right-ventricular infarction

is an important determinant of the clinical consequences observed If occlusion is proximal to the ventricular marginal branches but distal to the right-atrial branches, then the main effect is a decrease in right-ventricular systolic function and the preserved right-atrial contraction can enhance right-ventricular performance If, however, occlusion is proximal to the right-atrial branches, then loss of right-atrial function also occurs, and without the assistance from atrial contraction the impaired right-ventricular systolic func-tion is poorly tolerated

right-The net effect of right-ventricular infarction is that left-sided filling pressure may be low, despite elevated right-sided pressure, which is clinically apparent by the triad of hypotension, clear lung fields, and elevated jugular venous pressure The physical exam may also reveal the Kussmaul sign (paradoxical distension of the neck veins with inspiration), a feature that is both sensitive and specific for right-ventric-ular infarction.42 The physical findings may be confused with pericardial disease because right-ventricular infarction mimics both tamponade and constrictive pericarditis

Possible hemodynamic findings of right-ventricular infarction include elevated right-atrial pressure, typically exceeding the pulmonary capillary wedge pressure The right-atrial pressure often exceeds 10 mmHg, and the ratio of right-atrial pressure to pulmonary capillary wedge pressure is greater than 0.8.36,43These hemodynamic findings may be masked by intravascular volume depletion and only emerge with volume loading.44 The condition in which right-atrial pressure exceeds left-atrial pressure may cause right-to-left shunting in the presence of a patent foramen ovale This scenario should be suspected in the event of unexplained hypoxia not corrected with oxygen administration in the setting of right-ventricular infarction; however, it is very rare and has probably appeared more often on board examination questions than in patients

Elevated right-atrial pressure is primarily from right-ventricular diastolic dysfunction, but pericardial constraint and right-ventricular failure also contribute Impaired filling of the right ventricle is evidenced by

a blunted y descent on the right-atrial waveform (Fig 7.14) The a wave on the right-atrial tracing reflects

the strength of contraction of the right atrium In right-ventricular infarction, right-atrial contraction is

enhanced by the increased preload, resulting in augmentation of the height of the a wave The x descent may be steep because of enhanced atrial relaxation This may be seen as a W pattern on the right-atrial

waveform (Fig 7.15) These features benefit right-ventricular filling However, if infarction involves the right

atrium, then the a wave and x descents are depressed This produces a characteristic M pattern Thus two

hemodynamic subtypes exist based on the status of the right atrium, with both having a relatively blunted

y descent The first, or W pattern, is usually associated with right–coronary artery occlusion proximal

to the right-ventricular branches but distal to the right-atrial branches and is associated with better

Box 7.2 Important Variables That Impact the Pathophysiology of

Right-Ventricular Infarction

Right-Ventricular Systolic Dysfunction

Decreased left-sided preload

Right-ventricular dilatation

Right-Ventricular Diastolic Dysfunction

Diminished compliance of right ventricle

Elevated filling pressures

Pericardial Constraint

Increases right-sided filling pressures

Enhances systolic ventricular interactions via the septum

Systolic Ventricular Interactions via the Septum

Impaired left-ventricular function

Dependence on left-ventricular function to enhance pulmonary blood flow

Right-Atrial Function

Maintains preload

Loss of atrial function more important than other infarctions

Chapter 7 RIGHT-SIDED HEART DISORDERS 157

hemodynamics than the second, or M pattern, which is associated with occlusion of the right coronary

artery proximal to the right-atrial branches and worse hemodynamics Although the hemodynamics are

better in those with a W pattern than those with an M pattern, those with a W pattern can decompensate

quickly when they lose AV synchrony

Right-ventricular systolic dysfunction results in a right-ventricular pressure tracing characterized by a broad upstroke that reflects a depressed upstroke, reduced peak pressure, and delayed relaxation The dia-stolic portion of the right-ventricular pressure curve has been described as a “dip and plateau” that reflects decreased compliance as well as the constraining forces of the pericardium (Fig 7.16) This constraint imparted by the pericardium may also produce equalization of left-ventricular and right-ventricular diastolic pressures similar to constrictive pericarditis (Fig 7.17)

The treatment of ventricular infarction includes prompt reperfusion, maintenance of ventricular preload, reduction of right-ventricular afterload, and inotropic support of the failing ventricle The benefit of reperfusion in the setting of right-ventricular infarction has not been well defined, but several studies have shown lower rates of right-ventricular infarction and more rapid recovery in right-ventricular function in patients who undergo successful reperfusion of the infarct-related artery.39,45 It is our practice

right-at the University of Virginia to try to open occluded right-ventricular marginal branches in the setting of

Fig 7.14 Right-atrial waveform from a patient with right-ventricular infarction, demonstrating a large a wave with

promi-nent x descent and a blunted y descent a, a wave; RA, right-atrial; y, y descent.

Fig 7.15 Example of the W pattern seen on a right-atrial waveform in a patient with right-ventricular infarction Note the

prominent a wave RA, Right-atrial.

B

Fig 7.17 (A) and (B) Examples of equalization of the right-ventricular and left-ventricular diastolic pressures or

pseudo-constriction pattern (B) Note how the early left-ventricular diastolic pressure is lower than the right-ventricular diastolic

pressure due to impaired left-ventricular filling and reduced preload Green tracing is right-ventricular waveform, and yellow tracing is left-ventricular waveform.

Chapter 7 RIGHT-SIDED HEART DISORDERS 159

acute right-ventricular infarction and shock Because of preload dependence, volume infusion raises the blood pressure and cardiac output associated with right-ventricular infarction and often requires several liters of normal saline Once a patient is euvolemic, however, there is little additional benefit from volume infusion in improving cardiac output; more aggressive infusion of volume may lead to pulmonary edema, particularly if there is a large, associated left-ventricular infarction that impairs left-ventricular function

It is prudent to guide volume infusion in a critically ill patient with right-ventricular infarction with an indwelling right-heart catheter Recognition of preload dependence is important because many of the drugs typically used to treat patients with acute myocardial infarction, such as nitrates or diuretics, may produce deleterious hemodynamic effects if right-ventricular infarction is also present If volume replacement fails

to improve cardiac output and blood pressure, then inotropic support with dobutamine should be instituted Dobutamine may also improve forward flow by reducing pulmonary vascular resistance and therefore right-ventricular afterload Right-ventricular afterload may also be increased when left-ventricular dysfunc-tion accompanies right-ventricular infarction and elevates pulmonary venous pressures In this setting, afterload-reducing drugs such as nitroprusside or insertion of an intra-aortic balloon pump may be benefi-cial Maintenance of AV synchrony is extremely important because, as mentioned earlier, the loss of atrial contraction may have deleterious hemodynamic consequences in right-ventricular infarction Cardioversion

A

B

Fig 7.18 These hemodynamics were obtained in a patient with cardiogenic shock caused by right-ventricular infarction

who was subsequently treated with a percutaneous right-ventricular support device (A) The arterial pressure waveform

is consistent with shock and shows a very narrow pulse width (B) There is marked elevation of the right-atrial pressure (mean 33 mmHg) and right-ventricular diastolic pressure.

of atrial fibrillation should be performed promptly at the first sign of hemodynamic deterioration and AV pacing considered if heart block develops If reperfusion therapy, volume replacement, and parenteral inotropic support are inadequate, mechanical circulatory support of the right ventricle may be indicated Percutaneous methods to support the failing right ventricle are available and are able to effectively support the right heart and improve hemodynamics.46,47 An example of hemodynamics obtained in a patient with profound shock from right-ventricular infarction is shown in Fig 7.18 In this case, the pulmonary artery saturation increased from 40% to 59% and the mean right-atrial pressure decreased from 33 mmHg to 15 mmHg after insertion of a TandemHeart device (CardiacAssist, Pittsburg, PA, USA) configured to support the right side (Fig 7.19) Dedicated right-heart support catheters have been developed for TandemHeart as well

as the IMPELLA device (Abiomed, Inc., Danvers, MA); extracorporeal membrane oxygenation may also be needed if there is associated hypoxemia

C

D

Fig 7.18, cont’d (C) Right-ventricular pressure waveform shows marked elevation of the right-ventricular diastolic

pres-sure with a dip and plateau pattern (D) Right-atrial prespres-sure waveform after insertion of the percutaneous right-ventricular assist device with reduction of pressure to a mean of 15–18 mmHg.

Chapter 7 RIGHT-SIDED HEART DISORDERS 161

1 Bloomfield RA, Lauson HD, Cournand A, et al Recording of right heart pressures in normal subjects and in patients

with chronic pulmonary disease and various types of cardio-circulatory disease J Clin Invest 1946;25:639–664.

2 Roguin A, Rinkevich D, Milo S, et al Long-term follow-up of patients with severe rheumatic tricuspid stenosis Am Heart J 1998;136:103–108.

3 McCord MC, Swan H, Blount SG Tricuspid stenosis: clinical and physiologic evaluation Am Heart J 1954;48:405–415.

4 Whitaker W The diagnosis of tricuspid stenosis Am Heart J 1955;50:237–241.

5 Yu PN, Harken DW, Lovejoy FW, et al Clinical and hemodynamic studies of tricuspid stenosis Circulation

1956;13:680–691.

6 Killip T, Lukas DS Tricuspid stenosis: physiologic criteria for diagnosis and hemodynamic abnormalities Circulation

1957;16:3–13.

7 Van Garsse LA, Ter Bekke RM, van Ommen VG Percutaneous transcatheter valve-in-valve implantation in stenosed

tricuspid valve bioprosthesis Circulation 2011;123:e219–e221.

8 Calvert PA, Himbert D, Brochet E, et al Transfemoral implantation of an Edwards SAPIEN valve in a tricuspid

biopros-thesis without fluoroscopic landmarks EuroIntervention 2012;7:1336–1339.

9 Eicken A, Schubert S, Hager A, et al Percutaneous tricuspid valve implantation: two-center experience with midterm

results Circ Cardiovasc Interv 2015;8:e002155.

10 Nath J, Foster E, Heidenreich PA Impact of tricuspid regurgitation on long-term survival J Am Coll Cardiol

15 McCord MC, Blount SG The hemodynamic pattern in tricuspid valve disease Am Heart J 1952;44:671–680.

16 Sepulveda G, Lukas DS The diagnosis of tricuspid insufficiency Clinical features in 60 cases with associated mitral

valve disease Circulation 1955;11:552–563.

17 Hansing CE, Rowe GG Tricuspid insufficiency: a study of hemodynamics and pathogenesis Circulation 1972;45:793–799.

18 Cairns KB, Kloster FE, Bristow JD, et al Problems in the hemodynamic diagnosis of tricuspid insufficiency Am Heart J

1968;75:173–197.

Fig 7.19 TandemHeart (CardiacAssist, Pittsburg, PA, USA) configured to support the right heart A 21 French cannula is

inserted via the femoral vein into the pulmonary artery and another catheter inserted via the opposite femoral vein into the right atrium The device pulls from the right atrium and pumps into the pulmonary artery, allowing support of the failing

right ventricle PA, Pulmonary artery; RA, right atrium.

19 Rubeiz GA, Nassar ME, Dagher IK Study of the right atrial pressure pulse in functional tricuspid regurgitation and

normal sinus rhythm Circulation 1964;30:190–193.

20 Lingamnemi R, Cha SD, Maranhao V, et al Tricuspid regurgitation: clinical and angiographic assessment Cathet Cardiovasc Diagn 1979;5:7–17.

21 Pitts WR, Lange RA, Cigarroa JE, Hillis LD Predictive value of prominent right atrial V waves in assessing the presence

and severity of tricuspid regurgitation Am J Cardiol 1999;83:617–618.

22 Studley J, Tighe DA, Joelson JM, Flack 3rd JE The hemodynamic signs of constrictive pericarditis can be mimicked by

tricuspid regurgitation Cardiol Rev 2003;11:320–326.

23 Hurrell DG, Nishimura RA, Higano ST, et al Value of dynamic respiratory changes in left and right ventricular pressures

for the diagnosis of constrictive pericarditis Circulation 1996;93:2007–2013.

24 Balik M, Pachl J, Hendl J Effect of the degree of tricuspid regurgitation on cardiac output measurements by

thermodi-lution Intensive Care Med 2002;28:1117–1121.

25 Dow JW, Levine HD, Elkin M, et al Studies of congenital heart disease: IV Uncomplicated pulmonic stenosis tion 1950;1:267–287.

26 Moller JH, Rao S, Lucas RV Exercise hemodynamics of pulmonary valvular stenosis: study of 64 children Circulation

1972;46:1018–1026.

27 Herbert WH, Yellin E Left ventricular diastolic pressure elevation consequent to pulmonary stenosis Circulation

1969;40:887–892.

28 Moller JH, Adams Jr P A simplified method for calculating the pulmonary valve area Am Heart J 1966;72:463–465.

29 Warnes CA, Williams RG, Bashore TM, et al ACC/AHA guidelines for the management of adults with congenital heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

(writing committee to develop guidelines on the management of adults with congenital heart disease) Circulation

2008;118:e714.

30 Fawzy ME, Galal O, Dunn B, et al Regression of infundibular pulmonary stenosis after successful balloon pulmonary

valvuloplasty in adults Cathet Cardiovasc Diagn 1990;21:77–81.

31 Morton RF, Stern TN Isolated pulmonic valvular regurgitation Circulation 1956;14:1069–1072.

32 Kohout FW, Katz LN Pulmonic valvular regurgitation Report of a case with catheterization data Am Heart J

1955;49:637–642.

33 Bouzas B, Kilner PJ, Gatzoulis MA Pulmonary regurgitation: not a benign lesion Eur Heart J 2005;26:433–439.

34 Nemickas R, Roberts J, Gunnar RM, Tobin JR Isolated congenital pulmonic insufficiency Differentiation of mild from

severe regurgitation Am J Cardiol 1964;14:456–463.

35 Rommel JJ, Yadav PK, Stouffer GA Causes and hemodynamic findings in chronic severe pulmonary regurgitation

Catheter Cardiovasc Interv 2015 http://dx.doi.org/10.1002/ccd.26073.

36 Cohn JN, Guiha NH, Broder MI, et al Right ventricular infarction Clinical and hemodynamic features Am J Cardiol

1974;33(2):209–214.

37 Andersen HR, Falk E, Nielsen D Right ventricular infarction: Frequency, size and topography in coronary heart

disease: a prospective study comprising 107 consecutive autopsies from a coronary care unit J Am Coll Cardiol

1987;10(6):1223–1232.

38 Cabin HS, Clubb KS, Wackers FJ, et al Right ventricular myocardial infarction with anterior wall left ventricular

infarc-tion: an autopsy study Am Heart J 1987;113(1):16–23.

39 Berger PB, Ruocco NA, Ryan TJ, et al Frequency and significance of right ventricular dysfunction during inferior wall left ventricular myocardial infarction treated with thrombolytic therapy (results from the thrombolysis in myocardial

infarction [TIMI] II trial) The TIMI Research Group Am J Cardiol 1993;71(13):1148–1152.

40 Zehender M, Kasper W, Kauder E, et al Right ventricular infarction as an independent predictor of prognosis after

acute inferior myocardial infarction N Engl J Med 1993;328(14):981–988.

41 Jacobs AK, Leopold JA, Bates E, et al Cardiogenic shock caused by right ventricular infarction: a report from the

SHOCK registry J Am Coll Cardiol 2003;41:1273–1279.

42 Cintron GB, Hernandez E, Linares E, et al Bedside recognition, incidence and clinical course of right ventricular

infarc-tion Am J Cardiol 1981;47(2):224–227.

43 Lopez-Sendon J, Coma-Canella I, Gamallo C Sensitivity and specificity of hemodynamic criteria in the diagnosis of

acute right ventricular infarction Circulation 1981;64:515–525.

44 Dell’Italia LJ, Starling MR, Crawford MH, et al Right ventricular infarction: identification by hemodynamic

measure-ments before and after volume loading and correlation with noninvasive techniques J Am Coll Cardiol 1984;4(5):931–

939.

45 Bowers TR, O’Neil WW, Grines C, et al Effect of reperfusion on biventricular function and survival after right ventricular

infarction N Engl J Med 1998;338(14):933–940.

46 Kapur NK, Paruchuri V, Korabathina R, et al Effects of percutaneous mechanical circulatory support device for

medi-cally refractory right ventricular failure J Heart Lung Transplant 2011;30:1360–1367.

47 Goldstein JA Acute right ventricular infarction: insights for the interventional era Curr Probl Cardiol 2012;37:533–557.

PULMONARY HYPERTENSION

AND RELATED DISORDERS

LaVone A Smith and Jamie L.W Kennedy

DEFINITION AND CRITERIA

Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure (mPAP) of greater than or equal to 25 mmHg at rest, as measured during right-heart catheterization (RHC) PH is further divided into precapillary and postcapillary, with precapillary PH defined as a pulmonary capillary wedge pressure (PCWP) of less than or equal to 15 mmHg and postcapillary PH as a PCWP of greater than 15 mmHg.1Pulmonary arterial hypertension (PAH), a subclassification of PH, is a precapillary PH with a pulmonary vascular resistance (PVR) of greater than 3 Wood units (Table 8.1) Postcapillary PH is further divided into isolated postcapillary PH with low PVR and diastolic pressure gradient (DPG), and mixed precapillary and postcapillary PH with elevated PVR and DPG In 2013, the Fifth World Symposium on PH discussed

changes to the definition of PH, including adding the term borderline PH for patients with an mPAP

between 21 and 24 mmHg, reintroducing exercise-induced PH into the definition, and decreasing the PCWP cutoff for precapillary PH to 12 mmHg All of these changes were rejected, and the current defini-tions remain as above.2 

CLASSIFICATION

Previously classified as simply primary PH and secondary PH, the classification has since expanded into

a clinical classification system that groups subsets of PH patients sharing similar pathologic findings, hemodynamic characteristics, and management strategies PH is divided into five categories: group 1, PAH; group 2, PH caused by left-heart disease; group 3, PH caused by lung diseases and/or hypoxia; group 4, chronic thromboembolic PH (CTEPH); and group 5, PH with unclear multifactorial mechanisms (Box 8.1).3 

PH is diagnosed by elevated pulmonary pressures on RHC; however, initial screening of patients with suspected PH is typically done with transthoracic echocardiography Doppler echocardiography can estimate pulmonary artery systolic pressure (PASP) using the maximum TR velocity (TRVmax) and estimated right-atrial (RA) pressure, as determined by the inferior vena cava diameter and collapsibility, in the follow-ing equation:

PASP= 4(TRVmax(m/s))2+ RA pressure (mmHg)

An estimated PASP greater than 40 mmHg is generally considered abnormal, and in a patient with wise unexplained dyspnea it warrants further evaluation.5 In addition to evaluating pulmonary pressure,

other-it is equally important to evaluate right-heart size and function Pulmonary pressure measurements can

be underestimated in the setting of poor Doppler alignment or minimal tricuspid regurgitant jet, and an enlarged and/or dysfunctional right ventricle (RV) may be the only indication of PH Echocardiography is

also useful in evaluating causes of PH, such as left-heart disease and shunts Overt left-ventricular (LV)

systolic dysfunction, grade 2 or more diastolic dysfunction, severe aortic stenosis, or mitral valvular disease

suggests postcapillary PH due to left-heart disease Other signs favoring postcapillary PH on

echocar-diography include left-ventricular hypertrophy, left-atrial (LA) enlargement, and bowing of the intra-atrial

septum to the right.6

If echocardiographic findings are suggestive of PH, a personal and family history and risk

fac-tor assessment should be investigated After the exclusion of the more common causes of PH, such as

left-heart disease and lung disease, a search for the underlying cause must be undertaken A diagnostic

algorithm for the diagnosis of PH is shown in Fig 8.1. 

HEMODYNAMIC FINDINGS IN PULMONARY HYPERTENSION

The hemodynamic abnormalities observed in PH depend on the underlying condition, the magnitude of

pressure elevation, and its effect on the RV Pulmonary pressures can vary widely from modest elevation of

systolic pressure in the 40–50 mmHg range to severe elevation exceeding systemic pressure

The right-atrial pressure (RAP) may be elevated and the waveform may show a prominent a wave

when contracting against higher right-ventricular diastolic pressures In decompensated right-heart

failure, the RAP will be significantly elevated The RA waveform may also demonstrate a prominent v wave

representative of tricuspid valve regurgitation, which is commonly associated with PH Severe regurgitation

can result in obliteration of the c wave and replacement by a broad v wave termed the c-v wave (Fig 8.2).7

Large v waves can also be seen as a result of decreased atrial compliance from chronic pressure elevation

in right-ventricular failure Atrial arrhythmias can often be present in patients with postcapillary PH, and

less commonly in PAH In atrial fibrillation and atrial flutter, where there is no organized atrial activity, the

right-atrial waveform will show a loss of a waves.

In PH with normal right-ventricular function, the right-ventricular systolic pressure will elevate to

pump against an increased pulmonary resistance Under these conditions, the right-ventricular

end-diastolic pressure (RVEDP) will remain normal As the RV fails, the RVEDP rises Right-ventricular pressure

drops rapidly in early diastole during isovolumic relaxation, and on the right-ventricular pressure waveform

there will be a sharp early diastolic dip with a rise and plateau of elevated diastolic pressure.7 Additionally,

a prominent a wave may be seen, demonstrating noncompliance of the RV (Fig 8.3)

Table 8.1 Hemodynamic Definitions of Pulmonary Hypertension

DEFINITION CHARACTERISTICS CLINICAL GROUP(S) a

2 PH due to left-heart disease

5 PH with unclear multifactorial mechanisms

Mixed precapillary and

postcapillary PH mPAP ≥25 mmHg

PCWP >15 mmHgDPG ≥7 mmHg and/orPVR >3 WU

2 PH due to left-heart disease

5 PH with unclear multifactorial mechanisms

DPG, Diastolic pressure gradient; mPAP, mean pulmonary artery pressure; PAH, pulmonary arterial

hyperten-sion; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertenhyperten-sion; PVR, pulmonary vascular

resistance; WU, Wood units.

(Data from Lau E, Humber M A critical appraisal of the updated 2014 Nice pulmonary hypertension

clas-sification system Can J Cardiol 2015;31:367–374; Galiѐ N, Humbert M, Vachiery JL, et al 2015 ESC/ERS

Guidelines for the diagnosis and treatment of pulmonary hypertension Eur Heart J 2016;37:67–119.)

AKL-1, Activin receptor-like kinase 1; BMPR2, bone morphologic protein receptor type II; CAV1, caveolin-1; ENG, endoglin; KCNK3,

potassium channel subfamily K member; HIV, human immunodeficiency virus; SMAD9, mothers against decapentaplegic 9 (Data from Lau E, Humber M A critical appraisal of the updated 2014 Nice pulmonary hypertension classification system Can J Cardiol 2015;31(4):367–374; Simonneau G, Gatzoulis MA, Adatia I, et al Updated clinical classification of pulmonary hypertension J Am

Coll Cardiol 2013;62(suppl 25):D35–D41.)

CHAPTER 8 PULMONARY HYPERTENSION AND RELATED DISORDERS 165

The PASP will be elevated and should be equal to the right-ventricular systolic pressure in the absence of pulmonic valve stenosis Pulmonary artery (PA) diastolic pressure is an indirect measurement

of the LA and left-ventricular end-diastolic pressures (LVEDP) in the absence of downstream pulmonary vasculature or mitral valve obstruction In postcapillary PH (group 2), pulmonary diastolic pressure will also

be elevated (Fig 8.4) In very severe disease, the pulmonary pressures may decrease to near normal levels because of the inability of the failing RV to generate high pressures This will be seen in combination with a markedly elevated RAP and RVEDP

The PCWP distinguishes precapillary from postcapillary PH In postcapillary PH, the PCWP will be increased to greater than 15 mmHg (Fig 8.5) In some cases of severe PH, it may be difficult to obtain

an accurate PCWP Hybrid tracings are common and will overestimate the wedge pressure If there is uncertainty about the PCWP, it should be verified with a wedge oxygen saturation or direct measurement of the LVEDP (in the absence of mitral stenosis) Alternatively, LA pressure can be measured directly by trans-septal catheterization Importantly, great care should be taken when attempting to wedge the PA catheter

Box 8.1 Classification of Pulmonary Hypertension

1 Pulmonary arterial hypertension

1.1 Idiopathic pulmonary arterial hypertension

1.2 Heritable pulmonary arterial hypertension

1A Pulmonary venoocclusive disease and/or pulmonary capillary hemangiomatosis

1B Persistent pulmonary hypertension of the newborn

2 Pulmonary hypertension due to left-heart disease

2.1 Left-ventricular systolic dysfunction

2.2 Left-ventricular diastolic dysfunction

2.3 Valvular disease

2.4 Congenital/acquired left-heart inflow/outflow tract obstruction and congenital cardiomyopathies

3 Pulmonary hypertension due 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 lung diseases

4 Chronic thromboembolic pulmonary hypertension

5 Pulmonary hypertension with unclear multifactorial mechanisms

5.1 Hematologic disorders: chronic hemolytic anemia, myeloproliferative disorders, splenectomy

5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis

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

5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension

AKL-1, Activin receptor-like kinase 1; BMPR2, bone morphologic protein receptor type II; CAV1, caveolin-1; ENG, endoglin; KCNK3,

potassium channel subfamily K member; HIV, human immunodeficiency virus; SMAD9, mothers against decapentaplegic 9 (Data from Lau E, Humber M A critical appraisal of the updated 2014 Nice pulmonary hypertension classification system Can J Cardiol 2015;31(4):367–374; Simonneau G, Gatzoulis MA, Adatia I, et al Updated clinical classification of pulmonary hypertension J Am

Coll Cardiol 2013;62(suppl 25):D35–D41.)

Consider other causes or recheckEchocardiography compatible with PH

Diagnosis of heart disease or Iung disease confirmed?

PH unlikely

Consider most common causes of PH

(i.e., left-heart disease, Iung disease)

History, signs, risk factors, ECG, X-ray,

PFT incl, DLCO, consider BGA, HR-CT

No signs of severe PH/RV

dysfunction

Signs of severe PH/RV dysfunctionRefer to PH expert centerTreat underlying disease

CTEPH likely

CT angiography, RHC plus Pa

PAH likely,specific diagnostic tests

Refer to PH expert center

V/Q scintigraphyUnmatched perfusion defects?

NO

NONO

Fig 8.1 Diagnostic approach to pulmonary hypertension BGA, Blood gas analysis; CHD, congenital heart disease; CT,

computed tomography; CTD, connective tissues disease; CTEPH, chronic thromboembolic pulmonary hypertension; DLCO, diffusing capacity of the lung for carbon monoxide; ECG, electrocardiogram; HIV, human immunodeficiency virus; HR-CT, high resolution computed tomography; Pa, pulmonary angiography; PAH, pulmonary arterial hypertension; PCH, pulmonary capillary hemangiomatosis; PCWP, pulmonary capillary wedge pressure; PFT, pulmonary function testing; PH, pulmonary hypertension; PVOD, pulmonary venoocclusive disease; PVR, pulmonary vascular resistance; RHC, right-heart catheteriza- tion; RV, right ventricle; V/Q, ventilation/perfusion; WU, wood units (Adapted from Hoeper MM, Bogaard HJ, Condliffe R,

et al Definitions and diagnosis of pulmonary hypertension J Am Coll Cardiol 2013;62:D42–D50.)

CHAPTER 8 PULMONARY HYPERTENSION AND RELATED DISORDERS 167

a a

a aa a v

Fig 8.2 (A) Right-atrial pressure waveform showing prominent a waves (atrial contraction) and elevated right-atrial

pressure (B) Right-atrial pressure waveform in a patient with severe tricuspid regurgitation, showing prominent c-v waveform v, Venous filling.

Fig 8.3 Right-ventricular pressure waveform demonstrating an early diastolic dip and an a wave (see circled a wave in

figure) representative of ventricular noncompliance, as well as elevated systolic and end-diastolic pressures d, Diastole;

e, end-diastole; s, systole.

in severe PH, as there is an increased risk of PA rupture, a catastrophic and potentially fatal event Pressure tracings in the wedge position can appear similar to RAP tracings in the presence of mitral regurgitation and left-ventricular dysfunction Careful comparisons of the PA and PCWP waveforms are necessary when

there are large v waves, as there may be prominent notching on the PA waveform due to a reflection of the

v wave (Fig 8.6) Figs 8.7 and 8.8 are examples of pressure waveforms in patients with precapillary PH.The cardiac output is the final measurement needed to complete a baseline hemodynamic assess-ment The cardiac output may be normal in a patient who is well compensated, or it can be reduced in

right-ventricular failure From the hemodynamic measurements, further calculations can be made to mine the PVR and presence or absence of PAH PVR in Wood units is calculated using Ohm’s law as follows:

deter-PVR=mPAP (mmHg)−PCWP (mmHg)

Cardiac output (L/min)

A PVR of greater than 3 Wood units is associated with PAH and mixed precapillary and postcapillary PH To convert Wood units to dyn*s/cm5 (a measurement of vascular resistance), multiply by 80

Mortality from PH is strongly associated with right-ventricular dysfunction.8 The pulmonary artery pulsatility index (PAPi) shows promise as a predictor of right-ventricular failure in multiple disease states, including right-ventricular infarction and implantation of a left-ventricular assist device (LVAD).9,10 PADP is the pulmonary artery diastolic pressure

PAPi=PASP (mmHg)−PADP (mmHg)

RAP (mmHg)

In right-ventricular infarction and post-LVAD implant, a PAPi of less than 0.9–1.85 predicted short-term right-ventricular failure and death.9,10 The utility of PAPi in PAH is under investigation The Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) risk score has been validated in patients with PAH and incorporates RAP (>20 mmHg) and PVR (>32 Wood units) into a scoring algorithm which includes clinical data, exercise, and echocardiographic data to predict 1-year survival.11

Fig 8.4 Pulmonary artery pressure tracing showing severely elevated pulmonary pressures reaching systemic levels.

a a a

Fig 8.5 Pulmonary capillary wedge tracing in a patient with severe left-ventricular dysfunction and significantly elevated

wedge pressure This tracing shows significant respiratory variation, and pressure should be measured at end-expiration Thus in this case, the wedge pressure is about 40 mmHg and not 15 mmHg Pausing respirations briefly after exhalation

during the measurement can correct this artifact a, Atrial contraction; v, venous filling.

CHAPTER 8 PULMONARY HYPERTENSION AND RELATED DISORDERS 169

An elevated DPG of greater than or equal to 7 mmHg is associated with worse long-term survival in patients with mixed precapillary and postcapillary PH.12

HEMODYNAMIC EFFECTS OF PULMONARY DISEASE

Chronic obstructive lung disease (COPD), interstitial lung disease, and sleep disordered breathing are the most common respiratory diseases associated with PH (group 3).5 In pulmonary disease, PH is the result of chronic hypoxia that causes vasoconstriction and pulmonary vascular remodeling

The prevalence of PH in pulmonary disease is variable but tends to increase with the severity of pulmonary disease.14 One retrospective analysis of COPD patients undergoing RHC found a prevalence of 18% When exercise hemodynamics were measured, the prevalence increased to 71% and was found in all patients with severe COPD in this cohort Generally, patients with PH caused by lung disease present with

v v v

v v

v v

v v

Fig 8.6 (A) Pulmonary artery waveform showing prominent notching after peak systole, reflective of the large v waves

(venous filling) seen on the (B) pulmonary capillary wedge pressure tracing a, Atrial contraction; d, diastole; s, systole.

mild-to-moderate elevations in pulmonary pressures, and rarely with severe disease.14,15 Cor pulmonale

is the term given to right-ventricular dysfunction due to PH from chronic lung disease RHC will show evidence of right-ventricular dysfunction with elevated RAP and RVEDP, precapillary PH with mPAP greater than or equal to 25 mmHg, and PCWP less than or equal to 15 mmHg COPD is the most common cause

of cor pulmonale in North America, affecting greater than 40% of patients with COPD Patients with cor pulmonale tend to have milder PH, with mPAP less than or equal to 40 mmHg.16 Cor pulmonale in any chronic lung disease portends a very poor prognosis, so patients with more than mild PH or evidence of right-ventricular dysfunction should be referred for lung transplant evaluation. 

HEMODYNAMIC EFFECTS OF PULMONARY EMBOLISM

The hemodynamic response to pulmonary embolism (PE) depends on multiple factors including size, istent cardiopulmonary disease, and neurohumoral effects Acute PE increases the PVR through hypoxic vasoconstriction PA pressures can double in acute PE (Fig 8.9), to approximately 40 mmHg in previously normal patients or significantly higher in patients with prior cardiopulmonary disease The sudden increase

coex-in right-ventricular afterload can cause the RV to dilate and become dysfunctional.17 McConnell sign, a distinct pattern of right-ventricular dysfunction with mid-RV free wall akinesis, and normal apical wall motion, may be seen on echocardiography Cardiac hemodynamics will show an elevated RVEDP and RAP,

which can exceed the LA pressure, along with prominent v waves on the RAP tracing from TR In acute PE

with significant elevation in pulmonary pressure, the right-ventricular pressure overload causes a leftward shift in the intraventricular septum During diastole there is impaired LV filling due to septal displacement and as a result LV diastolic filling relies more on atrial contraction.17 This will result in a prominent a wave

v v

v v

Fig 8.7 (A) Pulmonary artery waveform in a patient with scleroderma, showing systemic pulmonary systolic pressure (B)

Simultaneous pulmonary capillary wedge pressure waveforms showing a low pressure, indicating a precapillary etiology of

pulmonary hypertension a, Atrial contraction; d, diastole; s, systole; v, venous filling.

CHAPTER 8 PULMONARY HYPERTENSION AND RELATED DISORDERS 171

Fig 8.8 Pressure waveforms in a patient with an atrial septal defect (A) Right-atrial pressure Atrial waveforms show

prominent a waves (atrial contraction) (B) Right-ventricular and (C) pulmonary artery systolic pressures are increased

to systemic levels (D) Left-atrial pressure was directly measured and was found to be equal to right-atrial pressure

d, Diastole; e, end-diastole; s, systole; v, venous filling.

A small percentage of patients fail to clear their thrombi after an acute PE Over time, persistent thrombi become organized and fibrotic, causing occlusion and vessel wall thickening Biopsies in patients with CTEPH have shown medial hypertrophy and intimal proliferation in the small distal arteries, similar to that seen in PAH It is the remodeling of the distal arteries that is believed to be the major cause of worsen-ing PH and the reason why PH can persist even after mechanical removal of thrombotic material.18,19Because of distal vessel remodeling, PA pressures tend to be higher in CTEPH than in acute PE (Fig 8.10) There is also a more direct correlation with percentage of obstruction and PA pressure in acute PE than there is in CTEPH.19 During RHC, PCWP can be erroneously elevated in CTEPH, and LVEDP measurement should be considered. 

VASODILATOR CHALLENGE: OPTIONS, PROTOCOLS,

AND EXAMPLES

In PAH, the two hemodynamic variables most closely correlated with outcomes are RAP and PVR.11 ment with acute vasodilator testing, defined as a decrease in mPAP by at least 10 mmHg to an absolute level of less than 40 mmHg without a decrease in cardiac output, correlates with better long-term prognosis and response to treatment with calcium channel blockers (CCBs).2,5,20 Pulmonary vasodilator testing to identify patients suitable for high-dose CCB treatment is recommended only for patients with idiopathic PAH, hereditary PAH, and drug-induced PAH In other forms of PAH or PH the results could be misleading, and often these patients are not responders.4 Inhaled nitric oxide is the preferred and most commonly used vasodilating agent It is the most specific and short-acting vasodilator for pulmonary vessels and has no systemic effects Other available agents include intravenous epoprostenol and intravenous adenosine CCB, sodium nitroprusside, and nitrates should not be used in PAH for vasodilator testing (Table 8.2).4,5

Improve-Pulmonary venoocclusive disease is a rare form of PH caused by obliteration of small pulmonary veins

by fibrous intimal thickening and patchy capillary proliferation Hemodynamically it is indistinguishable

C

Fig 8.9 (A–B) Pulmonary angiogram of a 52-year-old woman with acute pulmonary embolism (C) Computed tomography

angiogram of the same patient showing bilateral proximal pulmonary embolism.

CHAPTER 8 PULMONARY HYPERTENSION AND RELATED DISORDERS 173

from PAH, but the diagnosis is suggested when pulmonary edema develops during vasodilator challenge With vasodilators there is preferential dilation of pulmonary arterioles and flooding of pulmonary capillaries causing pulmonary edema There are no medical therapies with proven benefit in this disease; lung trans-plant, in appropriate candidates, remains the only definitive therapy.21

Evaluation of the pulmonary vasculature is critical in patients being evaluated for heart tion In the early post-transplant period, right-heart failure accounts for approximately 20% of deaths and

Fig 8.10 (A) Pulmonary artery, (B) pulmonary capillary wedge, and (C) simultaneous left-ventricular and pulmonary

capil-lary wedge pressure waveforms in a patient with chronic pulmonary thromboembolic disease Pulmonary capilcapil-lary wedge pressure was unexpectedly elevated, so left-ventricular end-diastolic pressure was measured and found to be lower, reflective of normal left-sided pressure There is the appearance of a gradient, suggesting mitral stenosis, but in this case the “wedge” pressure is not reflecting left-atrial pressure and the left-ventricular end-diastolic pressure is a more accurate

reflection of the left-sided pressures a, Atrial contraction; d, diastole; e, end-diastole; s, systole; v, venous filling.

is associated with elevated PVR Vasodilator challenge with sodium nitroprusside is recommended if the PA systolic pressure is greater than or equal to 50 mmHg and either a TPG of greater than or equal to 15 or a PVR of greater than 3 Wood units If the PVR remains greater than 5 Woods units, the PVR index is greater than 6 Woods units, or the TPG is greater than 15 or if the PVR decreases to less than 2.5 but systolic blood pressure falls to less than 85 mmHg with nitroprusside infusion, there is a high risk of post-transplant right-ventricular failure and death.22

In patients with significant exertional symptoms but normal baseline hemodynamics, exercise testing with invasive hemodynamic measurements can help unmask heart failure with preserved ejection fraction (HFpEF) During catheterization exercise is best done with a supine bicycle, so that the patient does not need to move from the catheterization table Exercise should start at a 20 Watts workload for 5 minutes and increase in 10 Watts increments every 3 minutes until the patient reports exhaustion (Fig 8.11) An alternative to the supine bicycle is light weight lifting with the arms while still on the catheterization table For patients unable to exercise, saline loading can be used as an alternative provocative maneuver This is done with a rapid infusion of 0.9% normal saline at a rate of

150 mL/min for a total volume of 10 mL/kg Exercise is the preferred method of provocation as it is more sensitive than saline loading for detection of hemodynamic changes indicative of HFpEF.23 After provocation, either with exercise or saline load, the PA pressure and PCWP are remeasured; if elevated above normal levels this confirms the diagnosis of HFpEF

Fig 8.12 is an example of a patient undergoing a hemodynamic and vasodilator challenge protocol Fig 8.13 shows the baseline hemodynamics and the response to sodium nitroprusside in a patient with PH due to left-heart disease. 

TREATMENT AND EFFECTS ON HEMODYNAMICS

Treatment for PH, specifically PAH, has evolved considerably in the past decade Treatment algorithms for PAH have been created by the collaboration of the American College of Chest Physicians, European Society

of Cardiology, and PH experts, and are based on clinical data from studies conducted in idiopathic PAH and PAH related to connective tissue disease and anorexigens (Fig 8.14) The goals of treatment are to improve symptoms, enhance functional capacity, lower PA pressure, normalize cardiac output, prevent progression

of disease, and improve survival.4,5

CCBs (nifedipine, diltiazem, and amlodipine) represent first-line medical therapy for PAH patients who are vasoresponsive during provocative testing Verapamil is specifically avoided in this group because of its negative inotropic effects Only a small number of patients will have a sustained response to these medications, with improvement to functional class I or II.4 For PAH patients who are not vasoresponsive or who fail to respond to CCBs, other targeted therapies are available and include endothelin receptor antagonists (ambrisentan, bosentan, and macitentan), phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, and vardenafil), guanylate cyclase stimulators (riociguat), prostacyclin

Table 8.2 Agents for Vasodilator Testing

every 2 min 2 ng/kg per min every 10–15 min

Side effects Increased left-heart

filling pressure in susceptible patients (PCWP >18 mmHg)

Dyspnea, chest pain, AV block Headache, nausea, lightheadedness

AV, Atrioventricular; PCWP, pulmonary capillary wedge pressure.

(Adapted 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 J Am Coll Cardiol 2009;53:1573–1619.)

B

C

D

Fig 8.11 This patient had (A) normal pulmonary artery and (B) normal pulmonary capillary wedge pressures at rest After

exercise, both (C) pulmonary artery and (D) pulmonary capillary wedge pressures are elevated The patient had normal left-ventricular systolic function and symptoms of heart failure These tracings suggest the diagnosis of heart failure with

preserved ejection fraction a, Atrial contraction; d, diastole; s, systole; v, venous filling.

analogues (epoprostenol, iloprost, and treprostinil), and selective prostacyclin receptor agonists (selexipag).4,5 Through various mechanisms, treatment with these medications results in pulmonary vasodilation In clinical studies, these medications have all been shown to decrease both PA pressure and PVR and increase cardiac index.24–28 For patients with poor functional class, overt right-heart failure, or other high-risk features, initial combination therapy or parenteral therapy is indicated If medical therapy is ineffective, patients are considered for lung transplantation Atrial septostomy, a procedure in which an interatrial communication is created by balloon dilation of the atrial septum, can be used in severe PH and right-ventricular failure as a bridge to transplantation, or for pallia-tion in patients who are not transplant candidates (Fig 8.15) Cardiac output is augmented with this procedure at the expense of lower systemic oxygen saturation.

Unfortunately pulmonary vasodilator therapy has not been proven effective in patients with other forms of PH (groups 2–5) In patients with PH due to left-heart failure, epoprostenol improved PCWP and PVR and increased cardiac index but was also associated with an increase in mortality Phosphodiester-ase-5 inhibitors have been studied in several small randomized controlled trials, but the results have been conflicting.29 Bosentan was associated with elevated liver transaminases and increased risk of early heart failure exacerbation.5 Riociguat was similar to placebo in reducing PA pressure in patients with systolic heart failure Two multicenter trials investigating sildenafil and macitentan in PH caused by left-heart disease are currently under way.4

Fig 8.12 Example of a hemodynamic and vasodilator challenge protocol for evaluation of patients with pulmonary

hyper-tension iNO, Inhaled nitric oxide; mPAP, mean pulmonary artery pressure; PA, pulmonary artery; PASP, pulmonary artery systolic pressure; PCWP, pulmonary capillary wedge pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RA, right-atrial; RV, right-ventricle; TPG, transpulmonary gradient.

B

C

D

Fig 8.13 Vasodilator challenge with sodium nitroprusside in a patient with left-heart disease (A) Baseline pulmonary artery

pressure of 76/35 mmHg (B) Baseline pulmonary capillary wedge pressure of 20–25 mmHg (C) Pulmonary artery pressure creased by 24 mmHg postintravenous sodium nitroprusside to 40/12 mmHg (D) Pulmonary capillary wedge pressure decreased

de-by 17 mmHg postintravenous sodium nitroprusside to 5 mmHg a, Atrial contraction; d, diastole; s, systole; v, venous filling.

PAH confirmed by PH expert center

Positive Acute vasoreactivity testing

(IPAH, HPAH, DPAH)

NegativeOral CCBs

(Class I, LOE C) risk (WHO FC ll-III) Low or intermediate (WHO FC IV) High risk

(Class I, LOE A-B)

Initial combo therapy:

Ambrisentan + Tadalafil (Class I, LOE B) Other ERA + PDE-5i Bosentan + Sildenafil +

iv Epoprostenol Bosentan + iv Epoprostenol (Class Ila, LOE C)

Initial combo therapy: Bosentan + Sildenafil + iv Epoprostenol

Bosentan + iv Epoprostenol (Class Ila, LOE C)

Inadequate clinical response

Consider listing for lung transplant

Consider referral for lung transplant

Fig 8.14 Pulmonary arterial hypertension treatment algorithm CCBs, Calcium channel blockers; DPAH, drug-induced

pulmonary arterial hypertension; ERAs, endothelin receptor antagonists; FC, functional class; HPAH, hereditary pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; LOE, level of evidence; PAH, pulmonary arterial hypertension; PDE-5i, phosphodiesterase-5 inhibitor; PH, pulmonary hypertension; SC, subcutaneous; WHO, World Health Organization (Adapted from Galiè N, Humbert M, Vachiery JL, et al 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Eur Heart J 2016;37:67–119; 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 col- laboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association J Am Coll Cardiol 2009;53:1573–1619.)

Patients with significant PH because of left-heart disease should be considered for advanced pies such as durable mechanical circulatory support and transplantation Elevated pulmonary pressure and PVR are risk factors for poor outcomes because of right-heart failure following transplant, and fixed PH may

thera-be a contraindication to transplantation.22 Unloading the left ventricle with an implantable LVAD in patients with group 2 PH can significantly decrease mPAP, PCWP, and PVR, such that some patients with initially prohibitively high pulmonary pressures can become transplant candidates.30

CHAPTER 8 PULMONARY HYPERTENSION AND RELATED DISORDERS 179

At this time there are no specific therapies for group 3 PH due to lung disease and/or hypoxia In patients with COPD, oxygen supplementation has been shown to reduce progression of PH, but its role

is less clear in interstitial lung disease Sleep disordered breathing should be treated to prevent episodic hypoxia and progression of PH PAH-specific medications have been ineffective in this group, but PA pres-sures rarely return to normal with treatment of the underlying conditions.4,5

In group 4 CTEPH, optimal medical therapy consists of lifelong anticoagulation along with ics and oxygen in the setting of heart failure or hypoxia Pulmonary endarterectomy is the treatment of choice in this group and is potentially curative Surgical success requires careful patient selection and

operator experience With successful surgery, patients often experience substantial symptom relief and

near normalization of hemodynamics In nonoperable patients or those with persistent PH after

endarter-ectomy, targeted medical therapy with PAH drugs may be indicated.4,5 Riociguat improves hemodynamics

(decrease in mPAP and PVR, and increase in cardiac index), functional status, and 6-minute walk distance

in patients with CTEPH.4,26

Group 5 PH includes disorders with unclear or multifactorial mechanisms such as sickle cell anemia,

chronic kidney disease, sarcoidosis, and others Treatment for this group is tailored to the underlying

disease process, and there are no randomized controlled trials evaluating the use of PAH drugs in this

group as a whole.4 A double-blind, placebo-controlled trial comparing sildenafil to placebo in patients with

sickle cell disease showed no improvement in 6-minute walk distance, and there was an increased rate

of hospitalization for pain in patients treated with sildenafil.31 PH is highly prevalent among patients with

chronic kidney disease and end-stage renal disease Kidney transplant in patients with PH has been

associ-ated with early graft dysfunction, but several small studies suggest kidney transplant may improve PH by

improving systemic blood pressure, LV hypertrophy, and LV systolic and diastolic function.32 Prostacyclins,

endothelin receptor antagonists, and phosphodiesterase inhibitors have all been used off label in patients

with pulmonary sarcoidosis and have shown some hemodynamic and clinical improvement in this

popula-tion No large randomized controlled trials have been done to approve their use in these patients.33

4 Galiè N, Humbert M, Vachiery JL, et al 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary

hyper-tension Eur Heart J 2016;37(1):67–119.

5 McLaughlin VV, Archer SL, Badesch DB, et al ACCF/AHA 2009 expert consensus document on pulmonary

hyperten-sion: 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 J Am Coll Cardiol 2009;53(17):1573–1619.

6 McLaughlin VV, Shah SJ, Souza R, Humbert M Management of pulmonary arterial hypertension J Am Coll Cardiol

2015;65(18):1976–1997.

7 Bloomfield RA, Lauson HD, Cournand A, Breed ES, Richards DW Recording of right heart pressures in normal subjects

and in patients with chronic pulmonary disease and various types of cardio-circulatory disease J Clin Invest

1946;25(4):639–664.

8 Vonk-Noordegraaf A, Haddad F, Chin KM, et al Right heart adaptation to pulmonary arterial hypertension J Am Coll

Cardiol 2013;62(suppl 25):D22–D33.

9 Morine KJ, Kiernan MS, Pham DT, Paruchuri V, Denofrio D, Kupur NK Pulmonary artery pulsatility index is associated

with right ventricular failure after left ventricular assist device surgery J Card Fail 2016;22(2):110–116.

10 Korabathina R, Heffernan KS, Paruchuri V, et al The pulmonary artery pulsatility index identifies severe right

ventricu-lar dysfunction in acute inferior myocardial infarction Catheter Cardiovasc Interv 2012;80(4):593–600.

11 Benza RL, Gomberg-Maitland M, Miller DP, et al The REVEAL registry risk score calculator in patients with newly

diagnosed pulmonary arterial hypertension Chest 2012;141(2):354–362.

12 Gerges C, Gerges M, Lang MB, et al Diastolic pulmonary vascular pressure gradient: a predictor of prognosis in

“out-of-proportion” pulmonary hypertension Chest 2013;143(3):758–766.

13 Vachiéry JL, Adir Y, Barberà JA, et al Pulmonary hypertension due to left heart diseases J Am Coll Cardiol

2013;62(suppl 25):D100–D108.

14 Voelkel NF, Gomez-Arroyo J, Mizuno S COPD/emphysema: the vascular story Pulm Circ 2011;1(3):320–326.

15 Solidoro P, Patrucco F, Bonato R, et al Pulmonary hypertension in chronic obstructive pulmonary disease and

pulmonary fibrosis: prevalence and hemodynamic differences in lung transplant recipients at transplant center’s

referral time Transplant Proc 2015;47(7):2161–2165.

16 Budev MM, Arroliga AC, Wiedemann HP, Matthay RA Cor pulmonale: an overview Semin Respir Crit Care Med

19 Azarian R, Wartski M, Collingnon MA, et al Lung perfusion scans and hemodynamics in acute and chronic pulmonary

embolism J Nucl Med 1997;38(6):980–983.

20 Badesch DB, Abman SH, Simmonneau G, Rubin LJ, McLaughlin VV Medical therapy for pulmonary arterial

hyperten-sion: updated ACCP evidence-based clinical practice guidelines Chest 2007;131(6):1917–1928.

21 Montani D, Lau EM, Dorfmüller P, et al Pulmonary veno-occlusive disease Eur Respir J 2016;47(5):1518–1534.

22 Mehra MR, Kobashigawa J, Starling R, et al Listing criteria for heart transplantation: International Society for Heart

and Lung Transplantation guidelines for the care of cardiac transplant candidates-2006 J Heart Lung Transplant

2006;25(9):1024–1042.

23 Andersen MJ, Olson TP, Melenovsky V, Kane GC, Borlaug BA Differential hemodynamic effects of exercise and volume

expansion in people with and without heart failure Circ Heart Fail 2015;8(1):41–48.

24 Galiè N, Beghetti M, Gatzoulis MA, et al Bosentan therapy in patients with Eisenmenger syndrome: a multicenter,

double-blind, randomized, placebo-controlled study Circulation 2006;114(1):48–54.

25 Galiè N, Ghofrani HA, Torbicki A, et al Sildenafil citrate therapy for pulmonary arterial hypertension N Engl J Med

2005;353(20):2148–2157.

26 Ghofrani HA, Hoeper MM, Halank M, et al Riociguat for chronic thromboembolic pulmonary hypertension and

pulmo-nary arterial hypertension: a phase II study Eur Respir J 2010;36(4):792–799.

27 Simonnaeu G, Torbicki G, Hoeper MM, et al Selexipag: an oral, selective prostacyclin receptor agonist for the

treat-ment of pulmonary arterial hypertension Eur Respir J 2012;40(4):874–880.

28 Sitbon O, Humber M, Nunes H, et al Long-term intravenous epoprostenol infusion in primary pulmonary hypertension

J Am Coll Cardiol 2002;40(4):780–788.

29 Hoeper MM, McLaughlin VV, Dalaan AM, Satoh T, Galiè N Treatment of pulmonary hypertension Lancet Respir Med

2016 Apr;4(4):323–336.

30 Gupta S, Woldendorp K, Muthiah K, et al Normalization of haemodynamics in patients with end-stage heart failure

with continuous-flow left ventricular assist device therapy Heart Lung Circ 2014;23(10):963–969.

31 Machado RF, Barst RJ, Yovetich NA, et al Hospitalization for pain in patients with sickle cell disease treated with

sildenafil for elevated TRV and low exercise capacity Blood 2011;118(4):855–864.

32 Lentine KL, Villines TC, Axelrod D, Kaviratne S, Weir MR, Costa SP Evaluation and management of pulmonary

hyper-tension in kidney transplant candidates and recipients: concepts and controversies Transplantation 2017;101(1):

166–181.

33 Baughman RP, Engel PJ, Nathan S Pulmonary hypertension in sarcoidosis Clin Chest Med 2015;36(4):703–714.

CHAPTER 8 PULMONARY HYPERTENSION AND RELATED DISORDERS 181

22 Mehra MR, Kobashigawa J, Starling R, et al Listing criteria for heart transplantation: International Society for Heart

and Lung Transplantation guidelines for the care of cardiac transplant candidates-2006 J Heart Lung Transplant

2006;25(9):1024–1042.

23 Andersen MJ, Olson TP, Melenovsky V, Kane GC, Borlaug BA Differential hemodynamic effects of exercise and volume

expansion in people with and without heart failure Circ Heart Fail 2015;8(1):41–48.

24 Galiè N, Beghetti M, Gatzoulis MA, et al Bosentan therapy in patients with Eisenmenger syndrome: a multicenter,

double-blind, randomized, placebo-controlled study Circulation 2006;114(1):48–54.

25 Galiè N, Ghofrani HA, Torbicki A, et al Sildenafil citrate therapy for pulmonary arterial hypertension N Engl J Med

2005;353(20):2148–2157.

26 Ghofrani HA, Hoeper MM, Halank M, et al Riociguat for chronic thromboembolic pulmonary hypertension and

pulmo-nary arterial hypertension: a phase II study Eur Respir J 2010;36(4):792–799.

27 Simonnaeu G, Torbicki G, Hoeper MM, et al Selexipag: an oral, selective prostacyclin receptor agonist for the

treat-ment of pulmonary arterial hypertension Eur Respir J 2012;40(4):874–880.

28 Sitbon O, Humber M, Nunes H, et al Long-term intravenous epoprostenol infusion in primary pulmonary hypertension

J Am Coll Cardiol 2002;40(4):780–788.

29 Hoeper MM, McLaughlin VV, Dalaan AM, Satoh T, Galiè N Treatment of pulmonary hypertension Lancet Respir Med

2016 Apr;4(4):323–336.

30 Gupta S, Woldendorp K, Muthiah K, et al Normalization of haemodynamics in patients with end-stage heart failure

with continuous-flow left ventricular assist device therapy Heart Lung Circ 2014;23(10):963–969.

31 Machado RF, Barst RJ, Yovetich NA, et al Hospitalization for pain in patients with sickle cell disease treated with

sildenafil for elevated TRV and low exercise capacity Blood 2011;118(4):855–864.

32 Lentine KL, Villines TC, Axelrod D, Kaviratne S, Weir MR, Costa SP Evaluation and management of pulmonary

hyper-tension in kidney transplant candidates and recipients: concepts and controversies Transplantation 2017;101(1):

166–181.

33 Baughman RP, Engel PJ, Nathan S Pulmonary hypertension in sarcoidosis Clin Chest Med 2015;36(4):703–714.

Pericardial diseases are an interesting and diverse group of disorders, and their effects on cardiac physiology are complex and fascinating A list of the causes of pericardial disease includes nearly the entire table of contents of an internal medicine textbook because most major disease processes have the potential to affect the pericardium (Box 9.1) Despite this wide array of inciting processes, pericardial disease presents as one or more of four distinct syndromes: acute pericarditis, effusion and tamponade,

Coxsackie, echovirus, adenovirus, Epstein–Barr virus

Human immunodeficiency virus

Cardiac perforation from interventional procedures

Drugs (warfarin, minoxidil, procainamide)