Outline
Pulmonary Hypertension: Definition and Classification 617
Clinical Features Raising the Suspicion of Pulmonary Hypertension 618
Diagnostic Evaluation of Pulmonary Hypertension 619
Echocardiographic Evaluation of Known or Suspected Pulmonary Hypertension 619
Laboratory Testing 621
Pulmonary Function Testing 621
Right Heart Catheterization 621
Group 1: Pulmonary Arterial Hypertension 621
Epidemiology and Clinical Features 621
Pulmonary Arterial Hypertension Associated Conditions 622
Connective Tissue Disease 622
Congenital Heart Disease 622
Drugs and Toxins 622
Chronic Liver Disease 622
Pulmonary Venoocclusive Disease and Pulmonary Capillary Hemangiomatosis 622
Pathophysiology of Group I Pulmonary Arterial Hypertension 622
Prognosis in Group I Pulmonary Arterial Hypertension 623
Management of Group I Pulmonary Hypertension 624
General Treatment Recommendations for Patients with Pulmonary Hypertension 624
Drug Therapy for Group I PAH-PAH Targeted Therapy 626
Drug Therapy for Group I Pulmonary Arterial Hypertension-Adjuvant Therapy 627
Group 2: Pulmonary Hypertension With Left Heart Disease 627
Pulmonary Hypertension Due to Left-Sided Valvular Heart Disease 628
Pulmonary Hypertension in Heart Failure With Preserved or Reduced Ejection Fraction 628
Pulmonary Hypertension Due to Left Atrial Disease 628
Treatment 628
Group 3: Pulmonary Hypertension Associated with Lung Diseases and/or Hypoxia 628
Pulmonary Hypertension Associated With Chronic Obstructive Pulmonary Disease 629
Pulmonary Hypertension Associated With Interstitial Lung Disease 629
Pulmonary Hypertension and Sleep-Disordered Breathing 630
Group 4: Pulmonary Hypertension Due to Thrombotic and/or Embolic Disease 630
Group 5: Pulmonary Hypertension Associated With Unclear Multifactorial Mechanisms 630
Pulmonary Hypertension: Definition and Classification
Pulmonary hypertension (PH) is a hemodynamic finding and is considered to be present when the mean pulmonary artery pressure (mPAP) is greater than 20 mm Hg as recently defined by the Sixth World Symposium on Pulmonary Hypertension. Historically, PH has been defined as a mPAP ≥25 mm Hg, but the definition was recently re-evaluated and changed to a mPAP of >20 mm Hg to reflect a value that is two standard deviations above the mean normal value for mPAP. It should be noted, however, that studies referenced in this chapter have used a mPAP ≥25 mm Hg to define PH and that the role of pulmonary hypertension targeted therapy for treatment of PH with a mPAP of 21–24 mm Hg is not known ( Table 43.1 ). PH is suspected based on clinical features or when echocardiography reveals an elevation in Doppler-derived estimates of PAPs and/or unexplained right ventricular enlargement or dysfunction. When the clinical situation and/or echocardiographic findings raise the suspicion of PH, a right heart catheterization must be performed to confirm the presence of PH and to determine the specific hemodynamic perturbation causing the elevation of mPAP: precapillary PH (PAH), isolated postcapillary PH, increased cardiac output, or some combination of these patterns (see Table 43.1 ). Finally, the underlying disease process or processes leading to PH must be defined.
| True Normal | PAH | Isolated Postcapillary PH | Combined Precapillary and Postcapillary PH | High Output State | ||
|---|---|---|---|---|---|---|
| Established Parameters | ||||||
| Mean PAP (mPAP, mm Hg) | <15 | >20 | >20 | >20 | >20 | |
| Systolic PAP (PASP, mm Hg) | <25 | >35–40 | >35–40 | >35–40 | >35–40 | |
| Mean PCWP (mm Hg) | <12 | ≤15 | >15 | >15 | variable | |
| PVR ([mPAP-PCWP]/CO, wood units) | <2 | ≥3 | < 3 | ≥ 3 | <3 | |
| Cardiac index (L/min/m 2 ) | >2.5 | variable | variable | variable | >5 | |
| Emerging Parameters | ||||||
| Mean TPG (mPAP-PCWP, mm Hg) | <7 | >12 | ≤12 | >12 | <12 | |
| Diastolic PG (PADP-PCWP, mm Hg) | <5 | ≥7 | <7 | ≥7 | <7 | |
| Reactivity testing in Group I PAH | Appropriate Agents | Positive Response | ||||
| Inhaled NO, IV Adenosine, IV Prostacyclin | ↓mPAP ≥10 mm Hg and to <40 mm Hg without ↓ in CO | |||||
A wide range of diseases can cause PH. The outdated separation of PH into primary and secondary causes has been replaced by a classification where PH is apportioned to five broad groups according to the underlying disease process and specific hemodynamic characteristics ( Table 43.2 ). In general, the clinical classification of PH, as defined by the Sixth World Symposium on Pulmonary Hypertension, identifies groups with common pathophysiology and treatment implications, and thus provides a context in which to structure the diagnostic evaluation.
| Group 1 PH: Pulmonary Arterial Hypertension | |
| |
| |
| 1.5PAH long-term responders to calcium channel blockers | |
| 1.6PAH with overt features of venous/capillaries (PVOD/PCH) involvement1.7Persistent PH of the newborn | |
| Group 2 PH: PH Due to Left Heart Disease | |
| |
| Group 3 PH: PH Associated With Lung Disease and/or Hypoxia | |
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| Group 4 PH: PH due to pulmonary artery obstructions | |
| |
| Group 5 PH: Pulmonary Hypertension With Unclear Multifactorial Mechanisms | |
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| |
The prevalence of PH and the contribution of each PH group to the global burden of PH have not been well defined, and will vary according to practice setting and adequacy of diagnostic evaluation. An observational cohort study of an echocardiographic laboratory serving a region of Australia reported an estimated minimum prevalence of 326 cases of PH per 100,000 individuals, with the predominance of cases due to left heart disease ( Fig. 43.1 ).
Clinical Features Raising the Suspicion of Pulmonary Hypertension
The symptoms of PH are nonspecific and influenced by the hemodynamic type and underlying disease, but PH should be suspected in patients complaining of dyspnea, fatigue, exercise intolerance, chest pain, syncope, or edema. The physical examination may reveal evidence of PH as well as clues to the etiology of PH ( Table 43.3 ).
| Finding | Implications | Finding | Etiologic Insights |
|---|---|---|---|
| Inspection | Clubbing | Congenital HD, PVOD | |
| ↑ JVP | RV failure | Central Cyanosis | Hypoxia; R→L shunt |
| ↑ A wave | Early RV failure | Sclerodactyly | Collagen vascular disease |
| V wave | Tricuspid regurgitation | Telangiectasia | |
| Ascites | RV failure | Rash | |
| Edema | RV failure | Raynaud’s | |
| Palpation | Varicose veins | Thromboembolic disease | |
| Right parasternal lift | RV enlargement | Stasis pigment/ulcer | |
| Hepatomegaly | RV failure | Splenomegaly | Portopulmonary PH |
| Pulsatile liver | Tricuspid regurgitation | Spider angioma | |
| Auscultation | Palmar erythema | ||
| ↑ S 2 P | Elevated PAP | Icterus | |
| Early systolic click | Elevated PAP | Caput medusa | |
| Holosystolic murmur RSB | Tricuspid regurgitation | Velcro rales | Interstitial lung disease |
| Inspiratory accentuation | Tricuspid regurgitation | Left sided murmur | Left heart disease |
| Diastolic murmur LUSB | Pulmonic regurgitation | Apical S 3 or S 4 | |
| S 3 or S 4 RSB | RV failure | Laterally displaced apex |
Enlargement of the central pulmonary arteries with peripheral pruning of the pulmonary vasculature may be present on chest radiograph (CXR) in patients with PAH. In the case of concomitant right ventricular failure, right ventricular enlargement (decrease in retrosternal space) and right atrial enlargement (enlarged right heart border) also may be seen ( Fig. 43.2 ). Findings on electrocardiography (ECG) include signs of right ventricular hypertrophy such as right axis deviation, tall R wave in V1, and inverted T waves and ST depression in lead V1 to V3, and tall p waves in lead II due to right atrial enlargement.
Diagnostic Evaluation of Pulmonary Hypertension
In general, evidence of PH is discovered when echocardiography is obtained during the evaluation of known or suspected left heart or lung disease. If the severity of PH at Doppler echocardiography is consistent with the severity of known left heart or lung disease, PH is usually attributed to the underlying process without further evaluation. However, if the severity of PH appears out of proportion to the severity of left heart or lung disease or if PH is found in the absence of known cardiopulmonary disease, a rigorous evaluation should be performed to characterize the severity of PH and ascertain the etiology. Guidelines recommend a comprehensive evaluation when the Doppler estimated right ventricular systolic pressure (RVSP) exceeds 40 to 50 mm Hg in the absence of a clear etiology, particularly in the setting of right heart structural and functional abnormalities, and in patient cohorts at an elevated risk of PAH; for example, scleroderma, chronic liver disease, or human immunodeficiency virus (HIV) infection.
Even in the setting of an obvious cause, the potential for an additional process contributing to PH should be entertained to address concomitant and potentially treatable causes of PH. For example, a diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) (Group 4 PH) should not be missed since this form of PH is potentially curable with surgery. Left heart or pulmonary disease are risk factors for sleep-disordered breathing (Group 3), and patients with pulmonary disease may have unrecognized left heart disease (and vice versa). Understanding the degree of PH expected in patients with left heart or pulmonary disease is required to appreciate when PH is “out of proportion” and suggestive of additional processes.
The accepted diagnostic evaluation of PH is shown in Table 43.4 and focuses on pivotal tests warranted in the evaluation of patients with PH in whom the etiology is not obvious from the history, physical examination, CXR, and ECG. When pivotal tests are positive, contingent tests are obtained. The order and extent of the evaluation will be influenced by clinical suspicion but echocardiography should be performed in all patients.
| Pivotal Tests | Contingent Testing | To Assess…. |
|---|---|---|
| History, physical exam, CXR and electrocardiogram | Suspect PH | |
| Transthoracic echo | Transesophageal echo (select cases) | Doppler estimated PASP RV size and function Presence of left heart disease Congenital abnormalities |
| Ventilation/perfusion scan | Pulmonary angiography, CT angiography, coagulopathy evaluation | Chronic thromboembolic disease Low probability: no further testing Intermediate or high probability: CT or invasive pulmonary angiography |
| Overnight oximetry | Polysomnography | Sleep-disordered breathing related PH |
| Pulmonary function testing | Arterial blood gas, chest CT | Lung disease related PH |
| HIV | Infectious disease evaluation | HIV related PH |
| Antinuclear antibody | Other CTD serologies, rheumatology evaluation | Connective tissue disease related PH |
| Liver function tests | Liver ultrasound | Portopulmonary hypertension |
| 6 Minute walk test; BNP or NT-proBNP, CPXT | Prognosis and baseline to assess therapeutic response | |
| Right heart catheterization | Presence, severity, and type of PH (see Table 43.1 ) Exclude intracardiac shunt PAH—Assess vasodilator response to guide therapy |
Echocardiographic Evaluation of Known or Suspected Pulmonary Hypertension
Echocardiography is a central test in the clinical evaluation of known or suspected PH. The echocardiogram should address three key features. The first is an assessment of pulmonary hemodynamics. With close attention to technical detail, the echocardiogram may provide reasonable accurate estimates of systolic, mean, and diastolic PAPs based on the Doppler velocity profiles of the peak tricuspid regurgitation (TR) and pulmonary valve regurgitation signals (see Fig. 43.2 ). This information is integrated with a two-dimensional and Doppler estimation of right atrial pressure based on imaging of the inferior vena cava and hepatic veins. Although a suspicion of PH can be based on echocardiographic estimates, the diagnosis cannot be established without right heart catheterization.
The second key feature in an echo evaluation of a PH patient is the evaluation for a host of variables that help define the severity of disease. These relate to quantitative assessment of right-sided enlargement and dysfunction. With regard to right ventricular contractility, a key feature to note is that in contrast to the left ventricle the predominant direction of contractility is in the longitudinal plane with the base of the right ventricle moving down toward the apex. Hence measures of longitudinal contractility, such as the tricuspid annular plane systolic excursion (TAPSE), the peak systolic velocity of the tricuspid annulus by tissue Doppler, and longitudinal systolic strain best reflect right ventricular performance and prognosis. Other findings that indicate more severe disease include the presence of a “ D -shaped” left ventricle, a delayed relaxation mitral inflow pattern, a high estimated right atrial pressure, more tricuspid valve regurgitation, and right-sided chamber enlargement. The presence of a pericardial effusion, common in PAH, reflects chronic central venous hypertension and/or the presence of connective tissue disease, which are both features that indicate an increased mortality risk in PAH.
The third important focus of an echocardiographic study in a patient with PH is the separation of precapillary from postcapillary PH. Indeed, many features of advanced left heart disease, such as significant left-sided valvular stenosis, or regurgitation, or myocardial disease, are easily characterized by echocardiography. While echocardiographic features, including left atrial size, may be helpful, the separation of a patient with heart failure with preserved ejection fraction (HFpEF) and advanced right heart dysfunction from a patient with a restricted pulmonary vascular mechanism of PH can be challenging solely on the basis of echo.
Laboratory Testing
All patients should have a routine chemistry panel, complete blood cell count, liver function tests, and thyroid function tests. Antinuclear antibody titer is used to screen for connective tissue disease. Although 40% of patients with idiopathic pulmonary arterial hypertension (IPAH) have positive but low antinuclear antibody (ANA) titers (≥1:80 dilutions), patients with a substantially elevated ANA or suspicious clinical findings require further serologic assessment and rheumatology consultation. HIV serology should be considered.
Pulmonary Function Testing
Pulmonary function testing (PFT) is used to diagnose and quantify the underlying airway or parenchymal lung disease and should be performed in all patients with PH. The diffusing capacity for carbon monoxide (DLCO) is reduced in patients with PAH. A patient with PAH would be expected to have normal spirometry and lung volumes. In all forms of PAH, desaturation during exercise is typically related to diffusion limitation during exercise and the inability of the right ventricle to augment cardiac output, resulting in further depression of mixed venous oxygen saturation. Overnight oximetry can screen for clinically significant sleep apnea or hypopnea during sleep. In the evaluation of all patients with PH, an assessment of sleep-disordered breathing is recommended.
Right Heart Catheterization
Right heart catheterization is mandatory to confirm the diagnosis of PH and should be completed on all patients prior to initiating therapy. Cardiac output, cardiac index, pulmonary vascular resistance (PVR), PA pressure, pulmonary artery wedge pressure (PAWP), and right atrial pressure should all be determined. Intracardiac shunting should also be excluded and vasodilator testing should be performed in patients with idiopathic PAH.
Group 1: Pulmonary Arterial Hypertension
PAH describes a group of various pulmonary hypertensive diseases that have similar histopathology, clinical presentations, and approaches to therapy. These include idiopathic and heritable causes and PH related to a number of associated conditions including: connective tissue diseases, chronic liver disease, HIV infection, schistosomiasis, and exposure to certain drugs or dietary products. In addition, pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) are included as a subgroup in this category of PAH (Group 1.6) because they also are characterized by precapillary PH, pulmonary arteriopathy, similar risk factors, and a genetic predisposition. Persistent PH of the newborn is categorized as a separate subgroup, classified as Group 1.7.
Epidemiology and Clinical Features
PAH, based on the previous definition of an elevated mPAP >25 mm Hg, is considered a rare disease with an estimated prevalence of 15 to 50 cases per million individuals.
Idiopathic Pulmonary Arterial Hypertension
Idiopathic PAH is defined as the presence of precapillary PH in the absence of an underlying risk factor. Idiopathic PAH, previously referred to as “primary pulmonary hypertension” is a rare disease with an annual incidence of 1 to 2 cases per million and occurs more commonly in women than men. In the Western world, idiopathic PAH is the most common subtype of PAH and accounts for almost half of patients with Group 1 PAH. Although previously regarded as a disease of the young, the epidemiology of PAH has changed over recent years with an increase in the average age at diagnosis. Historical registries reported an average age at diagnosis in the fourth decade, whereas more contemporary registries report an average age at diagnosis in the fifth to sixth decades of life. It is not known whether this finding is due to a change in disease phenotype, improved recognition and diagnosis of PAH in older individuals, or misclassification of PH due to left heart disease.
Heritable Pulmonary Arterial Hypertension
Heritable or familial causes of PAH include those patients with either a family history of PAH or those patients with a de novo mutation that imparts a heritable risk. These include alterations in genes from the transforming growth factor beta family, including bone morphogenetic protein receptor type 2 (BMPR2), activin-like kinase 1 (ALK1), Endoglin (ENG), and mothers against decapentaplegic 9 (SMAD9), as well as genes such as Caveolin-1 (CAV1), and potassium channel superfamily K member-3 (KCNK3). BMPR2 mutations are present in 20% of PAH cases, but have a lifetime penetrance of only 10% to 20%. Testing for BMPR2 mutations is available and should be considered in patients with idiopathic PAH, particularly in those with a family history of PAH, and to relatives of patients with heritable PAH, but should be preceded by genetic counseling.
Pulmonary Arterial Hypertension Associated Conditions
Connective Tissue Disease
PAH associated with connective tissue disease is the most common subtype of associated PAH. PAH can occur in conjunction with all forms of connective tissue diseases but occurs most commonly in systemic sclerosis (typically limited scleroderma and commonly associated with the anticentromere antibody), occurring in approximately 12% of cases. As such, routine screening for PAH with symptom assessment, PFT (evaluating for abnormalities in diffusion capacity), and echocardiography every 1 to 2 years should be considered in patients with systemic sclerosis. Patients with PAH associated with connective tissue diseases often have a less robust response to PAH-specific medications and a poorer prognosis than those with idiopathic PAH. All patients with unexplained PAH should have clinical and autoantibody testing for connective tissue disease.
Congenital Heart Disease (see also Chapter 27 )
PAH is a known complication of congenital heart disease, and is frequently associated with systemic to pulmonary shunts. Initially systemic-pulmonary shunts led to a period of high pulmonary flow, but low pulmonary resistance. However, over time the high vascular shear stress related to elevated blood flow induces endothelial damage and progressive irreversible pulmonary vascular remodeling. The term “Eisenmenger syndrome” refers to the irreversible state of PAH mediated through arterial shunts causing pulmonary vasculopathy and ultimately resulting in a right-to-left or bidirectional shunt. The likelihood of PAH developing usually depends on the site and severity of the defect with ventricular septal defects causing PAH more commonly than atrial septal defects or a patent ductus arteriosus. Rarely, PAH may develop even after the defect is corrected.
The early diagnosis of lesions and the appropriate timing of corrective surgery are critical to the prevention of PAH with congenital heart disease. While multifactorial, persistent exposure to increased blood flow can result in progressive endothelial dysfunction, vasoconstriction, and vascular remodeling in the pulmonary circulation, which is not always reversible. Some patients will have residual elevation in PVR and PAH even following repair if irreversible changes have occurred in the pulmonary circulation. Compared with a patient who has idiopathic PAH, a patient with PH associated with congenital heart disease and a comparable degree of PH has a greater probability of longer survival.
Drugs and Toxins
Drugs and toxins have been implicated in the pathogenesis of some cases of PAH, including the use of central nervous system stimulants and appetite suppressants. In the 1960s, the anorexigen aminorex was first reported to be associated with PAH, and was withdrawn from the market in 1972. In the 1980s and 1990s, fenfluramine and dexfenfluramine, were reported to be associated with a marked increase in the risk of PAH if used for greater than 3 months. The fenfluramines act by stimulating serotonin release; serotonin is a potent pulmonary vasoconstrictor and a smooth muscle mitogen. Central nervous system stimulants, such as amphetamine and methamphetamine, may also cause PAH. Severe PH has also been reported in patients treated with dasatinib, a tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. In some cases of dasatinib-associated PH, PH may be at least partially reversible with discontinuation of the drug.
Chronic Liver Disease
Patients with both cirrhotic and noncirrhotic portal hypertension have a greatly increased risk of PH. PH in the setting of liver disease may be due to a hyperdynamic circulation, volume overload, or pulmonary vascular remodeling with increased PVR. Right heart catheterization is necessary to distinguish these hemodynamic profiles. Precapillary PH in the setting of portal hypertension affects approximately 5% to 6% of patients with liver disease, and is referred to as portopulmonary hypertension. Portopulmonary hypertension is pathologically indistinct from idiopathic PAH. Untreated moderate to severe PH is associated with high perioperative mortality at the time of liver transplant, so screening transthoracic echocardiogram is recommended in all patients undergoing evaluation for liver transplantation.
Pulmonary Venoocclusive Disease and Pulmonary Capillary Hemangiomatosis
These are rare causes of PAH, but are commonly misdiagnosed as idiopathic PAH. Risk factors include connective tissue disease, occupational exposures to organic solvents, and receipt of some chemotherapeutic agents. Pathologically, PVOD is characterized by extensive occlusion of the pulmonary veins by fibrous tissue. In PCH there is proliferation of benign thin-walled capillary vessels in the lung parenchyma. These diseases should be suspected when patients present with precapillary PH, a severely reduced diffusion capacity and abnormalities on chest imaging, such as centrilobular ground glass nodules, mediastinal lymphadenopathy, interlobular septal thickening, and pleural effusions. Patients with PVOD and PCH may also develop pulmonary edema with the initiation of PAH targeted therapies. Typically the PAWP is normal or low. Lung biopsy is required to confirm the diagnosis; however, the procedural risk is often prohibitive. Genetic mutations in eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) occur in approximately 20% of patients with sporadic PVOD and PCH and can be helpful in establishing the diagnosis. Prognosis is poor, and there is a variable response to therapy. Lung transplantation is the only successful management strategy.
Pathophysiology of Group I Pulmonary Arterial Hypertension
In PAH, there is a disruption in the balance of vasodilators and vasoconstrictors, smooth muscle mitogens and growth inhibitors, and prothrombotic and anticoagulant compounds ( Fig. 43.3 ). As such, it is characterized by vasoconstriction, smooth muscle cell proliferation, and thrombosis.
