DEFINITIONS
Pulmonary hypertension (PH) is defined by the mean pulmonary artery pressure (mPAP) of >20 mm Hg at rest, which is an update from the previous 25 mm Hg or higher. The update is based on studies which found a mPAP of 14 + 3.3 mm Hg in normal individuals, the new definition of 20 mm Hg is 2 standard deviations above the normal mPAP. Furthermore, subsequent studies involving large cohorts of patients have demonstrated a notable rise in morbidity and mortality with the mPAP exceeding 20 mm Hg. As a result of these findings, a considerable subset of patients, previously considered within the normal range, have been reclassified as having PH. This change in the definition of PH highlights the importance of early diagnosis.
To fully characterize the hemodynamic derangements, it is important to integrate pulmonary capillary wedge pressure (PCWP) and pulmonary vascular resistance (PVR). PVR (in Wood units [WU]) is calculated as:
Cardiac Output
Precapillary PH is defined by the mean PCWP of < 15 mm Hg and PVR of > 3 WU. Postcapillary PH is defined by the mean PCWP of >15 mm Hg and is further divided into combined pre- and postcapillary PH (CpcPH) with PVR of 3 WU or more, and isolated postcapillary PH (IpcPH) with PVR of <3 ( Fig. 9.1 ). Prior studies had suggested that elevated transpulmonary gradient (TPG), calculated as:
and diastolic pulmonary gradient, calculated as:
Diastolic pulmonary gradient = Pulmonary artery diastolic pressure − mean PCWP
could be used to differentiate IpcPH from CpcPH, but these were not included in the sixth World Symposium on PH criteria, primarily reflecting the closest association between PVR and clinical outcomes.
CLASSIFICATION OF PULMONARY HYPERTENSION
The primary objective of clinical classification of PH is to group together clinical conditions that are linked by similar pathophysiologic mechanisms, hemodynamic characteristics, and therapeutic approaches. Group 1 includes pulmonary arterial hypertension (PAH) due to genetic causes, drugs/toxins, connective tissue disease, some congenital heart defects, and idiopathic pulmonary arterial hypertension (IPAH); it is characterized by precapillary hemodynamics. Group 2 is postcapillary PH, either isolated or combined, due to left heart disease such as left ventricular systolic or diastolic dysfunction, or left-sided valve disease. Group 3 consists of PH due to chronic lung disease, such as chronic obstructive pulmonary disease (COPD), interstitial lung disease, and sleep apnea, and is characterized by precapillary hemodynamics. Group 4 includes obstruction to pulmonary artery (PA) blood flow, primarily thromboembolic disease, and also typically has a precapillary hemodynamic picture. Group 5 covers multifactorial diseases such as sarcoidosis, hemolytic anemia, and complex congenital heart defects; hemodynamic profiles include precapillary PH and CpcPH ( Box 9.1 ).
- 1.
Pulmonary arterial hypertension
- 1.
Idiopathic pulmonary arterial hypertension
- 2.
Heritable pulmonary arterial hypertension
- 1.
BMPR2
- 2.
AKL-1 , ENG , SMAD9, CAV1, KCNK3
- 3.
Unknown
- 1.
- 3.
Drug and toxin induced
- 4.
Associated with
- 1.
Connective tissue disease
- 2.
HIV infection
- 3.
Portal hypertension
- 4.
Congenital heart diseases
- 5.
Schistosomiasis
- 1.
- 1.
- 2.
Pulmonary venoocclusive disease and/or pulmonary capillary hemangiomatosis
- 3.
Persistent pulmonary hypertension of the newborn
- 4.
Pulmonary hypertension due to left heart disease
- 1.
Left ventricular systolic dysfunction
- 2.
Left ventricular diastolic dysfunction
- 3.
Valvular disease
- 4.
Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies
- 1.
- 5.
Pulmonary hypertension due to lung diseases and/or hypoxia
- 1.
Chronic obstructive pulmonary disease
- 2.
Interstitial lung disease
- 3.
Other pulmonary diseases with mixed restrictive and obstructive pattern
- 4.
Sleep-disordered breathing
- 5.
Alveolar hypoventilation disorders
- 6.
Chronic exposure to high altitude
- 7.
Developmental lung diseases
- 1.
- 6.
Chronic thromboembolic pulmonary hypertension
- 7.
Pulmonary hypertension with unclear multifactorial mechanisms
- 1.
Hematologic disorders: Chronic hemolytic anemia, myeloproliferative disorders, splenectomy
- 2.
Systemic disorders: Sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
- 3.
Metabolic disorders: Glycogen storage disease, Gaucher disease, thyroid disorders
- 4.
Others: Tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension
- 1.
DIAGNOSIS
The diagnostic strategy for patients with known or presumed PH primarily revolves around the following key objectives: (1) early clinical suspicion of PH based on history and physical exam findings, (2) initiation of suitable screening (echocardiogram) and definitive diagnostic (right heart catheterization [RHC]) methods; and (3) identification of underlying causes. This comprehensive evaluation is necessary to ensure accurate classification, risk assessment, and appropriate treatment for patients with PH.
Dyspnea is the cardinal symptom of PH and is typically experienced during physical activity in early stages of the disease. Other associated symptoms such as fatigue, bendopnea (dyspnea when bending forward), and exertional lightheadedness or syncope can be indicative of disease progression. In advanced stages of PH, rare symptoms manifest. These include angina, due to either right ventricular (RV) ischemia or compression of a coronary artery by the dilated PA, and hoarseness of the voice due to compression of the left recurrent laryngeal nerve by the dilated PA. During cardiac examination, signs suggestive of PH may include a parasternal heave, an accentuated pulmonary component of the second heart sound, an S3 gallop, and a holosystolic murmur of tricuspid regurgitation (TR). Furthermore, distended jugular veins, ascites, hepatomegaly, and peripheral edema suggest right heart failure, whereas peripheral cyanosis, cool extremities, and prolonged capillary refill suggest inadequate cardiac output (CO).
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 and estimated right atrial pressure (RAP), as determined by the inferior vena cava diameter and collapsibility, in the following equation:
An estimated PASP greater than 40 mm Hg is generally considered abnormal, and in a patient with otherwise unexplained dyspnea, it warrants further evaluation. In addition to evaluating pulmonary pressure, 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, hypertrophied, or dysfunctional right heart may be the only indicator of PH. Echocardiography is also useful in evaluating causes of PH, such as left heart disease and shunts. Overt left ventricular systolic dysfunction and moderate or worse left-sided valve disease suggest postcapillary PH due to left heart disease. Other signs favoring postcapillary PH on echocardiography include left ventricular hypertrophy, left atrial enlargement, grade 2 or more diastolic dysfunction, and bowing of intraatrial septum to the right. Echocardiographic findings suggestive of PH are summarized in Table 9.1 .
| Right ventricular hypertrophy |
| Right ventricular enlargement |
| RV dysfunction (reduced TAPSE and FAC) |
| Right atrial enlargement |
| D-shaped LV on short axis |
| Significant TR (moderate or more) |
| Pulmonary regurgitation (moderate or more) |
| Reduced RV outflow tract velocity, short acceleration time pulmonary regurgitation (moderate or more) |
| Dilated inferior vena cava without respiratory variation |
| Pericardial effusion |
| Dilated pulmonary arteries |
If echocardiographic findings are suggestive of PH, a personal and family history and risk factor assessment should be investigated. A diagnostic algorithm for the diagnosis of PH is shown in Fig. 9.2 . It is important to note that while echocardiography can provide valuable information, it is not the definitive diagnostic tool for PH. RHC is required to confirm the diagnosis.
RIGHT HEART CATHETERIZATION
Invasive hemodynamic evaluation with an RHC is critical for diagnosing and phenotyping PH. Performing RHC in patients with PH can be a difficult procedure and demands specialized skills, meticulous data collection, and careful attention to detail. For accurate interpretation, it is necessary to have a systematic approach and follow standardized protocol in the cardiac catheterization laboratory. Additionally, comprehensive knowledge of normal and abnormal cardiac filling pressures ( Table 9.2 ) and calculated parameters as well as recognition of pathologic waveforms, as discussed in Chapter 2 , is crucial.
| Measured Variables | Normal Value | |
|---|---|---|
| 1. | Right atrial pressure, mean (RAP) | 2–6 mm Hg |
| 2. | Pulmonary artery pressure, systolic (sPAP) | 15–30 mm Hg |
| 3. | Pulmonary artery pressure, diastolic (dPAP) | 4–12 mm Hg |
| 4. | Pulmonary artery pressure, mean (mPAP) | 8–20 mm Hg |
| 5. | Pulmonary capillary wedge pressure, mean (PCWP) | < 15 mm Hg |
| 6. | Cardiac output (CO) | 4–8 L/min |
| 7. | Mixed venous oxygen saturation (SvO 2 ) | 65%–60% |
| Calculated Parameter | ||
| 1. | Pulmonary vascular resistance (PVR) | <3 WU |
| 2. | RAP/PCWP ratio | <0.6 |
| 3. | Pulmonary artery pulsatility index (PAPi) | >1 |
| 4. | Pulmonary artery compliance | >2.3 mL/mm Hg |
| Parameter | Equation |
|---|---|
| Pulmonary vascular resistance | mPAP − PCWP CO |
| RAP/PCWP ratio | RAP PCWP |
| Pulmonary artery pulsatility index (PAPi) | sPAP – PCWP CO |
| Pulmonary artery compliance | Stroke volume sPAP – dPAP |
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