Key points

Introduction and definition

Pulmonary hypertension (PH) is an increase in pulmonary artery pressure in the pulmonary vascular bed that ultimately may lead to progressive right heart strain and ultimately, right heart failure. It is defined as a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mm Hg in resting condition as measured by right heart catheterization. Pulmonary arterial hypertension (PAH) is a subgroup of PH, which is defined as increase in mPAP of greater than or equal to 25 mm Hg with a normal left atrial pressure (most often assessed as a pulmonary capillary wedge pressure [PCWP] of less than or equal to 15 mm Hg) and a normal or reduced cardiac output in the absence of intrinsic lung disease or chronic unresolved pulmonary emboli ( Table 1 ). Expanded criteria for defining PAH in patients being evaluated in the Registry to EValuate EArly and Long term pulmonary arterial hypertension management (REVEAL Registry) defines PAH as has been done previously, but is also evaluating the impact of including patients with a PCWP of 16 to 18 mm Hg within the definition. A previously proposed definition of PH during exercise (ie, mPAP greater than or equal to 30 mm Hg with exercise) is no longer being used, as there are no data supporting a single number to define the upper limit of normal mPAP during exercise ; factors such as age, type of exercise, and exercise workload appear to determine the normal response of PA pressures with exercise.

Introduction and definition

Pulmonary hypertension (PH) is an increase in pulmonary artery pressure in the pulmonary vascular bed that ultimately may lead to progressive right heart strain and ultimately, right heart failure. It is defined as a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mm Hg in resting condition as measured by right heart catheterization. Pulmonary arterial hypertension (PAH) is a subgroup of PH, which is defined as increase in mPAP of greater than or equal to 25 mm Hg with a normal left atrial pressure (most often assessed as a pulmonary capillary wedge pressure [PCWP] of less than or equal to 15 mm Hg) and a normal or reduced cardiac output in the absence of intrinsic lung disease or chronic unresolved pulmonary emboli ( Table 1 ). Expanded criteria for defining PAH in patients being evaluated in the Registry to EValuate EArly and Long term pulmonary arterial hypertension management (REVEAL Registry) defines PAH as has been done previously, but is also evaluating the impact of including patients with a PCWP of 16 to 18 mm Hg within the definition. A previously proposed definition of PH during exercise (ie, mPAP greater than or equal to 30 mm Hg with exercise) is no longer being used, as there are no data supporting a single number to define the upper limit of normal mPAP during exercise ; factors such as age, type of exercise, and exercise workload appear to determine the normal response of PA pressures with exercise.

Classification of PH

An initial classification of PH was published in 1973 following the First World Symposium on Pulmonary Hypertension, and divided the PH into 2 broad categories of primary and secondary PH. In 1998, the Second World Symposium on Pulmonary Hypertension revised the classification and divided PH in to 5 broad categories: (1) PAH, (2) pulmonary venous hypertension, (3) PH associated with disorders of the respiratory system or hypoxemia, (4) PH caused by thrombotic or embolic diseases, and (5) PH caused by diseases affecting the pulmonary vasculature. This classification was subsequently modified in the third and fourth World Symposia on PH in 2003 and 2008 respectively. The most recent modifications (adopted in 2008) were to Groups I, IV, V; however, the basic architecture of the PH classification was maintained. Group I PH is PAH and includes idiopathic PAH (IPAH), heritable PAH (HPAH), drug-induced and toxin-induced PAH, and associated PAH (APAH). Connective tissue disease (CTD)-related PAH falls within the category of APAH in Group I. A complete detailing of the current classification is presented in Table 1 .

Pathogenesis

The pulmonary circulation is normally a high-flow, low-resistance vascular bed that is in series with the systemic circulation and accommodates the entire cardiac output through one organ. The flow in this system is normally regulated by multiple factors, including oxygen and carbon dioxide tensions, the sympathetic nervous system, and hormonal stimuli. These factors result in either vasoconstriction or vasodilatation of the precapillary pulmonary vasculature, which alters the pulmonary vascular resistance and effects cardiac output and pulmonary arterial pressures. Alveolar hypoxia is one of the main stimuli that cause pulmonary arterial vasoconstriction, either directly or indirectly by contributing to the release of mediators. Several mediators impacting the pulmonary arterial vascular bed, including endothelin-1 (ET-1), nitric oxide (NO), prostacyclin, angiopoietin-1, serotonin, and members of the transforming-growth-factor-beta superfamily, have been identified, and serve as targets for therapeutic agents (available and investigational) for PH.

ET-1 is a potent endothelium-derived vasoconstrictor that also appears to be involved in remodeling of the pulmonary vasculature by initiating mitosis of pulmonary vascular smooth muscle cells and fibroblasts. It also acts to constrict the precapillary pulmonary vessels, thus increasing the pulmonary vascular resistance. It has been observed that there are elevated levels of ET-1 in patients with PH and these elevations correlate with the PH severity. Vasoconstriction from alveolar hypoxia and resulting endothelial dysfunction seems to be the major stimulus for overexpression of ET-1.

Endothelial dysfunction also causes impaired production of NO. NO is a potent vasodilator, smooth muscle cell regulator, and platelet inhibitor. In pulmonary vasculature, it is synthesized by endothelial nitric oxide synthetase (eNOS), whose activity is effected by stimuli, such as hypoxia, inflammation, and oxidative stress. Downregulation of the eNOS-NO-cyclic guanosine monophosphate (cGMP) pathway results in pulmonary vasoconstriction and increase in pulmonary vascular resistance. Endogenous NO production is also affected by the binding of ET-1 to ETB receptors and is the rationale for investigations of selective ETA receptor inhibition in the treatment of PH.

There is involvement of additional inflammatory pathways affecting the pulmonary vasculature in both IPAH and CTD-related APAH; these are more pronounced in the latter, perhaps contributing to the observed differences in treatment response and survival. The activation of platelets, disturbances in the coagulation cascade, and abnormal thrombolysis have also been observed to contribute to the development and progression of PAH. Disordered proteolysis of the extracellular matrix is also evident in PAH. Histologically, the lesions in both IPAH and CTD-related PAH appear quite similar. There is medial hypertrophy due to hypoxemia and vasoconstriction, intimal proliferation, and, later on, obliteration of vessels. Plexiform lesions, which are glomeruloid complex vascular structures originating from pulmonary arteries, may be present in severe PAH. Plexiform lesions are made up of a core of mesenchymal cells, smooth muscle cells, and apoptosis-resistant myofibroblasts surrounded by a proliferating network of vascular channels. Certain hormones, like estrogen, have been considered as having a potential role in the pathogenesis of PAH by promoting cellular proliferation and smooth muscle proliferation. This may, at least in part, account for the gender differences seen in the prevalence and natural history of some forms of PH. In CTD, the pulmonary parenchymal disease may lead to isolated medial hypertrophy in the precapillary pulmonary arterial bed with or without concurrent intimal fibrosis.

Clinical presentation

The most frequent initial symptom, seen in up to 60% of the PAH patient population, is dyspnea on exertion. This may be a result of hypoxia, cardiac dysfunction, and/or limitation to the cardiac output, which can be generated during exertion. By the time of diagnosis, more than 90% of patients will be noting dyspnea on exertion (or will be limiting their exertion to avoid the sensation of dyspnea). Approximately 50% of patients will ultimately complain of exertional chest discomfort, which can be due to right ventricular ischemia occurring because the right ventricle has increased muscle mass and is under strain. Other symptoms that occur in severe PH and ultimately in right heart failure are seen later in the course of disease and may include exertional presyncope, syncope, abdominal distension, peripheral edema, right upper quadrant abdominal pain, early satiety, hemoptysis, and hoarseness (due to compression of the left recurrent laryngeal nerve between the aorta and the left pulmonary artery [Ortner syndrome]). A delay in PAH diagnosis (several PAH registries have found a mean of 2+ years from onset of symptoms to establishment of a diagnosis) and therefore in treatment is mainly because the initial symptoms may occur only with exertion, and are nonspecific, and more specific or obvious symptoms may not manifest until late in the disease process. This may be because the normal pulmonary circulation has significant reserve (for recruitment and distention) and can accommodate large changes in flow with little or no change in pressures.

On examination of the patient, early findings may include a dominant a-wave in the jugular venous pulse; with disease progression, this a-wave becomes less prominent and the v-wave becomes larger. Cardiac examination is often remarkable for a loud P2 and a narrow split of S2. With advancement of disease, a right-sided S3 or S4 may become audible. A murmur of tricuspid regurgitation may often be heard on left sternal border; this murmur is higher pitched than the tricuspid regurgitation murmur noted in intrinsic tricuspid valvular disease. Other remarkable findings may include persistent hypoxia not responsive to oxygen supplementation and peripheral cyanosis.

Diagnosis

PH carries with it significant morbidity and a high mortality; therefore, the goal is to have early detection and treatment of the disease. The suspicion and confirmation of the diagnosis of PH can involve several different testing modalities. Testing can be divided into screening for PH, confirming the diagnosis and type of PH (ie, PAH), evaluating for disease severity, and assessing for etiology.

Diagnostic workup in CTD APAH

The investigations done in CTD APAH are similar to the modalities generally used in evaluating other etiologies of PH but there are some variations to be noted.

Criteria to use echocardiography in screening for PH in relatively asymptomatic patients are different for various CTDs and are related to the disease prevalence of PH observed in these disorders.

In a study by Rajaram and colleagues, tricuspid regurgitant gradient as measured by TTE and ventricular mass index as measured by MRI had greater correlation with mPAP and PVR as measured by RHC in CTD APAH patients whereas CT appears to be limited as a diagnostic and prognostic tool for PH in these patients.

PH in CTD

The pathogenesis of PH in connective tissue disease appears to be similar to that of IPAH. Endothelial dysfunction leads to myofibroblast activation and subsequent vasoconstriction and smooth muscle hypertrophy. There is increased production of endothelin and decreased production of nitric oxide and prostacyclins, which causes inflammation and fibrosis of small and medium-sized pulmonary arteries leading to increased resistance in pulmonary vasculature. The incidence of APAH in different connective tissue disorders and the known associations or risk factors for developing CTD APAH are presented in Table 2 .

Badesch and colleagues and Chung and colleagues have analyzed the data from the recent REVEAL Registry, which was established to characterize the clinical course, treatment, and predictors of outcomes in patients with PAH in the United States. This registry is the largest US cohort of patients with PAH confirmed by right-sided heart catheterization (RHC), and contains a substantial number of patients with CTD-PAH. Of the enrolled patients with PAH in this registry from 54 US centers, 50.7% of the patients had APAH, whereas 46.2% had IPAH. Among the associated patients with PH, 49.9% was CTD related, which highlights the clinical occurrence of this particular entity. In APAH in this registry of patients, there was an observed female-to-male prevalence of 3.8:1.0. Chung and colleagues analyzed 1-year mortality from the time of registry enrollment in patients with CTD APAH and compared those with systemic sclerosis (SSc) with those with systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA). SSc-related APAH had the worst 1-year survival at 82% versus 94% in SLE APAH, 88% in MCTD APAH, and 96% in RA APAH.

Scleroderma

The lung is currently the fourth most commonly involved organ in scleroderma, after skin, peripheral arterial vessels, and the esophagus. The pulmonary involvement is most frequently in the form of either interstitial lung disease or pulmonary vascular disease. The prevalence of PH in SSc is estimated to be 7% to 27%. In the United States, of all patients with SSc, about 10% suffer from PAH, making it more common than any other form of PAH in the World Health Organization group 1, including IPAH. There is concern that many patients with scleroderma-associated PAH are not suspected of having the condition, and that it is underdiagnosed and undertreated. The 1-year survival rate of patients with SSc-related PAH had been approximately 45% (before the current era of PAH therapies), as compared with the survival of patients with SSc who have parenchymal lung involvement (ie, interstitial lung disease) without PAH who had a 1-year survival rate of approximately 90%. With newer PAH therapies, the 1-year survival rate for patients with SSc APAH has increased to about 80% (emphasizing the importance of both appropriate diagnosis, and early treatment).

The patients with scleroderma with lower carbon monoxide diffusion capacity (DLCO) and higher BNP are more at risk of clinically manifesting PAH. The symptoms of PAH are unfortunately nonspecific and are similar to those observed in ILD, most commonly exertional dyspnea and fatigue. The symptoms of PAH in patients with SSc also can be confused with similar symptoms caused by the anemia, or muscle and skin involvement that occurs in scleroderma. Concomitant renal and myocardial dysfunctions are important predictors of mortality in SSc. Patients with scleroderma can have depressed RV function as well as left ventricle systolic and/or diastolic dysfunction. SSc-APAH patients also have a higher prevalence of pericardial effusion (up to 34%), as compared with IPAH patients (at about 13%). In PAH, the presence of a pericardial effusion is felt to be associated with right ventricular failure, and predicts a poorer prognosis. Literature has suggested annual screening of all patients with scleroderma with transthoracic echocardiograms for detecting PH, as it has such high prevalence and morbidity.

In scleroderma, interstitial changes in pulmonary parenchyma can be detected with HRCT at early stages of the disease when chest radiographs may be still appear to be normal.

According to Hesselstrand and colleagues, CMR in patients with APAH with scleroderma often demonstrates severe pathology with decrease in the RV end diastolic volume (RVEDV) and reduction in ejection fraction (RVEF), as well as fibrosis at the insertion point of right ventricle as compared with patients with scleroderma but not PAH who show less severe changes. Further studies are needed to see if these findings can be of value in screening for early signs of PAH in patients with SSc.

The sensitivity of PFTs for diagnosis of PAH in scleroderma is approximately 70%, as reported by Hsu and colleagues. PFTs may show decrease in DLCO and forced vital capacity (FVC) of similar magnitude in patients with interstitial lung disease. The DLCO may decrease at a more rapid rate than FVC in pulmonary vascular disease (PH) occurring without concurrent interstitial lung disease; this results in a high FVC (percent predicted)/DLCO (percent predicted) ratio. Patients with scleroderma with FVC/DLCO ratios greater than 1 are more likely to have PAH as compared with ratios of 1 or lower who are more likely to have interstitial lung disease.