There is no cure for pulmonary arterial hypertension (PAH), and mortality remains high despite the increasing treatment options. Early diagnosis of PAH can improve long-term survival, and therefore we need to screen for PAH in high-risk populations.
The most commonly used tool in current clinical practice is Doppler echocardiography. Existing studies have analyzed the role of evidence-based screening strategies, such as the DETECT study in patients with systemic sclerosis. The use of multimodal means and the combination of non-invasive examinations may improve the effectiveness of screening algorithms. However, confirmation of PAH must undergo right heart catheterization.
In addition, there is still disagreement regarding the definition and prognostic relevance of pulmonary hypertension during exercise, although there is growing evidence that stress testing of the pulmonary circulation can detect those with clinically significant early disease. Due to the paucity of available tools, there is an urgent need to develop novel tools for the early detection of pulmonary vascular disease.
I. Why is screening needed for pulmonary arterial hypertension?
1. 85% of PAH patients have NYHA class III or IV at diagnosis
Early clinical diagnosis of PAH is very difficult, as a sporadic disease, patients do not present with identifiable risk factors by which to determine whether they have PAH, and there is no systematic screening method for early diagnosis of PAH.
A UK and Irish PAH registry study between 2001 and 2009 found that approximately 85% of patients with disseminated congenital PAH had a NYHA functional class III or IV at the time of diagnosis. Similar results were reported by the French PAH Network, where 79% of newly diagnosed SSc-PAH patients from 2006-2009 were NYHA class III-IV.
This result is truly surprising in the context of major guidelines that strongly recommend screening for PAH in patients with systemic sclerosis. Therefore, if we screen patients only when they present with PAH symptoms and seek medical help, the vast majority of patients will only be diagnosed when the disease has progressed to a fairly advanced stage.
2. Early symptoms of PAH are unclear and less specific
The early symptoms associated with PAH are not clear and have low specificity. The main symptoms include fatigue and exertional dyspnea, which can occur with common respiratory diseases or just “discomfort”. Patients with systemic sclerosis or other connective tissue diseases experience physical weakness for a variety of reasons, including musculoskeletal problems. All of these factors make PAH difficult to diagnose early, so there is a long delay between when a patient first becomes symptomatic and when they receive a diagnosis of RHC. Studies in Australia have shown that the average delay in getting a diagnosis for patients with congenital PAH is 47 ± 35 months, requiring an average of 5.3 ± 3.8 GPs and 3.0 ± 2.1 specialists to reach a formal diagnosis.
Another major challenge is that the severity of the hemodynamic disturbance and the degree of functional impairment are not consistent in some patients, especially younger ones. In a randomized controlled study called EARLY, researchers specifically enrolled patients with mildly symptomatic PAH in NYHA class II, and the subjects had a mean PVR of about 10 wood units at the time of recruitment – hardly indicative of early disease. In patients who have long adapted to chronic increased right ventricular afterload, any slightest symptom may be indicative of a patient with a pulmonary vascular bed that has developed advanced occlusion.
3. Early diagnosis of PAH may improve survival
The results of several large national PAH registry studies consistently show that early diagnosis improves patient survival. Physicians in the French PH network reported that patients with congenital, hereditary, and anorexia-induced PAH survived significantly longer in NYHA class I or II than in NYHA class III or IV patients. In the UK registry study, patients with SSc-PAH had a 2-fold higher mortality rate in NYHA class III or IV than in NYHA class I or II patients. These results were mirrored by data from the North American REVEAL study, which enrolled 2716 patients with all types of PAH, with NYHA functional class being the strongest predictor of prognosis.
Randomized controlled screening studies with early intervention in high-risk populations are very difficult and unethical. However, the need for screening is well supported by biological evidence: evidence from PAH registry studies suggests that early diagnosis improves patient survival and that early intervention when patients present with very mild symptoms can significantly improve clinical outcomes.
A case-control study compared the baseline characteristics and long-term survival of two groups of patients with SSc-PAH: one group was diagnosed with a one-test program and the other group received daily clinical care. Both groups of patients were from the same time period (2002-2003), with negligible differences between treatments. The results showed that the test group had a lesser degree of pulmonary vascular disease at the time of diagnosis compared to the routine clinical care group.
Most importantly, the survival rate of patients with SSc-PAH diagnosed through the testing program was significantly higher than the survival rate of patients diagnosed in routine care. Survival rates at 1, 3, 5, and 8 years were 100%, 81%, 73%, and 64%, respectively, in the testing program group compared with 75%, 31%, 25%, and 17%, respectively, in the usual care group. This study provides more direct evidence to support screening for PAH in patients with systemic sclerosis and intervening early in the disease at the onset of mild symptoms, thereby improving patient survival.
II. Available PAH screening tools
A variety of tools are clinically available for PAH screening in high-risk populations. These tools can only be evaluated in specific risk populations, and direct generalization of data from just one population to other populations can be misleading. For example, pulmonary dysfunction in SSc-PAH patients is different from that in other PAH patients. In addition, patients with SSc-PAH have worse right ventricular function compared to patients with congenital PAH at similar levels of afterload, and this can affect biomarker NT-proBNP levels. The largest number of studies have been performed to screen patients with SSc-PAH because of the extra attention paid to this group of patients.
1. Resting-state echocardiography
Resting-state echocardiography is the most widely used screening modality in clinical practice to guide the need for RHC to confirm the diagnosis of PAH. although echocardiography has been widely accepted as an indispensable tool in the medical community, its availability as an independent test for PAH is still questionable, especially in the diagnosis of asymptomatic or minimally symptomatic patients. Therefore, it is critical to understand the advantages and limitations of Doppler echocardiography when screening for PAH.
Doppler echocardiography for the detection of PAH relies primarily on tricuspid regurgitation jet velocity (TRV), and TRV values can be converted into pressure values by Bernoulli’s equation to evaluate cardiac systolic P pa (systolic P pa = 4 × TRV2 + right atrial pressure). Several studies have been performed comparing P pa values detected by Doppler echocardiography and the gold standard RHC method (both methods performed simultaneously or within a short time difference). In one of these studies, researchers found by Bland-Altman analysis that Doppler echocardiography can accurately assess systolic P pa (mean deviation -0.5 mmHg), but the range of agreement is too wide (C19 mmHg-18 mmHg) and the accuracy is insufficient. This should be taken into account when making clinical diagnoses and guiding clinical decisions.
The performance of Doppler echocardiography also relies on the calculation of the optimal TRV threshold. Low TRV thresholds can increase the sensitivity of the test, but they can also increase the false-positive rate and lead to patients undergoing unnecessary invasive RHC tests. Conversely, high TRV thresholds can increase the specificity of the test, but can also omit patients who actually have the disease.
In a study of screening patients with systemic sclerosis, changing the TRV threshold from 2.7 m/s to 3.4 m/s (tricuspid valve pressure of 30-45 mmHg) decreased the sensitivity of the test from 88% to 47% and increased the specificity from 42% to 97%.
In another French multicenter SSc-PAH screening study, researchers designed an algorithm based on TRV values and symptoms to guide the need for RHC testing. SSc-PAH was suspected if patients had TRV >3 m/s or 2.5
The DETECT study provides additional information on Doppler echocardiography as a screening tool and is the first multicenter prospective study to mandate RHC in all patients with systemic sclerosis tested. Patients in the study with confirmed SSc-PAH with mild pulmonary vascular disease had a mean P pa value of 33 mmHg and a PVR of 371 dyn?s?cmC5. 7.1% of these patients with confirmed SSc-PAH had undetectable tricuspid regurgitation velocity, 20% had TRV <2.5 m/s, and 35.7% had TRV ≤2.8 m/s. Thus, if we take the commonly Therefore, if we use the commonly used TRV of 2.8 m/s as the threshold, many patients with PAH will be missed.
In addition, the performance of echocardiography depends on the severity of the disease. For example, in a population containing many patients with advanced PAH (substantially elevated P pa), echocardiography will tend to detect PAH more often; conversely, in a study population where most PAH patients have only slightly elevated P pa, the lack of echocardiographic accuracy will lead to an increased risk of misclassification.
In studies where echocardiography has been used for PAH screening, there are a number of parameters other than the most commonly used TRV that can be used for a comprehensive assessment of the clinical right cardiopulmonary circulation. These complementary parameters are useful in patients with inadequate TRV signal. PAH should be suspected if a patient presents with abnormal right chamber dimensions or function, regardless of whether the patient has elevated TRV, although the sensitivity of abnormal right chamber dimensions or function in the early detection of PAH remains questionable because right chamber dilatation generally indicates relatively severe disease with the potential to progress to right ventricular failure. In addition, the irregular shape of the ventricles makes accurate assessment of right ventricular volumes by ultrasound methods difficult.
If an adequate TRV signal cannot be obtained, we can estimate the mean P pa value using pulsed Doppler of the right ventricular outflow tract (RVOT). The acceleration time of blood flow from the start to the maximum flow rate is negatively correlated with the mean P pa value. An acceleration time >100 ms implies that the patient has no PH, whereas an acceleration time <70 ms implies a much higher likelihood of PH. In addition, systolic tangents in the RVOT Doppler signal are a specific marker of elevated PVR and are associated with enhanced reflection waves of impedance detuning, which trigger systolic flow deceleration.
High cardiac output or high left atrial pressure that is not associated with elevated PVR associated with pulmonary vascular disease may contribute to elevated P pa values. We can calculate the PVR value using an equation that gives a simple and well established evidence (PVR= TRV/velocity time integral RVOT × 10 + 0.16).
Heart failure with normal ejection fraction is a common cause of PH and must be distinguished from precapillary types of disease, especially in patients with systemic sclerosis, where both PAH and heart failure with normal ejection fraction are common complications. The associated indices of left ventricular diastolic insufficiency (E/A ratio and E/e’) and left atrial diameter may indicate the risk of postcapillary PH.
One study used a scoring system based on five echocardiographic variables with a positive predictive rate of 67.9% and a negative predictive rate of 77.5% in differentiating between pre-capillary and post-capillary PH. Therefore, mandatory invasive P pw evaluation is clinically required when an accurate diagnosis of pre-capillary or post-capillary disease is required. However, echocardiography is very dependent on the operator’s skill, and it is important that the reliability of the test data depends to a large extent on the operator.
2. B-type natriuretic peptide
During increased ventricular wall pressure, the ventricle releases B-type natriuretic peptide (BNP), one of the markers of ventricular strain. In patients with confirmed PAH, BNP and NT-proBNP (inactive precursor N-terminal fragment) levels correlate with exercise capacity, hemodynamics and mortality prediction in patients and can indicate right ventricular systolic dysfunction. Several case-control studies have consistently shown that patients with SSc-PAH have significantly higher NT-proBNP levels compared to patients with systemic sclerosis without PAH. However, because NT-proBNP levels are an important marker of ventricular dysfunction and the goal of existing PAH therapy is to reduce NT-proBNP levels to near normal levels, its sensitivity is low and is not sufficient as an independent criterion for the diagnosis of mild PAH. NT-proBNP is cleared by glomerular filtration, so its levels will affect the function of the kidney.
3.Pulmonary function tests
Standard pulmonary function tests include spirometry, CO diffusion (DLCO) and lung volume. Of these parameters, the ratio of DLCO to maximum lung volume (FVC) and DLCO (FVC/DLCO) is the most useful for the diagnosis of PAH in patients with systemic sclerosis.
DLCO was significantly lower in patients with SSc-PAH than in those with SSc-PAH without PAH. One study showed that the mean DLCO of SSc-PAH patients at diagnosis was 52% of the predicted value, compared with 80% of the predicted value in controls. In addition, patients with SSc-PAH had a significantly lower DLCO before developing significant PAH. In a French screening study, a DLCO predicted value <60% was associated with a significantly higher likelihood of PAH. < p="">
Studies have been performed to analyze the effect of combined pulmonary function and NT-proBNP for the diagnosis of PAH in patients with systemic sclerosis. One study showed that an algorithm based on DLCO, FVC/DLCO ratio, and NT-proBNP levels had a sensitivity of 94% and a specificity of 55% for the diagnosis of PAH. All patients in this study underwent RHC, and the study was recruited on the basis of echocardiographic detection of systolic P pa ≥40 mmHg, DLCO ≤50% predicted, FVC >85%, ≥20% reduction in DLCO compared to last year or unexplained dyspnea, resulting in a high incidence of PAH in the subject population (~35%). There is no evidence that DLCO reduction is applicable to screening for other subtypes of PAH (hereditary or portal PAH).
4. Cardiopulmonary exercise test
The cardiopulmonary exercise test (CPET) is mainly used clinically for the assessment of exertional dyspnea, and in recent years several studies have shown that CPET has an important predictive value for the diagnosis of PAH. CPET in patients with PAH has the following characteristics: lower peak oxygen consumption, earlier anaerobic threshold, lower oxygen pulse, higher VE/VCO2 ratio, lower end-expiratory pCO2, and variable oxygen desaturation. Clinically this type of typical CPET response is highly indicative of pulmonary vascular disease. However, due to the complexity of this test and the difficulty of data interpretation, CPET has not been used as a screening index in large screening studies.
III. Screening algorithms for different diseases
1. Systemic sclerosis
The DETECT study is the first multicenter prospective study combining clinical and laboratory parameters for PAH screening in patients with systemic sclerosis. All subjects underwent RHC, allowing the false-negative rate of the new screening algorithm to be determined.
A two-step scoring system was used in the study: in the first step, the need for Doppler echocardiography was determined on the basis of six parameters; in the second step, the scores from the first step and two echocardiographic variables were combined to determine whether the patient should undergo RHC to confirm the diagnosis. The clinical and laboratory variables used in the study are shown in Table 3. To reduce the false-negative rate, the algorithm sensitivity was set at 96% and the final specificity at 48%. As a result, 62% of patients ultimately underwent RHC, of which 35% had a confirmed diagnosis of SSc-PAH, with an underdiagnosis rate of only 4% (n=3), and 18% of patients with a confirmed diagnosis presented without symptoms.
Although there are still limitations, this study clearly shows that only one test is not sufficient to accurately diagnose PAH and that we should use a multimodal approach combining multiple non-invasive tools for screening.
2. Portal hypertension
Prior to liver transplantation, physicians generally recommend that patients be screened for PAH because portal hypertension significantly increases patient mortality at the time of transplantation. Most medical centers consider moderate and severe portal hypertension (mean P pa >35 mmHg) as a contraindication to organ transplantation. Doppler echocardiography is the only screening modality in portal hypertension that has undergone systematic evaluation.
Many patients with liver disease have low vascular resistance in the body circulation and are in a state of high cardiac output, so absolute values of P pa may be misleading, and elevated PVR values (indicative of the severity of pulmonary vascular disease) may not reach significant levels due to cardiac output.
3. Sickle cell disease
Previous echocardiography-based studies may have overestimated the incidence of PH in patients with sickle cell disease. In two recent new studies from France and Brazil with similar methodology, patients with TRV ≥2.5 m/s on echocardiographic screening were subjected to RHC to confirm the diagnosis. The results showed a prevalence of PH of 6.2% and 10% in the French and Brazilian studies, respectively. The incidence of post-capillary PH was 3.3% and 6.2%, respectively, while the incidence of pre-capillary PH was 2.9% and 3.8%.
A post hoc analysis of the French study showed that if the screening condition was changed to “TRV ≥2.9 m/s” or “TRV 2.5C2.8 m/s and NT-proBNP level >164.5 pg/ml or 6-minute walk distance <333 m ", which reduced the number of RHC examinations from 63 to 21. However, since RHC was not performed on all subjects, an accurate false-negative rate could not be calculated.
4. Congenital heart disease
Patients with certain types of congenital heart disease are prone to develop PAH, the most extreme example being Eisenmenger syndrome, in which the PVR is greatly increased, resulting in a “right-to-left” reverse shunt of deoxygenated blood flow, cyanosis and erythrocytosis. Most patients with PAH associated with congenital heart disease will develop Eisenmenger syndrome. Although there are no clear guidelines, we recommend that patients with congenital heart disease should be screened for PAH in pediatric and adult cardiology centers, as this group of patients is complex and PH can make the problem worse.
5. Hereditary PAH and BMPR2 mutations
The presence of familial PAH suggests that we should investigate family history in incidental cases. In addition, about 20% of disseminated cases carry BMPR2 mutations, which means that their PAH is hereditary. We should genetically examine family members carrying patients with known PAH-causing mutations to identify those at higher risk for PAH. However, because of the low ectopic rate of BMPR2 mutations, most asymptomatic mutation carriers do not develop PAH, and there is no means to determine which fraction of carriers will eventually develop PAH, although the results of studies that have been done show that women are at higher risk than men.
Currently, annual echocardiographic screening is recommended for all patients positive for the PAH-causing mutation, and immediate medical attention should be sought at the onset of new symptoms associated with pulmonary vascular disease. The algorithm also applies to first-degree relatives of patients with hereditary PAH who do not have a detectable causative mutation.