The 6th World Symposium on Pulmonary Hypertension proposed some
fundamental changes to the hemodynamic and clinical classification of
pulmonary hypertension (PH). We have summarized these changes below.
Change in Criteria for Diagnosis of PH - Based on the mean pulmonary artery pressure (mPAP) of 20 mmHg being 2
standard deviations above the mean value of 14.0 ± 3.3 mmHg, which was
the normal value of mPAP observed in recent published data, and the fact
that there have been multiple studies across different clinical types
of PH documenting poor outcomes in patients with mPAP between 20 and 25
mmHg, it was proposed to define PH as mPAP >20 mmHg instead of mPAP ≥25 mmHg at rest, measured by right heart catheterization.
Pulmonary Vascular Resistance (PVR) Added to Definition of all Forms of Pre-Capillary PH - To identify pre-capillary PH as representative of pulmonary vascular
disease, it was proposed to include PVR of ≥3 Wood units in the
definition of all forms of pre-capillary PH associated with mPAP >20
mmHg.
Combined Pre- and Post-Capillary PH - The cutoff of ≥3 Wood units was also proposed to identify the group
of patients that has combined pre- and post-capillary PH in addition to
the mandatory pulmonary capillary wedge pressure of >15 mmHg and mPAP
>20 mmHg, which is a prerequisite to be classified as having any
type of post-capillary PH. This group of patients has worse prognosis
compared with other patients with post-capillary PH.
Exercise PH - A definition for exercise PH could not reintroduced. The challenges
of getting accurate right heart catheterization measurements and the
lack of diagnostic discrimination power whether exercise PH is due to
elevated pulmonary capillary wedge pressure (left heart disease) or
pulmonary vascular disease makes it difficult to define exercise PH as
an entity.
Drug- or Toxin-Associated PH - Drugs and toxins were divided into those with definitive association
(epidemiologic outbreaks, case control and randomized control trials;
e.g., dasatinib and methamphetamines) and those with possible
association (e.g., cocaine).
Pulmonary Arterial Hypertension Long-Term Responders to Calcium Channel Blockers - These patients were introduced as a distinct group within Group I
because they have been shown to have significantly better prognosis,
unique management, and different pathophysiology. These patients are
defined by a reactive vasodilators stress (a reduction of mPAP ≥10 mmHg
to reach an absolute value of mPAP ≤40 mmHg with an increased or
unchanged cardiac output) and a sustained hemodynamic response a year
after being on calcium channel blockers and New York Heart Association
Functional Class I/II.
Pulmonary Veno-occlusive Disease/Pulmonary Capillary Hemangiomatosis - These were defined as pulmonary arterial hypertension with overt
features of venous/capillaries involvement was included in World Health
Organization (WHO) Group I because their clinical presentation and
hemodynamic profile are similar to PH.
WHO Group 4 Updates: PH due to Pulmonary Artery Obstructions - In addition to chronic thromboembolic PH, the entities included in
this group were expanded to include other etiologies of pulmonary artery
obstruction such as congenital pulmonary artery stenosis (Alagille
syndrome) and malignant and non-malignant tumors.
WHO Group 5 Simplified - In the WHO Group 5 group, splenectomy and thyroid disease was removed
as a subgroup and is considered as more of a risk factor for PH.
Lymphangioleiomyomatosis was reclassified as WHO Group 3 because almost
all cases of PH in lymphangioleiomyomatosis are associated with only
mild PH but severe pulmonary parenchymal disease.
Table 1: Updated Hemodynamic Definition of PH
Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions
and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;53:1801913.
PH in Left Heart Disease
Pulmonary hypertension (PH) due to left heart disease is a complex
condition encompassing different clinical phenotypes, pathophysiology,
and prognoses. In an effort to clarify the disease process and provide
clinical guidance, Vachiéry et al. propose a simplified phenotypic and
hemodynamic approach in light of recent literature findings.
PH due to left heart disease is defined as elevated pulmonary
pressure in response to elevated left atrial pressure. Elevated
left-sided pressures can result from different pathologies, but
generally speaking, left heart disease comprises three groups:
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1. Heart failure with reduced ejection fraction
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2. Heart failure with preserved ejection fraction (HFpEF)
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3. Valvular heart disease
Among these subsets, PH can exist as the following:
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1. Isolated post-capillary PH: Pulmonary artery wedge pressure (PAWP)
>15 mmHg and mean pulmonary artery pressure (mPAP) >20 mmHg and
pulmonary vascular resistance (PVR) <3 Wood units
-
2. Combined pre- and post-capillary PH: PAWP >15 mmHg and mPAP >20 mmHg and PVR ≥3 Wood units
Consistent acquisition of key components during invasive hemodynamic
testing with right heart catheterization remains challenging. Also,
there is considerable difficulty delineating PH due to left heart
disease from pulmonary arterial hypertension (PAH) with HFpEF because
PAH patients often have concurrent cardiovascular disease. As such, the
authors propose a three-phenotype classification system to refine PH due
to left heart disease pre-test probability and stratify which patients
require additional invasive studies (Figure 1):
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1. High probability of left heart disease as a cause of PH. The general management should be guided according to the recommendation for the underlying condition.
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2. Intermediate probability of left heart disease as a cause of PH. Invasive characterization may be performed in patients with risk
factors for PAH (e.g., systemic sclerosis), chronic thromboembolic PH,
or in cases of unexplained dyspnea. The presence of right ventricular
abnormalities also requires invasive assessment because it may influence
management.
Figure 1: Pre-Test Probability of PH due to Left Heart Disease Based on Clinical Phenotype
Resting Hemodynamic Evaluation of PH due to Left Heart Disease - If a patient exhibits an appropriate phenotype to warrant invasive hemodynamic studies, the following are proposed:
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1. Right heart catheterizations should be performed in stable,
non-critically ill patients and should be performed using proper
leveling techniques, namely leveling at the mid-chest and "zero"ing the
transducer to atmospheric pressure. Patients should be positioned supine
with legs flat and pressures recorded during spontaneous breathing (no
breath-hold).
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2. Measure PAWP at end expiration and during end diastole (i.e.,
typically as the mean of the a-wave) for accurate assessment of PVR with
special consideration during atrial fibrillation (when it is
appropriate to measure PAWP 130-160 ms after the onset of QRS and before
the V-wave).
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3. Large V-waves should be reported because this strongly suggests left heart disease regardless of resting PAWP.
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4. If there are discrepancies or ongoing diagnostic uncertainty,
provocative testing with exercise testing or fluid challenge to
elucidate the diagnosis is useful, particularly to distinguish between
healthy subjects and HFpEF or to uncover PH due to left heart disease in
patients with PAWP at the upper limit of normal (ULN) (i.e., 13-15
mmHg).
Provocative Hemodynamics - In patients with resting PAWP 13-15 mmHg and high/intermediate
probability of PH with HFpEF, provocative testing should be considered
to uncover PH due to HFpEF:
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1. For technical reasons and reliability of pressure recording, a fluid
challenge is preferred over exercise in the approach to differential
diagnosis.
-
2. An increase of PAWP >18 mmHg after fluid loading in patients with
resting values between 13 and 15 mmHg and intermediate/high probability
of HFpEF may be considered abnormal.
-
3. The ULN of mPAP during an incremental dynamic exercise challenge has
been suggested at >30 mmHg with a cardiac output (CO) <10 L•min−1, which corresponds to a total PVR (total peripheral resistance = mPAP/CO) of 3 Wood units.
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4. The ULN of PAWP during exercise is thought to be between 15 and 25
mmHg, but higher values can be recorded in elderly subjects. A cut-off
value of 25 mmHg is suggested for the diagnosis of heart failure,
although PAWP >25 mmHg has been found in elderly individuals free of
apparent cardiovascular disease.
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5. A flow-adjusted measure of PAWP may be more appropriate than PAWP (i.e., PAWP/CO).
Calculations
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Diastolic pressure gradient = diastolic pulmonary artery pressure – Wedge pressure
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Transpulmonary pressure gradient (TPG) = mPAP – Wedge pressure
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PVR = (mPAP – Wedge pressure) / CO
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Pulmonary arterial compliance = stroke volume / (systolic pulmonary artery pressure – diastolic pulmonary artery pressure)
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Pulmonary artery elastance = systolic pulmonary artery pressure / stroke volume
Prognostic Factors
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↑ Pulmonary artery elastance and ↓ pulmonary arterial compliance associated with worse prognosis
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↑ TPG, PVR, and diastolic pressure gradient associated with worse outcomes
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↑ PAWP/CO slope (>2 mmHg•L−1•min−1 is
associated with reduced functional capacity, higher N-terminal pro-brain
natriuretic peptide, and reduced heart failure-free survival)
Treatment of PH due to Left Heart Disease
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Mainstay of treatment is optimization of underlying left heart disease.
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No PAH therapies have been shown to be beneficial and may even lead
to worse outcomes, specifically sildenafil in valvular heart disease
post-intervention patients and macitentan in combined pre- and
post-capillary PH.
PH in Patients With End-Stage Heart Failure
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Presence of PH signals poor prognosis after transplant. In the
context of heart transplantation, PH is associated with an increased
30-day mortality in patients with TPG >15 mmHg and PVR >5 Wood
units. Risk of morbidity and mortality increases with progressive
elevation in mPAP, TPG, and PVR.
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It is recommended to perform right heart catheterization in all
candidates before listing and at 3- to 6-month intervals in listed
patients, especially in the presence of reversible PH or worsening heart
failure.
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Acute vasodilator testing should be performed if systolic pulmonary artery pressure >50 and TPG ≥15 or PVR >3 Wood units.
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Left ventricular unloading with left ventricular assist device
rapidly reverses PH due to left heart disease. Left ventricular assist
device recipients with at least one post-implant right heart
catheterization without PH likely require less frequent assessments.
Risk Stratification and Medical Treatment in PH
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1. The progress observed in medical therapy of pulmonary arterial
hypertension (PAH) over the last decade is not related to the discovery
of new pathways but to the development of new strategies for combination
therapy and on escalation of treatments based on systematic assessment
of clinical response.
-
2. The current treatment strategy is based on the severity of PAH as
assessed by a multiparametric risk stratification approach. Goals of
therapy and factors associated with better prognosis include functional
capacity Class I-II, 6-minute walk distance >400 meters, and normal
right ventricular function per echocardiography and hemodynamic
parameters.
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3. Current treatment recommendations call for upfront oral combination
therapy for low- and intermediate-risk patients with PAH and upfront
combination therapy that should include parenteral prostacyclin therapy
for patients with high-risk features.
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4. Patients should be re-evaluated 3-6 months from the start of
combination therapy. If goals of therapy are not met, sequential triple
therapy or escalation of therapy from oral to parenteral prostacyclin is
to be considered. Current recommendations are for evaluations every 3-6
months, particularly for the high-risk patients who may need lung
transplant referral if they are refractory to maximal medical therapy.
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5. Regarding vasoreactivity testing, it is recommended to evaluate
response to calcium channel blockers only for patients with idiopathic
PAH, heritable PAH, and PAH associated with drugs and toxins. If
positive, very high doses of calcium channel blockers should be used
(i.e., amlodipine 20 or 30 mg daily). If goals of therapy not achieved
after 3-6 months, it is recommended to start specific PAH therapy.
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6. Supportive therapy should include supervised exercise training.
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7. Anticoagulation is not recommended for associated PAH but may be
considered for idiopathic, heritable, or drug-induced PAH because data
in those groups are less controversial.
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8. Occasionally, patients have an extraordinary response to therapy,
and transition to a less-invasive therapy is considered. Because much of
the literature on this topic is retrospective, prospective but
observational, or prospective randomised but open label, this approach
is not recommended except in rare circumstances and under close expert
care. There have been conflicting outcomes in the transition from
parenteral prostacyclins to inhaled or oral prostacyclins. When
discontinuation of bosentan is necessary due to liver function test
elevations, transitioning to ambrisentan or macitentan is safe. At the
time of the 6th World Symposium of PH, there was insufficient evidence
to recommend transition from sildenafil or tadalafil to riociguat for
improving efficacy, although studies are underway.
Chronic Thromboembolic PH
Chronic thromboembolic pulmonary hypertension (CTEPH) (World Health Organization Group 4) is defined as follows:
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- Hemodynamic findings of mean pulmonary artery pressure ≥25 mmHg,
pulmonary artery wedge pressure ≤15 mmHg, and pulmonary vascular
resistance ≥3 Wood units
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- In the presence of chronic, organized thrombi or emboli in the
pulmonary arteries that persist despite at least 3 months of effective
anticoagulation
The precise pathogenesis of CTEPH remains unclear but appears to be
incited by acute pulmonary embolism with resultant altered vascular
remodeling and endothelial dysfunction in the pulmonary arterial system.
Chronic thromboembolic disease is characterized by similar symptoms and
perfusion defects but without pulmonary hypertension at rest. CTEPH is
an underdiagnosed condition that often presents with non-specific
symptoms and requires a high index of clinical suspicion. Lung
ventilation/perfusion scintigraphy is the screening test of choice;
however, this test is infrequently ordered despite guideline
recommendations.
Diagnosis is made by the following:
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History revealing signs and symptoms suggestive of CTEPH.
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Transthoracic echocardiography revealing evidence of pulmonary hypertension.
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VQ scan is the initial imaging test of choice. It has a high
sensitivity and specificity. If there is no evidence of mismatched
perfusion defect, CTEPH is effectively excluded.
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Computed tomography pulmonary angiogram then confirms diagnosis and assesses operability.
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Right heart catheterization and digital subtraction angiography are
used to obtain invasive hemodynamics and determine accessibility of
thrombi.
Treatment
-
- Lifelong anticoagulation therapy.
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- Definitive therapy should be made by an expert CTEPH team.
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- Operable with acceptable risk/benefit: pulmonary thromboendarterectomy (treatment of choice).
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- Non-operable or operable with unacceptable risk/benefit: Targeted medical therapy and/or balloon pulmonary angioplasty (BPA).
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- Persistent/recurrent symptomatic pulmonary hypertension: consider re-do surgery versus targeted medical therapy and/or BPA.
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- Riociguat is approved for inoperable CTEPH (CHEST [A Study to
Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With CTEPH]).
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- Macitentan also showed benefit for inoperable CTEPH (MERIT-1
[Clinical Study to Assess the Efficacy, Safety and Tolerability of
Macitentan in Subjects With Inoperable Chronic Thromboembolic Pulmonary
Hypertension]).
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- Unclear benefit of medical therapy as a bridge to pulmonary
thromboendarterectomy surgery or as a bridge to BPA. Combining
endarterectomy with BPA either as a hybrid or stepwise approach is being
evaluated at select expert programs.
Summary - Pulmonary endarterectomy remains the treatment of choice for operable
CTEPH. For those deemed inoperable, the best level of evidence supports
initiation of medical therapy and consideration for BPA.
Figure 1: CTEPH Revised Treatment Algorithm
PH in Chronic Lung Disease and Hypoxia
Chronic lung disease-associated pulmonary hypertension (PH) is
associated with reduced functional ability, impaired quality of life,
greater oxygen requirements, and increased risk of mortality compared
with patients with chronic lung disease. At this time, it is uncertain
whether the presence of PH is causative or a surrogate of worse outcomes
in chronic lung disease. However, patients with chronic lung
disease-associated PH have the worst outcomes of all patients with PH.
Screening for PH in Chronic Lung Disease - Elevated plasma levels of brain natriuretic peptide and N-terminal
pro-brain natriuretic peptide may increase suspicion for PH.
Echocardiography is the best noninvasive modality to screen for chronic
lung disease-associated PH. Ratio of main pulmonary artery to ascending
aorta >1 may also predict PH.
Diagnosis - Right heart catherization is the gold standard for diagnosis of chronic
lung disease-associated PH, but suspicion for underlying PH does not
mandate the completion of right heart catherization, especially if the
right heart catherization results will not influence therapy or
management decisions, including referral for transplantation. Right
heart catherization may be considered when clinical worsening,
progressive exercise limitation and/or gas exchange abnormalities are
not deemed attributable to ventilatory impairment and an accurate
prognostic assessment is considered important. There are no valid data
to support the routine use of acute vasodilator testing in chronic lung
disease-associated PH.
Hemodynamic Definition - Chronic lung disease with PH is defined as mean pulmonary arterial
pressure (mPAP) = 21-24 mmHg with pulmonary vascular resistance ≥3 Wood
units or mPAP = 25-34 mmHg. Chronic lung disease with severe PH is
defined as mPAP ≥35 mmHg or mPAP ≥25 mmHg with low cardiac index
(<2.0 L•min−1•m−2).
Treatment - Currently, there are no strong data proving pulmonary arterial
hypertension-specific therapy improves outcomes in chronic lung
disease-associated PH. It is recommended that these patients be referred
to expert centers for further treatment options.