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More than 75 percent of cases of pulmonary hypertension are directly related to left ventricular dysfunction or mitral or aortic valve disease (WHO group 2). Since group 2 differs markedly from group 1 (pulmonary arterial hypertension) in its pathophysiology and treatment, it is important to distinguish between them.
Compared with WHO group 1 patients, those in group 2 tend to be older, more of them are male, and more of them have comorbidities such as metabolic syndrome, hypertension, and coronary artery disease. A combination of risk factors and clinical findings should be considered in identifying these patients.
Transthoracic echocardiography is used to detect features of systolic and diastolic dysfunction. Left atrial enlargement is a clue that left heart disease may be present. In addition, signs of left ventricular or valvular dysfunction on electrocardiography or chest radiography are often helpful.
When estimated right ventricular systolic pressures are only minimally abnormal and no significant right ventricular dysfunction exists, further diagnostic evaluation is not warranted. However, because no single identifying feature or variable can readily distinguish group 2 from the other WHO groups, further evaluation should be considered if the right ventricular systolic pressure is significantly elevated or right ventricular dysfunction exists.
In patients for whom further evaluation is pursued, the diagnosis of WHO group 2 pulmonary hypertension is ultimately based on findings consistent with postcapillary or “passive” pulmonary hypertension on right heart catheterization. Although mean pulmonary arterial pressures must be at least 25 mm Hg to certify the diagnosis of pulmonary hypertension, a pulmonary artery occlusion pressure greater than 15 mm Hg (normal 6-12) and pulmonary vascular resistance of 3 Wood units or less (normal 0.3-1.6) suggests the pulmonary hypertension is due to elevated left atrial pressure (i.e., postcapillary) rather than precapillary pulmonary arterial remodeling.
Distinguishing pulmonary venous hypertension from PAH is important, since their management differs. In particular, PAH-specific therapies (i.e., prostacyclin analogues, prostaglandin I2 receptor agonists, endothelin receptor antagonists, phosphodiesterase-5 inhibitors and cyclic guanosine monophosphate stimulators) can have a detrimental effect in WHO group 2 patients by causing increased pulmonary capillary leakage with pulmonary edema.
In some patients, chronic passive congestion in the pulmonary venous circulation causes additional disruption of the homeostatic milieu regulating precapillary smooth muscle and endothelial function. These changes result in structural remodeling of precapillary arterioles and increased precapillary vascular resistance, creating a “mixed” pulmonary hypertension with both pre- and postcapillary abnormalities.
There is controversy over the ideal way to identify these patients but little disagreement that they face a worse prognosis than those without precapillary remodeling. In light of this, efforts have been made to characterize this cohort.
Historically, mixed pre- and postcapillary pulmonary hypertension was defined as the combination of all of the following:
However, the utility of the transpulmonary gradient for distinguishing mixed pulmonary hypertension has been questioned because of concerns over its susceptibility to variations in stroke volume and loading conditions.
The diastolic pulmonary gradient (the pulmonary arterial diastolic pressure minus the pulmonary artery occlusion pressure) has been proposed as an alternative to the transpulmonary gradient under the theory that it is less sensitive to fluctuation from variations in flow or loading.
Current guidelines suggest that a patient who has all of the following should be considered to have mixed pulmonary hypertension:
Currently, the diagnosis of WHO group 2 pulmonary hypertension is based on elevated resting pulmonary artery occlusion pressure. However, some patients with WHO group 2 pulmonary hypertension and transiently low preload from aggressive diuresis or fasting may have a low pulmonary artery occlusion pressure during right heart catheterization and be misdiagnosed as having WHO group 1 PAH.
This concern was acknowledged in the 2015 Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) study after investigators changed the protocol to exclude patients who technically met the criteria for WHO group 1 PAH, but had borderline-elevated pulmonary artery occlusion pressure and additional risk factors worrisome for left heart disease and occult WHO group 2 pulmonary hypertension.
Several strategies, including passive leg-raising, fluid challenge and exercise during diagnostic right heart catheterization, have been proposed to better classify these patients. Unfortunately, due to a lack of standardization of normal values and methodology for executing these maneuvers, consensus is lacking over their routine use, and recommendations for their use have not been provided.
Other posts discuss WHO groups 1 and 3-5.
Dr. Bhatnagar is staff in the Department of Regional Anesthesiology. Dr. Dweik is Interim Institute Chair, Respiratory Institute, Cleveland Clinic. Dr. Chaisson is staff in the Departments of Critical Care Medicine and Pulmonary Medicine, Respiratory Institute.
This abridged article originally appeared in Cleveland Clinic Journal of Medicine.