By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports he is a consultant for Alnylam Pharmaceuticals and Akcea Therapeutics.

SYNOPSIS: In a large cohort of patients referred for echocardiography, an estimated right ventricular systolic pressure > 30 mmHg was associated with higher mortality rates.

SOURCE: Strange G, Stewart S, Celermajer DS, et al. Threshold of pulmonary hypertension associated with increased mortality. J Am Coll Cardiol 2019;73:2660-2672.

Pulmonary hypertension (PH) is associated with a poor prognosis, regardless of etiology. The results of several studies have suggested the traditional criteria for PH, a mean pulmonary arterial (mPA) pressure ≥ 25 mmHg measured by right heart catheterization, may fail to identify all patients at risk for adverse events. Echocardiography is the most common initial diagnostic test in the evaluation of PH, and it is helpful to identify clinically meaningful echo-measured thresholds.

To determine the prognostic significance of increasing pulmonary pressures, Strange et al evaluated the National Echo Database Australia (NEDA), which contains data on more than 300,000 patients referred for echocardiography at 12 centers across Australia. The estimated right ventricular systolic pressure (eRVSP, which approximates the pulmonary artery systolic pressure) was calculated using the modified Bernoulli equation based on the tricuspid regurgitant velocity (TRV) and assuming a right atrial pressure of 5 mmHg (eRVSP = 4 × TRV2 + 5 mmHg). The authors examined the underlying distribution of RVSP among patients referred for echocardiography and the prognostic significance of incremental increases in eRVSP. The primary endpoints were all-cause and cardiovascular-specific mortality, with a median follow up of 4.2 years.

The authors included echocardiograms from 157,842 patients with adequate TR jets in the analysis. The average age was 65.7 years, 52.9% were women, and the median eRVSP was 25 mmHg. Using a criterion of eRVSP > 40 mmHg, 18.7% of all patients had at least mild PH, and the authors confirmed that patients with PH exhibited worse survival rates compared to those without PH. To evaluate the effects of incremental increases in pulmonary pressures, the cohort was divided into quintiles based on eRVSP and analyzed for one- and five-year mortality after adjusting for factors including age and presence of left heart disease.

The authors found that even patients in the third quintile (corresponding to an eRVSP of approximately 30 mmHg) experienced significantly higher mortality rates than those in the lowest quintile (hazard ratio [HR], 1.41; 95% confidence interval, 1.31-1.52). Patients in the fourth (HR, 1.98) and fifth (HR, 4.04) quintiles of eRVSP were at an even higher risk of mortality compared to the lowest quintile (P < 0.001). The authors concluded that a threshold of eRVSP greater than 30 mmHg by echocardiography can be used to identify patients at a higher risk of mortality.

COMMENTARY

PH develops because of several causes, including intrinsic disease of the pulmonary arteries (as occurs in pulmonary arterial hypertension) or (more commonly) left heart or pulmonary disease. Regardless of the etiology, PH is a hemodynamic diagnosis based on an elevated mean pulmonary arterial pressure measured by right heart catheterization. Traditionally, the threshold to diagnose PH has been a mean pressure ≥ 25 mmHg. However, the authors of multiple studies have shown that patients with even milder elevations in mean pulmonary arterial pressure are associated with worse outcomes. Acknowledging the traditional threshold of 25 mmHg may be too high, the 6th World Symposium on Pulmonary Hypertension recently changed the diagnostic criteria for PH from an mPA ≥ 25 mmHg to a lower threshold of 20 mmHg. This change will lead to a marked increase in the number of patients diagnosed with PH. It is important to determine how this change will be incorporated into clinical practice.

Strange et al used echocardiography rather than right heart catheterization to identify patients with elevated pulmonary arterial pressures. When it comes to diagnosing PH using echocardiography, there are multiple limitations, including the inability to directly measure mPA pressure. Echocardiographic estimates of RVSP rely on the presence of a tricuspid regurgitant jet, which is not always present and is prone to measurement error. For these reasons and more, it is important to remember that echocardiography cannot diagnose PH. However, despite these limitations, it remains the most common initial test in the evaluation of PH; thus, it is helpful to have a clear idea how to interpret the eRVSP.

An eRVSP of 40 mmHg is used often to identify patients with PH (correlating roughly to a mPA pressure of 25 mmHg). Here, Strange et al have used one of the largest echocardiography databases available to confirm that patients with an eRVSP > 40 mmHg are at a higher risk for mortality vs. those with no PH. However, they also found that a threshold of 40 mmHg misses a significant proportion of patients at a higher risk for mortality; an eRVSP threshold of 30 mmHg may be more appropriate. This is an important finding, since 28.6% of all patients in the cohort had an eRVSP of 30-39 mmHg and would be reclassified as higher risk using this lower threshold.

Although the authors demonstrated that an eRVSP > 30 mmHg is associated with higher mortality rates, it is unclear whether the elevated pulmonary pressure contributes to this, or if it is a marker of comorbidities. For example, is an eRVSP of 30 mmHg really enough to cause RV dysfunction and failure, or is the mildly elevated RVSP a marker of other disease? The authors found a sequential increase in the prevalence of right heart dilation and RV dysfunction with increasing eRVSP, starting with 30 mmHg. This suggests, but does not necessarily prove, that even a mild increase in pulmonary artery pressure may be sufficient to affect RV function. Therefore, mild PH may contribute to the observed relationship between eRVSP and mortality.

Identifying patients with elevated pulmonary pressures will not always lead to direct changes in medical therapy. Most patients in this cohort (and most patients with PH in general) exhibited associated left heart or lung disease. These patients have not been shown to benefit from pulmonary vasodilator therapy. Even in patients without these associated conditions, treating those with a mean pulmonary arterial pressure < 25 mmHg has not yet been shown to improve outcomes. For now, identifying optimal pressure thresholds is important for earlier diagnosis, earlier focus on treating factors that contribute to PH, and perhaps closer follow-up. Through earlier detection, we can move toward a more preventive approach to managing PH that aims to avoid right heart dysfunction before it develops.