Pulmonary Hypertension During Exercise Foretells Later Risk of Adverse CV Outcomes

Challenges include understanding whether inducible PH is a treatable condition as well as simplifying the test for wider use.

Pulmonary Hypertension During Exercise Foretells Later Risk of Adverse CV Outcomes

Pulmonary hypertension (PH) during exercise testing is linked to the combined risk of CV-related hospitalization and death among patients with chronic dyspnea, confirms a report on more than 700 people who underwent invasive hemodynamic monitoring.

The association was also seen in patients with no signs of rest abnormalities, suggesting that exercise-induced PH in and of itself may have prognostic value.

Importantly, the PH was diagnosed using minute-by-minute measurements of not only mean pulmonary artery pressure (PAP) during exercise but also cardiac output (CO), with the metric expressed as a ratio between the two.

“For some time there has been this growing body of evidence . . . that an exercise-based definition of pulmonary hypertension might warrant consideration. Our study is the first to show that that really is substantiated, in that exercise can be used to unmask abnormal pulmonary vascular responses that have important clinical implications,” lead author Jennifer E. Ho, MD (Massachusetts General Hospital, Boston), explained to TCTMD.

“This is a very early study—it’s a hemodynamic finding. Certainly there are a number of questions that result from our research,” she cautioned. “The first one is whether or not this is a treatable condition [that] we can target in the future to potentially alter a disease course.”

Definitions of PH have shifted over the years, Marius M. Hoeper, MD (Hannover Medical School and German Center of Lung Research, Hannover, Germany), notes in an accompanying editorial. For decades, there were set PAP cutoffs for both rest and exercise, though the latter fell out of favor about 10 years ago “because it became increasingly clear that mean PAP values > 30 mm Hg during exercise were not necessarily abnormal in certain subjects, for instance in athletes or elderly individuals,” he explains.

Interest in the PAP/CO ratio has been growing but previously was held back by the fact that “the prognostic value of exercise PH was largely unknown,” Hoeper says, adding, “This is where the paper by Ho et al [in JACC] comes into play.”

Prognostic Value of Exercise PH

For their study, published in the January 7/14 issue of the Journal of the American College of Cardiology, Ho and colleagues enrolled 714 people (mean age 57 years; 59% women) with chronic exertional dyspnea and preserved ejection fraction. Only 2% had previously been diagnosed with pulmonary arterial hypertension.

In the study, 296 (41%) had exercise-induced PH as evidenced by abnormal PAP/CO slopes of > 3 mm Hg/L/min on invasive hemodynamic monitoring during cardiopulmonary exercise testing. Patients with these high PAP/CO slopes were more likely to have diabetes, prior heart failure, chronic obstructive pulmonary disease, and interstitial lung disease (P < 0.05 for all) as well as a higher median level of N-terminal pro–B-type natriuretic peptide (P < 0.001).

Rest PH, defined as mean PAP > 20 mm Hg, was seen in 146 patients (20%), while 184 (26%) participants had exercise PH but not rest PH.

Over a mean follow-up period of 3.7 years, 208 patients had a nonelective CV hospitalization (32% for heart failure) and/or died. Patients with abnormal PAP/CO slopes at baseline had twice the risk of experiencing one of these outcomes over time (adjusted HR 2.03; 95% CI 1.48-2.78). After excluding the patients with rest PH alone, the relationship between exercise PH and CV outcomes was still significant (HR 1.75; 95% CI 1.21-2.54).

“These findings suggest incremental value of exercise hemodynamic assessment to resting measurements alone in characterizing the burden of PH in individuals with dyspnea,” the researchers conclude. This link was seen no matter whether PH’s origins were pre- or post-capillary.

Hope for Simpler, Noninvasive Tools

Currently, Ho told TCTMD, most patients who present with dyspnea or other PH symptoms undergo echocardiography to estimate PAP. Then, right-heart catheterization is used to confirm whether PH is present. At most centers, this invasive assessment is done at rest with the patient lying down. At Mass General, though, patients are also tested while using a stationary bicycle with the catheter in place.

“We’re very fortunate to have the luxury of doing this testing here. It’s a fairly specialized test,” she said, crediting senior author Gregory D. Lewis, MD, who directs the hospital’s Cardiopulmonary Exercise Testing Laboratory, for setting up the program. “This isn’t something widely available in the community, so we certainly recognize that. One of the exciting things about our study is we’ve now identified this subgroup of people we think might be at greater risk clinically for bad outcomes. One of the unknowns is whether there are noninvasive ways that we can identify this same subgroup of individuals in the community when this advanced testing isn’t necessarily widely available.”

This potential is something the Mass General researchers are interested in exploring further, Ho reported.

For his part, Hoeper predicts little impact on practice in the short term, “as evidence-based treatments for this condition are not yet available.”

Pulmonary hypertension, whether at rest or during exercise, “is not a disease per se, but a hemodynamic condition associated with symptoms and adverse outcomes,” he observes.

Still, there are some applications, Hoeper acknowledges. “Diagnosing exercise PH will occasionally help physicians and patients to better understand exertional dyspnea and to detect early pulmonary vascular disease in patients at risk. In addition, a globally accepted definition of exercise PH will form the basis for developing targeted management strategies.

“Finally,” he concludes, “as the main drawback of the mean PAP/CO slope is its reliance on sophisticated invasive measurements that can be performed only at highly specialized institutions, having a globally accepted gold standard will lay the groundwork on which simpler, noninvasive diagnostic tools can be developed and validated.”

Sources
Disclosures
  • This work was supported by grants from the National Institutes of Health/National Heart, Lung, and Blood Institute; a Gilead Sciences Research Scholar Award; and the American Heart Association and the MGH Heart Failure Research Innovation Fund.
  • Ho reports no relevant conflicts of interest.
  • Hoeper reports receiving fees for lectures and/or consultations from Actelion, Bayer, Merck Sharp and Dohme, and Pfizer.

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