Evan Brittain, MD, MSc

Right ventricular (RV) function is the strongest prognostic marker in patients with pulmonary arterial hypertension (PAH). The ability of the RV to adapt to elevated pressure varies among patients; RV failure occurs early in some patients but remains compensated for extended periods in others. An emerging method for detecting early RV dysfunction is to assess RV function during exercise. Increased pulmonary pressure, flow, and relative hypoxia with exercise may unmask subclinical RV dysfunction.

To further understand the effects of exercise on RV function, Jaijee et al performed cardiac magnetic resonance imaging (CMR) during exercise. Participants also underwent cardiopulmonary exercise testing to identify exercise predictors of impaired RV function. The investigators studied 14 patients with PAH who underwent submaximal exercise testing on room air and 34 matched healthy control subjects who exercised in both normoxic and hypoxic conditions. RV contractile reserve was defined as change in RV ejection fraction from rest to exercise. All PAH subjects had normal RV function at rest. Only 50% of PAH subjects had an increase in RV function with exercise and RV actually declined with exercise in the PAH cohort as a whole (54% vs. 51%), whereas RV function improved with exercise in control subjects (57% vs 70%).

Only 50% of PAH subjects had an increase in RV function with exercise and RV actually declined with exercise in the PAH cohort as a whole (54% vs. 51%), whereas RV function improved with exercise in control subjects (57% vs 70%).

Among control subjects, exercise during hypoxic conditions was associated with a slightly smaller increase in RV ejection fraction (59% at rest to 69% with exercise). The decline in RV function with exercise in the PAH cohort was associated with increases in both end-systolic and end-diastolic size, suggesting they were unable to increase RV contractility with exercise. Among exercise parameters, the ratio of minute ventilation to carbon dioxide production (VE/VCO

) was independently associated with RV contractile reserve (ie, improvement in RV function with exercise) in subjects with PAH.

The novel study showed that among PAH patients with normal resting RV function, half have an impaired response to exercise. This suggests that subclinical RV dysfunction may cause exercise-induced dyspnea in compensated subjects with PAH. These observations are also important because change in RV function over time is an important predictor of outcomes in PAH. Detection of subclinical RV function, either with exercise studies or more sensitive imaging modalities such as myocardial strain, may improve prognostic accuracy. Moreover, an impaired RV response to exercise despite normal resting function may warrant more aggressive treatment. Longitudinal studies are needed to examine outcomes in subjects with impaired response to exercise.

Jaijee SK, Quinlan M, Tokarczuk P, et al. 

Exercise cardiac MRI unmasks right ventricular dysfunction in acute hypoxia and chronic pulmonary arterial hypertension. 

Am J Physiol Heart Circ Physiol 2018, epub ahead of print.

Articles

A new study suggests that subclinical RV dysfunction may cause exercise-induced dyspnea in compensated subjects with PAH.

Exercise Study Detects Subclinical RV Dysfunction in PAH 

In epidemiologic cohorts, rates of idiopathic pulmonary arterial hypertension (iPAH) are higher among methamphetamine users compared with non-users. As a result, methamphetamines are considered a “likely” cause of drug-induced PAH. Despite this recognition, the clinical features and outcomes of patients with methamphetamine-associated PAH (Meth-PAH) have not been well described. To address this knowledge gap, Zamanian et al recently published a descriptive study of the largest Meth-PAH cohort to date, including clinical characteristics, hemodynamics, and survival data.

In the prospective cohort study, the investigators identified 90 incident cases of Meth-PAH and compared them with 97 patients with iPAH. The self-reported median exposure to methamphetamines in the Meth-PAH group was 60 months and 70% of the cohort reported daily use. Although of similar age, patients with Meth-PAH were less likely to be female (63% vs. 83%) and more likely to be non-Hispanic white (79% vs 53%). Patients with Meth-PAH had worse functional class at the time of presentation but similarly reduced 6-minute minute walk distance. The two groups had similar mean pulmonary pressure and pulmonary vascular resistance, but the Meth-PAH group had higher right atrial pressure and lower stroke volume index, suggesting compromise of right ventricular function.

On histopathologic specimens, Meth-PAH lungs had characteristic plexiform lesions similar to iPAH patients. Compliance with prescribed medical therapy for PAH was lower in Meth-PAH compared with iPAH (47% vs 60%) and intravenous prostacyclin analogs were less commonly prescribed to Meth-PAH patients, perhaps out of concern for abuse of easy venous access among active drug users. The median follow-up time was 47 months (IQR 20-87). The 5-year event-free (death, transplant, or PAH-related hospitalization) survival was 47% in Meth-PAH vs 65% in the iPAH group. After adjusting for age, sex, race, income, and time to prostacyclin use, Meth-PAH was associated with a two-fold increase in mortality (HR 2.04, 95%CI 1.28-3.25).

This report is an important addition to the literature because it demonstrates the burden of Meth-PAH in the community and its associated poor outcomes. This paper also highlights the challenges associated with treating Meth-PAH, including lower compliance and reluctance by physicians to use the most aggressive therapies, which require continuous venous access. Hemodynamic and echocardiographic data from this study suggest that methamphetamine exposure may have a negative effect on the right ventricle, which may contribute to worse outcomes.

The study’s main limitation is that findings from only a single center were reported. It is unknown whether the epidemiology and outcomes of Meth-PAH are similar in other parts of the US or world.

: Zamanian RT, Hedlin H, Greuenwald P, et al. 

Features and outcomes of methamphetamine-associated pulmonary arterial hypertension. 

Am J Respir Crit Care Med. 2018;197:788-800.

Treating patients with methamphetamine-associated PAH presents unique challenges including the pros and cons of placing venous access ports.

Methamphetamine-associated PAH: Features and Outcomes 

Pulmonary arterial hypertension (PAH) is a rare, but highly morbid complication of systemic lupus erythematosus (SLE). The characteristics of patients with SLE-PAH have not been well described in large, well-phenotyped cohorts. Hachilla and colleagues addressed this knowledge gap by comparing clinical features of patients with SLE-PAH in the French Pulmonary Hypertension Registry to patients with SLE without PAH (selected from SLE expert centers).

SLE-PAH was defined according to consensus recommendations.

A total of 51 patients with SLE-PAH were compared with 101 patients with SLE but no evidence of pulmonary hypertension on screening echocardiogram. There were no differences in age, gender, or duration of SLE between groups. The investigators did identify a higher prevalence of auto-antibodies (anti-Sm, anti-SSB, anti-SSA) among subjects with SLE-PAH.

The average time interval from SLE diagnosis to recognition of PAH was 4.9 years (range 2.8-12.9 years). Most patients with SLE-PAH had advanced NYHA functional class heart failure at the time of PAH diagnosis (71% NYHA class III or IV); 0/40 had a positive acute response to vasodilator testing. In univariate analysis, higher pulmonary vascular resistance and lupus nephritis were associated with worse survival. Use of hydroxychloroquine was associated with a trend toward improved survival. The authors urged caution in interpreting this result because nearly all subjects with SLE-PAH were on hydroxychloroquine. Survival at 3 years was 89%. Of note, no patients with anti-U1-RNP antibodies (0/14) died during the 10-year follow-up.

The authors also compared the French cohort to other published studies. The age, severity of disease, and survival rates were similar across several cohorts. One notable difference was that the association between anti-U1-RNP antibodies and PAH observed in a Chinese cohort was not replicated in the French cohort, suggesting ethnicity may play a role. Renal disease is an established independent prognostic factor in both SLE and PAH. In this study, renal involvement in patients with SLE-PAH was associated with a marked increase in the risk of mortality (HR 12.71, 95% CI 2.07-60.52) and was the strongest prognostic factor. The potential protective effect of hydroxychloroquine is intriguing because this class of medication prevents degradation of the BMPR2 receptor and low BMPR2 expression is a prominent feature of PAH.

The observational nature of these data do not suggest clinical practice should change but clinical trials may be warranted to test the prognostic effects of hydroxychloroquine against other agents used to treat SLE.

 Hachulla E, Jais X, Cinquetti G, et al. 

Pulmonary arterial hypertension associated with systemic lupus erythematosus: results from the French Pulmonary Hypertension Registry.

Pulmonary arterial hypertension is a rare, but deadly complication of systemic lupus erythematosus. French investigators sought to identify clinical features of patients with both. 

PAH Associated with SLE: A Step Toward a Clinical Profile 

Phosphodiesterase type-5 (PDE5) inhibitors are approved by the US FDA for the treatment of pulmonary arterial hypertension. This class of medications is sometimes prescribed for patients with pulmonary hypertension of other etiologies despite lack of data to support efficacy. The off-label practice is potentially dangerous and also costly. Kim and colleagues recently examined data in the Veteran’s Affairs (VA) system to better understand national clinical practice patterns with respect to PDE5 inhibitor use for pulmonary hypertension.

This retrospective analysis used pharmacy prescription data from 2005-2012. The investigators restricted the cohort to subjects with outpatient prescriptions for daily use (to exclude subjects prescribed PDE5 inhibitors for erectile dysfunction). Pulmonary hypertension and its underlying etiology was defined on the basis of an International Classification of Diseases code-based algorithm and validated by chart review of a random sample.

In total, 108 777 subjects with pulmonary hypertension were identified of whom 2,790 (2.6%) received a daily prescription for a PDE5 inhibitor. Based on the algorithm-defined etiology of pulmonary hypertension, only 19% received a prescription consistent with clinical guidelines. Appropriateness could not be determined in an additional 13% of subjects due to incomplete data.

Based on the algorithm-defined etiology of pulmonary hypertension, only 19% received a prescription consistent with clinical guidelines.

Patients inappropriately prescribed PDE5 inhibitors were more likely to be older white men with cardiac disease and hypoxemic lung disease. The use of PDE5 inhibitors contrary to guidelines increased over time, from 53 prescriptions in 2005 to 748 in 2012. The investigators also performed manual chart abstraction to determine the proportion of subjects who were referred for right heart catheterization, the gold standard diagnostic test for pulmonary hypertension. Only 110/230 (48%) patient records reviewed had a documented right heart catheterization and 74/230 (32%) had an echocardiogram with evidence of pulmonary hypertension.

This study is important because it brings to light potential widespread use of PDE5 inhibitors contrary to guideline recommendations. Trials of PDE5 inhibitors in patients with pulmonary hypertension due to left heart disease (WHO Group II) have failed to show benefit. An on-going trial is investigating the use of tadalafil in subjects with pulmonary hypertension and hypoxemic lung disease (WHO Group III). Clinical practice guidelines for pulmonary hypertension do permit a trial of PDE5 inhibition in patients with WHO Groups II and III, but most subjects identified for this study were on therapy long-term.

Clinical inertia may play a role in the surprising numbers receiving the drugs outside of guidelines recommendations as nearly 40% of the prescriptions from the VA were prescribed by an outside provider but were continued by a VA provider. Unfortunately, the methods used for this study did not allow investigation of the underlying rationale for prescribing PDE5 inhibition in a given patient. The use of electronic health record and administrative data is an important approach for identifying epidemiologic trends. However, the inability to extract hemodynamic and echocardiographic data in this study increases the risk of patient misclassification, as evident by a positive predictive value for pulmonary arterial hypertension of only 42%. Despite this limitation, the findings are compelling and raise awareness of the misuse of PDE5 inhibition among patients with pulmonary hypertension in the VA system.

Phosphodiesterase-5 inhibitor therapy for pulmonary hypertension in the United States. Actual versus recommended use. 

A study in the VA system found that only 19% of patients diagnosed with pulmonary hypertension received a PDE5 inhibitor prescription consistent with clinical guidelines.

PDE5i Misuse in Pulmonary Hypertension Treatment Appears Widespread

Improvements in surgical and medical management have led to an increase in the population of adults with congenital heart disease (CHD). Pulmonary hypertension is a common complication of CHD. Studies to date have described referral populations from tertiary care centers and have focused on patients with systemic-to-pulmonary shunts who develop pulmonary arterial hypertension. As a result, population-based incidence rates of pulmonary hypertension (PH) in CHD and the association with mortality have not been described.

, investigators used the Danish National Registry of Patients to identify individuals with adult-onset PH in the CHD population who had long-term follow-up data on file. Patients diagnosed with CHD and PH were identified on the basis of ICD codes. The Danish National Registry of Patients includes comprehensive data on hospitalizations, outpatient and emergency room visits, and surgical procedures. Patients with CHD were matched 1:10 for gender and birth year to individuals without CHD.

In total, 14,680 subjects with CHD were identified with a median follow-up of 22 years, 266 of whom were also diagnosed with PH. Compared with controls, patients with CHD and PH were older, more likely to be women, and more likely to have a systemic-to-pulmonary shunt. The cumulative incidence of adult-onset PH was 7.2% in the CHD population compared with 0.4% in the control cohort. The incidence of PH increased with both age and the severity of the congenital lesion. The incidence of PH in patients with systemic-to-pulmonary shunts was 8.3% compared with 5.3% in subjects with other types of defects. The overall prevalence of PH in adults with CHD was 1.1% and was similar in subjects with and without systemic-to-pulmonary shunts.

Cumulative short- and long-term all-cause mortality did not differ between CHD-PH patients with and without systemic-to- pulmonary shunts (24% at 1 year, 44% at 5 years, 52% at 10 years). However, after adjusting for gender, birth year, CHD severity, and the presence of noncardiac defects, PH in the setting of systemic-to-pulmonary shunts was associated with a hazard ratio of 1.8 (95% CI 1.1-2.9). The adjusted hazard for mortality was 4.3 (95% CI 3.3-5.6) for CHD subjects with PH compared with those without PH.

This study is important for several reasons. First, unlike prior studies, which were largely comprised of referral populations, the current population was unselected and included the population of an entire nation. Second, the investigators described long-term follow-up whereas prior studies have been cross-sectional. Finally, by virtue of the comprehensive health outcomes records maintained in Denmark, the authors were able to exclude subjects with PH that predated adulthood.

There are important limitations to this study that are inherent to electronic health record and administrative databases. The authors are unable to comment on the underlying etiology of PH in their population without access to right heart catheterization data and other relevant diagnostic tests (eg, echocardiography, pulmonary function testing, or polysomnography). Reliance on ICD codes introduces the risk of misclassification, particularly for the PH and heart failure diagnoses. Finally, no data on medical therapy are presented to examine whether differences in treatment influenced outcomes. The major point from this report is that PH is common and associated with increased mortality in adults with CHD. The clinical implication is that this population warrants surveillance for the development of PH and referral for specialty care if suspicion for PH arises.

Schwartz SS, Madsen N, Laursen HB, Hirsch R, Olsen MS. Incidence and mortality of adults with pulmonary hypertension and congenital heart disease. Am J Cardiol. Published online March 14, 2018 (doi: https://doi.org/10.1016/j.amjcard.2018.02.051) https://www.ajconline.org/article/S0002-9149(18)30287-X/abstract

Pulmonary hypertension is a common complication of CHD but a new Danish study is the first to report on population-based incidence and impact.

Congenital Heart Disease and Adult-onset Pulmonary Hypertension: Incidence and Impact on Mortality  

Atrial arrhythmias commonly complicate the clinical course of patients with pulmonary arterial hypertension (PAH). Despite this recognition, the prevalence of atrial arrhythmias and their impact on mortality has not been well described. To address this knowledge gap, investigators at Johns Hopkins University described their institutional experience with atrial arrhythmias. Their results appeared online, April 17, 2018, in

In total, 317 consecutive patients (201 scleroderma-associated PAH, 116 idiopathic PAH) were described (84% female, 76% white). Atrial arrhythmia was defined as atrial fibrillation, atrial flutter, or ectopic atrial tachycardia. Over a follow-up period of 67 ± 51 months, 42 (13%) patients developed an atrial arrhythmia. Male sex, older age, and a history of thyroid disease were more common in patients who developed an atrial arrhythmia. When assessed via invasive hemodynamics, right- and left-sided filling pressures were higher in patients with an atrial arrhythmia

There was no association with PAH pharmacotherapy.

Atrial fibrillation was the most common atrial arrhythmia (34 episodes in 42 patients), followed by atrial flutter (18 episodes). Electrical cardioversion to sinus rhythm was attempted in 13/42 (31%) cases, however, 64% of patients had a recurrent episode. In total, 13/42 (31%) patients underwent ablation for atrial fibrillation. Development of an atrial arrhythmia led to clinical worsening and hospitalization in 38/42 (90%) patients. Right heart failure was the most common clinical complication and required vasopressor support in 15/42 (36%) patients.

Over the follow-up period, 170/317 (54%) deaths occurred, including 69% of subjects who experienced an atrial arrhythmia compared with 51% of those who did not (p=0.32). The highest mortality was observed in patients with scleroderma-associated PAH who developed an atrial arrhythmia whereas the lowest mortality occurred in patients with idiopathic PAH without an atrial arrhythmia.

This study is an important addition to the literature because the authors specifically focused on World Health Organization Group 1 PH, while prior studies have reported on heterogeneous cohorts of patients with PH. The main conclusion is that atrial arrhythmias are common and associated with clinical worsening in patients with idiopathic and scleroderma-associated PAH. Right ventricular failure was the predominant complication of atrial arrhythmia, which the authors concluded was related to loss of right atrial contractility. The clinical implication of this observation is that a rhythm control strategy (ie, restoration of sinus rhythm and “atrial kick”) may be particularly important for this patient population. Although the incidence of atrial arrhythmia was similar between groups with idiopathic vs scleroderma-associated PAH, patients with scleroderma had a higher risk of death, drawing attention to a particularly high-risk subpopulation.

Important limitations of the study include the single-center cohort and potential for contamination with patients with left heart disease.

Mercurio V, Peloquin G, Khalil BI, et al. 

Pulmonary arterial hypertension and atrial arrhythmias: incidence, risk factors, and clinical impact.

Pulmonary arterial hypertension is often complicated by atrial arrhythmias; a new study sheds light on the clinical impact.