0
Editorial |

Physiologic Markers of Exercise as a Potential Screening Tool for the Detection of Pulmonary Hypertension: “α” Few Steps Forward FREE TO VIEW

Richa Agarwal, MD; Mardi Gomberg-Maitland, MD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: The authors have reported to CHEST the following: M. G.-M. reports that Actelion, Bayer, GeNo, Gilead, Medtronic, Novartis, Lung Biotechnology, and Reata, have provided funding to the University of Chicago during the last year to support her conduct of clinical trials; she has served as a consultant for Actelion, Bayer, Bellerophon (formerly known as Ikaria), GeNo, Gilead, Medtronic, and United Therapeutics as a member of steering committees and DSMB/event committees; she has received honoraria for CME from Medscape and ABComm; and she is a member of the PCORI Advisory Panel on Rare Diseases and a Special Government Employee for the FDA Cardio-Renal Division. None declared. (R. A.).

CORRESPONDENCE TO: Mardi Gomberg-Maitland, MD, Department of Medicine, Section of Cardiology, University of Chicago, 5841 S Maryland Ave, MC 5403, Chicago, IL 60637


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(2):295-297. doi:10.1016/j.chest.2015.08.024
Text Size: A A A
Published online

The normal pulmonary circulation is a high-flow and low-pressure circuit, capable of handling exercise-associated increases in cardiac output and transmural pressures through distension and recruitment of pulmonary capillaries, which in turn leads to decreased pulmonary vascular resistance. The distensible properties of the pulmonary capillaries represent an important advantage for the right ventricle (RV) during exercise, allowing it to operate with maximal efficiency and at lower energy consumption. If the field of pulmonary hypertension (PH) could identify when this vascular response to exercise becomes abnormal, we may have an advantage for tracking those subclinical, at-risk patients before the development of overt resting PH. The epidemiologic impact of early identification is sizeable when considering that severe delays in PH diagnosis and referral remain a problem in modern clinical practice and for population-derived registries.,,

Resistive vessel distensibility integrated over a wide range of blood flows and hematocrit values, designated as α, has been developed using a simple model of the pulmonary circulation.,, This coefficient α is a mechanical property of the lung vasculature and represents the percent change in vessel diameter per millimeter of mercury increase in transmural pressure. It is independent of vessel size and can be recalculated from given values of pulmonary artery pressure (PAP), wedge pressure, and cardiac output (CO). In vitro measurements on isolated vessel segments have indicated that normal pulmonary arteries distend approximately 2% of their diameter for each increase in millimeter of mercury, and these results have been replicated in healthy, normoxic volunteers during heart catheterization at rest and at exercise. Decreased α can be expected with chronic hypoxia and with aging, when vascular stiffening and arterial remodeling occur. In a small study of asymptomatic carriers of the bone morphogenetic protein receptor-2 (BMPR-2) mutation, multipoint mean PAP and CO plots from echocardiography were used to derive the α coefficient, which was found to be decreased in this high-risk population. Hence, α may carry high sensitivity for detecting pathological change in the pulmonary vasculature, using both invasive and noninvasive means.

To date, most of the knowledge of α has been derived and validated in normal healthy control subjects. In this issue of CHEST (see page 353), Lau and colleagues show that an exercise α model can serve as a valid descriptor of pulmonary vessel behavior in those with early pulmonary vascular disease (PVD). This study evaluated three groups: control subjects without PVD, patients with PVD and overt resting PH (PVD-PH), and the group of primary interest, patients with PVD without PH (PVD-noPH). The PVD-noPH group had normal resting hemodynamics but anatomically suggestive disease (mostly thromboembolic disease) or consisted of patients who later exhibited PH during follow-up.

The coefficient α proved resilient by both statistical methodology and clinical practicality. The authors showed that the PVD-noPH group’s α during exercise was dramatically reduced compared with that of the control group, with the PVD-PH group having the lowest α values. In the PVD-noPH group, α was not significantly different between patients with resting mean PAP ≤ 20 mm Hg versus those with resting mean PAP of 21 to 24 mm Hg. Furthermore, α did not appreciably differ among the patients with thromboembolic and nonthromboembolic disease, suggesting that decreased α is not just a function of vessel obstruction and late arteriopathy. Receiver operating characteristic curve analyses determined an α cut-point of 0.76%/mm Hg to have 88% sensitivity and 100% specificity for discriminating between those with and without vascular disease. It similarly upheld its discriminatory power for the group with mean PAP ≤ 20 mm Hg, emphasizing this marker’s strength for disease detection prior to any hemodynamic hint. They further validated the fit of the model and found reasonable agreement between measured and calculated mean PAP values.

Several important questions come to mind when reading the authors’ work: Is the physical property of the pulmonary vessel, captured by α, prognostically meaningful or is it solely descriptive for PVD, similar to how other vascular diseases (eg, coronary or peripheral vascular disease) might rely on angiography for anatomical and functional testing for disease confirmation? Is α immutable once it becomes abnormal, or can it be modified through pharmacologic interventions? Might we encounter a time when α as a unique vascular biomarker can be used like brain natriuretic protein for characterizing dynamic disease states and following patients serially?

This work contributes some noteworthy findings and avenues for future investigation. Most importantly, Lau and colleagues suggest that α can complement the PH workup of at-risk patients who require invasive hemodynamic assessment. The populations to critically benefit from α as a screening measure include families with hereditary PH and patients with connective tissue diseases (CTD), primarily those with scleroderma or mixed CTD with scleroderma features who are most likely to exhibit advanced or rapidly progressive disease because of false-negative testing and insufficient predictability for future disease burden using current screening tools. Recently, an exercise echocardiographic study found that greater exercise-related increases in mean PAP relative to CO, a relationship based on principles of pulmonary vascular distensibility and essentially akin to α, was shown to predict future PH in patients with CTD. Thus, exercise pressure-flow relationships as a means of presaging disease are proving appealing for use in this high-risk population and, if validated, could revamp screening programs.

The authors acknowledge that their control group’s average α value was lower than that of previously described normal subjects (1.4%/mm Hg compared with approximately 2%/mm Hg) and attribute this to the older age of the control population. Because current era PH demographics have shifted to an older population, a natural fallout from this study should be to understand expected α decline with age and to establish normative values that can then be referenced when phenotyping older patients with PH. This will aid in differentiating older patients with “age-related stiffness” in the pulmonary vessels from those who are truly disease susceptible and bear a worse prognosis.

As α was obtained through invasive measurements in the authors’ study, an appropriate corollary to this study is validating α noninvasively using stress echocardiography or stress cardiac magnetic resonance in patients with PVD. Previous noninvasive studies of α have used healthy patients with a normal pulmonary circulation. By validating a noninvasive method in patients with disease, we can broaden the scope of α as a screening marker. Noninvasive methods with exercise will require vigorous validation in the future, and invasive measurements may still be needed for equivocal cases. Therefore, it remains to be seen whether α can easily transform from the novel research realm into real-time clinical practice.

The authors should be commended for their work in further exploring this physiologic principle in healthy and diseased pulmonary vasculature. Through their efforts and characterization of α, we embark not only on an early, novel disease predictor of potential screening value, but also an opportunity to redefine abnormal exercise response. If α remains strong with validation and adaptable to clinical practice, we would encourage a closer look at RV interaction with the pulmonary arterial circuit by virtue of α. For instance, even subtle changes in RV adaption and performance in patients with early vascular disease, as in the PVD-noPH α group, could suggest the start of vital RV conditioning and offer another crucial lesson for disease mechanism and ultimate risk stratification.

References

Badesch D.B. .Raskob G.E. .Elliott C.G. .et al Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137:376-387 [PubMed]journal. [CrossRef] [PubMed]
 
Strange G. .Gabbay E. .Kermeen F. .et al Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: the delay study. Pulm Circ. 2013;3:89-94 [PubMed]journal. [CrossRef] [PubMed]
 
Deaño R.C. .Glassner-Kolmin C. .Rubenfire M. .et al Referral of patients with pulmonary hypertension diagnoses to tertiary pulmonary hypertension centers: the multicenter RePHerral study. JAMA Intern Med. 2013;173:887-893 [PubMed]journal. [CrossRef] [PubMed]
 
Linehan J.H. .Haworth S.T. .Nelin L.D. .Krenz G.S. .Dawson C.A. . A simple distensible vessel model for interpreting pulmonary vascular pressure-flow curves. J Appl Physiol. 1992;73:987-994 [PubMed]journal. [PubMed]
 
Naeije R. .Chesler N. . Pulmonary circulation at exercise. Compr Physiol. 2012;2:711-741 [PubMed]journal. [PubMed]
 
Naeije R. .D’Alto M. .Forfia P.R. . Clinical and research measurement techniques of the pulmonary circulation: the present and the future. Prog Cardiovasc Dis. 2015;57:463-472 [PubMed]journal. [CrossRef] [PubMed]
 
Reeves J.T. .Linehan J.H. .Stenmark K.R. . Distensibility of the normal human lung circulation during exercise. Am J Physiol Lung Cell Mol Physiol. 2005;288:L419-L425 [PubMed]journal. [CrossRef] [PubMed]
 
Pavelescu A. .Vanderpool R. .Vachiéry J.L. .Grunig E. .Naeije R. . Echocardiography of pulmonary vascular function in asymptomatic carriers of BMPR2 mutations. Eur Respir J. 2012;40:1287-1289 [PubMed]journal. [CrossRef] [PubMed]
 
Lau E.M.T. .Chemla D. .Godinas L. .et al Loss of vascular distensibility during exercise is an early hemodynamic marker of pulmonary vascular disease. Chest. 2016;149:353-361 [PubMed]journal
 
Kusunose K. .Yamada H. .Hotchi J. .et al Prediction of future overt pulmonary hypertension by 6-min walk stress echocardiography in patients with connective tissue disease. J Am Coll Cardiol. 2015;66:376-384 [PubMed]journal. [CrossRef] [PubMed]
 
Lam C.S.P. .Borlaug B.A. .Kane G.C. .Enders F.T. .Rodeheffer R.J. .Redfield M.M. . Age-associated increases in pulmonary artery systolic pressure in the general population. Circulation. 2009;119:2663-2670 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Badesch D.B. .Raskob G.E. .Elliott C.G. .et al Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137:376-387 [PubMed]journal. [CrossRef] [PubMed]
 
Strange G. .Gabbay E. .Kermeen F. .et al Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: the delay study. Pulm Circ. 2013;3:89-94 [PubMed]journal. [CrossRef] [PubMed]
 
Deaño R.C. .Glassner-Kolmin C. .Rubenfire M. .et al Referral of patients with pulmonary hypertension diagnoses to tertiary pulmonary hypertension centers: the multicenter RePHerral study. JAMA Intern Med. 2013;173:887-893 [PubMed]journal. [CrossRef] [PubMed]
 
Linehan J.H. .Haworth S.T. .Nelin L.D. .Krenz G.S. .Dawson C.A. . A simple distensible vessel model for interpreting pulmonary vascular pressure-flow curves. J Appl Physiol. 1992;73:987-994 [PubMed]journal. [PubMed]
 
Naeije R. .Chesler N. . Pulmonary circulation at exercise. Compr Physiol. 2012;2:711-741 [PubMed]journal. [PubMed]
 
Naeije R. .D’Alto M. .Forfia P.R. . Clinical and research measurement techniques of the pulmonary circulation: the present and the future. Prog Cardiovasc Dis. 2015;57:463-472 [PubMed]journal. [CrossRef] [PubMed]
 
Reeves J.T. .Linehan J.H. .Stenmark K.R. . Distensibility of the normal human lung circulation during exercise. Am J Physiol Lung Cell Mol Physiol. 2005;288:L419-L425 [PubMed]journal. [CrossRef] [PubMed]
 
Pavelescu A. .Vanderpool R. .Vachiéry J.L. .Grunig E. .Naeije R. . Echocardiography of pulmonary vascular function in asymptomatic carriers of BMPR2 mutations. Eur Respir J. 2012;40:1287-1289 [PubMed]journal. [CrossRef] [PubMed]
 
Lau E.M.T. .Chemla D. .Godinas L. .et al Loss of vascular distensibility during exercise is an early hemodynamic marker of pulmonary vascular disease. Chest. 2016;149:353-361 [PubMed]journal
 
Kusunose K. .Yamada H. .Hotchi J. .et al Prediction of future overt pulmonary hypertension by 6-min walk stress echocardiography in patients with connective tissue disease. J Am Coll Cardiol. 2015;66:376-384 [PubMed]journal. [CrossRef] [PubMed]
 
Lam C.S.P. .Borlaug B.A. .Kane G.C. .Enders F.T. .Rodeheffer R.J. .Redfield M.M. . Age-associated increases in pulmonary artery systolic pressure in the general population. Circulation. 2009;119:2663-2670 [PubMed]journal. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
Chronic Thromboembolic Pulmonary Hypertension. Epidemiology and Risk Factors. Ann Am Thorac Soc 2016;13(Supplement_3):S201-S206.
Diagnostic Evaluation of Chronic Thromboembolic Pulmonary Hypertension. Ann Am Thorac Soc 2016;13(Supplement_3):S222-S239.
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543