- Email: [email protected]
Full Circle on Pulmonary Flow Dynamics in Pulmonary Arterial Hypertension∗
JACC: CARDIOVASCULAR IMAGING
VOL. 10, NO. 10, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcmg.2016.12.022
EDITORIAL COMMENT
Full Circle on Pulmonary Flow Dynamics in Pulmonary Arterial Hypertension* Francois Haddad, MD, Myriam Amsallem, MD
I
n this issue of iJACC, Takahama et al. (1) provide novel insights into pulmonary flow dynamics in
F I G U R E 1 M-Mode Characteristic Motion of Posterior Pulmonary
Leaflet in a Patient With Pulmonary Hypertension
patients with pulmonary arterial hypertension
(PAH). The study builds on landmark work in pulmonary valve motion and pulmonary flow in pulmonary
hypertension (PH). In 1974, Nanda et al. (2) were the first to observe that the pulmonary valve in patients with PH appeared straight in diastole with rapid opening slopes (>350 mm/s) and prolonged pre-ejection periods. Weyman et al. (3) further described the presence of mid-systolic fluttering, closure or notching of the pulmonary valve (Figure 1) in most patients with PAH (n ¼ 20) and in none of the controls. The changes in pulmonary valve SEE PAGE 1268
motion and pulmonary flow in PH can be explained by the complex interplay between forward and reflected pulmonary pressure waves (4,5). Under normal conditions, the reflected wave only accounts for a small component of the total pressure wave. In patients with PH, the reflected pressure wave becomes significant and adds to the forward wave, imposing an added pressure burden on a stillejecting right ventricle (RV). The resulting reduction
Trace shows the mid-systolic notching of the leaflet. c ¼ fully
in flow velocity during mid-ejection changes the
open position of the leaflet during ventricular ejection;
normal dome-like contour into a notched contour. Although the notched pattern of pulmonary flow
n ¼ mid-systolic closure or notching of the leaflet; d ¼ position of the valve at the onset of valve closure. Adapted with permission from Weyman et al. (3).
was initially believed to be characteristic of PAH, it has been also observed in patients with chronic thromboembolic disease, and is a strong prognostic factor (6). The pulmonary notch has also been shown to be strongly suggestive of elevated pulmonary
vascular resistance in patients with predominantly “left heart failure” (7). The study by Takahama et al. (1) builds on those studies and offers a comprehensive analysis of the
*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the Division of Cardiovascular Medicine, Stanford School of Medicine, Stanford University, Stanford, California. Both authors have
pulmonary
flow
signal.
Perhaps
the
most
important finding is that pulmonary flow patterns reflect not only pulmonary impedance (“resistance” to flow) but also right ventricular adaptation to the increased load. The authors analyzed several pa-
reported that they have no relationships relevant to the contents of
rameters of pulmonary flow, including deceleration
this paper to disclose.
time
of
mid-systolic
deceleration
slope,
peak
Haddad and Amsallem
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 10, 2017 OCTOBER 2017:1278–80
Editorial Comment
F I G U R E 2 Prognostic Network of Correlates of Long-Term Outcomes in PAH
6MWTD ¼ 6 minute walk test distance; CI ¼ cardiac index; CTD ¼ connective tissue disease; DLCO ¼ diffusing capacity of the lung for carbon monoxide; HIV ¼ human immunodeficiency virus; NT-proBNP ¼ N-terminal type B natriuretic peptide; NYHA ¼ New York Heart Association; PAC ¼ pulmonary arterial capacitance; Peff ¼ pericardial; PVR ¼ pulmonary vascular resistance; RA ¼ right atrium; RAP ¼ right atrial pressure; RVESV ¼ right ventricular end-systolic volume; sBP ¼ systolic blood pressure; TAPSE ¼ tricuspid annular plane systolic excursion.
pre- (Vpre) and post-notching (Vpost) flow velocities,
along with New York Heart Association functional
and the V post /Vpre ratio. These parameters allowed
class and N-terminal pro-B type natriuretic peptide
characterization of 4 patterns of pulmonary flow
concentration
(i.e., non-notched, long deceleration time profile,
outcome in PH. Third, with the predictive value of
high notch velocity, and low notch velocity). These
large clinical scores such as those from the REVEAL
patterns were associated with transplantation-free
registry score, which has a C statistic of 0.77, the
were
the
strongest
predictors
of
survival in PAH patients, with the lower notch velocity profile having the worst survival. The authors further explain the pulmonary flow patterns according to forward and reflected pulmonary flow dynamics. Although the study has very strong merits from
T A B L E 1 Established or Potential Prognostic Markers in PAH
Predictive Markers
Demographics
Comments
Age and sex (need to be considered in response studies)
Vasoreactivity
Associated with response to calcium channel blockers
a physiological perspective, we are not convinced
Etiology
Scleroderma associated PAH
that the pulmonary notch profile will lead to signifi-
Severity markers
Patients with intermediate elevation of pulmonary impedance may show a greater improvement in response to therapy patients with greater likelihood to change pulmonary compliance (13).
“Omics”
Will likely play an emerging role in the future (e.g., oxidative stress markers and phosphodiesterase inhibitors response, still pending clinical validation) (14). Other markers are being studied.
Molecular imaging
Presence of altered metabolism (e.g., glycolytic metabolism) may be used for targeted therapy monitoring or response.
Fibrosis imaging
May be key, if validated, in deciding who would benefit from heart-lung versus double-lung transplantation.
cant reclassification of outcome in PAH. First, the findings are based on a derivation cohort, and further validation studies are needed for outcome prediction. Second, although pulmonary flow patterns appeared more predictive than tricuspid annular plane systolic excursion, a direct comparison with RV longitudinal strain, one of the emerging prognostic markers in PH, is needed. In fact, in a large study from Fine et al. (8), also from the Mayo Clinic, RV longitudinal strain
1279
1280
Haddad and Amsallem
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 10, 2017 OCTOBER 2017:1278–80
Editorial Comment
incremental value of any new molecular or imaging
for early diagnosis of PH in the community remains
biomarker will likely require a large sample size to
an unmet need in the field. This is even more relevant
demonstrate and at most lead to a small proportion of
as B-type natriuretic peptide is not a sensitive marker
reclassification of outcome (8–12). Fourth, different
for early PH. In this regard, pulmonary flow profiles
scores are likely to emerge with comparable risk
(acceleration time, notching) are useful signs that
stratification characteristics, and perhaps the greatest
may suggest PH, especially when the estimation of
value of a new score or metric would be simplification
pulmonary pressure is not reliable (17–19).
of current scores, which may improve clinical care as
In conclusion, the study by Takahama et al. (1)
well as stratified randomization in clinical trials.
adds novel physiological perspectives to pulmonary
Figure 2 summarizes some of the prognostic metrics
flow that highlight the pioneering work of Drs. Nanda
that have emerged more consistently in PH (8–12). The field of PH is ready to move from prognostic
and Weyman in the field of detection of PH, thus completing a full circle of pulmonary flow dynamics
scores to predictive markers of therapeutic response;
in PH research.
in addition, biomarkers may be very useful to guide
ACKNOWLEDGMENTS The
targeted therapies in PH such as mitochondrial mod-
Stanford Cardiovascular Institute, the Vera Moulton
ulation
Wall Center of Pulmonary Hypertension at Stan-
and
neurohormonal,
immune,
or
other
pathway-specific therapy. Table 1 summarizes some of the routine or emerging markers that will likely
authors
thank
the
ford, and the Pai Chan Lee Research Fund for their support.
prove to be useful in this era of biomarker-guided management (13–15). Recent examples include the use of molecular imaging as designed in the recent
ADDRESS FOR CORRESPONDENCE:
trial of dichloroacetate therapy led by Michelakis
Haddad, Division of Cardiovascular Medicine, Stan-
et al. (16) (NCT01083524).
ford School of Medicine, Stanford University, 300
In addition to outcome and predictive markers, identification of reliable and cost-effective markers
Dr. Francois
Pasteur Drive, Stanford, California 94305. E-mail: [email protected].
REFERENCES 1. Takahama H, McCully RB, Frantz RP, Kane GC. Unraveling the RV ejection Doppler envelope: insight into pulmonary artery hemodynamics and disease severity. J Am Coll Cardiol Img 2017;10: 1268–77. 2. Nanda NC, Gramiak R, Robinson TI, et al. Echocardiographic evaluation of pulmonary hypertension. Circulation 1974;50:575–81. 3. Weyman AE, Dillon JC, Feigenbaum H, et al. Echocardiographic patterns of pulmonic valve motion with pulmonary hypertension. Circulation 1974;50:905–10. 4. Parker KH, Jones CJ. Forward and backward running waves in the arteries: analysis using the method of characteristics. J Biomech Eng 1990; 112:322–6. 5. Chemla D, Castelain V, Simonneau G, et al. Pulse wave reflection in pulmonary hypertension. J Am Coll Cardiol 2002;39:743–4. 6. Castelain V, Hervé P, Lecarpentier Y, et al. Pulmonary artery pulse pressure and wave reflection in chronic pulmonary thromboembolism and primary pulmonary hypertension. J Am Coll Cardiol 2001;37:1085–92.
function assessment in 575 subjects evaluated for pulmonary hypertension. Circ Cardiovasc Imaging 2013;6:711–21.
targeting of phosphodiesterase type 5 from nitric oxide synthase-3 to natriuretic peptide signaling. Circulation 2012;126:942–51.
9. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial
15. Nasir K. Cardiovascular imaging research: time to think beyond risk prediction? J Am Coll Cardiol Img 2015;8:957–9.
Hypertension Disease Management (REVEAL). Circulation 2010;122:164–72. 10. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156–63. 11. Thenappan T, Shah SJ, Rich S, et al. Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur Respir J 2010;35:1079–87. 12. Haddad F, Spruijt OA, Denault AY, et al. Right heart score for predicting outcome in idiopathic, familial, or drug- and toxin-associated pulmonary arterial hypertension. J Am Coll Cardiol Img 2015; 8:627–38.
7. Arkles JS, Opotowsky AR, Ojeda J, et al. Shape of the right ventricular Doppler envelope predicts hemodynamics and right heart function in pulmonary hypertension. Am J Respir Crit Care Med 2011;183:268–76.
13. Lankhaar J-W, Westerhof N, Faes TJC, et al. Pulmonary vascular resistance and compliance stay inversely related during treatment of pulmonary hypertension. Eur Heart J 2008;29:
8. Fine NM, Chen L, Bastiansen PM, et al. Outcome
14. Zhang M, Takimoto E, Lee D, et al. Patholog-
prediction
ical
by
quantitative
right
ventricular
16. Michelakis ED, McMurtry MS, Wu XC, et al. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 2002;105:244–50. 17. Greiner S, Jud A, Aurich M, et al. Reliability of noninvasive assessment of systolic pulmonary artery pressure by Doppler echocardiography compared to right heart catheterization: analysis in a large patient population. J Am Heart Assoc 2014;3:e001103. 18. Amsallem M, Sternbach JM, Adigopula S, et al. Addressing the controversy of estimating pulmonary arterial pressure by echocardiography. J Am Soc Echocardiogr 2016;29: 93–102. 19. Lau EMT, Humbert M, Celermajer DS. Early detection of pulmonary arterial hypertension. Nat Rev Cardiol 2015;12:143–55.
1688–95.
cardiac
hypertrophy
alters
intracellular
KEY WORDS flow, pulmonary hypertension, right ventricular function, survival
VOL. 10, NO. 10, 2017
ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcmg.2016.12.022
EDITORIAL COMMENT
Full Circle on Pulmonary Flow Dynamics in Pulmonary Arterial Hypertension* Francois Haddad, MD, Myriam Amsallem, MD
I
n this issue of iJACC, Takahama et al. (1) provide novel insights into pulmonary flow dynamics in
F I G U R E 1 M-Mode Characteristic Motion of Posterior Pulmonary
Leaflet in a Patient With Pulmonary Hypertension
patients with pulmonary arterial hypertension
(PAH). The study builds on landmark work in pulmonary valve motion and pulmonary flow in pulmonary
hypertension (PH). In 1974, Nanda et al. (2) were the first to observe that the pulmonary valve in patients with PH appeared straight in diastole with rapid opening slopes (>350 mm/s) and prolonged pre-ejection periods. Weyman et al. (3) further described the presence of mid-systolic fluttering, closure or notching of the pulmonary valve (Figure 1) in most patients with PAH (n ¼ 20) and in none of the controls. The changes in pulmonary valve SEE PAGE 1268
motion and pulmonary flow in PH can be explained by the complex interplay between forward and reflected pulmonary pressure waves (4,5). Under normal conditions, the reflected wave only accounts for a small component of the total pressure wave. In patients with PH, the reflected pressure wave becomes significant and adds to the forward wave, imposing an added pressure burden on a stillejecting right ventricle (RV). The resulting reduction
Trace shows the mid-systolic notching of the leaflet. c ¼ fully
in flow velocity during mid-ejection changes the
open position of the leaflet during ventricular ejection;
normal dome-like contour into a notched contour. Although the notched pattern of pulmonary flow
n ¼ mid-systolic closure or notching of the leaflet; d ¼ position of the valve at the onset of valve closure. Adapted with permission from Weyman et al. (3).
was initially believed to be characteristic of PAH, it has been also observed in patients with chronic thromboembolic disease, and is a strong prognostic factor (6). The pulmonary notch has also been shown to be strongly suggestive of elevated pulmonary
vascular resistance in patients with predominantly “left heart failure” (7). The study by Takahama et al. (1) builds on those studies and offers a comprehensive analysis of the
*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the Division of Cardiovascular Medicine, Stanford School of Medicine, Stanford University, Stanford, California. Both authors have
pulmonary
flow
signal.
Perhaps
the
most
important finding is that pulmonary flow patterns reflect not only pulmonary impedance (“resistance” to flow) but also right ventricular adaptation to the increased load. The authors analyzed several pa-
reported that they have no relationships relevant to the contents of
rameters of pulmonary flow, including deceleration
this paper to disclose.
time
of
mid-systolic
deceleration
slope,
peak
Haddad and Amsallem
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 10, 2017 OCTOBER 2017:1278–80
Editorial Comment
F I G U R E 2 Prognostic Network of Correlates of Long-Term Outcomes in PAH
6MWTD ¼ 6 minute walk test distance; CI ¼ cardiac index; CTD ¼ connective tissue disease; DLCO ¼ diffusing capacity of the lung for carbon monoxide; HIV ¼ human immunodeficiency virus; NT-proBNP ¼ N-terminal type B natriuretic peptide; NYHA ¼ New York Heart Association; PAC ¼ pulmonary arterial capacitance; Peff ¼ pericardial; PVR ¼ pulmonary vascular resistance; RA ¼ right atrium; RAP ¼ right atrial pressure; RVESV ¼ right ventricular end-systolic volume; sBP ¼ systolic blood pressure; TAPSE ¼ tricuspid annular plane systolic excursion.
pre- (Vpre) and post-notching (Vpost) flow velocities,
along with New York Heart Association functional
and the V post /Vpre ratio. These parameters allowed
class and N-terminal pro-B type natriuretic peptide
characterization of 4 patterns of pulmonary flow
concentration
(i.e., non-notched, long deceleration time profile,
outcome in PH. Third, with the predictive value of
high notch velocity, and low notch velocity). These
large clinical scores such as those from the REVEAL
patterns were associated with transplantation-free
registry score, which has a C statistic of 0.77, the
were
the
strongest
predictors
of
survival in PAH patients, with the lower notch velocity profile having the worst survival. The authors further explain the pulmonary flow patterns according to forward and reflected pulmonary flow dynamics. Although the study has very strong merits from
T A B L E 1 Established or Potential Prognostic Markers in PAH
Predictive Markers
Demographics
Comments
Age and sex (need to be considered in response studies)
Vasoreactivity
Associated with response to calcium channel blockers
a physiological perspective, we are not convinced
Etiology
Scleroderma associated PAH
that the pulmonary notch profile will lead to signifi-
Severity markers
Patients with intermediate elevation of pulmonary impedance may show a greater improvement in response to therapy patients with greater likelihood to change pulmonary compliance (13).
“Omics”
Will likely play an emerging role in the future (e.g., oxidative stress markers and phosphodiesterase inhibitors response, still pending clinical validation) (14). Other markers are being studied.
Molecular imaging
Presence of altered metabolism (e.g., glycolytic metabolism) may be used for targeted therapy monitoring or response.
Fibrosis imaging
May be key, if validated, in deciding who would benefit from heart-lung versus double-lung transplantation.
cant reclassification of outcome in PAH. First, the findings are based on a derivation cohort, and further validation studies are needed for outcome prediction. Second, although pulmonary flow patterns appeared more predictive than tricuspid annular plane systolic excursion, a direct comparison with RV longitudinal strain, one of the emerging prognostic markers in PH, is needed. In fact, in a large study from Fine et al. (8), also from the Mayo Clinic, RV longitudinal strain
1279
1280
Haddad and Amsallem
JACC: CARDIOVASCULAR IMAGING, VOL. 10, NO. 10, 2017 OCTOBER 2017:1278–80
Editorial Comment
incremental value of any new molecular or imaging
for early diagnosis of PH in the community remains
biomarker will likely require a large sample size to
an unmet need in the field. This is even more relevant
demonstrate and at most lead to a small proportion of
as B-type natriuretic peptide is not a sensitive marker
reclassification of outcome (8–12). Fourth, different
for early PH. In this regard, pulmonary flow profiles
scores are likely to emerge with comparable risk
(acceleration time, notching) are useful signs that
stratification characteristics, and perhaps the greatest
may suggest PH, especially when the estimation of
value of a new score or metric would be simplification
pulmonary pressure is not reliable (17–19).
of current scores, which may improve clinical care as
In conclusion, the study by Takahama et al. (1)
well as stratified randomization in clinical trials.
adds novel physiological perspectives to pulmonary
Figure 2 summarizes some of the prognostic metrics
flow that highlight the pioneering work of Drs. Nanda
that have emerged more consistently in PH (8–12). The field of PH is ready to move from prognostic
and Weyman in the field of detection of PH, thus completing a full circle of pulmonary flow dynamics
scores to predictive markers of therapeutic response;
in PH research.
in addition, biomarkers may be very useful to guide
ACKNOWLEDGMENTS The
targeted therapies in PH such as mitochondrial mod-
Stanford Cardiovascular Institute, the Vera Moulton
ulation
Wall Center of Pulmonary Hypertension at Stan-
and
neurohormonal,
immune,
or
other
pathway-specific therapy. Table 1 summarizes some of the routine or emerging markers that will likely
authors
thank
the
ford, and the Pai Chan Lee Research Fund for their support.
prove to be useful in this era of biomarker-guided management (13–15). Recent examples include the use of molecular imaging as designed in the recent
ADDRESS FOR CORRESPONDENCE:
trial of dichloroacetate therapy led by Michelakis
Haddad, Division of Cardiovascular Medicine, Stan-
et al. (16) (NCT01083524).
ford School of Medicine, Stanford University, 300
In addition to outcome and predictive markers, identification of reliable and cost-effective markers
Dr. Francois
Pasteur Drive, Stanford, California 94305. E-mail: [email protected].
REFERENCES 1. Takahama H, McCully RB, Frantz RP, Kane GC. Unraveling the RV ejection Doppler envelope: insight into pulmonary artery hemodynamics and disease severity. J Am Coll Cardiol Img 2017;10: 1268–77. 2. Nanda NC, Gramiak R, Robinson TI, et al. Echocardiographic evaluation of pulmonary hypertension. Circulation 1974;50:575–81. 3. Weyman AE, Dillon JC, Feigenbaum H, et al. Echocardiographic patterns of pulmonic valve motion with pulmonary hypertension. Circulation 1974;50:905–10. 4. Parker KH, Jones CJ. Forward and backward running waves in the arteries: analysis using the method of characteristics. J Biomech Eng 1990; 112:322–6. 5. Chemla D, Castelain V, Simonneau G, et al. Pulse wave reflection in pulmonary hypertension. J Am Coll Cardiol 2002;39:743–4. 6. Castelain V, Hervé P, Lecarpentier Y, et al. Pulmonary artery pulse pressure and wave reflection in chronic pulmonary thromboembolism and primary pulmonary hypertension. J Am Coll Cardiol 2001;37:1085–92.
function assessment in 575 subjects evaluated for pulmonary hypertension. Circ Cardiovasc Imaging 2013;6:711–21.
targeting of phosphodiesterase type 5 from nitric oxide synthase-3 to natriuretic peptide signaling. Circulation 2012;126:942–51.
9. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial
15. Nasir K. Cardiovascular imaging research: time to think beyond risk prediction? J Am Coll Cardiol Img 2015;8:957–9.
Hypertension Disease Management (REVEAL). Circulation 2010;122:164–72. 10. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122:156–63. 11. Thenappan T, Shah SJ, Rich S, et al. Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation. Eur Respir J 2010;35:1079–87. 12. Haddad F, Spruijt OA, Denault AY, et al. Right heart score for predicting outcome in idiopathic, familial, or drug- and toxin-associated pulmonary arterial hypertension. J Am Coll Cardiol Img 2015; 8:627–38.
7. Arkles JS, Opotowsky AR, Ojeda J, et al. Shape of the right ventricular Doppler envelope predicts hemodynamics and right heart function in pulmonary hypertension. Am J Respir Crit Care Med 2011;183:268–76.
13. Lankhaar J-W, Westerhof N, Faes TJC, et al. Pulmonary vascular resistance and compliance stay inversely related during treatment of pulmonary hypertension. Eur Heart J 2008;29:
8. Fine NM, Chen L, Bastiansen PM, et al. Outcome
14. Zhang M, Takimoto E, Lee D, et al. Patholog-
prediction
ical
by
quantitative
right
ventricular
16. Michelakis ED, McMurtry MS, Wu XC, et al. Dichloroacetate, a metabolic modulator, prevents and reverses chronic hypoxic pulmonary hypertension in rats: role of increased expression and activity of voltage-gated potassium channels. Circulation 2002;105:244–50. 17. Greiner S, Jud A, Aurich M, et al. Reliability of noninvasive assessment of systolic pulmonary artery pressure by Doppler echocardiography compared to right heart catheterization: analysis in a large patient population. J Am Heart Assoc 2014;3:e001103. 18. Amsallem M, Sternbach JM, Adigopula S, et al. Addressing the controversy of estimating pulmonary arterial pressure by echocardiography. J Am Soc Echocardiogr 2016;29: 93–102. 19. Lau EMT, Humbert M, Celermajer DS. Early detection of pulmonary arterial hypertension. Nat Rev Cardiol 2015;12:143–55.
1688–95.
cardiac
hypertrophy
alters
intracellular
KEY WORDS flow, pulmonary hypertension, right ventricular function, survival