http://www.jhltonline.org
EDITORIAL COMMENTARIES
Measuring vasoreactivity in pulmonary hypertension: A simple test, but do we understand it? Irene M. Lang, MD From the Department of Internal Medicine II, Division of Cardiology, Vienna General Hospital, Medical University of Vienna, Austria.
Pulmonary vascular disease occurs in various clinical conditions, with idiopathic pulmonary arterial hypertension (PAH) being the disease prototype. Endothelial dysfunction, vasoconstriction, smooth muscle hypertrophy, intimal proliferation, uncontrolled cell proliferation, and in situ thrombosis are pathophysiologic characteristics of PAH.1 PAH represents a condition of severe occlusive vascular remodeling, with an uncertain component of vasoreactivity that has been speculated to be due to “spared territories” of the vasculature or due to “islets of less affected” vessels. At the present time, pulmonary vasoreactivity testing is recommended only for patients with idiopathic PAH or druginduced and toxin-induced PAH to identify patients who may be treated with high doses of calcium channel blockers,2,3 leading to potentially excellent survival4 at a low cost. Inhaled nitric oxide (iNO) at 10 to 20 ppm is the “gold standard” for pulmonary vasoreactivity testing5; intravenous epoprostenol (2–12 ng/kg/min), intravenous adenosine (50– 350 μg/min), and inhaled iloprost (5 μg) can be used as alternatives.4,6 However, unless rigorous criteria for the definition of a pulmonary vasoreactivity response (VR) are used7 (i.e., a decrease in mean pulmonary artery pressure [mPAP] of Z10 mm Hg to reach an absolute mPAP of o40 mm Hg), survival is poor. With iNO, resistance in small arteries and veins is decreased, with no effect on larger capacitance vessels,8 suggesting that iNO acts predominantly on arterioles and/or venules with a diameter o100 to 200 μm that are at a short distance from alveoli. Halliday et al9 found a 13% classic acute VR in idiopathic PAH and PAH secondary to connective tissue disease. These data are largely confirmatory. It was previously demonstrated that only a few adult patients are hemodynamic responders: 13.4% of anorectic patients with PAH, 12.2% of patients with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis, 10.1% of patients with PAH secondary to
See Related Article, page 312 connective tissue disease, 1.6% of patients with PAH secondary to human immunodeficiency virus, 1.3% of patients with portopulmonary hypertension,7 and 12.6% in patients with idiopathic PAH,5 with 5.2%9 and 7%5 long-term responders. In addition, the article by Halliday et al9 illustrates that a significant but non-classic VR is not associated with improved survival, and a classic VR conveys improved outcomes only in idiopathic PAH. Magnitude of response and underlying disease subset appear to determine outcomes, rather than patient age and disease stage. Recently, it was observed that acute vasodilator responsiveness is associated with significant microvascular recruitment which speaks against obstructive vascular remodeling and in favor of functional vasoconstriction as underlying mechanisms of vasoresponsive PAH.10 These observations and the fact that patients with PAH and a BMPR2 gene mutation typically do not demonstrate VR, despite earlier diagnosis,11 suggest that idiopathic PAH with VR and a long-term calcium channel blocker response is caused by a molecularly distinct mechanism. The regulation of pulmonary vascular tone is functionally determined largely by the operation and interaction of potassium and calcium channels and equilibrium of their internal store and sensitivity. An increase in cytosolic calcium ion concentration resulting from Ca2þ release from intracellular organelles or entry from the extracellular space mediated by voltage-gated Ca2þ channels, receptor-operated Ca2þ entry channels, and store-operated Ca2þ channels12 is required for pulmonary vasoconstriction. Cytosolic calcium also plays a role in cell proliferation and vascular remodeling.12 Potassium channel function also influences resting membrane potential in smooth muscle cells. A mutation in the potassium channel gene KCNK3 was found in and is
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.12.002
Lang
Vasoreactivity and Pulmonary Hypertension
presumably responsible for 1% to 2% of PAH cases.13 Similar to BMPR2, this mutation has incomplete penetrance, and none of the patients with the KCNK3 mutation responded to vasodilator challenge. Although ion channels play a critical role in regulating vascular tone, their direct mutation is not a common cause of PAH, presumably because of redundancy. Other, more recent genetic discoveries, such as EIF2AK4 responsible for pulmonary veno-occlusive disease, another recessive form of pulmonary hypertension,14 and SMAD proteins or cerebellin 2,15 have not yet provided more insights in the conundrum linking VR with gene expression. An even more complex picture comes from the observation of Skoro-Sajer et al16 demonstrating acute VR of some degree in 80 of 103 patients (77.7%) with chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH represents a subset of pre-capillary pulmonary hypertension in which misguided thrombosis and thrombus resolution are key for the generation of vascular lesions, occurring in the major pulmonary arterial bed and in the small pulmonary vessels.17 Small vessel disease, or “secondary vascular disease” of CTEPH, is present in an uncertain proportion of patients, is histologically indistinguishable from PAH,18 and presumably is responsible for a poor response to pulmonary endarterectomy (PEA).17 CTEPH has not been linked to ion channels and does not appear to exist in a heritable form. A 410.4% decrease in mPAP under iNO was a predictor of long-term survival/freedom of lung transplantation in adult patients with CTEPH undergoing PEA. This finding contradicts the report of Halliday et al, who found no significant response (change in mPAP Z 10 mm Hg) to nitric oxide administration in any patient with CTEPH using a similar iNO application system as in the study by Skoro-Sajer et al,16 albeit in a small group of 11 patients of whom only 7 underwent surgery. Consensus exists on the non-VR status of non-operable CTEPH.16,19 However, because CTEPH small vessel disease is variable before PEA and is sometimes successfully treated with PEA, VR in CTEPH may be based on different mechanisms than in idiopathic PAH. For a full understanding, one needs to define “secondary vascular disease” in CTEPH and how that relates to vascular territories distal to complete or incomplete obstructions and to hypoxic vasoconstriction. The combination of nitric oxide with oxygen presumably triggers another kind of VR in CTEPH. At the present time, vasoreactivity testing remains a simple clinical tool that provides more information than we are currently able to understand in detail. Despite all controversies, one may conclude that in any instance where VR is demonstrable and sustained, expensive medications or surgical therapy can be avoided with excellent prognosis.
Disclosure statement I.M.L. has relationships with drug companies including AOP Orphan Pharmaceuticals, Actelion, Bayer Schering Pharma, AstraZeneca, Servier, Cordis Corporation, Medtronic, GlaxoSmithKline, Novartis, Pfizer, and United Therapeutics. In addition to being an investigator in trials involving these companies,
307 relationships include consultancy service, research grants, and membership on scientific advisory boards. This study was supported by FWF F 54 (Austrian Science Fund project F 54).
References 1. Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014;115:165-75. 2. Chaumais MC, Macari EA, Sitbon O. Calcium-channel blockers in pulmonary arterial hypertension. Handb Exp Pharmacol 2013;218: 161-75. 3. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-537. 4. Rich S, Kaufmann E, Levy PS. The effect of high doses of calciumchannel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76-81. 5. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105-11. 6. Jing ZC, Jiang X, Han ZY, et al. Iloprost for pulmonary vasodilator testing in idiopathic pulmonary arterial hypertension. Eur Respir J 2009;33:1354-60. 7. Montani D, Savale L, Natali D, et al. Long-term response to calciumchannel blockers in non-idiopathic pulmonary arterial hypertension. Eur Heart J 2010;31:1898-907. 8. Roos CM, Rich GF, Uncles DR, Daugherty MO, Frank DU. Sites of vasodilation by inhaled nitric oxide vs. sodium nitroprusside in endothelin-constricted isolated rat lungs. J Appl Physiol 1994;77: 51-7. 9. Halliday SJ, Hemnes AR, Robbins IM, et al. Prognostic value of acute vasodilator response in pulmonary arterial hypertension: beyond the ‘classic’ responders. J Heart Lung Transplant 2015;34:312–18. 10. Langleben D, et al. Acute vasodilator responsiveness and microvascular recruitment in idiopathic pulmonary arterial hypertension. Ann Intern Med 2015;162:154-6. 11. Elliott CG, Glissmeyer EW, Havlena GT, et al. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation 2006;113:2509-15. 12. Kuhr FK, Smith KA, Song MY, Levitan I, Yuan JX. New mechanisms of pulmonary arterial hypertension: role of Ca(2)(þ) signaling. Am J Physiol Heart Circ Physiol 2012;302:H1546-62. 13. Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013;369:351-61. 14. Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet 2014;46:65-9. 15. Ma L, Chung WK. The genetic basis of pulmonary arterial hypertension. Hum Genet 2014;133:471-9. 16. Skoro-Sajer N, Hack N, Sadushi-Kolici R, et al. Pulmonary vascular reactivity and prognosis in patients with chronic thromboembolic pulmonary hypertension: a pilot study. Circulation 2009;119: 298-305. 17. Lang IM, Madani M. Update on chronic thromboembolic pulmonary hypertension. Circulation 2014;130:508-18. 18. Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993;103:685-92. 19. Suntharalingam J, Hughes RJ, Goldsmith K, et al. Acute haemodynamic responses to inhaled nitric oxide and intravenous sildenafil in distal chronic thromboembolic pulmonary hypertension (CTEPH). Vascul Pharmacol 2007;46:449-55.
EDITORIAL COMMENTARIES
Measuring vasoreactivity in pulmonary hypertension: A simple test, but do we understand it? Irene M. Lang, MD From the Department of Internal Medicine II, Division of Cardiology, Vienna General Hospital, Medical University of Vienna, Austria.
Pulmonary vascular disease occurs in various clinical conditions, with idiopathic pulmonary arterial hypertension (PAH) being the disease prototype. Endothelial dysfunction, vasoconstriction, smooth muscle hypertrophy, intimal proliferation, uncontrolled cell proliferation, and in situ thrombosis are pathophysiologic characteristics of PAH.1 PAH represents a condition of severe occlusive vascular remodeling, with an uncertain component of vasoreactivity that has been speculated to be due to “spared territories” of the vasculature or due to “islets of less affected” vessels. At the present time, pulmonary vasoreactivity testing is recommended only for patients with idiopathic PAH or druginduced and toxin-induced PAH to identify patients who may be treated with high doses of calcium channel blockers,2,3 leading to potentially excellent survival4 at a low cost. Inhaled nitric oxide (iNO) at 10 to 20 ppm is the “gold standard” for pulmonary vasoreactivity testing5; intravenous epoprostenol (2–12 ng/kg/min), intravenous adenosine (50– 350 μg/min), and inhaled iloprost (5 μg) can be used as alternatives.4,6 However, unless rigorous criteria for the definition of a pulmonary vasoreactivity response (VR) are used7 (i.e., a decrease in mean pulmonary artery pressure [mPAP] of Z10 mm Hg to reach an absolute mPAP of o40 mm Hg), survival is poor. With iNO, resistance in small arteries and veins is decreased, with no effect on larger capacitance vessels,8 suggesting that iNO acts predominantly on arterioles and/or venules with a diameter o100 to 200 μm that are at a short distance from alveoli. Halliday et al9 found a 13% classic acute VR in idiopathic PAH and PAH secondary to connective tissue disease. These data are largely confirmatory. It was previously demonstrated that only a few adult patients are hemodynamic responders: 13.4% of anorectic patients with PAH, 12.2% of patients with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis, 10.1% of patients with PAH secondary to
See Related Article, page 312 connective tissue disease, 1.6% of patients with PAH secondary to human immunodeficiency virus, 1.3% of patients with portopulmonary hypertension,7 and 12.6% in patients with idiopathic PAH,5 with 5.2%9 and 7%5 long-term responders. In addition, the article by Halliday et al9 illustrates that a significant but non-classic VR is not associated with improved survival, and a classic VR conveys improved outcomes only in idiopathic PAH. Magnitude of response and underlying disease subset appear to determine outcomes, rather than patient age and disease stage. Recently, it was observed that acute vasodilator responsiveness is associated with significant microvascular recruitment which speaks against obstructive vascular remodeling and in favor of functional vasoconstriction as underlying mechanisms of vasoresponsive PAH.10 These observations and the fact that patients with PAH and a BMPR2 gene mutation typically do not demonstrate VR, despite earlier diagnosis,11 suggest that idiopathic PAH with VR and a long-term calcium channel blocker response is caused by a molecularly distinct mechanism. The regulation of pulmonary vascular tone is functionally determined largely by the operation and interaction of potassium and calcium channels and equilibrium of their internal store and sensitivity. An increase in cytosolic calcium ion concentration resulting from Ca2þ release from intracellular organelles or entry from the extracellular space mediated by voltage-gated Ca2þ channels, receptor-operated Ca2þ entry channels, and store-operated Ca2þ channels12 is required for pulmonary vasoconstriction. Cytosolic calcium also plays a role in cell proliferation and vascular remodeling.12 Potassium channel function also influences resting membrane potential in smooth muscle cells. A mutation in the potassium channel gene KCNK3 was found in and is
1053-2498/$ - see front matter r 2015 International Society for Heart and Lung Transplantation. All rights reserved. http://dx.doi.org/10.1016/j.healun.2014.12.002
Lang
Vasoreactivity and Pulmonary Hypertension
presumably responsible for 1% to 2% of PAH cases.13 Similar to BMPR2, this mutation has incomplete penetrance, and none of the patients with the KCNK3 mutation responded to vasodilator challenge. Although ion channels play a critical role in regulating vascular tone, their direct mutation is not a common cause of PAH, presumably because of redundancy. Other, more recent genetic discoveries, such as EIF2AK4 responsible for pulmonary veno-occlusive disease, another recessive form of pulmonary hypertension,14 and SMAD proteins or cerebellin 2,15 have not yet provided more insights in the conundrum linking VR with gene expression. An even more complex picture comes from the observation of Skoro-Sajer et al16 demonstrating acute VR of some degree in 80 of 103 patients (77.7%) with chronic thromboembolic pulmonary hypertension (CTEPH). CTEPH represents a subset of pre-capillary pulmonary hypertension in which misguided thrombosis and thrombus resolution are key for the generation of vascular lesions, occurring in the major pulmonary arterial bed and in the small pulmonary vessels.17 Small vessel disease, or “secondary vascular disease” of CTEPH, is present in an uncertain proportion of patients, is histologically indistinguishable from PAH,18 and presumably is responsible for a poor response to pulmonary endarterectomy (PEA).17 CTEPH has not been linked to ion channels and does not appear to exist in a heritable form. A 410.4% decrease in mPAP under iNO was a predictor of long-term survival/freedom of lung transplantation in adult patients with CTEPH undergoing PEA. This finding contradicts the report of Halliday et al, who found no significant response (change in mPAP Z 10 mm Hg) to nitric oxide administration in any patient with CTEPH using a similar iNO application system as in the study by Skoro-Sajer et al,16 albeit in a small group of 11 patients of whom only 7 underwent surgery. Consensus exists on the non-VR status of non-operable CTEPH.16,19 However, because CTEPH small vessel disease is variable before PEA and is sometimes successfully treated with PEA, VR in CTEPH may be based on different mechanisms than in idiopathic PAH. For a full understanding, one needs to define “secondary vascular disease” in CTEPH and how that relates to vascular territories distal to complete or incomplete obstructions and to hypoxic vasoconstriction. The combination of nitric oxide with oxygen presumably triggers another kind of VR in CTEPH. At the present time, vasoreactivity testing remains a simple clinical tool that provides more information than we are currently able to understand in detail. Despite all controversies, one may conclude that in any instance where VR is demonstrable and sustained, expensive medications or surgical therapy can be avoided with excellent prognosis.
Disclosure statement I.M.L. has relationships with drug companies including AOP Orphan Pharmaceuticals, Actelion, Bayer Schering Pharma, AstraZeneca, Servier, Cordis Corporation, Medtronic, GlaxoSmithKline, Novartis, Pfizer, and United Therapeutics. In addition to being an investigator in trials involving these companies,
307 relationships include consultancy service, research grants, and membership on scientific advisory boards. This study was supported by FWF F 54 (Austrian Science Fund project F 54).
References 1. Rabinovitch M, Guignabert C, Humbert M, Nicolls MR. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014;115:165-75. 2. Chaumais MC, Macari EA, Sitbon O. Calcium-channel blockers in pulmonary arterial hypertension. Handb Exp Pharmacol 2013;218: 161-75. 3. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493-537. 4. Rich S, Kaufmann E, Levy PS. The effect of high doses of calciumchannel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992;327:76-81. 5. Sitbon O, Humbert M, Jais X, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105-11. 6. Jing ZC, Jiang X, Han ZY, et al. Iloprost for pulmonary vasodilator testing in idiopathic pulmonary arterial hypertension. Eur Respir J 2009;33:1354-60. 7. Montani D, Savale L, Natali D, et al. Long-term response to calciumchannel blockers in non-idiopathic pulmonary arterial hypertension. Eur Heart J 2010;31:1898-907. 8. Roos CM, Rich GF, Uncles DR, Daugherty MO, Frank DU. Sites of vasodilation by inhaled nitric oxide vs. sodium nitroprusside in endothelin-constricted isolated rat lungs. J Appl Physiol 1994;77: 51-7. 9. Halliday SJ, Hemnes AR, Robbins IM, et al. Prognostic value of acute vasodilator response in pulmonary arterial hypertension: beyond the ‘classic’ responders. J Heart Lung Transplant 2015;34:312–18. 10. Langleben D, et al. Acute vasodilator responsiveness and microvascular recruitment in idiopathic pulmonary arterial hypertension. Ann Intern Med 2015;162:154-6. 11. Elliott CG, Glissmeyer EW, Havlena GT, et al. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation 2006;113:2509-15. 12. Kuhr FK, Smith KA, Song MY, Levitan I, Yuan JX. New mechanisms of pulmonary arterial hypertension: role of Ca(2)(þ) signaling. Am J Physiol Heart Circ Physiol 2012;302:H1546-62. 13. Ma L, Roman-Campos D, Austin ED, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013;369:351-61. 14. Eyries M, Montani D, Girerd B, et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat Genet 2014;46:65-9. 15. Ma L, Chung WK. The genetic basis of pulmonary arterial hypertension. Hum Genet 2014;133:471-9. 16. Skoro-Sajer N, Hack N, Sadushi-Kolici R, et al. Pulmonary vascular reactivity and prognosis in patients with chronic thromboembolic pulmonary hypertension: a pilot study. Circulation 2009;119: 298-305. 17. Lang IM, Madani M. Update on chronic thromboembolic pulmonary hypertension. Circulation 2014;130:508-18. 18. Moser KM, Bloor CM. Pulmonary vascular lesions occurring in patients with chronic major vessel thromboembolic pulmonary hypertension. Chest 1993;103:685-92. 19. Suntharalingam J, Hughes RJ, Goldsmith K, et al. Acute haemodynamic responses to inhaled nitric oxide and intravenous sildenafil in distal chronic thromboembolic pulmonary hypertension (CTEPH). Vascul Pharmacol 2007;46:449-55.
