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Diagnosis & Treatment

WHO Group 2: PH due to Left Heart Disease

Overview | Definition | Pathophysiology | Diagnostic Evaluation | Treatment

WHO Group 2 Pulmonary Hypertension: PH due to Left

Overview

Pulmonary hypertension (PH) frequently complicates left sided heart disease which includes myocardial dysfunction, both preserved and reduced ejection fraction, and valvular heart disease. In many patients, PH will improve or resolve with diuresis, but in other patients the PH does not resolve (i.e. out-of-proportion or mixed PH). PH in the setting of left heart disease is associated with greater risk of morbidity and mortality. Furthermore, there is no consensus on treating WHO Group 2 PH with vasodilator therapies but it remains an area of interest and investigation.

Definition

WHO Group 2 pulmonary hypertension is defined as:

  • Mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg
  • Left ventricular (LV) filling pressure ≥ 15 mmHg (measured by the pulmonary artery occlusion pressure or left ventricular end-diastolic pressure)1

Other hemodynamic variables have been used to characterize PH with left heart disease.

  • A transpulmonary gradient (TPG) >12 mm Hg or pulmonary vascular resistance >3 Wood units have previously been used to differentiate between PH due to volume overload versus PH due to remodeled pulmonary vasculature.
  • More recently, the diastolic pressure gradient (DPG) has been used to further characterize PH in left heart disease, but conflicting data on the predictive value of the diastolic pressure gradient with regard to mortality has highlighted the limitations on depending solely on single hemodynamic values in PH with left heart disease.2-4

Terminology such as passive versus reactive or proportion versus disproportionate PH are often misleading and do not fully reflect the pathology of PH. Recently adopted terminology recognizes that while most types of Group 2 PH is due to volume overload or valvular heart disease and will resolve with correction of the left heart disease (post-capillary PH), other patients will have persistent PH with a wide transpulmonary gradient (TPG) or persistently elevated pulmonary vascular resistance (PVR) despite effective treatment of the left heart disease through diuresis or correction of the valvular abnormality (pre-capillary PH).1 

For example, a patient who presents with congestive heart failure who has persistent PH despite normalization of the LV filling pressure or a patient with a pulmonary capillary wedge pressure of 18 mm Hg, TPG of 20 mm Hg, and PVR 4 Wood units could both be described as having pre- and post-capillary PH. On the other hand, a patient who presented with mean PA pressure of 30 mm Hg and PCW pressure of 24 mm Hg and after diuresis has a mean PA pressure of 18 mm Hg and PCW pressure 10 mm Hg would be consistent with post-capillary PH.

Pathophysiology

In most cases of PH associated with left heart disease, passive pulmonary artery pressure elevation occurs as a consequence of maintaining forward circulation into left atrial and ventricular changes with elevated pressures. In these cases, diuresis restores normal left ventricular filling pressures and the pulmonary artery pressures normalize. However, in other cases, decrease in LV filling pressures does not always restore normal pulmonary artery pressures. In these cases, ‘out-of-proportion’ or a mixed etiology of PH is apparent. 

The exact mechanisms underlying this phenomenon are not fully understood but are felt to occur from barotrauma related to increased pressures or pulmonary edema itself results in localized injury. 

Metalloproteinase activation may cause when compromised microvascular function results in edema and result in tissue changes in the extracellular matrix. Angiotensin II and endothelin activation mediate not only vasoconstriction but also fibroblast proliferation resulting in more permanent vascular remodeling changes.9

Diagnostic Evaluation

The general goals of evaluating WHO Group 2 pulmonary hypertension are to discriminate left heart failure from pulmonary vascular disease, assess for underlying myocardial or valvular abnormalities which can be treated, and to ascertain whether the PH is entirely ‘passive’ or mixed with evidence of abnormal pulmonary vascular function. A comprehensive assessment of a patient suspected to have WHO Group 2 PH should include consideration of various imaging, stress, and hemodynamic tests.

Echocardiogram

In addition to estimating the pulmonary pressures, the echocardiogram assess myocardial function as well as valve function. With regard to myocardial function, the LV diastolic function is often overlooked in favor of the ejection fraction measure of systolic function. However, as diastolic HF is a frequent cause of Group 2 PH it is vital to characterize the diastolic properties of the LV based on mitral valve inflow pattern and tissue Doppler of the mitral annular velocity10. Although early diastolic dysfunction can be apparent with the early and late mitral inflow velocities are reversed, a pseudonormal pattern can occur when the left atrial pressures are increased, for example when there is concomitant mitral valve disease or in a volume overloaded state. A Valsalva maneuver can transiently increase the LV filling pressure which unmasks the reversed mitral inflow pattern. Volume status can be estimated based on the ratio of the mitral inflow E velocity and the mitral annular e’ velocity as well as the diameter and respiratory pattern of the inferior vena cava[11].

Right heart catheterization

The RHC is the gold standard for diagnosing PH and discriminating pre-capillary PH due to pulmonary vascular diseases (PAH and CTEPH) from left sided heart failure. Various provocative maneuvers can be done in addition to simply measuring the pulmonary pressures and cardiac output to either assess response to vasodilators or increase disease detection sensitivity. PH associated with systolic heart failure is associated with increased morbidity and mortality as well as a barrier to cardiac transplant in end-stage heart failure patients unless the PH is reversible. Patients with systolic HF who have a demonstrated vasodilator response with prostaglandin E1 or milrinone have been able to be bridged to cardiac transplantation. Some patients with normal or near normal hemodynamics may have masked hemodynamic abnormalities. Fluid challenge with a 500cc to 1000cc fluid bolus has been demonstrated to be well tolerated and can identify patients with impaired LV filling.8, 12  A more recent approach to provocative testing is use of exercise testing. Supine bicycle ergometry enables rigorous exercise with scheduled increases in workload to systematically assess the changes in pulmonary and LV filling pressures while also assessing for adequate increase in cardiac output. There is data that using this techniques allows clinicians to detect pulmonary hypertension at earlier disease stage and discriminate LV disease from pulmonary vascular disease.

Co-morbidities

It is reasonable to assume that PH secondary to left heart disease can be associated with co-morbid conditions. These may contribute to myocardial dysfunction (e.g. ischemic heart disease, hypertension) or pulmonary diseases (e.g. obstructive lung disease, sleep apnea). Other co-morbidities may be risk factors leading to left heart disease (e.g. diabetes mellitus) or co-morbid states which may increase the risk of heart failure symptoms or increase the risk of overall mortality, such as chronic kidney disease.

Thus, a comprehensive evaluation of WHO Group 2 pulmonary hypertension should consider these possibilities, and the management of a patient with WHO Group 2 pulmonary hypertension should also factor in any existing co-morbid conditions.

Treatment

Initial treatment of WHO Group 2 PH must first address the underlying myocardial or valve disease. Risk factor modification is crucial to improving long-term outcomes and reduction of morbidity. For example, blood pressures management, treatment of sleep apnea, weight reduction, managing valvular heart disease, and treatment of coronary artery disease according to ACC/AHA guidelines should occur before considering treating the PH. In patients where volume overload is evident on clinical exam or by hemodynamic data, diuretic therapy should be introduced or adjusted to improve volume status. In the majority of cases, the PH will resolve or significantly improve along with symptoms once the patient’s volume status has been corrected. For patients with valvular heart disease, PH can increase the morbidity of the valve disease but initiating pulmonary vasodilator therapy before the valve disease is treated also increases the risk of adverse drug effects and exacerbation of left heart failure symptoms.

  • Systolic heart failure should be treated according to ACC/AHA guidelines with neurohormonal blockade (beta-blockers, ACE inhibitors, angiotensin receptor blockers, and aldosterone antagonists).13 Sacubitril, a neprilysin inhibitor demonstrated to reduce the risk of heart failure related death or hospitalization when used in combination with an angiotensin receptor blocker, promises to add a novel first-in-class therapy to systolic heart failure but has yet to receive FDA approval.14 Therapy for diastolic heart failure can be more complicated. Aside from diuretic therapy, treatment is focused on modifying risk factors such as hypertension. Although no medications have proven to lower mortality in HFpEF, spironolactone15, 16 and angiotensin receptor blockers17 may improve morbidity.
  • The use of pulmonary vasodilators in WHO Group 2 PH remains controversial. Studies of the effects of sildenafil in smaller patient cohorts with WHO Group 2 PH have demonstrated the potential to improve hemodynamics and exercise capacity.18-20 In one particular long term study of patients with WHO Group 2 PH exhibiting evidence of ‘out-of-proportion’ PH, treatment with sildenafil was associated with improved hemodynamics as well as heart failure related symptoms.19 Furthermore, treatment over a 1-year period appeared safe with stable PCW pressure. On the other hand, the larger RELAX study did not detect a significant benefit of sildenafil in an HFpEF cohort which did not specify evidence of ‘out-of-proportion’ PH.21 
  • In systolic heart failure, secondary PH has been demonstrated to increase the risk of orthotopic heart transplant particularly in the immediate post-operative period.22 However, a positive vasodilator response with prostaglandin23 or milrinone24 can identify patients whose PH is reversible and who may be able to be bridged to transplant using inotropes. In patients who have undergone left ventricular assist device support with persistent PH and an elevated PVR despite reduction in the LV filling pressures, sildenafil has demonstrated the ability to further lower the mean PA pressures and PVR.25
  • There is no evidence for other pulmonary vasodilators currently. Prior experience with endothelin receptor antagonists suggests they increase the risk of HF,26, 27 and data from the FIRST study using epoprostenol in systolic heart failure was associated with an increased mortality risk despite evidence that epoprostenol improved PVR, cardiac output, and the PCW pressure.28 It should be noted that in these studies, patients were not required to be diuresed to a euvolemic state prior to pulmonary vasodilator therapy being initiated. For example, in the FIRST study, baseline PCW pressures was approximately 24 mm Hg. Thus, current practice is to avoid the use of these two drug classes when the primary cause of PH is left sided heart disease.

 

Author

David Ishizawar, MD
UPMC Heart and Vascular Institute
April 30, 2015

 

References

1. Vachiéry J-L, Adir Y, Barbera JA, et al. Pulmonary hypertension due to left heart diseases. J AM Coll Cardiol. 2013;62(25_S): p. D100-D108. doi:10.1016/j.jacc.2013.10.033

2. Gerges C, Gerges M, Lang MB, et al. Diastolic pulmonary vascular pressure gradient: A predictor of prognosis in “out-of-proportion” pulmonary hypertension. Chest. 2013 Mar;143(3):759-66. PMID:23580984

3. Tampakakis E, Leary PJ, Selby VN, et al. The Diastolic Pulmonary Gradient Does Not Predict Survival in Patients With Pulmonary Hypertension Due to Left Heart Disease. JACC Heart Fail. 2015 Jan;3(1):9-16. doi:10.1016/j.jchf.2014.07.010

4. Chatterjee NA and Lewis GD. Characterization of Pulmonary Hypertension in Heart Failure Using the Diastolic Pressure Gradient: Limitations of a Solitary Measurement. JACC Heart Fail. 2015 Jan;3(1):17-21. doi:10.1016/j.jchf.2014.09.002.

5. Miller WL, Grill DE, Borlaug BA. Clinical features, hemodynamics, and outcomes of pulmonary hypertension due to chronic heart failure with reduced ejection fraction: pulmonary hypertension and heart failure. JACC Heart Fail. 2013 Aug;1(4):290-9. doi:10.1016/j.jchf.2013.05.001.

6. Lam CS, Roger VL, Rodeheffer RJ, et al. Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Community-Based Study. J Am Coll Cardiol. 2009 Mar 31;53(13):1119-26. doi:10.1016/j.jacc.2008.11.051.

7. Thenappan T, Shah SJ, Gomberg-Maitland M, et al. Clinical characteristics of pulmonary hypertension in patients with heart failure and preserved ejection fraction. Circ Heart Fail. 2011;4(3):257-65. doi:10.1161/CIRCHEARTFAILURE.110.958801.

8. Robbins IM, Newman JH, Johnson RF, et al. Association of the metabolic syndrome with pulmonary venous hypertension. Chest. 2009;136(1):31-6. doi:10.1378/chest.08-2008.

9. Guazzi M. Pulmonary Hypertension in Heart Failure Preserved Ejection Fraction: Prevalence, Pathophysiology, and Clinical Perspectives. Circ Heart Fail. 2014;7(2):367-77. doi:10.1161/CIRCHEARTFAILURE.113.000823.

10. Redfield MM, Jacobsen SJ, Burnett JC Jr, et al. Burden of systolic and diastolic ventricular dysfunction in the community. JAMA. 2003;289(2):194-202. PMID:12517230.

11. Nagueh SF, Middleton KJ, Kopelen HA, et al. Doppler Tissue Imaging: A Noninvasive Technique for Evaluation of Left Ventricular Relaxation and Estimation of Filling Pressures. J Am Coll Cardiol. 1997;30(6):1527-33. PMID:9362412

12. Fox BD, Shimony A, Langleben D, et al. High prevalence of occult left heart disease in scleroderma-pulmonary hypertension. Eur Respir J. 2013;42(4):1083-91. doi:10.1183/09031936.00091212.

13. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):e147-239. doi:10.101/j.jacc.2013.05.019.

14. McMurray JJ, Packer M, Desai AS, et al. Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure. N Engl J Med. 2014;371(11):993-1004. doi:10.1056/NEJMoa1409077.

15. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2014;370(15):1383-92. doi:10.1056/NEJMoa1313731.

16. Pfeffer MA, Claggett B, Assmann SF, et al. Regional Variation in Patients and Outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) Trial. Circulation. 2015;131(1):34-42. doi:10.1161/CIRCULATIONAHA.114.013255.

17. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362(9386):777-81. PMID: 13678871.

18. Guazzi M, Samaja M, Arena R, et al. Long-Term Use of Sildenafil in the Therapeutic Management of Heart Failure. J Am Coll Cardiol. 2007;50(22):2136-44. PMID:18036451.

19. Guazzi M, Vicenzi M, Arena R, et al. Pulmonary Hypertension in Heart Failure With Preserved Ejection Fraction: A Target of Phosphodiesterase-5 Inhibition in a 1-Year Study. Circulation. 2011;124(2):164-74. doi:10.1161/CIRCULATIONAHA.110.983866.

20. Lewis GD, Shah R, Shahzad K, et al. Sildenafil Improves Exercise Capacity and Quality of Life in Patients With Systolic Heart Failure and Secondary Pulmonary Hypertension. Circulation. 2007;116(14):1555-62. PMID:17785618.

21. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: A randomized clinical trial. JAMA. 2013;309(12):1268-77. doi:10.1001/jama.2013.2024.

22. Murali S, Kormos RL, Uretsky BF, et al. Preoperative pulmonary hemodynamics and early mortality after orthotopic cardiac transplantation: The Pittsburgh experience. Am Heart J. 1993;126(4):896-904. PMID: 8213447.

23. Murali S, Uretsky BF, Armitage JM, et al. Utility of prostaglandin E1 in the pretransplantation evaluation of heart failure patients with significant pulmonary hypertension. J Heart Lung Transplant. 1992;11(4 Pt 1):716-23. PMID: 1498137.

24. Givertz MM, Hare JM, Loh E, et al. Effect of bolus milrinone on hemodynamic variables and pulmonary vascular resistance in patients with severe left ventricular dysfunction: a rapid test for reversibility of pulmonary hypertension. J Am Coll Cardiol. 1996;28(7):1775-1780. PMID: 8962566.

25. Tedford RJ, Hemnes AR, Russell SD, et al. PDE5A Inhibitor Treatment of Persistent Pulmonary Hypertension After Mechanical Circulatory Support. Circ Heart Fail. 2008;1(4):213-219. doi:10.1161/CIRCHEARTFAILURE.108.796789.

26. Packer M, McMurray J, Massie BM, et al. Clinical effects of endothelin receptor antagonism with bosentan in patients with severe chronic heart failure: results of a pilot study. J Card Fail. 2005;11(1):12-20. PMID: 15704058.

27. Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Int J Cardiol. 2002;85(2-3):195-7. PMID: 12208583.

28. Califf RM, Adams KF, McKenna WJ, et al. A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: The Flolan International Randomized Survival Trial (FIRST). Am Heart J. 1997;134(1):44-54. PMID: 9266782.



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