PH in Patients With End-Stage HF: Diagnostic and Therapeutic Approaches
Pulmonary hypertension (PH) is categorized into five groups as designated by the World Health Organization (WHO). PH in left heart failure (HF) is defined as WHO Group 2 PH, which occurs when PH is due to left ventricular (LV) systolic or diastolic dysfunction, valvular disease, left heart inflow or outflow obstruction, and/or congenital cardiomyopathies.1,2 Group 2 PH is hemodynamically defined by a resting mean pulmonary artery pressure (mPAP) ≥25 mmHg and pulmonary capillary wedge pressure (PCWP) >15 mmHg or LV end-diastolic pressure >18 mmHg.2,3
In assessing Group 2 PH, there are some relevant hemodynamic calculations:
- Transpulmonary gradient (TPG) = mPAP - PCWP
- An increasingly recognized calculation, pulmonary vascular resistance (PVR) = TPG/cardiac output
- Diastolic pulmonary gradient (DPG) = diastolic pulmonary artery (PA) pressure - PCWP
When elevations in left atrial pressure are transmitted to the pulmonary arteries, a "passive" increase in PA pressures occur, and in these scenarios, the TPG, PVR, and DPG are often normal. However, due to long-standing elevations in left atrial pressure and/or ill-defined genetic underpinnings, "reactive" elevations in PA pressures may occur as well.4 Under these circumstances, this is often reflected in elevations in the TPG, DPG, and/or PVR and is often referred to as combined pre- and post-capillary PH (Cpc-PH).2,4
Epidemiology and Prognosis
The estimated prevalence of Group 2 PH varies depending on patient population, type of HF, and method of diagnosis. When requiring invasive hemodynamic criteria, 60-80% of patients with HF with reduced ejection fraction (HFrEF) and 50-65% of patients with HF with preserved ejection fraction (HFpEF) have PH.4-6 Given the pathophysiology of Group 2 PH, it would be estimated that patients with end-stage HF would thus have a prevalence of PH that is at least this high. In other words, most patients with end-stage HF will likely have a component of PH present.
The presence of PH confers increased risk of adverse outcomes compared with the minority of patients with HF without PH. Increased PA systolic pressure (PASP) is significantly associated with increased risk of all-cause mortality in patients with HFrEF and HFpEF, and a 5 mmHg increase in PASP is associated with a 9% increase in risk for all-cause mortality.7 Similarly, progressive increases in estimated PASP were significantly associated with increased risk of the combined outcome of all-cause mortality, LV assist device (LVAD) implantation, or urgent heart transplantation in those with end-stage HF.8 Furthermore, patients with Cpc-PH have been shown to have a worse survival compared with patients with isolated post-capillary PH.4,9
Transthoracic echocardiography (TTE) is often used as a screening tool for PH. The estimation of PASP is based on Doppler evaluation of peak tricuspid regurgitation velocity combined with estimated right atrial pressure based on size and collapsibility of the inferior vena cava.2 The American College of Cardiology and American Heart Association guidelines recommend using the estimated PASP and sequelae of PH to assess likelihood of PH and need for invasive testing, with an estimated PASP ≥40 mmHg suggesting possible PH.2,10
However, under- or overestimation of PASP occurs frequently with TTE.2,10 For example, a comparative analysis of PASP measurements made during simultaneous TTE and right heart catheterization (RHC) revealed that TTE was inaccurate in approximately 50% of patients.11 Although other TTE findings such as right ventricular dilatation and/or dysfunction, right atrial dilatation, and flattening of the intraventricular septum may be suggestive of elevated PA pressures, such right-sided abnormalities may be present in the absence of significant PH and even in those with nominally elevated PA pressures. Thus, echocardiography may be used as a preliminary tool for identifying those with an increased likelihood of having PH, but its use is insufficient to definitively diagnose PH.
Right Heart Catheterization
Invasive hemodynamics derived from RHC are imperative to diagnose and confirm the presence of PH. In end-stage HF, the presence of PH, its severity, and response to provocative testing are critical aspects of the diagnostic assessment with important therapeutic implications. As described above, the presence of PH, especially when associated with elevations in TPG and PVR, is associated with poorer outcomes. In fact, when cardiac transplantation is performed as a treatment of end-stage HF, mortality is markedly worse when performed in the setting of PH with an elevated TPG and/or PVR.12,13 Thus, following confirmation of the presence of PH, additional testing in the form of a vasodilatory challenge is often performed, usually to assist in therapeutic decision-making (i.e., assessing the risk to proceed directly to cardiac transplantation versus the need for an LVAD as a bridge to future transplantation).4,9,14
In the presence of PH with a normal TPG and PVR, it is anticipated that lowering left-sided filling pressures will translate into a simultaneous lowering and perhaps near normalization of PA pressures. This is most commonly achieved using a potent systemic vasodilator such as intravenous nitroprusside. Although improvements in PA pressures often occur in response to a nitroprusside challenge, occasionally an "unmasking" of pulmonary vascular disease can be observed (i.e., the PCWP is lowered disproportionately to PA pressure lowering) with a realized increase in TPG and/or PVR. Thus, even in presumed passive elevations in PA pressures, a vasodilator challenge is advisable.
In the presence of PH with an elevated TPG or PVR, vasodilator testing is perhaps of even greater importance. As with passive elevations in PA pressures, PH in this setting is also a result of chronic left-sided pressure elevations, though additional vasoconstrictive and/or vascular remodeling processes have ensued in the pulmonary vasculature. Although intravenous nitroprusside testing can often be safely performed even in the presence of low systemic blood pressures, caution should be taken to not be reassured by significant lowering of PA pressures if occurring in the presence of significant, inducible systemic hypotension. In patients with low systemic blood pressure and in low cardiac output states, acute testing with intravenous milrinone could be considered.15 The use of nitric oxide in the setting of Group 2 PH is generally ill advised; not only does its use in this setting not conform with pathophysiologic principles, but there is also a risk of inducing flash pulmonary edema.3
The following are the main goals of treatment in Group 2 PH:
- Aggressively treat the underlying LV condition
- Optimize patient volume status
- Ameliorate concomitant non-cardiac conditions (e.g., chronic obstructive lung disease or obstructive sleep apnea)2
Because the presence of PH in end-stage HF is nearly always due to chronic elevations in left-sided filling pressures, the mainstay of treatment is aggressive, guideline-directed management of the underlying left HF.
Although it may be tempting to consider using targeted, pharmacologic therapies approved for Group 1 pulmonary arterial hypertension in those patients with Group 2 PH, particularly with an elevated TPG or PVR, doing so is generally of limited efficacy and may be associated with increased harm. Specifically, in FIRST (Flolan International Randomized Survival Trial), prostacyclin treatment resulted in decreased survival without any improvement in functional outcomes.16 With respect to endothelin receptor antagonists, an association with worsening HF and increased HF hospitalizations was observed in the ENABLE (Effects of the Endothelin Receptor Antagonist Bosentan on the Morbidity and Mortality in Patients With Chronic Heart Failure) trial and HEAT (Heart Failure ET(A) Receptor Blockade Trial).17,18 Finally, phosphodiesterase-5 inhibitors have also been tested in patients with left HF and were found to offer no benefit and perhaps increased harm.19,20 When conventional therapies aimed at stabilizing and improving left HF have been exhausted, the patient should be evaluated for advanced HF treatment considerations.
LVADs and Heart Transplantation
In the presence of end-stage HF with severe PH, proceeding directly with heart transplantation may be prohibitive. In this setting, the use of durable mechanical circulatory support has revolutionized the field as a bridge to transplant strategy. In nearly all cases of Group 2 PH including those with Cpc-PH, LVAD therapy lowers left atrial pressure and subsequently improves PA pressures significantly.2,21,22 An observational study supporting this principle demonstrated a decrease in mPAP from 37.2 ± 6.4 to 21.0 ± 7.5 mmHg, with an accompanying decrease in PVR from 3.5 ± 1.5 to 1.5 ± 0.7 WU and TPG from 15.0 ± 5.2 to 7.8 ± 3.2 mmHg. Moreover, nearly all these improvements were realized within 6 months of LVAD implantation.21 Additional observational data have shown the superiority of LVAD therapy in lowering PA pressures, PVR, and TPG compared with medical therapy alone for patients with Group 2 PH.23 Finally, use of an LVAD as a bridge to transplant does not appear to adversely affect short- or long-term transplant outcomes. Specifically, LVAD patients with Cpc-PH have been shown to achieve similar post-transplant survival up to 3 years compared with age- and sex-matched transplant patients without PH or LVAD support.3 In a separate analysis, LVAD patients with Group 2 PH had similar 10-year post-transplant survival compared with LVAD patients without PH.24
Group 2 PH is highly prevalent in end-stage HF and is associated with significantly increased risk of mortality. Although TTE can be useful as a screening tool, the definitive diagnostic test to fully characterize PH is with a RHC and possible vasodilator testing. The cornerstone of treatment for Group 2 PH remains management of the underlying LV disease with no current role for use of targeted PA vasodilator therapy. In most cases of PH in end-stage HF, LVAD therapy will result in near resolution of the PH and may be an effective bridge to heart transplantation in suitable cases.
- Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62:D34-41.
- Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67-119.
- Fang JC, DeMarco T, Givertz MM, et al. World Health Organization Pulmonary Hypertension group 2: pulmonary hypertension due to left heart disease in the adult--a summary statement from the Pulmonary Hypertension Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2012;31:913-33.
- Guazzi M, Naeije R. Pulmonary Hypertension in Heart Failure: Pathophysiology, Pathobiology, and Emerging Clinical Perspectives. J Am Coll Cardiol 2017;69:1718-34.
- Gerges M, Gerges C, Pistritto AM, et al. Pulmonary Hypertension in Heart Failure. Epidemiology, Right Ventricular Function, and Survival. Am J Respir Crit Care Med 2015;192:1234-46.
- Franco V. Management of Pulmonary Hypertension: Associated with Left Heart Disease. Heart Fail Clin 2018;14:545-51.
- Kjaergaard J, Akkan D, Iversen KK, et al. Prognostic importance of pulmonary hypertension in patients with heart failure. Am J Cardiol 2007;99:1146-50.
- Kalogeropoulos AP, Siwamogsatham S, Hayek S, et al. Echocardiographic assessment of pulmonary artery systolic pressure and outcomes in ambulatory heart failure patients. J Am Heart Assoc 2014;3:e000363.
- 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;143:758-66.
- McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573-619.
- Rich JD, Shah SJ, Swamy RS, Kamp A, Rich S. Inaccuracy of Doppler echocardiographic estimates of pulmonary artery pressures in patients with pulmonary hypertension: implications for clinical practice. Chest 2011;139:988-93.
- Costard-Jäckle A, Fowler MB. Influence of preoperative pulmonary artery pressure on mortality after heart transplantation: testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining a high risk group. J Am Coll Cardiol 1992;19:48-54.
- Mehra MR, Canter CE, Hannan MM, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update. J Heart Lung Transplant 2016;35:1-23.
- Guazzi M, Gomberg-Maitland M, Arena R. Pulmonary hypertension in heart failure with preserved ejection fraction. J Heart Lung Transplant 2015;34:273-81.
- Givertz MM, Hare JM, Loh E, Gauthier DF, Colucci WS. 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;28:1775-80.
- 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;134:44-54.
- Packer M, McMurray JJV, Krum H, et al. Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the ENABLE Trials. JACC Heart Fail 2017;5:317-26.
- Lüscher TF, Enseleit F, Pacher R, et al. Hemodynamic and neurohumoral effects of selective endothelin A (ET(A)) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT). Circulation 2002;106:2666-72.
- 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;309:1268-77.
- Bermejo J, Yotti R, García-Orta R, et al. Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: a multicenter, double-blind, randomized clinical trial. Eur Heart J 2018;39:1255-64.
- Mikus E, Stepanenko A, Krabatsch T, et al. Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients. Eur J Cardiothorac Surg 2011;40:971-7.
- Zimpfer D, Zrunek P, Sandner S, et al. Post-transplant survival after lowering fixed pulmonary hypertension using left ventricular assist devices. Eur J Cardiothorac Surg 2007;31:698-702.
- Kumarasinghe G, Jain P, Jabbour A, et al. Comparison of continuous-flow ventricular assist device therapy with intensive medical therapy in fixed pulmonary hypertension secondary to advanced left heart failure. ESC Heart Fail 2018;5:695-702.
- Moayedifar R, Zuckermann A, Aliabadi-Zuckermann A, et al. Long-term heart transplant outcomes after lowering fixed pulmonary hypertension using left ventricular assist devices. Eur J Cardiothorac Surg 2018;54:1116-21.
Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Cardio-Oncology, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Pulmonary Hypertension and Venous Thromboembolism, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Acute Heart Failure, Heart Transplant, Pulmonary Hypertension, Interventions and Imaging, Interventions and Structural Heart Disease, Echocardiography/Ultrasound
Keywords: Hypertension, Pulmonary, Ventricular Dysfunction, Left, Heart Failure, World Health Organization, Pulmonary Wedge Pressure, Pulmonary Artery, Blood Pressure, Atrial Pressure, Stroke Volume, Diastole, Systole, Cardiac Output, Vascular Resistance, Heart Transplantation, Echocardiography, Cardiomyopathies, Prognosis, American Heart Association, Cardiac Output, Low, Pulmonary Edema, Tricuspid Valve Insufficiency, Vena Cava, Inferior, Atrial Fibrillation, Atrial Pressure, Dilatation, Vasodilator Agents, Hemodynamics, Hypotension, Vascular Diseases, Cardiac Catheterization
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