Pulmonary Hypertension Due to Left Heart Disease—Combine or Not Combined? DPG In or Out? A Practical Approach to the Patient With Suspected Left Heart Disease

INTRODUCTION

Pulmonary hypertension due to left heart disease (PH-LHD), also known as Group 2 pulmonary hypertension (PH), is the most common form of PH in clinical practice.1 The increase in pulmonary capillary wedge pressure (PCWP) due to LHD initially causes a passive elevation in the mean pulmonary artery pressure (mPAP) that is reversible with a reduction in left-sided filling pressures. The passive increase in mPAP is not associated with precapillary vasoconstriction or remodeling and is referred to as isolated postcapillary PH (IpcPH). However, some patients with IpcPH, over time, develop global pulmonary vascular remodeling including intimal thickening of the precapillary distal pulmonary arteries, arterioles, and the postcapillary venules, commonly referred as combined precapillary and postcapillary PH (CpcPH).2 Both IpcPH and CpcPH lead to an increase in right ventricular pulsatile and static afterload, ultimately leading to right heart failure and death.3 Thus, PH-LHD, regardless of the underlying LHD, is associated with increased mortality.45 Compared to IpcPH, CpcPH is associated with worse exercise capacity, reduced survival, different genetic makeup, and closer phenotypic resemblance to PAH.56

During the most recent 6th World Symposium on PH (WSPH) in 2018, experts in the field of PH-LHD reviewed the literature in the last 5 years and created consensus proceedings that summarized key findings, challenges, and new proposals on how to approach patients with PH-LHD.78 In this article, we review the changes proposed by the 6th WSPH consensus document in the definition, classification, diagnostic evaluation, and treatment of PH-LHD.

DEFINITION OF PH-LHD

The 6th WSPH consensus proceedings have proposed important changes to the definition of PH-LHD. The proceedings define PH-LHD as mPAP > 20 mm Hg with a PCWP > 15 mm Hg.89 Previously, an mPAP ≥ 25 mm Hg was used to define PH.10 However, multiple recent observational studies show a linear increase in mortality with every 1 mm Hg increase in mPAP from a threshold value of 20 mm Hg.1112 Based on this, in the new proposed definition, the threshold value of mPAP to define PH is lowered to >20 mm Hg.8

The cutoff value for PCWP to differentiate postcapillary PH from precapillary PH remains at >15 mm Hg, similar to the previous definition. Since accurate measurement of PCWP is key for correct diagnosis of PH-LHD, the consensus proceedings provides multiple tips for proper PCWP measurement.8 First, PCWP should be measured at mid a-wave in patients with sinus rhythm. In patients with atrial fibrillation, it should be measured at 130–160 milliseconds after the onset of QRS and before the v-wave. The mid a-wave in sinus rhythm and 130–160 milliseconds after the onset of QRS in atrial fibrillation represents end diastole, where PCWP should ideally be measured. Second, the proceedings continue to support the measurement of PCWP at end expiration.8 Using computer-averaged mean PCWP can underestimate PCWP and lead to misclassification of postcapillary PH as precapillary PH.13 The end-expiratory PCWP correlates more closely to left ventricular end diastolic pressure than computer-averaged mean PCWP.14 Third, the document emphasizes the importance of zeroing the transducer properly at the midchest levels with the patient lying supine with legs flat. Fourth, the operator should take 3 PCWP values within 10% variation and average them. Fifth, if there is any question on the accuracy of PCWP, especially when it is higher than the expected value based on the patient's clinical profile, a PCWP saturation should be obtained. A PCWP saturation > 94% confirms true PCWP measurement. Alternatively, left ventricular end diastolic pressure should be measured through a left heart catheterization. Finally, the proceedings highlight the importance of a large v-wave. The presence of large v-wave is highly suggestive of underlying LHD, even in the presence of normal PCWP.8

CLASSIFICATION OF PH-LHD: CPCPH VERSUS IPCPH

The proceedings document also proposed important changes on how to classify PH-LHD as either IpcPH or CpcPH. The 5th WSPH proposed to use pulmonary vascular resistance (PVR) and diastolic pulmonary gradient (DPG) to classify IpcPH and CpcPH once a diagnosis of PH-LHD is confirmed by a PCWP > 15 mm Hg.15 To make a diagnosis of CpcPH, one requires the presence of PVR ≥ 3 Wood units or DPG ≥ 7 mm Hg.

However, at the 6^th WSPH, CpcPH is defined only based on PVR. CpcPH is defined as mPAP > 20 mm Hg with a PCWP > 15 mm Hg and a PVR ≥ 3 Wood units. DPG has been dropped from the definition.8 This is based on the literature published in the last 5 years. Several large observational studies and a meta-analysis have documented that many hemodynamic variables predict mortality in patients with PH-LHD including mPAP, PVR, pulmonary arterial compliance, transpulmonary gradient (TPG), and total elastance either alone or in combination.4516–18 The results are mixed with some studies suggesting one variable being better than the others. Thus, the consensus document acknowledges that the hemodynamic definition of CpcPH is debatable, and there is no single good answer. To overcome the inherent limitations with pure hemodynamic definitions, as it is not always practical to phenotype patients based on a binary value of a single pressure measurement, the document appropriately recommends future studies to evaluate nonhemodynamic diagnostics such as echocardiogram, cardiac magnetic resonance imaging, epidemiology-based risk scores, or biomarkers including genomics, proteomics, and metabolomics to differentiate CpcPH from IpcPH.8 The ongoing PVDOMICS study sponsored by the National Institutes of Health may hopefully provide some insight.19

DIAGNOSTIC EVALUATION OF PH-LHD

The 6th WSPH proceedings recommend a 3-step approach in the diagnostic evaluation of PH-LHD. The purpose of this 3-step approach is mainly to avoid misclassification of PH due to heart failure with preserved ejection fraction (PH-HFpEF) as pulmonary arterial hypertension (PAH). This has significant therapeutic and prognostic implications. None of the currently approved therapies for PAH are effective in PH-HFpEF, and in fact, some are detrimental with increased fluid retention.20 In addition, this 3-step approach reduces unnecessary overtesting by identifying the right patient population that will benefit from invasive hemodynamic assessment with or without provocative measures.

Step 2: Determining the Pretest Probability of PH-LHD

The consensus document categorizes patients into 3 different categories: low probability, intermediate probability, and high probability for PH-LHD based on the combination of 9 different noninvasive variables including age, presence of cardiovascular comorbities, presence of atrial fibrillation, prior cardiac intervention or structural LHD, electrocardiogram, echocardiographic findings, cardiac magnetic resonance imaging, and noninvasive cardiopulmonary exercise testing.8 Table 1 lists the detailed criteria for each variable for each pretest probability category.

Table 1. Pretest probability of left heart disease^a

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Patients in the low pretest probability category likely have precapillary PH either due to PAH or CTEPH and should undergo further workup for those conditions. Patients in the high pretest probability category probably have PH-LHD, and further evaluations, especially an invasive right heart catheterization, are not necessarily warranted to make the diagnosis, unless they are participating in a clinical trial. However, patients in the intermediate pretest probability category, especially those with abnormal right ventricular size or function, systemic sclerosis, or unexplained dyspnea, should undergo invasive hemodynamic testing with or without provocative measures to determine the exact etiology. This is the third and final step in the diagnostic evaluation of PH-LHD. Of note: this pretest probability categorization is based on prior observational studies and expert consensus but has not been prospectively validated.

TREATMENT OF PH-LHD

The main treatment of PH-LHD is proper treatment of the underlying LHD.10 The 6th WSPH proceedings document recommends strongly against the use of PAH-specific pulmonary vasodilator therapies in patients with PH-LHD. This is based on the lack of large, randomized, controlled trials showing safety and efficacy of pulmonary vasodilator therapies in patients with PH-LHD. In fact, 2 recent trials have reported negative results for pulmonary vasodilator therapies in specific subsets of PH-LHD patients. In the SIOVAC trial, sildenafil 40 mg 3 times a day for 6 months in patients with persistent PH after successful valve replacement or repair procedure at least 1 year before inclusion was associated with worse clinical outcomes.25 Patients treated with sildenafil had worsening composite clinical score of death, hospital admission for heart failure, change in functional class, and patient global self-assessment.25 In the Melody trial, macitentan 10 mg once a day for 3 months was associated with increased risk of fluid retention compared to placebo in 63 patients with CpcPH with no significant improvement in PVR, cardiac output, and N-terminal-Pro brain natriuretic peptide levels.20 The majority of patients in the Melody trial had PH-HFpEF, and all patients had a left ventricular ejection fraction ≥ 30%.20 Table 2 summarizes the recently completed as well as ongoing clinical trials for treatment of PH-LHD.

Table 2. Clinical trials for PH-LHD^a

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WHEN SHOULD WE DO ACUTE VASODILATOR TESTING IN PATIENTS WITH PH-LHD?

There is much uncertainty in clinical practice regarding the utility and clinical significance of acute vasodilator testing in patients with PH-LHD. The only clear indication for acute vasodilatory testing in patients with PH-LHD is in the context of cardiac transplantation in patients with end stage left ventricular systolic dysfunction. There is a linear increase in 30-day post-transplant mortality due to acute right ventricular dysfunction with increase in TPG > 15 mm Hg, PVR > 3 Wood units, and mPAP > 50 mm Hg.26 Based on this, the current heart transplant guidelines recommend an acute vasodilator challenge if systolic pulmonary artery pressure is ≥50 mm Hg with either TPG ≥ 15 mm Hg or PVR > 3 Wood units and systemic systolic arterial pressure > 85 mm Hg.27 Intravenous nitroprusside or milirinone are the 2 commonly used agents for acute vasodilatory challenge in patients with PH-LHD being evaluated for heart transplant.27 Intravenous nitroprusside is used if the systemic vascular resistance is elevated, whereas intravenous milirinone is preferred in the presence of normal or low systemic vascular resistance. There is no clear indication for acute vasodilatory challenge with inhaled nitric oxide alone in patients with PH-LHD.

CONCLUSIONS

The proposed definition of PH-LHD has been changed. Mean PAP > 20 mm Hg with a PCWP > 15 mm Hg defines PH-LHD. PVR > 3 Wood units in the presence of mPAP > 20 mm Hg and PCWP > 15 mm Hg differentiates CpcPH from IpcPH. DPG is no longer needed for the classification of CpcPH. A 3-step approach has been recommended for the diagnostic evaluation of PH-LHD. Careful hemodynamic assessment at expert centers should be considered in patients with intermediate pretest probability for PH-LHD. Treatment of underlying LHD continues to remain the main line of treatment for PH-LHD. Pulmonary vasodilator therapies are strongly not recommended in patients with PH-LHD at this time.