How does left heart failure cause pulmonary hypertension

Left heart failure is the most common cause of pulmonary hypertension (PH) but still remains a diagnostic and therapeutic challenge (1, 2). In these patients, mean pulmonary artery pressure (mPAP) increases by upstream transmission of increased left ventricular filling pressures. The pulmonary vascular resistance (PVR) equation rewritten as mPAP = PVR × cardiac output + wedge PAP (mPAWP) assumes pressure increases in a 1:1 manner. However, an “out of proportion” increase in mPAP may occur because of a pressure-induced decrease in pulmonary vascular compliance and a flow-dependent increase in mPAP compared with mPAWP (3). Another way mPAP may increase more than mPAWP is by pulmonary vascular remodeling. Accordingly, definitions and terminology of PH with heart failure were revised at the fifth World PH Symposium in Nice (2). There, PH defined by mPAP greater than 25 mm Hg was qualified as precapillary with mPAWP less than 15 mm Hg and postcapillary with mPAWP greater than 15 mm Hg. Postcapillary PH was further divided into isolated postcapillary PH (IpcPH) with a normal diastolic pulmonary pressure gradient (DPG: diastolic PAP − mPAWP), and combined pre- and postcapillary PH (CpcPH) with a higher than normal DPG. It was reasoned that DPG would be more specific for pulmonary vascular remodeling and less sensitive to pulmonary vascular compliance or pulmonary flow than the more commonly used transpulmonary pressure gradient (TPG: mPAP − mPAWP) (2, 3).

These renewed definitions and acronyms are important for the following reasons: (1) PH with heart failure has repeatedly been shown to decrease survival (1, 2), particularly in patients with a TPG greater than 12 mm Hg combined with a DPG greater than 7 mm Hg (4). In that study, survival of patients with CpcPH was as limited as patients with untreated pulmonary arterial hypertension (PAH). (2) Because of histological similarities with PAH (4), patients with CpcPH might benefit from targeted therapies shown effective in PAH, but this still needs to be proven. (3) IpcPH with heart failure is entirely reversible when mPAWP is normalized by medical or surgical interventions, mechanical support, or transplantation (5).

How common is CpcPH in heart failure? An answer to this question is proposed by Gerges and colleagues of the University of Vienna in this issue of the Journal (pp. 1234–1246) (6). The authors explored a retrospective and prospective database of nearly 4,000 cardiac catheterizations for a suspected PH or for valve replacements, percutaneous interventions, and surgical procedures. Heart failure was diagnosed in 30 to 50% of the patients, and PH was diagnosed in 50 to 80% of them (there was an increase in this number over time). Approximately 12 to 14% of the patients with PH met the CpcPH hemodynamic definition. The prevalence of CpcPH did not appear specific to systolic or diastolic heart failure, which were almost equally distributed in the database. Predictors of CpcPH were younger age, coexistent chronic obstructive pulmonary disease or valvular heart disease, and, interestingly, the echocardiography-derived tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (sPAP) ratio. The authors also estimated right ventriculoarterial coupling by the ratio of end-systolic (Ees) to arterial (Ea) elastances and found it deteriorated in CpcPH but preserved in IpcPH as well as in a small subset of PAH in their database. Gerges and colleagues conclude that CpcPH is uncommon in heart failure and may be a cause of clinical worsening because of associated right ventricle (RV) failure (6). One can only agree. The combination of pre- and postcapillary PH in heart failure may be even less common than estimated by Gerges and colleagues, as a significant proportion of their patients had been referred for a suspicion of PH, thereby introducing a selection bias.

Gerges and colleagues correctly underscore that PH with heart failure is basically a clinical diagnosis. In their hands, standard clinical echocardiography as an extension of clinical examination was disappointing at predicting CpcPH except for the TAPSE/sPAP ratio. However, this field is rapidly evolving. Development of prediction scores for pre- and postcapillary PH integrating chamber dimensions, estimates of right and left ventricular filling, and pulmonary flow wave morphology (7, 8) will surely improve the noninvasive diagnosis of PH with heart failure and clarify indications for cardiac catheterization.

The hemodynamic phenotype and epidemiologic knowledge of CpcPH are of great importance to the design of future trials of targeted therapies for PH with heart failure. These trials have been expectedly negative in unselected and mixed patient populations (9, 10). However, the recruitment of patients with CpcPH will be a challenge and require an active cooperation of referral centers with integrated dedication to both severe PH (PAH and chronic thromboembolic PH) and heart failure.

One of the many merits of the study by Gerges and colleagues is to call attention to RV function. They are not the first (11) but cleverly attempt measurements closer to load-independent gold standards (12). For this purpose, they analyzed RV pressure curves to calculate a maximum pressure (Piso) as an estimation of the pressure generated during a nonejecting beat and calculated Ees as (Piso − mPAP)/stroke volume (SV) and Ea as mPAP/SV (13). This approach relies on approximations but offers an elegant estimate of RV-arterial coupling by the Ees/Ea ratio simplified as (Piso/mPAP − 1) (14). The clinical relevance of this measurement compared with other estimates of RV function remains to be established. However, the results reported by Gerges and colleagues support the notion that RV adaptation to increased afterload is essentially systolic and that RV uncoupling precedes right heart chamber dilatation, negative ventricular interaction, and systemic congestion (12).

What does the TAPSE/sPAP ratio tell us? Gerges and colleagues believe that this ratio is an estimate of RV afterload, but there may be more to it. The TAPSE/sPAP ratio was recently introduced by Guazzi and colleagues as a potent prognostic marker in heart failure (15), particularly in combination with cardiopulmonary exercise testing (16). The TAPSE/sPAP ratio probably reflects RV-arterial coupling, as TAPSE is a surrogate of contractility and sPAP largely determines afterload. Thus, a decreased TAPSE/sPAP agrees with depressed Ees/Ea, even though Gerges and colleagues found the correlation between these composite variables to be looser than with their constituents. It is interesting that a depressed RV-arterial coupling, however measured, predicts CpcPH or, alternatively, that CpcPH is a cause of RV failure. The RV in heart failure is exquisitely sensitive to afterload (17), which is explained by the fact that cardiac diseases generally do not spare the right heart. As shown by Gerges and colleagues, RV afterload may also increase more than estimated from PVR because of a disproportionate decrease in pulmonary arterial compliance (18).

Refined terminology, new acronyms, and most recent contributions by Gerges and colleagues allow for an updated view of PH in heart failure as illustrated in Figure 1, which integrates the impact of pulmonary vascular gradients on the severity of PH, right ventricular function, and prognosis.

Figure 1. Updated integrated view of pulmonary hypertension (PH) with heart failure. PH in heart failure affects right ventricular function and decreases survival in proportion to increased pulmonary vascular pressures. Survival is shortest and right ventricular function is decreased in combined pre- and postcapillary PH, but the condition is rare. DPG = diastolic pulmonary pressure gradient; Ea = arterial elastance; Ees = end-systolic elastance; iPAH = idiopathic pulmonary artery hypertension; mPAP = mean pulmonary artery pressure; mPAWP = mean pulmonary arterial wedge pressure; RV-PV = right ventricle–pulmonary vascular; sPAP = systolic pulmonary artery pressure; TAPSE = tricuspid annular plane systolic excursion.

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Newly introduced acronyms are accepted, even though nonexperts might find them difficult to use. CpcPH could well be more easily understood if replaced by “combined pre- and postcapillary PH” and IpcPH by “postcapillary PH.” The acronyms CpcPH and IpcPH will face the test of daily clinical practice. In the meantime, thanks to the efforts of Gerges and colleagues, we know better how uncommon but clinically relevant combined pre- and postcapillary PH is and how to diagnose it. Their landmark studies pave the way for progress in the diagnosis and treatment of PH with heart failure.

References

Section:

Does heart failure cause pulmonary hypertension?

Is pulmonary hypertension caused by right or left heart failure?