Impaired Right Ventricular Function and Elevated Pulmonary Artery Pressure: A Lethal Combination

This editorial refers to ‘Prognostic relevance of a non-invasive evaluation of right ventricular function and pulmonary artery pressure in patients with chronic heart failure’, by S. Ghio et al., published in this issue on pages 408–414. About two decades ago, the first data became available showing that pulmonary hypertension (PH) predicts mortality and morbidity in patients with LV systolic heart failure.1 More recently, the deleterious effect of secondary PH was also confirmed in patients with heart failure (HF) with preserved LVEF2 and in a population with the whole spectrum of heart failure.3 In the current European guidelines for HF,4 PH is acknowledged only indirectly as a prognostic factor by mentioning right ventricular (RV) failure, a restrictive filling pattern of the LV, and elevated wedge pressure as commonly described prognostic variables in HF. Ghio et al. now shed some light on the value of above-mentioned prognostic factors, describing their study results in an Italian cohort of 658 patients with congestive heart failure (CHF) due to a LVEF <45%.5 We have to commend the authors in that they combined two simple echocardiographic measurements [pulmonary artery systolic pressure (PASP) and tricuspid annular plane systolic excursion (TAPSE) or, alternatively, PASP and E wave deceleration time of the mitral flow Doppler profile (EDT)], to improve risk stratification. Their data suggest that reduced RV function alone is not the crucial factor for the patient's prognosis. It is the co-existence with elevated PASP that is associated with decreased survival, indicating that PH is the main driver of poor prognosis. In this context, it is important to know that other studies evaluating the prognostic value of impaired RV function in patients with LV failure did not focus on the cause of RV dysfunction.6,7 Also, in the study by Ghio et al., the cause of RV failure is not further specified, although for the patients with elevated PASP the adoption of exclusion criteria such as COPD and pulmonary embolism made it likely that PH secondary to LV failure would be the main cause of RV failure. Echocardiography is the screening tool of first choice for evaluation of HF symptoms. The assessment of systolic as well as diastolic parameters is part of the daily routine of a sonographer. Ghio et al. used two types of measurement (either TAPSE or EDT) in combination with PASP. Yet, for risk stratification and diagnosis, all single parameters have their limitations. First of all, the estimation of PASP by echocardiography has well known limitations compared with invasive measurements. Secondly, although TAPSE is an important representative of RV function and an established predictor of mortality, an estimation of RV dysfunction by TAPSE alone is rather a simplification, especially in studies that investigate the role of PH. TAPSE represents an estimation of longitudinal contraction, while radial contraction gains importance in the pressure-loaded right ventricle. Recently Damy et al.8 compared four RV systolic echocardiographic parameters to predict adverse outcomes in CHF patients and found only the tissue Doppler measurement of RV peak systolic velocity [PSV(tdi)] to be an independent predictor of outcome in HF (and, surprisingly, TAPSE was not). Thirdly, previous literature on diastolic dysfunction shows that no single echocardiographic parameter is sufficiently accurate and reproducible to make a reliable diagnosis. Normally, a combination of characteristics such as dilated left atrium, LV hypertrophy, mitral flow profile including EDT, pulmonary venous flow profile, and mitral annulus tissue Doppler profile is used.9,10 In addition, a short EDT, the parameter used in the study by Ghio et al., is one marker of restrictive filling, but may be not the strongest. The ratio of mitral peak velocity of early filling to tissue Doppler early diastolic mitral annular velocity (E/e′) is currently the best parameter for a non-invasive estimation of elevated left atrial pressure, although a recent study has raised some doubts for patients with isolated diastolic LV failure.11 Furthermore, in patients with AF, a common complication of left-sided HF, echocardiographic parameters of diastolic function are not validated at all. In summary, the strength of the results of Ghio et al. lies in the combination of two easy to obtain and simple echocardiographic measurements (TAPSE or EDT in combination with PASP) for risk prediction, but, at the same time, it needs to be resolved whether other parameters of RV function and restrictive filling could lead to comparable or better risk prediction. Findings could possibly be extended in the future with tissue Doppler parameters (e′, E/e′, and strain) and simultaneously derived invasive measurements. Also, increasing knowledge will probably arise from cardiac magnetic resonance imaging (MRI) which has emerged as an extremely useful technique in the evaluation of RV function. In pulmonary arterial hypertension, MRI data on RV volumes and function help clinicians increasingly in making risk stratification and therapeutic decisions. Recently, promising data were also published on the relationship between RV measurements by MRI and prognosis in patients with chronic HF.12 The integration of echocardiographic measurements and cardiac MRI is a promising approach for an accurate evaluation of patients with HF. The suggestion that the estimation of PASP with echocardiography can be replaced by EDT, a parameter of the restrictive filling pattern of the left ventricle, needs some consideration. Are these parameters interchangeable in terms of risk prediction? Although Ghio et al. show that both parameters have predictive power in combination with TAPSE, it needs to be emphasized that patients with restrictive filling do not always have PH. Vice versa, patients without restrictive LV filling patterns are not always protected from elevated PASP. In fact, the interplay between diastolic LV function and the development of PH is a complex one. Recent studies show that PH due to left-sided HF is more dependent on diastolic than on systolic function of the left ventricle.3,13 As soon as patients develop significant diastolic dysfunction with elevated filling pressures, an increase in PASP is a more or less obligatory part of the condition due to passive venous congestion.13 However, the increase in PASP is also dependent on the reaction of the pre-capillary component of the pulmonary vasculature. A pulmonary arteriopathy could develop, leading to the so-called ‘reactive PH’ or ‘PH out of proportion’ that is characterized by an increase of pulmonary vascular resistance (PVR) due to a myriad of processes. To illustrate the magnitude of this phenomenon, Butler et al.14 found that the majority of HF patients (i.e. 72%) with PH that were screened for heart transplantation had reactive PH. For patients with reactive PH, elevated PASP may be a stronger indicator of disease progression than a parameter of restrictive LV filling. Since this distinction was not made in the study by Ghio et al., it remains to be elucidated whether the subgroup of patients with reactive PH have a more advanced course of disease progression with faster increase of PH, RV failure, and, as a consequence, diminished survival. In fact, in their study, the percentage of reactive PH was probably low, given the low mean PASP in the study population of 38 mmHg and the low best cut-off RV peak pressure of 40 mmHg found to identify patients at higher risk. Taken together, although both models have predictive power in patients with LV failure, some caution is reasonable. The absence of data on PVR means that EDT is not simply an alternative for PASP for the purpose of risk prediction. One should be particularly cautious when comparing these findings with other HF studies dealing with patients with higher PASP. For further evaluation of this question, data are needed combining invasive and non-invasive measurements in a well-defined patient cohort. Finally, the question arises of why RV failure due to PH had a worse prognosis than RV failure without PH in this HF study polulation. An explanation could be that the right ventricle, which is adapted to a low afterload, tolerates chronic pressure overload very badly. This was, for example, recently illustrated in an interesting animal study which compared the consequences of pressure overload and volume overload of the right ventricle.15 Bartelds et al. showed that pressure load of the right ventricle rapidly induces RV remodelling, a decrease of exercise capacity, and an increased expression of modulatory calcineurin-interacting protein 1 (MCIP1), indicating calcineurin activation. Increasing knowledge about adaptive mechanisms of the right ventricle to pressure overload could lead to new therapeutic pathways in PH complicating left-sided HF. Conflicts of interest: none declared.