Pulmonary Arterial Hypertension With Right Ventricular Failure: The Left Forgotten Ventricle

Abstract

Right ventricular failure (RVF) is a complex clinical syndrome of impaired filling or ejection of blood from the right ventricle. As a syndrome of newly recognized clinical importance, with diverse causes, its clinical epidemiology is not well characterized.1Voelkel NF Quaife RA Leinwand LA National Heart, Lung, and Blood Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure et al.Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure.Circulation. 2006; 114: 1883-1891Crossref PubMed Scopus (965) Google Scholar For patients with advanced pulmonary arterial hypertension (PAH), acute RVF exacerbations have an estimated 29% to 41% mortality rate.2Haddad F Fuh E Peterson T et al.Incidence, correlates, and consequences of acute kidney injury in patients with pulmonary arterial hypertension hospitalized with acute right-side heart failure.J Card Fail. 2011; 17: 533-539Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 3Sztrymf B Souza R Bertoletti L et al.Prognostic factors of acute heart failure in patients with pulmonary arterial hypertension.Eur Respir J. 2010; 35: 1286-1293Crossref PubMed Scopus (190) Google Scholar Despite the high mortality rate, acute RVF management continues to be based on animal data and anecdotal clinical experience.4Vlahakes GJ Turley K Hoffman JI The pathophysiology of failure in acute right ventricular hypertension: hemodynamic and biochemical correlations.Circulation. 1981; 63: 87-95Crossref PubMed Scopus (435) Google Scholar, 5Gomberg-Maitland M Defend the right ventricle with what you know.Eur Respir J. 2010; 35: 1203-1205Crossref PubMed Scopus (4) Google Scholar In addition, the only known prognostic factors for acute RVF in PAH are based on simple clinical (mean systemic arterial pressure, respiratory rate), laboratory (estimated glomerular filtration rate), and imaging (tricuspid regurgitation velocity) measures, which reflect impaired right ventricular (RV) function and systemic hypoperfusion.2Haddad F Fuh E Peterson T et al.Incidence, correlates, and consequences of acute kidney injury in patients with pulmonary arterial hypertension hospitalized with acute right-side heart failure.J Card Fail. 2011; 17: 533-539Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 3Sztrymf B Souza R Bertoletti L et al.Prognostic factors of acute heart failure in patients with pulmonary arterial hypertension.Eur Respir J. 2010; 35: 1286-1293Crossref PubMed Scopus (190) Google Scholar A better characterization of the presentation and the interventricular interdependence in patients with PAH and acute RVF could improve prognostication and clinical care. In this issue of CHEST (see page 1512), Sztrymf et al6Sztrymf B Günther S Artaud-Macari E et al.Left ventricular ejection time in acute heart failure complicating precapillary pulmonary hypertension.Chest. 2013; 144: 1512-1520Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar studied the prognostic value of left ventricular ejection time (LVET), as measured by radial artery tonometry, in 53 consecutive patients with PAH admitted to a single-center ICU for clinical deterioration. They found that both ICU and 90-day mortality were significantly higher in patients with a decreased LVET on admission. However, when they examined LVET 3 to 5 days after ICU admission, the change in LVET did not predict adverse outcomes. No other tonometric variables were statistically significant predictors on admission; however, multiple clinical and biologic parameters, including dose of furosemide and use of dobutamine on admission, brain natriuretic peptide, creatinine, and sodium were found to be predictive of outcomes in the ICU and 90-day mortality both on admission and 3 to 5 days after ICU admission. LVET on admission could prognosticate but the change in LVET could not. This may be due to the severity of disease and the lack of significant variability at the time point chosen once the patient is extremely sick. Whether LVET is the right biomarker and if the focus should be on the left ventricle is, therefore, not yet clear. The authors are to be commended for focusing on this RV/left ventricular (LV) interaction and exploring noninvasive variables that are relatively simple to evaluate and are not related to the right side of the heart alone. Just as the right ventricle frequently becomes an innocent bystander in most LV diseases, the left ventricle can also suffer as a result of PAH and RVF. The authors chose to examine LVET with the assumption that it is an easy, pain-free, and accurate measurement of LV stroke volume. It is generally believed that patients with PAH and acutely decompensated RVF have reduced LV stroke volume due, in part, to marked RV volume and pressure overload impeding LV filling and resulting in decreased cardiac output. In addition, this RV overload causes RV ischemia, further limiting function, and worsening overall cardiac output.1Voelkel NF Quaife RA Leinwand LA National Heart, Lung, and Blood Institute Working Group on Cellular and Molecular Mechanisms of Right Heart Failure et al.Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure.Circulation. 2006; 114: 1883-1891Crossref PubMed Scopus (965) Google Scholar To date, few studies have explored the interventricular interdependence in this patient population and how the consequences of this relationship may affect outcomes. Indeed, several articles have shown that the eccentricity index, which is a measure of the degree of septal flattening by echocardiography or MRI, is not only an independent predictor of adverse events in patients with PAH but also significantly changes in response to treatment.7Wilkins MR Paul GA Strange JW et al.Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study.Am J Respir Crit Care Med. 2005; 171: 1292-1297Crossref PubMed Scopus (332) Google Scholar, 8Sciancalepore MA Maffessanti F Patel AR et al.Three-dimensional analysis of interventricular septal curvature from cardiac magnetic resonance images for the evaluation of patients with pulmonary hypertension.Int J Cardiovasc Imaging. 2012; 28: 1073-1085Crossref PubMed Scopus (23) Google Scholar Although MRI is not feasible in acutely ill patients, the eccentricity index can be measured by echocardiography, and its use should be pursued in future studies. The question remains, though: Is LVET an appropriate marker for this interventricular interdependence? Although LVET has been shown to correlate with LV stroke volume, the authors correctly point out that their main pathophysiologic hypothesis cannot be documented because no imaging modality was used to correlate increased septal bulging with decreased LVET. Without this key association, LVET may be measurable and interpretable but not necessarily clinically relevant. In addition, the authors state that LVET may be influenced by numerous factors including age, sex, thyroid abnormalities, valvular disease, and even food eaten. Because of the small population size and the low number of adverse events, one cannot determine whether LVET is truly an independent predictor of mortality in this patient population, a critically important step when identifying strong prognostic parameters. Establishing clinically relevant and independently prognostic parameters, whether they are clinical, biologic, functional, imaging, or hemodynamic, is very challenging. Not only should these markers differ between subjects with and without outcome in a prospectively designed trial, but they should also add incremental value to already established markers and change predicted risk sufficiently to alter therapy and improve clinical status.9Biomarkers Definitions Working Group Biomarkers and surrogate endpoints: preferred definitions and conceptual framework.Clin Pharmacol Ther. 2001; 69: 89-95Crossref PubMed Scopus (4679) Google Scholar With an area under the curve of only 0.587 and data to suggest the change in LVET is not significantly associated with clinical outcomes, it is not clear whether LVET will become an important variable to measure in patients with PAH who develop RVF. This study underscores the idea that to develop clinically useful prognostic markers, particularly for rare diseases, researchers must pool their resources so that the appropriate statistical analysis can be performed. Numerous small-scale studies involving patients with PAH profess the predictive strength of certain parameters, but many of these studies contradict the results of other publications. The true prognostic strength of the parameter cannot be known until it is studied on a much larger scale The pulmonary hypertension community has had recent success in creating collaborations to better understand the epidemiology and clinical predictors of the disease, as evidenced by the multicenter North American (United States and Canada) Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL Registry)10Benza RL Miller DP Barst RJ Badesch DB Frost AE McGoon MD An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry.Chest. 2012; 142: 448-456Abstract Full Text Full Text PDF PubMed Scopus (723) Google Scholar and the Comparative Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) study.11Hoeper MM, Huscher D, Ghofrani HA, et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: Results from the COMPERA registry [published online ahead of print November 16, 2012]. Int J Cardiol. doi:10.1016/j.ijcard.2012.10.026Google Scholar So, too, perhaps with a more focused agenda, should a collaborative international research effort be developed for patients with PAH and RVF.12Gomberg-Maitland M Michelakis ED A global pulmonary arterial hypertension registry: is it needed? Is it feasible? Pulmonary vascular disease: the global perspective.Chest. 2010; 137: 95S-101SAbstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The impact of LVET on the management of patients with PAH and RVF is still not known, but the authors are correct in stating that the consequences of their findings on daily management deserve to be evaluated further. This study is the first step in increasing our understanding of the dynamic interplay between the right, the left, and the center (lung).