Curr Cardiol Rep (2012) 14:366–373 DOI 10.1007/s11886-012-0253-2
ECHOCARDIOGRAPHY (RM LANG, SECTION EDITOR)
Redefining the Role of Cardiovascular Imaging in Patients with Pulmonary Arterial Hypertension Benjamin H. Freed & Amit R. Patel & Roberto M. Lang
Published online: 12 February 2012 # Springer Science+Business Media, LLC 2012
Abstract While pulmonary arterial hypertension is a disease primarily affecting the pulmonary vasculature, the right ventricle plays an integral part in the disease process. Although widely used, two-dimensional echocardiography is limited in visualizing the right ventricle and, therefore, assessment of its structure and function has been largely subjective or invasive. Advanced imaging modalities such as real-time three-dimensional echocardiography and cardiovascular magnetic resonance overcome many challenges of two-dimensional echocardiography and have provided further insight into the pathophysiology of pulmonary arterial hypertension. Indices of right ventricular function obtained from these noninvasive techniques are being assessed for their prognostic capabilities as well as their ability to monitor response to pulmonary arterial hypertension–specific therapies. Future research is needed to compare the accuracy, reproducibility, and prognostic value of each of these parameters to definitively establish the role of cardiovascular imaging in the management of patients with pulmonary arterial hypertension. B. H. Freed : A. R. Patel : R. M. Lang Section of Cardiology, Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA A. R. Patel e-mail:
[email protected] R. M. Lang e-mail:
[email protected] B. H. Freed (*) University of Chicago MC 5084, 5841 South Maryland Avenue, Chicago, IL 60637, USA e-mail:
[email protected]
Keywords Right ventricle . Pulmonaryarterial hypertension . Cardiovascular imaging . Two-dimensional echocardiography . Real-time three-dimensional echocardiography . Cardiovascular magnetic resonance . Prognostic parameters . Clinical end points
Introduction Pulmonary arterial hypertension (PAH) is an insidious and debilitating disease with no known cure. Without treatment, the estimated median survival is 2.8 years [1]. PAH encompasses a group of diseases such as idiopathic PAH, familial PAH, and pulmonary hypertension (PH) associated with drugs/toxins, connective tissue disease, congenital heart disease, or HIV. All of these diseases are grouped together as PAH or World Health Organization Class I PH, because they are thought to share a common pathophysiology that includes pulmonary arterial endothelial dysfunction, smooth muscle and endothelial cell proliferation, and pulmonary arterial vasoconstriction [2]. From a hemodynamic standpoint, remodeling of the pulmonary vasculature leads to increased pulmonary vascular resistance and pulmonary arterial pressure which, in turn, induces right ventricular (RV) hypertrophy, dilation, tricuspid regurgitation, ischemia, and eventual RV dysfunction. From a clinical standpoint, patients with PAH progressively become more short of breath, fluid overloaded, and unable to perform simple activities of daily living. While this is a disease primarily of the pulmonary vasculature, the cause of death is usually RV failure [3]. Significant advances in our understanding of the pathophysiology of PAH in the last two decades have led to multiple therapies that have improved quality of life and decreased mortality. In this decade, 1-year survival rate is
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85% versus 68% in the 1980s [4]. Despite this significant improvement in short-term survival, the long-term prognosis of patients with PAH remains poor [5]. Clinical management of these patients is driven, in part, by the ability to predict survival and monitor response to therapy. Since the response of the right ventricle to increased afterload is what determines an individual patient’s symptoms and survival, the ability to image the right ventricle, assess its structure, and quantify its function is essential for the management of these patients. To underscore the important role cardiovascular imaging has in improving the course of this disease, an expert panel from the 4th World Symposium on Pulmonary Hypertension wrote “…techniques that image the RV morphologic and functional change in the face of increasing outflow obstruction can greatly advance our understanding of the disease” and “RV function has potent prognostic abilities, and it is reasonable to consider indexes of RV function as endpoints in pivotal clinical trials” [6]. Despite this, noninvasive imaging has had a limited role in the management of patients with PAH. For example, in an effort to better risk stratify these patients, a recently published risk score was developed that included many well-known hemodynamic and functional independent predictors of adverse outcomes. The only echocardiographic imaging parameter used in this score was the presence of a pericardial effusion [7••]. While known to be a powerful independent predictor of mortality in this patient population, it reveals little information on the pathophysiology of the right ventricle [8]. In terms of treatment, the primary end point in most of the major randomized placebo-controlled PAH-specific therapy trials has been and continues to be the 6-minute walk test [9, 10]. Imaging parameters have rarely been used as primary or secondary end points even though they would
likely provide greater insight into what effects drugs are having on the RV structure and function. In addition, as will be discussed in detail later, imaging modalities such as cardiovascular magnetic resonance (CMR) provide such excellent reproducibility of RV measurements that using CMR-derived parameters in future PAH-specific therapy trials will allow researchers to have to recruit less patients to detect a statistically significant change in a shorter amount of time [11•]. To understand the reason noninvasive imaging modalities have been relatively underutilized in this patient population, it is important to discuss the strengths and weaknesses of two-dimensional (2D) echocardiography (2DE), real-time three-dimensional (3D) echocardiography (RT3DE), and CMR in terms of their ability to assess the right ventricle and provide parameters to predict adverse outcomes and monitor response to therapy (Table 1). This article reviews the current role of these imaging modalities in the management of patients with PAH and discusses potentially new noninvasive markers that may further contribute to our understanding of this disease.
Two-Dimensional Echocardiography One of the biggest reasons imaging has not had a major impact in the care of patients with PAH is because the most widely used imaging modality, 2DE, is quite limited when it comes to visualizing the right ventricle. Unlike the left ventricle, the right ventricle has a complex crescent shape and its extensive trabeculations makes it difficult to define the endocardial border [12]. The retrosternal position of the right ventricle can limit 2DE windows and the more dilated the right ventricle is, the more difficult it is to visualize the entire RV cavity.
Table 1 Strengths and weaknesses of imaging modalities in the assessment of RV size and function Imaging modality
Strengths
Two-dimensional echocardiography Widely accessible Least costly modality Rapid image acquisition Real-time three-dimensional echocardiography
Cardiovascular magnetic resonance
Facilitates diagnosis of PH Accurate and reproducible RV assessment Rapid image acquisition
Weaknesses Limited acoustic windows Load- and angle-dependant parameters Lack of standardized normal values for parameters
Limited ability to quantify actual degree of dysfunction Limited acoustic windows Operator-dependent Not widely available Requires custom software for post-processing Accurate and reproducible RV assessment Not widely available Facilitates diagnosis of PH More costly and time consuming Imaging is independent of patient’s body habitus Can provoke claustrophobia Patients must lie completely supine
PH pulmonary hypertension, RV right ventricular.
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Recognizing these challenges, the American Society of Echocardiography (ASE) published comprehensive guidelines in 2010 for the systematic assessment of the right ventricle using, primarily, 2DE [13••]. The document details a variety of RV parameters that can be used for the determination of both RV structure and function. While it is outside the scope of this article to discuss each RV measure in detail, the focus will be to describe a few parameters in the context of predicting outcomes in patients with PAH and monitoring response to PAH-specific therapy. Prognostic Value of 2DE-Derived RV Parameters Tricuspid annular plane systolic excursion (TAPSE) is an indirect measurement of RV function and is acquired by placing an M-mode cursor through the tricuspid annulus in the apical four-chamber view to measure the amount of longitudinal motion of the annulus at peak systole [13••]. Since the right ventricle primarily contracts in the longitudinal direction due to an abundance of longitudinal myocardial fibers, TAPSE is thought to be fairly accurate in assessing the contractility of the right ventricle. The prognostic role of TAPSE was tested in 47 patients with PAH who were followed for 2 years for the primary end point of mortality [14]. These authors found that patients with a TAPSE ≥ 18 mm were significantly more likely to survive than those patients with a TAPSE less than 18 mm. In other words, for every 1-mm decrease in TAPSE, the risk of death increases by 17%. While TAPSE is easy to obtain, it is significantly load- and angle-dependent and assumes that the displacement of a single segment represents the function of the entire right ventricle [13••]. Another RV parameter that is described in the ASE document is the myocardial performance index, which is commonly referred to as the Tei index. This measure is a global estimate of both RV systolic and diastolic function and is obtained by calculating the sum of isovolumic contraction and relaxation time divided by RV ejection time [13••]. It is acquired by using the pulsed Doppler method or the tissue Doppler method. As a prognostic variable, patients with PAH who had a Tei index less than 0.83 had significantly better survival than patients with a Tei index ≥ 0.83 [15]. While the Tei index is a powerful independent predictor of outcomes in patients with PAH and its acquisition is not affected by the complex geometry of the right ventricle, it can be challenging to acquire and unreliable in patients with irregular heart rates [13••]. 2D longitudinal strain, like TAPSE, assesses RV function in the longitudinal direction by measuring percentage change in myocardial deformation throughout the cardiac cycle [13••]. 2D longitudinal strain is obtained by using the Doppler or speckle tracking methods. The speckle tracking method measures changes in position of myocardial
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acoustic markers (speckles) in relation to each other throughout the cardiac cycle [16]. The more negative the longitudinal strain value, the greater the deformation of the myocardial fibers and the better the contractility. In a study involving 80 patients with PAH, patients with an RV longitudinal strain more negative than −12.5% were significantly more likely to survive than patients with an RV longitudinal strain more positive than −12.5% [17•]. In other words, for every 5% worsening in strain, the risk of death increased over threefold. Unlike TAPSE, 2D longitudinal strain takes the whole right ventricle into account when measuring function but is load-dependent and requires customized software [16]. Utility of 2DE-Derived RV Parameters as Clinical End Points There are only a few studies evaluating the role of 2DE-derived parameters as clinical end points in randomized, placebo-controlled PAH-specific therapy trials [8, 18]. In separate trials evaluating the effects of the nonselective endothelin receptor antagonist, bosentan, and the prostacyclin analogue, epoprostenol, treatment with these therapies showed improvement in a variety of 2DE-derived RV measurements including RV end-systolic area, curvature of the interventricular septum, and maximum tricuspid regurgitant jet velocity. Unfortunately, many of these makers are difficult to reproduce and have yet to be validated in larger patient-population studies. 2DE is currently the most widely accessible and least costly imaging modality. While this imaging modality technique produces independent, prognostic parameters of RV function that may serve as clinical end points in PAHspecific therapy trials, it is quite limited in providing a truly accurate and reproducible assessment of the right ventricle (Fig. 1). Furthermore, many of the 2DE-derived RV measurements are load- and angle-dependent, lack standardized normal values, and predominantly provide information as to whether the right ventricle is normal or abnormal rather than the actual degree of dysfunction.
Real-Time Three-Dimensional Echocardiography Fortunately, cardiovascular imaging technology has improved considerably in the last decade creating imaging modalities that overcome many of the challenges of 2DE by providing greater coverage than 2DE and real-time 3D data sets. RT3DE is one such imaging modality (Fig. 1). Matrix array technology using transthoracic echocardiography (TTE) enables the rapid acquisition of full-volume 3D data of the right ventricle allowing more accurate and reproducible measures of RV size and function than 2DE [19].
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Fig. 1 a Two-dimensional echocardiography modified apical fourchamber and end-diastolic short-axis view showing dilated RV with interventricular septal flattening representing right ventricular volume overload. M-mode cursor through tricuspid annulus shows a “normal” TAPSE of 22 mm. b Three-dimensional echocardiography postprocessing segmental analysis of the RV in the same patient showing inlet (green), outlet (yellow), and apex (pink). Three-dimensional reconstruction of the RV shows an abnormal RVEF of 39%. c
Cardiovascular magnetic resonance short-axis plane of the right and left ventricle at end-diastole in the same patient. Endocardial tracing (yellow line) of the RV from base to apex at end-diastole and endsystole show an abnormal RVEF of 41%. Note that apical slices and end-systolic short-axis slices are not pictured. LA—left atrium; LV— left ventricle; RA—right atrium; RV—right ventricle; RVEF—right ventricular ejection fraction; TAPSE—tricuspid annular plane systolic excursion
Accuracy and Reproducibility of RT3DE in Assessment of the Right Ventricle
[20•]. The study included 28 patients referred for a clinically indicated CCT study (5 of whom had PAH). While volumetric analysis of CMR images yielded the most accurate RV measurements among the three imaging modalities, there was a strong correlation between RT3DE and CMR (0.89, 0.87, and 0.87 for end-systolic volume
Our group previously published a multimodality study comparing the ability of RT3DE, CMR, and cardiac computed tomography (CCT) to quantitatively assess the right ventricle
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[ESV], end-diastolic volume [EDV], and ejection fraction [EF], respectively), with RT3DE only slightly underestimating the volumes and EF (9 mL, 14 mL, and 2% for EDV, ESV, and EF, respectively). A recent metaanalysis of multiple studies examining the accuracy of RV size and function confirms that this underestimation exists but it is not statistically significant. Interestingly, in this study, intra-observer and inter-observer variability for RT3DE was somewhat lower than CMR (~10% vs 12%). Although CCT slightly overestimated the volumes and EF, it also provided a highly accurate and reproducible analysis of RV volume and function. The excellent accuracy and reproducibility of RT3DE is not diminished in patients with an abnormal right ventricle. Grapsa et al. [21] showed that, in 60 patients with PAH who underwent CMR and RT3DE imaging on the same day, RT3DE RV volume, function, and mass correlated well with CMR measurements and were highly reproducible. It is clear that RT3DE rapidly and efficiently provides an accurate assessment of the right ventricle that is far superior to 2DE, but image acquisition is operator-dependent, specialized software is required for post-processing, and, similar to 2DE, the retrosternal position of the right ventricle sometimes limits the ability to achieve adequate TTE imaging windows. These weaknesses are likely somewhat responsible for why, to the best of our knowledge, there is no published data regarding the prognostic ability of RV parameters using RT3DE in patients with PAH or the use of RT3DE-derived RV parameters as end points in clinical trials.
Cardiovascular Magnetic Resonance CMR is a multiparametric imaging modality that can provide information related to several aspects of PAH such as assessment of RV size and function, assessment of myocardial tissue characteristics, and even assessment of the pulmonary artery “function” itself. Similar to RT3DE, CMR has been shown to provide accurate and reproducible measurements of RV size and function and is, in fact, regarded by many as the reference standard [22]. Imaging is typically accomplished by acquiring a series of sequential cines spanning the entire right ventricle using the steady-state free precession pulse sequence. Breathhold times are minimized by implementing parallel imaging. The 3D CMR data set allows complete coverage of the RV inflow, RV apex, and RV outflow regardless of ventricular size or shape. The short-axis imaging plane is used most often for analysis; however, some authors advocate imaging in the axial plane because it potentially provides better measurement reproducibility [23]. RV EDVs and ESVs are calculated using the method of disk by tracing the RV endocardium in each slice
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spanning from base to apex at the point of the cardiac cycle where the right ventricle has the largest and smallest cavity, respectively (Fig. 1). RV mass is calculated by multiplying the myocardial volume by the specific density of myocardium (1.05 g/cm3) and right ventricular ejection fraction (RVEF) is calculated by using the standard formula [(RVEDV–RVESV)/ RVEDV *100] [24]. More recently, techniques such as late gadolinium enhancement are being used to characterize the extent of myocardial damage or fibrosis that occurs in some of these patients. Other techniques, such as velocity-encoded imaging, provide insights about the function of the pulmonary artery itself via measurements such as pulmonary artery pulsatility. Accuracy and Reproducibility of CMR in Assessment of the Right Ventricle The reproducibility of RV volumes, EF, and mass using CMR was recently examined in 60 patients (20 with normal right ventricle, 20 with dilated right ventricle due to an atrial septal defect, and 20 with dilated right ventricle due to Tetralogy of Fallot) [11•]. The inter- and intra-observer comparisons of the right ventricle were excellent for RV volume, good for RVEF, and fair for RV mass. Most importantly, these authors found that for a randomized controlled trial with a power of 80% and a P value of 0.05, only 34 patients were required to detect a 10-mL change in RV EDV, 3% change in RVEF, and a 10-g change in RV mass. Another study showed that, in 111 patients with PAH who underwent CMR and 6-minute walk test at baseline and 1 year later, a 10-mL increase in stroke volume was clinically relevant because it correlated with an increase in 6-minute walk distance by greater than 41 m [25•]. Although some might argue if a change in 6-minute walk distance by 41 m is clinically meaningful, it is clear that the reproducibility of CMR is excellent, permitting fewer patients and shorter follow-up to detect statistical changes in clinical trials. Prognostic Value of CMR-Derived RV Parameters There are very few publications regarding the use of CMR as a tool for providing noninvasive predictors of survival in patients with PAH. In 2007, van Wolferen et al. [26] reported that, in 64 patients with PAH who underwent CMR imaging at baseline and after 1 year, CMR-derived parameters of RV function such as stroke volume index, RV EDV index, and left ventricular EDV index were all independent predictors of mortality. RV mass index trended in that direction while other authors found that a ventricular mass index (ratio of right and left ventricular end-diastolic mass) of ≥ 0.7 predicted significantly worse 1- and 2-year outcomes [27]. Additionally, Gan et al. [28] found that, in 70 patients
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with PAH who underwent CMR imaging at baseline, pulmonary artery pulsatility (relative change in pulmonary artery lumen area during cardiac cycle) was a strong, independent predictor of adverse outcomes in this patient population. Several studies have reported that, when using contrastenhanced CMR in patients with PAH, late gadolinium enhancement of the RV insertion points strongly correlated with multiple indices of RV function [29–33]. Our group found that the presence of late gadolinium enhancement of the RV insertion points was a marker for more advanced disease and poor prognosis in patients with PH [34]. We also found that CMR-derived RVEF, much like nuclear-derived RVEF, is an independent noninvasive imaging predictor of adverse outcomes in this patient population [35, 36]. Recently, van de Veerdonk et al. [37••] confirmed that, in 110 patients with newly diagnosed PAH, CMR-derived RVEF measured at baseline was an independent predictor of mortality. In addition, they found that even though pulmonary vascular resistance measured at baseline was also predictive of mortality, after a year of PAH-targeted therapy, only changes in RVEF were associated with survival. This finding suggests that RVEF, as measured by CMR, is a clinically important determinant of prognosis. Utility of CMR-Derived RV Parameters as Clinical End Points Regarding the use of CMR-derived parameters for clinical end points, Wilkins et al. [38] showed that patients who were randomized to receive sildenafil, a phosphodiesterase inhibitor, had a significant decrease in RV mass of 8 - 9 g in the first 4 months of treatment compared to patients who received bosentan. Whether sildenafil decreased RV mass via direct cardiac effects or through decreasing RV afterload is not entirely clear but the continued use of CMR-derived imaging parameters as end points in PAH-specific therapy trials will likely help in answering these questions. The inherently 3D nature of CMR makes it much more conducive to measuring the complex geometry of the right ventricle compared to 2DE. Unlike echocardiography in general, CMR is not limited by good acoustic windows and can accurately assess the RV geometry regardless of how abnormal it is. In addition, although right heart catheterization is still the gold standard for diagnosing PH, CMR can help facilitate the diagnosis by noninvasively locating and quantifying intra- and extracardiac shunts as well as identifying chronic thromboembolic disease. Of course, CMR has its own limitations. Unlike echocardiography, it is expensive and not widely available. Data acquisition and post-processing can be time consuming and the need for
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patients to lie flat in the scanner can be somewhat challenging. However, with improved technology, many of the parameters mentioned above can be attained in almost the same amount of time as a standard 2DE.
Noninvasive Markers for the Future The application of advanced imaging technology to patients with PAH has allowed further mechanistic insights into the pathophysiology of this disease. New noninvasive markers are being identified that clearly discriminate patients with disease versus patients without disease and even allow the differentiation between different severities of the disease. Several of these markers are mentioned below. The prognostic capabilities and the use of these parameters as clinical end points have yet to be tested. Although abnormal interventricular septal motion is a well-known sign of increased pulmonary artery pressure and predicts poor outcomes in patients with PH, it is not used to quantify the severity of disease. Using dynamic 3D analysis of septal curvature from CMR, our group was able to show that the curvature value progressively decreased with the severity of PH, discriminating patients with no PH and mild PH from patients with moderate to severe PH [39]. This curvature value correlated very well with invasive measurements of PH and had better correlation than when we applied the same method using 2D imaging. Another marker exploits the right ventricle and pulmonary vasculature relationship. Normally the right ventricle ejects blood into a highly distensible and low impedance pulmonary circulation. In PH, pulmonary vessel remodeling leads to increased vessel stiffness that elevates RV pulsatile workload and decreases RV contractility [40]. Sanz et al. [41] reported that, although patients with exerciseinduced PH have normal pulmonary pressures at rest, CMR-derived measurements of pulmonary artery stiffness are significantly decreased compared to patients without PH. This suggests that indices of pulmonary artery stiffness might be used to detect PH before overt changes in pulmonary pressures. Much like 2D longitudinal strain using speckle-tracking techniques, CMR is also able to measure RV longitudinal strain using strain-encoded imaging. Shehata et al. [42] showed that, using a pulse sequence that is able to rapidly quantify RV longitudinal strain in a single heart beat, patients with PH have significantly reduced peak systolic longitudinal strain in the basal, mid, and apical regions of the right ventricle compared to patients without PH. RV perfusion and metabolism using noninvasive imaging techniques have also been studied as potential markers of
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disease in patients with PH. In one study, RV perfusion was assessed using adenosine-stress CMR. The RV myocardial perfusion reserve was significantly decreased in patients with PAH versus patients without PAH [43]. In another study, RV perfusion and metabolism was assessed using positron emission tomography in 16 patients with PAH [44]. Using 13N-NH3 for perfusion imaging and 18 F-FDG for metabolic imaging, the authors found that myocardial blood flow was reduced and myocardial glucose uptake was significantly increased in patients with PAH.
Conclusions The right ventricle plays a central role in the pathophysiology of PAH. The inability to accurately measure RV size and function by 2DE has made it particularly difficult to use these parameters as predictors of adverse outcomes or end points in PAH-specific therapy trials. In its place, clinical trials often utilize parameters such as the 6-minute walk test, which is effort-dependent, and becoming a less valuable surrogate [45], and right heart catheterization, which is still the gold standard but an invasive procedure. The identification of RV parameters that are noninvasive, accurate, reproducible, easy to obtain, assess prognosis, and monitor response to therapy are essential for comprehensive risk stratification and for providing clues as to how PAH-specific drugs are affecting the heart. Advanced imaging modalities such as RT3DE and CMR allow the visualization of the right ventricle in ways that have dramatically improved our understanding of a variety of cardiovascular diseases and have the potential to provide many of these sorely needed parameters. There are still many limitations to the use of RT3DE and CMR, and multimodality studies comparing the reproducibility and prognostic power of a variety of right heart parameters from 2DE, RT3DE, and CMR are necessary. A direct comparison of these parameters is needed in an effort to streamline studies and provide physicians with the best noninvasive test for this patient population. Either way, the role of cardiovascular imaging in assessing RV structure and function is rapidly evolving and its inclusion in the management of PAH will undoubtedly help in improving outcomes in these patients. Disclosure Conflicts of interest: B.H. Freed: none; A.R. Patel: has received grant support from Astellas; and has received speaking fees from the Medical Education Speakers Network (MESN); R.M. Lang: none.
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