Advanced imaging plays an emerging role in the diagnosis and clinical follow-up of patients with pulmonary hypertension (PH) (1,2). Although cardiovascular magnetic resonance (CMR) imaging becomes increasingly important in the evaluation of different types of PH (3), echocardiography still remains the first-line imaging technique if PH is suspected (4). Furthermore, invasive assessment by heart catheterization is required to confirm diagnosis and to evaluate pulmonary vasoreactivity to nitric oxide (NO) (5). Data derived from CMR, however, can provide valuable information both at initial diagnosis, for monitoring the response to PH targeted therapy and for risk stratification (3,6-11). Because CMR enables precise and reliable quantification of biventricular volumes, function and cardiac output, it is recommended as part of the routine clinical assessment of children with PH (12). In this review, we aim to provide practical information for the use of CMR in children and adolescents with PH. In view of recently published research in this area, we particularly thought to focus on novel CMR based concepts and developments that may be helpful in the evaluation of pediatric PH patients.
Standard CMR parameters in children and adolescents with suspected PH
The principles and applications of CMR for the evaluation of PH in children have been described in literature and include practical recommendations for its use in clinical routine (12). Examinations can be performed with 1.5 or 3.0 Tesla systems and standard equipment for performing a cardiac magnetic resonance (MR) examination must include cardiac coils, electrocardiogram (ECG) and respiratory monitoring, an appropriately equipped resuscitation cart and a CMR compatible infusion system. Gadolinium-based intravenous MR contrast agents are frequently administered in children for angiographic and tissue characterization studies. Overall, the incidence of adverse events in children is very low and reactions, if present, are mild in the majority of cases. However, the “off-label” use of contrast agent should be reconsidered in-depth on an individual basis and its advantages need to be weighed up against the potential risks (3,13). In brief, the following components are frequently included in the CMR study protocol of a pediatric patient with suspected PH (see Table 1).
Quantification of biventricular size and function by cine CMR
Quantification of biventricular volumes and function represents the most important part of a CMR study in patients with PH. Balanced steady state free precession (SSFP) cine sequences are typically applied that cover up the entire heart using a stack of short-axis or axial slices that provide 25–30 images per heartbeat. By measuring right (RV) and left ventricular (LV) volumes separately in both end-systole and end-diastole, stroke volume and ejection fraction (EF) can be quantified (3,12). CMR derived RV EF and LV stroke volume strongly correlate with survival in pediatric PH patients. In the largest CMR study including 100 children and adolescents with various types of PH, an up to 2.6-fold increase in mortality was observed per decrease of these values by one standard deviation (9). van Wolferen et al. showed that RV measurements contain prognostic information in idiopathic pulmonary arterial hypertension (PAH) in adults: larger RV volumes, reduced RV stroke volume and smaller LV dimensions were independent predictors for mortality and therapy failure (35). Accordingly, since RV failure is the most common cause of mortality (36), cine CMR represents an ideal modality for follow-up monitoring (7,35,37). Even in more complex forms of PH, cine CMR derived impaired biventricular systolic function proved to be of prognostic importance as demonstrated in a cohort of adult patients with Eisenmenger syndrome (38).
Phase contrast blood flow measurements
Standard two-dimensional phase contrast velocity measurements allow accurate flow quantification in each vessel of interest (12,39,40). Accordingly, calculation of cardiac output and shunt flow (Qp/Qs) both at baseline and during administration of pulmonary vasodilators is possible that may help to guide further therapy (21). Furthermore, right and left lung perfusion ratios, collateral flow and valvar regurgitation can be calculated. If considered necessary, pulmonary vein flows can be measured separately for each lung (41). Importantly, measurement of peak velocity by phase contrast to assess pressure gradients is less accurate with CMR and needs confirmation by Doppler echocardiography and cardiac catheterization.
In patients without any structural heart disease (PAH), the sustained increase in pulmonary artery pressure (PAP) leads to distension of the pulmonary artery system (Figures 1,2). The enlargement of these vessels in relation to the diameters of the ascending aorta is suggestive for the presence of PH (15,42). Signs of increased intracavitary RV pressure may also be expressed by a flattened position of the interventricular septum with leftward shift in systole (see Figure 1) (43-45). Although typically ruled out by echocardiography, CMR helps to detect congenital heart disease (CHD) as the underlying cause for PH such as ventricular septal defect (Figures 2,3), a persistent arterial duct (Figure 4) and vascular abnormalities (anomalous pulmonary venous return, major aortopulmonary collateral arteries). Furthermore, other secondary causes such as pulmonary thromboembolism (16,17), peripheral pulmonary artery stenosis or pulmonary venous obstruction can be detected using contrast-enhanced CMR angiography (7).
Myocardial tissue characterization
Myocardial tissue can be characterized using T1 and T2 weighted sequences, late gadolinium enhancement (LGE) and parametric myocardial mapping techniques. Thus, myocardial insult with edema, focal scarring and diffuse myocardial fibrosis may be visualized and quantified. While no study has yet assessed LGE in children with PH, inconsistent data exists in the adult PH population regarding the incidence and prognostic relevance of focal fibrosis (18,46-50). A study by Saunders et al. further showed that native T1 mapping may not be of additive value in the diagnostic or prognostic evaluation of patients with PAH although increased natives T1 times are frequently detected at the interventricular insertion points (19,20). However, other studies evaluated the extracellular volume (ECV) fraction within the RV and LV and found diffuse RV fibrosis to correlate with RV functional parameters and global hemodynamics (51-53).
Novel concepts and imaging biomarkers in pediatric PH using CMR
Novel concepts and CMR derived imaging biomarkers become increasingly important in pediatric patients with PH. Ideally, such parameters should enable comprehensive assessment of both myocardial and pulmonary vascular remodeling and provide additional prognostic information. In recent years, several groups aimed to investigate PH hemodynamics by applying sophisticated CMR imaging techniques (see Table 1).
Non-invasive estimation of RV afterload and pulmonary vascular stiffness
Estimation of RV afterload parameters using non-invasive CMR imaging techniques helps to establish diagnosis of PH and to monitor chronic changes of pulmonary vascular resistance (PVR) under therapy. Several experimental studies in animals and clinical studies in patients found correlations between PAP and PVR with various measures of pulmonary stiffness such as pulsatility, compliance, capacitance and distensibility (22). These parameters can be quantified using a cross-sectional cine image through the pulmonary trunk and/or the branch pulmonary arteries and are combined with invasively assessed pulmonary artery pulse pressure (22,23,54,55). Analysis of pulmonary artery stiffness by measuring blood flow velocity in the pulmonary arteries with two-dimensional phase contrast flow sequences has been validated in children with PH. Importantly, flow sequences with a high temporal resolution are required to allow assessment of flow and vessel area that enable to calculate measures of arterial stiffness such as pulse wave velocity (PWV) (24) or wave intensity using post-processing workflows (25,56). In 40 children with PAH, Schäfer and colleagues demonstrated that different measures of wave intensity correlated with mean PAP, RV size and function (25). The same group also demonstrated that pulmonary artery stiffness is associated with functional worsening of disease severity and might therefore be helpful for determining prognosis and monitoring disease progression in children with PAH (24,25).
As an alternative to quantify RV afterload, Pandya and colleagues verified a technique to analyze the position of the interventricular septum (septal curvature) (57-59) in pediatric PH patients using real-time CMR cine imaging. This group compared septal curvature metrics with simultaneously assessed invasive PAP at baseline and during vasodilator testing with NO (21). They found a significant correlation between mean PAP the interventricular septal curvature that also accurately tracked changes of PAP during pulmonary vasodilation.
Pulmonary arterial wall shear stress (WSS)
Pulmonary vascular endothelial dysfunction is an important mechanism involved in the pathophysiology of PH (60). Reduced WSS impairs vasorelaxation properties in the pulmonary vasculature and acts as a major contributor to adverse remodeling and PH. By using CMR phase contrast flow, quantification of WSS along the main pulmonary artery (MPA) lumen has been performed and demonstrated significant lower values compared to healthy controls (see Figure 5) (24). Lower WSS was also related to increased proximal pulmonary artery stiffness and reduced RV myocardial function (26). Whether assessment of WSS serves as an early indicator of clinical decline or allows monitoring of the response to PH targeted therapy remains unknown.
RV myocardial deformation and synchrony
RV dysfunction is associated with significant morbidity and mortality in patients with PH and represents the leading cause for death in the adult PH population (36,61). As seen with LV dysfunction, myocardial deformation parameters seem potentially more sensitive to detect an early decline in RV function before global pump function (i.e., EF) decreases. Several echocardiographic studies in adults and children with PH found RV myocardial strain to correlate with disease severity, global hemodynamics and outcome (62). CMR based techniques to characterize myocardial contraction include (time consuming) tagging techniques and post-processing software tools such feature tracking/tissue tracking techniques that allow rapid strain quantification from standard cine images. Data regarding CMR based RV strain analysis in PH patients is limited to a study in adult patients by de Siqueira et al. that demonstrated the feasibility to quantify RV strain in this population, correlated with disease severity and was an independent predictor of poor outcome (see Figure 6) (30). In children with PH, Schäfer and colleagues analyzed RV mechanics including strain and synchrony by CMR and found important associations with the presence of electrical dyssynchrony (assessed by QRS z-scores) and impaired RV function (31). Finally, characterization of right atrial deformation, either by echocardiography or CMR, seems to add important hemodynamic and prognostic information (63-65).
RV-pulmonary arterial coupling
The framework of ventricular-arterial coupling (VAC) has emerged as an important parameter in patients with PAH that carries prognostic significance in both the adult and pediatric PH population (66-68). VAC is estimated as the ratio of the two measures pulmonary arterial elastance Ea and ventricular elastance Ees. Pulmonary arterial elastance Ea is defined as the ratio of ventricular end-systolic pressure divided by stroke volume and incorporates all elements of total ventricular afterload including peripheral resistance, arterial compliance and characteristic impedance. Ventricular end-systolic elastance Ees describes a load-independent parameter of myocardial contractility and is defined as the ratio of ventricular end-systolic pressure and end-systolic volume. It has been demonstrated that normal RV functional adaptation to afterload is associated with maintenance of an Ea/Ees ratio of about 0.5 to 1.0, allowing for flow output at a low amount of oxygen consumption. Although usually determined by invasive assessment of ventricular pressure-volume loops under various loading conditions, Sanz and colleagues demonstrated that VAC can be determined non-invasively using CMR by the measure end-systolic volume divided by stroke volume (27). Although the proposed assumption seems error-prone (69), Truong and colleagues were able to confirm its usefulness in a smaller cohort of pediatric patients with miscellaneous types of PH (28). They also noted that VA uncoupling was already present in non-responders to NO suggesting that this concept is particularly valuable to serially follow PH patients over time (70). In an extension of their previous study and including data from a second pediatric PH centre, this group demonstrated that both invasively and non-invasively assessed VAC correlated with functional and hemodynamic measures of disease severity (29).
Ventricular and vascular right-left heart interactions
Although LV and RV function are usually considered separately, a considerable myocardial cross-talk between the two ventricles exists through a shared septum and pericardium (71,72). In the presence of increased RV pressure due to a rise in PA pressures, abnormalities in systolic and diastolic LV function evolve (73). Attempts to identify underlying pathophysiological mechanisms and assessing the clinical relevance of LV dysfunction in pediatric patients with PH have been made. As a result of an altered position of the interventricular septum, impaired LV diastolic filling (74,75) and reduced LV torsion have been reported in PH patients (76). Progressive electrical dyssynchrony occurring with RV dilatation and dysfunction further contributes to systolic LV dysfunction and a discoordinate contraction pattern that, in turn, is of prognostic relevance (31,32). Accompanied by adverse interactions on the ventricular level, increased stiffness of the ascending aorta seems to be present and is directly related to MPA distension. As a consequence of increased afterload, VA uncoupling and LV dysfunction may occur that compromise systemic arterial hemodynamics (77).
Combined CMR with cardiac catheterization
If PH is suspected, right-heart catheterization with vasoreactivity testing is considered as the gold standard for diagnosis and also provides information to guide medical therapy and to assess prognosis. New options for PAP evaluation by CMR-guided cardiac catheterization make it feasible to perform the procedure without ionizing radiation (see example in Figure 7) (33,78,79). This represents a very attractive option for diagnosis of PH especially in children and might become more widely available in the near future even in conventional CMR environments. Recently, Knight et al. showed in 50 adult patients, the majority presenting with PH, that the examination is feasible with short examination times (34). Additionally, simultaneous assessment of cardiac output by phase contrast flow allows a more reliable calculation of PVR compared to conventional techniques (thermodilution or oximetry). In a study by Pushparajah and colleagues (14), both CMR and invasive fluoroscopic guided cardiac catheterization were performed to calculate PVR in 108 patients with biventricular circulation and left-to-right shunt lesions that were evaluated for suitability for surgical correction. The authors were able to define a cut-off in baseline Qp/Qs of ≤2.75 predicted a PVR ≥6 WU.m2 with 100% sensitivity and 48% specificity (14). Accordingly, CMR augmented cardiac catheterization allows accurate stratification for intervention in patients with biventricular CHD. Finally, creation of pressure-volume loops from simultaneous assessment of RV pressure and volume by CMR cine images may provide a more precise calculation of ventricular contractility Ees, load-independent parameters of ventricular stiffness and VAC (79-81).
Innovative CMR imaging techniques and potential future applications
The role of 4-dimensional (4D) CMR flow imaging has been evaluated in patients with PH. Visualization of flow pattern with vortex formation (82), WSS (83), PWV, kinetic energy loss (84) and intraventricular flow (85) were derived from a 4D data set and may add in the non-invasive diagnosis and hemodynamic assessment of PH patients. By comparing pulmonary artery flow hemodynamics in children and adults with PAH matched for similar PVR, Schäfer and colleagues demonstrated that the variability in flow hemodynamic abnormalities was higher in children whereas reduced WSS contributed to adverse pulmonary vascular hemodynamics in both groups (86). Furthermore, this group demonstrated the usefulness of 4D flow in a patient after complex palliation with a Potts shunt by illustrating a primary right-to-left shunt through the shunt (87). At last, based on CMR data, developments in the area of artificial intelligence with deep learning algorithms (88) and computational modeling (89) may improve risk stratification in PH patients.
Provenance and Peer Review: This article was commissioned by the Guest Editors (Christian Apitz and Astrid Lammers) for the series “Pediatric Pulmonary Hypertension” published in Cardiovascular Diagnosis and Therapy. The article has undergone external peer review.
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure forms (available at http://dx.doi.org/10.21037/cdt-20-270). The series “Pediatric Pulmonary Hypertension” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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