Author + information
- Received March 13, 2014
- Revision received August 7, 2014
- Accepted August 15, 2014
- Published online December 1, 2014.
- Andrew J. Swift, PhD∗,†∗ (, )
- Smitha Rajaram, MD∗,
- Dave Capener, MSc∗,
- Charlie Elliot, MBChB‡,
- Robin Condliffe, MD‡,
- Jim M. Wild, PhD∗ and
- David G. Kiely, MD‡
- ∗Unit of Academic Radiology, University of Sheffield, Sheffield, United Kingdom
- †INSIGNEO, Institute for In Silico Medicine, University of Sheffield, United Kingdom
- ‡Sheffield Pulmonary Vascular Disease Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
- ↵∗Reprint request and correspondence:
Dr. Andrew J. Swift, Academic Unit of Radiology, C Floor, Royal Hallamshire Hospital, University of Sheffield, Glossop Road, Sheffield S10 2J, United Kingdom.
Objectives The goal of this study was to determine the prognostic value of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) features in patients with pulmonary hypertension.
Background The prognostic significance of LGE in the clinical assessment of patients with pulmonary hypertension remains uncertain.
Methods Consecutive patients with suspected pulmonary hypertension seen at a specialist pulmonary hypertension referral center who underwent right heart catheterization and CMR with LGE imaging within 48 h were identified. Short-axis late-enhancement imaging was performed using a 3-dimensional gradient spoiled echocardiography sequence on a 1.5-T scanner. Three groups were identified: 1) no late enhancement of the myocardium; 2) late enhancement at the right ventricular insertion points (LGE-IP); and 3) late enhancement involving the right ventricular insertion points and the interventricular septum (LGE-S).
Results Of 194 patients, 162 had pulmonary hypertension. LGE was identified in 135 of 162 (83%) patients with pulmonary hypertension, and 47 (29%) of patients demonstrated LGE-S. Patients with LGE-S had significantly higher right ventricular end-diastolic volume index (p = 0.013) and lower mixed venous oxygen saturation (p = 0.045) than patients with LGE-IP alone. The presence of LGE-S (p = 0.022), but not LGE-IP alone, right ventricular end-systolic volume (p = 0.045), right ventricular ejection fraction (p = 0.034), mixed venous oxygen saturation (p = 0.021), mean right atrial pressure (0.027), and male sex (p = 0.002) predicted mortality. At multivariate analysis, male sex was the only significant predictor of mortality independent of covariate predictors (p = 0.027).
Conclusions The presence of LGE at the right ventricular insertion points is suggestive of the presence of pulmonary hypertension. LGE may also be more extensive, involving the septum; however, after multivariable analysis including other factors associated with pulmonary hypertension, septal LGE was not associated with an increase in overall mortality.
- cardiac magnetic resonance
- idiopathic pulmonary arterial hypertension
- prognosis right ventricle
- pulmonary hypertension
Pulmonary hypertension is defined as a mean pulmonary artery pressure (mPAP) ≥25 mm Hg at right heart catheterization. Pulmonary hypertension is classified into 5 groups: 1) pulmonary arterial hypertension (PAH); 2) pulmonary hypertension because of left-sided heart disease; 3) pulmonary hypertension associated with lung disease and/or hypoxemia; 4) pulmonary hypertension that is due to chronic thromboembolic disease (CTEPH); and 5) a miscellaneous group (1). Given the nonspecific nature of the symptoms of pulmonary hypertension, there is increasing interest in improving noninvasive approaches to diagnosis. Specific treatments are available for PAH and CTEPH where severe elevation of pulmonary vascular resistance (PVR) usually occurs (2). The optimal treatment strategy is not clear, but there is a general consensus that patients with more severe disease should have intensive therapy. Consequently, there is increasing interest in the role of various modalities in risk stratification.
Right ventricular failure occurs as a result of prolonged elevation of mPAP and PVR, and is considered the key determinant of adverse outcome in patients with PAH and CTEPH (3–6). Improving our understanding of the nature of right ventricular failure in pulmonary hypertension is, therefore, of value. Cardiac magnetic resonance (CMR) is a noninvasive, nonionizing, and reproducible method of assessing right ventricular morphology and function (7–11). The addition of LGE CMR allows evaluation of the health of the myocardium through the accumulation of gadolinium. Several patterns of myocardial LGE have been described in ischemic and nonischemic pathologies (12–14), and studies have assessed LGE in patients with pulmonary hypertension (5,15–18).
The clinical significance of LGE as a clinical marker in the context of pulmonary hypertension remains uncertain. Two typical patterns of LGE exist in pulmonary hypertension: involvement of the right ventricular insertion points alone and LGE of the interventricular septum and the insertion points. The prognostic significance of these 2 subphenotypes and the clinical value of LGE in relation to CMR right ventricular indexes and invasive metrics measured at right heart catheterization remain uncertain. The aim of this study was to evaluate the prognostic value of LGE, CMR, and invasive hemodynamics in patients with suspected pulmonary hypertension.
Consecutive treatment-naive patients undergoing right heart catheterization and CMR for suspected pulmonary hypertension were identified at a high-volume, nationally designated pulmonary hypertension referral center. Patients with suspected pulmonary hypertension attending the Sheffield Pulmonary Vascular Disease Unit routinely undergo CMR as part of their diagnostic work-up. Inclusion criteria required the patients’ right heart catheter and CMR imaging to be performed within 48 h. Exclusion criteria were as per standard criteria for patients undergoing CMR. Approval for retrospective analysis of imaging techniques was granted by the local research ethics committee.
CMR image acquisition
CMR imaging was performed on a 1.5-T whole-body scanner GE HDx (GE Healthcare, Milwaukee, Wisconsin), using an 8-channel cardiac coil. Four-chamber and short-axis cine images were acquired using a cardiac gated multislice balanced steady-state free precession sequence (20 frames per cardiac cycle, slice thickness 8 mm, FOV 48, matrix 256 × 256, BW 125 KHz/pixel, TR/TE 3.7/1.6 ms). A stack of images in the short-axis plane with slice thickness of 8 mm (2-mm interslice gap) were acquired fully covering both ventricles from base to apex. End-systole was considered to be the smallest cavity area. End-diastole was defined as the first cine phase of the R-wave–triggered acquisition.
Ten minutes following gadolinium contrast injection (0.1 mmol/kg of gadolinium-DTPA; Gadovist, Bayer, Germany), late-enhancement imaging was performed using a 2-dimensional inversion-recovery prepped fast gradient echocardiography sequence (repetition time 7.1 ms, echo time 3.4 ms, slice thickness 8 mm, FOV 45 × 40.5, matrix 256 × 224). Effective myocardial nulling was achieved with TI, typically ranging from 100 to 160 ms, with the inversion-recovery sequence triggered on each R-R interval with triggering on each heartbeat. A selective 180° inversion-recovery triggered to end-diastole was acquired in the short axis, obtaining limited 3 to 5 slices through the ventricles. Studies were performed with patients in the supine position with a surface coil and with retrospective electrocardiogram gating.
Image analysis was performed on a GE Advantage Workstation 4.1, by a radiologist experienced in CMR, who was blinded to the patient’s clinical information and cardiac catheter parameters. A second observer experienced in CMR analyzed the LGE images blinded to the clinical data and blinded to the first observer’s results. The scans were defined as nondiagnostic when image quality significantly affected cardiac measurements or volumetric analysis could not be accurately performed.
Right and left ventricular volumes
Endocardial surfaces were manually traced from the stack of short-axis cine images, using our MR workstation software (GE Advantage Workstation ReportCard) to obtain right ventricular end-diastolic volume (RVEDV), right ventricular end-systolic volume (RVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV). The RVEF was calculated as: RVEF = (RVEDV − RVESV)/RVEDV × 100). Right ventricular stroke volume (SV) was calculated: as RVEDV − RVESV. Right ventricular volume measurements were indexed for body surface area (BSA) where appropriate, for example, RVEDV indexed for BSA is represented as RVEDVI. Left ventricular ejection fraction was defined as: LVEDV − LVESV/LVEDV × 100 and left ventricular SV as LVEDV − LVESV.
Right ventricular mass and ventricular mass index
The right ventricular epicardial and endocardial borders on each end-diastolic short-axis slice image were outlined. The interventricular septum was considered as part of the left ventricle. The myocardial volume for each slice was calculated by multiplying the area of the right ventricular wall by the slice thickness. The product of the sum total of the myocardial slice volumes for each ventricle and the density of myocardium (1.05 g/cm3) was used to estimate right ventricular end-diastolic mass (RVEDM) (10). RVEDM index was defined as RVEDM/BSA measured in g/m2. The left ventricular epicardial and endocardial borders on each end-diastolic short axis slice were outlined, left ventricular end diastolic mass was thus derived. Ventricular mass index (VMI) was defined as RVEDM divided by left ventricular end-diastolic mass.
Late gadolinium enhancement
Late gadolinium–enhanced images were qualitatively assessed for hyperintensity at the interventricular insertion points or along the interventricular septum. The presence or absence of delayed enhancement was also recorded. We scored images as no LGE, LGE involving the right ventricular insertion points (LGE-IP), and LGE involving both the right ventricular insertion points and the interventricular septum (LGE-S), as previously described (15) (Figure 1).
Right heart catheterization and clinical evaluation
Right heart catheterization was performed using a balloon-tipped 7.5-F thermodilution catheter (Becton-Dickinson, Franklin Lakes, New Jersey). Patients referred for the investigation of suspected pulmonary hypertension also underwent detailed clinical evaluation including blood testing, echocardiography, computed tomography scanning, lung function testing, exercise testing, and perfusion lung imaging as appropriate. Patients with mPAP ≥ 25 mm Hg were classified as having pulmonary hypertension, with patients with mPAP < 25 mm Hg classified as having no pulmonary hypertension. Diagnostic classification of the form of pulmonary hypertension was by standard criteria following multidisciplinary assessment. PVR was determined as follows: PVR in dynes = 80 × (mPAP − pulmonary capillary wedge pressure/cardiac output). Data are also provided for the mixed venous oxygen saturation sampled from the pulmonary artery.
Comparisons of CMR measurements between patients with “no pulmonary hypertension” and patients with pulmonary hypertension were analyzed using the independent Student t test for continuous data and the chi-square for categorical data. World Health Organization (WHO) functional class was dichotomized into groups I and II versus groups II and IV. The Fisher exact test was used to determine the diagnostic strength of the presence of LGE, and the sensitivity, specificity, negative predictive value, positive predictive value, and likelihood ratios were calculated. Kaplan-Meier analysis assessed the prognostic value of LGE imaging in patients with pulmonary hypertension. Groups were compared by means of the log-rank test. The interval from completion of evaluation with CMR and right heart catheterization until all-cause death, transplantation, or census was regarded as the overall follow-up period. The prognostic value of LGE, CMR and right heart catheter data, and patient age and sex were assessed using univariate Cox proportional hazards regression analysis in patients with pulmonary hypertension. Variables significant at p < 0.05 were entered into a multivariate Cox proportional hazards model. Stepwise backwards elimination was used to determine independent prognostic significance. To perform and display the statistics, SPSS version 18 (SPSS, Chicago, Illinois) and GraphPad Prism version 5.03 (GraphPad Software, San Diego, California) software were used. A p value <0.05 was considered statistically significant.
A total of 198 patients with suspected pulmonary hypertension who underwent CMR including LGE imaging were identified. Four patients had studies that were excluded because of suboptimal scans, leaving 194 patients. One hundred sixty-two patients were diagnosed with pulmonary hypertension, and 32 patients with no pulmonary hypertension. Of the patients with pulmonary hypertension, 81 had PAH (36 idiopathic PAH, 35 PAH-connective tissue disease, 7 PAH-congenital heart disease, 3 PAH-portal), 20 had pulmonary hypertension because of left heart disease, 17 had pulmonary hypertension associated with lung disease and/or hypoxemia (PH-lung), and 44 had CTEPH.
Table 1 presents demographic, invasive hemodynamic, and CMR indexes in patients with pulmonary hypertension, and those with no pulmonary hypertension. The presence of LGE was identified in 135 of 162 (83%) patients with pulmonary hypertension, and LGE was present in 3 of 32 (9%) patients with no pulmonary hypertension. Thus, the presence of LGE had high diagnostic accuracy for the detection of pulmonary hypertension, but could not confidently exclude the presence of disease, with sensitivity 83% (77% to 89%), specificity 90% (75% to 98%), positive predictive value 98% (94% to 100%), and negative predictive value 52% (38% to 65%). Table 2⇓ details the demographic, hemodynamic, and CMR indexes in individual subgroups of pulmonary hypertension.
Eighty-eight of 162 (54%) had LGE-IP alone, and 47 (29%) demonstrated LGE-S. Patients with LGE-S had significantly higher RVEDV (p = 0.019) than patients with LGE-IP alone. LVEDV and SV were significantly lower in patients with PH when compared with controls (p = 0.001 and p = 0.001, respectively); however, there was no significant difference in LVESV, LVEDV, left ventricular ejection fraction, or LVSV between patients with LGE-IP versus LGE-S (p = 0.282 to 0.907). The mixed venous oxygen saturation of blood sampled from the pulmonary artery was also lower in patients with LGE-S compared with those with LGE-IP alone (p = 0.045) (Table 3). No significant differences in mPAP, mean right atrial pressure, PVR, cardiac index, and VMI were identified between LGE-S and LGE-IP groups.
The median time between baseline measurements to the end of the study was 36 months (interquartile range: 12 to 48 months); during the follow-up period, 39 patients with pulmonary hypertension died. As shown in Figure 2, at Kaplan-Meier analysis, patients with LGE-S had worse outcome than those patients with LGE-IP (p = 0.026). LGE-S (p = 0.022) was associated with adverse outcome at Cox proportional hazards analysis (Table 4), whereas the presence of LGE-IP alone was not associated with adverse outcome (p = 0.773). RVEF and RVESV were also significant CMR predictors of mortality (p = 0.034 and p = 0.045, respectively). VMI was not a predictor of adverse outcome (p = 0.384). Nonsurvivors with pulmonary hypertension had higher mean right atrial pressure (p = 0.027), higher WHO functional class (p = 0.029), and lower mixed venous oxygen saturation (p = 0.021) than survivors. Male sex was also associated with worse outcome (p = 0.002) at univariate analysis and was the only significant predictor of outcome at multivariate analysis (p = 0.027); of particular note, LGE-S was not predictive of mortality at multivariate analysis.
Interobserver agreement for LGE
There was good interobserver agreement for grading the LGE appearances (K = 0.81).
The results of this study demonstrate that the presence of LGE-IP is a characteristic feature of pulmonary hypertension, but the presence of LGE in these insertion points does not forecast mortality. Subsets of patients with pulmonary hypertension exhibit more extensive LGE that occurs throughout the interventricular septum. Importantly, after considering other factors associated with the severity of pulmonary hypertension, the presence of LGE-S does not forecast an additional increase in mortality risk.
The prevalence of LGE in this study is similar to that previously found by Blyth et al. (15) (23 of 25 patients with pulmonary hypertension) and Sanz et al. (16) (41 of 42 patients with pulmonary hypertension), supporting the hypothesis that LGE in pulmonary hypertension is characteristic. It has recently been suggested by Freed et al. (5) that the presence of LGE at the right ventricular insertion points is a feature of poor outcome in patients with pulmonary hypertension. In our study, LGE of the right ventricular insertion points alone was not associated with adverse outcome; these patients had a similar outcome to the pulmonary hypertension patients without visible LGE. By contrast, patients identified with LGE involving the interventricular septum in addition to the insertion points had a worse outcome. We postulate that simple enhancement at the right ventricular insertion points is a diagnostic metric, with clinical utility for screening for pulmonary hypertension. Whereas the severity of the enhancement, in particular extension of the LGE into the interventricular septum in our study, is a feature associated with poor outcome, we note however that LGE of the septum was not an independent marker of adverse outcome.
CMR measurements of RVEDV, RVEF (19), mass (20,21), pulsatility (22–24), and flow (25,26) have proven to be of clinical value in the assessment of patients with pulmonary hypertension, and recent studies have identified the prognostic value of volumetric and functional CMR measurements in the baseline and serial assessment of patients with PAH (3,4,27). van Wolferen et al. (4) studied the prognostic value of CMR measurements in 64 patients with idiopathic PAH. They found, a large RVEDV, low LVEDV, and low SV to be associated adverse outcome, and changes in these metrics at follow-up were predictive of mortality. More recently from the same group, van de Veerdonk et al. (3) showed that progressive reduction in RVEF at follow-up predicts mortality independent of pulmonary vascular resistance. In our study, RVEF like LGE involving the interventricular septum predicted mortality at univariate analysis but was not found to be independent of sex. Shehata et al. (28) studied LGE in pulmonary hypertension patients. They found the mass of LGE correlated with invasive hemodynamics, reduced RVEF, increased right ventricular mass, and reduced eccentricity index (28). We note that low LVEDV (3) and SV have previously been identified as prognostic markers in patients with PAH and in selected idiopathic PAH cohorts (29); however, LVEDV, LVESV, and LVEF and SV were not found to be significantly predictive in this mixed cohort of patients with pulmonary hypertension.
Measuring the severity of LGE CMR is challenging, Blyth et al. (15) measured the mass of late gadolinium–enhanced myocardium, which correlated well with right ventricular volume, mass, RVEF, and mPAP. The authors also qualitatively assessed the severity of LGE by dividing patients into with and without septal enhancement, as in our study. Patients with paradoxical septal motion evident in early diastole characteristically demonstrated late septal gadolinium enhancement, suggesting that late enhancement is related to strain at interventricular insertion points. When these 2 groups were compared, patients with LGE-S had significantly larger right ventricular volume and lower mixed venous oxygen saturation than those with LGE-IP.
Mechanism of LGE in pulmonary hypertension
The underlying mechanism of LGE in pulmonary hypertension is not fully understood. Myocardial fibrosis as a result of mechanical stress on the myocardium at the right ventricular insertion points in pulmonary hypertension is believed to be an etiological factor leading to LGE. In a study by McCann et al. (17), histology was obtained in 2 patients with PAH who died and underwent autopsy. Fibrosis was present at the right ventricular insertion points. However, there was also evidence of interstitial space expansion, which may result in accumulation of gadolinium and resultant hyperenhancement. Unfortunately, no direct correlation with LGE imaging was possible because the 2 patients did not undergo CMR. Bradlow et al. (30) undertook a pathological correlation of insertion-region enhancement in PAH with LGE images in a patient who died from idiopathic PAH. Microscopy of myocardium from the insertion point revealed myocardial disarray and increased collagen and fat between fiber bundles, but no evidence of replacement fibrosis. The authors suggest that LGE in PAH may not directly infer underlying myocardial fibrosis. The mechanism leading to myocardial LGE and changes in the LGE appearance over time in patients with pulmonary hypertension warrants further investigation. Methods such as native T1 mapping, extracellular volume imaging, and T2 mapping may allow for quantitation of the myocardial changes in pulmonary hypertension, and may better characterize the presence and extent of changes such as edema, fibrosis, and disarray.
The presence of LGE of the myocardium is a common feature of pulmonary hypertension. Characteristically, the right ventricular insertion points are involved with frequent extension of LGE into the interventricular septum. Whereas the presence of LGE at the right ventricular insertion points is of diagnostic value, the presence of LGE at the interventricular septum is associated with more right ventricular dilation despite a similar afterload. Importantly, however, after multivariable analyses considering other factors associated with pulmonary hypertension, the presence of septal LGE confers no additional increase in mortality.
Dr. Condliffe has received funding for advisory boards from Actelion, GlaxoSmithKline, Bayer and Pfizer; and honoraria and conference fees from Actelion, GlaxoSmithKline, Bayer and Pfizer. Dr. Kiely has received payment for participation in advisory boards from Actelion, Bayer, Chiesi, GlaxoSmithKline, Pfizer, and United Therapeutics; speaker fees from Actelion, Bayer, Chiesi, GlaxoSmithKline, Pfizer, and United Therapeutics; and his department has received unrestricted educational grants to fund staff for education and research from Actelion, Bayer, and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- body surface area
- cardiac magnetic resonance
- chronic thromboembolic disease
- late gadolinium enhancement
- late gadolinium enhancement at the right ventricular insertion points
- late gadolinium enhancement at the interventricular septum
- left ventricular end-diastolic volume
- left ventricular end-systolic volume
- mean pulmonary artery pressure
- pulmonary arterial hypertension
- pulmonary vascular resistance
- right ventricular end-diastolic mass
- right ventricular end-diastolic volume
- right ventricular ejection fraction
- right ventricular end-systolic volume
- stroke volume
- ventricular mass index
- World Health Organization
- Received March 13, 2014.
- Revision received August 7, 2014.
- Accepted August 15, 2014.
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