Author + information
- Received April 19, 2017
- Revision received February 12, 2018
- Accepted February 15, 2018
- Published online April 18, 2018.
- Daniel S. Knight, MBBS, MD(Res)a,
- Giulia Zumbo, MDa,
- William Barcella, PhDb,
- Jennifer A. Steeden, M.Eng, PhDc,
- Vivek Muthurangu, MDc,
- Ana Martinez-Naharro, MDa,
- Thomas A. Treibel, MBBSd,
- Amna Abdel-Gadir, MBBSd,
- Heerajnarain Bulluck, MBBS, PhDe,
- Tushar Kotecha, MBChBa,
- Rohin Francis, MBBSa,
- Tamer Rezk, MBBSa,
- Candida C. Quarta, MD, PhDa,
- Carol J. Whelan, MDa,
- Helen J. Lachmann, MDa,
- Ashutosh D. Wechalekar, MD, PhDa,
- Julian D. Gillmore, MD, PhDa,
- James C. Moon, MDd,
- Philip N. Hawkins, PhD, FMedScia and
- Marianna Fontana, MD, PhDa,∗ ()
- aNational Amyloidosis Centre, University College London, Royal Free Hospital, London, United Kingdom
- bDepartment of Statistical Science, University College London, United Kingdom
- cCentre for Cardiovascular Imaging, Institute of Cardiovascular Science, University College London and Great Ormond Street Hospital for Children, London, United Kingdom
- dBarts Heart Centre, St. Bartholomew’s Hospital, London, United Kingdom
- eThe Hatter Cardiovascular Institute, Institute of Cardiovascular Science, University College London, United Kingdom
- ↵∗Address for correspondence:
Dr. Marianna Fontana, Centre for Amyloidosis & Acute Phase Proteins, Division of Medicine (Royal Free Campus), University College London, Rowland Hill Street, London NW3 2PF, United Kingdom.
Objectives This cross-sectional study aimed to describe the functional and structural cardiac abnormalities that occur across a spectrum of cardiac amyloidosis burden and to identify the strongest cardiac functional and structural prognostic predictors in amyloidosis using cardiac magnetic resonance (CMR) and echocardiography.
Background Cardiac involvement in light chain and transthyretin amyloidosis is the main driver of prognosis and influences treatment strategies. Numerous measures of cardiac structure and function are assessed by multiple imaging modalities in amyloidosis.
Methods Three hundred twenty-two subjects (311 systemic amyloidosis and 11 transthyretin gene mutation carriers) underwent comprehensive CMR and transthoracic echocardiography. The probabilities of 11 commonly measured structural and functional cardiac parameters being abnormal with increasing cardiac amyloidosis burden were evaluated. Cardiac amyloidosis burden was quantified using CMR-derived extracellular volume. The prognostic capacities of these parameters to predict death in amyloidosis were assessed using Cox proportional hazards models.
Results Left ventricular mass and mitral annular plane systolic excursion by CMR along with strain and E/e’ by echocardiography have high probabilities of being abnormal at low cardiac amyloid burden. Reductions in biventricular ejection fractions and elevations in biatrial areas occur at high burdens of infiltration. The probabilities of indexed stroke volume, myocardial contraction fraction, and tricuspid annular plane systolic excursion (TAPSE) being abnormal occur more gradually with increasing extracellular volume. Ninety patients (28%) died during a median follow-up of 22 months (interquartile range: 10 to 38 months). Univariable analysis showed that all imaging markers studied significantly predicted outcome. Multivariable analysis showed that TAPSE (hazard ratio: 1.46; 95% confidence interval: 1.16 to 1.85; p < 0.01) and indexed stroke volume (hazard ratio: 1.24; 95% confidence interval: 1.04 to 1.48; p < 0.05) by CMR were the only independent predictors of mortality.
Conclusions Specific functional and structural abnormalities characterize different burdens of cardiac amyloid deposition. In a multimodality imaging assessment of a large cohort of amyloidosis patients, CMR-derived TAPSE and indexed stroke volume are the strongest prognostic cardiac functional markers.
Systemic amyloidosis is a fatal disease caused by the progressive deposition of abnormal insoluble protein fibrils in the extracellular space, leading to the loss of normal tissue architecture and function (1). Cardiac amyloidosis is due to intramyocardial amyloid infiltration, which leads to progressive structural and functional changes (2,3). The most frequent types of systemic amyloidosis associated with clinically relevant cardiac involvement are light-chain amyloidosis (AL) due to a clonal plasma cell dyscrasia, which produces the immunoglobulin light chains of the fibrillary deposits; hereditary, transthyretin (TTR)–related form (ATTRm), which can be caused by more than 100 mutations of TTR, a transport protein mainly synthesized by the liver; and wild-type (non-mutant) TTR-related amyloidosis (ATTRwt), which mainly affects the hearts of elderly men (1).
Cardiac involvement in both AL and ATTR amyloidosis is the main predictor of mortality and influences therapeutic choices (4,5). Late gadolinium enhancement (LGE) and extracellular volume (ECV) assessment by cardiac magnetic resonance (CMR) are known to be diagnostic and prognostic in cardiac amyloidosis (2). Echocardiography and CMR are both commonly used imaging modalities to assess cardiac amyloidosis that generate a plethora of functional and structural metrics aside from tissue characterization parameters. Many of these cardiac functional and structural parameters show prognostic value when studied in isolation (3,6–12). However, their relative prognostic importance and their behavior in the natural history of cardiac infiltration have never been investigated.
The aims of this study were to describe the functional and structural cardiac abnormalities that occur across a spectrum of cardiac amyloid burden in AL and ATTR cardiac amyloidosis, and to identify the strongest cardiac functional predictors of prognosis in systemic amyloidosis.
Subjects were recruited at the National Amyloidosis Centre, Royal Free Hospital, London, United Kingdom, from 2010 to 2015. A retrospective, cross-sectional analysis of 433 patients who underwent CMR and echocardiography was performed. Patients with datasets not containing all of the structural and functional cardiac metrics selected for analysis in this study were excluded. The remaining 322 patients were categorized into 3 groups:
1. Subjects with AL amyloidosis: 133 patients with biopsy-proven systemic AL amyloid (86 men, 65%; age 66 [range 57 to 71] years), with biopsy specimens from the myocardium (n = 7, 5%) or other tissues (n = 126, 95%).
2. Subjects with ATTR amyloidosis: 158 patients (139 men, 88%; age 74 ± 8 years) with cardiac ATTR amyloidosis and 20 with suspected cardiac ATTR amyloidosis (12 men, 60%; age 70 ± 15 years) were recruited. The definitions of definite and suspected cardiac ATTR amyloidosis have been previously described (13,14). To summarize, cardiac ATTR amyloidosis was defined as the combination of symptoms with an echocardiogram consistent with or suggestive of cardiac amyloidosis, grade 2 or 3 cardiac uptake on the technetium 99m (99mTc)–labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy in the absence of a monoclonal gammopathy or, in the presence of monoclonal gammopathy, a cardiac biopsy positive for TTR. Suspected cardiac ATTR amyloidosis was defined by grade 1 cardiac uptake on 99mTc-DPD in the absence of monoclonal gammopathy. Seventy-two percent (n = 128) of patients with ATTR amyloidosis had histologic proof of ATTR amyloidosis by Congo red and immunohistochemical staining of myocardial (n = 40, 22%) or other tissues (n = 88, 49%). All subjects underwent sequencing of exons 2, 3, and 4 of the TTR gene.
3. TTR gene mutation carriers: In addition, there were 11 subjects with amyloidogenic TTR gene mutations (4 men, 36%; age 46 ± 8 years) defined as individuals with no evidence of clinical disease (including no cardiac uptake on 99mTc-DPD scintigraphy and normal echocardiography, CMR, N-terminal pro-brain natriuretic peptide and troponin T).
We excluded all patients with datasets not containing all of the structural and functional cardiac metrics selected for analysis. Patients with contraindications to CMR (such as CMR-incompatible devices) were excluded from the original study cohort. Patients with a glomerular filtration rate <30 ml/min underwent a noncontrast study protocol (n = 5) unless informed consent was obtained for a contrast study protocol for clinical diagnostic purposes (n = 4). All ethics were approved by the UCL/UCLH Joint Committees on the Ethics of Human Research Committee, and all participants provided written informed consent.
Echocardiography acquisition and analysis
Echocardiographic assessments were performed using a Vivid E9 ultrasound machine (GE Healthcare, Milwaukee, Wisconsin). Image quality was optimized by adjusting probe frequency (range 1.7 to 2.0 MHz) and temporal resolution (60 to 120 frames/s). Left ventricular (LV) structure, systolic, and diastolic assessment was performed according to published recommendations (15–17). This included the analysis of multiple beats in atrial arrhythmia at the discretion of the clinical study operator. All echocardiography analysis was performed by investigators blinded to the CMR results. The echocardiographic functional parameters assessed in the multivariable model were E/e′ and apical 4-chamber longitudinal global strain (LGS). For the former measure, pulsed-wave tissue Doppler imaging of the septal and lateral mitral annuli in the 4-chamber view was performed to obtain peak early diastolic (e′) tissue velocities, with septal and lateral velocities averaged to obtain a mean value. The peak early diastolic transmitral inflow wave (E) was obtained by pulsed-wave Doppler imaging with the sample volume placed at the tips of the mitral valve in the apical 4-chamber view. Myocardial deformation was assessed using commercially available speckle-tracking software (EchoPac PC dimension software version 112, GE Healthcare). Between 2 to 3 cardiac cycles from an apical 4-chamber view were acquired with appropriate image optimization and digitally stored for offline analysis. The endocardium of the LV was manually traced from the medial and lateral mitral valve annuli and a region of interest (ROI) automatically generated to cover the LV myocardium. The ROIs were adjusted to optimize the tracking quality if needed.
All participants underwent standard CMR on 1.5-T clinical scanners (either Avanto or Aera, Siemens Healthcare, Erlangen, Germany). A standard volume and LGE study was performed in all patients. Retrospectively gated balanced steady state free precession end-expiratory breath-hold cines were acquired covering the bases to apices of both ventricles in the short-axis for patients in sinus rhythm. Patients with atrial arrhythmia had a similarly planned short-axis biventricular stack of cine images acquired using either prospectively gated balanced steady state free precession cines or real-time cine imaging at the discretion of the clinical study operator. Slice thickness was 7 mm with a 3-mm slice gap. The gadolinium-based contrast agent used was 0.1 mmol/kg of gadoterate meglumine (gadolinium-DOTA, marketed as Dotarem, Guerbet SA, Paris, France) for LGE imaging as previously described (2). For native T1 mapping, basal and mid-ventricular short axis images and 4-chamber long-axis images were acquired using the shortened modified look-locker inversion recovery or modified look-locker inversion recovery sequences after regional shimming, as previously described (18).
CMR image analysis
All CMR images and maps were analyzed offline. All CMR analysis was performed by investigators blinded to the echocardiography results. Endocardial borders of both ventricles were manually traced at end-diastole and end-systole, the time points of which were identified by the largest and smallest cavity areas respectively. LV stroke volume (SV) was the difference between the LV end-diastolic volume (EDV) and LV end-systolic volume (ESV), and ejection fraction (EF) was calculated as: (SV/EDV) × 100. LV mass was calculated from the end-diastolic frames by manually tracing an epicardial contour. The papillary muscles and trabeculae were excluded from the blood pool by the endocardial contour (thus they were included when measuring mass and excluded when measuring cavity volumes). Annular plane systolic excursion for both the mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE) was analyzed for the lateral valvular annulus. Maximal biatrial areas were manually traced at the ventricular end-systolic frames from a 4-chamber cine.
ECV was used as the primary measure of cardiac amyloidosis burden, and was calculated as previously described (19). To summarize, T1 values were obtained by drawing a single ROI in each of the 4 required areas: myocardial T1 estimates (basal to mid septum in 4-chamber map) and blood T1 estimates (LV cavity blood pool in 4-chamber map, avoiding the papillary muscles) before and after contrast administration. Hematocrit was obtained in all subjects immediately before each CMR study. ECV was calculated as: myocardial ECV = (1-hematocrit) × (ΔR1myocardium/ΔR1blood), where R1 = 1/T1.
Statistical analysis was performed using SPSS version 24.0 (IBM Corporation, Armonk, New York) and R programming language (R Foundation for Statistical Computing, Vienna, Austria). Data were examined for normality using the Kolmogorov-Smirnov normality test. Descriptive statistics are expressed as mean ± SD when normally distributed and median (interquartile range) when non-normally distributed. Proportions are expressed as percentages. Systematic differences between measurements were evaluated with the Student's t-test (2-tailed) to compare parametric data, and the Mann-Whitney U test was used to compare nonparametric data. The chi-square test or Fisher exact test (2-sided) was used to compare proportions data as appropriate. Comparisons between groups were performed by 1-way analysis of variance for parametric data and by the Kruskal-Wallis 1-way analysis of variance for nonparametric data. Values of p < 0.05 were considered statistically significant.
Eleven functional and structural cardiac variables by echocardiography (E/e′, LGS) and CMR (indexed left atrial [LA] area, indexed LV mass, indexed right atrial [RA] area, indexed SV, LVEF, MAPSE, right ventricular [RV] EF, TAPSE, myocardial contraction fraction [MCF]) were selected a priori based upon clinical relevance. The focus of this study is on the effects of myocardial infiltration on cardiac structure and function, since the prognostic capacities of LGE and ECV assessment in cardiac amyloidosis are already well established (2). Therefore, the statistical analyses included only structural and functional cardiac imaging biomarkers (and no tissue characterization parameters) as the variables under investigation. Biventricular function and biatrial areas were assessed using CMR rather than echocardiography due to the superior accuracy and reproducibility of the former imaging modality for these purposes. MAPSE and TAPSE were also assessed by CMR on the same 4-chamber view as biatrial area measurements as per the standard clinical CMR protocol at our institution. The MCF, defined as the ratio of SV to myocardial volume, has been shown to be prognostic in cardiac amyloidosis (20). Simple logistic regression analysis was performed for evaluating the probability of the selected cardiac structural and functional parameters being abnormal across the spectrum of ECV. Cut-offs for defining abnormalities in these variables were chosen according to published reference guidelines: E/e′ >8 (21), indexed LA area >15 cm2/m2 (22), indexed RA area >16 cm2/m2 (22), LGS <–20% (23), LVEF <57% (22), RVEF <52% (22), indexed SV <42 ml/m2 (22), indexed LV mass >81 g/m2 (22), MAPSE < 11 mm, TAPSE <16 mm, and MCF <38% (24).
Survival was evaluated with Cox proportional hazards regression analysis, providing estimated hazard ratios with 95% confidence intervals (CIs) and Kaplan–Meier curves. The 11 echocardiography and CMR variables along with heart rate at the time of CMR study were first explored with simple Cox regression analysis. The variables that were statistically significant predictors of outcome on simple Cox regression analysis were entered into a multivariable Cox proportional hazards analysis to determine which covariates were independent predictors of mortality. The relationships between candidate predictors were first explored with correlational analysis. Possible collinearity among candidate predictors was subsequently assessed using variance inflation factors with threshold equal to 5. Separate multivariable models were performed to exclude parameters that are derived from one another (e.g., LVEF and MCF both are derived from SV; MCF being derived from SV and myocardial mass). Thus, model A included indexed LV SV and mass (and excluded MCF and LVEF); model B included LVEF and LV mass (SV and MCF were excluded); and model C included MCF (SV, LV mass and LVEF were excluded). Subanalyses of the AL and ATTR amyloidosis patient cohorts were also performed. The Harrell C statistic was calculated for the different models.
Study population characteristics
Details of the 322 subjects are shown in Table 1. The TTR mutations in the 158 patients with definite cardiac ATTR amyloidosis were as follows: V122I, n = 30; T60A, n = 16; V30M, n = 3; E89K, n = 2; and E54G, D38Y, F44L, and I73V, n = 1 each. Of 20 patients with suspected cardiac ATTR amyloidosis, the TTR mutations were as follows: S77Y, n = 3; V122I and V30M, n = 2 each; E54G, G47V, I84S, and I107F, n = 1 each. Of the 11 asymptomatic individuals with TTR mutations, 6 had TTR V30M, 4 had T60A, and 1 had S77Y. Patients with ATTR amyloidosis were older, had poorer renal function, and a higher prevalence of electrocardiographic conduction abnormalities. Twenty-three patients were excluded from ECV analysis due to significant renal impairment precluding gadolinium administration (n = 5) or due to constraints specific to the clinical circumstances (n = 18).
Relationship between noninvasive functional metrics and ECV
The ECV values in the 299 patients who underwent this assessment by CMR were divided into tertiles. Increasing myocardial amyloid burden across these ECV tertiles was associated with several structural and functional changes in both the AL and ATTR patient cohorts (Table 2): more severe diastolic dysfunction and worsening LGS by echocardiography; increased LV mass, increased biventricular end-systolic volumes, decreased biventricular EFs, decreased SV, and worsening biventricular longitudinal function. In ATTR, increasing ECV burden was also associated with increased biventricular end-diastolic volumes and increased biatrial areas.
When using ECV as a marker of cardiac infiltration burden, the CMR and echocardiography functional metrics can be grouped by the probability of becoming abnormal at low or high disease burdens or gradually across the spectrum of myocardial infiltration (Figure 1). Indexed LV mass and MAPSE by CMR along with LGS and E/e′ by echocardiography have a high probability of being abnormal at low cardiac amyloid burdens. Conversely, biventricular EFs and biatrial areas become abnormal at higher burdens of cardiac infiltration. The probabilities of MCF, TAPSE, and indexed SV becoming abnormal increase gradually across the spectrum of ECVs.
Noninvasive functional and structural metrics and prognosis
Ninety patients (28%) died during a median follow-up period of 22 months (interquartile range: 10 to 38 months). All of the imaging metrics studied except for heart rate were predictive of mortality on simple Cox regression analysis (Table 3). Only CMR-derived TAPSE (hazard ratio [HR]: 1.46; 95% CI: 1.16 to 1.85; p < 0.01) and indexed SV (HR: 1.24; 95% CI: 1.04 to 1.48; p < 0.05) remained independently predictive of mortality in a multivariable Cox model adjusted for age and sex (Table 4, Figure 2). Harrell’s C-statistic for this model was 0.73. When performing different multivariable models to avoid statistical coupling of the entered variables, TAPSE remained independently predictive of mortality (Table 4). The marked differences in significance levels from univariable to multivariable analyses are partly due to the correlation among covariates (Online Table 1). However, exploring variance inflation factors and using a threshold equal to 5 found no evidence of collinearity among the parameters entered into the multivariable analyses.
Functional parameters by echocardiography and CMR were also entered into multivariable Cox regression models for AL and ATTR patient subgroups (Online Tables 2 and 3, respectively). In ATTR cardiac amyloidosis, TAPSE was consistently significantly associated with mortality (HR: 1.53; 95% CI: 1.08 to 2.16; p < 0.05; Harrell’s C-statistic 0.729). Three metrics were consistently significantly associated with mortality in AL cardiac amyloidosis, namely, LA area indexed (HR: 1.53; 95% CI: 1.12 to 2.09; p < 0.01), SV indexed (HR: 1.37; 95% CI: 1.03 to 1.83; p < 0.05) and TAPSE (HR: 1.54; 95% CI: 1.08 to 2.18; p < 0.05; Harrell’s C-statistic 0.797).
Relationship between RV LGE and TAPSE
Evidence of RV cardiac amyloidosis involvement, defined by the presence of RV LGE, was determined given the significant association of TAPSE with mortality. An increasing prevalence of RV LGE was observed in both AL and ATTR patient cohorts with increasing amyloid burden measured by ECV (Table 2). Two hundred twenty-nine subjects (70%; 73 [63%] of AL amyloidosis patients, 156 [85%] of ATTR subjects including mutation carriers) on LGE assessment had evidence of RV cardiac amyloidosis, with corresponding significantly lower TAPSE across all patient subgroups (Table 5).
In this study, we comprehensively describe the structural and functional cardiac abnormalities associated with cardiac infiltration using commonly used CMR and echocardiography parameters. To our knowledge, this is also the largest study to identify the strongest prognostic, structural, and functional cardiac imaging metrics in amyloidosis.
EF is a ubiquitous marker conventionally used to describe cardiac function, especially in the setting of heart failure. However, symptoms and signs of cardiac decompensation are known to commonly precede significant deterioration in EF in amyloidosis (25). Our data confirm that biventricular EFs tend to be preserved up until higher burdens of cardiac infiltration, with abnormalities in biatrial size also reflecting the most advanced stages of the disease process. Echocardiography and CMR functional metrics can be divided into a cascade of 3 groups that become abnormal sequentially with increasing cardiac amyloid burden as assessed by ECV quantification. Variables more likely to become abnormal at low levels of cardiac infiltration reflect impairment of LV diastolic function and LV longitudinal dysfunction, both of which are not accounted for by global EF. Despite E/e′ and myocardial mass being generated by different imaging modalities (echocardiography and CMR, respectively), they become abnormal in parallel across increasing amyloid deposition. This reflects the close relationship between amyloid burden and diastolic dysfunction, particularly in early cardiac involvement. LGS and MAPSE also tend to become abnormal at the lower end of the ECV spectrum. Both of these parameters reflect longitudinal impairment, an early marker of systolic dysfunction that is not accounted for by global EF (26). This is especially pertinent in cardiac amyloidosis due to infiltration starting in the subendocardium, predominantly consisting of longitudinal fibers.
LV SV, MCF, and TAPSE constitute the intermediate group of variables with a probability of being abnormal that rises progressively across the spectrum of increasing amyloid burden. In contrast to EF, SV has a high probability of being abnormal in the earlier stages of cardiac amyloid infiltration. This could be due to the initial increase in myocardial mass conferring a smaller end-diastolic cavity volume. However, the likelihood of SV being abnormal then continues to rise with increasing levels of amyloid burden, possibly reflecting the later development of impaired radial function with progression from subendocardial to transmural amyloid deposition. Thus, abnormal SV is likely to represent a composite signal of diastolic dysfunction at low burdens of cardiac amyloidosis and systolic contractile impairment at higher burdens of cardiac infiltration. The progressively increasing likelihood of MCF becoming abnormal with rising ECV reflects the behaviors of the variables from which it is derived, namely, SV and myocardial mass. The likelihood of TAPSE being abnormal also increases gradually across the spectrum of rising myocardial infiltration, whereas global RVEF becomes abnormal at high burdens of cardiac involvement. This difference is likely to be due to TAPSE reflecting infiltration of subendocardial longitudinal fibers in the earlier stages of the disease, whereas radial dysfunction and congestive heart failure manifest late in the natural history of the disease.
Interestingly, TAPSE and indexed SV were the only prognostic markers for mortality in the multivariable model of all amyloidosis patients. TAPSE was the most statistically significant independent marker of prognosis, and was the only prognostic marker common to the subgroup analyses of both AL and ATTR patient cohorts. RV dysfunction is common in cardiac amyloidosis (7). Furthermore, RV failure is a well-documented independent predictor of prognosis in patients with primary left heart failure (27–29). However, direct RV subendocardial infiltration is likely to be the principal reason behind the prognostic importance of TAPSE in amyloidosis, rather than RV dysfunction as a consequence of LV impairment. This is evidenced by the high prevalence of RV LGE in both AL and ATTR patient cohorts, and explains why TAPSE rather than RVEF is the key prognostic marker in amyloidosis overall. This is also in contrast to RV pressure-overload states, whereby radial rather than longitudinal contraction more closely reflects global RV function, with global RVEF being a consistently strong predictor of outcome (30–32). The main finding on subgroup analysis of the AL and ATTR patient cohorts was that LA area was an additional significant prognostic marker in the AL patient cohort, consistent with previous echocardiography studies in AL amyloidosis (33,34). Thus, LA dilatation could represent a structural marker of more advanced disease.
The study was retrospective, with approximately one-quarter of patients excluded due to incomplete data acquisition. However, the number of events in the remaining 322 patients is sufficient for the multivariable analyses. The study design was also cross-sectional, with patients scanned at different stages of presentation and treatment. This might include chemotherapy for patients with AL amyloidosis, with some agents having known cardiotoxic side effects that could also influence the measurement of the variables under investigation. Furthermore, the assessment of disease progression would require serial assessments of these measures in the same individuals over time. Patients with ATTR amyloidosis might be more likely to present at later stages of cardiac infiltration when symptoms of cardiac failure are manifest, reflected by the smallest proportion of ATTR patients being in the lowest ECV tertile (19%). This might affect the changes observed in cardiac markers at low amyloid burdens in this cohort. The inclusion of 20 suspected ATTR cases and 11 asymptomatic TTR gene mutation carriers, all of whom potentially may have subclinical or very early disease, might at least partly offset this limitation. Conversely, the largest proportion of AL patients were in the lowest ECV tertile (62%), again likely representing the manner of clinical presentation. Overall, 23 patients did not have ECV measured either due to significant renal dysfunction or clinical constraints at the time of scanning. Patients with implanted cardiac defibrillators or permanent pacemakers were also excluded from CMR study. Given that these patients are known to have an adverse prognosis, their exclusion could affect the survival analysis. However, these limitations all reflect real-world practice and the presentation of patients for clinical evaluation. The simple logistic regression analysis dichotomized each variable as abnormal or normal according to pre-defined cut-off values derived from healthy populations, rather than from patient populations with cardiac amyloidosis. Although these cut-off values from a normal population would have less direct clinical relevance to a cardiac amyloidosis predominant population, our aim was to describe the behavioral changes in cardiac markers across the spectrum of cardiac infiltration rather than specify the diagnostic threshold of the cut-off values themselves. Finally, cardiac biopsy was performed in a minority of patients, but the entire cohort underwent comprehensive composite noninvasive evaluation including DPD scanning. This is our routine clinical protocol, and is known to deliver high diagnostic accuracy.
In the multimodality cardiac imaging assessment of patients with amyloidosis, TAPSE and LV indexed SV measured by CMR are the most powerful prognostic cardiac functional parameters. They are standard and simply obtained measures, with a likelihood of being abnormal that increases with rising cardiac amyloid burden.
COMPETENCY IN MEDICAL KNOWLEDGE: Cardiac involvement in amyloidosis is the main determinant of prognosis. The behavior and prognostic importance of common cardiac functional and structural markers by echocardiography and CMR have been evaluated in a cross-sectional study of patients with systemic amyloidosis. Both TAPSE and indexed SV have an increasing likelihood of becoming abnormal with rising cardiac amyloid burden, and are independently prognostic in systemic amyloidosis.
TRANSLATIONAL OUTLOOK: The behavior of cardiac structural and functional parameters can be interpreted in relation to the pathophysiology of amyloidosis across the spectrum of cardiac disease burden. Prospective clinical studies of serial cardiac imaging assessments are required to evaluate the progression of structural and functional cardiac measures with increasing myocardial amyloid burden.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Knight and Zumbo contributed equally to this work and are joint first authors.
- Abbreviations and Acronyms
- light-chain amyloidosis
- transthyretin-related amyloidosis
- cardiac magnetic resonance
- extracellular volume
- ejection fraction
- left atrial
- late gadolinium enhancement
- longitudinal global strain
- left ventricular
- mitral annular plane systolic excursion
- myocardial contraction fraction
- right atrial
- right ventricular
- stroke volume
- tricuspid annular plane systolic excursion
- Received April 19, 2017.
- Revision received February 12, 2018.
- Accepted February 15, 2018.
- 2018 American College of Cardiology Foundation
- Fontana M.,
- Pica S.,
- Reant P.,
- et al.
- Quarta C.C.,
- Solomon S.D.,
- Uraizee I.,
- et al.
- Rapezzi C.,
- Merlini G.,
- Quarta C.C.,
- et al.
- Bellavia D.,
- Pellikka P.A.,
- Dispenzieri A.,
- et al.
- Bodez D.,
- Ternacle J.,
- Guellich A.,
- et al.
- Cueto-Garcia L.,
- Reeder G.S.,
- Kyle R.A.,
- et al.
- Klein A.L.,
- Hatle L.K.,
- Taliercio C.P.,
- et al.
- Koyama J.,
- Falk R.H.
- Ternacle J.,
- Bodez D.,
- Guellich A.,
- et al.
- Gillmore J.D.,
- Maurer M.S.,
- Falk R.H.,
- et al.
- Martinez-Naharro A.,
- Treibel T.A.,
- Abdel-Gadir A.,
- et al.
- White S.K.,
- Sado D.M.,
- Fontana M.,
- et al.
- Nagueh S.F.,
- Smiseth O.A.,
- Appleton C.P.,
- et al.
- Akwo E.
- Koyama J.,
- Ray-Sequin P.A.,
- Falk R.H.
- de Groote P.,
- Millaire A.,
- Foucher-Hossein C.,
- et al.
- Ghio S.,
- Gavazzi A.,
- Campana C.,
- et al.
- Moledina S.,
- Pandya B.,
- Bartsota M.,
- et al.
- Zhao L.,
- Tian Z.,
- Fang Q.