Transthyretin (TTR) familial amyloidosis, also known as familial amyloid polyneuropathy (TTR-FAP), is an autosomal dominant inherited disorder caused by mutations in the TTR gene.1

In this disorder, mutated TTR protein precipitates as extracellular amyloid deposits, mainly in peripheral nerves and in the heart.1,2 Although neurological impairment usually dominates clinical manifestations, heart involvement frequently determines the prognosis.2–4

Available treatments for TTR-FAP include liver transplantation5 and the TTR stabilizer tafamidis.6 Several other compounds are under investigation with promising initial results.7 Currently, it is recommended to start drug therapy or proceed with liver transplantation when the first signs and symptoms of neurological impairment are identified.8,9

Unfortunately, when the first symptoms appear, amyloid deposits could be large enough to compromise the patient's clinical course thereafter. Methods to detect early amyloid deposits are therefore needed. Moreover, a method that quantifies the amount of amyloid in the tissues over time would be desirable to monitor treatment response and to establish a cutoff point to start treatment.2

Amyloidotic cardiomyopathy (AC) is one of the leading causes of death in TTR-FAP patients2,3,5 and a significant number of TTR-FAP patients have underdetected cardiac involvement.2,10

The definitive diagnosis of AC requires histological evidence of amyloid deposits2–4; however, endomyocardial biopsy has associated risks and a noninvasive diagnostic approach with imaging techniques is commonly preferred. In patients with genetically confirmed TTR-FAP, AC is accepted in cases of unexplained increased ventricular thickness/mass and typical findings of AC either on 99mTC-DPD scintigraphy or on cardiac magnetic resonance (CMR).2,8,11

T1 mapping CMR techniques allow, through a simple equation, an estimate of the heart volume occupied by extracellular components.12,13 As TTR amyloid deposits are extracellular, cardiac extracellular volume (ECV) value reflects the amount of TTR amyloid deposits in the myocardium and could serve as a tool to diagnose AC and to monitor its progression.13,14 Furthermore, cardiac ECV could reflect the amount of amyloid deposits that are present in other tissues.

The purpose of this study was 2-fold: to determine if increased ECV allows the identification of AC in TTR-FAP patients, and to explore if cardiac ECV correlates with the degree of neurological impairment caused by TTR amyloid extracardiac deposits.

Thirty-one patients (mean age, 49 ± 12 years [range, 34-71]; 19 men [61%]) with genetically diagnosed TTR-FAP were studied. The most common mutation was Val30Met (n = 26 [84%]). Other mutations were delV122 (n = 3 [10%]), Glu89Gln (n = 1 [3%]), and Glu89Lys (n = 1 [3%]). Twenty-one patients (68%) came from the 2 Spanish Val30Met TTR-FAP endemic regions: Huelva (n = 14) and Mallorca (n = 7). Five participants (4 men) with a mean age of 40 ± 6 years were considered mutation carriers, defined as individuals with no evidence of disease. Mutations of asymptomatic genetic carriers were delV122 (n = 3), Glu89Lys (n = 1), and Val30Met (n = 1).

Thirteen patients (42%) had undergone liver transplantation previously and no patient was receiving tafamidis when the CMR study was performed. All transplanted patients in this cohort were Val30Met and belonged to one of the endemic regions. None of them were in the subgroup of asymptomatic carriers as this treatment is only indicated when there are disease manifestations. However, only 1 of these patients had cardiac involvement.

Nineteen patients (61%) showed signs of isolated neurological impairment. Orthostatic hypotension was present in 9 patients (33%) and 12 patients (39%) had gastrointestinal disturbances (constipation/diarrhea). No patient reported urinary tract infections.

Five patients (4 men; mean age, 65 ± 8 years) were diagnosed with AC (Figure 1). Patients with AC were Val30Met (n = 4) and Glu89Gln (n = 1). All patients with AC showed also some degree of neurological impairment.

On CMR study, all patients with AC showed LVH and fast wash-out of gadolinium. The pattern of LGE in patients with AC was diverse: global transmural LGE (n = 2), transmural LGE except in lateral basal and middle segments (n = 1), nonischemic patched LGE (n = 1), and no LGE (n = 1). None of the patients with transmural LGE pattern had other features that suggested the existence of a previous myocardial infarction, such as wall motion abnormalities or thinning of the ventricular wall.

A summary of clinical features and CMR findings is presented in Table 1.

Extracellular Volume and Clinical Features

Mean ECV values increased across clinical groups: 0.242 ± 0.02, 0.296 ± 0.027 and 0.490 ± 0.130) for asymptomatic mutation carriers, only neurological symptoms, and AC, respectively (P < .001) (Figure 3). Inter- and intraobserver variability in ECV showed no significant differences (R = 0.66; P < .005 and R = 0.94; P < .005, respectively).

Figure 3.

Cardiac ECV according to TTR-FAP clinical status. ECV, extracellular volume; TTR-FAP, transthyretin-familial amyloid polyneuropathy.

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Although there was a direct correlation between ECV and age (Table 2), we found no differences in mean ECV by sex (male, 0.325 ± 0.103 vs female, 0.316 ± 0.085; P = .794), cardiovascular risk factors (hypertension 0.357 ± 0.125 vs no hypertension 0.307 ± 0.078; P = .184; and diabetes 0.305 ± 0.000 vs no diabetes 0.322 ± 0.096; P = .864) or type of mutation (Val30Met 0.324 ± 0.084 vs other mutations 0.309 ± 0.151; P = .752).

Table 2.

Correlations of Myocardial Extracellular Volume With Diverse Parameters

ECV	R	P
Age	0.467	< .01
mBMI	–0.185	.364
Symptomatic disease duration*	0.366	< .05
LV maximum wall thickness	0.621	< .01
RV thickness	0.440	< .05
LV mass indexed	0.685	< .01
LVEDVi	0.018	.925
LVESVi	0.143	.442
LVEF	–0.378	< .05
LA area index	0.592	< .01
LA volume index	0.418	< .05
NT-proBNP*	0.820	< .01
NIS-LL*	0.604	< .01
Norfolk QOL*	0.529	< .01
Karnofsky*	–0.517	< .01

ECV, extracellular volume; LA, left atrium; LV, left ventricle; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESVI, left ventricular end-systolic volume index; mBMI, modified body mass index; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NIS-LL, Neuropathy Impairment Score-Lower Limbs; QOL, quality of life; RV, right ventricle.

*

Rho Spearman coefficient. R represents Pearson correlation coefficient except in variables with asterisk.

Extracellular Volume and Cardiac Parameters

Extracellular volume correlated with several cardiac parameters (Table 2). Cardiac ECV correlated directly with indexed left ventricular mass, left ventricle maximum wall thickness, right ventricular thickness, and indexed left atrial area/volume and NT-proBNP. Extracellualr volume also correlated inversely with left ventricular ejection fraction (Table 2); however, the strongest correlation occurred with NT-proBNP (RS = 0.820; P < .001).

Cardiac ECV and T1 native values were significantly higher in patients with positive LGE (0.522 ± 0.126 vs 0.292 ± 0.037; P = .034, and 1263 ± 35 vs 1188 ± 49ms; P = .007, respectively) and with rapid gadolinium kinetics (0.461 ± 0.137 vs 0.288 ± 0.036; P = .027, and 1264 ± 27 vs 1181 ± 45 ms; P < .001, respectively).

All patients with AC showed increased ECV values. Mean ECV was increased in patients with AC vs patients without AC (0.490 ± 0.131 vs 0.289 ± 0.035; P = .026). Furthermore, the cutoff value of ECV = 0.357 calculated by ROC (receiver operating characteristic) curve was diagnostic of AC with 100% sensitivity and specificity (P < .001) (Figure 4).

Figure 4.

Accuracy of ECV for the diagnosis of amyloid cardiomyopathy. ECV, extracellular volume; TTR, transthyretin.

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To our knowledge, this study is the first to evaluate the value of cardiac ECV determined by CMR T1 mapping techniques for the diagnosis of AC in a population of exclusively TTR-FAP patients. This study shows that cardiac ECV is severely increased among TTR-FAP patients with AC and that ECV increases across the clinical spectrum of the condition. Furthermore, our study shows that cardiac ECV correlates with neurological manifestations of the condition.

Amyloidosis is the paradigm of deposition diseases affecting the extracellular space.1–4 In TTR-FAP, amyloid deposits grow progressively and affect mainly the nerves and the heart.1–4,23 While neurological symptoms usually dominate clinical features, heart involvement frequently determines the prognosis.2–4,23 Nerve and cardiac biopsies could be employed to confirm amyloid deposition2–4 but cannot be used as a follow-up method due to patchy amyloid deposition and the impossibility of repeating biopsies on the exact same site.

Both cardiac and neurological tests employed in TTR-FAP follow-up have shown several limitations. On the one hand, neurological tests rely on physicians’ ability to gather data and they are not specific to a single type of neuropathy.24 On the other hand, CMR and 99mTc-DPD scintigraphy provide a yes/no answer to the presence of cardiac amyloid disease but do not provide a precise value of the amyloid burden that could be tracked over time.

A noninvasive technique that permits early detection of amyloid deposits and estimates the amyloid burden in tissues would be particularly useful in TTR-FAP. Furthermore, despite recent advances in noninvasive techniques, the diagnosis of AC is still challenging, and characteristic and easily recognizable features are often found only at advanced stages.2,11 If our findings are confirmed by additional studies, ECV could be extremely useful to diagnose early cardiac involvement in TTR-FAP.

Calculation of ECV by CMR and T1 mapping techniques have the potential to become the method of choice for objective amyloid quantification in TTR-FAP.

T1 mapping has already shown its usefulness in the differential diagnosis of LVH and both ECV and T1 native values have been reported to be higher in patients with AC than in healthy controls, patients with hypertrophic cardiomyopathy, and those with severe aortic stenosis.13

To date, ECV has been studied in a AC setting mainly in AL (amyloid light-chain) amyloidosis patients.25–28 The first ECV values of cardiac involvement in amyloidosis were published by Sado et al13 in 27 cardiac AL amyloidosis patients using a 1.5T scanner and a fast low-angle single-shot inversion recovery (FLASH IR) sequence at increasing inversion times from 140 to 900ms to allow quantification of T1. That study revealed a dramatic difference in ECV between AC patients and patients with other cardiac conditions.13 Later, several other groups reported their experience mainly in AL amyloidosis and also with a 1.5T scanner.25–28 The reported ECV values ranged between 0.44 ± 0.12 and 0.46 ± 0.07. Some of the published data for AL amyloidosis were reported on the basis of T1 values, with precontrast T1 times of 1140 ± 61,27 1130 ± 68,25 and 1080 ± 8728 in a 1.5T scanner with a ShMOLLI sequence. Thus far, only 1 group has reported their experience in ATTR (amyloidogenic transthyretin) AC, but only precontrast T1 values were reported.25 In that study, a group of 85 patients with ATTR (35 with hereditary ATTR) showed a native T1 time of 1097 ± 43 ms and ECV data were not reported. Considering prior ECV data, our ECV results in TTR-FAP patients with cardiac involvement, 0.490 ± 0.131, are in agreement with previous reports on AL cardiac amyloidosis.

In our cohort, an ECV value of 0.357 was diagnostic of AC with 100% sensitivity and specificity. Studies with a larger sample size are needed to adequately address the spectrum of ECV in this disease and to determine the best diagnostic cutoff value.

That ECV accurately reflects cardiac involvement in TTR-FAP is further supported in our study by the fact that ECV correlated with several cardiac parameters and very strongly with NT-proBNP values (RS = 0.820; P < .001). The NT-proBNP has been reported as a prognostic factor in AL amyloidosis,29 but there are limited data in TTR amyloidosis.10,30 Recent evidence suggests that NT-proBNP and change in LV mass are markers of disease progression in TTR-FAP patients.31,32

Finally, our study has shown that ECV correlates with neurological involvement in TTR-FAP patients and that ECV progresses across the disease spectrum of the condition. These findings support the concept that ECV monitoring of amyloid burden could be possible in TTR-FAP patients as has already been reported in murine models.33

As discussed before, liver transplantation is a therapeutic alternative for these patients that avoids the production of amylogenic protein. Only 1 of the 13 liver transplanted patients in our study had evidence of AC. The “protective cardiac effect” of liver transplantation in these individuals could be argued based on our results, but we believe that prospective studies with a larger sample size are still needed to determine the usefulness of ECV in monitoring the different treatments for ATTR-FAP.

Finally, ECV is a promising tool for human research and could be used as a surrogate marker of the response to new compounds, facilitating the performance of clinical trials in a rare disease. From a clinical viewpoint, ECV could be used to monitor drug response and to help with decision-making on liver transplantation, even though simple amyloid burden quantification may not reflect the unique pathological mechanism of amyloidosis.

Cardiac ECV quantification by CMR allows identification of AC and correlates with the degree of neurological impairment in TTR-FAP patients. Furthermore, ECV increases across the disease spectrum of the condition. This noninvasive technique could become a highly useful tool for early diagnosis of AC and to track cardiac and extracardiac amyloid deposits in this disease if our findings are confirmed by additional studies.

This work was partially funded by a research grant from Fundación Mutua Madrileña and by Instituto de Salud Carlos III (RD12/0042/0066 and RD12/0042/0054). Grants are supported by the Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 and the European Regional Development Fund “A way of making Europe”.

J. Sánchez-González is an employee of Philips.