|Year : 2021 | Volume
| Issue : 1 | Page : 17-22
Early impairment of right ventricular morphology and function in transthyretin-related cardiac amyloidosis
Roberto Licordari1, Fabio Minutoli2, Antonino Recupero1, Mariapaola Campisi1, Rocco Donato2, Anna Mazzeo3, Giuseppe Dattilo1, Sergio Baldari2, Giuseppe Vita3, Concetta Zito1, Gianluca Di Bella1
1 Department of Clinical and Experimental Medicine, Cardiology Unit, University of Messina, AOU “Policlinico G. Martino,” Messina, Italy
2 Department of Biomedical Sciences and Morphologic and Functional Images, University of Messina, Messina, Italy
3 Department of Clinical and Experimental Medicine, Neurology Unit, University of Messina, AOU “Policlinico G. Martino,” Messina, Italy
|Date of Submission||08-Oct-2020|
|Date of Acceptance||06-Nov-2020|
|Date of Web Publication||20-May-2021|
Department of Clinical and Experimental Medicine, Cardiology Unit, University of Messina, AOU Policlinico G. Martino
Source of Support: None, Conflict of Interest: None
Background: Our study aimed to evaluate right ventricular (RV) morphology and strain (S) in the early stage of familial transthyretin (TTR) cardiac amyloidosis (CA). Methods and Results: Thirty-seven patients with transthyretin mutation underwent 99mTc-3,3-diphosphono-1,2 propanodicarboxylic acid (99mTc-DPD) scans and/or cardiac magnetic resonance (CMR) to identify TTR CA. Each patient underwent echocardiography to quantify RV dimensions, tricuspid annular plane systolic excursion (TAPSE), systolic pulmonary artery pressure (sPAP), longitudinal (L) strain of the RV free wall, left ventricular (LV) septal thickness (ST), ejection fraction, E/E', LV global (G) L, radial (R), and circumferential (C) S. 99mTc-DPD and CMR revealed the accumulation in 22 of 37 patients (CA group) and no accumulation in 15 patients (no-CA group). Left ventricular (LV) septal thickness (ST) was higher (P < 0.0001) while LV ejection fraction and E/E' were lower (P < 0.05) in the CA group than the no-CA group. LV-global longitudinal strain (LS) was lower (P < 0.0001) in the CA-group than the no CA-group, whereas LV-global circumferential strain and LV-global radial strain were similar. The CA group showed higher values of RV dimensions (P < 0.05) and sPAP (0.02) and a lower (P = 0.002) TAPSE. Globally, RV-LS was lower (P = 0.005) in the CA group than the no-CA group. Basal and mid segments of the RV free wall showed a lower LS in the CA group than the no-CA group (P < 0.01), while apical S was similar between groups. Conclusions: RV deformation, particularly in basal and mid segments, is early impaired in CA.
Keywords: Cardiac amyloidosis, myocardial strain imaging, right ventricle
|How to cite this article:|
Licordari R, Minutoli F, Recupero A, Campisi M, Donato R, Mazzeo A, Dattilo G, Baldari S, Vita G, Zito C, Di Bella G. Early impairment of right ventricular morphology and function in transthyretin-related cardiac amyloidosis. J Cardiovasc Echography 2021;31:17-22
|How to cite this URL:|
Licordari R, Minutoli F, Recupero A, Campisi M, Donato R, Mazzeo A, Dattilo G, Baldari S, Vita G, Zito C, Di Bella G. Early impairment of right ventricular morphology and function in transthyretin-related cardiac amyloidosis. J Cardiovasc Echography [serial online] 2021 [cited 2021 Jun 25];31:17-22. Available from: https://www.jcecho.org/text.asp?2021/31/1/17/316515
| Introduction|| |
Familial amyloid polyneuropathy due to a mutation of the gene coding for transthyretin (TTR) is one of the three most frequent subtypes, together with light chain and senile systemic amyloidosis.,,
The involvement of myocardium with the clinical expression of heart failure (HF) due to cardiac amyloidosis (CA) is common in each subtype, and it shows a negative prognostic impact.,, Many studies have investigated left ventricular (LV) myocardial appearance and deformation in both the early and end stages of CA.,,
On the contrary, very few data are available about right ventricular (RV) function in CA. In a recent study, Bellavia et al. showed that the measures of the RV are impaired early in amyloid light chain amyloidosis. No data are available regarding RV morphology and function in TTR familial CA. Cardiac magnetic resonance (CMR) has showed high accuracy to identify both ischemic and nonischemic cardiomyopathies.
99mTc-3,3-diphosphono-1,2 propanodicarboxylic acid (DPD) scintigraphy has demonstrated high accuracy in the early identification of amyloid deposition in the myocardium of patients with TTR-related amyloidosis.,,
As echocardiography remains a first-line test in HF and continues to provide valuable information on LV function, the aim of our study is to assess RV morphology and function by echocardiography in the early stage of TTR CA.
| Methods|| |
We included 37 patients (14 men and 23 women; mean age –51 ± 12 years) belonging to seven unrelated families with TTR gene mutation (Glu89Gln, Phe64 Leu, Thr49Ala) followed at the Department of Neurosciences of our University Hospital. None of the included patients had evidence of monoclonal protein in the serum or urine, a monoclonal population of plasma cells in the bone marrow, or other diseases that could be responsible for secondary amyloidosis.
All patients underwent one the following examinations on the same day: Two-dimensional (2D) standard echocardiography, strain echocardiography, 99mTc-DPD scan, or CMR. At enrollment, all patients were in New York Heart Association (NYHA) functional class I–II and had no clinical history of previous cardiac disease. The study was approved by our institutional review board. Informed consent was obtained from all patients.
Standard echocardiography data acquisition and analysis
Standard echocardiographic examinations were performed in all patients using a commercial ultrasound machine (My Lab ALFA, Esaote, Florence, Italy) equipped with a 2.5-MHz phased-array transducer. Parasternal short-axis views at the basal, mid, and apical levels and three standard apical views (four chamber, two chamber, and LV outflow long axis) were acquired. The same cardiologist performed all examinations. The following measurements were obtained according to the recommendations of the American Society for Echocardiography: Diastolic thickness of the LV basal anterior septum (LVST), basal posterior wall thickness, LV volumes (end-diastolic volume and end-systolic volume), ejection fraction, RV end-diastolic diameters at basal and mid-ventricular levels, proximal RV outflow tract (RVOT) on parasternal long-axis, end diastolic and end-systolic four chamber areas, RV fractional area change (FAC) ([100 × [RV diastolic area −RV systolic area]/RV diastolic area]), and tricuspid annular plane systolic excursion (TAPSE). LV mass was calculated using the Devereux formula. RV dysfunction was defined by a FAC of <40%., LV diastolic function was quantified by the ratio between the E-wave velocity of the pulsed-wave Doppler mitral flow image and the early diastolic velocity of the septum at the mitral annulus level (E' wave) on tissue Doppler imaging. Systolic pulmonary artery pressure (sPAP) was calculated by simplified Bernoulli equation from the tricuspid regurgitation peak velocity, obtained with continuous-wave Doppler. Velocity of the tricuspid regurgitation jet was assessed comparing the quality and peak measurement of the continuous-wave Doppler waves obtained either in the apical four chamber view or in the parasternal-axis view.,
Strain acquisition and analysis
A dedicated software package (XStrain™, Esaote, Florence, Italy) was used for an offline quantification of right and left strain. A 16-segment model was used to divide the LV. LV longitudinal strain (LS) was acquired on four and two chamber apical views and LV circumferential and radial strain on basal, mid, and apical short-axis views. Global LS (GLS) was obtained from the average LS of the 16 segments on apical views while global circumferential strain (GCS) and global radial strain (GRS) were obtained as the average of circumferential and radial strain of the 16 segments on short-axis views.,,,
A 6-segment model was used to describe RV deformation. RV LS was acquired with a four-chamber apical view modified to obtain optimal visualization of the right chambers.
The LS (%) of the RV lateral wall and the right side of the interventricular septum, at the base, mid, and distal levels, were analyzed using 2D strain. Global strain of the RV was subsequently obtained from the average of the six segments obtained on the four-chamber view. The LS (%) of the lateral wall was obtained from the average performed on the three segments of RV lateral wall.
Cardiac magnetic resonance imaging data acquisition and analysis
CMR was performed with a 1.5-T system (Gyroscan NT, Philips Healthcare, Andover, Massachusetts, USA) with a cardiac phased-array coil and vectorcardiogram synchronization.
Contrast-enhanced images were acquired in the same short- and long-axis views with a 2D gradient-echo inversion recovery sequence 4–20 min after bolus injection of 0.2 mmol/kg of gadobutrol (Gadovist, Bayer Schering Pharma) using different inversion times (80–350 ms with a 30 ms increment). A total of 8–12 short-axis views, one 4-chamber view, one 2-chamber view, and one LV outflow view were acquired.
For data analysis, all images were transferred to the workstation and reviewed offline.
All contrast-enhanced images were analyzed by the consensus of two radiologists, each with 10 years of experience in CMR. Both reviewers were unaware of the other results of echocardiography and scintigraphy contrast-enhanced images were judged as positive in the presence of or negative in the absence of contrast-enhanced abnormalities (subendocardial circumferential, focal, and diffuse enhancement). A diminished difference of signal intensity between the myocardium and blood pool was considered a sign of diffuse myocardial enhancement.
99mTc-3,3-diphosphono-1,2 propanodicarboxylic acid data acquisition and analysis
Whole-body scans (anterior and posterior projections) were obtained 5 min and 3 h after the intravenous injection of 740 MBq of 99mTc-DPD by using a dual-headed gamma camera (MillenniumVG, GE Healthcare, Milwaukee, Wisconsin, USA) equipped with low-energy, high-resolution collimators.
The whole-body scans were visually evaluated by a consensus of two experienced nuclear medicine physicians who searched for cardiac radiotracer accumulation; readers were blinded to echocardiographic data.
Readers evaluated the eventual presence of cardiac radiotracer accumulation as positive or negative for CA accumulation.,
Quantitative data are expressed as mean ± standard deviation, qualitative data as frequency and percentage. The one-sample Kolmogorov–Smirnov test was applied to test the normal distribution of values. The strength of correlation between the variables was assessed by Pearson coefficient (R). The difference among groups in the average values of each parameter was tested by the analysis of variance (ANOVA) or Welch ANOVA when variances were not equal by Levene's test. For skewed variables, the difference between median values of each group was tested by the Kruskal–Wallis nonparametric test. P < 0.05 was considered statistically significant. All tests were two-tailed. Statistical analyses were carried out using JMP statistical software (SAS Institute Inc., version 4.0.0, Cary, North Carolina, USA) and MedCalc™ 6.00.014 (MedCalc Software, Mariakerke, Belgium).
| Results|| |
Total population was composed by 37 participants with a TTR mutation. CA was found in 15 of the 27 patients who underwent a 99mTc-DPD whole-body scan and in 7 of the 16 patients who underwent CMR imaging.
Therefore, CA was found in 22 of 37 patients (59%) (CA group) and no CA was found in the remaining 15 patients (41%) (no-CA group). The age (P = 0.55) and sex (P = 0.143) of patients in the groups were similar.
Echocardiographic findings: Left ventricular dimensions and function
The CA group showed higher values of anterior septal thickness, LV posterior wall thickness, LV mass, and E/E' than the no-CA group and the control group. Left ventricular ejection fraction (LVEF) was significantly lower, but still within the normal range, in the CA group than the no-CA group [Table 1].
|Table 1: Left and right ventricular echocardiographic findings in patients with and without cardiac amyloidosis|
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GLS of the LV was lower (P ≤ 0.0001) in the CA group (−13 ± 4) than the no-CA group (−19 ± 3.2), whereas GCS and GRS were similar in the CA group (−19 ± 5.6 and 23 ± 5, respectively) and the no-CA group (−19 ± 4 and 27 ± 11.5, respectively) [Figure 1].
|Figure 1: Left ventricular deformation in patients with and without cardiac amyloidosis. LV = Left ventricular, GLS = Global longitudinal strain, GCS = Global circumferential strain, GRS = Global radial strain|
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Echocardiographic findings: Right ventricular dimensions and function in cardiac amyloidosis
As demonstrated in [Table 2], the CA group showed higher values of RV dimensions (RV longitudinal diameter, P = 0.01; RV basal diastolic diameter, P = 0.03; RV systolic area, P = 0.04), sPAP (P = 0.02), and a lower TAPSE (P = 0.002). On the contrary, FAC was similar between CA and no-CA group.
|Table 2: Right ventricular echocardiographic findings in patients with and without cardiac amyloidosis|
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RV GLS (−13 ± 6 vs. −19 ± 6, P = 0.004), RV LS of the free wall (−13 ± 7 vs. −22 ± 10, P = 0.006), and RV LS of the septum were lower (−12 ± 6 vs. −18 ± 7, P = 0.007) in the CA group than the no-CA group [Figure 2].
|Figure 2: Right ventricular deformation in patients with and without cardiac amyloidosis. RV = Right ventricular, GLS = Global longitudinal strain, LS = Longitudinal strain|
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As shown in [Table 3] and [Figure 3], the basal and mid segments of the RV free wall had a lower deformation in the CA group than those in the no-CA group while apical segments showed similar values between the groups.
|Table 3: Right ventricular basal-, mid-, and distal-level deformation in patients with and without cardiac amyloidosis|
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|Figure 3: Right ventricular myocardial deformation in no cardiac and early phase of CA. Note the RV longitudinal dysfunction in mid and basal LV segment in early CA. Green = Normal strain, yellow = Mild-moderate strain impairment, RV = Right ventricular, CA = Cardiac amyloidosis|
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A statistically significant correlation was found among RV GLS and selected LV parameters including LVST (r = 0.392; P = 0.03), E/E' (r = 0.406; P = 0.04), LV GLS (r = 0.438; P = 0.02), and LV GCS (r = 0.478; P = 0.02). There was no correlation among RV GLS and the other LV parameters.
Furthermore, many RV parameters were interrelated; specifically, a statistically significant correlation was found among RV GLS and many RV parameters, including TAPSE (r = 0.555; P = 0.001), RV middle diastolic diameter (r = −0.348; P = 0.047), RV longitudinal diastolic diameter (r = −0.489; P = 0.004), RVOT proximal (r = −0.447; P = 0.009), RV end systolic area (r = −0.400; P = 0.023), and RV end diastolic area (r = −0.451; P = 0.01). There was no correlation among RV GLS and the other LV parameters.
| Discussion|| |
To the best of our knowledge, this is the first study analyzing RV longitudinal function detected by strain echocardiography in early CA due to TTR deposition. The main results of the present study are as follows: (1) RV longitudinal dysfunction is observed in patients with CA in the early stages; (2) RV longitudinal dysfunction is strongly related to the degree of LV amyloid deposition (i.e., LVST) and function (diastolic dysfunction GLS), suggesting biventricular involvement and/or ventricular interdependency; and (3) RV apical segments of the lateral free wall showed a lesser impairment than the mid and basal RV segments.
Our data were obtained in an early stage of CA revealed by 99mTc-DPD and CMR in patients with a high risk of developing future overt disease because of the presence of genetic mutations with high penetrance. That our results were obtained in patients without abnormalities of LVEF, FAC, or sPAP and who were in NYHA Class I–II confirms that RV longitudinal dysfunction can be observed early in TTR CA. Early RV involvement also has been described in other types of CA including amyloid light-chain amyloidosis and detected by using other echocardiographic techniques.,,
This evidence may hold a very important clinical role, considering that RV dysfunction has been largely recognized as an important key point in the management of many heart diseases.,,
The strong relation between RV LS and amount of LV amyloid deposition and the consequent impairment of LV diastolic function, LV longitudinal deformation, and LV circumferential deformation represents another important finding of our study. This result could be explained with morphological and functional data. In a previous study with CMR, we observed that hyper-enhancement areas due to deposition of gadolinium are constantly evident in the right chambers (100% in the right atrium and 50% in the RV) of asymptomatic patients with LV CA. On the other hand, several studies have documented that the left and right ventricles are interdependent.
Both human observational studies and animal models showed that the same molecular and cellular mechanisms (particularly apoptosis and hypertrophy), occurring in the remote zone of LV damage, can be observed in the right ventricle and are related with RV dilatation and dysfunction.
Furthermore, experimental studies on animals showed that from 20% to 40% of the RV systolic pressure and volume outflow result from LV contraction.,
Therefore, our data suggests that RV systolic functional impairment runs parallel to the same alterations of the LV.
Moreover, in our study, a clear baso-apical gradient (”inverse pattern”), with lower deformation in the basal segments with relative sparing of the apical ones, has been observed in the RV in patients with CA, similar to what is usually observed in the LV., Most likely, the degree of amyloid infiltration is greater in the basal segments of the RV than the apex, as it commonly happens in the LV.
A major limitation of our study was the small number of patients. However, the prevalence of the disease is very low and collecting a more numerous population is challenging. Another major weakness was the lack of cardiac biopsy specimens available for histopathology. However, this procedure could not be indicated in our asymptomatic patients. Nevertheless, the existence of previous studies on the histopathologic changes of CA allows us to hypothesize reliably on the pathologic abnormalities that may correlate with and explain the imaging findings.,,
Furthermore, because of the very small sample size of the subgroup that had CMR examination, it was not possible to obtain statistical power data for RV volumes and function.
| Conclusions|| |
RV function is impaired early in mutated TTR CA, and such alteration is related to abnormalities of LV morphology and function. Basal segments of the RV show a greater impairment of the longitudinal function, similar to what already has been described in the LV. Further studies in a larger sample of patients with amyloid deposition are needed to confirm our results.
The authors gratefully acknowledge Jennifer Pfaff and Susan Nord of Aurora Cardiovascular Services for editorial preparation of the manuscript and Brian Miller and Brian Schurrer of Aurora Research Institute for help with the figures.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]