Abstract
Introduction
Amyloidosis is a group of diseases characterized by the deposition of misfolded protein fragments, forming insoluble fibrils in organs and tissues. Transthyretin (ATTR) amyloidosis, particularly cardiac amyloidosis (CA), leads to myocardial stiffness and heart failure. Right ventricular (RV) involvement is common in CA, but assessing RV stiffness noninvasively is challenging. This study aimed to evaluate RV stiffness using shear wave elastography (SWE) and correlate the findings with clinical, laboratory, and echocardiographic parameters.
Materials and Methods
In this prospective, single-center, cross-sectional study, 60 patients were divided into three groups: 20 with cardiac ATTR amyloidosis (ATTR-CM), 20 with non-cardiac ATTR amyloidosis (ATTR non-CM), and 20 healthy controls. Myocardial stiffness was measured using SWE in the free wall of the RV. Pearson’s and Spearman’s correlation coefficients were used for statistical analysis, with significance set at p < 0.05.
Results
RV SWE values showed a strong positive correlation with functional class and a moderate correlation with BNP and troponin I levels. A significant negative correlation was found between RV SWE values and the 6-minute walk test distance. SWE also correlated with echocardiographic variables like interventricular septum thickness and RV basal diameter. An SWE cutoff of ≥ 4.6. kPa was associated with cardiac involvement, showing 65 % sensitivity and 76 % specificity.
Conclusions
SWE is a valuable noninvasive technique for assessing RV stiffness in CA patients, correlating well with clinical and echocardiographic parameters. An RV SWE value of ≥ 4.6 kPa could aid in early detection of cardiac involvement in ATTR amyloidosis, improving diagnosis and management.
Introduction
Amyloidosis refers to a group of diseases characterized by the pathogenic deposition of highly stable, misfolded protein fragments in the extracellular space of organs and tissues, forming insoluble fibrils. Among the various types of amyloidosis, transthyretin (ATTR) amyloidosis is particularly significant and can be classified into two subtypes: wild-type transthyretin amyloidosis (ATTRwt) and hereditary or variant transthyretin amyloidosis (ATTRv) , . ATTR amyloidosis is notable for its systemic deposition, with the heart being one of the most frequently affected organs, leading to significant clinical consequences. This specific deposition in the interstitial space of cardiac myocytes is referred to as cardiac amyloidosis (CA), which results in cellular damage that compromises myocardial compliance. This condition causes myocardial stiffness, severe diastolic dysfunction, and ultimately leads to left ventricular (LV) dysfunction and heart failure (HF), commonly known as “stiff heart syndrome” .
The initial stages of LV involvement are marked by altered relaxation, which inevitably progresses to restrictive cardiomyopathy . Amyloid deposition in the LV is closely linked to right ventricular (RV) dysfunction, even in the early stages of the disease, suggesting biventricular involvement. Notably, the apical segments of the RV, particularly the lateral free wall, are less affected than the middle and basal segments . Increased myocardial stiffness in the LV leads to diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF), a condition associated with high rates of cardiovascular morbidity and mortality .
Cardiac shear wave elastography (SWE) is an emerging method for assessing myocardial stiffness, with correlations to the end-diastolic pressure-volume relationship, the gold standard measurement obtained via right heart catheterization . SWE provides a powerful noninvasive measure of diastolic dysfunction and has demonstrated its ability to distinguish between healthy individuals and those with heart disease, such as CA
Shear wave elastography (SWE) is an advanced imaging technique that assesses tissue stiffness non-invasively by measuring the propagation speed of shear waves generated by an external force, such as an ultrasound pulse. This speed is expressed in kilopascals (kPa) and is directly related to tissue stiffness . Stiffness can be estimated from the propagation speed of these shear waves in an isotropic medium with uniform density, using the equation µ = 3⋅ρ⋅c 2 , where “µ” represents myocardial stiffness (kPa), “ρ” is tissue density, and “c” is the shear wave propagation speed .
Understanding the role of RV diastolic function and stiffness, two phenomena closely associated with CA, remains challenging. Although echocardiography is commonly used to assess RV diastolic function, its effectiveness in characterizing relaxation and stiffness as noninvasive parameters is limited. , . However, the prognostic significance of RV stiffness has been demonstrated in patients with pulmonary hypertension (PH) Despite this, little is known about assessing RV myocardial stiffness using the SWE technique. Prior research has shown that increased liver stiffness, as measured by SWE, correlates with elevated pressures in the right heart chambers. This finding suggests the potential to directly study RV stiffness using the same technique, which could aid in the early detection of stiffness, a common occurrence in patients with CA .
Therefore, the primary objective of this study was to evaluate RV stiffness using SWE and correlate these findings with known echocardiographic, laboratory, and clinical variables.
Materials and methods
This prospective, single-center, cross-sectional study was conducted between 2020 and 2021. Sixty patients of both sexes, aged 18 years or older, were enrolled from the outpatient clinic of the Cardiomyopathy Clinical Unit at the Heart Institute-HC-FMUSP. The study population consisted of three groups: 20 patients with ATTRv with cardiac involvement (ATTR-CM), 20 patients with ATTRv without cardiac involvement (ATTR non-CM) (genetic mutation carriers), and 20 healthy control patients ( Table 1 ).
| Inclusion criteria |
|---|
| 1. Presence of TTR mutation or ATTRwt amyloidosis. |
| 2. Confirmation of ATTRwt amyloidosis was determined by the absence of a known TTR genetic mutation via genetic testing. |
| For cardiac involvement, one of the following criteria were necessary: |
| • By echocardiogram, characterized by an average left ventricular wall thickness > 12 mm, and the presence of: |
| Amyloid protein in cardiac biopsy tissue confirmed as TTR amyloid by mass spectrometry or immunohistochemistry; or |
| Amyloid protein in non-cardiac tissue confirmed as TTR amyloid by mass spectrometry or immunohistochemistry; or |
| Amyloid protein in cardiac tissue confirmed indirectly by 99mTC-DPD scintigraphy, 99mTC-PYP, or 99mTC-HMDP with Perugini degree equal to or greater than 2 without evidence of primary amyloidosis (light chain) |
| Exclusion criteria |
| Presence of another cardiomyopathy, such as valvular, hypertensive or ischemic disease |
| Presence of other diseases that may affect functional capacity (chronic obstructive pulmonary disease, peripheral arterial disease, or orthopedic limitation or procedure that limits the ability to walk, uncontrolled hypo or hyperthyroidism, neoplasia in the last 36 months, acute coronary syndrome in the last 3 months) |
| Previous liver or heart transplant |
| Pregnancy |
| Alcohol abuse |
Myocardial elasticity was assessed at a single center in São Paulo. Images were obtained using the APLIO i800 ultrasound device (Canon, Japan), equipped with a multifrequency convex probe (fundamental frequency 3.5 MHz) and settings optimized for elastographic studies. The free wall of the right ventricle was evaluated through the parasternal long-axis acoustic window. Myocardial elasticity measurements were taken at the end of diastole, when cardiac motion is minimal. The results, expressed in KiloPascals (kPa), represent tissue stiffness. One kPa is equivalent to the force of 1 N applied uniformly over a surface area of 1 m² x 1000. These measurements were correlated with data from patients’ imaging and laboratory tests.
This study, ELAST-2D (NCT04456582), was financially supported by Pfizer (application-ID 55925015) and approved by the INCOR Ethics Committee under the consolidated opinion (CAAE 27437019.5.0000.0068).
Statistical analysis
The statistical correlation technique was employed to determine the association between pairs of variables. Pearson’s correlation coefficient was used for parametric variables, while Spearman’s rank correlation coefficient (rho) was used for nonparametric variables. These coefficients range from -1 to +1, where values closer to +1 or -1 indicate stronger correlations.
Statistical analysis was performed using the JASP Team software (2022). JASP (Version 0.16.3) [Computer software]. A p-value of <0.05 was considered statistically significant for all tests.
Results
The clinical and structural profile of the patients is listed in Table 1 . The differences between the groups are noticeable, reinforcing the intention to form an ATTR-CM group with individuals already showing cardiac involvement as predicted by reliable methods. These patients exhibit conditions associated with prolonged exposure to amyloid deposits: they are older, have a higher cardiac mass index, greater septum thickness, atrial enlargement, lower left ventricular ejection fraction (LVEF), lower global longitudinal strain of the LV (GLSLV) and RV (GLSRV), more advanced degrees of diastolic dysfunction, worse functional capacity, and poorer performance in the 6-minute walk test with a shorter total distance covered, in addition to elevated cardiac markers such as troponin and BNP.
These patients also have a higher prevalence of chronic conditions such as hypertension, diabetes, and hypothyroidism; however, they do not exhibit decompensated or difficult-to-control conditions. There were no historical reports of anginal symptoms, coronary atherosclerotic disease, use of anti-ischemic medications, or previous revascularization in either group.
In both groups with pathological variants of the transthyretin gene, the most prevalent mutations were Val142Ile, followed by Val50Met and Thr80Ala, with no statistically significant differences in the type of mutation between the groups ( Table 2 ). The cardiac elastography characteristics of the three groups evaluated are presented in Table 3 .
| ATTR-CM (n = 20) | ATTR non-CM (n = 20) | Control (n = 20) | p | |
|---|---|---|---|---|
| Clinical variables | ||||
| Age (years) | 69,6 ± 8,2 | 41,6 ± 10,8 | 51,7 ± 13,3 | p < .001 ⁎⁎⁎ |
| Male sex (%) | 16 (80.0) | 11 (55.0) | 11 (55.0) | |
| BMI (kg/m2) | 23,85 ± 3 | 25,8 ± 4,7 | 25,9 ± 2,6 | P = 0,1 |
| Heart rate (bpm) | 74,4 ± 10,5 | 69,9 ± 9,5 | 68,4 ± 14,6 | P = 0,2 |
| SAP (mmHg) | 117,95 ± 21,38 | 128 ± 17,94 | 122,8 ± 12,94 | P = 0,2 |
| Carpal tunnel syndrome (%) | 13 (65.0) | 3 (15.0) | 0 (0.0) | P = 0,005 |
| 6MWT Distance^ (m) | 336,9 ± 83,7 | 420,4 ± 112,8 | 460 ± 56,9 | p < .001* |
| Functional class NYHA | P = 0,001 | |||
| -NYHA I | 4 (20.0) | 20 (100.0) | – | – |
| -NYHA II | 14 (70.0) | 0 (0.0) | – | – |
| Laboratory variables | – | |||
| HS- Troponin I (ng/L) | 63,7 ± 41,2 | 7,15 ± 10,7 | 6,9 ± 11,9 | p < .001* |
| BNP (pg/mL) | 435 ± 321,9 | 20,9 ±20,2 | 17,5 ± 12,9 | p < .001* |
| Echocardiogram variables | ||||
| LVEF (%) | 43,1 ± 12.7 | 59,2 ± 2,9 | 62,6 ± 4,1 | p < .001* |
| GLSLV (%) | 9,2 ± 3,3 | 17,8 ± 1,9 | 19,1 ± 2,5 | p < .001* |
| Septum (mm) | 17,8 ± 3,5 | 8,6 ± 1,3 | 8 ± 0,9 | p < .001* |
| Wall posterior (mm) | 17,5 ± 3,3 | 8,4 ± 1,3 | 7,8 ± 0,9 | P < .001* |
| LVDD (mm) | 44 ± 5,5 | 47 ± 2,8 | 48,7 ± 4,8 | P < 0.01 ⁎⁎ |
| LVSD (mm) | 35 ± 6,2 | 31,2 ± 2,8 | 31,7 ± 5,2 | P = 0,06 |
| Index mass LV (g/m2) | 194 ± 52,9 | 74,158 ± 16,2 | 70,2 ± 11,1 | P < .001* |
| Basal RV diameter (mm) | 40,8 ± 7,7 | 34,21 ± 5,2 | 33,6 ± 4,1 | p < .001* |
| LAV (ml) | 61 ± 16,6 | 28,4 ± 4 | 27,3 ± 7,7 | p < .001* |
| RAV (ml) | 47,5 ± 17,36 | 19,2 ± 4,8 | 21,4 ± 6,6 | p < .001* |
| Apical sparing (%) | 19 (95.0) | 20 (10.0) | 0 (0.0) | |
| Diastolic dysfunction (%) | ||||
| -Grade II | 5 (25.0) | 0 (0.0) | — | P = 0,017 |
| -Grade III | 12 (60.0) | 0 (0.0) | — | P < 0,001 |
| -E/e’ relationship | 20,6 ± 10,5 | 8,37 ± 9,2 | 6,3 ± 2,2 | p < .001* |
| Right ventricle | ||||
| -GLSRV | 16,1 ± 6,1 | 25,8 ± 3,6 | 24,4 ± 3,0 | p < .001* |
| -FAC | 33,2 ± 8,8 | 46,2 ± 10,6 | 44,3 ± 8 | p < .001* |
| -S wave | 6,5 ± 3,3 | 11,1 ± 2,1 | 11,8 ± 1,8 | p < .001* |
| -TAPSE | 13,2 ± 4,5 | 20,8 ± 3,2 | 22,5 ± 9 | p < .001* |
| Scintigraphy PYP 99 TC | ||||
| 1st hour uptake | 1,7 ± 0,2 | 1,1 ± 0,2 | — | p < .001 |
| 3rd hour uptake | 1,6 ± 0,1 | 1,1 ± 0,1 | — | p < .001 |
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