INTRODUCTION
Amyloid cardiomyopathy (ACM) is characterized by the deposition of misfolded proteins in cardiac tissue, leading to progressive dysfunction of the heart. In its transthyretin-associated form (ATTR-CM), these proteins adopt abnormal folding and form fibrillar aggregates that accumulate mainly in the myocardium. This process initially affects diastolic function, and in advanced stages leads to heart failure (HF) with a significant impact on patients' quality of life. (1,2,3)
Historically, attention in ACM has been focused on left ventricular (LV) function, characterized by the development of cardiomyopathy with restrictive physiology. (4,5) The importance of the right ventricle (RV)has been underestimated, despite its growing recognition as a key determinant of prognosis in this disease. (6,7) Right ventricular dysfunction not only aggravates systemic venous congestion, but, together with tricuspid regurgitation and elevated pulmonary pressures, contributes to the functional and clinical deterioration of patients. (8,9)
In this context, the aim of our study was to evaluate the frequency of RV systolic dysfunction in patients with ATTR-CM and its prognostic impact. A deeper understanding of this alteration could improve risk stratification and favor the implementation of more effective therapeutic strategies aimed at optimizing the prognosis and quality of life of patients.
METHODS
Study design
A retrospective observational study was performed using data prospectively obtained from the electronic medical records of patients at Instituto Cardiovascular de Buenos Aires. Patients with ATTR-CM diagnosis under ambulatory follow-up performed by physicians from the cardiomyopathy clinic of the institution, were included between January 2011 and March 2024, according to the usual diagnostic criteria in force during that period. (10) Baseline demographic, clinical, laboratory, and echocardiographic data were collected, as well as risk factors and cardiovascular events before and after the diagnosis of amyloidosis.
Confirmation of cardiac amyloidosis by transthyretin.
Transthyretin amyloid cardiomyopathy was defined as the combination of typical echocardiographic imaging features (e.g., wall thickness ≥12 mm) with grade 2 or 3 cardiac up-take on 99mTc-HMDP (hydroxymethylene diphosphonate) scintigraphy, plus exclusion of clonal dyscrasia by serum free light chain assay (Freelite, Binding Site) and immunofixation in blood and urine to detect a monoclonal component. (11,12) Scintigraphy was performed in all patients with 20 mCi of 99mTc-HMDP administered intravenously, taking planar images 2 hours after dose administration. The degree of cardiac uptake in relation to bone tissue was assessed using two methods: 1) Semi-quantitative procedure, following the Perugini visual scale, where cardiac uptake was compared with the sternum: grade 0 =no cardiac uptake, 1=cardiac uptake less than the sternum, 2=cardiac uptake equal to the sternum, 3 = cardiac uptake greater than the sternum; and
2) Quantitative procedure: heart-lung ratio.
The final diagnosis of ATTR-CM was based on the results of clinical evaluation, electrocardiograms, echocardiograms and scintigraphy, after exclusion of plasma cell disease (free light chains, serum and urine immunofixation). (6,7) Magnetic resonance imaging with gadolinium was performed in selected patients. In inconclusive cases, a tissue biopsy was performed.
Objective
To evaluate the frequency of RV systolic function involvement in our population with ATTR-CM and its prognostic impact.
Definition of right ventricular function impairment by echocardiography (Figure 1)
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Tricuspid annular plane systolic excursion (TAPSE) <17 mm
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Right ventricular S-wave by tissue Doppler imaging (TDI) <9.5 cm/s. (13)
Events analyzed in the follow-up
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Hospitalization or urgent emergency department visit for HF
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Development of atrial fibrillation (AF)
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Cardiovascular death
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All-cause mortality
Statistical analysis
Discrete variables were expressed as percentages and continuous variables were described using mean and standard deviation (SD) or median and interquartile range (IQR), according to normal or non-normal distribution, respectively. Normality of distribution was assessed using the Kolmogorov-Smirnov method. Categorical variables were analyzed using the Chi-square test or Fisher's exact test, and quantitative variables were analyzed with Student's t-test or the Mann-Whitney U test, depending on the distribution.
Univariate analysis was performed with Cox regression, including all variables biologically relevant to the event. After confirming statistical significance, multiple Cox regression was performed using a backward selection strategy, based on the Z value associated with each variable (Wald test), estimated from the ratio of each coefficient over its standard error. In this multivariate analysis, variables with a level of statistical significance in the univariate analysis with p <0.10 were included.
Event-free survival during follow-up was analyzed using the Log-Rank test and plotted on Kaplan-Meier curves. Statistical significance was considered with p <0.05 (two-tailed test). All data analyses were performed using IBM SPSS version 29.0 software.
Ethical considerations
This study was evaluated and approved by the institutional Ethics Committee. The study was registered in the PRIISA. BA platform of the Ministry of Health of the Autonomous City of Buenos Aires and was conducted in accordance with national and international regulations for the protection of research subjects, such as the latest version of the Declara- tion of Helsinki, (14) Resolution 1480/2011 of the National Ministry of Health, Law 3301 of the City of Buenos Aires, and ANMAT Resolution 6677/10 and its amendments 4008 and 4009.
RESULTS
A total of 154 patients were included in the study, 95% male (n=147), and with median age of 81 years (IQR 75-85). Most patients had comorbidities: 77% hyper tension, 17% diabetes, 58% dyslipidemia and 41% had a history of smoking or were ex-smokers. Regarding other relevant conditions, 25% had coronary artery disease and 8% previous coronary artery bypass grafting (CABG). Twenty-seven percent of patients had a permanent pacemaker (PPM) and only one patient had an implantable cardioverter-defibrillator (ICD). Atrial fibrillation was present in 53% of cases before diagnosis. Among the red flags associated with ATTR-CM, 6% had neuropathy, 29% carpal tunnel syndrome and 6.5% narrow spinal canal.
Laboratory parameters showed a median N-terminal pro-B-type natriuretic peptide (NT-proBNP) of 3800 ng/L (IQR 1200-7600) and high-sensitivity troponin T of 62 ng/L (IQR 42-91), along with an estimated glomerular filtration rate of 54 ml/min/1.73 m² (IQR 40-68).
Echocardiogram showed a median left ventricular ejection fraction (LVEF) of 50% (IQR 42-60), interventricular septum (IVS) of 16 mm (IQR 14-19) and posterior wall of 13 mm (IQR 12-15).
Median TAPSE was 17 mm (IQR 14-19), and RV S-wave 9 cm/s (IQR 8-10). Median left atrial (LA) area was 29 cm2 (IQR 26-32). Tricuspid regurgitation (TR) was mild in 47% of patients (n=67), moderate in 17% (n=25) and severe in 4.2% (n=6). In 6.2% of cases (n=9), patients had mild aortic stenosis, 10.3% (n=15) moderate and 5.5% (n=8) severe. Sixty per cent of patients (n=85) had mild mitral regurgitation, 17.5% (n=25) moderate, and there were no cases of severe mitral regurgitation (Tables 1 and 2).
Table 1
Population characteristics
| Variable | Value |
|---|---|
| Male sex | 147 (95.2%) |
| Age, years | 81 (75-85) |
| Hypertension | 126 (77.3%) |
| DM | 29 (17.8%) |
| Dyslipidemia | 95 (58.3%) |
| Smoking | 66 (41.3%) |
| Stroke / TIA | 20 (12.4%) |
| PCI | 34 (21.1%) |
| CABG | 14 (8.7%) |
| Coronary artery disease | 41 (25.5%) |
| PPM | 44 (27%,3) |
| VRS | 10 (6.3%) |
| ICD | 1 (0.6%) |
| CRT | 2 (1.3%) |
| Previous AF | 82 (50.9%) |
| Neuropathy | 9 (6.2%) |
| Carpal tunnel | 46 (29.3%) |
| Narrow medullary canal | 10 (6.5%) |
AF: atrial fibrillation; CTA: coronary transluminal angioplasty; CABG: coronary artery bypass grafting; CRT: cardiac resynchronization therapy, DM: diabetes mellitus; ICD: implantable cardioverter-defibrillator; PCI: percutaneous coronary intervention; PPM: permanent pacemaker; TIA: transient ischemic attack; VRS: valve replacement surgery.
Qualitative variables are presented as frequency and percentage, and quantitative as median and interquartile range.
Table 2
Baseline laboratory and echocardiogram characteristics
| Variable | Value |
|---|---|
| Laboratory | |
| NT-proBNP, ng/L | 3800 (1200-7600) |
| Glomerular filtration rate, mL/min/1.73 m2 | 54 (40-68) |
| Ultra-sensitive troponin T, ng/L | 62 (42-91) |
| Echocardiographic characteristics | |
| LVEF, % | 50 (42-60) |
| IVS, mm | 16 (14-19) |
| PW, mm | 13 (12-15) |
| LVDD, mm | 44 (40-49) |
| LVSD, mm | 30 ( 25-25) |
| Lateral S-wave, cm/s | 5.8 (5- 6.8) |
| Medial S-wave, cm/s | 4.65 (3.9- 5.4) |
| LA, cm2 | 29 (26-32) |
| Filling pattern | |
| Prolonged relaxation | 8 (5.6%) |
| Pseudonormal | 41 (29%) |
| Restrictive | 34 (24%) |
| Monophasic | 57 (40%) |
| TAPSE , mm | 17 (14-19) |
| PASP, mmHg | 40 (33-50) |
| RV S-wave, cm/s | 9 (8-10) |
| E/e' ratio | 16 (12-19) |
| Septal E, cm/s | 5 (4-5.3) |
| Lateral E, cm/s | 6.7 (5.3-8) |
| Tricuspid regurgitation | |
| M | 67 (47%) |
| Mod | 25 (17%) |
| S | 6 (4.2%) |
| Aortic stenosis | |
| M | 9 (6.2%) |
| Mod | 15 (10.3%) |
| S | 8 (5.5%) |
| Mitral regurgitation | |
| M | 85 (60%) |
| Mod | 25 (17.5%) |
| S | 0 (0%) |
LA: left atrium; IVS: interventricular septum; LVDD: left ventricular diastolic diameter; LVSD: left ventricular systolic diameter; LVEF: left ventricular ejection fraction; M: mild; Mod: moderate; NT-proBNP: N-termimnal pro-B-type natriuretic peptide; PW: posterior wall; PASP: pulmonary artery systolic pressure; RV: right ventricular. S: severe; TAPSE: tricuspid annular plane systolic excursion.
Qualitative variables are presented as frequency and percentage and quantitative variables as median and interquartile range.
With respect to the study objective, 47% presented TAPSE value <17 mm and 52% RV S-wave <9.5 cm/s. Median follow-up was 528 days (IQR 159-1004), during which total mortality was 19.3% and cardiovascular mortality 11.8%. In addition, 30.5% of patients were hospitalized for HF and 30.4% of those free of AF at baseline developed this arrhythmia during follow-up.
Univariate analysis identified TAPSE as an independent predictor of adverse clinical events. Even after adjusting for multiple echocardiographic (LVEF, IVS, LV lateral and medial S-wave, filling pattern, pulmonary systolic pressure, RV S-wave and E/e´ ratio), demographic (age and sex) and clinical (previous HF, diabetes, PPM, previous coronary artery disease, and previous AF) variables, TAPSE remained as an independent predictor of total mortality (HR 0.847; 95% CI 0.730-0.983, p=0.028), cardiovascular mortality (HR 0.725; 95% CI 0.600-0.875, p=0.001), hospitalization for HF (HR 0.859; 95% CI 0.755-0.977, p=0.001)and development of AF (HR 0.84; 95% CI 0.727-0.972, p=0.019). (Figure 2)
DISCUSSION
This study evaluated a cohort of patients diagnosed with ATTR-CM followed up by physicians from the cardiomyopathy service of a single center in Argentina. The frequency of RV systolic dysfunction was analyzed in this population and its prognostic impact was investigated. We consider it is important to highlight three aspects of our work.
Firstly, it is relevant to know the prevalence of RV impairment in our population. In the echocardiogram, we found TAPSE <17 mm in 47% of patients and RV S-wave < 9.5 cm/s in 52%, as an expression of right ventricular dysfunction. In the study by Diane Bodez et al. non-survivors showed worse RV systolic function on echocardiography assessed by TAPSE and RV free wall deformation. Significantly, RV free wall deformation was independently associated with all-cause mortality in several multivariate Cox regression models, with incremental prognostic value over conventional parameters of RV function. (15) Right ventricular involvement is common in patients with cardiac amyloidosis. (16) It is proposed that this dysfunction may be mediated by amyloid infiltration of the RV wall itself, by increased afterload in cases of pulmonary hypertension, and by ventricular interdependence.
e. Secondly, it is crucial to understand the role of the right ventricle in the prognosis of patients with car- diac amyloidosis. Right ventricular dysfunction, often underestimated in clinical practice, plays a crucial role in the progression of HF and in the development of AF, probably due to pressure overload and fibro sis induced by amyloid infiltration. TAPSE, a simple and widely available echocardiographic parameter, emerged in our study as an independent predictor of adverse clinical events even after adjusting for other demographic and echocardiographic variables. Our results are in the same direction of published data in patients with light chain (AL) amyloidosis. (17,18,19) In 2007, Ghio et al. reported the association of TAPSE <17 mm with BNP elevation and mortality in patients with AL amyloidosis. (17)
Finally, the findings of our study, which show an inverse association between TAPSE and heart failure, mortality, and atrial fibrillation events in patients with ATTR-CM, reinforce its potential value as a prognostic tool in this disease. It is essential to have a widely available and simple to obtain parameter, to stratify risk in this population. Although our observational design does not allow us to establish causality, the detection of RV dysfunction could motivate closer clinical surveillance, favoring the early detection of events such as AF, in which case timely intervention -such as the initiation of anticoagulation- could have a relevant clinical impact. (20,21)
Limitations
The retrospective and single-center nature of the study limits the generalization of results, highlighting the need to reproduce them in other cohorts. Furthermore, it was not possible to evaluate myocardial de formation parameters in all patients, which prevented the inclusion of this variable, despite its recognized diagnostic and prognostic value, as well as right ventricular ejection fraction by a 3-dimensional method. Nevertheless, the fact that simple and accessible parameters, such as TAPSE, demonstrate prognostic value reinforces its clinical relevance.
CONCLUSION
Echocardiographic RV impairment is common in patients with ATTR, and TAPSE stands out as a simple and accessible echocardiographic parameter, due to its predictive capacity in the clinical course of these patients. A reduced TAPSE is associated with a higher risk of total and cardiovascular mortality, hospitalizations for HF and development of AF in the mid-term, highlighting the importance of its evaluation in clinical practice for better risk stratification and disease management.
Conflict of Interest
None declared. (See authors' conflict of interests forms on the web).