Article ID: CR-25-0066
Background: Although tafamidis is used to treat patients with transthyretin amyloid cardiomyopathy (ATTR-CM), its specific effects on cardiac function remain unclear. Thus, this study aimed to investigate the effect of tafamidis on left atrial (LA) and left ventricular (LV) functions using speckle-tracking echocardiography after 1.5 years of treatment in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM).
Methods and Results: We included 27 patients (mean age, 76 years) with ATTRwt-CM confirmed by biopsy. We analyzed LV and LA strains using 2-dimensional speckle-tracking echocardiography and compared these parameters before and after a 1.5-year follow up between 20 patients with and 7 patients without tafamidis treatment. Echocardiography speckle tracking examination showed no significant changes in global longitudinal strain (GLS) or LA reservoir strain (LASr) in patients with ATTRwt-CM after 1.5 years of tafamidis treatment. However, significant deterioration of GLS (–9.3 [–11, –7.4] to –8.0 [–9, –6.7]; P=0.0381) and LASr (11 [6, 16] to 6 [5, 11]; P=0.0074) were observed in patients with ATTRwt-CM without tafamidis.
Conclusions: The LA and LV functions of patients with ATTRwt-CM treated with tafamidis were more favorable than those of untreated patients.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease characterized by the deposition of transthyretin (TTR) amyloid fibrils in the myocardium, which affects the atria, ventricles, and conduction system.1,2
ATTR-CM is classified as hereditary when it has the pathogenic TTR variant (ATTRv-CM), and wild-type (ATTRwt-CM) without the ATTR variant. Tafamidis is available for treating ATTR-CM because it has been shown to reduce all-cause mortality and cardiovascular hospitalization in patients with ATTR-CM compared with placebo.3–9
Some echocardiography studies have evaluated the effectiveness of tafamidis on ATTR-CM,5,8,10–13 and a few echocardiography studies have evaluated the effectiveness of tafamidis on ATTR-CM, including left atrial (LA) function.14,15 However, only 1 report was on the effects of tafamidis on atrial and ventricular functions compared with those without tafamidis treatment.15 Thus, this study aimed to evaluate the effect of 1.5 years of tafamidis treatment on atrial and ventricular function using 2-dimensional speckle-tracking echocardiography (2D STE) in patients with ATTRwt-CM compared with those without tafamidis treatment.
We retrospectively studied 31 consecutive patients with ATTRwt-CM who underwent a 1.5-year follow up at Nagasaki University between September 2018 and August 2024. TTR deposition was confirmed by cardiac or extracardiac biopsy in all patients, and genetic examination revealed no variants. Twenty-three patients were treated with tafamidis, and 8 were not. One patient who did not receive tafamidis was excluded because of a lack of evidence of left ventricular (LV) hypertrophy. Two patients treated with tafamidis were excluded due to poor visualization on transthoracic echocardiography. One patient had no echocardiographic data at the 1.5-year follow-up visit. Therefore, 27 patients were retained in this study (20 patients treated with tafamidis [tafamidis group], and 7 not treated with tafamidis because of side-effects or refusal of treatment [control group]).
This study was approved by the Ethics Committee of Nagasaki University Hospital (23022016-3) and was conducted in accordance with the Declaration of Helsinki.
Standard Echocardiography AssessmentEchocardiography was performed using a GE Vivid E95 system version 203 (GE Healthcare, IL, USA), and images were acquired from standard views. Cardiac function and morphology were assessed using transthoracic echocardiography before and 1.5 years after tafamidis treatment. All standard echocardiography measurements were performed according to the European Association of Cardiovascular Imaging (EACVI) guidelines.16
Speckle Tracking LV and LA AnalysisSpeckle-tracking analysis was performed offline using a software package (EchoPAC, General Electric version 204) to evaluate LV global longitudinal strain (GLS) and LA strain (LAS).
GLSRegarding GLS deformation analysis, the longitudinal strain was calculated using an automated contouring detection algorithm. The averaged peak longitudinal strain of 17 segments from apical 4-, 2-, and 3-chamber views was generated as a ‘bull’s-eye’ map (Figure A). In patients with atrial fibrillation (AF), it was sometimes difficult to construct a bull’s eye map due to fluctuations in heart rate. In such cases, we selected heart rates with relatively stable RR intervals to evaluate GLS. If this was still difficult, we calculated the average strain value of each segment and performed the evaluation.
Echocardiography imaging of (A) global longitudinal strain (GLS), and (B) left atrial strain (LAS). LAScd, left atrial conduit strain; LASct, left atrial contractile strain; LASr, left atrial reservoir strain.
LAS
The LAS was analyzed using a standard 2D apical 4-chamber view (offline analysis, EchoPAC, GE). The LAS was measured in all patients including 10 AF patients using the LAS reservoir strain (LASr), conduit strain (LAScd), and contractile strain (LASct) in accordance with the recommendations of the consensus document from the EACVI/ASE/Industry guidelines using a non-foreshortened apical 4-chamber view of the LA (Figure B).17 The region of interest was adjusted to a 3-mm full-wall or endocardial contouring tool. The LA was contoured by extrapolation across the pulmonary veins and the LA appendage orifice. The average of 3 measurements was used in the final strain analysis, following the committee’s recommendations for patients with normal sinus rhythm.
Interobserver VariabilityA single physician performed all analyses. To ensure reproducibility, GLS, and LAS were re-measured in a random sample of 10 anonymized studies by another experienced operator who was blinded to the treatment and echo timing. Interobserver variability was determined using the intraclass correlation coefficient (ICC).
Statistical AnalysisBaseline characteristics were summarized as mean±standard deviation, or median and interquartile range for continuous variables with normal and non-normal distribution, respectively, and counts (%) for categorical variables. Parameters at baseline and 1.5 years post-treatment were compared using a paired t-test or Wilcoxon signed-rank test, as appropriate.
All hypothesis tests were 2-sided, and statistical significance was set at P<0.05. All analyses, except the ICC, were performed using JMP statistical software (JMP 17Pro, SAS Institute, Cary, NC, USA). The ICC analysis was performed using IBM SPSS Statistics (version 23.0; SPSS, Chicago, IL, USA).
No significant differences were found in the baseline clinical and laboratory characteristics between the tafamidis and control groups (Table 1). Regarding baseline echocardiography parameters, the LV end-diastolic diameter and LV end-systolic diameter were larger in the tafamidis group than in the control group (Table 2).
Baseline Clinical and Laboratory Data Characteristics
| Characteristic | All (n=27) |
Tafamidis (n=20) |
Control (n=7) |
P value (T vs. C) |
|---|---|---|---|---|
| Age (years) | 75±5 | 76±5 | 74±4 | 0.3854 |
| Sex, male | 27 (100) | 20 (100) | 7 (100) | 1.0000 |
| Hypertension | 18 (67) | 13 (65) | 5 (71) | 1.0000 |
| Diabetes | 9 (33) | 8 (40) | 1 (14) | 0.3632 |
| Dyslipidemia | 11 (41) | 8 (40) | 3 (43) | 1.0000 |
| Obesity | 6 (22) | 4 (20) | 2 (29) | 0.6334 |
| AF or pacemaker implantation | 11 (41) | 6 (30) | 5 (71) | 0.0840 |
| BMI (kg/m2) | 22.3±2.8 | 22.5±2.6 | 21.9±3.6 | 0.7096 |
| NYHA class II | 20 (74) | 14 (70) | 6 (86) | 0.6334 |
| NYHA class III | 7 (26) | 7 (30) | 1 (14) | 0.6334 |
| SBP (mmHg) | 118±22 | 120±21 | 111±25 | 0.3836 |
| DBP (mmHg) | 72±15 | 74±16 | 67±11 | 0.2358 |
| Heart rate (beats/min) | 71±11 | 70±8 | 72±18 | 0.7355 |
| Hb (g/dL) | 14.1±1.6 | 14.3±1.3 | 13.8±2.4 | 0.6064 |
| eGFR (mL/min/1.73 m2) | 49±16 | 47±14 | 54±22 | 0.4181 |
| AST (IU/L) | 24 [19, 27] | 24 [18.5, 27] | 23 [19, 24] | 0.4372 |
| ALT (IU/L) | 17 [11, 20] | 17 [10.5, 19.75] | 15 [11, 21] | 0.7815 |
| CK (IU/L) | 84 [65, 160] | 79 [65.75, 167.5] | 91 [49, 149] | 0.8033 |
| Hs-TnT (ng/mL) | 0.059 [0.042, 0.084] | 0.058 [0.04375, 0.09525] | 0.063 [0.033, 0.07] | 0.7398 |
| LDL-C (mg/dL) | 96±30 | 99±31 | 87±27 | 0.3479 |
| NT-proBNP (pg/mL) | 1,711 [1,228, 2,824] | 1,722 [1,014.25, 3,058.75] | 1,488 [1,357, 2,824] | 0.8034 |
| ACEI/ARB | 14 (52) | 10 (50) | 4 (57) | 1.0000 |
| β-blocker | 15 (56) | 11 (55) | 4 (57) | 1.0000 |
| MRA | 10 (37) | 6 (30) | 4 (57) | 0.3648 |
| Diuretics | 23 (85) | 18 (90) | 5 (71) | 0.2692 |
| ARNI | 2 (7) | 2 (10) | 0 (0) | 1.0000 |
| SGLT2I | 7 (26) | 6 (30) | 1 (14) | 0.6334 |
| CCB | 5 (19) | 2 (10) | 3 (43) | 0.0913 |
Unless indicated otherwise , data are presented as n (%), median [IQR] or mean±SD. ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ALT, alanine aminotransferase; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; AST, aspartate aminotransferase; BMI, body mass index; C, control; CCB, calcium channel blocker; CK, creatine kinase; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; Hs-TnT, high-sensitivity troponin T; LDL-C, low-density lipoprotein cholesterol; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro B-type natriuretic peptide; NYHA, New York Heart Association; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2; T, tafamidis.
Baseline Echocardiography Parameters
| All (n=27) |
Tafamidis (n=20) |
Control (n=7) |
P value (T vs. C) |
|
|---|---|---|---|---|
| Two-dimensional measurement | ||||
| LVEDD (mm) | 42.3±5.0 | 43.5±5.3 | 39.7±2.7 | 0.0257 |
| LVESD (mm) | 31.5±5.0 | 32.6±5.2 | 28.3±2.9 | 0.0142 |
| IVS (mm) | 16 [14, 18] | 16 [13, 18] | 16 [15, 18] | 0.4022 |
| PW (mm) | 15.4±3.0 | 15.1±2.8 | 16.4±3.7 | 0.3963 |
| LVEF (%) | 53.8±11.1 | 52.3±11.6 | 58.3±8.4 | 0.1635 |
| LVMI (g/m2) | 151.6 [135.3, 192.8] | 154.1 [136.5, 194.8] | 151.6 [125.2, 179] | 0.9779 |
| LAD (mm) | 43.3±4.7 | 43.0±4.3 | 44.3±5.9 | 0.5982 |
| LA area (cm2) | 25.6±4.9 | 24.7±4.9 | 28.1±4.1 | 0.0897 |
| LAVI (mL/m2) | 51.0±15.4 | 48.1±14.6 | 59.3±15.8 | 0.1298 |
| Doppler measurement | ||||
| E velocity (cm/s) | 80.2±24.1 | 76.6±21.8 | 90.7±29.0 | 0.2695 |
| E′ lateral (cm/s) | 5.1±1.3 | 5.2±1.3 | 5.0±1.1 | 0.7701 |
| E′ septal (cm/s) | 3.7±1.0 | 3.6±1.1 | 4.0±1.0 | 0.5021 |
| Average E/E′ | 19.3±6.1 | 18.6±5.8 | 21.1±7.0 | 0.4179 |
| DT (ms) | 194 [155, 237] | 191.5 [152, 219.5] | 237 [179, 298] | 0.1581 |
| Speckle-tracking measurement | ||||
| GLS (%) | −9.8±2.9 | −9.7±2.9 | −10.1±3.3 | 0.7810 |
| GLS 4ch (%) | −9.3±3.0 | −9.1±3.1 | −9.7±2.9 | 0.6710 |
| GLS 2ch (%) | −10.4±3.4 | −10.5±3.2 | −10.4±4.3 | 0.9739 |
| GLS 3ch (%) | −9.4 [−11.2, −8] | −9.9 [−11.8, −6.9] | −9.4 [−11.2, −8.6] | 0.7398 |
| LASr (%) | 10.0±6.2 | 9.0±5.0 | 13.0±8.4 | 0.2657 |
| LAScd (%) | −6 [−10, −5] | −6 [−8, −4] | −10 [−15, −5] | 0.1060 |
| LASct (%) | 0 [−4, −5] | −0.5 [−3.5, 0] | −1 [−4, 0] | 0.9546 |
| RELAPS | 1.5±0.6 | 1.5±0.5 | 1.4±0.7 | 0.6991 |
Unless indicated otherwise, data are presented as median [IQR] or mean±SD. C, control; DT, deceleration time; GLS, global longitudinal strain; IVS, interventricular septal; LA, left atrial; LAD, left atrial dimension; LAScd, left atrial conduit strain; LASct, left atrial contractile strain; LASr, left atrial reservoir strain; LASr, left atrial reservoir strain; LAVI, left atrial volume index; LVEDD, left ventricular end-diastolic diameter; LVEDVI, left ventricular end-diastolic volume index; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; LVESVI, left ventricular end-systolic volume index; PW, posterior wall; RELAPS, relative apical sparing; T, tafamidis.
Echocardiography examination using 2D and Doppler measurements revealed no significant changes in all parameters except for E′ septal in patients with ATTRwt-CM after 1.5 years of tafamidis treatment (Table 3).
Echocardiography Parameters Before and at 1.5 Years in the Tafamidis Group
| Before (n=20) |
1.5 years (n=20) |
P value | |
|---|---|---|---|
| Two-dimensional measurement | |||
| LVEDD (mm) | 43 [40, 47] | 44 [42.25, 47] | 0.0586 |
| LVESD (mm) | 32 [28.3, 35.8] | 34.5 [31.25, 37] | 0.0575 |
| IVS (mm) | 15.3±2.8 | 15.3±2.6 | 0.8037 |
| PW (mm) | 15.1±2.8 | 15.0±2.8 | 0.6493 |
| LVEF (%) | 52.3±11.6 | 51.0±11.6 | 0.3951 |
| LVMI (g/m2) | 162.1±39.1 | 170.9±41.4 | 0.0465 |
| LAD (mm) | 43.0±4.3 | 42.9±5.3 | 0.9091 |
| LA area (cm2) | 24.7±4.9 | 24.5±4.3 | 0.8211 |
| LAVI (mL/m2) | 48.1±14.6 | 47.1±12.5 | 0.6080 |
| Doppler measurement | |||
| E velocity (cm/s) | 76.6±21.8 | 70.6±20.7 | 0.0766 |
| E′ lateral (cm/s) | 5.2±1.3 | 4.6±1.5* | 0.0928 |
| E′ septal (cm/s) | 3.6±1.1 | 3.1±0.9* | 0.0355 |
| Average E/E′ | 18.6±5.8 | 20.1±7.0* | 0.3640 |
| DT (ms) | 191.5 [152, 219.5] | 220 [165, 275.25] | 0.1384 |
| Speckle-tracking measurement | |||
| GLS (%) | −9.7±2.9 | −9.5±2.7 | 0.4275 |
| GLS 4ch (%) | −9.1±3.1 | −9.5±2.7 | 0.4086 |
| GLS 2ch (%) | −10.5±3.2 | −9.7±2.7 | 0.0961 |
| GLS 3ch (%) | −9.6±2.7 | −9.4±3.1 | 0.4622 |
| LASr (%) | 8 [5, 12] | 8 [5.25, 16.9] | 0.0553 |
| LAScd (%) | −6 [−8, −4] | −6.5 [−8, −5] | 0.3209 |
| LASct (%) | −0.5 [−3.5, 0] | −1 [−6.25, −0.25] | 0.0268 |
| RELAPS | 1.5±0.5 | 1.5±0.5 | 0.7858 |
Unless indicated otherwise, data are presented as median [IQR] or mean±SD. *n=19 because 1 patient had no Doppler measurement for E′. Abbreviations as in Table 2.
Echocardiography speckle tracking examination showed no significant changes in the GLS and LAS in patients with ATTRwt-CM after 1.5 years of tafamidis treatment (Table 3).
However, echocardiography examination showed an increase in LAD (44.3±5.9 mm to 47.8±5.0 mm; P=0.0368), but not in the LA area and LA volume index in patients with ATTRwt-CM without tafamidis at the 1.5-year follow up (Table 4). Furthermore, echocardiography examination of speckle tracking showed a significant decrease in GLS (−9.3 [−11, −7.4]% to −8.0 [−9, −6.7]%; P=0.0381), LASr (11 [6, 16]% to 6 [5, 11]%; P=0.0074), and LAScd (10.6±6.2% to 6.4±3.7%; P=0.0292) in the patients with ATTRwt-CM without tafamidis (Table 4).
Echocardiography Parameters Before and at 1.5 Years in the Control Group
| Before (n=7) |
1.5 years (n=7) |
P value | |
|---|---|---|---|
| Two-dimensional measurement | |||
| LVEDD (mm) | 39 [37, 42] | 39 [38, 42] | 0.8211 |
| LVESD (mm) | 29 [26, 30] | 29 [27, 31] | 0.3999 |
| IVS (mm) | 16 [15, 18] | 17 [16, 18] | 0.5222 |
| PW (mm) | 16.4±3.7 | 16.4±4.1 | 1.0000 |
| LVEF (%) | 58.3±8.4 | 56.4±7.9 | 0.0593 |
| LVMI (g/m2) | 151.6 [125.2, 179] | 153.3 [141.5, 196.8] | 0.5003 |
| LAD (mm) | 44.3±5.9 | 47.8±5.0 | 0.0368 |
| LA area (cm2) | 28.1±4.1 | 30.0±3.9 | 0.1087 |
| LAVI (mL/m2) | 59.3±15.8 | 66.3±13.7 | 0.0763 |
| Doppler measurement | |||
| E velocity (cm/s) | 90.7±29.0 | 75.5±24.0 | 0.1919 |
| E′ lateral (cm/s) | 5.0±1.1 | 4.2±0.8* | 0.0374 |
| E′ septal (cm/s) | 4.0±1.0 | 3.1±0.8* | 0.0658 |
| Average E/E′ | 21.1±7.0 | 21.5±6.0* | 0.2423 |
| DT (ms) | 237 [179, 298] | 229.5 [224, 255] | 0.9283 |
| Speckle-tracking measurement | |||
| GLS (%) | −9.3 [−11, −7.4] | −8 [−9, −6.7] | 0.0381 |
| GLS 4ch (%) | −9.7±2.9 | −9.0±2.5 | 0.2042 |
| GLS 2ch (%) | −10.4±4.3 | −8.7±3.0 | 0.0469 |
| GLS 3ch (%) | −9.4 [−11.2, −8.6] | −8.1 [−8.6, −7.2] | 0.0087 |
| LASr (%) | 11 [6, 16] | 6 [5, 11] | 0.0074 |
| LAScd (%) | −10.6±6.2 | −6.4±3.7 | 0.0292 |
| LASct (%) | 0 [−8, −0] | 0 [−4, 0] | 0.1723 |
| RELAPS | 1.1 [0.8, 1.8] | 1.1 [0.9, 2.1] | 0.2847 |
Unless indicated otherwise, data are presented as median [IQR] or mean±SD. *n=6 because 1 patient had no Doppler measurement for E′. Abbreviations as in Table 2.
The interobserver variability between the 2 blinded readers, assessed by ICC with 95% confidence intervals (CIs), was good to excellent: GLS 0.99 (95% CI 0.98, 0.99); LASr 0.98 (95% CI 0.91, 0.99); LAScd 0.90 (95% CI 0.64, 0.97); and LASct 0.93 (95% CI 0.74, 0.98).
This study demonstrated that 1.5 years of tafamidis treatment prevented worsening of GLS or LV function, LAS or LA function in ATTRwt-CM.
Previous studies have demonstrated that tafamidis prevents the worsening of LV function using GLS after the administration of tafamidis.10,11,15,18 These results are consistent with our data. Although there was no significant difference in LV ejection fraction (LVEF) between before and the 1.5-year follow up in the control group, it showed a tendency to decrease. Thus, a further follow up may reveal a significant difference in LVEF.
In cardiac amyloidosis, including ATTRwt-CM, LA function is severely impaired,1 and LAS has important prognostic associations with survival19 and cardiovascular events.20 Furthermore, baseline LA reservoir function is closely associated with cardiovascular events after tafamidis administration in patients with ATTR-CM.12
Rettl et al.15 have demonstrated that the LAS was not changed by tafamidis treatment, although untreated patients with ATTR-CM showed LAS (LASr, LAScd and LASct) progression. In their study, follow up was performed after a median of 8.5 months in the tafamidis-free acid 61 mg treated cohort and after 10.5 months in the historical treatment naïve control cohort.15 The follow-up period (1.5 years) of the present study was longer than theirs, and the same in patients with and without tafamidis. Thus, our results are compatible with their data , and may be more accurate than their data in patients with ATTRwt-CM. Summarily, these results suggest that tafamidis treatment may prevent worsening of LV and LA function and the progression of myocardial damage.
However, in our study, LASr and LAScd decreased, but LASct was not changed in the control group. We included AF patients, although LA strain analyses were performed in patients in sinus rhythm only in the study by Rettl et al.15 Moreover, the EACVI/ASE/Industry Task Force states that LAScd has the same value as LASr in patients with AF and that LASct is measured only in patients with sinus rhythm.17 Thus, AF may affect the result of LASct.
As this study included cases of AF patients, the evaluation was performed using the R-R gating method; the LA strain curve was monophasic, and the focus was mainly on the latter half of the reservoir function. Thus, LASr may not be fully evaluated especially in patients with AF. Even so, as LASr significantly decreased in the control group, and LAScd also decreased, we concluded that LA function decreased in the control group.
Study LimitationsThe present study has several limitations. This was a single-center retrospective study with a small sample size, particularly in the control group, because tafamidis is currently available to patients with ATTRwt-CM. However, the LV and LA functions in the present study were similar to those reported in larger studies.10,15,19 Moreover, our study of current patients may be better than those studies on comparison of cardiac function between patients with tafamidis and without tafamids in the past when tafamidis could not be used because the management for heart failure and the accuracy of echocardiography analysis may be different between them.
Patients’ background factors, including comorbidities, heart failure severity, and concomitant medications, may have influenced the results. Because the number of cases was not sufficient to perform multivariate analysis, we performed analyses for each factor. There were no significant differences except for the decrease in GLS in hypertensive patients (Supplementary Table). The proportion of hypertensive patients was similar in the treatment and control groups, so hypertension is unlikely to have influenced the GLS data. Thus, these factors may not influence the results. However, a further large study is required for evaluation of these factors.
LA and LV function and myocardial damage in patients with ATTRwt-CM treated with tafamidis were more favorable than those in patients not treated with tafamidis.
None.
M.U. received lecture fees, research funds, and travel expenses from Pfizer, and Alnylam Pharmaceuticals. K.M. is a member of Circulation Reports’ Editorial Team.
Ethics committees at Nagasaki University Hospital (registration no. 23022016-3).
None.
Please find supplementary file(s);
https://doi.org/10.1253/circrep.CR-25-0066
