Abstract
Aims
Transthyretin cardiac amyloidosis (ATTR‐CA) is most often associated with heart failure with preserved ejection fraction (HFpEF). However, patients may present with impaired systolic function at the time of diagnosis, which has not been widely investigated. We sought to explore the prevalence of various heart failure (HF) phenotypes and their associated clinical characteristics at the time of ATTR‐CA diagnosis.
Methods
We performed a single‐centre retrospective cohort study of consecutive patients with ATTR‐CA evaluated between February 2016 and December 2022. Data on patient demographics, comorbidities, imaging and laboratory findings were compared across HF phenotypes (age: 78.1 ± 8.6 years, with 91.1% male). A total of 21.6% (n = 46) presented with heart failure with reduced ejection fraction (HFrEF), 17.8% (n = 38) with heart failure with mildly reduced ejection fraction (HFmrEF) and 60.6% (n = 129) with HFpEF at the time of diagnosis with ATTR‐CA. Those presenting with HFrEF or HFmrEF were more likely to be African American and had significantly worse New York Heart Association (NYHA) functional class, higher N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and higher serum creatinine levels as compared with those with HFpEF.
Conclusions
Although ATTR‐CA is traditionally thought to be seen primarily among patients with HFpEF, our data suggest that ATTR‐CA has a higher prevalence among patients with HFrEF, which underscores the importance of heightened clinical suspicion regardless of ejection fraction when considering ATTR‐CA. Furthermore, although comorbidities are similar, patients with HFmrEF and HFrEF had a worse symptom burden.
Keywords: cardiac amyloidosis, ejection fraction, heart failure
Introduction
Transthyretin amyloidosis (ATTR) is a rare multi‐system life‐threatening syndrome caused by the accumulation of transthyretin (TTR) amyloid fibrils in the nerves, heart, kidney and gastrointestinal tract, among other organ systems. 1 ATTR‐CA results from myocardial deposition of TTR fibrils and progressive heart failure (HF), along with a poor prognosis. 2 , 3 , 4 , 5 In the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry, more than 70% of the patients from the United States were older men with transthyretin cardiac amyloidosis (ATTR‐CA) due to the wild‐type (48%) or Val122iIe TTR (23%) mutation, as compared with the rest of the world. 6 , 7 With the increased utilization of non‐invasive diagnostic tools, such as cardiac scintigraphy, ATTR‐CA is increasingly recognized globally. 2 , 8 In the United States, 5000–7000 new cases are identified annually. 2
Although ATTR‐CA is historically linked to heart failure with preserved ejection fraction [HFpEF; left ventricular ejection fraction (LVEF) ≥ 50%], patients may present with impaired systolic function, including heart failure with reduced ejection fraction (HFrEF; LVEF < 40%) or heart failure with mildly reduced ejection fraction (HFmrEF; LVEF 40%–49%). 9 , 10 , 11 To the best of our knowledge, only a few small studies compare the clinical characteristics and outcomes of patients with ATTR‐CA across HF phenotypes. 9 , 11 , 12 , 13 Identifying clinical characteristics that indicate a more progressive disease course or advanced disease status at the time of ATTR‐CA diagnosis can provide valuable insights into this challenging patient population and inform current clinical practice. Therefore, we sought to explore the prevalence of various HF phenotypes and their associated clinical characteristics at the time of ATTR‐CA diagnosis in a single‐centre experience.
Methodology
Study population and design
The Cleveland Clinic Florida Amyloid Center Registry records data on all amyloid patients seen in consultation. Consecutive patients with a confirmed diagnosis of ATTR‐CA between February 2016 and December 2022 formed the study cohort. Both wild‐type ATTR and hereditary ATTR (hATTR) patients were included, but patients with light chain (AL) amyloidosis were excluded. Data on patient demographics, comorbidities, medical history, echocardiographic and laboratory findings and vitals were collected retrospectively through chart review of the electronic medical records at the time of ATTR‐CA diagnosis. This study was approved by the Cleveland Clinic Foundation Institutional Review Board (FLA 23‐002).
Study variables and definitions
The ATTR‐CA diagnosis was confirmed through verification of endomyocardial biopsy tissue samples or 99Tc‐pyrophosphate scanning combined with single photon emission computed tomography (SPECT) imaging. The presence of AL amyloidosis was ruled out by laboratory testing and, if indicated, either bone marrow or endomyocardial biopsy. All included patients underwent genetic testing, and genotypes were described for those found to have hATTR. HF phenotypes were classified by LVEF according to the latest American College of Cardiology/American Heart Association/Heart Failure Society of America guidelines. HFrEF was defined as LVEF ≤ 40%, while HFmrEF and HFpEF were defined as ejection fraction (EF) of 41%–49% and EF ≥ 50%, respectively. 14 The history of chronic kidney disease (CKD) was defined as having an estimated glomerular filtration rate of <60 mL/min/1.73 m2 based on the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation. Patients were also stratified into one of the three National Amyloidosis Centre (NAC) ATTR stages, as previously described by Gillmore et al. 15 Neuropathy included any diagnosis of peripheral polyneuropathy or autonomic neuropathy.
Statistical analysis
The assumption of a normal distribution was tested with the Shapiro–Wilk test. Categorical variables were reported as percentages (n), and continuous variables were reported as mean ± SD (if normally distributed) or median with interquartile range (IQR) (if non‐normally distributed). The cohort was stratified into three groups according to HF classification by LVEF. Differences in patient characteristics were evaluated using the χ 2 test for categorical variables and the analysis of variance (if normally distributed) or Kruskal–Wallis tests (if non‐normally distributed) for numerical variables. A P‐value < 0.05 was considered statistically significant. All statistical analyses were performed with JMP® Data Analysis (Software Version 16, SAS Institute Inc., Cary, NC, USA).
Results
Between February 2016 and December 2022, 213 unique patients were recorded in the registry. The mean age was 78.1 ± 8.6 years, and 91.1% (n = 194) of the patients were males (Table 1). A total of 80.7% (n = 171) of patients were White, and 14.6% (n = 31) were African American. A total of 80.2% (n = 170) of patients had wild‐type ATTR, with the remainder having hATTR. Patients with ATTR‐CA had a high burden of hypertension (78.9%), ischaemic heart disease (55.9%), atrial fibrillation (72.8%) and CKD (63.4%). At the time of the ATTR‐CA diagnosis, a history of neuropathy was present in half of the population (Table 1). About half of the patients (50.7%, n = 108) presented with a New York Heart Association (NYHA) class of ≥III. The median N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) was 1884 [IQR (837–3769) pg/mL], and the mean LVEF measured was 49.8% ± 10.7% (Table 2). Among patients with hATTR with available data on their genotype (n = 40), the most frequently identified mutation was Val122iIe (67.5%), followed by Thr60Ala (20%) and Val30Met (5%). The African American race was more predominant in the Val122iIe group (P < 0.001), with no significant differences in the prevalence of impaired left ventricular (LV) function across various genotypes (P = 0.2) (Table 3). Use of guideline‐directed medical therapy (GDMT) with beta‐blockers, ACEIs (angiotensin‐converting enzyme inhibitors)/ARBs (angiotensin receptor blockers)/ARNIs (angiotensin receptor/neprilysin inhibitors), MRAs (mineralocorticoid receptor antagonists) and SGLT‐2 (sodium‐glucose co‐transporter 2) inhibitors was 36.7%, 31.9%, 27.7% and 11.8%, respectively (Figures 1). Furthermore, 83.6% (n = 178) of patients received tafamidis after diagnosis.
Table 1.
Baseline characteristics and medications of patients with ATTR cardiac amyloidosis according to their heart failure phenotype at the time of diagnosis.
| Demographics and comorbidities | All (N = 213) | HFrEF (n = 46) | HFmrEF (n = 38) | HFpEF (n = 129) | P‐value |
|---|---|---|---|---|---|
| Age (years, mean ± SD) | 78.1 ± 8.6 | 76.8 ± 7.5 | 78.5 ± 6.8 | 78.4 ± 9.4 | 0.5 |
| Male gender, n (%) | 194 (91.1%) | 44 (95.7%) | 34 (89.5%) | 116 (89.9%) | 0.5 |
| African American, n (%)* | 31 (14.6%) | 12 (26.1%) | 7 (18.4%) | 12 (9.3%) | 0.02 |
| Wild‐type ATTR, n (%) | 170 (80.2) | 33 (71.7%) | 31 (81.6%) | 106 (82.8%) | 0.3 |
| Hypertension, n (%) | 168 (78.9%) | 39 (84.8%) | 31 (81.6%) | 98 (76%) | 0.4 |
| Diabetes mellitus, n (%)* | 43 (20.2%) | 12 (26.1%) | 12 (31.6%) | 19 (14.7%) | 0.04 |
| Atrial fibrillation, n (%) | 155 (72.8%) | 34 (73.9%) | 31 (81.6%) | 90 (69.8%) | 0.3 |
| Ischaemic heart disease, n (%) | 119 (55.9%) | 25 (54.4%) | 23 (60.5%) | 71 (55%) | 0.8 |
| Chronic kidney disease, n (%)* | 135 (63.4%) | 33 (71.7%) | 27 (71.1%) | 75 (58.1%) | 0.1 |
| Neuropathy, n (%) | 104 (48.8%) | 23 (50%) | 19 (50%) | 62 (48.1%) | 0.96 |
| Carpal tunnel syndrome, n (%) | 108 (50.7%) | 24 (52.2%) | 17 (44.7%) | 67 (51.9%) | 0.72 |
Abbreviations: ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor/neprilysin inhibitor; ATTR, transthyretin amyloidosis; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IQR, interquartile range; MRA, mineralocorticoid receptor antagonist; SGLT‐2, sodium‐glucose co‐transporter 2.
The P‐value was significant at <0.05 when comparing HFpEF versus any impaired left ventricular function (HFrEF + HFmrEF).
Table 2.
Clinical, echocardiographic and laboratory findings of patients with transthyretin amyloidosis cardiac amyloidosis according to their heart failure phenotype at the time of diagnosis.
| All (N = 213) | HFrEF (n = 46) | HFmrEF (n = 38) | HFpEF (n = 129) | P‐value | |
|---|---|---|---|---|---|
| Clinical findings | |||||
| NYHA classification* | |||||
| Class I | 23 (11%) | 3 (6.5%) | 4 (10.5%) | 16 (12.5%) | <0.001 |
| Class II | 81 (38.2%) | 10 (21.7%) | 14 (36.8%) | 57 (44.5%) | |
| Class III | 98 (46.2%) | 27 (58.7%) | 19 (50%) | 52 (40.6%) | |
| Class IV | 10 (4.7%) | 6 (13%) | 1 (2.6%) | 3 (2.3%) | |
| NYHA class ≥ III* | 108 (50.9%) | 33 (71.7%) | 20 (52.6%) | 55 (42.9%) | 0.003 |
| Systolic blood pressure (mmHg, mean ± SD)* | 126.7 ± 17.2 | 121.8 ± 18.1 | 124.7 ± 15.7 | 129.1 ± 17.1 | 0.04 |
| Heart rate (b.p.m., mean ± SD) | 73.4 ± 13.1 | 75.3 ± 11.9 | 72.8 ± 13.7 | 72.8 ± 13.3 | 0.5 |
| Echocardiographic findings | |||||
| LVEF% (mean ± SD)* | 49.8 ± 10.7 | 33.5 ± 5.5 | 45.4 ± 2.1 | 56.8 ± 5.3 | <0.001 |
| LVIDd (cm, mean ± SD)* | 4.4 ± 0.7 | 4.7 ± 0.7 | 4.4 ± 0.7 | 4.2 ± 0.6 | <0.001 |
| LVIDs (cm, mean ± SD)* | 3.2 ± 0.8 | 3.8 ± 0.7 | 3.4 ± 0.6 | 3 ± 0.7 | <0.001 |
| LA size (cm, mean ± SD) | 4.6 ± 0.8 | 4.9 ± 0.7 | 4.4 ± 0.8 | 4.6 ± 0.8 | 0.065 |
| TAPSE (cm, mean ± SD) | 1.5 ± 0.32 | 1.56 ± 0.5 | 1.6 ± 0.4 | 1.9 ± 0.5 | 0.001 |
| Posterior wall thickness (cm, mean ± SD) | 1.5 ± 0.32 | 1.6 ± 0.29 | 1.6 ± 0.31 | 1.5 ± 0.33 | 0.26 |
| LVMI (g/m2, mean ± SD)* | 143 ± 43 | 159.6 ± 41.6 | 160.5 ± 34.8 | 130.7 ± 42.5 | <0.001 |
| GLS% (mean ± SD)* | −11.3 ± 5.6 | −8.2 ± 5 | −9.5 ± 7 | −13.1 ± 4 | <0.001 |
| Laboratory findings | |||||
| Serum creatinine (mg/dL, mean ± SD)* | 1.35 ± 0.54 | 1.5 ± 0.7 | 1.4 ± 0.5 | 1.3 ± 0.5 | 0.02 |
| eGFR (mL/min/1.73 m2, mean ± SD)* | 58.8 ± 20.7 | 54.9 ± 21.5 | 54.8 ± 20.7 | 61.4 ± 20.1 | 0.08 |
| Albumin (g/dL, mean ± SD) | 4.1 ± 0.44 | 4.1 ± 0.4 | 4.1 ± 0.4 | 4.1 ± 0.5 | 0.9 |
| NT‐proBNP [pg/mL, median (IQR)]* | 1884 [837–3769] | 2498 [1295–6350] | 2780 [1165–5510] | 1441 [614–2763] | 0.001 |
| NAC stage* | |||||
| NAC stage I | 123 (57.8%) | 19 (41.3%) | 17 (44.7%) | 87 (67.4%) | 0.005 |
| NAC stage II | 60 (28.2%) | 17 (37%) | 12 (31.6%) | 31 (24%) | |
| NAC stage III | 30 (14.1%) | 10 (21.7%) | 9 (23.7%) | 11 (8.6%) | |
Abbreviations: eGFR, estimated glomerular filtration rate; GLS, global longitudinal strain; HF, heart failure; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IQR, interquartile range; LA, left atrial; LVIDd, left ventricular internal diameter end‐diastole; LVIDs, left ventricular internal diameter end‐systole; LVMI, left ventricular mass index; NAC, National Amyloidosis Centre; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide; NYHA, New York Heart Association; TAPSE, tricuspid annular plane systolic excursion.
The P‐value was significant at <0.05 when comparing HFpEF versus any impaired function (HFrEF + HFmrEF).
Table 3.
Prevalence of African American race and HFrEF among variously identified genotypes in the hereditary transthyretin amyloidosis cohort (n = 40).
| Mutation | Val122iIe | Thr60Ala | Val30Met | Others | P‐value |
|---|---|---|---|---|---|
| Patients (n = 40) | 27 (67.5%) | 8 (20%) | 2 (5%) | 3 (7.5%) | ‐ |
| African American race, n (%) | 21 (77.8%) | 0 | 0 | 1 (33.3%) | <0.001 |
| HFrEF or HFmrEF, n (%) | 15 (55.6%) | 2 (25%) | 0 | 2 (66.6%) | 0.2 |
Abbreviations: HFmrEF, heart failure with mildly reduced ejection fraction; HFrEF, heart failure with reduced ejection fraction.
Figure 1.
Medications at the time of diagnosis (%). ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor/neprilysin inhibitor; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT‐2, sodium‐glucose co‐transporter 2.
At the time of diagnosis with ATTR‐CA, approximately 21.6% (n = 46) of patients were classified as HFrEF, 17.8% (n = 38) as HFmrEF and 60.6% (n = 129) as HFpEF. When comparing patient characteristics according to HF phenotype, there was no significant difference in age (P = 0.5) or gender (P = 0.5). HFrEF was more prevalent among African Americans at the time of diagnosis compared with HFpEF (26.1% vs. 9.3%, P = 0.01). Baseline comorbidities were comparable across groups, except for diabetes mellitus, which was less prevalent in the HFpEF group (14.7%) compared with the HFrEF (26.1%) and HFmrEF (31.6%) groups (P = 0.04) (Table 1). At the time of diagnosis, ATTR‐CA patients presenting with HFrEF or HFmrEF were more likely to exhibit NYHA functional class ≥ III (P = 0.003), higher NT‐proBNP (P = 0.001) and higher serum creatinine levels (P = 0.02) as compared with those with HFpEF. In line with these findings, higher proportions of patients in NAC stage II or III were observed in those with HFrEF or HFmrEF as compared with those with HFpEF (58.7% in HFrEF vs. 55.3% in HFmrEF vs. 32.6% in HFpEF, P = 0.002) (Table 2). Statistically significant differences in left ventricular internal diameter end‐diastole (LVIDd; 4.7 ± 0.7 in HFrEF vs. 4.4 ± 0.7 in HFmrEF vs. 4.2 ± 0.6 cm in HFpEF, P < 0.001), left ventricular internal diameter end‐systole (LVIDs; 3.8 ± 0.7 in HFrEF vs. 3.4 ± 0.6 in HFmrEF vs. 3 ± 0.7 in HFpEF, P < 0.001), left ventricular mass index (LVMI; 159.6 ± 41.6 in HFrEF vs. 160.5 ± 34.8 in HFmrEF vs. 130.7 ± 42.5 g/m2 in HFpEF, P < 0.001) and global longitudinal strain% (GLS%, −8.2 ± 5 in HFrEF vs. −9.5 ± 7 in HFmrEF vs. −13.1 ± 4 in HFpEF, P < 0.001) were also present (Table 2). Patients in the HFpEF group had higher systolic blood pressure (129 vs. 125 mmHg among HFmrEF vs. 122 mmHg among HFrEF, P = 0.04) and were less likely to receive loop diuretics or MRAs. Among those patients with HFrEF, only 41.3% (n = 19), 32.6% (n = 15), 45.6% (n = 21) and 28.3% (n = 13) of the patients were on beta‐blockers, ACEIs/ARBs/ARNIs, MRAs and SGLT‐2 inhibitors, respectively. In addition, tafamidis prescription rates were similar across groups regardless of EF stratification (P = 0.8) (Figures 1).
Discussion
Cardiac involvement in ATTR is common and poses a significant morbidity and mortality burden. 16 Without appropriate treatment, the survival of patients after diagnosis with ATTR‐CA is estimated at 2.5 and 3.6 years for the hereditary and wild types, respectively. 17 Despite advances in treatment strategies for ATTR, areas of ambiguity remain in screening and disease progression. Early diagnostic evaluation is essential, as the progression of this infiltrative cardiomyopathy may lead to a reduction in EF in more advanced stages. This limits treatment modalities because therapy for ATTR‐CA may be most effective when administered before significant cardiac dysfunction. 18 In a recent meta‐analysis of 11 studies involving 3303 patients, the pooled prevalence of cardiac amyloidosis (CA) among patients with HF was 13.7%, and these estimates ranged from 11.3% in those with HFrEF to 15.1% in those with HFpEF. 10
In our study, almost 40% of patients presented with either HFrEF or HFmrEF, which reflects the heterogeneity across LV function at the time of diagnosis and goes against the traditional association of ATTR‐CA with HFpEF alone. Our findings were consistent with the previously published finding by Martyn et al., in which they reported that at the time of diagnosis, ATTR‐CA patients (n = 585) presented with HFrEF and HFmrEF in 28% and 17% of the cases, respectively. 11 It should also be noted that a larger than expected proportion of patients are likely diagnosed later in the disease course and perhaps with a more ‘burned out’ physiology, as suggested by a relatively high proportion of reduced EF with remodelled ventricles. Although more data are needed, this may also reflect disparities in diagnostic and treatment algorithms. Considering that current treatment modalities do not reverse disease and only abate its progression, the need for earlier detection is imperative.
As ATTR‐CA development is age dependent, many patients suffer from multiple comorbid conditions before ATTR‐CA develops. 19 Our population exhibited a significant pre‐existing comorbidity profile at the time of the ATTR‐CA diagnosis, including hypertension, atrial fibrillation, CKD and ischaemic heart disease. Interestingly, the prevalence of these comorbidities was comparable, irrespective of the degree of LV systolic dysfunction observed, although the prevalence of diabetes mellitus was lower in the HFpEF group.
When stratifying patients according to HF phenotype, there was no significant between‐group difference in gender or age. In contrast, Asif et al. reported a younger age at the time of diagnosis in ATTR‐CA patients presenting with HFrEF compared with HFpEF (72 ± 9 vs. 85 ± 7; P = 0.0001). 9
In our study, African Americans were more likely to be defined as having HFrEF at the time of diagnosis, consistent with previous findings by Martyn et al. and Bhattacharya et al. 11 , 12 We postulate that this could be due to less access to care as well as the genetic phenotypes associated with a more aggressive clinical course among African American patients, highlighting the need to be more aggressive in screening, particularly among patient populations that may be at higher risk.
When comparing patient presentation at the time of ATTR‐CA diagnosis across HF phenotypes, we found that patients with HFrEF or HFmrEF had worse symptom burden with an NYHA class of ≥III and higher NT‐proBNP and serum creatinine levels as compared with the HFpEF group, similar to previously published findings. 12 , 13 In addition, more advanced NAC stages were observed in patients with impaired systolic function, indicating a worse prognosis. It has been previously estimated that survival is approximately 69.2, 46.7 and 24.1 months in NAC stages I, II and III, respectively. 15
Additionally, with the decline in systolic function, there was a significant increase in LV internal diameters and an increased LVMI, reflecting remodelling that may occur with disease progression. This further supports the need to identify and treat patients as early in the disease spectrum as possible.
Guidelines regarding the use of GDMT in patients with ATTR‐CA remain limited, and expert consensus documents caution against their use. ACEIs/ARBs/ARNIs and beta‐blockers may worsen the restrictive physiology in these patients. In a small case series describing the outcomes of patients with ATTR‐CA and HFrEF treated with GDMT, 50% of those patients responded favourably to GDMT with improved EF, decreased creatinine and improved functional capacity, but, conversely, the other 50% remained decompensated, requiring hospice care. 20 A recent study from the United Kingdom investigated prescription patterns and GDMT utilization in 2371 patients with ATTR‐CA and found that GDMT was more likely to be prescribed in those with advanced cardiac disease. Also, they concluded that beta‐blockers and ACEIs/ARBs were often discontinued and found a significant association between low‐dose beta‐blockers and reduced mortality risk in those with HFrEF. Additionally, their data demonstrated that MRAs were rarely discontinued and were associated with a reduced risk of mortality among the overall population. 21 In regard to SGLT‐2 inhibitors, recent studies highlighted these agents' favourable effects on HF symptoms, renal function and diuretic agent requirement over time in patients with ATTR‐CA, as well as their association with reduced risk of HF hospitalization and mortality, regardless of the EF. 22 , 23 More data are needed to assess whether and how GDMT should be utilized among patients with ATTR‐CA.
Several study limitations exist. This is a single‐centre observational retrospective study of patients with ATTR‐CA, and, therefore, limitations of such a study exist. Our amyloid clinic is also part of a tertiary referral centre, and patients may be referred later in the disease course compared with what is generally seen in the community, which may partly explain the higher proportion of reduced EF patients in this cohort. Second, the small sample size of the study may limit the ability to assess significant differences in patient characteristics across different HF phenotypes and may potentially increase the likelihood of type II errors. Lastly, data on findings of the apical sparing pattern were not reported, and we did not evaluate other clinical outcomes, such as mortality or quality of life measures.
Conclusions
ATTR‐CA presents a heterogeneous clinical picture that can be challenging as patients may have normal, intermediate or reduced LV function at the time of diagnosis (almost 40% of patients in this cohort). Our population had a high morbidity burden expressed across the spectrum of ventricular function. Those with impaired systolic function had reduced functional capacity, worse renal function, a larger LV size and highly elevated NT‐proBNP. Our study emphasizes the need to shift from the historical paradigm of the ATTR‐CA association with HFpEF and expand diagnostic algorithms to include patients with HFrEF and HFmrEF.
Conflict of interest statement
There are no conflicts of interest.
Funding
No funding was required to produce this article.
Alonso, M. , Neicheril, R. K. , Manla, Y. , McDonald, M. L. , Sanchez, A. , Lafave, G. , Seijo De Armas, Y. , Camargo, A. L. , Uppal, D. , Wolinsky, D. , Thakkar‐Rivera, N. , Velez, M. , Baran, D. A. , Estep, J. D. , and Snipelisky, D. (2024) Transthyretin cardiac amyloid: Broad heart failure phenotypic spectrum and implications for diagnosis. ESC Heart Failure, 11: 3649–3655. 10.1002/ehf2.15035.
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