Abstract
Aim: To evaluate the prevalence of TTR amyloid cardiomyopathy (ATTR-CM) in severe aortic stenosis (SAS) patients, and to determine the independent predictors of major adverse events (MAE).
Patients & methods: 91 SAS patients >65 years with an interventricular septum thickness ≥12.5 mm were referred for aortic valve replacement (AVR). 99mTc-DPD scintigraphy was applied to diagnose ATTR-CM, in the absence of monoclonal protein.
Results: ATTR-CM was found in 11%. 78% of patients underwent AVR, but only 2 had ATTR-CM. There were no significant differences in the composite of all cause-mortality or cardiovascular hospitalizations. Lower left ventricle ejection fraction and not performing AVR were independent predictors of MAE.
Conclusion: Not performing AVR was an independent predictor of MAE, regardless the ATTR-CM diagnosis.
Keywords: : aortic stenosis, aortic valve replacement, prevalence, prognosis, TTR amyloid cardiomyopathy
Plain Language Summary
Our study aimed to evaluate the number of people with severe narrowing of the aortic valve (SAS) and damage to the heart muscle caused to the deposition of filamentous structures composed of TTR (ATTR-CM), and to determine the independent predictors of severe undesirable medical occurrences (MAE). 91 patients >65 years with SAS and increased thickness of the heart muscle were referred to perform an aortic valve prosthesis implantation (AVR). A nuclear medicine exam was used to diagnose ATTR-CM, after excluding the deposition of filamentous structures composed of blood proteins in the heart muscle. ATTR-CM was found in 11%. 78% of patients underwent AVR, but only two had ATTR-CM. There were no significant differences in both death rate from all causes or hospitalizations from cardiovascular causes. A lower percentage of blood pumped out of the heart in each beat and not performing AVR independently predicted the occurrence of MAE in SAS patients, regardless the ATTR-CM diagnosis.
Plain language summary
Article highlights.
The prevalence of TTR amyloid cardiomyopathy (ATTR-CM) in our population of severe degenerative aortic stenosis (AS) patients was 11%.
AS patients with concomitant ATTR-CM were older, had a higher frequency of carpal tunnel syndrome, a higher median NT-proBNP, and a lower voltage on electrocardiogram (ECG). They had a more severe left ventricular hypertrophy (LVH), more right ventricular hypertrophy (RVH) and low-flow low-gradient AS, worse LV diastolic dysfunction, higher pulmonary artery systolic pressure, lower left ventricular global longitudinal strain (LV-GLS) and a higher frequency of the relative apical sparing pattern.
An increased awareness of ATTR-CM red-flags is needed to promote its timely diagnosis.
Patients with ATTR-CM were less submitted to aortic valve replacement (AVR) than patients with lone AS, mainly due to higher frequency of refusals to intervention in the AS + ATTR-CM group, despite similar surgical risk.
We did not find a statistically significant association of ATTR-CM with the composite of all cause-mortality or cardiovascular hospitalizations in our population, despite a relative higher frequency of adverse events in ATTR-CM patients.
Not performing AVR was an independent predictor of all-cause mortality and cardiovascular hospitalizations in AS patients, regardless of the presence of ATTR-CM.
AVR should not be withheld in patients with both AS and ATTR-CM.
There is an urgent need to improve the healthcare response of transcatheter AVR to AS patients.
1. Introduction
The prevalence of both severe degenerative aortic stenosis (AS) and TTR amyloid cardiomyopathy (ATTR-CM) increases with age, with severe AS being documented in more than 3% of patients aged >75 years [1] and cardiac TTR amyloid deposits in 21,4% of those ≥75 years [2], reaching 25% in those ≥85 years [3]. In symptomatic severe AS, aortic valve replacement (AVR) modify its natural history and improve a patient's life expectancy to close of the general population [4].
Cardiac amyloidosis (CA) is characterized by extracellular deposits of amyloid fibrils within the heart, being TTR and immunoglobulin light chains the two predominant amyloid precursor proteins [5]. Previously believed to be a rare condition, the growing awareness of the ATTR-CM diagnosis is, in part, driven by the non-invasive diagnostic strategy through the use of a bone scintigraphy combined with a negative search for a plasma cell dyscrasia, allowing the detection of TTR deposition with high sensitivity and specificity, preventing the need for myocardial biopsy [6–8].
The recent emergence of disease-modifying therapies, aiming to improve the natural history of the disease, has also contributed to the active search for ATTR-CM, highlighting the need for its timely diagnosis [4,5,9,10]. Genetic study is needed to distinguish between hereditary and wild-type (wt) ATTR [11], by assisting with the cascade testing of at-risk relatives and impacting the therapeutic decision [7]. Tafamidis is approved to both forms of ATTR-CM and has been shown to reduce all-cause mortality and cardiovascular hospitalizations [12], while patisiran is currently only indicated to patients with hereditary ATTR and neurological or mixed phenotype [13]. Novel therapeutic strategies, including the use of monoclonal antibodies, are under investigation [10].
The coexistence of AS and ATTR-CM is notably higher than previously anticipated, mainly among low-flow low-gradient AS patients [14,15]. The prevalence of dual AS and ATTR-CM (AS + ATTR-CM) has been reported in up to 6% of AS patients undergoing surgical AVR (SAVR) [15] and in 16% of elderly patients who performed transcatheter AVR (TAVR) [14,16]. In these patients, significant myocardial thickening is generally attributed to long-standing pressure overload in the AS context and it is often not recognized as potentially derived from the coexistence of an infiltrative disease [17]. Hence, ATTR-CM screening and diagnosis protocol should be considered in AS patients presenting with red-flags for CA [4].
In fact, AS + ATTR-CM patients have worse functional capacity and exhibit a higher mortality than lone AS patients [15,17,18]. Recent evidence has suggested a beneficial impact of TAVR in these patients, when compared with medical therapy alone [17–19]. Additionally, TAVR appears not to be associated with an increased risk of periprocedural complications in AS + ATTR-CM patients, except for a numerically increased risk of permanent pacemaker implantation [19]. There is still no consensus regarding the optimal management strategy in AS + ATTR-CM patients [4] due to limited and conflicting studies data concerning the outcomes after AVR [20,21], remaining essential to clarify its role as a therapeutic strategy in these patients.
Therefore, there is an urgent need to standardize and optimize the diagnostic evaluation and therapeutic management of patients with concomitant severe AS and ATTR-CM. Accordingly, the present study was designed to: (i) determine the prevalence of ATTR-CM in patients with severe degenerative AS referred to surgical or transcatheter AVR; (ii) compare the occurrence of major adverse events in patients with and without coexisting ATTR-CM; and (iii) identify independent predictors of adverse events in this population.
2. Methods
2.1. Study population
This prospective multicenter study included consecutive patients with severe AS, who were referred for surgical or transcatheter AVR at two Portuguese hospitals (Hospital Senhora da Oliveira-Guimarães (HSOG) and Unidade Local de Saúde do Algarve (ULSA)) between 2019 and 2021.
The inclusion criteria were: (i) age ≥65 years-old; (ii) symptomatic severe AS referred to AVR, and (iii) left ventricular hypertrophy (LVH), defined as an interventricular septum (IVS) thickness ≥12.5 mm measured by transthoracic echocardiography (TTE). Exclusion criteria were congenital or rheumatic causes of AS and life expectancy lower than 1 year.
2.2. Diagnostic evaluation
All selected patients underwent clinical and laboratory assessment, electrocardiogram (ECG), TTE complemented by left ventricle (LV) global longitudinal strain (GLS) analysis whenever feasible, and 99m Tc-DPD bone scintigraphy. The genetic testing of the TTR gene was also requested in the presence of a positive result on bone scintigraphy.
2.2.1. Laboratory & electrocardiographic assessment
Biochemistry analyzes were measured at baseline and prior to AVR and included NT-proBNP and estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. ECG was performed in all patients at baseline. Low voltage was defined as a peak-to-peak QRS amplitude of <0.5 mV in the limb leads and/or <1 mV in the precordial leads.
2.2.2. Echocardiography & speckle strain imaging
Comprehensive echocardiographic examinations were performed using commercially available ultrasound systems (General Electric® (GE) Echo PAC and echocardiographs (GE Vivid E95, Vivid E9 and Vivid S70).
All patients underwent TTE mainly to assess the severity and mechanism of AS, as well as systolic and diastolic ventricular function according to the international guidelines [22,23]. Severe AS was defined according to the European Association of Cardiovascular Imaging guidelines [23], as well as classical low-flow, low gradient AS and paradoxical low-flow, low-gradient AS.
LV ejection fraction (LVEF) was calculated using Simpson's biplane method and stroke volume was quantified using the LV outflow tract velocity-time integral and the LV outflow tract diameter and then indexed to body surface area. Standard measurements of cardiac dimensions were performed [24]. Measurement of right ventricular (RV) free wall thickness was performed at end-diastole in a zoomed subcostal view focusing on the RV midwall. RV hypertrophy (RVH) was defined as RV wall thickness >5 mm [24]. TAPSE <17 mm or RV S′ velocity <9.5 cm/s were considered indicative of RV systolic dysfunction.
LV strain analysis was performed offline using a dedicated software (EchoPAC v204, GE-Healthcare®) on the standard LV apical views (four, two, and three chambers) at a frame rate >55 frames per second, according to the European recommendations [25]. Peak systolic longitudinal strain by 2D speckle tracking echocardiography (STE) was assessed in 17 LV segments and averaged to calculate LV global longitudinal strain (GLS) [25]. After LV-GLS measurement, relative apical sparing pattern (RASP) was quantitatively assessed using the formula: qRASP = [average apical LS]/[average basal LS + average mid LS] [26]; qRASP ≥1 was defined as positive.
2.2.3. DPD bone scintigraphy & diagnosis of cardiac amyloidosis
All patients underwent 99mTc-DPD bone scintigraphy either before AVR or within the first 12 months after the procedure. The scans were performed using two different General Electric (GE) single-photon emission computed tomography-computed tomography (sPECT) gamma camera (Millenium MG and Discovery NM 630). Planar whole-body images were performed 3 h after tracer administration. DPD scans were analyzed by two readers from each institution, using the semi-quantitative visual score (range 0–3) according to the Perugini classification, and a score ≥2 was considered positive [27].
Serum and urine protein immunofixation and serum free light-chain quantification were performed in all DPD-positive patients, in order to exclude light chain CA. The diagnosis of ATTR-CM was established in patients with a grade ≥2 DPD and negative hematological tests for monoclonal proteins [11].
2.2.4. Pre-aortic valve intervention risk stratification
Euroscore (European System for Cardiac Operative Risk Evaluation) II was calculated for each patient according to the planned treatment, applying the online calculator developed by researchers at Royal Papworth Hospital in Cambridge and the center Hospitalier Universitaire de Martinique.
2.3. Prognosis assessment
After a minimum follow-up of one-year, patients with severe AS with and without ATTR-CM were compared regarding the occurrence of major adverse events. The composite of cardiovascular (CV) hospitalizations (namely heart failure decompensation or arrhythmias) and all-cause mortality was defined as the primary endpoint. All-cause mortality, CV mortality and CV hospitalizations were selected as secondary endpoints. Periprocedural complications were defined using the Valve Academic Research Consortium-2 criteria [28].
In those who underwent AVR in the follow-up, patients with and without ATTR-CM were also compared regarding periprocedural complications. Since some patients were still waiting for AVR at the time of follow-up, the global population was divided in four subgroups: AS without ATTR-CM, not submitted to AVR; AS without ATTR-CM, submitted to AVR; AS with ATTR-CM, not submitted to AVR; AS with ATTR-CM, submitted to AVR. The prognosis was also compared between the subgroups.
2.4. Statistical analysis
All statistical analyzes were performed using SPSS version 25.0 (IBM Corporation, USA). Where appropriate, results were described as mean ± standard deviation (SD) or median and first - third quartile (Q1-Q3). Normality was initially assessed using the Kolmogorov–Smirnov test and plotted on a histogram when indicated.
Differences between the groups were evaluated using the Student's t test or Mann–Whitney U test to compare continuous variables and either chi-square or Fisher's exact testing for categorical data.
Univariate and multivariate analysis were performed using Cox regression analysis to determine the independent predictors of the primary endpoint. Kaplan– Meier event free survival curves were performed according to the presence of ATTR-CM and also the management strategy at follow-up. Survival functions of the four subgroups were estimated using the Kaplan-Meier method with the Log rank test and represented in the form of Kaplan-Meier curves. A two-sided P-value < 0.05 was considered significant.
3. Results
3.1. Baseline characteristics of the overall cohort
This study included 91 patients with symptomatic severe AS (45 males and 46 females), with a median age of 78 years (73–83). The median LVEF was 59% (51.5–65), the median mean aortic gradient was 47 (41–57) mmHg, and the median LV mass index was 124.95 (111.4–166.73) g/m2. The frequency of significant coronary artery disease in our population was 45.1%, with 46.2% having diabetes mellitus type 2, 38.5% atrial fibrillation (AF) and 13.2% carpal tunnel syndrome. The median eGFR was 55 ml/min/1.73 m2. More than half of patients (51.6%) were in New York Heart Association (NYHA) functional class III or IV.
Most patients (63.7%) were evaluated in HSOG, including all ATTR-CM patients. When comparing the populations from both centers regarding all demographic, clinical and echocardiographic parameters evaluated, the only significant difference between them was the prevalence of AF (46.6% in HSOG and 24.2% in ULSA, p = 0.035).
3.2. Prevalence of ATTR-CM in patients with severe symptomatic AS
The prevalence of ATTR-CM in the overall cohort of patients with severe symptomatic AS was 11.0% (n = 10). Six patients had a Perugini score 2 and four patients had a score 3. All of them had a negative genetic test for TTR gene, confirming the wtATTR-CM diagnosis. In the subgroup of octogenarians, the prevalence of wtATTR-CM reached 20.5% (N = 8).
3.3. Baseline characteristics of patients with isolated AS vs. AS + ATTR-CM
Patients with ATTR-CM were older (median age 83 vs. 77 years, p = 0.002) and had a higher frequency of carpal tunnel syndrome (100.0 vs. 2.5%, p < 0.001), mostly bilateral (n = 7, 70.0%), higher frequency of low voltage on ECG (60.0 vs. 3.8%, p < 0.001) and higher median value of NT-proBNP (1436 vs 980 pg/ml, p = 0.019), as shown in Table 1.
Table 1.
Baseline characteristics of severe symptomatic AS patients with and without ATTR-CM.
| Baseline characteristics | AS + ATTR-CM (n = 10) | Lone AS (n = 81) | p-value |
|---|---|---|---|
| Demographic and clinical characteristics: | |||
| Age (years), median (Q1-Q3) | 83 (81–89) | 77 (73–82) | 0.002 |
| Male gender, n (%) | 4 (40%) | 41 (50.6%) | 0.526 |
| Arterial hypertension, n (%) | 10 (100%) | 76 (93.8%) | 0.971 |
| Diabetes mellitus, n (%) | 2 (20%) | 40 (49.4%) | 0.079 |
| Coronary artery disease, n (%) | 3 (30%) | 38 (46.9%) | 0.310 |
| Atrial fibrillation, n (%) | 5 (50%) | 30 (3%) | 0.427 |
| Pacemaker implanted, n (%) | 1 (10%) | 7 (8.9%) | 0.906 |
| Carpal tunnel syndrome, n (%) • Bilateral, n (%) |
10 (100%) 7 (70%) |
2 (2.5%) 1 (1.2%) |
<0.001 |
| eGFR, mean ± SD | 56.3 ± 15.7 | 55 ± 20.2 | 0.846 |
| NT-proBNP (pg/ml), median (Q1-Q3) | 1436 (1266–6624) | 980 (346–1883) | 0.019 |
| Euroscore II (%), median (Q1-Q3) | 3.7% (3.2–5.2) | 2.9% (1.7–4.9) | 0.177 |
| NYHA functional class, mean ± SD • Class II, n (%) • Class III-IV, n (%) |
2.8 ± 0.42 2 (20%) 8 (80%) |
2.43 ± 0.65 41 (51.9%) 38 (48.1%) |
0.080 0.057 |
| Electrocardiographic characteristics • First degree atrioventricular block, n (%) • Bundle branch block, n (%) • Low voltage on ECG, n (%) • Pseudoinfarct pattern, n (%) |
4 (40%) 6 (60%) 6 (60%) 4 (40%) |
12 (15.8%) 35 (43.8%) 3 (3.8%) 17 (21.3%) |
0.064 0.331 <0.001 0.186 |
| Echocardiographic characteristics | |||
|---|---|---|---|
| IVS wall thickness (mm), mean ± SD | 17.6 ± 4.1 | 14.9 ± 2.8 | 0.008 |
| Posterior wall thickness (mm), mean ± SD | 14.8 ± 2.9 | 11.4 ± 2.3 | <0.001 |
| IVS/posterior wall ratio | 1.2 ± 0.2 | 1.4 ± 0.4 | 0.219 |
| LV mass index (g/m2), median (Q1-Q3) | 173.3 (122.6–216.3) | 122.6 (111.0–148.3) | 0.312 |
| RV hypertrophy, n (%) | 6 (60%) | 2 (2.5%) | <0.001 |
| S’ wave (cm/s), mean ± SD | 12.2 ± 2.5 | 11.9 ± 2.7 | 0.745 |
| RV systolic dysfunction, n (%) | 1 (10%) | 6 (7.4%) | 0.149 |
| Left atrium volume index (ml/m2), mean ± SD | 54.0 ± 17.2 | 46.8 ± 13.6 | 0.134 |
| E/e', mean ± SD | 18.9 ± 7.5 | 14.8 ± 5.3 | 0.019 |
| Pulmonary artery systolic pressure (mmHg), mean ± SD | 38.8 ± 4.2 | 32.4 ± 11.7 | 0.002 |
| Maximum aortic velocity (m/s), mean ± SD | 3.9 ± 0.48 | 4.5 ± 0.7 | 0.009 |
| Mean aortic gradient (mmHg), median (Q1-Q3) | 41.5 (34.0–45.0) | 48 (41.4–54.0) | 0.036 |
| Low-flow low-gradient AS, n (%) • Paradoxical, n (%) |
5 (50%) 3 (30%) |
12 (14.8%) 1 (1.2%) |
0.007
<0.001 |
| Aortic valve area (cm2), mean ± SD | 0.73 ± 0.15 | 0.73 ± 0.14 | 0.963 |
| Indexed aortic valve area (cm2/m2), median (Q1-Q3) | 0.41 (0.39–0.48) | 0.40 (0.37–0.47) | 0.984 |
| LV ejection fraction, median (Q1-Q3) | 55.0 (43.0–65.0) | 59.5 (53.0–65.0) | 0.796 |
| LV systolic dysfunction, n (%) | 3 (30%) | 16 (19.8%) | 0.452 |
| LV- GLS (%), mean ± SD (N = 60) • Basal LS (%), mean ± SD • Medium LS (%), mean ± SD • Apical LS (%), mean ± SD |
-11.0 ± 1.8 -5.7 ± 1.1 -9.4 ± 1.8 -19.1 ± 3.2 |
-15.7 ± 2.3 -13.0 ± 3.4 -15.4 ± 2.8 -19.1 ± 1.7 |
<0.001 <0.001 <0.001 0.713 |
| Apical sparing pattern (qRASP >1), n (%) (N = 60) • qRASP, mean ± SD |
10 (100%) 1.07 ± 0.04 |
5 (11.4%) 0.6 ± 0.19 |
<0.001
<0.001 |
AS: Aortic stenosis; ATTR-CM: TTR amyloid cardiomyopathy; ECG: Electrocardiogram; eGFR: Estimated glomerular filtration rate; GLS: Global longitudinal strain; IVS: Interventricular septum; LS: Longitudinal strain; LV: Left ventricle; NYHA: New York Heart Association; Q: Quartile; qRASP: Quantitative relative apical sparing pattern; RV: Right ventricle; SD: Standard deviation.
The bold terms represent the significant p-values. A two-sided P-value < 0.05 was considered significant.
ATTR-CM patients had a higher IVS thickness (17.6 ± 4.1 vs. 14.9 ± 2.8 mm, p = 0.008), a higher LV mass index (177 ± 51 vs 131 ± 31 g/m2, p < 0.001) and a higher frequency of RVH (60.0 vs. 2.5%, p < 0.001). They also had a higher E/e' ratio (18.9 ± 7.5 vs 14.8 ± 5.3, p = 0.019) and pulmonary artery systolic pressure (38.3 ± 4.2 vs. 32.4 ± 11.7 mmHg, p = 0.002). These patients had higher frequency of low-flow low-gradient AS (50.0% vs 14.7%, p = 0.007), and therefore a lower maximum aortic valve velocity (3.9 ± 0.48 vs. 4.5 ± 0.7 m/s, p = 0.009) and a lower median aortic valve gradient (41.5 vs 48 mmHg, p = 0.036). Indexed aortic valve area was similar between both groups (p = 0.984).
Although a preserved LVEF was present across the majority of patients, strain analysis showed that ATTR-CM patients had significantly lower LV-GLS (-11.0 ± 1.8% vs. -15.7 ± 2.3%, p < 0.001). qRASP was higher in ATTR-CM group (1.07 ± 0.04 vs 0.6 ± 0.19, p < 0.001). The apical sparing pattern was present in all ATTR-CM patients, but it was also seen in 11% of lone AS (p < 0.001) (Figure 1).
Figure 1.
The distribution of the RASP values in severe symptomatic aortic stenosis patients with and without TTR amyloid cardiomyopathy.
3.4. Pre-aortic valve intervention risk stratification
The frequency of comorbidities was not statistically different in severe symptomatic AS patients with and without wtATTR-CM, and both groups had similar low-intermediate surgical risk, as assessed by Euroscore II (3.7% vs. 2.9%, p = 0.117).
3.5. Aortic valve intervention & periprocedural complications
At a median follow-up of 2.5 (2.1–2.9) years, AVR had been performed in only 71 of the 91 patients (78.0%), through SAVR in 45 patients (63.4%) and TAVR in 26 patients (36.6%). Six (6.6%) patients were still waiting for AVR, nine (9.9%) patients were refused by the tertiary center due to high interventional risk, and five (5.5%) patients died before the valve intervention. Surprisingly, only two patients with AS + ATTR-CM were submitted to AVR (20.0 vs. 85.2%, p < 0.001), while three patients are still waiting for TAVR, two were refused by the tertiary center due to the high interventional risk and three died before the procedure. It is also worth mentioning that there was a tendency to a higher waiting time to perform AVR for patients with ATTR-CM (30.1 ± 4.7 vs. 22.8 ± 10.3 months, p = 0.079) (Table 2). There were no periprocedural complications in the two AS + ATTR-CM patients submitted to AVR. In the lone AS group (n = 69), acute kidney injury (23.2%) and permanent pacemaker implantation (17.4%) were the most frequent complications (Table 2).
Table 2.
Surgical or transcatheter AVR and periprocedural complications of severe symptomatic AS patients with and without ATTR-CM.
| Aortic valve intervention | AS + ATTR-CM (n = 10) | Lone AS (n = 81) | p-value |
|---|---|---|---|
| Patients who underwent AVR, n (%) • SAVR • TAVR |
2 (20.0%) 1 (10.0%) 1 (10.0%) |
69 (85.2%) 44 (54.3%) 25 (30.9%) |
<0.001 0.690 0.690 |
| Patients still on waiting list to intervention at follow-up, n (%) • Time on waiting list (months), mean ± SD |
3 (30.0%) 30.1 ± 4.7 |
3 (3.7%) 22.8 ± 10.3 |
<0.001 0.079 |
| Patients refused to intervention by the tertiary center, n (%) | 2 (20.0%) | 7 (8.6%) | <0.001 |
| Patients who died while waiting for intervention, n (%) | 3 (30.0%) | 2 (2.5%) | <0.001 |
| Periprocedural complications, n (%) • Acute kidney injury • Stroke • Permanent pacemaker implantation • Moderate/Severe Prosthetic valve dysfunction • Vascular access site and access-related complications |
0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) |
16 (23.2%) 1 (1.4%) 12 (17.4%) 0 (0.0%) 2 (2.9%) |
– – – – – |
| Length of hospital stay (days), mean ± SD | 4.5 ± 2.1 | 5.3 ± 2.5 | 0.641 |
AS: Aortic stenosis; ATTR-CM: TTR amyloid cardiomyopathy; AVR: Aortic valve replacement; SAVR: Surgical aortic valve replacement; SD: Standard deviation; TAVR: Transcatheter aortic valve replacement.
The bold terms represent the significant p-values. A two-sided P-value < 0.05 was considered significant.
3.6. Prognosis of patients with isolated AS vs. ATTR-CM + AS
During the follow-up, there were no significant differences between AS patients with and without ATTR-CM regarding the occurrence of primary end point (60.0% vs. 30.9%, p = 0.067), despite a relative higher frequency of adverse events in AS + ATTR-CM group. The same occurred for all-cause mortality (30.0% in AS + ATTR-CM vs 16.0%, p = 0.274) and CV hospitalizations (40% in AS + ATTR-CM vs. 23.5%, p = 0.256), but not for CV death, which did not occur in the AS + ATTR-CM group (0% vs 3.7%, p = 0.552).
3.7. Prognosis of the four subgroups of AS
When comparing the four subgroups of severe symptomatic AS, defined according to the presence of ATTR-CM and the AVR status, the frequency of the primary endpoint seems higher in the subgroups of patients not submitted to AVR (66.7% with lone AS and 62.5% with AS + ATTR-CM) than in the subgroups submitted to AVR (24.6% with lone AS and 50.0% with AS + ATTR-CM) - Table 3. Likewise, the frequency of all-cause mortality appears to be higher in the subgroups of patients not submitted to AVR (41.7% with lone AS and 37.5% with AS + ATTR-CM) than in the subgroups submitted to AVR (11.6% with lone AS and 0% with AS + ATTR-CM). Figure 2 shows the Kaplan-Meier event free survival curves of the four subgroups.
Table 3.
Adverse events in the four subgroups of severe symptomatic AS, defined according to the presence of ATTR-CM and the performance of AVR.
| Adverse event | Lone AS without AVR (n = 12) | Lone AS submitted to AVR (n = 69) | AS + ATTR-CM without AVR (n = 8) | AS + ATTR-CM submitted to AVR (n = 2) |
|---|---|---|---|---|
| Primary endpoint, n (%) • Time to endpoint (months), mean ± SD |
8 (66.7%) 20.4 ± 3.9 |
17 (24.6%) 34.4 ± 1.5 |
5 (62.5%) 27.1 ± 3.4 |
1 (50.0%) 21.5 ± 10.3 |
| All-cause mortality, n (%) • Unknown cause • Time to endpoint (months), mean ± SD |
5 (41.7%) 1 (8.3%) 20.4 ± 3.9 |
8 (11.6%) 1 (1.4%) 36.3 ± 1.4 |
3 (37.5%) 1 (12.5%) 28.6 ± 3.4 |
0 (0.0%) N/A N/A |
| CV mortality, n (%) | 2 (16.7%) | 1 (1.4%) | 0 (0.0%) | 0 (0.0%) |
| CV hospitalizations, n (%) • Time to end point (months), mean ± SD |
8 (66.7%) 20.4 ± 3.9 |
11 (15.9%) 36.3 ± 1.4 |
3 (37.5%) 28.6 ± 3.4 |
1 (50.0%) 21.5 ± 10.3 |
| All-cause hospitalizations, n (%) | 9 (75.0%) | 35 (50.7%) | 4 (50.0%) | 2 (100.0%) |
AS: Aortic stenosis; ATTR-CM: TTR amyloid cardiomyopathy; AVR: Aortic Valve Replacement; CV: Cardiovascular; N/A: Not applicable; SD: Standard deviation.
Figure 2.
Kaplan–Meier event free survival curves over a median follow-up of 2.5 years: (A) Primary end point in patients with severe symptomatic aortic stenosis (AS): lone AS vs. AS + TTR amyloid cardiomyopathy (ATTR-CM); (B) Primary end point in the four subgroups of severe symptomatic AS: lone AS submitted to aortic valve replacement (AVR) vs. lone AS not submitted to AVR vs. AS + ATTR-CM submitted to AVR vs. AS + ATTR-CM not submitted to AVR; (C) All-cause mortality across the four subgroups; and (D) Cardiovascular (CV) hospitalizations across the four subgroups.
3.8. Predictors of prognosis in patients with severe symptomatic AS
Patients who reached the primary endpoint had a higher frequency of AF (p = 0.006) and carpal tunnel syndrome (p = 0–011), a higher NYHA functional class (p = 0.027) and a higher median NT-proBNP (p = 0.005) (Table 4). A higher frequency of RVH (p = 0.036), RV systolic dysfunction (p = 0.026), higher left atrium volume index (LAVI) (p = 0.003) and pulmonary artery systolic pressure (p = 0.016) were also documented. Low-flow low-gradient AS was also more common in patients reaching the primary endpoint (p = 0.017). They also had lower LVEF (p = 0.037), lower LV-GLS (p = 0.002), lower LS in basal (p < 0.001) and mid segments (p = 0.012), and therefore a higher qRASP (p < 0.001) and higher frequency of the apical sparing pattern (p = 0.001). Patients reaching the primary endpoint also had lower rates of AVR (p = 0.001), with no differences regarding the AVR strategy (surgical or transcatheter) (p = 0.425).
Table 4.
Comparison of characteristics of patients with severe symptomatic AS, according to the occurrence of the primary end point.
| Characteristics |
Patients with primary end point (n = 31) |
Patients without primary end point (n = 60) |
p-value |
|---|---|---|---|
| Demographic and clinical: | |||
| Age (years-old), median (Q1-Q3) | 80 (76–83) | 78 (73–83) | 0.428 |
| Male gender, n (%) | 16 (51.6%) | 29 (48.3%) | 0.767 |
| ATTR-CM, n (%) | 6 (19.4%) | 4 (6.7%) | 0.067 |
| Arterial hypertension, n (%) | 30 (96.8%) | 56 (93.3%) | 0.495 |
| Diabetes mellitus, n (%) | 16 (51.6%) | 26 (43.3%) | 0.453 |
| Atrial fibrillation, n (%) | 18 (58.1%) | 17 (28.3%) | 0.006 |
| Coronary artery disease, n (%) | 17 (54.8%) | 24 (40.0%) | 0.178 |
| Carpal tunnel syndrome, n (%) | 8 (25.8%) | 4 (6.7%) | 0.011 |
| NT-proBNP (pg/ml), median (P1-P3) | 1451 (893–4997) | 932 (334–1500) | 0.005 |
| NYHA functional class III-IV, n (%) | 21 (67.7%) | 25 (43.1%) | 0.027 |
| Glomerular filtration rate, mean ± SD | 57 ± 18 | 54 ± 21 | 0.618 |
| Euroscore II (%), median (Q1-Q3) | 3.1 (2.4–5.2) | 2.9 (1.6–4.9) | 0.284 |
| Electrocardiographic characteristics: • Bundle branch block, n (%) • Low voltage on ECG, n (%) • Pseudoinfarct pattern, n (%) |
16 (51.6%) 4 (12.9%) 10 (32.3%) |
25 (42.4%) 5 (8.5%) 11 (18.6%) |
0.403 0.506 0.147 |
| Echocardiographic: | |||
|---|---|---|---|
| IVS wall thickness (mm), mean ± SD | 15.6 ± 3.0 | 15.0 ± 3.1 | 0.410 |
| Posterior wall thickness (mm), mean ± SD | 12.0 ± 2.5 | 11.7 ± 2.7 | 0.678 |
| Indexed LV mass (g/m2), median (Q1-Q3) | 141 (120.5–170.9) | 121.6 (109.7–152.4) | 0.359 |
| LV ejection fraction: • Preserved LVEF, n (%) • Median (Q1-Q3) |
21 (67.7%) 54.0 (41.0–61.0) |
51 (85.0%) 62.0 (56.0–67.0) |
0.055 0.037 |
| RV hypertrophy, n (%) | 6 (19.4%) | 2 (3.3%) | 0.036 |
| RV dysfunction, n (%) | 5 (16.1%) | 2 (3.3%) | 0.026 |
| Left atrium volume index (ml/m2), mean ± SD | 54.0 ± 16.0 | 44.0 ± 12.0 | 0.002 |
| Lateral e' (cm/s), mean ± SD | 7.1 ± 2.5 | 6.4 ± 2.2 | 0.471 |
| Septal e' (cm/s), mean ± SD | 5.0 ± 2.3 | 5.2 ± 1.7 | 0.828 |
| E/e', mean ± SD | 16.3 ± 5.8 | 14.8 ± 5.7 | 0.270 |
| Pulmonary artery systolic pressure (mmHg), mean ± SD | 37.0 ± 9.3 | 31.0 ± 11.8 | 0.016 |
| Maximum aortic velocity (m/s), mean ± SD | 4.3 ± 0.8 | 4.5 ± 0.7 | 0.221 |
| Mean aortic gradient (mmHg), median (Q1-Q3) | 44.0 (37.0–52.8) | 51.0 (42.0–59.0) | 0.033 |
| Low-flow low-gradient AS, n (%) | 10 (32.3%) | 7 (11.7%) | 0.017 |
| Aortic valve area (cm2), median (Q1-Q3) | 0.70 (0.60–0.80) | 0.77 (0.60–0.85) | 0.387 |
| Indexed aortic valve area (cm2/m2), median (Q1-Q3) | 0.41 (0.35–0.46) | 0.40 (0.37–0.49) | 0.08 |
| Global longitudinal strain (%), mean ± SD (N = 60) • Basal LS (%), mean ± SD • Mid LS (%), mean ± SD • Apical LS (%), mean ± SD |
-13.2 ± 2.9 –8.7 ± 3.9 –12.4 ± 3.6 –19.5 ± 2.5 |
-15.6 ± 2.5 –13.1 ± 3.6 –15.3 ± 3.1 –19.0 ± 1.7 |
0.002 <0.001 0.012 0.905 |
| Apical sparing pattern (RASP >1), n (%) (N = 60) • qRASP, mean ± SD |
10 (55.6%) 0.86 ± 0.26 |
5 (13.9%) 0.60 ± 0.20 |
0.001
<0.001 |
| Valvular intervention, n (%) • SAVR • TAVR |
18 (58.1%) 10 (55.6%) 8 (44.4%) |
53 (88.3%) 35 (66.0%) 18 (34.0%) |
0.001 0.425 |
AS: Aortic stenosis; ATTR-CM: TTR amyloid cardiomyopathy; ECG: Electrocardiogram; IVS: Interventricular septum; LS: Longitudinal strain; LV: Left ventricle; LVEF: Left ventricle ejection fraction; NYHA: New York Heart Association; qRASP: Quantitative relative apical sparing pattern; Q: Quartile; SAVR: Surgical aortic valve replacement; SD: Standard deviation; RV: Right ventricle; TAVR: Transcatheter aortic valve replacement.
The bold terms represent the significant p-values. A two-sided P-value < 0.05 was considered significant.
Univariate analysis was performed to identified possible prognostic factors for the occurrence of the primary endpoint (Supplementary Table S1). Multivariate analysis identified higher LVEF (HR = 0.936 [0.879–0.997], p = 0.039) and performing AVR (HR = 0.325 [0.108–0.983], p = 0.047) as independent protectors against the occurrence of the primary endpoint (Table 5). Lower LVEF remained an independent predictor of the primary endpoint even when only the patients submitted to AVR were considered (N = 71).
Table 5.
Identification of prognostic factors for the occurrence of the primary endpoint based on multivariate Cox analysis.
| Characteristics | Multivariate analysis | |
|---|---|---|
| HR (95% CI) | p-value | |
| Atrial fibrillation | 0.992 (0.322–3.059) | 0.989 |
| Left ventricle ejection fraction | 0.936 (0.879–0.997) | 0.039 |
| Left atrium volume index | 1.013 (0.975–1.052) | 0.514 |
| Pulmonary artery systolic pressure | 1.042 (0.986–1.101) | 0.142 |
| Low-flow low-gradient AS | 1.111 (0.326–3.787) | 0.867 |
| Global longitudinal strain | 1.111 (0.843–1.463) | 0.455 |
| Valvular intervention | 0.325 (0.108–0.983) | 0.047 |
AS: Aortic stenosis; CI: Confidence interval; HR: Hazard ratio.
The bold terms represent the significant p-values. A two-sided P-value < 0.05 was considered significant.
4. Discussion
To our knowledge, this is the first multicenter prospective study addressing the prevalence and outcomes of ATTR-CM in a Portuguese cohort of patients with severe symptomatic AS.
In our study, the prevalence of ATTR-CM in severe AS was 11% (20.5% in octogenarians), compatible with previous reports, which state a prevalence of ATTR-CM up to 16% in severe AS [14–16,29]. The simultaneous occurrence of these pathologies could be related to similar pathophysiological mechanisms that create a complex interplay, including oxidative stress, inflammation and extracellular remodeling [30–32], most likely associated with advancing aging [30]. However, the causative link has not yet been demonstrated and remains to be elucidated why some individuals develop both cardiac diseases and others present them only in isolation [33].
AS patients with concomitant ATTR-CM matched the typical presentation described in previous studies, being older [2,3] and having a higher frequency of carpal tunnel syndrome [34], a higher median NT-proBNP value [14], and a lower voltage on ECG [35,36]. Additionally, they had a more severe LVH with higher IVS thickness and LV mass index [18,37], as well as higher frequency of RVH, worse LV diastolic dysfunction with higher E/e' ratio and pulmonary artery systolic pressure [4]. They also had a higher frequency of low-flow low-gradient AS [37], lower LV-GLS and a higher frequency of the RASP [38]. We highlight these parameters as red flags for the wtATTR-CM diagnosis, as previously reported in larger cohorts [14,26,39]. However, we recognize that some parameters overlap between both diseases, hindering the differential diagnosis. Despite being described in other reports [39,40], we did not find a statistically significant association regarding the pseudoinfarct pattern on ECG and left atrium dilation (evaluated by LAVI) with ATTR-CM.
Surprisingly, the sex distribution in our cohort diverges from previous reports, with a slightly higher prevalence of female patients in ATTR-CM group (60%), but probably strongly influenced by the low absolute number of patients. Indeed, cumulative evidence showed a male predominance (>80%) in both wild-type and hereditary ATTR-CM, that could be associated to genetic and environmental factors, as well as diagnosis bias such as the lack of sex-specific cut-offs or the use of non-indexed parameters [41,42]. THAOS registry also reveals an advanced age at diagnosis in women and a less severe cardiac impairment [43], probably contributing to considerable cases of delayed or missed diagnosis.
Furthermore, LV myocardial strain analysis showed the presence of RASP in 11% of patients with lone AS. Phelan et al. already described the existence of an apex-to-base absolute LS gradient in AS patients, despite stating that this gradient is higher in CA and that it gains specificity and sensitivity for CA diagnosis when qRASP >1 criterium is used [26]. As such, RASP may also be found in severe symptomatic AS, reflecting advanced LV disease and worse outcomes, allowing an additional risk stratification refinement and being generally reversible after AVR [38,44].
Some scores have already been developed to predict the ATTR-CM diagnosis [35,45]. The recently developed T-Amylo prediction model includes clinical, electrocardiographic and echocardiographic factors, namely carpal tunnel syndrome, age ≥80 years, male gender, LVH (IVS ≥16 mm) and low QRS voltage on ECG [35]. All of these factors are similar to our findings, except for the gender. To date, there is still no cost-effectiveness study performed on the screening of ATTR-CM in patients with severe degenerative AS in an European setting [37,46].
It is also noticeable the null prevalence of ATTR-CM in ULSA, in the south of Portugal, comparing with HSOG, located in north of Portugal, despite the worldwide distribution of wtATTR-CM arguing against any possible geographic differences in Portugal. Besides the difference in AF prevalence between the patients from the two hospitals, no other difference was found that could explain these data. At the time of the writing of this article, HSOG has significantly more ATTR-CM patients followed in the Cardiology Department comparing to ULSA. That could be due to a growing awareness of LVH in the primary healthcare providers in the north of the country, due to the founder effect of Fabry disease in Guimarães region [47], culminating in more referrals of these patients to the Cardiology Department to be submitted to LVH etiologic study.
In our study, although the frequency of the primary endpoint was higher in AS + ATTR-CM patients than in lone AS, it did not reach statistical significance, and the same phenomenon was verified for all-cause mortality and CV hospitalizations when assessed individually. Of note, CV mortality was null in ATTR-CM patients, opposing to 3 CV deaths in the lone AS subgroup. However, the small number of AS + ATTR-CM patients could have contributed to these results. The prognostic impact of ATTR-CM in AS patients remains unclear across the literature, with studies showing a worse prognosis [15,17,18] and others reporting the absence of a significant adverse impact of ATTR-CM [16,37]. In our study, the presence of ATTR-CM was not significantly associated with adverse events.
In the other hand, our study has found that a lower LVEF and not performing AVR were independent predictors of the primary endpoint. Indeed, the frequency of the primary endpoint, all-cause mortality and CV hospitalizations seemed to be higher in untreated AS + ATTR-CM patients than in those who underwent AVR. Furthermore, the evaluation of the prognosis in the four subgroups of AS shows that the worst event free survival was documented in lone AS patients not submitted to AVR. These findings support the recent evidence showing a survival benefit of TAVR compared with medical therapy in patients with concomitant dual pathology [18,19,21]. In addition, our study also showed a similar frequency of periprocedural complications between lone AS and AS + ATTR-CM patients, including permanent pacemaker implantation rate, in line with other cohorts [14,18].
However, in our population, patients with AS + ATTR-CM were less submitted to AVR than patients with lone AS (20.0% vs. 85.2%), similarly to the described by Nitsche et al. [18], mainly due to higher frequency of refusals to intervention in the AS + ATTR-CM group, despite similar surgical risk assessed by Euroscore II. In fact, patients with AS + ATTR-CM had a longer mean waiting time for AVR than the subgroup with lone AS, culminating in 30.0% of wtATTR-CM patients dying while on the waiting list for TAVR, significantly more than lone AS. These results emphasize how the coexistence of ATTR-CM in AS patients may still have a negative influence on the decision of AS management and how AVR is often yet considered a futile treatment of AS in AS + ATTR-CM patients in current clinical practice.
An important limitation to be acknowledged in our study is the small number of patients with ATTR-CM, which limited our statistical power mainly regarding the analysis of ATTR-CM predictors and prognostic factors in patients with severe symptomatic AS. Also, DPD scintigraphies were performed in two different clinics by two different operators. The use of quantitative methods to assess myocardial uptake could have increased the diagnostic accuracy. Finally, not all patients underwent AVR at the end of follow-up, particularly in the AS + ATTR-CM group, which implies a careful interpretation of these results. In the other hand, it allowed us to analyze the adverse events between patients submitted or not to AVR.
Taken together, our results corroborate the non-negligible prevalence of ATTR-CM in patients with severe AS, alerting to the need of a high degree of suspicion due to the recent emergence of disease-modifying therapies. It adds to other studies that attempt to clarify its prognostic impact, since we did not find a statistically significant association of ATTR-CM with adverse events in our population. We also underline the prognostic benefit of performing AVR in AS patients, regardless of the presence of ATTR-CM and highlight the need to improve the healthcare response of TAVR to these patients.
5. Conclusion
Our study is the first prospective multicenter Portuguese study addressing ATTR-CM in patients with severe degenerative AS, confirming a prevalence above 10% in this population. Hence, strong efforts should be made to increase the awareness of ATTR-CM red-flags in AS patients in order to promote its timely diagnosis. Furthermore, considering the low cost and non-invasive nature of ATTR-CM screening, combined with the recent availability of disease-modifying therapeutics, larger multicenter studies are increasingly needed to evaluate the cost-effectiveness of a more widespread screening of ATTR-CM in patients with severe AS.
We also highlight that not performing AVR was identified as an independent predictor of all-cause mortality and cardiovascular hospitalizations in AS patients, regardless of the presence of ATTR-CM. Therefore, AVR should not be withheld in patients with both AS and ATTR-CM. Further studies are needed to longitudinally address the adverse events in the population submitted to both ATTR-CM and AS treatment.
Supplementary Material
Supplemental material
Supplemental data for this article can be accessed at https://doi.org/10.1080/14796678.2024.2393031
Author contributions
T Pereira, RM Fernandes and O Azevedo were the writers of this document and revised the entire paper. E Mata performed the statistical analysis. D Bento helped gathering bibliographic information and also revised the entire paper. I Jesus and A Lourenço reviewed the final version of this article.
Financial disclosure
O Azevedo received consulting and speaker fees, such as travel and/or accommodation support for conferences, from Pfizer and Alnylam. T Pereira, RM Fernandes and D Bento received travel and/or accommodation support to attend conferences, from Pfizer, Alnylam and/or Akcea. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Competing interests disclosure
The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Ethical conduct of research
This study complied with the Declaration of Helsinki and was approved by institutional ethics committees (Comissão de Ética para a Saúde) of both hospitals (Unidade Local de Saúde (ULS) Alto Ave - Hospital Senhora da Oliveira-Guimarães and ULS Algarve – Hospital de Faro) and the approval number of the study is 84/2021 - CAF. All patients provided written informed consent.
References
Papers of special note have been highlighted as: • of interest; •• of considerable interest
- 1.Thaden JJ, Nkomo VT, Enriquez-Sarano M. The global burden of aortic stenosis. Prog Cardiovasc Dis [Internet]. 2014;56:565–571. doi: 10.1016/j.pcad.2014.02.006 [DOI] [PubMed] [Google Scholar]
- 2.Porcari A, Bussani R, Merlo M, et al. Incidence and characterization of concealed cardiac amyloidosis among unselected elderly patients undergoing post-mortem examination. Front Cardiovasc Med. 2021;8:1–10. doi: 10.3389/fcvm.2021.749523 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Tanskanen M, Peuralinna T, Polvikoski T, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med. 2008;40:232–239. doi: 10.1080/07853890701842988 [DOI] [PubMed] [Google Scholar]
- 4.Ternacle J, Krapf L, Mothy D, et al. Aortic stenosis and cardiac amyloidosis: JACC Review Topic of the Week. J Am Coll Cardiol. 2019;74:2638–2651. doi: 10.1016/j.jacc.2019.09.056 [DOI] [PubMed] [Google Scholar]; •• An excellent review of the association of ATTR-CM and AS.
- 5.Kittleson MM, Maurer MS, Ambardekar AV, et al. Cardiac Amyloidosis: evolving diagnosis and management: a scientific statement from the American Heart Association. Circulation. 2020;141:E7–E22. doi: 10.1161/CIR.0000000000000792 [DOI] [PubMed] [Google Scholar]
- 6.Bay K, Gustafsson F, Maiborg M, et al. Suspicion, screening, and diagnosis of wild-type TTR amyloid cardiomyopathy: a systematic literature review. ESC Hear Fail [Internet]. 2022;9:1524–1541. doi: 10.1002/ehf2.13884 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kittleson MM, Ruberg FL, Ambardekar AV, et al. ACC Expert Consensus Decision pathway on comprehensive multidisciplinary care for the patient with cardiac amyloidosis: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023;81:1076–1126. doi: 10.1016/j.jacc.2022.11.022 [DOI] [PubMed] [Google Scholar]
- 8.Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: part 1 of 2 - Evidence Base and Standardized Methods of Imaging. Circ. Cardiovasc. Imaging. 2021;14:685–725. doi: 10.1161/HCI.0000000000000029 [DOI] [PubMed] [Google Scholar]
- 9.Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: part 1 of 2—evidence base and standardized methods of imaging. J Nucl Cardiol [Internet]. 2019;26:2065–2123. doi: 10.1007/s12350-019-01760-6 [DOI] [PubMed] [Google Scholar]
- 10.Cantone A, Sanguettoli F, Passo BD, et al. The treatment of amyloidosis is being refined. Eur Hear Journal, Suppl [Internet]. 2022;24:I131–I138. doi: 10.1093/eurheartjsupp/suac104 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Maurer MS, Bokhari S, Damy T, et al. Expert consensus recommendations for the suspicion and diagnosis of TTR cardiac amyloidosis. Circ Hear Fail. 2019;12:1–11. doi: 10.1161/CIRCHEARTFAILURE.119.006075 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with TTR amyloid cardiomyopathy. N Engl J Med. 2018;379:1007–1016. doi: 10.1056/NEJMoa1805689 [DOI] [PubMed] [Google Scholar]
- 13.Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary TTR amyloidosis. N Engl J Med. 2018;379:11–21. doi: 10.1056/NEJMoa1716153 [DOI] [PubMed] [Google Scholar]
- 14.Castano A, Narotsky DL, Hamid N, et al. Unveiling TTR cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur Heart J. 2017;38:2879–2887. doi: 10.1093/eurheartj/ehx350 [DOI] [PMC free article] [PubMed] [Google Scholar]; •• A relevant study of ATTR-CM in patients with AS.
- 15.Treibel TA, Fontana M, Gilbertson JA, et al. Occult TTR cardiac amyloid in severe calcific aortic stenosis. Circ Cardiovasc Imaging. 2016;9:1–10. doi: 10.1161/CIRCIMAGING.116.005066 [DOI] [PubMed] [Google Scholar]
- 16.Scully PR, Patel KP, Treibel TA, et al. Prevalence and outcome of dual aortic stenosis and cardiac amyloid pathology in patients referred for transcatheter aortic valve implantation. Eur Heart J. 2020;41:2759–2767. doi: 10.1093/eurheartj/ehaa170 [DOI] [PMC free article] [PubMed] [Google Scholar]; •• A relevant study of ATTR-CM in patients with AS.
- 17.Cavalcante JL, Rijal S, Abdelkarim I, et al. Cardiac amyloidosis is prevalent in older patients with aortic stenosis and carries worse prognosis. J Cardiovasc Magn Reson. 2017;19:98. doi: 10.1186/s12968-017-0415-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Nitsche C, Scully PR, Patel KP, et al. Prevalence and outcomes of concomitant aortic stenosis and cardiac amyloidosis. J Am Coll Cardiol. 2021;77:128–139. doi: 10.1016/j.jacc.2020.11.006 [DOI] [PMC free article] [PubMed] [Google Scholar]; • An interesting study of ATTR-CM in patients with AS.
- 19.Cannata F, Chiarito M, Pinto G, et al. Transcatheter aortic valve replacement in aortic stenosis and cardiac amyloidosis: a systematic review and meta-analysis. ESC Hear Fail. 2022;9:3188–3197. doi: 10.1002/ehf2.13876 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Elzeneini M, Gupta S, Assaf Y, et al. Outcomes of transcatheter aortic valve replacement in patients with coexisiting amyloidosis: mortality, stroke, and readmission. JACC Adv. 2023;2. doi: 10.1016/j.jacadv.2023.100255 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Khawaja T, Jaswaney R, Arora S, et al. Transcatheter aortic valve replacement in patients with aortic stenosis and cardiac amyloidosis. IJC Hear Vasc [Internet]. 2022;40:101008. doi: 10.1016/j.ijcha.2022.101008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Nagueh SF, Smiseth OA, Appleton CP, et al. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr [Internet]. 2016;29:277–314. doi: 10.1016/j.echo.2016.01.011 [DOI] [PubMed] [Google Scholar]
- 23.Baumgartner H, Hung J, Bermejo J, et al. Recommendations on the echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J Cardiovasc Imaging. 2017;18:254–275. doi: 10.1093/ehjci/jew335 [DOI] [PubMed] [Google Scholar]
- 24.Lang RM, Badano LP, Victor MA, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr [Internet]. 2015;28:1–39.e14. doi: 10.1016/j.echo.2014.10.003 [DOI] [PubMed] [Google Scholar]
- 25.Voigt J-U, D'Hooge J, Pedrizzetti G, et al. Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/industry task force to standardize deformation imaging. Eur Heart J Cardiovasc Imaging. 2015;16:1–11. doi: 10.1093/ehjci/jeu184 [DOI] [PubMed] [Google Scholar]
- 26.Phelan D, Collier P, Thavendiranathan P, et al. Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart. 2012;98:1442–1448. doi: 10.1136/heartjnl-2012-302353 [DOI] [PubMed] [Google Scholar]
- 27.Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol [Internet]. 2005;46:1076–1084. doi: 10.1016/j.jacc.2005.05.073 [DOI] [PubMed] [Google Scholar]
- 28.Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. Eur Heart J. 2012;33:2403–2418. doi: 10.1093/eurheartj/ehs255 [DOI] [PubMed] [Google Scholar]
- 29.Nitsche C, Aschauer S, Kammerlander AA, et al. Light-chain and TTR cardiac amyloidosis in severe aortic stenosis: prevalence, screening possibilities, and outcome. Eur J Heart Fail. 2020;22:1852–1862. doi: 10.1002/ejhf.1756 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Zhao L, Buxbaum JN, Reixach N. Age-related oxidative modifications of TTR modulate its amyloidogenicity. Biochemistry. 2013;52:1913–1926. doi: 10.1021/bi301313b [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Park JY, Ryu SK, Choi JW, et al. Association of inflammation, myocardial fibrosis and cardiac remodeling in patients with mild aortic stenosis as assessed by biomarkers and echocardiography. Clin Exp Pharmacol Physiol. 2014;41:185–191. doi: 10.1111/1440-1681.12206 [DOI] [PubMed] [Google Scholar]
- 32.Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med. 2003;349:583–596. doi: 10.1056/NEJMra023144 [DOI] [PubMed] [Google Scholar]
- 33.Bonelli A, Paris S, Nardi M, et al. Aortic valve stenosis and cardiac amyloidosis: a misleading association. J Clin Med. 2021;10. doi: 10.3390/jcm10184234 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Fosbøl EL, Rørth R, Leicht BP, et al. Association of carpal tunnel syndrome with amyloidosis, heart failure, and adverse cardiovascular outcomes. J Am Coll Cardiol. 2019;74:15–23. doi: 10.1016/j.jacc.2019.04.054 [DOI] [PubMed] [Google Scholar]
- 35.Arana-Achaga X, Goena-Vives C, Villanueva-Benito I, et al. Development and validation of a prediction model and score for TTR cardiac amyloidosis diagnosis: t-amylo. JACC Cardiovasc Imaging. 2023;16:1567–1580. doi: 10.1016/j.jcmg.2023.05.002 [DOI] [PubMed] [Google Scholar]
- 36.Cipriani A, De Michieli L, Porcari A, et al. Low QRS voltages in cardiac amyloidosis: clinical correlates and prognostic value. JACC CardioOncology. 2022;4:458–470. doi: 10.1016/j.jaccao.2022.08.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Dobner S, Pilgrim T, Hagemeyer D, et al. Amyloid TTR cardiomyopathy in elderly patients with aortic stenosis undergoing transcatheter aortic valve implantation. J Am Heart Assoc. 2023;12:e030271. doi: 10.1161/JAHA.123.030271 [DOI] [PMC free article] [PubMed] [Google Scholar]; • An important study of ATTR-CM in patients with AS.
- 38.Abecasis J, Lopes P, Reis Santos R, et al. Prevalence and significance of relative apical sparing in aortic stenosis: insights from an echo and cardiovascular magnetic resonance study of patients referred for surgical aortic valve replacement. Eur Hear J - Cardiovasc Imaging. 2023;24:1033–1042. doi: 10.1093/ehjci/jead032 [DOI] [PubMed] [Google Scholar]
- 39.González-López E, Gagliardi C, Dominguez F, et al. Clinical characteristics of wild-type TTR cardiac amyloidosis: disproving myths. Eur Heart J. 2017;38:1895–1904. doi: 10.1093/eurheartj/ehx043 [DOI] [PubMed] [Google Scholar]
- 40.Barge-Caballero G, Vázquez-García R, Barge-Caballero E, et al. Light chain and TTR cardiac amyloidosis: clinical characteristics, natural history and prognostic factors. Med Clin (Barc). 2021;156:369–378. doi: 10.1016/j.medcli.2020.04.031 [DOI] [PubMed] [Google Scholar]
- 41.Aimo A, Panichella G, Garofalo M, et al. Sex differences in TTR cardiac amyloidosis. Heart Fail Rev [Internet]. 2023;29(2):321–330. doi: 10.1007/s10741-023-10339-w [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Patel RK, Ioannou A, Razvi Y, et al. Sex differences among patients with TTR amyloid cardiomyopathy – from diagnosis to prognosis. Eur J Heart Fail. 2022;24:2355–2363. doi: 10.1002/ejhf.2646 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Campbell CM, LoRusso S, Dispenzieri A, et al. Sex differences in wild-type TTR amyloidosis: an analysis from the TTR amyloidosis outcomes survey (THAOS). Cardiol Ther. 2022;11:393–405. doi: 10.1007/s40119-022-00265-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Ferreira V V, Rosa SA, Pereira-da-Silva T, et al. Prevalence and prognostic impact of apical sparing contractility pattern in patients with aortic stenosis referred for transcatheter aortic valve implantation. Am J Cardiovasc Dis [Internet]. 2021;11:283–294. http://www.ncbi.nlm.nih.gov/pubmed/34322299%0Ahttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC8303034 [PMC free article] [PubMed] [Google Scholar]
- 45.Davies DR, Redfield MM, Scott Christopher G. A simple score to identify increased risk of TTR amyloid cardiomyopathy in heart failure with preserved ejection fraction. JAMA Cardiol. 2022;7(10):1036–1044. doi: 10.1001/jamacardio.2022.1781 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Aimo A, Merlo M, Porcari A, et al. Redefining the epidemiology of cardiac amyloidosis. A systematic review and meta-analysis of screening studies. Eur J Heart Fail. 2022;24:2342–2351. doi: 10.1002/ejhf.2532 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Azevedo O, Gal A, Faria R, et al. Founder effect of Fabry disease due to p.F113L mutation: clinical profile of a late-onset phenotype. Mol Genet Metab [Internet]. 2020;129:150–160. doi: 10.1016/j.ymgme.2019.07.012 [DOI] [PubMed] [Google Scholar]
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