The Role of Cardiac Magnetic Resonance in patients with Amyloidosis and Aortic Stenosis

Cardiac magnetic resonance imaging (CMR) plays an important role in the diagnosis and prognosis of various heart diseases. The incidence of cardiac amyloidosis and aortic stenosis has been increasing in recent years, especially with the aging population, and their possible coexistence has created frequent diagnostic challenges in clinical practice. CMR assumes an important value in this context due to its unique capacity for multiparametric assessment evaluations that include anatomical, functional, and histopathological aspects. The present review aimed to increase our knowledge of the diagnosis and prognosis of amyloidosis in the presence of aortic stenosis and highlighted the importance of CMR in this scenario.


Introduction
The coexistence of cardiac amyloidosis (CA) and aortic stenosis (AS) has increasing relevance in clinical practice due to its high prevalence, diagnostic difficulty, and therapeutic management challenges.Primary CA forms feature amyloid light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) as the main presentations affecting up to 25% of octogenarians, 1 especially the latter.On the other hand, AS has a prevalence of up to 4% among individuals over 70 years, 2 with calcific degeneration as its main etiological landmark.CA 3 affects an estimated 5-16% of patients with major AS, reaching 30% in cases of low-flow low-gradient AS. 2 The correlation between the two diseases can be explained by several factors, with the common prevalent age group being the most important.The second factor is related to the histological analysis of valves removed in valve replacement surgeries, demonstrating amyloid deposits in 74% of stenotic aortic valves, inferring the possibility of AS and CA having a similar pathophysiological pathway. 4Another possible factor is mediated by increased AS afterload, which would potentially trigger amyloid protein accumulation in the ventricular myocardium. 4e prognosis of patients with CA and AS tends to be worse than that of patients with isolated AS, which directly interferes with its therapeutic management.CA alone has a variable prognosis.The reported median survival of patients with ATTR is 24.1-69.2months, while that of patients with AL is 3.5-26.4months 5 (Figure 1).In a retrospective study, patients with ATTR + major AS had significantly better 1-year overall mortality than those with major AS alone (56% vs. 20%, p < 0.0001). 6A study of patients with ATTR + AS versus AS alone showed that the former had an overall mortality that was almost twice as high (mean follow-up, 1.7 years) regardless of transcatheter aortic valve replacement (TAVR) or exclusive clinical maintenance (24.5% vs. 13.9%;p < 0.05).There is also evidence of no difference in 2-year mortality rates between patients with isolated ATTR and those with major ATTR + AS (33% vs. 37%, respectively; hazard ratio, 1.22; 95% confidence interval, 0.62-2.42;p = 0.566), even among the latter undergoing valve replacement, which suggests that ATTR would have a greater impact on mortality. 6On the other hand, there is evidence of improved prognosis among patients with ATTR + AS undergoing valve replacement versus those remaining on clinical treatment, 3,7 while small studies reported the superiority of TAVR to surgical aortic valve replacement (SAVR) in patients with ATTR + AS. 2 Due to the higher prevalence of ATTR versus AL, it is important to emphasize that most patients with CA + AS included in the studies have the ATTR form.
Due to the high prevalence and impact of the association between CA and AS, it is essential to investigate CA in patients with AS who are eligible for valve replacement.Diagnostic flow involves three main steps: 1) identifying suspected signs; 2) performing scintigraphy/monoclonal protein peak surveys; and 3) defining the diagnosis (with vs. without biopsy or genotyping).Cardiac magnetic resonance imaging (CMRI) is a fundamental diagnostic method for CA in the presence of AS (Figure 2) due to its ability to detect relevant morphological functional changes.CMRI can also individualize the prognosis of CA and AS by aiding the identification of patients who will benefit most from valve replacement.

CMRI diagnosis
Cardiac adaptations to increased afterload by AS are similar to those that occur in CA (e.g., concentric left ventricle remodeling).In addition, the presence of other diseases, such as coronary insufficiency and systemic arterial hypertension, interferes with the accuracy of several methods in the diagnosis of AS-associated CA.In this context, CMRI performs well (sensitivity, 85%; specificity, 92%) for diagnosing CA. 8 Due to its multiparameter analysis, it is also fundamental in the diagnosis of AS-associated CA (Figure 2) or AS alone.

Anatomical functional parameters
Left ventricular (LV) myocardial mass thickening and increases, atrial dilatation, and LV diastolic and systolic dysfunction are common in ATTR and AS but more severe when coexistent.
Patients with ATTR + AS versus AS alone have a higher LV mass index (105 ± 21 vs. 73 ± 21 g/m 2 ) as well as a lower LV ejection fraction and stroke volume (43 ± 17 vs.52 ± 18% and 33 ± 10 vs. 44 ± 13 mL/m 2 , respectively). 1 Myocardial thickening tends to be septally asymmetrical in the presence of ATTR, with a prevalence of 79%, versus concentrically thickened in AL.
Characteristics that are common in CA but uncommon in

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AS are pericardial effusion, interatrial septal thickening, biatrial dilatation (Figure 3), atrioventricular valve thickening, and RV thickening (with or without isolated systolic RV dysfunction).Atrial wall thickening occurs in up to 70% of patients with ATTR + AS. 6

Histological parameters
Noninvasive myocardial histological analysis by CMRI is based on the proton relaxation properties of each tissue used to identify the presence of localized or diffuse fibrosis.Different techniques (late enhancement, native myocardial T1 mapping, myocardial extracellular space volume calculations, myocardial-blood inversion time rate analysis, and myocardial edema investigation) can be used for cardiac tissue characterizations with quantitative measurements that assess the extent of damaged induced by amyloid substance deposits.

Native myocardial T1 mapping
Native myocardial T1 mapping, which analyzes the magnetic characteristic of tissue proton relaxation, is performed without a gadolinium injection.Its primary advantage involves the early identification of myocardial fibrosis, especially that with diffuse distribution, which may not be identified by late enhancement, making the diagnostic evaluation more sensitive.Normal myocardial T1 values may vary according to the machine used and are usually between 950 and 1,050 ms.Patients with isolated CA, CA + AS, or isolated AS may present with a prolonged T1, being significantly higher in patients with CA.Patients with ATTR + AS have higher native T1 values than those with isolated AS (native T1: 1,125 ± 49 vs. 1,035 ± 60 ms; p = 0.002). 6

Myocardial edema research
Myocardial edema may be present in CA but is uncommon in isolated AS.It is diagnosed through T2 time mapping or specific T2-weighted sequences without the need for a gadolinium injection.The presence of myocardial edema with AS should prompt the investigation of other concomitant heart diseases.

Late myocardial enhancement
Late enhancement, which is based on preferential gadolinium uptake in tissues rich in extracellular matrix, aids in the contrast of healthy and pathological myocardium minutes after its administration.The enhancement pattern changes according to etiology.In ATTR, there a basal-apical enhancement distribution occurs that can spare the apical segments (Figure 4).AL has its own characteristics with circumferential subendocardial involvement.The presence of late enhancement in the atrial myocardium (Figure 5) or the RV is frequent in CA, with a prevalence of atrial enhancement of up to 90% and of RV enhancement of 37-97% of ATTR + AS cases. 6Late enhancement occurs in up to 40% of isolated AS cases, being mainly present in the LV with a focal mesocardial pattern.
Extracellular volume (ECV) analysis is estimated based on native myocardial T1 time, post-contrast T1 time, and patient hematocrit at the time of the examination (normal ECV values are <25 to 27%). 9Both CA and AS can increase myocardial ECV, but greater increases are seen in the presence of CA, particularly the ATTR type.Patients with ATTR + AS have higher ECV values than those with isolated AS (41.2 ± 16.7 vs. 27.9 ± 4.1%; p < 0.001). 6ECV values > 40% are rare in diseases other than CA.In advanced CA stages, ECV can be more important for the diagnosis than T1 mapping.

Prognosis by CMRI
Patients with CA + AS lack formal therapeutic recommendations regarding the approach to AS, which makes its treatment challenging.A prognostic evaluation before valve replacement is essential, and CMRI can aid the decision, especially through late enhancement analysis and

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ECV.Late enhancement is a poor independent prognostic factor for all heart diseases.Moderate to severe AS carries an eight-fold increased risk of mortality regardless of stenosis severity.An increased relative risk of major cardiovascular events after aortic valve replacement in the presence of late enhancement has also been documented, as has the possibility of left ventricular dysfunction maintenance post-aortic valve replacement in the presence of late enhancement. 10V has excellent prognostic value in patients with ATTR + AS since it is correlated with mortality (Figure 6).An ECV < 25% is protective regardless of exclusive clinical treatment or valve replacement, with no reports of cardiovascular death within 1 year. 1 Increased native myocardial T1 mapping interpreted in isolation showed only a tendency to be correlated with prognosis in patients with ATTR + AS, but the difference was not statistically significant (Figure 6). 1 Further studies with a greater number of patients may provide additional information about the use of native myocardial T1 mapping in the prognostic definition of this patient group.

Conclusion
CA and AS are increasingly encountered in clinical practice, mainly due to an increased number of diagnoses and continued population aging.The diagnosis of CA  Source: adapted from Cavalcante et al. 1 should be considered in cases of suspicious signs or when phenotypic cardiac changes are noted beyond those expected according to AS severity.CMRI, which plays an important role in the diagnosis and prognosis of patients with CA + AS, is a fundamental test that enables more assertive therapeutic decisions.

Figure 1 -
Figure 1 -Median survival of patients with AL vs. ATTR amyloidosis.

Figura 2 -
Figura 2 -Proposed diagnostic algorithm for CA in the presence of AS.Positron emission tomography diagnostic criteria: target-to-blood pool ratio > 1.5 or retention index > 0.030 min-1.
protein peak (serum and urine immunofixation + light chain assay) Consider cardiac or extracardiac biopsy to diagnose AL-type CA Cardiac or extracardiac biopsy to diagnose ATTR-type CA Conduct genotyping (wtATTR/hATTR) Consider cardiac biopsy to diagnose ATTR-type CA Cardiac biopsy to diagnose ATTR-type CA or extracardiac biopsy in case of echocardiogram or PET criteria ECHO signs: LV thickness >15 mm Severe LV LSD Normal apical strain RV thickening or IAS Granular sparkling Low flow-low gradient or paradoxical AoS Red flags Presence of one or more red flags Resonance Cardiac Value in Patients with Amyloidosis and Aortic Stenosis Arq Bras Cardiol: Imagem cardiovasc.2022;35(3):eabc320

Figura 4 -
Figura 4 -Images taken of a patient with AS and ATTR amyloidosis.(A) Computed tomography image demonstrating calcific AS (valve area, 1 cm2; valvular calcium score, 1,270).(B) Cardiac magnetic resonance images showing diffuse late myocardial enhancement more evident in the mid-basal segments compatible with the diagnosis of ATTR CA (orange arrow: late enhancement present; blue arrow: late enhancement absent).

Figure 5 -Figure 6 -
Figure 5 -Images of atrial fibrosis (white arrows) in a patient with ATTR amyloidosis.