Wild-type transthyretin cardiac amyloidosis: a case of multisystemic involvement and review of literature

Abstract

Introduction: Cardiac amyloidosis (CA) represents a progressively evolving infiltrative pathology, defined by the myocardial accumulation of amyloid fibrils. The condition predominantly originates from transthyretin-derived (ATTR) or immunoglobulin light chain-related (AL) amyloidosis. ATTR cardiomyopathy (ATTR-CM), particularly the wild-type (wt) form (wtATTR-CM), is becoming more widely acknowledged as a contributor to cardiac dysfunction in the elderly population. However, diagnosing ATTR-CM remains challenging due to its clinical similarity to other cardiac conditions and a history of frequent misdiagnoses. Recent advancements in nuclear imaging using bone-avid radiotracers have greatly improved the ability to diagnose ATTR-CM non-invasively. Case presentation: This case involves an 86-year-old male with documented peripheral joint disease, supraspinatus tendon rupture affecting both limbs, referred for exertional dyspnea. Echocardiography indicated left ventricular hypertrophy, diastolic dysfunction, reduced global longitudinal strain, accompanied by severe mitral regurgitation (MR) secondary to prolapse of the posterior mitral leaflet. Cardiac magnetic resonance (CMR) imaging revealed concentric hypertrophy, elevated T1 mapping, and increased extracellular volume, highly suggestive of amyloid deposition. Bone scintigraphy confirmed the diagnosis of ATTR-CM with a Perugini score of 3. A biopsy of the abdominal fat pad revealed amyloid deposits. Conclusions: Such presentations of ATTR-CM emphasize its systemic nature and the need for early recognition and treatment. An important aspect of this case is the uncommon association between CA and posterior mitral valve prolapse, which leads to significant MR.

Introduction

Cardiac amyloidosis (CA) is a serious condition characterized by structural and functional impairment of the myocardium due to abnormal protein deposition [1]. It can arise from rare genetic variants in hereditary forms or develop due to acquired conditions [1].

CA is defined by the extracellular accumulation of misfolded proteins in the heart, with histopathological (HP) confirmation achieved through Congo Red staining and observation of green birefringence under polarized microscopy [2]. While over 30 amyloidogenic proteins have been identified, CA primarily results from the aggregation of misfolded transthyretin (TTR) or immunoglobulin (Ig) light chains [3]. Protein conformation can be altered by various processes, such as abnormal proteolysis or post-translational modifications [4]. When the body’s homeostatic mechanisms fail to efficiently eliminate abnormal proteins, it promotes the formation and accumulation of amyloid fibrils within tissues, ultimately leading to organ dysfunction [5]. Amyloidosis may present as a localized form, characterized by protein production and deposition at a single anatomical site, or as a systemic condition, which is typically associated with widespread involvement and multiorgan dysfunction [4].

Transthyretin amyloid cardiomyopathy (ATTR-CM) is categorized into two main types: a hereditary (h) form, known as hATTR-CM, which results from pathogenic variants in the TTR gene, and a non-hereditary (wild-type; wt) form, referred to as wtATTR-CM, that arises in the absence of TTR gene mutations [6]. Recent findings suggest that wtATTR-CM may be more prevalent than previously estimated in elderly patients presenting with heart failure (HF) [6]. Although traditionally regarded as a rare disease, its presence has been increasingly highlighted among cardiologists, and suspicion must be high, especially when a secondary cause of cardiomyopathy (CM) is suspected.

Pathophysiology

TTR, formerly referred to as prealbumin, is a tetrameric protein composed of four β-sheet-rich subunits, functioning primarily in the transport of thyroxine and retinol-binding protein (RBP) [7]. TTR is primarily produced in the liver, and its misfolding and aggregation in various organs contribute to the clinical presentation of ATTR amyloidosis (Figure 1) [6].

Figure 1.

Pathophysiology, multimodal cardiac imaging, and multisystemic manifestations of wtATTR. The normal TTR tetramer dissociates into monomers, which then misfold and aggregate into insoluble amyloid fibrils that deposit in the organism. The central panel highlights the multimodal cardiac imaging findings characteristic of wtATTR-CM. The right side of the figure summarizes the multisystem involvement associated with wtATTR. CMR: Cardiac magnetic resonance; Echo: Echocardiography; ECV: Extracellular volume; GLS: Global longitudinal strain; H/CL: Heart-to-contralateral lung; LGE: Late gadolinium enhancement; LV: Left ventricular; TTR: Transthyretin; wtATTR: Wild-type transthyretin amyloidosis; wtATTR-CM: Wild-type transthyretin amyloid cardiomyopathy. Image created with Biorender

The deposition of amyloid fibrils varies in terms of location, distribution, and extent. In the heart, these fibrils primarily accumulate in the subendocardial interstitium, disrupting the architecture of cardiomyocytes and leading to increased myocardial fibrosis. Two distinct patterns of interstitial deposition have been identified: the pericellular pattern, where fibrils encircle cardiomyocytes and contribute to cellular atrophy, and the nodular pattern, which typically distorts the surrounding myocardial structure [8]. In ATTR amyloidosis, amyloid deposition is generally nodular and diffuse, though it may also present as localized or multi-focal. In contrast, amyloid light-chain (AL) amyloidosis is characterized by a diffuse, predominantly pericellular and endomyocardial deposition pattern [4]. Vascular amyloid deposits are frequently observed in both intramural and epicardial vessels and are believed to contribute to ischemic symptoms in a substantial proportion of patients without obstructive epicardial coronary artery disease [9]. Also, microvascular dysfunction is increasingly recognized as a key contributor to myocardial ischemia in individuals affected by this condition [10].

Epidemiology

wtATTR-CM is most commonly observed in elderly individuals, typically around the age of 74 at the time of diagnosis, although earlier-onset cases, including those in patients under 45, have also been described [11]. wtATTR-CM is certainly the most prevalent form of ATTR-CM, yet the exact population prevalence is still unclear. Post-mortem analyses indicate that the frequency of myocardial TTR deposits increases with advancing age, with estimated prevalence rates of approximately 20–25% in individuals in their 80s and up to 37% in those over 95 years of age [12, 13]. A multicenter study conducted in Italy reported a prevalence of CA of 23.5 cases per million, with an annual increase of 17% [14]. The implementation of bone scintigraphy in the diagnostic evaluation of ATTR-CM has revealed that approximately 13% of elderly patients hospitalized with HF with preserved ejection fraction (HFpEF) are affected by this condition [15].

Multisystemic manifestations

Patients may exhibit a spectrum of clinical presentations, ranging from predominantly neurological to cardiomyopathic features, or a combination of both [5]. Although cardiac involvement is central, the most frequent extracardiac manifestations occur at the level of the peripheral and autonomic nervous systems, as well as in the musculoskeletal system. Other organs that may be affected include the eyes, kidneys, and gastrointestinal (GI) tract (Figure 1) [16]. Distal biceps tendon rupture has been reported in approximately one-third of individuals diagnosed with wtATTR-CM [17]. HP examination of tissue obtained during rotator cuff repair surgery identified wtATTR-CM deposits in 38% of cases [18]. GI symptoms may involve nausea, diarrhea, and severe or alternating constipation. Musculoskeletal involvement can lead to muscle weakness and fatigue. Ocular complications (such as vitreous opacities or glaucoma) and auditory impairment may also be present. These multisystem features often lead to functional decline, chronic pain, malnutrition, impaired mobility and dexterity, and may result in social isolation and depression [19].

ATTR and the heart

The cardiovascular (CV) manifestations of ATTR-CM span a broad clinical spectrum, from asymptomatic cases to severe presentations [16]. Patients may present with significant left ventricular hypertrophy (LVH), restrictive filling pattern, and progressive deterioration of cardiac function [20]. Additionally, autonomic dysfunction related to ATTR-CM can lead to symptoms such as orthostatic hypotension and syncope [21].

Patients with ATTR-CM may experience clinical manifestations indicative of cardiac dysfunction, including reduced exercise tolerance, which may progress to orthopnea and pulmonary edema [16]. Left ventricular ejection fraction (LVEF) is generally preserved but may decline in advanced stages [6]. Amyloid fibrils can infiltrate various cardiac structures, including the valves, leading to stenosis or regurgitation [22], and the conduction system, resulting in conduction disturbances [22]. Atrial involvement promotes the development of atrial fibrillation (AF) [4]. Additionally, myocardial fibrosis may create reentry circuits in the ventricles, predisposing to ventricular tachycardia [23]. Amyloid deposition typically begins at the base of the heart and progresses toward the apex, causing ventricular wall thickening and reduced compliance [16]. These structural and functional alterations result in a pseudohypertrophic restrictive CM, characterized by impaired diastolic function and reduced longitudinal systolic function, typically with apical sparing [16].

The electrocardiogram (ECG) may suggest the presence of CA, especially in the context of LVH associated with low-voltage QRS complexes, despite the fact that only between 25% and 40% of ATTR-CM patients fulfill this criterion [24]. Additional electrocardiographic indicators may include diminished R-wave amplitude in anterior leads (mimicking infarction), occurrences of AF, and various conduction disturbances, such as atrioventricular (AV) or bundle branch blocks [25].

Echocardiography (Echo) is a widely accessible imaging modality and frequently provides the first indication of CA. Key Echo features include thickening of the left ventricular wall, generally measuring 1.2 cm or more, and preserved left ventricle (LV) dimensions [26]. Other indicative features may include enlargement of both atria, impaired diastolic filling, accumulation of pericardial fluid, and thickened AV valves, interatrial septum, and right ventricular wall, along with a distinctive speckled or ‘granular’ appearance of the myocardium [26]. Functional abnormalities, including a reduction in mitral annular systolic velocity (s’) and a decline in global longitudinal strain (GLS), along with relative apical sparing, provide further corroboration for the diagnosis [26].

Cardiac magnetic resonance (CMR) is an important non-invasive imaging technique used to evaluate CA [16, 27]. Important CMR imaging findings in amyloidosis comprise increased extracellular volume (ECV), abnormal gadolinium kinetics, and widespread late gadolinium enhancement (LGE), which typically begins in the subendocardium and may extend transmurally as the disease advances [16, 27]. These LGE patterns correlate with myocardial amyloid burden and have prognostic implications, including right ventricular involvement being associated with poorer outcomes [28, 29]. Quantitative evaluation of amyloid deposition can be achieved using T1 mapping, conducted both pre- and post-contrast. Elevated native T1 and ECV measurements have been observed in ATTR-CM and AL cardiomyopathy (AL-CM), reflecting the extent of amyloid accumulation and its clinical significance [30]. Despite its diagnostic and prognostic utility, CMR alone is neither sufficient nor specific to distinguish between amyloid subtypes [16, 31].

The diagnostic process for ATTR-CM is often complicated by several factors. First, its clinical manifestations, such as thickening of the ventricular walls and symptoms of HF, are frequently mistaken for more common cardiac conditions like hypertensive heart disease, aortic stenosis, or hypertrophic CM. Second, misclassification with AL amyloidosis contributes to the misconception that ATTR-CM is rare. Third, a lack of familiarity with appropriate diagnostic protocols among clinicians further complicates the identification of the condition. Finally, the belief that treatment options are limited has fostered a general sense of pessimism regarding effective management [6]. The development of bone radiotracers used in nuclear imaging has made it possible to identify ATTR-CM non-invasively, eliminating the requirement for tissue biopsy [32].

Cardiac nuclear scintigraphy using bone-avid tracers offers a valuable non-invasive imaging approach for the reliable diagnosis of ATTR-CM. This method eliminates the need for an invasive cardiac biopsy, provided that the serum and urine tests for AL amyloidosis yield negative results [33]. Assessing myocardial radiotracer retention is essential for diagnosing ATTR-CM using bone scintigraphy. Evaluation may be performed either by visually assessing myocardial uptake relative to rib uptake on planar or single-photon emission computed tomography (SPECT) scans, or through quantitative analysis using the heart-to-contralateral lung (H/CL) ratio [34]. Cardiac uptake is graded according to the Perugini system: grade 0 indicates absence of uptake; grade 1 reflects faint myocardial uptake that is less intense than bone; grade 2 denotes uptake intensity comparable to bone; and grade 3 is characterized by strong myocardial uptake with minimal or absent bone signal [35]. Positive planar scintigraphy is defined by a Perugini score of ≥2 and/or H/CL chest ratio of ≥1.5 at one hour or >1.3 at three hours post-injection [36]. SPECT enhances the accuracy of assessing tracer distribution between the myocardium and blood pool, and its use is endorsed by leading national and international clinical guidelines [36].

How to diagnose

CA diagnosis relies on a combination of clinical features, imaging assessments, and, when necessary, HP confirmation (Figure 2) [37]. Both non-invasive and invasive methods are available for establishing the diagnosis. The first step in the diagnostic algorithm is screening for monoclonal proteins to detect a potential plasma cell disorder, which would suggest AL-CM. While bone scintigraphy is instrumental in the non-invasive detection of ATTR-CM, radiotracer uptake corresponding to Perugini grades 2 or 3 may also be observed in 10–30% of AL-CM cases [38]. Therefore, identifying monoclonal protein status is essential for selecting the correct diagnostic pathway [39]. Scintigraphy alone is insufficient to reliably differentiate ATTR-CM from AL-CM [38].

Figure 2.

Diagnostic algorithm for cardiac amyloidosis modified after Brito et al. (2023) [16]. If clinical suspicion is present, AL amyloidosis is first excluded through monoclonal protein screening. If negative, diphosphonate scintigraphy is used to diagnose ATTR-CM. Grade 2–3 uptake confirms ATTR-CM and prompts genetic testing. If uptake is grade 0–1 or the tests are abnormal, a tissue biopsy is required for a definitive diagnosis. AL: Amyloid light-chain; ATTR-CM: Transthyretin amyloid cardiomyopathy; CMR: Cardiac magnetic resonance; ECG: Electrocardiogram; Echo: Echocardiography; EMB: Endomyocardial biopsy; hATTR-CM: Hereditary transthyretin amyloid cardiomyopathy; wtATTR-CM: Wild-type transthyretin amyloid cardiomyopathy. Image created with Biorender

The initial step in the diagnostic approach involves ruling out AL amyloidosis, which can be effectively achieved through monoclonal protein screening using a combination of serum free light chain testing, serum immunofixation, and urine immunofixation electrophoresis [40]. When all three tests return within normal limits, the likelihood of AL amyloidosis is considered negligible, with a negative predictive value exceeding 99% [40].

Once AL amyloidosis has been ruled out, bone scintigraphy serves as the primary non-invasive diagnostic tool. Detection of radiotracer uptake corresponding to Perugini grade 2 or 3 supports a diagnosis of ATTR-CM and warrants subsequent genetic testing. In cases where imaging results are negative or inconclusive (grade 0 or 1), further assessment through Echo, CMR imaging, and clinical reevaluation is advised, with a tissue biopsy remaining a consideration if clinical suspicion persists (Figure 2) [16].

Once ATTR-CM is confirmed, genetic testing for TTR mutations is necessary to distinguish between hereditary and wt forms, regardless of the patient’s age. This distinction is crucial for family screening [41].

Endomyocardial biopsy (EMB) is recommended in subjects who have a strong suspicion of CA, with a monoclonal protein, negative or unclear scintigraphy, or when imaging is unavailable [16]. Though rarely needed, a biopsy can also reveal coexisting AL and ATTR amyloidosis. When EMB is not feasible, alternative biopsy sites include abdominal fat, kidney, bone marrow, or mucosal tissues [16]. Once amyloid is confirmed, tissue typing using mass spectrometry or immunohistochemistry is essential for determining the specific subtype (Figure 2) [36].

Treatment

Management of ATTR-CM involves both symptomatic treatment to control cardiac manifestations and comorbidities and disease-modifying therapy that targets the amyloidogenic process to slow or alter disease progression [42].

Historically, treatment for hATTR focused primarily on liver transplantation and symptomatic management, due to the unavailability of disease-specific interventions for ATTR-CM [43, 44]. The therapeutic landscape began to evolve in the mid-2000s with the investigation of pharmacological agents designed to prevent TTR misfolding, notably Diflunisal and Tafamidis [45, 46]. Authorization for the use of Tafamidis in the treatment of ATTR was first granted in Europe in 2011, followed by regulatory approval in the United States in 2019, specifically targeting TTR-related CM [47]. Growing awareness and advances in diagnostic techniques have since spurred a significant increase in clinical research focused on ATTR-CM, including continuing studies of not limited to existing TTR stabilizers [48], but also gene silencers and fibril depleting agents [44, 49, 50].

Case presentation

This case emphasizes the clinical relevance of evaluating CA in elderly individuals presenting with HF symptoms and preserved systolic function without hypertension, presenting with significant concentric hypertrophy but lacking the classical ECG signs of concentric hypertrophy. Additionally, the patient has posterior mitral valve (MV) prolapse, resulting in severe mitral regurgitation (MR).

This case concerns an 86-year-old male with documented peripheral arthritic disease, Dupuytren’s contracture, and bilateral supraspinatus tendon rupture in his medical background. He was referred to cardiology due to exertional dyspnea – shortness of breath during moderate physical activity. His past medical history also included chronic respiratory failure, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV chronic obstructive pulmonary disease (COPD), and diffuse pulmonary fibrosis. Furthermore, he reported longstanding pain in the left hypochondrium, which was attributed to impaired relaxation of the left diaphragm.

On clinical examination, his general condition was good, with normal skin and mucous membrane color. Pulmonary auscultation revealed bilateral vesicular murmurs without additional rales. CV examination showed a heart rate of 90 beats per minute (bpm), rhythmic heart sounds, a blood pressure of 130/70 mmHg, and a grade 4/6 systolic murmur in the mitral focus. Peripheral arteries were pulsating. The abdomen was mobile and painless on palpation.

Electrocardiographic evaluation revealed a sinus rhythm at 80 bpm, presence of a left anterior fascicular block, and delayed R-wave progression across leads V1 to V4. The PQ interval was extended to 320 ms, and the Sokolow–Lyon index measured 32 mm, based on an S wave of 13 mm in lead V2 and an R wave of 19 mm in lead V6 (Figure 3A, 3B).

Figure 3.

(A and B) ECG and Echo: the voltage observed on the patient’s 12-lead ECG does not correlate with the extent of concentric LVH observed on transthoracic Echo in the parasternal long-axis view. ECG: Electrocardiogram; Echo: Echocardiography; LVH: Left ventricular hypertrophy

Echo revealed LVH with a posterior wall thickness of 17 mm and an interventricular septum of 18.5 mm.

Color Doppler imaging demonstrated severe MR, thickened MV cusps, and posterior MV prolapse (Figure 4A) with an eccentric subvalvular jet (Figure 4B).

Figure 4.

– In the parasternal long-axis view, the prolapse of the mitral valve is observed (arrow A), along with the eccentric jet (arrow B).

The assessment of diastolic function showed grade I diastolic dysfunction with elevated LV filling pressures (E/e’ ratio of 12). Speckle-tracking Echo analysis revealed a reduction in GLS (-10.9%), with an apical sparing pattern (Figure 5).

Figure 5.

Speckle-tracking analysis with apical sparing in the LV longitudinal strain and with a reduction in the GLS (-10.9%). GLS: Global longitudinal strain; LV: Left ventricle

The radiographic findings are consistent with diaphragmatic relaxation and support the electrophysiological evidence of left-sided phrenic nerve palsy. The left diaphragmatic recess appears rounded, raising differential considerations of subtle fibrosis or minimal pleural effusion. There are no visible parenchymal infiltrates or acute signs of pulmonary venous congestion. A triangular-shaped infrahilar opacity is noted on the right side, most likely representing an area of atelectatic change. The cardiac silhouette appears mildly enlarged. Figure 6 illustrates a chest radiograph showing a sharply demarcated diaphragm with a slight elevation of the left hemidiaphragm.

Figure 6.

Chest X-ray suggestive of left-sided diaphragmatic relaxation

The electrophysiological assessment revealed severe axonal mononeuropathy of the left phrenic nerve, with a complete absence of diaphragmatic response on stimulation, suggesting significant functional impairment. In contrast, the right phrenic nerve showed a preserved but low-amplitude response, indicating possible subclinical involvement. Motor conduction studies demonstrated an absent motor response of the right median nerve, consistent with advanced carpal tunnel syndrome, and a reduced amplitude of the right ulnar nerve, suggestive of concomitant axonal involvement. A mild reduction in amplitude was also observed at the right fibular head, indicative of early or partial peroneal neuropathy. These findings, as seen in Figure 7, collectively support the diagnosis of a multifocal axonal neuropathy, prominently affecting the phrenic, median, ulnar, and peroneal nerves.

Figure 7.

Electrophysiological profile: limb and diaphragmatic nerves. ADM: Abductor digiti minimi; AH: Abductor hallucis; APB: Abductor pollicis brevis; EDB: Extensor digitorum brevis

Laboratory evaluation revealed an N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration of 2621 pg/mL, a mild elevation in total serum protein at 8.9 g/dL, and an IgG value of 1705 mg/dL, classified as borderline high. Serum protein electrophoresis combined with immunofixation demonstrated diffuse bands for IgA, IgG, and kappa chains, along with a faintly migrating lambda chain band. Nevertheless, these findings were inconclusive. Repeating electrophoresis was recommended in three to six months. Urine electrophoresis showed no Bence–Jones protein or monoclonal bands.

Angiographic assessment revealed a 60% narrowing of the left anterior descending artery (LAD), which did not require interventional treatment.

A CMR imaging was performed, which identified normal LV volumes with preserved systolic function (LVEF 58%). There was concentric hypertrophy and an increased LV mass index. T1 mapping was elevated at 1470 ms (reference value in our Institute is 1140–1195 ms), and ECV was increased to 64%, suggesting diffuse fibrosis (Figure 8). LGE sequences showed diffuse contrast uptake, with an inability to null the myocardium, highly suggestive of amyloid deposition (Figure 8A, 8B). The right ventricle had normal function with an ejection fraction of 60%. The MV showed severe regurgitation with a regurgitant volume of 43 mL and a regurgitant fraction of 50%, which was associated with posterior MV prolapse. The left atrium was significantly dilated, with an indexed volume of 67 mL/m2.

Figure 8.

CMR imaging: (A) Increased native T1 (1470 ms) and postcontrast T1 showing extracellular fibrosis; (B) The impossibility to null the myocardium and extensive LGE. CMR: Cardiac magnetic resonance; LGE: Late gadolinium enhancement.

Tissue sampling from subcutaneous adipose tissue was undertaken, and HP examination revealed amyloid material based on Congo Red affinity, with birefringence observed under polarized microscopy (Figure 9A, 9B, 9C, 9D).

Figure 9.

Abdominal adipose tissue biopsy stained with Congo Red: (A and B) Amyloid deposits in the deep dermis and around sweat glands under transmitted light; (C and D) Apple-green birefringence under polarized light, confirming the presence of amyloid, including deposits between adipose lobules toward the hypodermis. Original magnifications: (A and C) ×40; (B and D) ×100

Whole-body bone scintigraphy with Technetium-99m–Pyrophosphate (99mTc–PYP) showed radiotracer uptake in the myocardium, with a Perugini score of 3 and an H/CL ratio of 1.63 (Figure 10A, 10B). These findings were strongly suggestive of cardiac TTR amyloidosis. Additional findings included degenerative vertebral changes in the cervical, thoracic, and lumbar spine, inflammatory-degenerative joint disease in multiple joints, and an ectopic right kidney with increased radiotracer uptake.

Figure 10.

(A and B) Whole-body bone scintigraphy with 99mTc–PYP showed radiotracer uptake in the myocardium, with a Perugini score of 3 and an H/CL ratio of 1.63. 99mTc–PYP: Technetium-99m–Pyrophosphate; H/CL: Heart-to-contralateral lung.

Genetic sequencing aimed at detecting TTR mutations was negative.

Discussions

wtATTR amyloidosis often presents with CM in older adults, although symptoms such as tendinopathies, spinal stenosis, and carpal tunnel syndrome may occur 10–15 years before the onset of CM [51]. This is also the case in the present study, where the patient presented with bilateral supraspinatus tendon rupture for several years prior to the diagnosis. Although this is a nonspecific symptom, it still emphasizes the role of multidisciplinary management in addressing amyloidosis.

Changes observed in the patient’s arthritic joints could be partially linked to wtATTR amyloidosis, as supported by prior studies reporting its presence in osteoarthritic tissues with a relatively frequent occurrence [52, 53] and that its overexpression may accelerate osteoarthritis [54].

In our patient, the presence of polyneuropathy symptoms, including dizziness, paresthesias, and left hemidiaphragm relaxation may also be linked to wtATTR amyloidosis. Polyneuropathy associated with wtATTR amyloidosis is quite common, with up to 30% of patients experiencing sensory neuropathy and 15% showing motor neuropathy [55, 56]. Given that wtATTR amyloid deposits can affect both small and large nerve fibers, the patient’s paresthesias may be due to axonal neuropathy, the predominant form described in this condition [57]. Additionally, dizziness in CA could be related to autonomic dysfunction, which has been documented in ATTR amyloidosis, potentially contributing to orthostatic hypotension and dysautonomia [58].

Transthoracic Echo should be the first non-invasive test used to help diagnose ATTR-CM, given its relative accessibility and low cost. Amyloid deposition in the heart walls causes visible changes with great sensitivity detected through Echo, such as thickened ventricular walls, a small LV cavity, valve thickening, atrial enlargement, and apical sparing on strain imaging [59]. These classic signs are also red flags for raising suspicion and further investigation into the etiology, especially in the context of preserved LVEF but with longitudinal dysfunction [60].

Available studies indicate a significant frequency of amyloid deposits in the heart valves, including the MV [61]. In a multicenter study of 120 individuals diagnosed with MR who received transcatheter edge-to-edge repair (TEER), the prevalence of CA was 11.7%, with 86% of cases being ATTR-CA [62].

From an etiological perspective, MR in CA involves elements of both primary and secondary MR [63]. Amyloid deposition alters the structure and function of the MV leaflets as well as the (sub)valvular apparatus itself [64, 65]. In addition, more unusual presentations of MR in CA, such as ruptured chordae tendineae, have also been reported [66]. Furthermore, CA is associated with significant remodeling of the LV, which may lead to inadequate MV closure [61, 67]. Left atrial enlargement, a characteristic of restrictive cardiomyopathies, frequently results in MV annular dilation and functional MR [62]. Finally, MR in CA can have mixed etiologies, and it is not uncommon for it to present as Carpentier classes I–III [68]. In patients with CA, both percutaneous MV repair [69, 70] and MV replacement are viable treatment options, although our patient chose to decline any intervention.

CMR imaging is a fundamental part of a comprehensive imaging approach to further evaluate the possibility of ATTR-CM [71]. Under normal conditions, cardiomyocytes are tightly packed, constituting about 85% of the myocardial volume, with the normal ECV typically ranging from 22% to 28% [29]. CA is a primary interstitial condition that leads to the progressive expansion of the extracellular space, with increased myocardial gadolinium uptake, reflected by areas of hyper-enhancement. As a result, CA presents with a distinct appearance on LGE imaging, starting with diffuse subendocardial LGE that evolves into widespread transmural deposition in the terminal stages, as is the case with our patient (Figure 8). The LGE encountered here is, however, a non-specific sign and can appear in multiple cardiac diseases, including myocardial infarction with non-obstructive coronary arteries (MINOCA), myocarditis, Takotsubo CM, etc. However, its diffuse distribution pattern, as well as the other volumetric and ventricular kinetic signs, provides a key. For instance, abnormal gadolinium kinetics, where the myocardium and blood are nullified simultaneously, are also encountered in CA [72].

In ATTR-CM, several new pharmaceutical treatments have been developed to target the disease at different stages. These include TTR stabilizers and therapies like antisense oligonucleotides and ribonucleic acid (RNA) interference [73]. Currently, these treatments yield the best outcomes when delivered before advanced myocardial dysfunction develops [5, 74]. Follow-up at six months after diagnosis showed a good clinical condition of the patient, with mild symptoms associated with HF.

Conclusions

This case illustrates that ATTR-CM is more prevalent than previously recognized. Clinicians should maintain a high level of diagnostic awareness in patients with signs of HF and normal systolic function, particularly in the setting of significant concentric hypertrophy without a history of hypertension. A distinctive feature of this case is the uncommon association between CA and posterior MV prolapse, resulting in severe MR. While the extent of cardiac involvement offers critical prognostic information, it is important to recognize that CA is a systemic disease. Extracardiac manifestations – such as tendon ruptures or neurological impairments – can appear early in the disease course and significantly affect a patient’s quality of life. It is important to emphasize the need for collaboration among different specialties.

Conflict of interests

The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript.