Challenges in diagnosis and management of severe aortic stenosis with coexisting cardiac amyloidosis: a case report

Abstract

Background

Transthyretin amyloid cardiomyopathy (ATTR-CM) coexists in up to 15% of elderly patients with severe aortic stenosis (AS), presenting complex diagnostic and therapeutic challenges due to overlapping clinical phenotypes.

Case summary

An 85-year-old female presented with a 2-month history of heart failure and a previous medical history of total knee replacement. Echocardiography and computed tomography confirmed severe AS, alongside left ventricular hypertrophy out of proportion to the valvular load and an ‘apical sparing’ strain pattern. Due to the accompanying red flags, a Tc99m-PYP bone scintigraphy was done. This showed a Grade 3 cardiac uptake, and further testing confirmed wild-type ATTR-CM. Given her recent symptom onset, preserved ejection fraction, and high-gradient AS, the Heart Team prioritized transcatheter aortic valve implantation (TAVI). Following a successful procedure, she demonstrated excellent functional recovery at one month, which clinically justified the subsequent initiation of transthyretin stabilizers.

Discussion

Concomitant ATTR-CM must be suspected in elderly AS patients presenting with disproportionate hypertrophy or other clinical/imaging ‘red flags’. A sequential management strategy—prioritizing TAVI to relieve the haemodynamic bottleneck, followed by clinical reassessment—can effectively identify appropriate candidates for long-term, disease-modifying transthyretin stabilizer therapy.

Learning points.

• Coexisting cardiac amyloidosis is not infrequent in severe aortic stenosis, and correct diagnosis needs meticulous attention to clinical and imaging clues.

• Valve interventions or specific medical treatment for cardiac amyloidosis might not be beneficial in all patients, thus emphasizing the need for individualized management plans.

• Recent onset of symptoms with good functional capacity prior to symptoms and preserved ejection fraction with high-gradient aortic stenosis may be factors associated with good outcomes after valve intervention.

Introduction

Aortic stenosis (AS) affects nearly 10% of octogenarians, up to 25% of whom have coexisting transthyretin amyloid cardiomyopathy (ATTR-CM)—a dual pathology portending poor outcomes.^1–7 Because the clinical and imaging phenotypes of AS and ATTR-CM overlap significantly, diagnosing concomitant ATTR-CM is challenging and often delayed. Co-diagnosis introduces complex management dilemmas, as the prognostic benefit of valve intervention versus the initiation of ATTR-CM-specific medical therapy remains poorly defined.⁷ This manuscript reports on an 85-year-old female with severe AS and heart failure who was diagnosed with ATTR-CM during pre-procedural workup. We outline a stepwise approach to diagnosing ATTR-CM in the presence of severe AS and propose a sequential management strategy.

Summary figure

Case report

An 85-year-old woman with a 15-year history of hypertension was referred to our centre due to recent exertional dyspnoea and hospitalization for heart failure within the past 2 months. Her surgical history included a total knee replacement 4 years prior. On admission, her blood pressure was 120/80 mmHg, heart rate was 92 beats per minute (irregular), and oxygen saturation was 96% on room air. Physical examination revealed a 3/6 aortic ejection murmur and bibasilar crackles. She was on bisoprolol 5 mg qd, apixaban 5 mg bid, and furosemide 40 mg qd for atrial fibrillation and heart failure, and these drugs were well-tolerated. Electrocardiography (ECG) demonstrated atrial fibrillation, a QS pattern in leads V1–V3, and delayed R-wave progression on the precordial leads (Figure 1).

Figure 1.

Electrocardiogram of the patient at admission. Note that there were no low-voltage QRS complexes on precordial leads, but there were QS complexes on V1 to V3 and a delay in R progression.

Transthoracic echocardiography (TTE) revealed severe, normal-flow high-gradient AS (mean gradient 46 mmHg; calculated aortic valve area 0.69 cm² and indexed aortic valve area 0.46 cm²/m², stroke volume index 40.7 mL/m²) with heavy bi-leaflet calcification. Notably, there was severe left ventricular (LV) hypertrophy out of proportion to the afterload (posterior wall thickness 17 mm; relative wall thickness 0.76; LV mass index 233 g/m²). Additional findings included left atrial dilatation, moderate-to-severe right ventricular (RV) hypertrophy with normal RV systolic function and mild pulmonary hypertension. Global longitudinal strain (GLS) was reduced (−7.5%) with apical sparing (‘cherry-on-top’) pattern, with a preserved ejection fraction of 57% (Figure 2A–C) (Videos 1 and 2). Pre-procedural ECG-gated computed tomography was also consistent with severe left ventricular thickening (Figure 2D). The aortic calcium score was calculated as 1512 Agatston Units.

Figure 2.

Transthoracic echocardiographic images obtained from parasternal short axis views showing significant thickening of the left ventricle (A) and a calcified degenerative aortic valve (B). Panel C shows findings from speckle-tracking imaging, including a preserved ejection fraction, a low global longitudinal strain and the cherry-on-top sign. Significant thickening of the left ventricle is also seen on the ECG-gated cardiac CT images, along with a significantly calcified mitral valve annulus (D). Ao, aorta; AoV, aortic valve; CT, computed tomography; ECG, electrocardiography; LA, left atrium; LV, left ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle; RVOT, right ventricular outflow tract.

Given the disproportionate LV hypertrophy and apical sparing, a diagnostic work-up for amyloidosis was initiated. Serum and urine immunofixation, along with a free kappa/lambda ratio (1.43), ruled out light-chain amyloidosis. Technetium-99 m pyrophosphate scintigraphy demonstrated Grade 3 myocardial uptake, confirming the diagnosis of ATTR-CM (Figure 3).

Figure 3.

Whole-body bone scintigraphy imaging done with Technetium-99 m pyrophosphate tracer showing dense cardiac uptake together with a cardiac/lung uptake ratio higher than 1.5, consistent with cardiac amyloidosis.

The Heart Team opted for transcatheter aortic valve implantation (TAVI), viewing the high-gradient AS as the primary driver of her recurrent decompensation. Pre-procedural coronary angiography was unremarkable. Via a 16F right femoral approach, a 24.5 mm balloon-expandable valve was successfully deployed following balloon aortic valvuloplasty. As the patient had bulky aortic calcification and a relatively low left main ostium (annulus-to-left main ostial distance: 9.7 mm), a 3.5 × 10 mm balloon was pre-positioned in the left anterior descending artery for bailout protection for left main obstruction. Post-deployment aortography and TTE confirmed excellent valve function with trace paravalvular leak (Figure 4) (Video 3). Aortic pressure measured after valve deployment was 113/78 mmHg, and there was no dynamic left ventricular outflow gradient on TTE, thus ruling out post-deployment LV outflow tract obstruction (LVOTO).

Figure 4.

Angiographic images recorded during transcatheter valve implantation showing crossing the valve with a soft guidewire (A), balloon inflation in the aortic valve during valve implantation (B) and the implanted valve in the aortic annulus with minimal residual aortic regurgitation. A guidewire and balloon were placed in the left anterior descending artery prior to the procedure pre-emptively to bail out the left main ostium in case of acute occlusion. Ao, aorta; AoV, aortic valve; LMCA, left main coronary artery; LV, left ventricle; RV, right ventricle.

The patient was discharged on post-operative Day 2 on oral anticoagulation, bisoprolol, and furosemide. At the 1-month follow-up, she was able to climb a couple of stairs, corresponding to a NYHA Class II–III functional capacity. Her N-terminal pro-BNP levels dropped from 6747 pg/mL prior to procedure to 2718 pg/mL 1 month after the procedure. Given her excellent functional recovery, genetic testing was performed (confirming wild-type ATTR-CM), and treatment with tafamidis was initiated. At the 3-month follow-up, she remained asymptomatic with no further hospitalizations.

Discussion

The coexistence of ATTR-CM and AS presents unique diagnostic and therapeutic challenges. The diagnosis of ATTR-CM is often obscured because its clinical and echocardiographic hallmarks are easily misattributed to severe AS. Extracardiac manifestations of amyloidosis (e.g. neuropathy, orthopaedic manifestations, gastrointestinal symptoms, ‘normalization’ of hypertension) are frequently overlooked or mimic common geriatric complaints.^7,8 Similarly, the concentric LV ‘pseudo-hypertrophy’ of ATTR-CM may be dismissed as an expected compensatory response to AS, though wall thickness and LV mass are typically higher in dual pathology. Indeed, her LV mass (233 g/m²) far exceeded the expected compensatory hypertrophy (113 ± 21 g/m²) reported for severe AS alone.⁹ While an apical sparing pattern on GLS is highly specific for ATTR-CM in isolated hypertrophy, its diagnostic accuracy is diminished in the presence of AS, as severe AS alone can produce similar strain patterns.¹⁰ In our patient, the magnitude of LV thickening served as the primary ‘red flag’, while the history of a total knee replacement provided an additional clue that prompted further investigation.

Prognosis in coexisting ATTR-CM and AS is predominantly driven by the amyloid cardiomyopathy. The survival benefit of surgical or transcatheter valve replacement in this cohort remains an area of active investigation.^10–12 Observational data suggest TAVI confers a survival advantage over medical therapy alone, though results should be interpreted cautiously in the absence of dedicated randomized trials.¹³ Treatment decisions must be individualized, weighing frailty, LV function, and procedural feasibility. In our case, the patient's recent symptom onset, previously robust functional capacity, and preserved LV ejection fraction with high-gradient AS suggested a favourable trajectory post-intervention. TAVI is generally preferred over surgical valve replacement in this demographic to minimize perioperative morbidity.¹⁰

Given that ATTR-CM is characterized by increased wall thickness and small LV cavity volumes, pre-procedural planning for valve replacement must account for the risk of post-procedural haemodynamic collapse. This phenomenon, often termed the ‘suicide ventricle,’ is driven by dynamic LVOTO following the abrupt reduction in afterload. Anticipating dynamic LVOTO—documented even in isolated ATTR-CM with reduced contractility—is vital; therefore, optimizing pre-procedural hydration and avoiding overdiuresis or inotropes should be prioritized to minimize the risk of this potentially catastrophic complication.¹⁴

The role and timing of transthyretin stabilizers (e.g. tafamidis, acoramidis) in the context of uncorrected AS are debated. While effective in modifying the disease course of wild-type ATTR-CM, their high cost and time-dependent efficacy make patient selection critical.^15,16 Initiating costly, disease-modifying ATTR-CM therapy in a patient with untreated, symptomatic severe AS—a condition with an independently dismal prognosis—is clinically counterintuitive. Thus, in this case, we considered that prioritizing TAVI to relieve the haemodynamic bottleneck, followed by a period of ‘watchful waiting’ was reasonable. As the patient demonstrated meaningful functional recovery, the initiation of transthyretin stabilizers became clinically justified. Although a ‘one-fits-all’ approach could not be recommended for all similar cases, we consider that this stratified approach should be reasonable as a blueprint for these patients.

Conclusions

Elderly patients presenting with severe AS require a high index of suspicion for coexisting ATTR-CM. While the management of dual pathology remains complex, selected patients with high-gradient AS, preserved ejection fraction, and a recent symptom onset could be considered as candidates for valve intervention. A staged approach—relieving the valvular obstruction first, assessing functional recovery, and subsequently initiating long-term treatment with transthyretin stabilizers—offers a practical paradigm for managing these complex cases.

Lead author biography

Rengin Çetin Güvenç is currently an associate professor at the Department of Cardiology of Okan University Hospital in Turkey. Her research and clinical areas include adult congenital heart disease, heart failure, and multimodality cardiac imaging. She is a member of the Adult Congenital Heart Disease Group of the Turkish Society of Cardiology and the European Society of Cardiology.

Supplementary material

Supplementary material is available at European Heart Journal – Case Reports online.

Author contributions

Rengin Çetin Güvenç (Data curation, Investigation, Resources [lead], Writing—original draft, Writing—review & editing [equal]), Tolga Sinan Güvenç (Data curation, Investigation, Resources, Writing—review & editing [equal], Writing—original draft [lead]), and Müslüm Sahin (Investigation, Writing—review & editing [equal], Writing—original draft [supporting])

Consent: The authors confirm that informed consent has been obtained from the patient for the publication of this article in accordance with COPE guidelines.

Funding

This research received no specific grant from any funding agency.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.