Red Flags Suggesting Cardiac Transthyretin Amyloidosis (ATTR) in Clinical Practice

Cardiac amyloidosis

Amyloidosis is not a single disease but a group of diseases sharing a common feature: the extracellular deposition of misfolded, insoluble, fibrillar proteins in organ tissues [1, 2]. In the 19^th century, the botanical term amyloid, meaning starch or cellulose, was adopted to describe abnormal extracellular material in the liver [3]. Even though generaly considered a systemic disease, organ manifestation patterns vary between different types of amyloidosis. While multiple proteins are known to be capable of aggregating as amyloid, there are three relevant types of amyloidosis mainly affecting the heart (Figure 1): light-chain (AL) amyloidosis, hereditary/variant transthyretin amyloidosis (vATTR), and wild-type transthyretin amyloidosis (wtATTR), formerly known as senile amyloidosis. AL amyloidosis derives from misfolded immunoglobulin light chains as a result of a monoclonal gammopathy. It is a very serious, rapidly progressing, and irreversible disease which requires prompt diagnosis and therapy of the hematologic disease to avoid unfavorable prognosis [4, 5]. The second common type, transthyretin (TTR) amyloidosis, results from accumulation of the transport protein TTR, which is produced in the liver [1]. The hereditary form vATTR is a very rare disease, deriving from a mutated form of TTR, prone to misfolding. Depending on the mutation, the clinical picture may involve the heart, however it usually mainly affects the peripheral nervous system [6].

Even though its prevalence is unknown, it seems more and more obvious that wtATTR is the most common form of cardiac amyloidosis [1]. These patients, in most cases men over 60 years of age, usually present with heart failure, atrial fibrillation or stroke due to ATTR cardiomyopathy. However, also other organs can be affected, sometimes causing polyneuropathy and in most cases orthopedic problems. Often, the diagnosis is established rather late, since patients develop heart failure symptoms only after the deposition of large amounts of amyloid in the heart muscle. However, elevation of cardiac biomarkers as well as surgery for orthopedic/neurological problems – in particular bilateral carpal tunnel syndrome – often manifest years before this stage (Figure 2).

Due to the lack of therapeutic options the awareness of ATTR has stayed low for many decades, but in recent years novel and effective therapeutic concepts have been introduced, [7, 8] of which several are available in Switzerland [6]. Tafamidis in particular has been observed to have an impressive beneficial effect on mortality and morbidity in wtATTR as well as vATTR patients [9]. To ensure that patients can profit from these effective and evidence-based therapies, it is crucial to identify patients at risk and to establish the correct diagnosis.

Red Flags

Given the systemic nature of the disease, it is not surprising that red flags indicating cardiac amyloidosis can involve cardiac findings as well as extracardiac findings. Cardiac red flags (Figure 3) include signs and symptoms of heart failure (usually with preserved ejection fraction), a pathologic electrocardiogram (ECG), troponin elevation, elevated N-terminal fragment of prohormone brain natriuretic peptide (NT-proBNP), and typical findings in the echocardiogram as well as cardiac magnetic resonance imaging (CMR). ECG changes are non-specific and often include pseudo-infarction patterns (Q waves), poor R-progression in the precordial leads, and sometimes (but not so frequently) peripheral low voltage. Since the conduction system is also affected, high-grade atrioventricular block and bundle branch block are common [10]. Atrial amyloid causes atrial dysfunction leading to a high susceptibility to thrombus formation (even in sinus rhythm) as well as atrial tachycardia, atrial flutter, and very commonly atrial fibrillation. The echocardiogram typically reveals hypertrophied left and right ventricular walls (due to the amyloid deposition in the muscle) and relevant diastolic dysfunction. Strain analysis, assessing left ventricular myocardial deformation, very commonly exhibits a strain preservation pattern in the left ventricular apex with marked impairment at the base, called apical sparing or cherry-on-top sign [11]. In CMR, a typical patchy late gadolinium enhancement pattern is present [12]. Bone scintigraphy showing radiotracer uptake in the heart is part of the diagnostic algorithm for ATTR [13]. However, if conducted for other reasons, a cardiac signal can suggest cardiac ATTR as a coincidental finding.

Extracardiac red flags (Figure 4) include different musculoskeletal problems and polyneuropathy. Carpal tunnel syndrome affects >50% of wtATTR patients, is usually bilateral and requires surgery. Interestingly, the respective symptoms and surgery often precede the onset of heart failure by about eight years [14]. Recent studies found amyloid deposits in the excised tissue from the carpal tunnel, emphasizing the potential for early diagnosis prior to the development of cardiac symptoms [15]. Other common orthopedic problems are lumbar spinal stenosis and biceps tendon rupture [16]. In addition, patients with wtATTR need knee and hip arthroplasty three to five times more often and earlier than age- and sex-matched controls [17]. Furthermore, peripheral neuropathy (which is usually the main finding in vATTR) may also be present in wtATTR. It is most commonly symmetric, sensory, and might be easily missed [18].

Another very typical feature of ATTR patients is the intolerance of antihypertensive or heart failure medication, often because of orthostatic problems. In particular, betablockers are poorly tolerated because the augmentation of cardiac output depends on the ability to increase the heart rate due to the fixed and low stroke volume in ATTR. In addition, ATTR can be suspected in patients who needed antihypertensive medication for many years but begin to show normal or low blood pressure with age (caused by cardiac dysfunction).

Answers to the study questions

1. Answer d) is correct.

2. Answer c) is correct.