Amyloid Cardiomyopathy

Amyloid cardiomyopathy (cardiac amyloidosis) is a form of restrictive cardiomyopathy that can result in significant progressive diastolic congestive heart failure.

As the name suggests, amyloid cardiomyopathy results from the accumulation of amyloid — fibrous, insoluble protein aggregates — in the heart muscle. Amyloid aggregates can form from a number of different proteins — indeed, more than 30 proteins have to date been identified as amyloidogenic in vivo. [Kittleson 2020;1a] Thus, a number of distinct disease entities are grouped together under the general term “amyloidosis.”

Amyloid cardiomyopathy is just one possible manifestation of amyloidosis, as organs other than the heart can also be affected by pathogenic amyloid deposition. [Benson 2020;1a] Furthermore, amyloid deposition can occur in any heart tissue, including the endocardium, valves, myocardium, epicardium and parietal pericardium. However, the deposition in the myocardium, where amyloid infiltration disrupts calcium transport, receptor modulation, and cellular metabolism, causes restrictive cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). [Ash 2020;5b]

Amyloidoses which can affect the heart include:

• Amyloid light-chain (AL) amyloidosis (also known as primary amyloidosis), caused by aggregation of monoclonal kappa or lambda light chains. [Yancy 2013;15a]
• Serum amyloid A (AA) amyloidosis (also called secondary amyloidosis), caused by aggregation of the inflammatory protein serum amyloid A. [Yancy 2013;15a; Ash 2020;3a,4d]
• Transthyretin (TTR) amyloidosis, caused by aggregation of its eponymous protein, which can be divided into two distinct types:

• Hereditary (or familial) TTR amyloidosis is caused by a number of point mutations in the TTR gene which increase the likelihood for the normal TTR tetramer protein to dissociate into monomers, which form amyloids. It is inherited in an autosomal dominant fashion. [Yancy 2013;15a; Muchtar 2017;3e]
• Wild-type (also known as sporadic and [now rarely] senile) TTR amyloidosis is caused by aggregation of the wild-type (non-mutant) TTR protein, and is largely restricted to men aged older than 60 years. [Yancy 2013;15a; Ash 2020;3b]
• Dialysis-associated amyloidosis, caused by aggregation of beta-2-microglobulin. [Yancy 2013;15a]

Of the cardiomyopathy-causing amyloidoses listed above, the most common are AL amyloidosis and hereditary and wild-type TTR amyloidosis. [Muchtar 2017;3g] It is these three cardiac amyloidoses (CAs) that are the focus of this topic review.

Amyloid Cardiomyopathy - Pathophysiology

Both AL and TTR cardiac amyloid deposits disrupt the normal function of the myocardium and other heart tissues. Amyloid is deposited in both ventricles, but signs of right HF (including pedal edema, raised jugular-venous pressure, ascites and hepatomegaly) are more commonly seen. [Ash 2020;4c]

HF caused by AL cardiac amyloidosis is typically more severe than that caused by TTR cardiac amyloidosis; myotoxicity caused by circulating light chain-induced oxidative stress has been invoked to explain this difference, although the cause remains unknown. [Ash 2020;3c,5a] AL cardiac amyloidosis may also cause rhythm disturbances, and atrial fibrillation may develop as the amyloidosis progresses. [Ash 2020;5b]

The pathophysiological manifestations of TTR cardiac amyloidosis depend on the origin (hereditary or wild-type), with rhythm disturbances being more common in wild-type TTR cardiac amyloidosis. The characteristics of hereditary TTR cardiac amyloidosis also depend on the specific amino acid substation found in the mutant protein, with some mutations causing conduction issues and others causing cardiovascular system dysfunction. [Ash 2020;5b]

Amyloid Cardiomyopathy - Diagnosis

Cardiac involvement with amyloid should be part of the differential diagnosis when 2D and Doppler echocardiographic findings are consistent with HF with preserved or borderline left ventricular function.

The gold standard for diagnosing cardiac amyloidoses is histopathological examination of endomyocardial tissue samples, which documents the presence and composition of amyloid deposits. However, endomyocardial biopsies are invasive procedures that involve small, but not negligible, risks. Biopsy of noncardiac sites such as fat pads or bone marrow offers an alternative; the sensitivity of fat pad biopsy for detection of AL cardiac amyloidosis is acceptable (84%) but is much lower for TTR (45% for heritable; 15% for wild-type). In addition, several noninvasive diagnostic modalities have been developed, with varying rates of specificity and sensitivity. [Ash 2020;7c]

AL cardiac amyloidosis may be detected though the use of serum and urinary quantitative free light chain (FLC) measurements and immunofixation electrophoresis (IFE) to calculate the kappa/gamma free light chain ratio, since the ratio is abnormal in more than 90% of untreated AL cardiac amyloidosis cases. However, other serious conditions, including multiple myeloma, can also affect the ratio. Therefore, a potential diagnosis should be confirmed via bone marrow biopsy or other tests with high specificity. [Ash 2020;6a]

TTR cardiac amyloidosis can be detected via technetium pyrophosphate scintigraphy (PYP scan). This nuclear imaging technique is less invasive, but still requires injection of a radioactive tracer molecule (TC-PYP), which binds to amyloid fibrils and allows for their detection throughout the body. PYP scintigraphy has high (> 90%) sensitivity and specificity for identifying TTR cardiac amyloidosis, can detect TTR amyloid before the onset of pathological anatomical and electrophysiological changes, and, in the context of normal kappa/lambda light chain ratios, permits accurate differentiation between TTR and AL cardiac amyloidosis. [Ash 2020;7b,7e] These qualities distinguish it from other imaging modalities, including echocardiography and cardiac MRI (CMR), which can provide diagnostically useful data but cannot easily distinguish one amyloid cardiomyopathy from another. [Ash 2020;6d,7a]

The wild type and hereditary forms of TTR cardiac amyloidosis can be distinguished by genetic testing (genotyping) at the TTR locus. This is typically performed after TTR cardiac amyloidosis has been diagnosed by cardiac biopsy or PYP scanning. It is important to discriminate between the inherited and sporadic form of TTR cardiac amyloidosis, as both treatment decisions and the need (or lack thereof) for genetic counseling are informed by TTR genotype. [Ash 2020;6d,7a]

Electrocardiography can be useful in the diagnosis of cardiac amyloidosis, as there are several characteristic features, including low voltage QRS complexes in the limb leads and poor R-wave progression in the precordial leads. [Ash 2020;6b]

Below is an ECG from a patient with amyoloid cardiomyopathy. Note the low voltage despite left and right ventricular hypertrophy on echocardiography.

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