Abstract
“Amyloidosis” is a term that reminds us of our days in medical school because it was often tested in our pathology practical examinations and during general medicine examinations. However, most of us grew up even without making a diagnosis of cardiac amyloidosis (CA) in our clinical practice. The condition is now increasingly being recognized with advances in imaging and biochemical/pathology laboratory testing. With the rise in the aging population, its incidence is expected to increase. More importantly, there is increasing evidence that it is an under-recognized entity, and the recent data has kindled hope for new therapeutic strategies.
There are little data on CA in the Indian literature. As of early 1992, Talwar et al. 1 reported six cases of CA proven by endomyocardial biopsies in all cases. Only two of the six had suggestive features of echocardiography in their series. Raut et al. 2 could identify only six cases of CA from data spanning from 2008 to 2015. Certain features on echocardiography, late gadolinium enhancement (LGE) pattern on cardiac magnetic resonance (CMR), abdominal fat pad, and rectal biopsies were diagnostic in all. Mazumdar et al. 3 described a 56-year-old Indian patient who had syncope with heart failure. Echocardiogram suggested amyloidosis and fat pad histology confirmed amyloidosis. The study by Jain et al. 4 is published in this issue of IJCC. The authors showed that in a short span of 6 months, six patients were detected with echocardiographic features indicating CA. All of them could be confirmed as CA on bone marrow biopsy and other tests. The authors rightly concluded that a high degree of suspicion helps in early diagnosis.
The transthyretin cardiac amyloidosis (ATTR-CA) and light-chain amyloidosis (AL-CA) are the two common types of CA. ATTR-CA is more common than it was previously appreciated. In a recent paper, Scully et al. 5 observed that one in seven patients undergoing TAVR had occult CA; the incidence of CA among degenerative aortic stenosis is approximately 16%. Recent similar observations were made by Singal et al. 6 from AIIMS, New Delhi who studied 42 cases of severe aortic stenosis undergoing surgical replacement. Of them, ATTR-CA was detected in three by 99m-technetium pyrophosphate (PYP) scan. In their observation, examination of aortic valve specimens after aortic valve replacement surgery, approximately 72% showed amyloid deposits. They concluded that isolated valve amyloidosis is not uncommon.
Amyloidosis is a disease process in which altered (misfolded insoluble fibril) proteins get deposited in the extracellular spaces of various tissues due to an intrinsic tendency, excess protein production, or an abnormality or mutation of the native protein. Despite the wide spectrum of presentations, cardiac involvement is a major factor in deciding mortality. Heart failure with preserved EF (HFpEF), aortic stenosis, conduction disorders, arrhythmias, and thrombotic phenomena are the major cardiac manifestations. 7 Table 1 shows the major cardiac and extracardiac manifestations of amyloidosis. Clinically heart failure, especially in the elderly that is poorly responding to conventional therapies, associated musculoskeletal/neurological manifestations, proteinuria, nephrotic syndrome, and autonomic disturbances are highly suggestive to work up for CA.
Major Cardiac and Extra-cardiac Manifestations of Amyloidosis.
Electrocardiogram often reveals low-voltage complexes that are discordant with echocardiographic ventricular wall thickness (>12 mm). Other features on echocardiography include biatrial enlargement, thickened interventricular septum, speckled appearance of myocardium, preserved ventricular size, and systolic function with restrictive filling pattern with mild-to-moderate pulmonary hypertension and apical sparing with cherry on top pattern on strain imaging. Kyrouac et al. 8 suggested that apical sparing and increased left ventricular ejection fraction (LVEF)/global longitudinal strain (GLS) can identify the risk of patients for CA. LGE shows foci of deposits especially in the left ventricular and the atria. T1 mapping detects early infiltrative myocardial involvement. Myocardial T1 mapping time > 1048ms has a high sensitivity and specificity to differentiate it from hypertrophic cardiomyopathy. Serial measurement of extracellular volume is helpful in assessing the progress and response to treatment. 9 In a recent elegant study, 868 patients with the final diagnosis of cardiac light-chain (AL) amyloidosis (n = 222), cardiac transthyretin (ATTR) amyloidosis (n = 214), and amyloidosis without cardiac involvement (n = 427) were subjected to CMR with LGE, T1 mapping, and other relevant tests. T1 was elevated in both types of CA and showed high diagnostic accuracy. Native T1 >1164ms had a 98% positive predictive value for CA and a cutoff value of < 1036ms was associated with a 98% negative predictive value. These authors proposed that LGE studies can be limited to the intermediate zone of these cutoffs. 10 CMR is emerging as a very useful test for the evaluation of cardiomyopathies and heart failure, including CA, which is now increasingly available in most cities and larger towns of India. Testing for monoclonal proteins by serum/urine electrophoresis with immunofixation, serum free light chain ratio, bone marrow study, tests specific for ATTR amyloidosis such as Tc-PYP (pyrophosphate scan), and TTR genetic studies can help in more precise diagnosis, guiding therapy, and prognostication. Immunological analysis is needed to precisely diagnose the type of CA, which helps in choosing the specific therapy.
For TTR amyloidosis, silencing the expression of TTR protein and their dissociation into amyloidogenic fragments is an effective strategy to control CA. Patisiran is a TTR gene silencer used in TTR-CA with polyneuropathy. Tafamidis has been found to stabilize TTR tetramers and inhibit protein dissociation and can be used for both wild-type/acquired and hereditary types. Mauer et al. 11 observed promising results with Tafamidis in reducing CV hospitalizations by 32% (versus placebo) and a reduction in all-cause mortality in CA. Additionally, myocardial function and quality of life also improved. For AL-CA chemotherapy with bortezomib, lenalidomide and dexamethasone were reported to cause remission and improve survival. Kastritis et al. 12 successfully treated AL-CA with Daratumumab (monoclonal anti-38 antibody) along with cyclophosphamide and dexamethasone. For a select for few, autologous stem cell transplantation is an option in AL-amyloidosis. Digoxin is contraindicated and diuretics, angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers may be used with increased caution. Supportive therapies like anti-coagulants are used as per conventional indications. There is a progressive deterioration of most patients in the absence of effective treatment. Overall prognosis is guarded in the advanced stages.
In essence, CA is not an uncommon entity. Newer diagnostic and treatment options are increasingly available, and benefit a subset of our patients, especially if detected early in the course of the disease. CA should be considered a differential for any cardiomyopathy in the elderly. High index of suspicion is needed to diagnose and appropriately manage these patients.