Cardiac Amyloidosis: An Updated Review With Emphasis on Diagnosis and Future Directions

Author’s Accepted Manuscript Cardiac Amyloidosis- An Updated Review with Emphasis on Diagnosis and Future Directions Sukhdeep Bhogal, Vatsal Ladia, Puja Sitwala, Emilie Cook, Kailash Bajaj, Vijay Ramu, Carl J. Lavie, Timir K. Paul www.elsevier.com/locate/buildenv

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S0146-2806(17)30070-1 http://dx.doi.org/10.1016/j.cpcardiol.2017.04.003 YMCD345

To appear in: Current Problems in Cardiology Cite this article as: Sukhdeep Bhogal, Vatsal Ladia, Puja Sitwala, Emilie Cook, Kailash Bajaj, Vijay Ramu, Carl J. Lavie and Timir K. Paul, Cardiac Amyloidosis- An Updated Review with Emphasis on Diagnosis and Future D i r e c t i o n s , Current Problems in Cardiology, http://dx.doi.org/10.1016/j.cpcardiol.2017.04.003 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Cardiac Amyloidosis- An Updated Review with Emphasis on Diagnosis and Future Directions Authors Sukhdeep Bhogal1, Vatsal Ladia2, Puja Sitwala2, Emilie Cook3, Kailash Bajaj1, Vijay Ramu2, Carl J. Lavie,4 Timir K Paul2

Affiliations Department of Internal Medicine, East Tennessee State University1 Division of Cardiology, East Tennessee State University2 Department of Pathology, East Tennessee State University, Johnson City, TN, USA 3 Department of Cardiology, Oschsner Clinical School-the University of Queensland School of Medicine, New Orleans, LA, USA4

Corresponding author: Timir K Paul, MD, PhD 329 N State of Franklin Rd Johnson City, TN 37604 Phone: 423-979-4100 Fax: 423-979-4134 Email: [email protected] Conflict of interest- None

Abstract Cardiac amyloidosis occurs as a result of abnormal protein (amyloid) deposition in the cardiac tissue. Even with advanced diagnostic techniques and treatments, the prognosis of amyloidosis remains poor. The diagnosis of cardiac amyloidosis particularly needs to be in the differential in patients presenting with heart failure with preserved ejection fraction. This entity remains underdiagnosed due to lack of suspicion on the part of many clinicians. Involvement is cardiac tissue is the utmost determinant factor for available treatment options and prognosis. Many cases of cardiac amyloidosis usually remain undiagnosed or diagnosed only in advanced stages when treatment options are limited and associated with poor survival. Hence, early recognition of cardiac amyloidosis is indispensable in halting the disease process before irreversible changes occurs. The purpose of this review is to summarize the recent updates in the evaluation and management of cardiac amyloidosis and discuss potential future treatments options.

Introduction Amyloid is defined as the extracellular tissue deposition of amyloid fibrils which are comprised of low molecular weight subunit proteins. Cardiac amyloidosis in one of the common infiltrative cardiomyopathies associated with an unfavorable prognosis. The pathophysiology involves the adoption of normal protein into an amyloid state, resulting from cleavage, denaturation or excess production of abnormal protein, 1 which eventually assume antiparallel beta-pleated sheet configuration forming amyloid fibrils. Clinical outcome depends on the extent of tissue involvement and the type of amyloid fibril deposits.

Types of Amyloidosis The major subtypes of systemic amyloidosis classified based on the underlying etiologies are: Primary (AL) amyloidosis, Secondary (AA) amyloidosis (or reactive amyloidosis), Familial amyloidosis (ATTR or hereditary amyloidosis), Dialysis related amyloidosis and Senile systemic amyloidosis (SSA; Table 1). Of these, AL, ATTR and SSA commonly involve the myocardium. However, AA rarely impacts the cardiac function.

Primary Amyloidosis Being a relatively rare but rapidly progressive disease, the amyloid fibrils in AL are composed of monoclonal light chains and is usually associated with plasma cell disorders, such as multiple

myeloma or other B cell dyscrasias. Cardiac involvement is common in primary amyloidosis and is a crucial factor for determining the clinical prognosis. Mortality is high when cardiac involvement is present and prognosis remains poor.

Familial or Hereditary Amyloidosis Transthyretin, also called TTR or preablumin gene, is located on the long arm of chromosome 18, and more than 120 TTR mutations have been described in the literature, and almost all of them are found to be amyloidogenic. Mutations could be at a single location, compound mutations or deletions 2 and manifest as an autosomal dominant pattern of inheritance. Most patients with ATTR have heterozygous mutations of TTR. While non-cardiac manifestations, such as polyneuropathy, ocular infiltration, alteration of autonomic function are present with some TTR mutations in European or Japanese populations, cardiac manifestations are frequently noted in United States (US) populations, more commonly in African Americans and frequently result from mutations causing substitution of isoleucine for valine at 122 position (Val 122l1e mutation) 3, which is the most frequent mutation present in the US.

Senile Systemic Amyloidosis Also known as wild type transthyretin (TTRwt), a transport protein synthesized by liver, SSA usually involves male populations predominantly more than 70 years of age. Other tissues infiltrated by this amyloidogenic protein are pancreas, brain, kidneys, and lungs. This disease is less aggressive than AL because of slower rate of disease progression. After suspicion, endomyocardial biopsy is required due to isolated cardiac involvement in most cases; SSA is the diagnosis of exclusion after ruling out AL and ATTR 4.

Types

Primary Light chain amyloidosis

Familial amyloidosis

Nomenclature Epidemiology

AL Exact incidence is unknown, estimated incidence is 6-10 cases per 1,000,000 population

ATTR 3.5 -4 % of AfricanAmericans in US with Val 7 122lle mutation

SSA or ATTRwt 1-2% in blacks and 0.4% 8 in non-Hispanic whites

Median age 60-75 years, 6 >60 % cases are men

Variable according to mutations, Val122l1e mutation almost always 3 more than 60 years Variants of transthyretin 2 with >120 mutations HFpEF, atrial/ventricular arrhythmias and first/second degree or 3 advanced heart block Hepatomegaly, nephrotic syndrome, purpura, easy bruising, carpel tunnel, peripheral 3 polyneuropathy

Predominantly males, 3, age more than 70 years

Technetium pyrophosphate, Genetic testing, EMB (47,50,53)

Diagnosis of exclusion, EMB (4,53)

5

5

Senile cardiac amyloidosis 5

6

Age

9

Protein involved

Monoclonal light chain

Cardiac features

HFpEF, atrial/ventricular arrhythmias and first/second degree or 9 advanced heart block Characteristic findingsPeri-orbital edema and macroglossia Other findingsHepatomegaly, nephrotic syndrome, purpura, easy bruising, carpel tunnel, peripheral 9 polyneuropathy

Extracardiac features

Diagnostic modalities

Treatment

serum protein electrophoresis, urine protein electrophoresis, detection of serum free light chains, EMB (17,53) Heart failure therapy, chemotherapy, Heart transplant followed by autologous stem cell transplant (22,58-60,6373)

Heart failure therapy, chemotherapy, orthotropic liver transplantation, combined liver and heart transplant, new novel agents (58-60,74-83) HFpEF-Heart failure with preserved ejection fraction, EMB- Endomyocardial Biopsy

4

Wild type Transthyretin

5

HFpEF, atrial/ventricular arrhythmias and first/second degree or 4 advanced heart block Bilateral carpel tunnel 10, 11 syndrome

Heart failure therapy, Isolated heart transplant, new novel agents (11,5860,84)

Table 1- Summarizes various types of amyloidosis with brief clinical features, diagnostic modalities and treatment

Clinical Manifestation of Cardiac Amyloidosis Symptoms While systemic involvement of amyloidosis varies according to organ involvement, cardiac manifestations predominantly include symptoms of right sided heart failure (HF). Infiltration of amyloid fibrils results in stiffening and thickening of ventricles causing decreased compliance and increased pressure altering the mechanics of ventricular function manifesting as diastolic dysfunction (DD). Furthermore, cytotoxic effects of amyloid fibrils result in apoptotic and fibrotic changes, thus eventually causing systolic function. This leads to presenting symptoms of HF, such as dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, abdominal distension and lower extremity edema. Involvement of cardiac conduction system causes first degree, second degree or advanced heart block or arrhythmias that can be symptomatic secondary to direct amyloid deposits in conduction system or due to ischemia resulting from it 3. Syncope can be due to heart block or arrhythmias and could be an indicator for poor survival outcome 12. Atrial fibrillation (AF) is the most common arrhythmia described in approximately 10-20% of patients and heightens the risk of thromboembolism 13. In one study, complex ventricular arrhythmias were seen almost in half of the patients 14. Sudden cardiac death (SCD) can occur and is likely due to electromechanical dissociation (EMD) instead of ventricular arrhythmias 12. Also, angina or infarction can occur in patients with amyloid deposition in coronary arteries 15. Pleural and pericardial effusion is seen with the advanced cardiac dysfunction. Regardless of type, cardiac amyloidosis generally presents as restrictive cardiomyopathy with DD and eventually ensue biventricular systolic dysfunction.

Physical Examination Physical examination could be of high yield even though there is no pathognomonic finding or sign. Patients could be completely asymptomatic or may present with various signs and symptoms. Careful inspection may reveal elevated neck veins or elevated jugular venous pressure (JVP). The apical beat is generally not shifted and could be barely palpable or impalpable in advanced stages. Right sided S3 can be evident in advanced cases of right sided ventricular dysfunction. Even though this is typically a restrictive cardiomyopathy resulting in loss of relaxation function of ventricle, the fourth heart sound is an exceedingly rare finding secondary to loss of atrial kick due to atrial amyloid infiltration 16. It also explains associated finding of loss of a wave on JVP. Hypotension or resolving hypertension in previously hypertensive patients could be seen as a result of low cardiac output. Orthostatic hypotension may be present in patients secondary to autonomic neuropathy.

Extracardiac manifestations should also be examined carefully in suspicious cases, which may include purpura, bruising, macroglossia or peri-orbital ecchymosis. Hepatomegaly and ascites are seen in advanced cases of right heart HF. A history of bilateral carpel tunnel syndrome could be an important clue for the patients suspected for SSA 10, 11. Nephrotic syndrome in AL and HF or hypoalbuminemia secondary to liver failure in ATTR can lead to progressive lower extremity edema. Painful neuropathy could be another nonspecific sign demanding additional work up in suspected cases.

Diagnostic Modalities for Cardiac Amyloidosis In suspected cases of cardiac amyloidosis, diagnostic approach is depicted in Figure 4 and 5. Table 2 summarizes the characteristic findings, early diagnostic findings, sensitives and specificity for various modalities for diagnosis of amyloidosis. Except for clinical findings, laboratory and non-invasive tests are the main next steps in the diagnosis of amyloidosis.

Laboratory As AL amyloidosis is mostly associated with plasma cell disorder, further evaluation should be undertaken to detect paraproteinemia or monoclonal proteins, which include serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), immunofixation electrophoresis and detection of serum free light chains. Serum free light chain is a quantitative test which can detect light chains with higher sensitivity than immunofixation electrophoresis 17. It measures the kappa to lambda ratio that ranges from 0.26 – 1.65 with ratio more than 1.65 suggesting the abundance of kappa light chain and less than 0.26 the abundance of clonal lambda chains. The presence renal failure results in decreasing the sensitivity from 81% to 60% 18. Serum free light chain testing is usually done by freelite technique, which is currently the gold standard. Recently, mass spectrometry, another evolving technique, can quantitatively measure the monoclonal light chains and replaces the need for kappa to lambda ratio 19.

Role of B-Type Natriuretic Peptide Local myocyte destruction along with wall stress results in elevated levels of troponins and Btype natriuretic peptide (BNP) or N-terminal pro BNP (NT- pro BNP). If seen along with AL, elevated BNP levels considered as a marker of cardiac involvement even before the onset of HF. Although BNP levels are elevated in all causes of HF and are non-specific, but they do have prognostic value in cardiac amyloidosis. In a Mayo clinic study 20, patients were categorized as Mayo stage I, II and III based on the levels of following biomarkers; NT- proBNP (≥332 pg/ml)

and cardiac troponin T (≥0.035 ng/ml) or troponin I (≥ 0.1 ng/ml). Stage I patients had none, stage II patients had either one of these and stage III patients had both aforementioned findings. This study demonstrated median survival of 26, 11 and 4 months in stages I, II and III, respectively, demonstrating their role as risk stratification in AL. Elevated NT-BNP is a sensitive marker of cardiac infiltration and particularly levels more than 152 pmol/L are associated with grim prognosis in AL 21. Also, serial measurement of NT-proBNP after chemotherapy is an important tool to assess survival outcomes 22. Recently, new novel biomarkers, named as soluble ST2 and galectin -3, serving as a marker of cardiac remodeling and fibrosis, has been demonstrated to have prognostic value in HF, myocardial infarction and AL 23, 24. There is no single noninvasive test pathognomonic of cardiac amyloidosis. Various modalities such as the electrocardiogram (ECG), echocardiography (Echo), cardiac magnetic resonance imaging (CMR), tissue biopsy and 99m-technetium pyrophosphate scanning (99mTc-PYP) are being used to establish the diagnosis.

Electrocardiogram The ECG is one of the easily available and cost effective modality that can provide invaluable information regarding the underlying disease. Amyloid fibrils lead to deposition of completely electrically silent material in the myocardium which is not detected by ECG. It results in low voltage in limb leads (<5 mm) and poor R wave progression, also known as pseudoinfarction pattern. This finding has been demonstrated in up to half of patients with AL 25. Furthermore, these deposits also result in various arrhythmias, such as various heart blocks, AF and complex ventricular tachycardia. The sum of amplitudes of S wave in V1 and R wave in V5 or V6 26 more than 3.5 mV is considered as a measure of left ventricular hypertrophy (LVH) and less than 1.5 mV are found to be associated with dismal outcomes in all three types of amyloidosis with cardiac involvement 27. The concentric LVH along with low voltage on the ECG is suspicious for amyloidosis but it does not hold a sequential relationship with it 28. Also, combined R wave voltage in I and aVR has better sensitivity and specificity of almost around 90% for distinguishing amyloidosis from nonobstructive hypertrophic cardiomyopathy 29.

Echocardiogram The Echo is recommended in all patients with suspected amyloidosis, and findings include biatrial enlargement, thickening of ventricular wall and/or valves, decreased diastolic filling and classic granular sparkling appearance. However, none of these findings are specific for diagnosing amyloidosis. It is important to individually correlate the findings based on the clinical presentation and case suspicion. For example, thickened left ventricular wall in patients without history of hypertension is peculiarly suspicious. The wall thickness is attributed to infiltrative amyloid deposition instead of myocytes hypertrophy 30. Frequently, DD, particularly the abnormal relaxation of the ventricle, is seen in early stages 31. If remain undiagnosed, DD worsens and reaches to a point where systolic dysfunction ensues. Decreased left ventricular ejection fraction (LVEF) is of grim prognostic significance 32. Recently, myocardial contraction fraction, computed by dividing stroke volume to myocardial volume, is found to exhibit better prognostic value as compared to LVEF 33. Doppler Imaging has particularly revolutionized the world of cardiac imaging in terms of assessing cardiac amyloidosis. Doppler measurements include the assessment of ratio (E/A) of early (E) and late (A) diastolic peak velocities along with deceleration time (time taken by peak E velocity to return to baseline). Klein et al has demonstrated that findings such as short deceleration time and increased early diastolic filling velocity to atrial filling velocity has prognostic significance for mortality assessment 31. Assessing strain and strain rate (longitudinal axis dysfunction) using Doppler can reveal cardiac amyloidosis in its subclinical stages 34 and is helpful in determining the survival outcomes. With advances in imaging techniques, development of speckle tracking echo, overcoming the limitation of Doppler imaging, is a much better tool for analyzing the longitudinal axis, particularly radial and circumferential strain. The significant decrease of longitudinal strain in the mid and basal-wall regions with relative preservation of the apical region have been found to be diagnostic findings in patients of cardiac amyloidosis with high sensitivity and specificity ranges from 90-95% and 80-85%, respectively 35. Nevertheless, even with advancement in technologies, there are no specific findings that can be used to diagnose amyloidosis based on echo alone.

Cardiac Magnetic Resonance Imaging Recently, CMR is an important diagnostic and prognostic tool in the assessment of severity of cardiac amyloidosis. Various techniques are currently used and include strain analysis and tissue imaging with contrast and without contrast. Strain analysis based on CMR can be accomplished with the recent advances, a technique known as Displacement Encoding with Stimulated Echoes with high sensitivity and specificity close to echo 36. Though not extensively studied in amyloidosis patients, it is a highly precise

modality and hold promises in generation of strain time curves with “tissue tracking” techniques. In contrast, CMR is the most studied technique for diagnosis of amyloidosis. Injury to the myocardium secondary to deposition of amyloid fibrils in interstitium serves as a reservoir for gadolinium accumulation leading to characteristic late gadolinium enhancement (LGE) 37 (Figure1). This technique has a sensitivity of close to 80% and impressive specificity of 94% 38. Syed et al has demonstrated that global transmural or diffuse subendocardial LGE could be invaluable to detect amyloidosis in early phase even before the onset of left ventricular wall thickening and has correlation with the severity of disease 39. Recently, another study showed that transmural LGE is more prevalent in ATTR (97%) as compared to AL patients (37%) 40. However, LGE imaging poses some limitations in terms of a) diffuse enhancement of myocardium resulting in difficulty analyzing normal versus abnormal myocardium especially in ATTR patients 37, b) missing patchy myocardial involvement and c) underappreciating disease burden as compared to 99mTc-PYP 41. These limitations can be addressed by the use of new advances, which includes visual T1 tissue enhancement, quantitative T1 mapping and phase correction recovery LGE imaging technique. T1 tissue enhancement is simply based on the concept of accumulation of contrast in the extracellular space results in short inversion time (T1). This leads to delayed hyperenhancement of extracellular space when compared to normal cardiac tissue. This hyperenhancement is usually not limited to single coronary artery territory in amyloidosis. In suspected patients of cardiac amyloidosis, it has found to have an impressive diagnostic and prognostic value 42. Visual T1 mapping imaging is based on the concept of assessing images pre-and postgadolinium contrast and reconstructing images in the form to generate T1 maps of voxels representing T1 relaxation time of the relative cardiac tissue. By comparing pre and post contrast mapping, extracellular volume can be calculated 43. Short T1 time and large extracellular volume represents the accumulation of amyloid fibrils in the extracellular matrix. Recently, Benyaparsad et al found that in patients with AL amyloidosis, non-contrast T1 mapping demonstrated prolonged relaxation time in the cardiac tissue with a strong promise to diagnose amyloidosis in subclinical stages as well as quantifying the severity of cardiac involvement 44. LGE when coupled with phase-sensitive inversion recovery has shown to provide a better assessment of the extent of cardiac involvement. This evolving new technique overcomes the limitations of T1 imaging by adjusting the signal intensities to accurate the wrong inversion times. Recently, Fontana et al in patients with AL and ATTR classified patients in three subcategories (normal, subendocardium and transmural) based on phase-sensitive inversion recovery LGE images 45. Of these, transmural is associated with the worst prognosis, with a 5.4fold increase in mortality. They also formulated that progression of

normalsubendocardiumtransmural LGE reveals proportional relationship with extracellular volume expansion 45. Altogether, CMR is an invaluable tool to establish the diagnosis of amyloidosis.

Nuclear Imaging Use of radiotracers has been used to diagnose amyloidosis. Most commonly, 99mTc-DPD (technetium-3, 3-diphosphono-1, 2-propanodicarboxylic acid) and 99m Tc- PYP is used. The exact mechanism by which these radiotracers accumulate in myocardium is not clear, although various hypotheses have been proposed. Of these, one suggests that phosphate in the radiotracers binds to high calcium level in the amyloidosis 46. Another hypotheses is based on duration of amyloid deposition which occurs in less time frame in AL patients relative to more

indolent course of ATTR patients 47. As 99m Tc- PYP preferentially binds to ATTR relative to AL fibrils, this technique also serves as a noninvasive way to distinguish the aforementioned amyloidosis subtypes 47. 99m

Tc- DPD is not approved by the Federal Drug Administration in the US but has been mainly used in Europe and was found to have high sensitivity for patients with ATTR. In two studies, the specificity was found to be ranging from 70% 48 to 100% 49 to distinguish ATTR patients from AL. On the other hand, 99m Tc- PYP is available in the US, which is used by Bokhari et al by calculating heart to contralateral ratio score and found that ratio score >1.5 had excellent sensitivity and specificity of 97% and 100%, respectively in differentiating ATTR and AL amyloidosis 47. In this study, AL patients were also found to have radiotracer uptake but calculating heart to contralateral ratio score can differentiate ATTR from AL. 99m Tc- PYP was also used in a study by Yamamoto et al based on the concept of PYP score. It is calculated by the ratio of myocardial mean count to the ventricular mean count and found to have a sensitivity of close to 84% and specificity close to 94%, 50 differentiating cardiac amyloidosis patients from other types. Positron emission tomography (PET) offers higher spatial resolution than other nuclear imaging, but it has sparse data as a diagnostic imaging in patients of amyloidosis. One of the studies using tracer N [methyl-(11) C]2-(4-methylamino-phenyl)-6-hydroxybenzothiazole((11)C-PIB) revealed that there was selective tracer uptake in ATTR and AL amyloidosis relative to healthier volunteers 51. Most recently, a pilot study using 18F-florbetaben as a tracer found higher percentage of tracer accumulation in amyloidosis patients as compared to hypertensive heart disease patients, differentiating the two 52. The scope of PET imaging needs to be further explored as a non-invasive diagnostic utility in amyloidosis. In conclusion, nuclear imaging offers a diagnostic and prognostic value in amyloidosis particularly in ATTR patients.

Histopathological diagnosis Besides all these modalities, biopsy with histopathology remains the gold standard showing deposition of amorphous deposits of amyloid fibrils as shown in Figure 2. With advancement in techniques, various methods have been evolved for the tissue diagnosis. Endomyocardial biopsy (EMB) is a relatively safe procedure with sensitivity of almost 100% for diagnosing amyloidosis 53. But it is not always necessary to perform EMB, as diagnosis can be suggested by alternative tissues, such as abdominal fat, rectal tissue and other involved organs. Fine needle aspiration is a simple, quick technique that have been used to diagnose amyloidosis with overall positive results in 88% of cases 54, having a sensitivity of approximately 75% and specificity of 92% 55. If diagnosis remains unconfirmed even after biopsy of another tissue but index of suspicion is high, EMB would be the next step and gold standard for the diagnosis 56.

The amyloid fibrils lead to characteristic apple green birefringence under polarized light microscopy by binding to Congo red stain, as shown in Figure 3 and to Thioflavin producing an intense yellow-green fluorescence. On electron microscopy they are straight, rigid and with unbranching pattern along with 8-10mm width 57.

Figure 2- showing deposition of amorphous deposits of amyloid fibrils on tissue biopsy

Figure 3- Amyloid fibrils leads to characteristic apple green birefringence under polarized light microscopy by binding to Congo red stain.

Diagnostic modalities

Characteristic findings

Echocardiography

1.Granular sparkling appearance

Strain imaging

2. Significant decrease in longitudinal strain in the mid and basal wall regions with relative preservation of apical region of longitudinal strain 35 LGE 37

CMR

Visual T1 mapping imaging

Early diagnostic finding Abnormal relaxation of ventricle 31

Sensitivity and Specificity

Sensitivity and specificity ranges from 90-95% and 8085% respectively 35

Global transmural or diffuse subendocardial LGE 39

Sensitivity close to 80% and specificity of 94% 38

Prolonged relaxation time in the cardiac tissue in AL amyloidosis 44

99m

Tc- PYP

Endomyocardial biopsy- Gold standard

Heart to contralateral ratio score >1.5 is significant in differentiating ATTR and AL amyloidosis 47 Deposition of amorphous deposits of amyloid fibrils

Fine needle Deposition of aspiration of involved amorphous deposits of organs amyloid fibrils

Sensitivity of 97% and specificity of 100% 47

Sensitivity close to 100% 53

Sensitivity of 75% and specificity of 92% 55

CMR- Cardiac magnetic resonance imaging, 99m Tc- PYP- Technetium pyrophosphate, LGE- Late gadolinium enhancement, AL- Primary amyloidosis, ATTR- Familial amyloidosis Table 2- Summarizes the characteristic findings, early diagnostic findings, sensitives and specificity for various modalities for diagnosis of amyloidosis

Diagnostic approach in Cardiac amyloidosis

Figure 4- Showing diagnostic work up flow chart in suspicous cases of Amyloidosis EKG- Electrocardiogram, BNP- Brain Natriuretic peptide, Echo- Echocardiography, CMR- Cardiac Magnetic Resonance Imaging

Figure 5- Showing diagnostic flow chart for diagnosing individual Amyloidosis AL-Primary amyloidosis, AA- Secondary amyloidosis, TTR- transthyretin, SSA- senile systemic amyloidosis, 99Tc-PYP- Technetium pyrophosphate

Treatment of Amyloidosis The prognosis of cardiac amyloidosis is poor in general, yet it depends on the type of amyloidosis. Treatment can be divided into HF therapy, specific therapy for each amyloidosis, along with organ transplantation, as well as future new novel agents currently under trials.

Heart Failure Therapy Supportive therapy for HF includes the use of loop diuretics, which are the mainstay of the treatment along with fluid and salt restriction. Often judicious use is required and maintaining adequate fluid balance is difficult, as these patients are preload dependent. While Angiotensin Converting Enzyme Inhibitors and Beta-Blockers (BBs) are the cornerstone of treatment for other cardiomyopathies, they might be contraindicated in amyloid cardiomyopathy, as they could worsen renal function or lead to postural hypotension. Calcium Channel Blockers are also not helpful and can even worsen left ventricular function 58. Digoxin is generally avoided as it can bind to amyloid fibrils causing toxicity 59 and should be used only if patient develops AF with associated hypotension limiting the use of BBs. Along with pharmacotherapy, patient education on HF is an important key for successful management. Recurrent or resistant pleural effusion generally indicates involvement of pleura by amyloid infiltration and requires pleural tap or pleurodesis 60. Anticoagulation with warfarin or other newer anticoagulants (dabigatran, rivoroxaban, apixaban) is strongly recommended in patients with AF secondary to increase risk of stroke unless contraindicated.

Pacemaker and Implantable Cardioverter-Defibrillator Pacemakers are a reasonable option to consider for symptomatic therapy in patients with advanced heart block. The role of prophylactic Implantable Cardioverter-Defibrillator (ICD) remains indefinable in preventing SCD as electromechanical dissociation is the most common cause of death. In a retrospective analysis of 53 patients (33 patients of AL ), out of which 41 underwent ICD implantation for primary prevention and 12 for secondary prevention, there was no survival benefit of ICD implantation 61. Also, there was significant difference in terms of ICD shocks with highest rate in AL amyloidosis and lower rate in ATTR and SSA. Similarly, other study in Germany observed SCDs secondary to EMD even after ICD implantation 62. Better approach for understanding of arrhythmia induced SCD attributable to amyloidosis is required. Altogether, data on ICD implantation for primary prevention remains sparse with no survival benefit.

Specific Therapy for Primary Amyloidosis Chemotherapy is based on the concept of reducing number of amyloid fibrils and retarding the disease process. In AL, chemotherapy and autologous hematopoietic stem cell transplant (ASCT) is the mainstay of treatment. Chemotherapy in AL amyloidosis is aimed at reducing free light chains. Bortezomib is a proteasome inhibitor that induces rapid hematological response either alone or in combination with dexamethasone 22. Bortezomib along with dexamethasone and cyclophosphamide is the first line treatment in these patients. Using Mayo staging as

stratification, an analysis of 230 patients treated with bortezomib, dexamethasone and cyclophosphamide demonstrated better response and benefit in patients with stage I and II 63. A matched case control study revealed higher hematological response of 42% to bortezomib along with oral melphalan and dexamethasone as compared to 19% response to melphalan and dexamethasone alone 64. Also, bortezomib and dexamethasone has shown to improve the hematological response following ASCT in newly diagnosed AL patients 65. Standard dose melphalan and dexamethasone has reported better survival outcomes in stage II patients when compared to high risk stage III 66. Use of thalidomide has been shown to improve response to therapy but also increases the risk of toxicities. It is usually better tolerated in lower dose in combination with dexamethasone and cyclophosphamide 67. Patients with NT-pro BNP levels > 8500 ng/ml and systolic blood pressure <100 mm Hg are poor responders to chemotherapy and have higher mortality rate 68.

Heart Transplantation The role of orthotropic heart transplantation (OHT) in AL amyloidosis is still controversial and is a challenging decision due to progressive disease course and recurrence of disease in the transplanted heart 69, 70. Also, most of patients with AL amyloidosis have significant amyloidosis load in other organ systems making them ineligible for OHT, which is more suitable for candidates who have isolated cardiac amyloidosis. If performed, OHT should be followed by chemotherapy and ASCT within a year. In 11 patients who received ASCT 6 months following OHT, survival rate of 82% and 65% at 1 and 5 years, respectively was noted (two patients died initially following complications of ASCT and three died subsequently between 55-66 months interval due to progressive amyloidosis) 71. Similarly, another study at Massachusetts General Hospital, Boston showed that sequential OHT and ASCT have demonstrated improved survival rate on 4.6 year follow up with no evidence of recurrent amyloid disease in the grafts 72.In fact, results are excellent with median survival of more than 10 years in patients who have demonstrated complete hematological response and predominant heart involvement 73. In general, younger patient <60years without associated plasma cell dyscrasias or other major organ involvement are better candidates of to be considered for OHT.

Specific Therapy for Familial Amyloidosis As mutant amyloid ATTR is produced in liver, orthotropic liver transplantation (OLT) is the established treatment since 1990. Outcomes seem to be mutant dependent with favorable outcomes in Val30Met mutation following OLT. In one study, 5-year survival rate was 100% vs 59% in Val30Met and non Val30Met patients 74. Retrospective analysis of world transplant registry in patients of ATTR who underwent OLT demonstrated the survival rate of 55.3% along with favorable outcomes in patients with Val30Met mutation as compared to non Val30Met

mutation at 20 year of follow up 75. Unfortunately, in patients with nonVal30Met mutation, cardiac disease can still progress following OLT, which is attributed to deposition of native TTRwt amyloid in the cardiac tissue similar to SSA 76, 77. Combined OHT and OLT is a viable option for selected patients with good outcomes 78. Overall, neuropathy and organ dysfunction continues to progress following OLT. On the other hand, as an exception to above rule of combined OHT/OLT was reported in Val 122lle mutation, common in African American, in which no recurrent heart disease has been reported even after 5 years of OHT 79. TTR tetramer stabilizers (Tafamidis and Diflunisal) works by binding to TTR and stabilizing its normal tetrameric structure preventing amyloid fibril formation 80, 81. Tafamidis is being used as a pharmacological agent in Europe and Japan for treatment of ATTR. A non-randomized control trail showed that it has not been able to halt the progression of neuropathy and morbidity in Val30Met mutation patients 82. An international randomized, double-blind, placebo-controlled study demonstrated diflunisal (non-steroidal anti-inflammatory drug) has reduced the progression rate of polyneuropathy in ATTR patients 83.

Specific Therapy for Senile Cardiac Amyloidosis Patients with HF secondary to SSA are treated symptomatically on presentation. In future, drugs such as tafamidis and diflunisal, currently be studied in clinical trials, could have role in treatment of SSA 11. Although patients with SSA usually have isolated involvement of the heart, consideration of life expectancy along with other comorbidities should be undertaken because of late presentation in seventh or eighth decade. Cases have been reported at earlier age and successful OHT 84.

Future Directions The evolving newer novel agents currently under trials are summarized in Table 3. Besides these, another agent, Curcumin, with antioxidant and anti-inflammatory properties, has shown promising results in decreasing TTR deposition in tissue and tissue toxicity in mice models and could serve as an therapeutic agent for advanced stage transthyretin amyloidosis 85. Furthermore, surprisingly, an observational study in Germany reported reductions in amyloid burden and left ventricular mass on one year follow up in patients using green tea extract 86. These emerging newer therapeutic agents may be able to revolutionize the treatment of amyloidosis in future.

New novel agents

Trial Number

Trail phase

Mechanism of action Type of Amyloidosis

Pomalidomide and dexamethasone

NCT01510613

II

Antiangiogenic and immunomodulatory

AL

Ixazomib and Carfilzomib

NCT01659658, NCT01789242

III I

Proteasome inhibitors

Tafamidis 80, 81

NCT01994889

III

Binds to TTR and stabilizing its normal tetrameric structure preventing amyloid fibril formation Anti-transthyretin small interfering ribonucleic acid (siRNA) lipid nanoparticles focus on reducing the production mutant and non-mutant forms of transthyretin Works on the principle of antisense oligonucleotide and knocks down both mutant and nonmutant form of transthyretin. Suppresses the TTR amyloid deposit in transgenic Val30EMet mutation Monoclonal antibodies targeting Serum amyloid P component (antiSAP)

Relapsed or treatment resistant AL amyloidosis ATTR

siRNA lipid nanoparticles ALNTTR01, ALN-TTR020 87 Patisiran (ALNTTR02) and Revusiran (ALNTTRsc) ISIS-TTRRx 88

NCT01148953 NCT01559077

I I

NCT01961921

II

NCT02319005

III

NCT01737398

III

Doxycycline and NCT01171859 tauroursodeoxycholic acid 89

II

GSK3039294

I

NCT02603172

ATTR

ATTR

ATTR

AL

AL-Primary amyloidosis, AA- Secondary amyloidosis, ATTR-Familial amyloidosis Table 3- Summarizing evolving newer novel agents currently under trials

Conclusion Cardiac amyloidosis is a life-threatening disease in which myocardial involvement is the main driver of prognosis of systemic amyloidosis, so stratification of patients is essential for prognosis and accurate medical or surgical management. Although no single pathognomonic test is available to diagnose amyloidosis, noninvasive tests, including low voltage ECG coupled with echo findings of LVH and/or DD in the absence of hypertension could be strongly suggestive of early lead in the diagnosis. CMR with LGE and phase-sensitive inversion recovery is valuable in finding the disease in its early phase. It is important to diagnose the individual cardiac amyloidosis as treatment options vary. In general, supportive therapy for HF, chemotherapy, ASCT and organ transplant (OHT/OLT) are the currently available options for treatment, while the newer therapies are being studied with the anticipation of making the prognosis better in the future. Even with recent advances in the treatment, the overall prognosis remains overall quite dismal. In suspected cases, clinicians should have a high index of suspicion and low threshold to use available diagnostic techniques for early diagnosis, as it could be of paramount importance in improving the potential survival outcomes.

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