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Amyloid Heart Disease:Diagnosis & Treatment

Sitaramesh Emani, MDAdvanced Heart Failure &

Cardiac Transplant

Relevant Disclosures

• St. Jude Medical (Thoratec)‒ Consultant‒ Grant Funding

• Gilead‒ Grand Funding

• Boston Scientific‒ Advisory Board

• CareDx‒ Advisory Board

• I will discuss investigational agents

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Amyloid Review

• Defined by the deposition of abnormal fibrils‒ Misfolding of proteins

causing insolubility• Abnormal β-sheet cross

formation

‒ Abnormality a common final finding – various underlying causes

‒ Deposition into organ tissue leads to dysfunction

• Pathognomonic feature is apple green birefringence on Congo Red staining

3Wechalekar AD, et al., Lancet 2016;387:2641-54

Amyloid Review

• Light-chain amyloid (AL)‒ Related to plasma cell dyscrasias (MGUS, myeloma)

• Hereditary amyloid‒ Often liver based

• Transthyretin‒ Familial ATTR or wild-type ATTR

• Reactive amyloid (AA or SAA)‒ Secondary to chronic inflammatory conditions

• Senile amyloidosis (SSA)

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Amyloid Review

• Many organs can be affected

• Cardiac involvement associated with increased morbidity and mortality

• High prevalence of cardiac involvement, especially with certain types‒ AL‒ ATTRwt

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Clinical Findings

• Can affect many/multiple organs

• Cardiac involvement most associated with M&M

• Non-cardiac involvement‒ Kidneys‒ Neuropathy‒ GI system

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Clinical Cardiac Findings

• Development of restrictive cardiomyopathy

• Right-heart failure symptoms

• Low cardiac output

• Hypotension

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When to suspect amyloid

• “Classic Findings”‒ Macroglossia‒ Periorbital purpura‒ Low-voltage EKG‒ Speckled pattern on echocardiogram‒ Unanticipated/unexpected LV thickening

• In presence of other problems‒ Renal disease (especially proteinuria)‒ Hematologic disease (MGUS, myeloma)‒ Unexplained neuropathy with heart failure symptoms

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Role of Cardiac Imaging

• Echo findings:‒ LV thickening‒ Increased echogenicity of myocardium (“sparkling”)‒ Preserved EF‒ Pericardial effusion‒ Diastolic abnormalities/restrictive pattern

• Findings not specific to amyloid

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Cardiac MRI

• Key component of evaluation

• Major feature: diffuse, sub-endocardial LGE

• 4 chamber thickening

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Biopsies

• “Tissue is the issue”

• Pathological specimen needed to evaluate subtype‒ Mass spectroscopy

• Any potentially involved organ is fair game‒ Fat pad – poor negative predictive value but easy to

get‒ Rectal biopsy‒ Endomyocardial biopsy

• Biopsies are not 100% sensitive

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Treatment of Cardiac Amyloid

• Standard GDMT ‒ No/poor evidence to support use‒ Difficult to tolerate for most (hypotension)

• Supportive/symptomatic therapies‒ Diuretics (sometimes need combination therapy)‒ But also pre-load dependent

• Device Therapy‒ Increased risk of SCD/ventricular arrhythmias‒ However, primary prevention ICD survival benefit unclear‒ Bradycardia risk with evidence of conduction disease

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Stanford Protocol for ICD

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Varr BC, et al., Heart Rhythm 2014;11:158-162

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Treatment of Amyloid

• Current strategies‒ RNA inhibitors‒ Fibril formation stabilizers & inhibitors‒ Immunotherapeutic targeting of fibrils

• Therapy in conjunction with hematology

• Dependent on type of amyloid

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Therapies for Amyloid

• AL type‒ Chemotherapy aimed at plasma cells‒ Doxycycline – reduces light chain fibril formation

• ATTR‒ Liver transplant if discovered early‒ Combined heart-liver if a candidate

• Unfortunately, disease often discovered late in process‒ Diflunisal (NSAID) – binds and stabilizes fibrils‒ Tafamidis – protein stabilizer (in clinical trials)‒ RNA inhibitors – reduce production (in early trials)

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References

Beal EW, Mumtaz K, Hayes D, Jr., Whitson BA, Black SM. Combined heart-liver transplantation: Indications, outcomes and current experience. Transplantation reviews 2016.

Chakraborty R, Muchtar E, Gertz MA. Newer Therapies for Amyloid Cardiomyopathy. Curr Heart Fail Rep 2016.

Fontana M, Martinez-Naharro A, Hawkins PN. Staging Cardiac Amyloidosis With CMR: Understanding the Different Phenotypes. JACC Cardiovasc Imaging 2016.

Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, Prognosis, and Therapy of TransthyretinAmyloidosis. J Am Coll Cardiol 2015;66:2451-66.

Judge DP, Lee YZ, Sharma K. Untangling Wild-Type Transthyretin Amyloidosis. J Am Coll Cardiol2016;68:1021-3.

Narotsky DL, Castano A, Weinsaft JW, Bokhari S, Maurer MS. Wild-Type Transthyretin Cardiac Amyloidosis: Novel Insights From Advanced Imaging. Can J Cardiol 2016;32:1166 e1- e10.

Selvanayagam JB, Hawkins PN, Paul B, Myerson SG, Neubauer S. Evaluation and management of the cardiac amyloidosis. J Am Coll Cardiol 2007;50:2101-10.

Varr BC, Zarafshar S, Coakley T, et al. Implantable cardioverter-defibrillator placement in patients with cardiac amyloidosis. Heart Rhythm 2014;11:158-62.

Wechalekar AD, Gillmore JD, Hawkins PN. Systemic amyloidosis. Lancet 2016;387:2641-54.

Zhao L, Fang Q. Recent advances in the noninvasive strategies of cardiac amyloidosis. Heart Fail Rev 2016.

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Thank youSitaramesh.emani@osumc.edu

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