Amyloid Archives - Cardionerds

CardioNerds (Drs. Rick Ferraro and Georgia Vasilakis Tsatiris) discuss ATTR cardiac amyloidosis with expert Dr. Justin Grodin. This episode is a must-listen for all who want to know how to diagnose and treat ATTR with current available therapies, as well as management of concomitant diseases through a multidisciplinary approach. We take a deep dive into the importance of genetic testing, not only for patients and families, but also for gene-specific therapies on the horizon. Dr. Grodin draws us a roadmap, guiding us through new experimental therapies that may reverse the amyloidosis disease process once and for all.  Audio editing by CardioNerds academy intern, Christiana Dangas.

This episode was developed in collaboration with the American Society of Preventive Cardiology and supported by an educational grant from BridgeBio. 

Enjoy this Circulation Paths to Discovery article to learn more about the CardioNerds mission and journey. 

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Notes: Notes drafted by Dr. Georgia Vasilakis Tsatiris. 

You must have a strong index of suspicion, meaning you THINK that the patient could have cardiac amyloidosis, to consider it diagnostically. Some characteristics or “red flags” to not miss:  

NOTE: It is critical to differentiate between amyloid light chain (AL amyloidosis) and transthyretin ATTR amyloidosis, as both make up 95-99% of amyloidosis cases.  

Treatments since 2019 have utilized the amyloidogenic cascade: 

Drs. Rick Ferraro and Sneha Nandy discuss ‘Diagnosis of ATTR Cardiac Amyloidosis’ with Dr. Venkatesh Murthy.  In this episode, we explore the diagnosis of ATTR cardiac amyloidosis, a condition once considered rare but now increasingly recognized due to advances in imaging and the availability of effective therapies. Dr. Venkatesh Murthy, a leader in multimodality imaging, discusses key clinical and laboratory features that should raise suspicion for the disease. We also examine the role of nuclear imaging and genetic testing in confirming the diagnosis, as well as the importance of early detection. Tune in for expert insights on navigating this challenging diagnosis and look out for our next episode on treatment approaches for cardiac amyloidosis! Audio editing for this episode was performed by CardioNerds Intern, Julia Marques Fernandes.

Enjoy this Circulation Paths to Discovery article to learn more about the CardioNerds mission and journey. 

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscripts here. 

CardioNerds Cardiac Amyloid Page
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1. Recognizing the Red Flags – ATTR cardiac amyloidosis often presents with subtle but telling signs, such as bilateral carpal tunnel syndrome, low-voltage ECG, and a history of lumbar spinal stenosis or biceps tendon rupture. If you see these features in a patient with heart failure symptoms, think amyloidosis!  

 2. “Vanilla Ice Cream with a Cherry on Top” – On strain echocardiography, apical sparing is a classic pattern for cardiac amyloidosis. While helpful, it’s not foolproof—multimodal imaging and clinical suspicion are key!  

3. Nuclear Imaging is a Game-Changer – When suspicion for cardiac amyloidosis is high à a positive PYP scan with SPECT imaging (grade 2 or 3 myocardial uptake) in the absence of monoclonal protein (ruled out by SPEP, UPEP, and free light chains) is diagnostic for ATTR amyloidosis—no biopsy needed!  

4. Wild-Type vs. Hereditary? Know the Clues – Older patients (70+) are more likely to have wild-type ATTR, while younger patients (40s-60s), especially those with neuropathy and a family history of heart failure, should raise suspicion for hereditary ATTR. Genetic testing is crucial for distinguishing between the two. Note that some ATTR variants may predispose to a false negative PYP scan! 

5. Missing Amyloidosis = Missed Opportunity – With multiple disease-modifying therapies now available, early diagnosis is critical. If you suspect cardiac amyloidosis, don’t delay the workup—early treatment improves outcomes!  

What clinical features should raise suspicion for ATTR cardiac amyloidosis?  

What is the differential diagnosis for a thick left ventricle (LVH) and how does ATTR amyloidosis fit into it?   

What are the key imaging modalities used to diagnose ATTR cardiac amyloidosis?  

What lab tests are used to diagnose ATTR cardiac amyloidosis?  

Why is ruling out AL amyloidosis critical before diagnosing ATTR?  

When should genetic testing be performed in suspected ATTR amyloidosis?  

When is a biopsy necessary to confirm ATTR amyloidosis?   

https://pubmed.ncbi.nlm.nih.gov/31468376

https://pubmed.ncbi.nlm.nih.gov/36697326

CardioNerds Cardiac Amyloidosis Series Chair Dr. Rick Ferraro and Episode Lead Dr. Anna Radakrishnan discuss the biology of transthyretin amyloid cardiomyopathy (ATTR-CM ) with Dr. Daniel Judge.  Notes were drafted by Dr. Anna Radakrishnan. The audio was engineered by student Dr. Julia Marques. 

This episode provides a comprehensive overview of transthyretin (ATTR) cardiac amyloidosis, a complex and rapidly evolving disease process. The discussion covers the key red flags for cardiac amyloidosis, the diagnostic pathway, and the implications of hereditary versus wild-type ATTR. Importantly, the episode delves into the current and emerging therapies for ATTR, including stabilizers, gene silencers, and promising treatments like CRISPR-Cas9 and antibody-based approaches. Dr. Judge shares his insights and excitement about the rapidly advancing field, highlighting the need for early diagnosis and the potential to improve long-term outcomes for patients with this condition. 

Enjoy this Circulation Paths to Discovery article to learn more about the CardioNerds mission and journey. 

US Cardiology Review is now the official journal of CardioNerds! Submit your manuscripts here. 

CardioNerds Cardiac Amyloid Page
CardioNerds Episode Page

The importance of recognition and diagnosis of cardiac amyloidosis is at an all-time high due to its high prevalence and improved therapeutic strategies. Here we discuss what CardioNerds need to know about the manifestations, diagnosis, and management of transthyretin (ATTR) and light chain (AL) cardiac amyloidosis. Join Dr. Dan Ambinder (CardioNerds Cofounder), Dr. Dinu-Valentin Balanescu (Series Cochair, Chief Resident at Beaumont Health, and soon FIT at Mayo Clinic), and Dr. Dan Davies (Episode FIT Lead and FIT at Mayo Clinic) as they discuss cardiac amyloidosis with Dr. Omar Siddiqi, cardiologist at the Boston University Amyloidosis Center and program director for the general cardiovascular fellowship program at Boston University, a CardioNerds Healy Honor Roll Program. Episode notes were drafted by Dr. Dan Davies. Audio editing by CardioNerds Academy Intern, student doctor Chelsea Amo Tweneboah.

Access the CardioNerds Cardiac Amyloidosis Series for a deep dive into this important topic.

This episode is supported by a grant from Pfizer Inc.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan. 

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

Pearls • Notes • References • Production Team

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1. What is cardiac amyloidosis and how common is it?

2. What are some non-cardiac clues to the presence of cardiac amyloidosis?

3. What are common multimodality imaging features used for the diagnosis of cardiac amyloidosis?

4. How are heart failure and arrhythmias managed in patients with cardiac amyloidosis?

5. What specific therapies can be used for transthyretin (ATTR) amyloidosis and light chain (AL) amyloidosis?

International Cardio-Oncology Society ( IC-OS). IC-OS exits to advance cardiovascular care of cancer patients and survivors by promoting collaboration among researchers, educators and clinicians around the world. Learn more at https://ic-os.org/.

CardioNerds (Amit Goyal and Daniel Ambinder) join Dr. Loie Farina (Northwestern University CardioNerds Ambassador), Dr. Josh Cheema, and Dr. Graham Peigh from Northwestern University for drinks along the shores of Lake Michigan at North Avenue Beach. They discuss a case of a 52-year-old woman with limited cutaneous systemic sclerosis who presents with progressive symptoms of heart failure and is found to have a severe, non-ischemic cardiomyopathy. The etiology of her cardiomyopathy is not clear until her untimely death. She is ultimately diagnosed with cardiac AL amyloidosis with isolated vascular involvement a real occam’s razor or hickam’s dictum conundrum. We discuss the work-up and management of her condition including a detailed discussion of the differential diagnosis, the underlying features of systemic sclerosis with cardiac involvement as well as cardiac amyloidosis, the role of a shock team in managing cardiogenic shock, and how to identify those with advanced or stage D heart failure. Advanced heart failure expert Dr. Yasmin Raza (Northwestern University) provides the ECPR segment. Episode introduction by CardioNerds Clinical Trialist Dr. Liane Arcinas. Audio editing by CardioNerds Academy Intern, Christian Faaborg-Andersen.

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Disclosures: None
Jump to: Pearls – Notes – References

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This is a case of a 52-year-old woman with limited cutaneous systemic sclerosis who presented with progressive dyspnea on exertion and weight loss over the course of 1 year. Her initial work-up was notable for abnormal PFTs and finding of interstitial pneumonia on high-resolution CT, an ECG with frequent PVCs and normal voltage, a transthoracic echocardiogram with a mildly reduced ejection fraction of 40%, and a right/left heart catheterization with normal coronary arteries, filling pressures, and cardiac output. Scleroderma-related cardiac involvement is suspected. She is placed on GDMT, but her condition worsens over the next several months, and repeat echocardiogram shows severely reduced biventricular function, reduced LV global longitudinal strain (GLS) with apical preservation of strain, severely reduced mitral annular tissue Doppler velocities, and a normal left ventricular wall thickness. Scleroderma-related cardiac involvement remains highest on the differential, but because of some findings on the echo that are concerning for cardiac amyloidosis, an endomyocardial biopsy was obtained. It showed vascular amyloid deposition without interstitial involvement. The diagnosis of cardiac amyloid was discussed but deemed unlikely due to lack of interstitial involvement. However, a serologic work-up soon revealed a monoclonal serum lambda light chain and a follow-up bone marrow biopsy showed 20% plasma cells. She was discharged with very near-term follow-up in oncology clinic with a presumptive diagnosis of AL amyloidosis, but she unfortunately returned in shock and suffered a cardiac arrest. She initially survived and underwent emergent veno-arterial extracorporeal membrane oxygenation (VA ECMO) cannulation with subsequent left ventricular assist device placement (LVAD). However, she passed away due to post-operative hemorrhage. Autopsy was consistent with a final diagnosis of cardiac AL amyloidosis with isolated vascular involvement. 

1. Scleroderma causes repeated focal ischemia-reperfusion injuries which result in patchy myocardial fibrosis. Cardiac involvement in scleroderma is frequent but often not clinically evident; when symptomatic, it is associated with a poor prognosis. 

1. Myocardial dysfunction in cardiac AL amyloidosis can result from myocardial infiltration, vascular deposition causing microvascular dysfunction and ischemia, and direct cardiotoxicity from circulating light chains. 

1. While isolated vascular amyloid is very rare, it can occur and can be seen without key characteristics of interstitial amyloid deposition, namely left ventricular hypertrophy and low voltage on an ECG.  

1. Cardiogenic shock outcomes are improved by multi-disciplinary discussions, commonly referred to as a “shock team call.”  

1. Heart failure is a progressive, morbid, and potentially fatal condition. LVADs and heart transplantation improve life expectancy and decrease morbidity among patients with stage D heart failure. Identification of patients with advanced heart failure can be challenging – a helpful mnemonic is “I NEED HELP 

1. How does scleroderma affect the heart? 

• Scleroderma is a connective tissue disorder characterized by extracellular matrix deposition, with widespread fibrosis of the skin and visceral organs, microvascular injury, and evidence of immune system activation.  
• Cardiac involvement is common, although likely underestimated as it is often subclinical, and the estimated prevalence varies widely. Myocardial involvement is identified in up to 80% of patients in histological studies and clinical myocardial dysfunction is recognized in 15-25%. When clinically evident, cardiac involvement portends a poor prognosis, with up to a 70% mortality at 5 years. Approximately 25% of scleroderma-related deaths are due to cardiac causes. 
• Primary involvement is thought to be mediated by repeated focal ischemic-reperfusion injury, impaired microcirculation, inflammation, and eventual focal irreversible fibrosis leading to heart failure and arrhythmias. 
• Cardiac involvement can also occur secondary to lung or renal disease, pulmonary arterial hypertension, or other cardiovascular risk factors.  
• Cardiac manifestations: 
  • Myocardial failure: diastolic dysfunction is frequently reported but less commonly associated with diastolic heart failure. Systolic dysfunction can also occur, but severe systolic dysfunction is rare.  
  • Electrical failure: arrhythmias and conduction disorders 
  • Pericardial failure: pericarditis and pericardial effusion 
  • Coronary failure: coronary microvascular dysfunction 
  • Valvular failure: valvular involvement (uncommon)  

2. What is cardiac amyloidosis (CA) and what is the pathophysiology?  

• For an in-depth review of Cardiac Amyloidosis, enjoy the CardioNerds Cardiac Amyloid Series! 
• Amyloidosis is a process in which proteins misfold, aggregate, and form amyloid fibrils that deposit in various organs, thereby causing tissue injury and organ malfunction. The most common types of cardiac amyloidosis are AL (light chain) and TTR (transthyretin).  
• AL amyloidosis is a hematologic disorder of clonal plasma cells that overproduce light chains, which may deposit in any organ sparing the central nervous system, and commonly deposit in the heart and kidneys.  
• Delayed diagnoses are common, with an estimated one-third of patients visiting five or more physicians before receiving the diagnosis. Cardiac involvement with heart failure portends a particularly poor prognosis, with a median survival from onset of heart failure of less than six months without treatment. Stem cell transplantation has been shown to improve survival if performed prior to the diagnosis of advanced heart failure. Unfortunately, about 80% of patients are not candidates for aggressive therapy due to advanced stage of disease. 
• In CA, amyloid deposits infiltrate and expand the extracellular space which results in increased ventricular wall thickness and classically manifests as a restrictive cardiomyopathy with relatively preserved EF; however, a subset of patients may present with reduced LVEF and minimal or no ventricular wall thickening.  
• Patients with AL cardiac amyloidosis tend to have greater severity of heart failure than TTR despite less morphological involvement (in terms of LV wall thickness), felt due to the toxic effect of light chain amyloid fibrils on the tissue resulting in a toxic-infiltrative cardiomyopathy.  
• Additional mechanisms thought to play a major contributing role in cardiac AL amyloidosis: 
  • Circulating light chains cause direct cardiotoxicity through cardiomyocyte oxidant stress and abnormal vascular reactivity, impairing vasodilation  
  • Vascular amyloid deposition in the small intramural coronary vessels results in microvascular dysfunction and global myocardial ischemia. Vascular involvement is common in AL cardiac amyloidosis (much more common than in TTR cardiac amyloid). A pathology study demonstrated obstructive intramural coronary amyloidosis in 63 of 96 patients (66%) and 86% of these patients had microscopic evidence of myocardial ischemia. Isolated vascular involvement, however, is rare – 97% of patients in this study had interstitial involvement.  
  • Coronary microvascular dysfunction occurs via 3 major mechanisms:  
    • Structural – with amyloid deposition in the vessel wall causing wall thickening and luminal stenosis 
    • Extravascular – through extrinsic compression of the microvasculature from perivascular and interstitial amyloid deposits and decreased diastolic perfusion 
    • Functional – through autonomic and endothelial dysfunction 

3. What are common cardiac MRI (CMR) findings in scleroderma heart disease and cardiac amyloidosis? 

• First, a review of a few key concepts in CMR (also, enjoy Episode #33. Cardiac MRI with Dr. Deborah Kwon): 
  • Native T1 signals are increased by edema (e.g. acute infarction) and an increase in interstitial space (e.g. fibrosis, amyloidosis). T1 signals are decreased by lipid and iron overload.  
  • Gadolinium contrast agents are distributed throughout the extracellular space and shorten the T1 relaxation times of myocardium in proportion to local concentrations of gadolinium – areas of fibrosis/scar will exhibit shorter T1 relaxation times (due to higher gadolinium proportion). 
  • Extracellular volume fraction is calculated using myocardial and blood T1 before and after contrast is administered. It serves as a marker of myocardial tissue remodeling; ECV is increased in amyloid and excessive collagen deposition and serves as a robust marker of myocardial fibrosis. 
  • Late gadolinium enhancement (LGE) – depicts relative difference in the T1 recovery times between enhancing areas of fibrosis or scar (T1 shortened due to accumulation of extracellular gadolinium contrast agent) and normal nulled myocardium (longer T1 as gadolinium contrast agent is more rapidly washed out). 
  • T2 weighted imaging – sensitive to regional or global increases in myocardial water content (i.e. edema). 
• Scleroderma CMR findings:  
  • Perfusion defects – predominantly stress perfusion abnormalities, less common at rest 
  • Increased signal intensity on T2-weighted sequences 
  • Increase in ECV 
  • Delayed enhancement – mainly linear and typically mid-wall (spares the endocardium)  
  • Accurate assessment of RV function, which is particularly important given risk of PAH in these patients 
• Amyloid CMR findings: 
  • T1 signal abnormalities 
  • Increase in ECV 
  • Classically, causes global subendocardial LGE in a noncoronary distribution; however, LGE can also be diffuse and transmural or more localized and patchy 
  • Difficulty nulling the myocardium (the myocardium appears similar to the blood pool) 
    • Myocardial nulling” refers to an inversion recovery pulse sequence that is used to null the signal from a desired tissue to accentuate surrounding pathology.  
    • Normally, the blood pool nulls before the myocardium but in amyloid myocardium nulls simultaneously or before the blood pool 

4. How do we identify if someone has Stage D or advanced heart failure? 

• A topic of critical importance is identifying which patients have advanced or Stage D heart failure, those that are so sick that GDMT alone or interventions including cardiac resynchronization therapy, implantable pulmonary artery pressure monitor, or percutaneous mitral valve repair are unlikely to prolong life and prevent suffering. These patients benefit from timely evaluation for advanced heart failure therapies: left ventricular assist device (LVAD) or orthotopic heart transplant (OHT).  
• Heart failure is a progressive condition. A study in JACC HF in 2017 with Dr. Javed Butler as the senior author showed that in a cohort of outpatients with Stage C HF, 25% progressed to Stage D or died within a 3-year span. They estimated that 100,000 patients a year progress from Stage C to Stage D.  
• Unfortunately, it is not always clear who has made this transition until it is too late. This was reinforced by a study published in 2021 in the Journal of Cardiac Failure. This was a multi-center retrospective analysis of referral patterns for LVAD/transplant, and they showed that 40% of the 515 patients studied were deemed to be too sick to qualify for an advanced therapy, and 60% of the referrals coming from the inpatient setting, clearly too late in the disease course. 

• So how do we identify patients with advanced HF? In addition to the guideline document mentioned, there is a popular mnemonic that can help you remember red flags. 

The mnemonic is “I NEED HELP.” 

This identification schema is not perfect, and neither are our definitions for staging patients with heart failure. This is an area in need of active research.  

5. What is a “shock team” and what is its role in the management of cardiogenic shock?  

• In cardiogenic shock, diminished cardiac output leads to systemic hypoperfusion and resultant ischemia, inflammation, vasoconstriction, and salt/fluid retention with volume overload. The short-term mortality in CS is >40%. 
• A multidisciplinary shock team, composed of advanced heart failure, cardiac surgery, interventional cardiology, and critical care facilitates timely consultation and decision making. Observational studies suggest that a shock team approach may improve CS outcomes. A 2019 study published in JACC evaluated the impact of a standardized team-based approach in 204 consecutive patients with CS. 204 consecutive patients with CS were enrolled. They found that 30-day survival in 2017 and 2018 was 57.9% and 76.6%, respectively compared with a 30-day survival of 47% in 2016 (P<0.01).  
• For more on this, enjoy Episode #168. Cardiogenic Shock – Initial Assessment and The Shock Team Call with Dr. Anu Lala as part of the CardioNerds Cardiac Critical Care Series. 

1. Bissell LA, Anderson M, Burgess M, et al. Consensus best practice pathway of the UK Systemic Sclerosis Study group: management of cardiac disease in systemic sclerosis. Rheumatology (Oxford). 2017;56(6):912-921. https://pubmed.ncbi.nlm.nih.gov/28160468/ 

1. Bissell LA, Md Yusof MY, Buch MH. Primary myocardial disease in scleroderma-a comprehensive review of the literature to inform the UK Systemic Sclerosis Study Group cardiac working group. Rheumatology (Oxford). 2017;56(6):882-895. https://pubmed.ncbi.nlm.nih.gov/27940590/ 

1. Tehrani BN, Truesdell AG, Sherwood MW, et al. Standardized Team-Based Care for Cardiogenic Shock. Journal of the American College of Cardiology. 2019;73(13):1659-1669. https://pubmed.ncbi.nlm.nih.gov/30947919/ 

1. Haaf P, Garg P, Messroghli DR, Broadbent DA, Greenwood JP, Plein S. Cardiac T1 Mapping and Extracellular Volume (ECV) in clinical practice: a comprehensive review. Journal of Cardiovascular Magnetic Resonance. 2016;18(1):89. https://pubmed.ncbi.nlm.nih.gov/27899132/ 

1. Hachulla A-L, Launay D, Gaxotte V, et al. Cardiac magnetic resonance imaging in systemic sclerosis: a cross-sectional observational study of 52 patients. Annals of the Rheumatic Diseases. 2009;68(12):1878-1884. https://pubmed.ncbi.nlm.nih.gov/19054830/ 

1. Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis. Circulation. 2017;135(14):1357-1377. https://pubmed.ncbi.nlm.nih.gov/28373528/ 

1. Falk RH, Alexander KM, Liao R, Dorbala S. AL (Light-Chain) Cardiac Amyloidosis: A Review of Diagnosis and Therapy. J Am Coll Cardiol. 2016;68(12):1323-1341. https://pubmed.ncbi.nlm.nih.gov/27634125/ 

1. Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120(13):1203-1212. https://pubmed.ncbi.nlm.nih.gov/19752327/ 

1. Kalogeropoulos AP, Samman-Tahhan A, Hedley JS, et al. Progression to Stage D Heart Failure Among Outpatients With Stage C Heart Failure and Reduced Ejection Fraction. JACC Heart Fail. 2017;5(7):528-537. https://pubmed.ncbi.nlm.nih.gov/28624484/ 

1. Fang JC, Ewald GA, Allen LA, et al. Advanced (stage D) heart failure: a statement from the Heart Failure Society of America Guidelines Committee. J Card Fail. 2015;21(6):519-534. https://pubmed.ncbi.nlm.nih.gov/25953697/ 

1. Herr JJ, Ravichandran A, Sheikh FH, et al. Practices of Referring Patients to Advanced Heart Failure Centers. J Card Fail. https://pubmed.ncbi.nlm.nih.gov/34146684/ 

1. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med. 2001;345(20):1435-1443. https://pubmed.ncbi.nlm.nih.gov/11794191/ 

1. Alanna A. MorrisMD, MSc, FAHA, Chair, Prateeti Khazanie, MD, MPH, Vice Chair, Mark H. Drazner, MD, MSc, Vice Chair, Nancy M. Albert, PhD, Khadijah Breathett, MD, MS, FAHA, Lauren B. Cooper, MD, MHS, Howard J. Eisen, MD, Patrick O’Gara, MD, Stuart D. Russell, MD, on behalf of the American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Radiology and Intervention; and Council on Hypertension. https://www.ahajournals.org/doi/10.1161/CIR.0000000000001016 

CardioNerd Amit Goyal is joined by Dr. Erika Hutt (Cleveland Clinic general cardiology fellow), Dr. Aldo Schenone (Brigham and Women’s advanced cardiovascular imaging fellow), and Dr. Wael Jaber (Cleveland Clinic cardiovascular imaging staff and co-founder of Cardiac Imaging Agora) to discuss nuclear and complimentary multimodality cardiovascular imaging for the evaluation of multimodality imaging evaluation for cardiac amyloidosis. Show notes were created by Dr. Hussain Khalid (University of Florida general cardiology fellow and CardioNerds Academy fellow in House Thomas). To learn more about multimodality cardiovascular imaging, check out Cardiac Imaging Agora!

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Episode Abstract:

Previously thought to be a rare, terminal, and incurable condition in which only palliative therapies were available, multimodality imaging has improved our ability to diagnose cardiac amyloidosis earlier in its disease course. Coupled with advances in medical therapies this has greatly improved the prognosis and therapeutic options available to patients with cardiac amyloidosis. Multimodality imaging involving echocardiography with strain imaging, 99mTc-PYP Scan, and cardiac MRI can help diagnose cardiac amyloidosis earlier, monitor disease progression, and even potentially differentiate ATTR from AL cardiac amyloidosis.

Five Take Home Pearls

1. Cardiac amyloidosis results from the deposit of amyloid fibrils into the myocardial extracellular space. The precursor protein can either be from immunoglobulin light chain produced by clonal plasma cells (in the setting of plasma cell dyscrasias) or transthyretin (TTR) produced by the liver (which can be  “wild type” ATTR caused by the deposition of normal TTR or a mutant ATTR  which is hereditary). These represent AL Cardiac Amyloidosis and ATTR Cardiac Amyloidosis respectively.
   
2. Remember that amyloidosis can affect all aspects of the heart:the coronaries, myocardium, valves, electrical system, and pericardium! Be suspicious in a patient with history of HTN who has unexpected decrease in the need for antihypertensive agents with age or presents with a lower-than-expected blood pressure.
   
3. Multimodality imaging can assist with the diagnosis of cardiac amyloidosis in patients with a high clinical suspicion, monitor disease progression, and even potentially differentiate ATTR from AL cardiac amyloidosis.
   
4. Strain imaging assessment of global longitudinal strain (GLS) in patients with amyloid may demonstrate relatively better longitudinal function in the apex compared to the base, termed “apical sparing” or “cherry on top” (though in advanced stages the base to apex strain difference tends to become smaller). This has a 93% sensitivity and 82% specificity in identifying patients with cardiac amyloidosis and is particularly helpful with differentiating true cardiac amyloidosis from “mimics” such as hypertrophic cardiomyopathy, aortic stenosis, or hypertensive heart disease.
   
5. When the clinical suspicion for cardiac amyloidosis is high, a semiquantitative grade ≥ 2 (myocardial uptake ≥ bone) on 99mTc-PYP Scan combined with negative free light chain and immunofixation assays (to rule out AL cardiac amyloidosis) can diagnose ATTR cardiac amyloidosis and exclude AL cardiac amyloidosis w/ 100% PPV! Furthermore, this can circumvent the need for endomyocardial biopsy. Echocardiography and cardiac MRI (CMR) are helpful for building the clinical suspicion for cardiac amyloidosis.
   
6. When there is suspicion for AL cardiac amyloidosis, tissue biopsy is mandatory.

Quotable: – Nuclear and Multimodality Imaging: Cardiac Amyloidosis

“Even if you’re starting fresh, you should not do this test (technetium pyrophosphate scan) without a SPECT CT; you could be sending patients to therapy that costs anywhere between $25,000 to $250,000 per year for a disease that they don’t have.” –13:22

Detailed Show Notes

1. What is amyloidosis? What are the main precursor proteins in cardiac amyloidosis?

• Amyloidoses are protein-folding disorders in which proteinaceous deposits known as amyloid can infiltrate multiple organs. Cardiac amyloidosis is typically secondary to two main subtypes: 1) immunoglobulin light chain produced by clonal plasma cells (AL cardiac amyloidosis), and 2) transthyretin produced by the liver (ATTR cardiac amyloidosis). AL and ATTR account for >95% of cardiac amyloidosis. Rare precursors include serum amyloid A (AA) and apolipoprotein A-1 (ApoA-1).
  • AL cardiac amyloidosis
    • Overall incidence of AL amyloidosis is estimated to be 8.0-14.4 million persons per year in the USA with cardiac involvement in ~50% of patients. Median survival of patients with cardiac AL amyloidosis is 6 months from the onset of heart failure. Survival has improved with earlier detection and advancements in oncologic treatments.
    • AL may deposit in any tissue outside the CNS and so patients often have multiorgan involvement (kidneys, liver, etc).
  • ATTR cardiac amyloidosis
    • ATTR typically results in cardiac amyloidosis, peripheral neuropathy, and MSK sequelae (i.e., bilateral carpal tunnel, lumbar spinal stenosis, biceps tendon rupture) with relative proportions dependent on the mutant variant.
    • Transthyretin amyloidosis can occur secondary to the deposition ofnormal TTR (known as “ATTR wild type” or “ATTRwt”) or a mutant form (hereditary form known as “ATTR mutant” or “ATTRm”).
      • ATTRwt
        • Has a 15:1 male to female prevalence ratio and usually occurs in older patients  (>65 y.o.)
        • Almost always involves the heart
          • May be responsible for as many as 30% of heart failure with preserved ejection fraction (HFpEF) cases in patients >75 years old!
      • ATTRm
        • Has only a slight male predominance and occurs in younger patients (>40 y.o.)
        • Inherited in an autosomal dominant fashion with multiple genotypes with variable degrees of penetrance and cardiac involvement
        • There are more than 100 genetic variants of ATTR that are associated with amyloidosis. However, only a few of these variants, including Val30Met, Thr60Ala, Ser77Tyr, and Val122Ile, are responsible for the majority of cases of hereditary ATTR
          • As stated in Podcast Episode #7, the specific mutation is closely linked with the age of onset, natural history, and phenotype of the affected individual!
          • The Val122Ile mutation is the most common variant in the USA and a has prevalence of 3-4% in the US African American population. It is associated with cardiac amyloidosis with minimal neuropathy.
          • Thr60Ala is the 2nd most common variant in the USA and is seen most commonly in those of Irish descent. It is associated with a mixed cardiomyopathy and neuropathy phenotype.
          • Val30Met causes a prototypical hATTR polyneuropathy (heriditary ATTR with polyneuropathy also known as “Familial Amyloid Polyneuropathy”
          • The specific genetic variant affects treatment decision and screening is indicated for individuals with known or suspected familial amyloidosis presenting w/ new symptomatic heart failure.

2. What are some classic cardiac and extracardiac manifestations of amyloidosis?

• For fantastic case presentations of cardiac amyloidosis including suggestive history and physical exam findings, diagnostic considerations, and recommended management, tune in to CardioNerds Podcast Episodes #7-10 and #54! As  described in Podcast Episode #7, amyloidosis is associated with many classic extracardiac findings based on which organ it deposits in, and can also deposit in every layer of the heart—coronary, ventricular, valvular, electrical, and pericardial tissues! Below is a brief outline of some of the classic extracardiac and cardiac manifestations of amyloidosis.
  • Extracardiac:
    • ATTR: peripheral nerves (sensorimotor and autonomic defects) and musculoskeletal sequelae (bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture). Degree of cardiac vs nerve involvement differs by mutant variant as above. A prior Cleveland Clinic study showed Congo red staining of tenosynovial tissue detected amyloid deposits in 10.2% of patients undergoing carpal tunnel release surgery
    • AL: any tissue outside the CNS. For instance, typical organs involved include the kidneys (nephrotic syndrome), liver, intestines, and nervous system. On exam one may find macroglossia and periorbital bruising.
  • Cardiovascular:
    • Decreased antihypertensive medication requirements with increasing age or presenting with lower than expected blood pressure
    • Postural hypotension
    • Coronary microvascular disease
      • Chronically elevated but flat troponin (infiltration into the coronary microvasculature)
      • Almost all patients with cardiac amyloidosis have significantly reduced peak stress myocardial blood flow (<1.3 ml/g/min) which may explain symptoms of angina in these patients with absence of epicardial coronary artery disease
    • Myocardial
      • Signs and symptoms of both left and right heart failure
      • Restrictive physiology
      • LVH tends to be greater in ATTR than in AL by time of symptom onset. This is because AL is also directly toxic, thereby causing a toxic-infiltrative cardiomyopathy. ATTR is more likely to deposit asymmetrically and thus may more closely mimic hypertrophic cardiomyopathy
    • Valvular
      • Thickened AV valves and interatrial septum
      • Paradoxical low-flow, low-gradient severe aortic stenosis (~15% of patients who undergo transcatheter aortic valve replacement have ATTRwt). The low flow and low gradient are because of restrictive filling and significant diastolic dysfunction
    • Electrical
      • AV Block, Bundle Branch Block
      • Atrial fibrillation from infiltration of the atria (especially ATTR), chronically high left atrial pressure, and/or aging.
      • Low voltage EKG[NJ1] [GU2]  (in most cases, however in up to ~10% of cases you may see voltage criteria for LVH on the EKG. However, the magnitude of electrocardiographic LVH  would still pale in comparison to the degree of hypertrophy you would see on echocardiography)
      • Pseudoinfarct pattern with septal Q-waves mimicking an anteroseptal MI
    • Pericardium
      • Pericardial Effusion

3. How can multimodality imaging help in the evaluation and management of cardiac amyloidosis? What are features suggestive of cardiac amyloidosis on echocardiography, Technetium-99m pyrophosphate (99mTc-PYP) scan, and cardiac MRI (CMR)?

• Multimodality imaging has several roles in the evaluation of possible cardiac amyloidosis: establishing the clinical suspicion, diagnosing ATTR CA, surveillance of ATTR mutation carriers, monitoring disease progression, and assessing response to therapy.
  • Echocardiography
    • RV and LV wall hypertrophy (>12 mm) with normal chamber size
    • Biatrial enlargement
    • Thickened AV valves and interatrial septum
    • Possible concurrent LFLG aortic stenosis
    • Reduced Global Longitudinal Strain (GLS) with relatively preserved longitudinal function in the apex compared to the base. This “apical sparing” or “cherry on top” pattern has a 93% sensitivity and 82% specificity in identifying patients with cardiac amyloidosis in differentiating from “mimics” such as hypertrophic cardiomyopathy, aortic stenosis, or hypertensive heart disease.
    • Speckled pattern of the myocardium (less apparent with contemporary imaging)
    • Restrictive filling pattern on mitral inflow with ≥ Grade 2 Diastolic Dysfunction
    • Small pericardial effusion
  • Technetium-99m pyrophosphate (99mTc-PYP) Scan
    • 99mTc-PYP is a bone-avid radiotracer. In the 1980s there was excitement in the possibility of using 99mTc-PYP scan for diagnosis of cardiac amyloidosis however, enthusiasm waned when there started to be reports of low sensitivity. There was a resurgence of interest after the 2005 paper by Perugini et al. that showed that PYP scan can differentiate ATTR cardiac amyloidosis from AL cardiac amyloidosis with high sensitivity and specificity. It is likely that the previously reported low sensitivities were due to cases of AL amyloidosis.
    • How does 99mTc-PYP bind to amyloid protein and how does this differentiate ATTR from AL cardiac amyloidosis? 
      • Mechanisms of 99mTc-PYP binding to amyloid include the possible binding to “amyloid P component” (which binds the amyloid fibrils together via a calcium-dependent mechanism) via a calcium mediated mechanism or 99mTc-PYP binding to small microcalcifications which are much more prevalent in ATTR cardiac amyloidosis than with AL cardiac amyloidosis.
      • Usually there is no reason to have large myocardial uptake of 99mTc-PYP unless an individual has ATTR cardiac amyloidosis! Patients with AL cardiac amyloidosis can have myocardial uptake of 99mTc-PYP but usually at a much lower quantity. One rare caveat of this is in patients who are treated with hydroxychloroquine as hydroxychloroquine toxicity can present with restrictive cardiomyopathy in which you can have myocardial uptake of 99mTc-PYP. Remember that PYP was used to grade the size of myocardial infarction in the past, and following an acute MI we may see uptake as well (see below).
    • How and why is a 99mTc-PYP Scan combined with Single-photon emission computerized tomography (SPECT) to evaluate for ATTR amyloidosis?
      1. The 99mTc-PYP radiotracer is injected into the patient
      2. Planar imaging (a 2-D Nuclear image similar to CXR A/P) AND Cardiac SPECT images are obtained either 1 or 3 hours after injection of the radiotracer
      3. The planar images are examined both quantitatively and semiquantitatively.
         • Quantitative: Two circular regions of interest of the same size are drawn over the heart  and the contralateral chest (to account for background and ribs). The total and absolute mean counts are measured from both regions of interest. The heart to contralateral (H/CL) ratio is calculated. A ratio of ≥1.5 is considered positive for ATTR amyloid on a 1 hour protocol and a ratio of ≥1.3 is considered positive for ATTR amyloid on a 3 hour protocol
           • 99mTc-PYP radiotracer has peak myocardial counts 60 minutes after injection with gradual decline at 2 and 3 hours. Bone counts, however, increase gradually and peak 2-3 hours after injection. Because of this, the sensitivity of a 1 hour protocol is increased and specificity decreased (myocardial counts + blood pool counts which are at close to peak / Bone counts which are not at peak will give a higher H/CL). The sensitivity of the 3 hour protocol is decreased and the specificity is increased (myocardial counts + blood pool counts which are now reduced from peak / Bone counts which are now at peak will give a lower H/CL ratio). Because of this, the H/CL uptake ratio threshold of ≥ 1.5 has been established for 1 hour imaging and a lower cutoff of ≥ 1.3 established for 3-hour imaging. These cutoffs have been suggested to identify ATTR amyloid and distinguish it from AL amyloid with high sensitivity and specificity.
         • Semiquantitative: The myocardial uptake of 99mTc-PYP is visually compared to bone uptake
           • Grade 0: no myocardial uptake
           • Grade 1: myocardial uptake < bone uptake
           • Grade 2: myocardial uptake equal to bone uptake
           • Grade 3: myocardial uptake > bone uptake
      4. The Cardiac SPECT images are examined to:
         • Distinguish overlying rib uptake adding to counts over the region of interest over the heart on planar imaging
         • Distinguish blood pool activity from myocardial activity
         • This co-registration with CT is important to make sure you’re not counting tracer in the blood pool of the ventricle chamber (perhaps due to low cardiac output) or in the ribs (perhaps from rib fracture(s)) as myocardial uptake!
      5. Information from the planar Images (in point 3 above) and the Cardiac SPECT images (point 4 above) are synthesized to obtain a final interpretation regarding diagnosis of ATTR Cardiac Amyloidosis
         • Positive scan: Semiquantitative Grade ≥ 2 w/ confirmation of myocardial uptake on SPECT (rather than bone or blood-pool uptake). When there is Semiquantitative Grade ≥ 2 combined with negative free light chain and immunofixation assays this can diagnose ATTR cardiac amyloidosis and exclude AL cardiac amyloidosis w/ 100% PPV!
         • Equivocal scan: Semiquantitative Grade 1 with H/CL ratio 1-1.5 (on a 1 hour protocol) or 1-1.3 (on a 3 hour protocol). May represent AL cardiac amyloidosis or early ATTR cardiac amyloidosis. These patients need further specialized assessment for diagnosing cardiac amyloid; histological confirmation and typing of cardiac amyloidosis is recommended.
         • Negative scan: Semiquantitative Grade 0 with H/CL ratio <1
    • What are some limitations of 99mTc-PYP Scan and examples of why concomitant Cardiac SPECT is useful?
      • Most early experience highlighting the high accuracy of 99mTc-PYP scans for diagnosis of ATTR cardiac amyloidosis was with patients who were presenting with advanced disease and clinical heart failure where all the manifestations of amyloidosis including the imaging manifestations were more readily apparent
        • Sensitivity: More and more we are starting to send genetic testing for ATTRm and we may identify family members who are asymptomatic but have high risk genes. These are NYHA Functional Class 1, Stage A patients  at risk for disease but without clinical manifestations. We don’t have large scale population studies on these groups of patients and thus we don’t have sensitivity data.
        • Specificity: In the setting of rib fracture on the left, you can have active bone regeneration overlying the heart on planar images and your H/CL ratio will be increased resulting in false positive. Alternatively, rib fractures on the right can lead to a false negative. Persistent blood pool presence of the radiotracer even up to 3 hours despite no uptake in the myocardium will give ratios in the 1.3 to 1.4 range and can be misdiagnosed as ATTR cardiac amyloidosis
        • Originally, several decades ago, 99mTc-PYP Scan was done to identify the infarct area in the setting of acute MI. However, after around 1-2 weeks, you should no longer have 99mTc-PYP Scan uptake in that area. So early after MI, you may have a false positive result for ATTR and late following MI (when muscle is replaced by scar) you may have a false negative (lack of amyloid deposition and PYP tracer uptake in the scarred segments).
        • Patients who are high risk based on genetics and family history but do not yet have clinical disease can have negative blood work, ECG, imaging, and then a few years later—while they are still asymptomatic—can have a positive 99mTc-PYP Scan. These tests are not static—they can change over time! We don’t know what the appropriate intervals for follow-up testing for these patients with preclinical disease
        • Phe64Leu and Val30Met mutations are associated with false negative 99mTc-PYP scans!
  • Cardiac MRI (CMR)
    • Same anatomical evaluation as with echocardiography: diffuse increase in wall thickness, longitudinal apical function better than basal, etc.
    • Additionally, we get tissue characterization looking for scar
    • As the amyloid fibrils deposit into the myocardium, there is edema and infiltration, with increased space between cells (extracellular space) leading to elevated T1 times. As T1 relaxation time prolongs compared to normal myocardium, that is reflective of edema or diffuse fibrosis.
    • The space between the cells, the extracellular volume, is significantly increased by amyloid fiber deposition. Global extracellular volume (ECV) > 40% increase is suggestive of cardiac amyloidosis. This is not a specific sign for cardiac amyloidosis—anything that can give inflammation or fibrosis in the myocardium can increase the extracellular volume; however, the degree of elevation is far beyond what we see with other pathologies.
    • GLS on echocardiography and CMR w/ECV may be useful in monitoring response to therapy!
    • Gadolinium deposits into the extracellular space in areas that have been expanded by fibrosis. The classic area of deposition of amyloid fibrils is in the subendocardium. Diffuse subendocardial late gadolinium enhancement (LGE) in a non-coronary artery distribution with a dark blood pool is classic for cardiac amyloidosis; as the disease becomes more advanced, this can evolve into transmural LGE
    • Cardiac MRI does not have the power to discriminate between AL or ATTR cardiac amyloidosis. You can get some suggestion of the difference. Because AL cardiac amyloidosis is a relatively acute process, you may have more subendocardial LGE, a little less increased wall thickness, and some evidence of edema along with fibrosis when we look at T2 imaging compared to ATTR cardiac amyloidosis which is a more indolent process that takes years to develop.
  • What is in the works regarding the multimodality imaging evaluation of Cardiac Amyloidosis?
    • Novel Cardiac SPECT radiotracers and Cardiac PET radiotracers have shown promise in being able to follow response to treatment and assess prognosis respectively
    • PET radiotracers originally developed for imaging B-amyloid and Alzheimer’s disease (e.g. 18-F-florbetapir) can bind to the beta-pleated motif of amyloid fibrils regardless of the precursor protein (e.g., can bind to both ATTR and AL cardiac amyloid).
      • Researchers are also attempting to repurpose clinically available radiotracers to adequately image AL amyloid burden in the heart
      • PET tracers are quantitative and allow the possibility of quantifying amyloid burden and detecting changes in burden of disease (potential use for monitoring response to therapy). The 18-F-tracers have a long half-life of 109.7 minutes and allows delivery to sites without a cyclotron on site.

4. What are the ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis? A summary of the consensus recommendations is provided below. A link to the recommendations is provided in the “References” section below.

• In the absence of a clonal plasma cell process, 99mTc-PYP/DPD/HMDP scintigraphy consistent with ATTR cardiac amyloidosis combined with consistent echo or CMR findings obviates the need for invasive endomyocardial or extracardiac biopsy!
• For asymptomatic gene carriers, echocardiography and 99mTc-PYP Scan were rated as “Appropriate” while CMR was rated as “May Be Appropriate”
  • ECV has the potential to identify disease earlier in asymptomatic gene carriers compared with echocardiography
  • In patients with suspicion for cardiac AL amyloidosis (biopsy-proven systemic AL amyloidosis or MGUS w/abnormal FLC levels) 99mTc-PYP was rated as “Rarely Appropriate”
• For patients with new symptomatic heart failure or those who are ATTR gene carriers/patients with AL or ATTR amyloidosis with new or worsening cardiac symptoms (chest pain, fatigue, effort intolerance, dyspnea, palpitations, dizziness/lightheadedness, syncope, orthopnea, PND, bloating, leg swelling, leg or jaw claudication) in which we are screening for cardiac amyloidosis, echocardiography, CMR, and 99mTc-PYP were rated as “Appropriate”
  • Again, for patients suspicion for cardiac AL amyloidosis (biopsy-proven systemic AL amyloidosis or MGUS w/abnormal FLC levels) 99mTc-PYP was rated as “Rarely Appropriate” apart from the rare instance in long-term survivors of AL amyloidosis where concurrent ATTR cardiac amyloidosis is suspected
• For patients with biopsy-proven AL and ATTR cardiac amyloidosis, CMR and echocardiography were rated as “Appropriate” for assessing amyloid burden, response to therapy, or eligibility for stem cell transplant.
  • 99mTc-PYP was rated as “Rarely Appropriate”
  • 24 month assessment of response to therapy for echocardiography or CMR was rated as “Appropriate” with more frequent evaluation varying across expert amyloidosis centers
• For patients with conditions with high risk for potential cardiac amyloidosis (bilateral carpal tunnel syndrome; biceps tendon rupture; unexplained neuropathy; arrhythmias in the absence of usual risk factors and no signs/symptoms of heart failure) echocardiography was rated as “Appropriate” and CMR and 99mTc-PYP were rated as “May Be Appropriate”
• For patients with prior suggestive echocardiogram of cardiac amyloidosis, CMR was rated as “Appropriate”. For patients with prior suggestive CMR of cardiac amyloidosis, echocardiography was rated as “Appropriate”
  • 99mTc-PYP was rated as “May Be Appropriate” as it should only be used in cases of suspected ATTR cardiac amyloidosis.

Wael Jaber, MD, is a staff cardiologist in the Section of Cardiovascular Imaging, Robert and Suzanne Tomsich Department of Cardiovascular Medicine, at the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at Cleveland Clinic. Dr. Jaber specializes in cardiac imaging (both nuclear cardiology and echocardiography) and valvular heart disease. Dr. Jaber attended college at the American University in Beirut, graduating with a Bachelor of Science in biology. He then went on at the American University to receive his medical degree while making the Dean’s honor list. He completed his residency in internal medicine at the St. Luke’s-Roosevelt Hospital Center at Columbia University College of Physicians and Surgeons, where he also completed fellowships in cardiovascular medicine and nuclear cardiology. Dr. Jaber is currently is the Medical Director of the Nuclear Lab and of the Cardiovascular Imaging Core Laboratory in C5Research. He is fluent in English, French and Arabic. He is the author of Nuclear Cardiology review: A Self-Assessment Tool and cofounder of Cardiac Imaging Agora.

Dr. Aldo L Schenone is one of the current Chief Non-Invasive Cardiovascular Imaging Fellows at the Brigham and Women’s Hospital. He completed medical school at the University of Carabobo in Valencia, Venezuela, and then completed both his Internal Medicine residency and Cardiology fellowship at the Cleveland Clinic where he also served as a Chief Internal Medicine Resident.

Dr. Erika Hutt @erikahuttce is a cardiology fellow at the Cleveland Clinic. Erika was born and raised in Costa Rica, where she received her MD degree at Universidad de Costa Rica. She then decided to pursue further medical training in the United States, with the goal of becoming a cardiologist. She completed her residency training at Cleveland Clinic and went on to fellowship at the same institution. Her passions include infiltrative heart disease, atrial fibrillation, valvular heart disease and echocardiography among many. She is looking forward to a career in advanced cardiovascular imaging.

Bokhari S, Castaño A, Pozniakoff T, Deslisle S, Latif F, Maurer MS. (99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circ Cardiovasc Imaging. Mar 2013;6(2):195-201.

2.         Bullock-Palmer R. Top 10 Things To Know When Performing Cardiac Imaging to Assess Cardiac Amyloidosis. 2020. https://www.acc.org/latest-in-cardiology/articles/2020/02/27/14/47/top-10-things-to-know-when-performing-cardiac-imaging-to-assess-cardiac-amyloidosis.

3.         Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 1 of 2-Evidence Base and Standardized Methods of Imaging. J Card Fail. Nov 2019;25(11):e1-e39.

4.         Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 2 of 2-Diagnostic Criteria and Appropriate Utilization. J Card Fail. Nov 2019;25(11):854-865.

5.         Dorbala S, Bokhari S, Miller E, Bullock-Palmer R, Soman P, Thompson R. 99m Technetium-Pyrophosphate Imaging for Transthyretin Cardiac Amyloidosis. https://www.asnc.org/Files/Practice%20Resources/Practice%20Points/ASNC%20Practice%20Point-99mTechnetiumPyrophosphateImaging2016.pdf. Accessed March 11, 2021.

6.         Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis. Circulation. Jun 2016;133(24):2404-2412.

7.         Grogan M, Dispenzieri A, Gertz MA. Light-chain cardiac amyloidosis: strategies to promote early diagnosis and cardiac response. Heart. 07 2017;103(14):1065-1072.

8.         Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing Common Questions Encountered in the Diagnosis and Management of Cardiac Amyloidosis. Circulation. Apr 2017;135(14):1357-1377.

9.         Perugini E, Guidalotti PL, Salvi F, et al. Noninvasive etiologic diagnosis of cardiac amyloidosis using 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. J Am Coll Cardiol. Sep 2005;46(6):1076-1084.

10.       Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin Amyloid Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 06 2019;73(22):2872-2891.

11.       Singh V, Falk R, Di Carli MF, Kijewski M, Rapezzi C, Dorbala S. State-of-the-art radionuclide imaging in cardiac transthyretin amyloidosis. J Nucl Cardiol. 02 2019;26(1):158-173.

12.       Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and Cardiac Amyloidosis in Patients Undergoing Carpal Tunnel Release. J Am Coll Cardiol. 10 2018;72(17):2040-2050.

• Wael Jaber, MD

CardioNerd (Amit Goyal) join Washington University in St. Louis cardiology fellows (Adam Lick, Manny Rivera Maza, and Sam Lindner) for some amazing local St. Louis craft brews! They discuss a fascinating case of  wild-type aTTR cardiac amyloid. Prior to meeting up with the group, Amit bumps into Rachita Navara: a Wash U #FIT, aspiring electrophysiologist, & a rock star of the band “The Pacemakers” (be sure to check out their performance at the end of the episode!) who shares thoughts about the program and her cutting edge contributions to the field of EP. Dr. Katie Zhang provides the E-CPR and program director Dr. Andy Kates provides a message for applicants. Episode notes were developed by Johns Hopkins internal medicine resident Colin Blumenthal with mentorship from University of Maryland cardiology fellow Karan Desai.  

Jump to: Patient summary – Case figures & media – Case teaching – References – Production team

The CardioNerds Cardiology Case Reports series shines light on the hidden curriculum of medical storytelling. We learn together while discussing fascinating cases in this fun, engaging, and educational format. Each episode ends with an “Expert CardioNerd Perspectives & Review” (E-CPR) for a nuanced teaching from a content expert. We truly believe that hearing about a patient is the singular theme that unifies everyone at every level, from the student to the professor emeritus.

We are teaming up with the ACC FIT Section to use the #CNCR episodes to showcase CV education across the country in the era of virtual recruitment. As part of the recruitment series, each episode features fellows from a given program discussing and teaching about an interesting case as well as sharing what makes their hearts flutter about their fellowship training. The case discussion is followed by both an E-CPR segment and a message from the program director.

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A man in his early 70s, with a history of hypertension, a bicuspid aortic valve, chronic kidney disease and carpal tunnel syndrome presents with two weeks of worsening dyspnea on exertion. At baseline, he is an avid cyclist and noticed he can now only bike ½ mile when before he could bike extended distances. In addition, he noted abdominal swelling and palpitations. Vitals signs showed mild tachycardia, irregularly irregular rhythm, and no clear evidence of volume overload. Labs demonstrated acute on chronic kidney disease, an elevated NT-proBNP and elevated troponin. ECG demonstrated atrial flutter with variable conduction block. TTE demonstrated marked concentric left ventricular hypertrophy with preserved ejection fraction, biatrial enlargement, reduced global longitudinal strain with apical sparing, and bicuspid aortic valve with moderate aortic stenosis. Further diagnostics revealed normal serum kappa/lambda light chains and PYP scan was positive. Patient underwent EMB which demonstrated ATTR amyloid deposition and genetic screening did not show mutations commonly associated with hereditary ATTR. 

• A
• B
• C
• D

A. CXR: Stable mild enlargement of the cardiac silhouette; mildly tortuous aorta. Lung fields are clear, no pneumonia, pleural effusions, or pneumothorax.
B. AV continuous wave Doppler
C. Strain Image
D. Tc-99 PYP Scan

• Created by Dr. Karan Desai
• Created by Dr. Carine Hamo (updated 9.2020)

1. Cardiac amyloidosis can have a range of cardiac and extra-cardiac findings as amyloid fibrils can deposit in many different tissues, depending on the amyloid protein involved. The first step in diagnosis is maintaining a high index of suspicion. 
   1. The presence of prominent right-sided HF symptoms, low voltage on ECG, biatrial enlargement, ventricular hypertrophy, conduction disease, and pericardial effusion should prompt a high suspicion for cardiac amyloid. These are typical features of infiltrative or storage restrictive cardiomyopathies. PEARL: ATTR CM can cause asymmetric LVH and is an important HCM phenocopy! 
   2. Remember, amyloidosis is a systemic disease and extra-cardiac findings are common. ATTR amyloid has a predilection for the musculoskeletal system (including bilateral carpal tunnel syndrome, lumbar spinal stenosis, and biceps tendon rupture) and peripheral nerves. Conversely, AL amyloid is widely deposited outside the CNS an can result in protean manifestations, including periorbital ecchymoses from vascular fragility, macroglossia, and visceral organ involvement (including nephrotic syndrome, hepatic infiltration, and gut amyloid). 
      
2. When considering cardiac amyloid, there are four primary etiologies: 
   1. Wild-Type (non-hereditary) ATTR amyloidosis is caused by deposition of misfolded transthyretin proteins. It is an under-recognized cause of HFpEF, with incidence increasing with age. 
   2. Hereditary ATTR is caused by a genetic mutation that leads to instability of the transthyretin tetramer. The most common mutation is the Val30Met variant. Specific mutations tend to have templated organ manifestations, natural history, and prognosis.  
   3. AL amyloidosis is caused by deposition of light-chains from a clonal plasma cell dyscrasia. 
   4. AA amyloidosis is a rare form of cardiac amyloid caused by deposition of the acute phase reactant serum amyloid A protein due to a chronic inflammatory process. 
      
3. Evaluating for AL amyloid with appropriate lab workup is crucial. “Missing AL amyloid is like missing a STEMI” – Dr. Paul Cremer (Episode #8)! Workup should include SPEP, UPEP, serum/urine immunofixation, and serum kappa/lambda free light chains to maximize sensitivity. Note: SPEP and UPEP alone are insensitive and inadequate! 
   
4. Like many cardiac diseases, multimodal diagnostics are key in the diagnosis of cardiac amyloid 
   1. ECG: Low voltage, pseudoinfarct pattern, variable conduction disease, atrial arrhythmias. PEARL: 10% of patients with cardiac amyloid may have high voltages on ECG. LVH on imaging out of proportion to EKG voltages is a red flag! 
   2. TTE: We have discussed typical features of an infiltrative or storage restrictive cardiomyopathy previously , including marked LVH with normal LV volumes and bi-atrial enlargement. Other features include: RV hypertrophy, thickened valve leaflets, thick interatrial septum, speckled appearance of the myocardium, and small pericardial effusion. Bi-atrial enlargement may lead to functional MR and TR as well as atrial arrhythmias. Mitral inflow pattern and tissue doppler will show varying degrees of diastolic dysfunction depending on stage. Systolic function may be borderline and progressively decline in “burned-out” disease. Reduced global longitudinal strain with apical sparing may help differentiate cardiac amyloid from hypertensive heart disease. There is an overlap with aortic stenosis which will frequently manifest as a low flow and/or low gradient phenotype due to reduce stroke volumes. 
   3. Cardiac MRI: There are characteristic findings of early subendocardial late gadolinium enhancement (LGE) and later transmural LGE with abnormal blood-pool-to-myocardial nulling (an MRI technique to accentuate pathology).  
   4. PYP scan: >99% sensitivity for cardiac ATTR amyloid. If monoclonal gammopathy is excluded, the positive predictive value is 100%. 
   5. RHC +/- EMBx: the hemodynamic profile is that of restrictive cardiomyopathy with elevated filling pressures, blunted x descent, and steep y descent. There may be diastolic pressure equalization. If EMBx is pursued, pathology will reveal amyloid protein as a salmon-pink color when congo red stain is applied and when placed under polarized light the amyloid proteins have an apple-green birefringence. Amyloid fibrils are seen with electron microscopic study.  Mass spec for protein identification. 
      
5. Cardiac amyloid can be very difficult to treat with typical HF regimens, as beta blockers and ACE-I/ARB can lead to excessive hypotension in the setting of autonomic neuropathy and restrictive hemodynamics.  For TTR amyloid, there are treatment options like tafamidis (a transthyretin protein stabilizer) which can reduce mortality considerably in selected patients.  Investigational RNA-targeted therapies (i.e., patisiran) are increasing the options for treating TTR, but cost remains a major barrier to care. For AL amyloid, a multidisciplinary cardio-oncology team is vital to coordinate chemotherapy and cardiovascular care. Heart transplant +/- bone marrow transplant may be options in advanced stages of disease. The challenges of managing advanced disease highlight the importance of early recognition.  

References

• TTR Ca Review – JACC 2019 
• Amyloid CM Case – JACC Case Reports 2019 
• CardioNerds Amyloid Page 
• Strain Imaging Echocardiography: What Imaging Cardiologists Should Know 
• Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy 

• Bibin Varghese, MD
• Rick Ferraro, MD
• Tommy Das, MD
• Eunice Dugan, MD
• Evelyn Song, MD
• Colin Blumenthal, MD
• Karan Desai, MD
• Amit Goyal, MD
• Daniel Ambinder, MD

Dr. Ron Witteles from Standford university provides an approach to cardiac amyloid and specifically AL (Light-Chain) Cardiac Amyloidosis. The discussion is lead by Amit and Dr. Ashley Bock. This episode is the fourth and final part of our immersive journey into the jungle of beta-pleated sheets in the heart. We focus on AL amyloidosis in this episode. Flutter moment by Lois Adamski.

On the CardioNerds Cardiac Amyloid Topic Page you will find podcast episodes, infographic, references, guest contributors, flutter stars, and so much more.

Take me to the Amyloid Topic Page

Dr. Ronald Witteles is a graduate of Northwestern University where he earned his B.A. in Biology, and of the University of Chicago Pritzker School of Medicine, where he earned his M.D. with Honors.  He then moved west to Stanford University where he completed IM residency and Cardiology fellowship training, serving as both Chief Resident and Chief Fellow. He subsequently joined the faculty at Stanford, and is currently appointed as Professor of Medicine (Cardiovascular Medicine). He has served as Program Director for the Stanford University Internal Medicine Residency Training Program for more than 10 years, where he leads a residency program of approximately 140 residents.  He is Co-Director of the Stanford Amyloid Center – one of the nation’s largest centers in the country which specializes in the treatment of patients with amyloidosis, and he leads an active research program in this area. He also serves as Co-Director of the Stanford Multidisciplinary Sarcoidosis Program, and he is a national leader in Cardio-Oncology, serving as Associate Editor for the country’s premier journal dedicated to the field, JACC: CardioOncology. 

Dr. Ashley Bock earned her medical degree at the University of Colorado and completed her internal medicine residency training at Duke University.  From there she came to the Cleveland Clinic for general cardiology fellowship and advanced heart failure training. She joins our team today to discuss AL cardiac amyloidosis with Dr. Witelles.

Cardionerds (Daniel Ambinder and Carine Hamo) chat with Dr. Virginia Hahn about her work profiling HFpEF patients via endomyocardial biopsy only to find a significant proportion of patients with unsuspected cardiac amyloid. This is followed by a high yield discussion with Dr. Joban Vaishnav about ATTR cardiac amyloid treatment and management options. Flutter moment by David Ambinder (MS IV).

On the CardioNerds Cardiac Amyloid Topic Page you will find podcast episodes, infographic, references, guest contributors, flutter stars, and so much more.

Take me to the Amyloid Topic Page
Take me to episode topics page
Cardiac imaging for Amyloid – Youtube 

Dr. Virginia Shalkey Hahn is a fourth-year Cardiology fellow at Johns Hopkins in Baltimore, MD. She earned her medical degree from the Perelman School of Medicine at the University of Pennsylvania, where she stayed for residency. She moved to Johns Hopkins for Cardiology fellowship (after a 1 year hiatus as an ICU hospitalist). During fellowship, she completed 2 years on the NIH T32 Training grant and one year as chief fellow. She feels passionate about translational heart failure research and mothering her 2 young children.

Dr. Joban Vaishnav completed her undergraduate and medical school training at St. Louis University. She has since been at Johns Hopkins for residency, cardiology fellowship, and advanced heart failure fellowship. Her early research pursuits were in heart failure with preserved ejection fraction. From this, and from her advanced heart failure training, she developed a strong clinical interest and research interest in early diagnosis and treatment of cardiac amyloidosis.

In addition to the great discussion on Cardiac Amyloid ATTR treatment, we are excited to have Dan’s brother, David, join the Cardionerds cardiology podcast to share a special flutter moment! David Ambinder is a 4th year medical student at the University of Maryland and will be starting urology residency this coming July at Westchester Medical Center. He grew up in New York and graduated from Touro College before heading to Baltimore for medical school. He enjoys spending time with his wife Samantha and 3 lovely children.

• Carine Hamo, MD
• Daniel Ambinder, MD

Amit and Dr. Zach Il’Giovine learn about multimodality imaging in amyloid from Dr. Paul Cremer at the Cleveland Clinic. On their way to Dr. Cremer’s office, they run into Dr. Eoin Donnellan and discuss some incredible fellow research related to cardiac amyloid from an electrophysiologic perspective.

On the CardioNerds Cardiac Amyloid Topic Page you will find podcast episodes, infographic, references, guest contributors, flutter stars, and so much more.

Take me to the Amyloid Topic Page

Dr. Paul Cremer earned a Bachelor’s degree in molecular biology from Princeton University, Princeton, NJ, and his medical degree from Harvard Medical School, Boston, MA. Following completion of his internal medicine residency at Massachusetts General Hospital, he worked as a physician for two years at the Navajo IHS Chinle Comprehensive Health Care Facility in Chinle, Ariz. He then continued his postdoctoral training with a three-year fellowship in cardiovascular medicine and a subsequent two-year fellowship in advanced cardiovascular imaging, both at Cleveland Clinic. He joined the Cleveland Clinic staff in 2017. He is the director of the Cleveland Clinic CCU.  He enjoys swimming and reading fantasy books with his daughters. He joins the cardionerds cardiology podcast to shed insight on cardiac amyloid imaging.

Dr. Eoin Donnellan is a 3rd year Cardiology Fellow at the Cleveland Clinic and all-around nice guy. He received his medical degree from University College Cork in Ireland before heading to the big city to continue his training at the Mater Hospital in Dublin. He completed his Internal Medicine Residency at the Cleveland Clinic and will start EP Fellowship this July. Outside of the hospital he enjoys long nature walks, whispering sweet nothings, searching for the deeper meaning in little things, and watching thought-provoking and highly entertaining television programs such as This is Us and The Bachelor.

Dr. Zachary Il’Giovine is a general cardiology fellow at the Cleveland Clinic. He received his medical degree from the Wright State University Boonshoft School of Medicine before completing internal medicine training at Duke University. He has clinical interests in advanced heart failure and cardiac critical care. Outside of the hospital he loves playing soccer and spending time with his wife Clare and son Luca.