109. Nuclear and Multimodality Imaging: Cardiac Amyloidosis

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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Show Notes & Take Home Pearls – Nuclear and Multimodality Imaging: Cardiac Amyloidosis

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.

Guest Profiles

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.

References and Links

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.

54. Case Report: Wild type aTTR Cardiac Amyloid – Washington University in St. Louis

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 summaryCase figures & mediaCase teachingReferencesProduction team

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.
Episode graphic by Dr. Carine Hamo

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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Cardionerds Cardiology Podcast Presents CardioNerds Case Report Series

Patient Summary

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. 

Case Media

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

TC-99 PYP Scan
Strain video 1
Strain video 2
Strain video 3

Episode Schematics & Teaching

The CardioNerds 5! – 5 major takeaways from the #CNCR case

  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.  


CardioNerds Case Reports: Recruitment Edition Series Production Team

10. AL (Light-Chain) Cardiac Amyloidosis with Dr. Ronald (Ron) Witteles

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
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Cardiac imaging for Amyloid – Youtube 

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.

9. Cardiac Amyloid Associated with HFpEF & Cardiac ATTR treatment with Drs. Virginia Hahn & Joban Vaishnav ​

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).

Drs. Joban Vaishnov and Virginia Hahn from Johns Hopkins Cardiology join the Cardionerds Cardiology Podcast

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
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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.

8. Cardiac Amyloid Imaging & EP Considerations with Drs. Paul Cremer and Eoin Donnellan

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
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Cardiac imaging for Amyloid – Youtube 

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.

7. Cardiac Amyloid part 1: case discussion

A new case of congestive heart failure due to cardiac amyloid is presented by Yuxuan Wang and discussed by Carine, Heather, Dan and Amit. Guest oncology star: Jackie Zimmerman. Flutter moment by Mark Heslin.

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
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Cardiac imaging for Amyloid – Youtube 

Dr. Yuxuan Wang completed her undergraduate studies at the University of Texas at Austin. She then received her MD and PhD degrees through the Medicine Scientist Training Program at Johns Hopkins School of Medicine. She trained under Bert Vogelstein, focusing on the early detection of cancer. She is currently finishing the last year of residency and fast-tracking into fellowship in Hematology-Oncology.

Dr. Jackie Zimmerman completed the Medical Scientist Training Program at University of Alabama School of Medicine. She completed her internal medicine training and served as assistant chief resident (ACS) for the Longcope firm at The Johns Hopkins Hospital. She is currently a medical oncology fellow at Johns Hopkins and investigating tumor-stromal interactions in pancreatic cancer in the lab of Dr Elizabeth Jaffee.

Mark Heslin is a current 3rd year medical student at Cooper Medical School of Rowan University in Camden, New Jersey. He completed his undergraduate studies at James Madison University with a degree in biology. Mark will be applying to internal medicine residency programs this upcoming fall with the hope of applying for a cardiology fellowship in the future. His clinical interests include clinical reasoning and the management of atherosclerotic cardiovascular disease. Outside of medical school, Mark enjoys spending time on Long Beach Island with his friends and family.