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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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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. 

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Episode Schematics & Teaching

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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.  

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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 

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CardioNerds Case Reports: Recruitment Edition Series Production Team

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