Learning From Experts
A Plug for the NEJM Clinical Cases
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I’m an advocate for reading the Massachusetts General Hospital case discussions in the New England Journal of Medicine. (1) The cases are interesting and are discussed by expert clinicians so they are practical. I look for cases that might apply to cardiology or to one of my other interests. You get an excellent summary of a topic by an expert. These are much more useful than individual papers or a single trial result. I almost always learn something and, as I have recommended (2), I usually take notes. Here are my notes from 2025’s Case #3, a case of AL (for amyloid light chain) amyloidosis.(1)
The patient was a 50-year-old male athlete who presented with 17 months of dyspnea, exertional chest discomfort and decreased exercise tolerance. The case title used the word “pain,” but by now you may know my campaign against “pain” and my preference for the term “discomfort.” (3) Nevertheless, this “pain” was a “discomfort” that felt like “not being able to get a full breath” during exercise. His electrocardiogram had normal QRS voltage, but an echocardiogram showed a hyperdynamic left ventricle (LV), cavity obliteration during contraction and concentric wall thickening of 17 mm. The echo also showed mitral valve and right ventricular wall thickening. There was better contraction at the LV apex, than at the base. The mitral valve tracing showed a very small atrial or “A” wave, consistent with restricted ventricular filling with atrial contraction. An MRI showed some late gadolinium enhancement, and was interpreted as consistent with, but not diagnostic of, hypertrophic cardiomyopathy (HCM). Genetic testing for 56 genes associated with HCM was unrevealing, and echocardiograms of his adult children did not show any left ventricular thickening.
This patient had a history of bilateral rotator cuff repairs. He also developed hoarseness at some point during his clinical course.
He was extremely active and started doing triathlons in his 30s but was no longer able to do them.
He had Kussmaul sign on physical exam. Normally, venous pressure is reduced with inspiration because pulmonary arterial pressure is reduced and more blood is ejected into the lungs reducing right-side venous distention. Kussmaul sign is when the jugular venous pressure either does not change or actually increases.
Ultimately, severely increased monoclonal kappa light chains were detected on serum free light chain assay and a monoclonal kappa light chain was demonstrated on serum immunofixation. A bone marrow biopsy showed monotypic kappa expression in plasma cells but no amyloid deposits. The fat biopsy showed AL (kappa) amyloid deposits in fat pad vasculature. He was diagnosed with AL amyloidosis, and referred to oncology for treatment similar to multiple myeloma treatment. He subsequently developed atrial fibrillation, and later died suddenly of cardiac arrest at home.
Here are what I consider to be the key teaching points from the discussion. Some I knew, some I did not, which means you still can teach a very old dog new tricks, just not Spanish. (You may know that my wife and I have spent the last four autumns in a Seville language school, but I am still far from proficient in Spanish.)
- Left ventricular wall thickening without ECG evidence of left ventricular hypertrophy suggests an LV infiltrative process.
- The NEJM patient had increased right ventricular wall thickness on echo. This does not often happen in HCM so should prompt a search for other pathologies.
- The echocardiogram in amyloidosis often shows normal apical contraction and strain (called “apical sparing”), although this can disappear as the disease progresses.
- The echocardiogram’s atrial filling or “A wave” is often diminutive in amyloidosis not only because the left ventricle is thick and non-compliant, but also because amyloid infiltration of the atrium reduces its mechanical contractility.
- Both AL and ATTR amyloidosis can infiltrate the mitral leaflets causing thickening and mitral regurgitation. Not discussed in the case report is that amyloid can also infiltrate all cardiac valves, thereby causing stenosis and regurgitation.
- This patient had competed in sports in college and had always been active. He started competing in triathlons in his 40s. But it is extremely rare to see athletes, especially white athletes, with very thick hearts due to athletic training. My friend, Antonio Pelliccia, who was the cardiologist for the Italian Olympic teams, reported that out of 947 Italian Olympians, (207 women) only 16 athletes, all men, had left ventricular wall thicknesses greater that 12 mm.(4) All of these athletes were rowers or canoe paddlers, sports that employ all extremities during training and competition, and thereby require large exercise cardiac outputs. These sports also produce isometric stress, so they increase exercise systolic blood pressure. Only one athlete had a wall thicker than 16 mm.
- It is now widely known that amyloidosis is associated with tendon problems, specifically carpal tunnel syndrome, biceps tendon rupture, spinal stenosis and trigger fingers. I have seen several physicians refer to me for lipid problems in whom we diagnosed transthyretin amyloidosis because of a history of trigger finger, biceps tendon rupture or bilateral carpal tunnel syndrome. We reported a case of what I thought was statin-associated tendon rupture (5), but turned out to be transthyretin amyloidosis.(6).
- I did not know, however, that rotator cuff tears were associated with amyloidosis, and that these were actually included in the first report of this association.(7) I also did not know that both transthyretin and AL amyloid are associated with tendon problems.
- Hoarseness can be a sign of increased left atrial pressures because the left recurrent laryngeal nerve hooks under the left pulmonary vein. Increased left atrial pressure can distend that vein, compressing the nerve, leading to hoarseness. I remember being a third-year medical student and interviewing a patient from Maine whose first symptoms of mitral stenosis was that he got hoarse splitting firewood by hand. But hoarseness can also be a sign of AL amyloid because the light chains can infiltrate the vocal cords. Transthyretin (TTR) amyloid does not do this.
- Even though atrial contraction may not be forceful for amyloid patients even when they are in sinus rhythm, these patients often deteriorate rapidly with the onset of atrial fibrillation because their ventricles are so non-compliant and even the loss of a weak atrial contraction is consequential. Patients with both AL and ATTR cardiac amyloidosis have a proclivity for developing left atrial appendage thrombi even in sinus rhythm. This is because of impaired atrial contractility due to amyloid infiltration. This increases the risk for systemic emboli even in patients in sinus rhythm. Some experts preemptively start anticoagulation in patients with cardiac amyloidosis who demonstrate decreased atrial strain on echocardiography, even if the patient is in sinus rhythm. Remember the rule: One stroke ruins your day if it’s yours or your patient’s.
- Atrial fibrillation ablation procedures are rarely successful in these patients because the atrium is so extensively infiltrated with amyloid.
- A critical point in making the diagnosis of AL amyloid is that you need increased free light chains on serum or urine immunofixation. Of note, traditional serum electrophoresis (not immunofixation) is rarely positive in AL. Serum electrophoresis helps diagnose multiple myeloma. So you must order serum immunofixation and urine immunofixation and not electrophoresis in addition to measuring serum free light chains and the ratio to diagnose AL amyloid.
- Contrary to a popular misconception – Bone marrow biopsy rarely demonstrates amyloid in patients with AL amyloidosis. This is because AL amyloid does not usually deposit in the bone marrow interstitium. But a bone marrow biopsy does help exclude multiple myeloma – a related plasma cell neoplasia. In order to confirm AL amyloid you need tissue for the diagnosis from a cardiac or other organ biopsy or from a fat aspirate. Fat pad aspiration is 85% sensitive for AL amyloid.
The NEJM article did not discuss using a Tc-99m pyrophosphate (Tc-99m PYP) scan to identify cardiac amyloidosis. The is the typical way of detecting “old man’s” cardiac amyloid or transthyretin amyloid (ATTR). ATTR is most frequent in older people (average age 75) and seven times more frequent in men than women. Tc-99m PYP is not as useful in diagnosing AL amyloid. This may be because the light chains present in AL amyloid are not as avid for the radioactive tracer. Thus, the need for other imaging techniques like cardiac MR and diagnostic techniques like the fat biopsy and protein immunoelectrophoresis.
References
1. Vancy CW, Guseh JS, Ghoshhahjra BG, Falk RH, Yee AJ, Hutchison BM. Case 3-2025: A 54-Year-Old Man with Exertional Dyspnea and Chest Pain. Engl J Med. 2025 Jan 23;392(4):383-394. PMID: 39842015
2. https://pauldthompsonmd.substack.com/p/please-make-a-note-of-this
3. https://pauldthompsonmd.substack.com/p/no-more-pain
4. Pelliccia A, Maron BJ, Spataro A, Proschan MA, Spirito P.The upper limit of physiologic cardiac hypertrophy in highly trained elite athletes. N Engl J Med. 1991 Jan 31;324(5):295-301. PMID: 1824720
5. Pullatt RC, Gadarla MR, Karas RH, Alsheikh-Ali AA, Thompson PD. Tendon rupture associated with simvastatin/ezetimibe therapy. Am J Cardiol. 2007 Jul 1;100(1):152-3. PMID: 17599460
6. Thompson PD, Arora S, Duvall WL. Tendonopathy Due to Simvastatin and Ezetimibe, Amyloidosis or Both? Am J Cardiol. 2020 Sep 1;130:165. PMID: 32682502
7. Sueyoshi T, Ueda M, Jono H, et al. Wild-type transthyretin-derived amyloidosis in various ligaments and tendons. Hum Pathol 2011;42:1259-1264.
Sabeena Arrora, MD, Director of the Amyloidosis Program at Hartford Healthcare and W. Lane Duvall, MD, Director of Cardiac Imaging at Hartford Healthcare, reviewed this post, but I am responsible for its final content. Dr. Duvall taught me about the orthopedic complications of amyloidosis before that was widely known. So he is directly responsible for my diagnosing cardiac amyloidosis in three physicians sent to me with lipid disorders who also had a history of either bilateral carpal tunnel, biceps tendon rupture or trigger finger. Teaching is a great way to enhance medical care.
#amyloid #cardiacamyloid #atrialfibrillation #hypertrophiccardiomyopathy #cardiachypertrophy #atrium #infiltrativeheartdisease




Very interesting !!!
Thank you for the amazing article!