Hello, my name is Jan Griffin. I'm an advanced heart failure and transplant cardiologist at the Medical University of South Carolina. Today, I will present a case on the diagnosis of cardiac amyloidosis. Here are my disclosures. So this is the case of an 82-year-old white man who presented to my clinic with a three-month history of shortness of breath on minimal exertion. He had three-pillow orthopnea. He denied paroxysmal nocturnal dyspnea. He reported progressive leg swelling and was now developing blisters on both lower legs. He was occasionally dizzy on standing and had a chronic cough which had become worse at night. His medications included lisinopril, metoprolsuccinate, prednisone, and furosemide. He had a long history of hypertension which had recently improved and was now borderline hypotensive necessitating the de-escalation of his antihypertensive medications. He had a right pleural effusion for several years and had undergone frequent thoracentesis which yielded a transudated fluid. He had left ventricular hypertrophy on echo and this was thought to be hypertensive in etiology. He had a history of bilateral carpal tunnel syndrome and had undergone bilateral carpal tunnel release approximately eight years prior. He had recently suffered a transient ischemic attack. He's an ex-smoker of 40-pack years, drank occasional social alcohol, married with three children, and had no family history of heart failure or sudden cardiac death. On physical exam, he had a heart rate of approximately 100 beats per minute with a regular rhythm. His blood pressure was 95 over 70. He was sat in 97% on room air and had a respiratory rate of 16. He appeared comfortable sitting. He had JVP to the angle of his mandible and this was at about 45 degrees. His rhythm was regular and he had a prominent S3. He had decreased breath sounds to the right mid-lung posteriorly and clear left lung fields. His abdomen was distended but non-tender and he had 2-3 plus pitting lower extremity edema all the way to the thigh and was developing fluid-filled blisters on his anterior shins. This was his ECG at presentation. As you can see, he was in sinus rhythm. He had a first degree AV block, a left bundle branch block with occasional PVCs, and a pseudo-infarct pattern in the inferior leads. And this was his echo. You can see in the parasternal long axis view, he had a thick-wooled ventricle, which is again displayed in the short axis view. On the four-chamber view, you can see a severely enlarged left atrium and a moderately enlarged right atrium. You can also appreciate the pulse-wave Doppler demonstrating a restrictive pattern. And on the bottom right, you can see myocardial speckle tracking, which shows apical sparing or also known as cherry-on-top appearance. This is where the longitudinal strain in the basal and mid-segments of the ventricle is more severely impaired compared with the strain values in the apical segments. A cut-off value of one can differentiate cardiac amyloidosis from other left ventricular hypertrophic phenotypes with good sensitivity and specificity. So what are the next steps in his evaluation? Well, this is a diagnostic and treatment algorithm for transthyretin amyloidosis, which was published in Circulation this year. Of course, as always, we start with a thorough history and physical exam, and there will also be imaging consistent with cardiac amyloidosis, which has heightened our suspicion. Then we must evaluate for the presence of light chain amyloid, and this is done with serum and urine immunofixation and serum-free light chains. If there is a monoclonal protein present, this should prompt hematology referral for further evaluation. In the setting of suspicion for cardiac involvement, endomyocardial biopsy should be pursued with liquid chromatography mass spectrometry for amyloid typing. On the other hand, if there is no monoclonal protein, you can proceed with the non-biopsy diagnosis, beginning with a PYP scan, in which if there is no uptake, this effectively rules out TTR amyloidosis, albeit with a few exceptions. A positive PYP scan, that is, a grade 2 or 3 uptake, should lead to performing TTR gene sequencing to determine whether this patient So back to our patient. These were his lab tests on presentation. You can see here that his antiprop BNP was elevated, and he had a creatinine of 1.5, which yielded an EGFR of 52, so he had You can see here that his antiprop BNP was elevated, and he had a creatinine of 1.5, which yielded an EGFR of 52, so he had CKD3. His kappa free light chain level was slightly elevated, above the upper limit of normal. He had a normal lambda free light chain, and a mildly elevated kappa lambda ratio of 1.78. The upper limit of normal is 1.65. Importantly, he had no monoclonal protein present on serum and urine immunofixation. We should note here the mild elevation in the kappa free light chains. In this case, this is in the setting of renal insufficiency. As we saw, he had an EGFR of 52. This is reflective of decreased clearance of kappa light chains and not light chain amyloidosis, and this is particularly important given the absence of a monoclonal protein on serum and urine immunofixation. So the question is whether this patient needs a biopsy. While historically, definitive diagnosis of cardiac amyloidosis required histologic confirmation, ideally with endomyocardial biopsy, but this often led to delays in diagnosis and therapy outside of larger academic centers. However, more recently a pathway for the non-biopsy diagnosis of TTR cardiac amyloidosis has been developed. In those with suspected cardiac amyloidosis, nuclear scintigraphy using bone-avid radiotracers without the need for histologic confirmation can be used to diagnose TTR cardiac amyloid, provided that the following criteria are satisfied. So firstly, the patient should have unexplained heart failure or be a pathogenic TTR mutation carrier. They must also have echo or cardiac MRI findings consistent with or suggestive of amyloidosis, and in the setting of an MRI, you'll often see diffuse late gadolinium enhancement. This would be reflective of an infiltrative cardiomyopathy. Thirdly, they must have grade two or three cardiac uptake on bone scintigraphy, and finally, the absence of a monoclonal protein on serum and urine immunofixation with a normal free light chain ratio. If all of these criteria are satisfied, the diagnosis of TTR amyloidosis can be made with a specificity and positive predictive value of 100%. Otherwise, additional testing with histologic diagnosis must be pursued. So this was our patient's PYP scan. On the left here, you can see grade three peregrine uptake. In other words, this is greater than bone, and the spect on the lower right-hand side shows absence of blood pool uptake in the LV walls, thus confirming the diagnosis of TTR amyloidosis. So who do we biopsy? Well, AL amyloidosis can result in grade one or higher grade of uptake on bone scintigraphy. We know that the sensitivity and specificity of grade two or three cardiac uptake on nuclear scintigraphy for diagnosing TTR amyloidosis as opposed to AL amyloidosis in patients who had a monoclonal protein were 92 and 91% respectively. So in any patient with a monoclonal protein present in serum or urine immunofixation, in whom you have a suspicion for cardiac amyloidosis who also has uptake on bone scintigraphy, they must undergo additional testing, including histologic diagnosis and amyloid typing. Furthermore, any patient with equivocal testing in whom you continue to have a high suspicion for cardiac amyloidosis should undergo biopsy diagnosis. So what about the sensitivity of biopsy sites and where should we biopsy? So although amyloid can be identified on extracardiac tissue, the sensitivity is variable. The sensitivity of fat pad and bone marrow biopsies is amyloid type dependent. So although extracardiac biopsies may be useful, a negative result must not be interpreted as conclusive. As such, biopsy of the clinically affected organ is the most useful for diagnosis. You can see here, for light chain amyloidosis, the sensitivity of a fat pad biopsy is only 70% to 90%, while bone marrow is about 60%. In variant ATTR, the biopsy of a fat pad is only 60% to 70% sensitive, bone marrow being approximately 40% sensitive. And in wild type ATTR, fat pad biopsy is only around 15% sensitive, bone marrow being about 30% sensitive. When it comes to identifying the type of amyloid present in a biopsy, Conger red staining does not distinguish amyloid type. And so amyloid protein typing must be performed using mass spectrometry. Missing a diagnosis of AL amyloidosis can be rapidly fatal, particularly if there is cardiac involvement, which occurs in about 50% to 60% of cases. So the point here is you must refer to hematology if there is a monoclonal protein present and be aware of the sensitivity of the various biopsy sites. So our patient was ultimately diagnosed with wild type ATTR cardiac amyloidosis. And this was based on genetic testing, which was negative for ATTR mutation, left ventricular hypertrophy on echo. He had grade three uptake on PYP scan and no monoclonal protein on serum and urine immunofixation. So as such, he fulfilled criteria for the non-biopsy diagnosis of ATTR cardiac amyloidosis. So we will finish up with some of the things to watch out for. Serum or urine electrophoresis can fail to detect a monoclonal spike in up to 30% of patients with AL amyloidosis. So the universal recommendation is that electrophoresis with immunofixation be performed in all cases. Abnormal serum free light chain reaction is not recommended for AL amyloidosis. In addition to immunofixation increases the ability to detect a monoclonal protein in patients with AL amyloidosis with a sensitivity of up to 99% for the two tests in combination. Beware, however, that in very rare cases of AL amyloidosis, there may be no monoclonal protein detected on serum or urine immunofixation. A negative fat pad biopsy does not rule out AL amyloidosis. And the phenotype of cardiac amyloidosis can appear as similar to hypertrophic cardiomyopathy. In one study, 5% of patients diagnosed with hypertrophic cardiomyopathy actually had variant TTR on genetic testing. And following that variant TTR, cardiac amyloidosis was confirmed by centigraphy and cardiac MRI. When interpreting nuclear centigraphy, you need to be sure that SPECT or SPECT-CT is performed in addition to planar imaging. This is necessary to confirm that uptake is myocardial because blood pool can be misinterpreted on planar imaging. So what about causes of a false positive PYP scan? Well, AL cardiac amyloidosis or rare forms of cardiac amyloidosis, such as apolipoprotein A1, can show uptake on PYP scan. Old myocardial infarctions can cause focal uptake, and this is thought to be due to the deposition of calcium in the infarct area. Old rib fractures over the heart can also be a cause of PYP scan. And this is more relevant to studies where the heart to contralateral lung ratio is reported. Blood pool can be interpreted as positive uptake if SPECT or SPECT-CT is not performed. Antihydroxychloroquine toxicity can also appear positive on a PYP scan. What about false negative PYP scans? Well, these are fewer. So some mutations, such as the phenylalanine 64-leucine mutation, which is of Italian descent, and the valine 30-methionine mutation, which is found in Portugal, can appear negative on a PYP scan. So again, if you have a high suspicion for cardiac amyloidosis, do not stop investigating. Do not stop investigating. Minimal amyloid infiltration as an early disease can also appear as a negative PYP scan. So in summary, non-biopsy diagnosis of TTR cardiac amyloidosis can only be performed if there is grade 2 or 3 uptake on bone scintigraphy in the absence of a monoclonal protein in serum or urine immunofixation. And not just electrophoresis. A negative FATPAD or bone marrow biopsy does not rule out AL amyloidosis if there is a high clinical suspicion. And we must always perform SPECT or SPECT-CT for accurate interpretation of PYP scans. Thank you very much for your time.

cardiac amyloidosis

transthyretin amyloidosis

wild-type ATTR

advanced imaging techniques

differentiation TTR AL