A 74-year-old retired postal carrier is referred after his third hospitalization for decompensated heart failure in eight months. Each admission improved with intravenous diuresis, but exertional dyspnea has persisted despite increasing doses of oral furosemide. He now takes 80 mg twice daily and becomes breathless after climbing one flight of stairs.

He reports fatigue, light-headedness on standing, and an unintentional 10-lb weight loss over six months. On two occasions, he has needed to sit down to avoid fainting. He has not lost consciousness.

His history includes hypertension, but his blood pressure has progressively declined over the past two years. Lisinopril was stopped four months ago because of symptomatic hypotension. Metoprolol was subsequently discontinued because of fatigue and dizziness.

His first carpal tunnel release was six years ago; the contralateral procedure followed 18 months later. He also has lumbar spinal stenosis. He has no known family history of cardiomyopathy or hereditary neuropathy. He reports no angina, orthopnea, or paroxysmal nocturnal dyspnea.

After five minutes supine, his blood pressure is 104/68 mmHg and heart rate is 72/min. After three minutes standing, his blood pressure is 86/56 mmHg and heart rate is 76/min, accompanied by light-headedness.

The jugular venous pulsation is visible 8 cm above the sternal angle. Examination reveals bibasilar crackles, a soft systolic murmur at the left sternal border, and bilateral pitting edema to the mid-shins. Pinprick sensation is reduced in a stocking distribution.

© 2021 Ashraf, Hafeez, and Vilaro. Source: Figure 1 Cropped. Licensed under CC BY 4.0.

Reference intervals below are illustrative and vary by laboratory.

Transthoracic echocardiography reveals left ventricular ejection fraction 55%, interventricular septum 16 mm, posterior wall 15 mm, concentric. Grade 2 diastolic dysfunction, bi-atrial enlargement, small pericardial effusion, mildly thickened valve leaflets, right ventricular free wall 7 mm.

Coronary CT angiography eight months ago showed no obstructive coronary disease.

While his congestion and symptomatic hypotension are being addressed, which diagnostic strategy is most appropriate to establish the cause of his cardiac findings?

A. Obtain 99mTc-pyrophosphate scintigraphy with SPECT; grade 2 or 3 myocardial uptake is sufficient to diagnose transthyretin cardiac amyloidosis (ATTR) without additional laboratory testing.

B. Obtain serum free light chains with a κ/λ ratio and serum and urine immunofixation; if the monoclonal screen is negative, proceed with 99mTc-pyrophosphate scintigraphy with SPECT.

C. Proceed directly to endomyocardial biopsy because tissue confirmation from the heart is required in every patient with suspected cardiac amyloidosis.

D. Obtain cardiac MRI; diffuse subendocardial late gadolinium enhancement and increased extracellular volume are sufficient to distinguish ATTR from light-chain cardiac amyloidosis (AL).

E. Order TTR gene sequencing first; identification of a pathogenic variant establishes ATTR without further cardiac testing.

Choose your answer before reading on.

The findings raise strong suspicion for cardiac amyloidosis but do not establish its type.

Increased wall thickness with low limb-lead voltage is a discordance that ordinary hypertensive remodeling usually does not produce, because hypertrophied myocardium generates more voltage, not less. Infiltration adds thickness while displacing working myocardium, and the voltage falls. That is depicted in the EKG.

The rest of the history supports it. Bilateral carpal tunnel release years before the cardiac presentation, lumbar spinal stenosis, a stocking-distribution sensory deficit, orthostatic hypotension with a blunted heart-rate response, hypertension that became easier rather than harder to control, and intolerance of both an ACE inhibitor and a beta-blocker. A persistently elevated troponin without an ischemic event and a very high NT-proBNP complete the picture.

So, the diagnosis is not the difficult part. The sequence is.

99mTc-pyrophosphate scintigraphy is the correct imaging test, and a grade 2 or 3 scan is powerful. But it is only diagnostic of ATTR in the absence of a monoclonal protein. AL amyloidosis can also produce myocardial tracer uptake. If you read a positive scan as ATTR without having screened for a clonal plasma cell process, you can label a man with AL amyloidosis as having ATTR, start him on the wrong pathway, and lose the window in which AL amyloidosis is treatable. Untreated AL cardiac amyloidosis has a median survival measured in months.

The screen must be all three tests together: serum free light chains with a κ/λ ratio, serum immunofixation, and urine immunofixation. Serum protein electrophoresis alone is not sufficient and misses a substantial proportion of clonal processes.

Order them at the same time as the scan. Interpret them before the scan.

With a negative monoclonal screen and a compatible cardiac phenotype, grade 2 or 3 myocardial tracer uptake confirmed by SPECT can establish ATTR without biopsy. SPECT distinguishes myocardial uptake from blood-pool activity.

The missing step is the monoclonal protein screen. AL amyloidosis can also produce myocardial tracer uptake, so even grade 2 or 3 uptake confirmed by SPECT does not independently establish ATTR.

SPECT confirms where the tracer is located; it does not replace testing for a monoclonal process. A non-biopsy diagnosis of ATTR requires a compatible cardiac phenotype, diagnostic myocardial uptake, and a negative monoclonal screen.

The error is making cardiac biopsy mandatory. Patients who meet validated non-biopsy criteria for ATTR can be diagnosed without endomyocardial sampling.

Biopsy remains important when a monoclonal process is detected, imaging is equivocal, or clinical suspicion remains high despite negative scintigraphy. The appropriate tissue site depends on the presentation; an extracardiac biopsy may establish amyloidosis, while cardiac biopsy may be needed to resolve the diagnosis or identify the protein deposited in the heart.

Cardiac MRI can strongly support cardiac amyloidosis and assess its extent. However, diffuse subendocardial enhancement and increased extracellular volume occur in both AL amyloidosis and ATTR. These findings cannot reliably determine the amyloid type.

MRI is useful when the diagnosis or cardiac involvement remains uncertain, but it cannot replace monoclonal screening or tissue typing when indicated. The error in this option is the claim that MRI establishes the subtype.

A pathogenic TTR variant identifies a hereditary/variant predisposition (ATTRv or hATTR); it does not prove that amyloid has accumulated in the heart or caused this patient’s heart failure.

Conversely, negative sequencing does not exclude wild-type ATTR (ATTRwt), which occurs without a pathogenic TTR variant.

Once ATTR is established, genetic testing with counseling distinguishes hereditary from wild-type disease and guides family screening. It should be offered regardless of age or an apparently negative family history.

When wall thickness and ECG voltage disagree, stop and ask what is occupying the wall. This discordance is a clue; not a diagnosis.

A non-biopsy diagnosis of ATTR requires a compatible cardiac phenotype, grade 2 or 3 myocardial tracer uptake confirmed by SPECT, and a negative monoclonal protein screen.

A positive monoclonal screen does not prove AL amyloidosis. It means tissue confirmation and amyloid typing are needed. Neither test should be interpreted alone.

A positive 99mTc-pyrophosphate scintigraphy alone does not establish ATTR, and a positive monoclonal screen does not establish AL amyloidosis. Non-biopsy ATTR diagnosis requires a compatible cardiac phenotype, grade 2–3 myocardial uptake confirmed by SPECT, and a negative monoclonal screen. If monoclonality is present, tissue confirmation and amyloid typing are needed.

Before using scintigraphy to make a non-biopsy diagnosis of ATTR, obtain all three components of the monoclonal screen:

A negative screen means no monoclonal protein detected by either immunofixation test and a free light-chain ratio within the appropriate reference interval. A normal ratio alone is not enough.

The complication in this patient is his kidney function.

As renal clearance declines, both κ and λ free light-chain concentrations rise. With the commonly used Freelite assay, the κ/λ ratio can also shift upward without a clonal disorder. An elevated absolute light-chain concentration, or a mildly increased ratio, does not automatically indicate AL amyloidosis.

The traditional Freelite ratio interval is 0.26–1.65. An older renal interval of 0.37–3.10 has also been used, but it should not be applied indiscriminately to everyone with CKD.

The iStopMM study proposed more specific Freelite intervals based on kidney function. For eGFR 45–59 mL/min/1.73 m², which includes this patient, the proposed κ/λ ratio interval is 0.46–2.62. These limits are assay-specific and should be interpreted using the laboratory’s validated approach.

The practical lesson is to avoid errors in both directions: do not label a modest renal-related elevation as monoclonality, but do not dismiss an abnormal result simply because the patient has CKD. A monoclonal band on immunofixation is not explained by reduced renal clearance. Uncertain or discordant results warrant discussion with the laboratory or hematology.

Check which assay was used and whether the reported interval accounts for kidney function. Read the ratio alongside both immunofixation results, not in isolation.

Only when the monoclonal screen is negative can a compatible cardiac phenotype and grade 2–3 myocardial tracer uptake confirmed by SPECT establish ATTR without biopsy. If monoclonality is present, tissue confirmation and amyloid typing are needed.

SPEP may be included in the workup, but a normal result does not exclude AL amyloidosis.

The problem is sensitivity. In AL amyloidosis, the underlying clone may produce only a small amount of monoclonal protein; sometimes predominantly free light chains, without a clearly detectable spike on SPEP. SPEP is not limited to detecting intact immunoglobulins, but it can miss these low-level abnormalities.

That is why the screen requires serum immunofixation, urine immunofixation, and serum free light chains with the κ/λ ratio. Together, these tests have approximately 99% sensitivity for detecting a monoclonal abnormality in patients with AL amyloidosis. That is highly sensitive, not infallible; and a positive result still requires tissue confirmation and amyloid typing to establish AL.

Do not rely on the name “myeloma screen.” Check which tests were actually performed, including any reflex-testing rules.

If only SPEP was run, the monoclonal screen needed for the cardiac amyloidosis pathway is incomplete.

He became hypotensive on lisinopril and exhausted on metoprolol. Both were stopped and recorded as adverse effects.

That description was reasonable. What deserved further attention was why he tolerated them so poorly.

In cardiac amyloidosis, ventricular stiffness limits filling, and stroke volume may be reduced with little capacity to increase. Cardiac output can therefore become more dependent on heart rate. Vasodilators may worsen hypotension, particularly when autonomic dysfunction is present; excessive rate slowing may worsen fatigue and reduce output.

With his symptomatic hypotension and marked fatigue, stopping these medications was reasonable. Their intolerance, combined with wall thickening, low ECG voltage, and extracardiac clues, should also have prompted investigation. It does not establish amyloidosis by itself.

This is not a reason to abandon all heart failure therapy. Tolerance varies, and selected patients may benefit from conventional treatments. Contemporary guidance supports considering mineralocorticoid receptor antagonists and SGLT2 inhibitors in ATTR cardiomyopathy, with careful monitoring. Evidence specific to amyloidosis remains largely observational; treatment should reflect blood pressure, renal function, congestion, and other indications.

Avoid verapamil and diltiazem in this patient. These drugs can depress contractility, slow atrioventricular conduction, and worsen hypotension. They are generally avoided in cardiac amyloidosis and are particularly unsuitable here given his symptomatic hypotension and existing AV conduction delay. The clinical caution is more useful than presenting amyloid binding as the sole explanation.

Digoxin requires a specific indication and close supervision. Historical concerns include binding to amyloid deposits and increased toxicity. Small retrospective studies suggest that carefully selected patients can receive it, but they do not establish routine safety. If used, dosing and monitoring must account for renal function, electrolytes, serum concentrations, and conduction abnormalities. This patient, in sinus rhythm with preserved EF, has no clear indication for it.

Diuretics remain central to controlling congestion. The aim is euvolemia without excessive intravascular depletion. Follow breathlessness, edema, jugular venous pressure, daily weight trends, seated and standing blood pressure, kidney function, and electrolytes. An individualized target weight can help, but should not override the examination or evidence of hypotension and renal deterioration.

Address the orthostasis directly. His blood pressure falls from 104/68 to 86/56 mmHg, while his pulse rises only from 72 to 76/min. This supports possible autonomic dysfunction, but volume depletion, medications, and cardiac disease may also contribute.

Review contributing medications and volume status. Encourage slow positional changes, sitting at the bedside before standing, and practical precautions against nighttime falls. Consider an abdominal binder or waist-high compression garments when clinically appropriate and tolerated. Persistent symptoms may warrant specialist-directed treatment. Routine salt or fluid loading is unsuitable while he remains congested.

Once ATTR is established, offer TTR sequencing with genetic counseling, regardless of age, ancestry, or family history. Testing distinguishes hereditary (hATTR) from wild-type (ATTRwt) disease and guides family screening. It may also be appropriate earlier when hereditary neuropathy or a known familial variant is being investigated.

One important variant encountered in the US is p.Val122Ile, approximately 3–4% of self-identified Black Americans carry it. It is associated with West African ancestry.

His sensory loss and orthostatic symptoms warrant evaluation regardless of the genetic result.

If a pathogenic variant is found, offer counseling and targeted cascade testing to at-risk adult relatives. Each child of a heterozygous carrier has a 50% chance of inheriting the variant, but inheritance does not guarantee disease: penetrance is incomplete and age-dependent.

Cardiac amyloidosis can impair atrial contraction even when sinus rhythm is maintained. Blood stasis may therefore allow intracardiac thrombus to form without documented atrial fibrillation (AF).

AF is common and may be poorly tolerated because loss of effective atrial contraction, rapid rates, and irregular ventricular filling can further compromise cardiac output.

When AF occurs in cardiac amyloidosis, anticoagulation is recommended regardless of CHA₂DS₂-VASc score, unless contraindicated. Before elective cardioversion, ACC guidance recommends transesophageal echocardiography to exclude thrombus even when anticoagulation has been adequate; a short reported arrhythmia duration should not provide reassurance.

For this patient, currently in sinus rhythm with no documented AF, suspected amyloidosis alone is not an indication for routine anticoagulation. If amyloidosis is confirmed, severe atrial mechanical dysfunction or documented thrombus warrants specialist assessment and an individualized decision balancing thromboembolic and bleeding risks. Evidence for preventive anticoagulation in sinus rhythm remains limited.