The Diagnosis of Cardiac Amyloidosis: The Echo and EKG Clues
The Diagnosis of Cardiac Amyloidosis: The Echo and EKG Clues
Introduction: The Silent Infiltrator
Ladies and gentlemen, imagine you're evaluating a 68-year-old patient presenting with progressive dyspnea and bilateral pedal edema. The echocardiogram shows beautiful, symmetrical left ventricular hypertrophy—walls measuring 15mm. Your instinct says hypertensive heart disease or perhaps hypertrophic cardiomyopathy. But then you glance at the EKG: the voltage is paradoxically low. This cognitive dissonance—this beautiful contradiction—should make you pause. Because what you're witnessing may not be hypertrophy at all, but infiltration. Welcome to the world of cardiac amyloidosis, where the heart becomes a repository for misfolded proteins, and where early diagnosis can literally change the trajectory of a patient's life.
Why does early diagnosis matter so profoundly? Because we now have disease-modifying therapies. Tafamidis for transthyretin amyloidosis (ATTR) has demonstrated mortality reduction. The treatments for light chain (AL) amyloidosis continue to improve. But these interventions work best when initiated early, before irreversible cardiac damage occurs. The average delay from symptom onset to diagnosis historically ranged from two to four years—a delay we can no longer accept. And the beautiful irony? The clues have been sitting in front of us all along, on two of the most basic cardiac investigations: the echocardiogram and the electrocardiogram.
The Echo Paradox: When Thick Walls Tell a Different Story
The Classic Appearance: Concentric LVH That Isn't Quite Right
When you first see cardiac amyloidosis on echocardiography, the finding that captures your attention is concentric left ventricular hypertrophy. The walls are symmetrically thickened, often exceeding 12mm, sometimes reaching 15 to 20mm. The interventricular septum and posterior wall demonstrate equal thickening. The left ventricular cavity remains normal-sized or even small. At first glance, this looks like the concentric remodeling we see in long-standing hypertension or aortic stenosis.
But look closer. In true pressure-overload hypertrophy, the myocytes themselves enlarge—genuine hypertrophy. In amyloidosis, the wall thickness increases not because the myocytes are bigger, but because the extracellular space is filled with amyloid protein deposits. The heart isn't growing stronger; it's becoming infiltrated, stiffened, and progressively dysfunctional. This is pseudohypertrophy—an impostor that mimics hypertrophy but represents something entirely different pathophysiologically.
The Sparkling Myocardium: A Textural Clue
Now direct your attention to the myocardial texture itself on two-dimensional echocardiography. In many patients with cardiac amyloidosis, the myocardium displays a characteristic "granular" or "sparkling" appearance—a speckled, bright texture that looks almost crystalline. This finding results from the heterogeneous acoustic properties created by amyloid deposits scattered throughout the myocardium. Think of it as the ultrasound beam encountering multiple tiny interfaces between normal myocardium and proteinaceous deposits, creating multiple small reflections that manifest as this granular sparkling.
I must emphasize: while this finding is suggestive when present, it's neither perfectly sensitive nor specific. Not all amyloid hearts sparkle, and occasionally other infiltrative processes or technical artifacts can produce similar appearances. But when you see it in combination with other features, it becomes part of a compelling clinical picture.
Biatrial Enlargement and Valvular Thickening
Amyloid doesn't respect anatomic boundaries. While the left ventricle bears the brunt, the atria become enlarged—both right and left. This biatrial enlargement reflects elevated filling pressures and the restrictive physiology that characterizes advanced disease. Look at the atrial septum; you'll often see thickening there as well.
The atrioventricular valves may also show thickening. The mitral and tricuspid valves can appear diffusely thickened without the focal characteristics of rheumatic disease or degenerative calcification. Small pericardial effusions are common, adding to the constellation of findings.
Diastolic Dysfunction: The Restrictive Pattern
Functionally, cardiac amyloidosis produces severe diastolic dysfunction. On Doppler assessment, you'll see a restrictive filling pattern: shortened mitral deceleration time, often less than 150 milliseconds, elevated E-wave velocity with diminished A-wave, and an E/A ratio greater than 2. The E/e' ratio—which estimates left ventricular filling pressure—is markedly elevated, often exceeding 15 to 20.
This isn't the gradual diastolic dysfunction of aging or hypertension. This is a stiff, non-compliant ventricle that cannot relax adequately during diastole. The heart muscle, infiltrated with amyloid protein, has lost its compliance. Imagine trying to fill a leather bag versus a plastic bag—one stretches easily, the other resists. The amyloid heart resists.
The Strain Pattern: A Revolutionary Diagnostic Tool
Understanding Global Longitudinal Strain
Here's where echocardiography becomes truly elegant. Speckle-tracking echocardiography allows us to quantify myocardial deformation by tracking acoustic markers (speckles) in the myocardium throughout the cardiac cycle. Global longitudinal strain (GLS) measures the percentage change in myocardial length from end-diastole to end-systole in the longitudinal direction. Normal GLS is typically -18% to -22% (the negative sign indicates shortening).
In cardiac amyloidosis, GLS is severely reduced—meaning the magnitude of shortening is diminished. You might see values of -8% to -12%, indicating profound impairment of longitudinal myocardial function. But here's the critical insight: even when left ventricular ejection fraction appears preserved (often 50-55%), the GLS reveals subclinical systolic dysfunction. The heart looks like it's squeezing adequately in the circumferential direction (radial thickening), but longitudinal function is devastated.
The Apical Sparing Pattern: A Highly Specific Finding
Now we arrive at one of the most specific echocardiographic findings in cardiac amyloidosis: the apical sparing pattern. When you examine regional longitudinal strain, you'll notice something remarkable—the basal and mid-ventricular segments show severely reduced strain (less negative, indicating less deformation), but the apical segments are relatively preserved.
This creates a characteristic "cherry on top" appearance on the bull's-eye plot—the apex appears red (indicating preserved strain) while the base and mid-ventricle appear yellow or green (indicating reduced strain). The mechanism? Amyloid deposition preferentially affects the basal and mid-ventricular regions first, with relative sparing of the apex until later in the disease course.
Quantitatively, we can calculate the relative apical longitudinal strain ratio: divide the average apical strain by the sum of basal and mid-ventricular strain. A ratio greater than 1.0 is highly suggestive of cardiac amyloidosis. Some studies have shown this pattern to have specificity exceeding 90% for amyloidosis when differentiating it from other causes of left ventricular hypertrophy.
The EKG Paradox: The Voltage-Mass Discordance
Low Voltage in the Presence of Thick Walls
This is perhaps the most striking and counterintuitive finding: despite prominent left ventricular hypertrophy on echocardiography, the electrocardiogram shows low QRS voltage. By criteria, low voltage is defined as QRS amplitude less than 5mm (0.5 mV) in all limb leads or less than 10mm (1.0 mV) in all precordial leads.
Why does this happen? In true myocyte hypertrophy—as seen in hypertensive heart disease or athletic hearts—the increased muscle mass generates increased electrical voltage. The Sokolow-Lyon criteria and Cornell criteria for LVH depend on this principle: more muscle creates bigger QRS complexes. But in cardiac amyloidosis, the infiltrative amyloid protein acts as an electrical insulator. The deposits disrupt normal electrical conduction pathways, attenuate the electrical signal, and prevent the typical voltage amplification. You have increased wall thickness without increased electrical output—the voltage-mass discordance.
Pseudoinfarct Patterns: Q Waves Without Coronary Disease
Look at the precordial leads carefully. In many patients with cardiac amyloidosis, you'll see poor R-wave progression in V1 through V3, or even pathological Q waves in these leads or in the inferior leads. These patterns suggest prior myocardial infarction—hence the term "pseudoinfarct pattern."
The mechanism involves progressive loss of viable myocardium due to amyloid infiltration, particularly affecting the septum and anterior wall. The amyloid deposits replace functional myocardium with electrically inert material, creating the electrical equivalent of scar tissue. When the coronary angiogram returns showing pristine vessels, your suspicion for infiltrative disease should escalate dramatically.
Conduction Abnormalities and Arrhythmias
The infiltrative process doesn't spare the conduction system. You may see first-degree atrioventricular block (prolonged PR interval), bundle branch blocks (particularly left bundle branch block), or more advanced conduction disease. Atrial fibrillation is extremely common in advanced disease, occurring in 50-70% of patients, reflecting atrial dilation and infiltration.
Ventricular arrhythmias can occur, though they're less common than in other cardiomyopathies. However, the risk of sudden cardiac death exists, particularly in AL amyloidosis, often related to electromechanical dissociation rather than purely arrhythmic causes.
The "Red Flag" Combo: Recognition Triggers Action
Pattern Recognition as Clinical Excellence
Let me be explicit about this: when you see a patient with increased left ventricular wall thickness on echocardiography (particularly >12-15mm) AND low voltage on EKG, you must think of cardiac amyloidosis. This combination should trigger an immediate, specific diagnostic pathway. Add in any of the following, and your clinical suspicion should approach near-certainty:
- Granular sparkling myocardial texture on echo
- Apical sparing pattern on strain imaging
- Biatrial enlargement
- Pseudoinfarct pattern on EKG
- Symptoms of heart failure with preserved ejection fraction in an elderly patient
- History of carpal tunnel syndrome or lumbar spinal stenosis (particularly in ATTR)
- Peripheral or autonomic neuropathy
- Macroglossia or periorbital purpura (particularly in AL)
This isn't about waiting for absolute certainty before acting. This is about recognizing a pattern that demands immediate, directed investigation. The threshold for suspicion must be low because the consequences of missed diagnosis are high.
The Clinical Context Matters
Cardiac amyloidosis comes in two main forms, and the clinical context helps differentiate them. Light chain (AL) amyloidosis tends to affect younger patients (50s-60s), progresses more rapidly, and often presents with multi-organ involvement—renal dysfunction, hepatomegaly, neuropathy, or bleeding diathesis. The presence of a monoclonal protein (plasma cell dyscrasia) drives this disease.
Transthyretin amyloidosis (ATTR) typically affects older patients (>60 years, often >70). It can be hereditary (variant ATTR) due to mutations in the transthyretin gene, or wild-type ATTR (previously called senile cardiac amyloidosis), where normal transthyretin protein misfolds with aging. Wild-type ATTR particularly affects elderly men and may masquerade as age-related heart failure. Red flags include carpal tunnel syndrome requiring surgery, lumbar spinal stenosis, bilateral knee or shoulder replacements—all resulting from amyloid deposition in these tissues years before cardiac involvement becomes apparent.
Next Steps: Not More Imaging, But Specific Testing
Why Not Just Order More Echocardiography?
Once you've identified the red flags, your next step is not to order another echo with strain imaging from a different angle, or a cardiac MRI (though MRI has a role). Your next steps are specific blood tests and nuclear imaging designed to diagnose amyloidosis and determine its type. This distinction is critical because diagnostic certainty requires tissue characterization, and treatment differs dramatically between AL and ATTR amyloidosis.
Serum Free Light Chains: Ruling Out AL Amyloidosis
The first blood test you must order is serum free light chains (FLC) with calculation of the kappa/lambda ratio. In AL amyloidosis, clonal plasma cells produce excess immunoglobulin light chains (either kappa or lambda). These free light chains deposit as amyloid fibrils in tissues.
A normal free light chain ratio (typically 0.26-1.65) makes AL amyloidosis highly unlikely. An abnormal ratio—particularly if the involved free light chain is markedly elevated—suggests AL and requires immediate hematology consultation and consideration of bone marrow biopsy. This is urgent because AL amyloidosis can progress rapidly, and the treatment involves suppressing the clonal plasma cell population with chemotherapy, immunomodulatory drugs, or autologous stem cell transplantation.
You should also order serum protein electrophoresis (SPEP) and immunofixation, and 24-hour urine protein electrophoresis (UPEP) and immunofixation, though serum free light chains are more sensitive for detecting small clonal populations.
Technetium-99m Pyrophosphate Scan: Diagnosing ATTR
If serum free light chains are normal (ruling out AL), your next test is technetium-99m pyrophosphate (PYP) scintigraphy, also known as bone scintigraphy. This nuclear imaging technique has revolutionized ATTR diagnosis. The radiotracer binds preferentially to ATTR cardiac amyloid deposits (the mechanism involves binding to microcalcifications within amyloid).
The scan is graded visually by comparing cardiac uptake to rib uptake: Grade 0 (no cardiac uptake), Grade 1 (mild uptake, less than ribs), Grade 2 (moderate uptake, equal to ribs), Grade 3 (strong uptake, greater than ribs). Grade 2 or 3 uptake, in the absence of a monoclonal protein, has greater than 99% specificity for ATTR cardiac amyloidosis.
This is extraordinary. With a normal free light chain assay and a positive PYP scan, you can diagnose ATTR cardiac amyloidosis non-invasively—no endomyocardial biopsy required. This represents a paradigm shift. Historically, definitive diagnosis required tissue biopsy with Congo red staining and immunohistochemistry or mass spectrometry. Now, in appropriately selected patients, we can diagnose with blood tests and nuclear imaging.
When Biopsy Is Still Needed
If free light chains are abnormal but the clinical picture suggests cardiac involvement, endomyocardial biopsy may be needed to confirm cardiac amyloidosis and differentiate AL from ATTR (since some patients have a monoclonal protein of uncertain significance that's incidental). Fat pad aspiration or biopsy of other affected organs (kidney, liver) can also provide diagnostic tissue in AL amyloidosis.
In hereditary ATTR, genetic testing (TTR gene sequencing) identifies the specific mutation, which has implications for family screening and sometimes for treatment selection.
Conclusion: Changing the Diagnostic Paradigm
We stand at a remarkable juncture in cardiovascular medicine. Cardiac amyloidosis, once considered rare and uniformly fatal, is now recognized as underdiagnosed and, in many forms, treatable. The tools for early detection—echocardiography with strain imaging and electrocardiography—are available in every cardiology practice. The diagnostic tests—serum free light chains and PYP scanning—are widely accessible. The treatments—tafamidis for ATTR, chemotherapy and emerging therapies for AL—can improve survival and quality of life.
But the critical link in this chain is clinical recognition. We must train ourselves and our trainees to pause when we see the paradoxes: thick walls with low voltage, preserved ejection fraction with reduced strain, apical sparing in the presence of basal dysfunction. These aren't merely interesting findings—they're calls to action.
To my fellow educators and clinicians: teach this pattern relentlessly. Show the bull's-eye plots with apical sparing. Put the echo and EKG side by side and let the discordance speak. Make this a reflexive thought process: "I see LVH on echo but low voltage on EKG—I must evaluate for amyloidosis." Because in that moment of recognition, you're not just making a diagnosis. You're opening a window for intervention that may add years of meaningful life to your patient's journey.
The clues are there. We simply need to recognize them and act.
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