When Athletic Performance Declines: A Case of Heart Failure Revealing Hidden Amyloidosis. a25

Table of Contents

• Key Points
• Case Presentation: The Athlete's Mystery Symptoms
• Initial Diagnostic Testing
• Progressive Symptoms and Evolving Findings
• Cardiac Performance Program Evaluation
• Differential Diagnosis: Sorting Through Possibilities
• Clinical Impression and Testing
• Pathological Diagnosis
• Additional Cardiac Features of Amyloidosis
• What This Means for Patients
• Limitations of This Case
• Patient Recommendations
• Frequently Asked Questions
• Source Information

Key Points

• A 54-year-old athlete developed progressive exertional dyspnea and chest pain over 17 months.
• Initial tests ruled out coronary artery disease, but symptoms worsened with new ECG and echo findings.
• Cardiac MRI showed concentric left ventricular thickening and late gadolinium enhancement.
• Elevated kappa:lambda ratio (1178.68) and bone marrow biopsy confirmed AL amyloidosis.
• Early diagnosis is crucial as treatments can slow or halt disease progression.

Case Presentation: The Athlete's Mystery Symptoms

A 54-year-old male athlete was evaluated at a cardiovascular performance clinic for progressive exertional dyspnea (shortness of breath with activity) and chest pain that had developed over 17 months. He had previously maintained excellent health and engaged in vigorous exercise including cycling, hockey, rowing, and triathlons.

The patient first noticed intermittent non-radiating chest pressure and inability to "get a full breath" during high-intensity aerobic exercise 17 months before evaluation. His only prior cardiac history was an episode of dull left-sided chest pain after airline travel 5 years earlier, which had been evaluated with normal troponin levels (a heart enzyme marker) and sinus bradycardia (slow heart rate) on electrocardiogram.

Initial Diagnostic Testing

Five years before his current symptoms, the patient underwent coronary computed tomographic angiography (CTA) for chest pain evaluation. This advanced imaging showed:

• CAD-RADS score of 0 (indicating no atherosclerotic plaque)
• Coronary artery calcium score of 0 (no calcifications)
• No luminal narrowing or noncalcified plaque
• Normal heart chamber size and wall thickness
• Preserved resting systolic function (normal pumping ability)

These results effectively ruled out coronary artery disease as the cause of his current symptoms.

Progressive Symptoms and Evolving Findings

One month after his symptoms began (16 months before current presentation), his primary care physician detected a new grade 2/6 midsystolic murmur. Electrocardiography showed concerning changes including:

• New rightward axis
• Reduced R-wave progression
• New inferolateral T-wave inversions

Normal chest radiography and laboratory tests prompted initiation of aspirin therapy. Stress echocardiography 10 days later revealed exercise-induced ST depressions (2 mm) in inferolateral leads despite no wall motion abnormalities.

Fourteen months before presentation, cardiology evaluation found persistent symptoms and more pronounced T-wave inversions plus a new Q wave in lead aVL. Echocardiography now showed:

• Hyperdynamic left ventricle with symmetric wall thickening (17 mm)
• Systolic intracavitary left ventricular obliteration
• Biatrial and inferior vena cava dilatation
• Right ventricular wall thickening
• Mitral valve thickening

Cardiac MRI performed 14 months before presentation revealed:

• Concentric left ventricular wall thickening up to 18 mm
• Lack of tapering of wall thickness from base to apex
• Focal late gadolinium enhancement affecting 3% of left ventricular myocardium
• Mild anterior mitral leaflet elongation

Genetic testing for 56 genes associated with hypertrophic cardiomyopathy was negative, and the patient's adult children showed no cardiac abnormalities on screening echocardiograms.

Cardiac Performance Program Evaluation

Upon referral to the cardiovascular performance clinic, the patient reported an insidious decline in exercise tolerance, difficulty recovering after exercise, upper abdominal discomfort after eating, and a 2-week history of hoarseness. He denied syncope, lightheadedness, palpitations, or other concerning symptoms.

Examination revealed:

• Heart rate: 81 beats per minute
• Blood pressure: 116/70 mm Hg
• Jugular venous pressure: 13 cm of water
• Kussmaul's sign (paradoxical increase in jugular venous pressure during inspiration)
• Small angiomas (<4 mm) on truncal skin

Electrocardiography showed worsening changes compared to 5 years prior:

• Rightward axis
• T-wave inversions
• Decreased QRS amplitudes

Cardiopulmonary exercise testing revealed severe impairment:

• Peak oxygen consumption: 19.7 ml/kg/min (only 59% of predicted value)
• Normal peak work output: 213 watts (100% of predicted)
• Ventilatory threshold at 83% of peak oxygen consumption
• Impaired oxygen pulse augmentation (indicating reduced stroke volume increase)

Laboratory testing showed elevated cardiac biomarkers:

• High-sensitivity troponin T: 91 ng/liter (normal <9 ng/liter)
• N-terminal pro-B-type natriuretic peptide: 2099 pg/ml (normal <900 pg/ml)

Differential Diagnosis: Sorting Through Possibilities

The medical team considered several potential causes for this athlete's declining cardiac function:

Hypertrophic Cardiomyopathy was initially considered due to the thickened ventricular walls (17-18 mm), mitral valve abnormalities, and late gadolinium enhancement on MRI. However, the rapid 17-month progression was unusual for genetic hypertrophic cardiomyopathy, and genetic testing was negative.

Restrictive Cardiomyopathy became a stronger consideration based on several findings:

• Kussmaul's sign indicating impaired right ventricular filling
• Decreasing QRS voltage despite wall thickening (suggesting infiltrative process)
• Biatrial enlargement with normal ventricular chamber sizes
• Cardiopulmonary testing showing reduced stroke volume augmentation

Among restrictive causes, the team evaluated:

• Noninfiltrative diseases (systemic sclerosis, diabetic cardiomyopathy) - unlikely given history
• Storage diseases (Fabry's, Gaucher's) - no supporting features except skin angiomas
• Hydroxychloroquine toxicity - possible but no history of use
• Sarcoidosis - possible given hoarseness (possibly from laryngeal nerve involvement)
• Amyloidosis - strongly suspected due to ligamentous disease history (rotator cuff tears) and progressive restrictive physiology

Clinical Impression and Testing

The clinical team was struck by the discordance between the patient's previously high aerobic fitness and his severely reduced peak oxygen consumption (59% of predicted). The rapid decline and Kussmaul's sign pointed toward restrictive cardiomyopathies, particularly amyloidosis.

Diagnostic testing for amyloidosis revealed:

• Serum IgG: 715 mg/dl (normal 700-1600)
• Serum IgA: 29 mg/dl (normal 66-436) - low
• Serum IgM: 13 mg/dl (normal 43-279) - low
• Monoclonal kappa light chain protein on immunofixation
• Free lambda light chains: 3.1 mg/liter (normal 5.7-26.3) - low
• Free kappa light chains: 3653.9 mg/liter (normal 3.3-19.4) - severely elevated
• Kappa:lambda ratio: 1178.68 (normal 0.30-1.70) - extremely elevated

These findings were highly suggestive of AL amyloidosis (light chain amyloidosis), prompting referral for bone marrow biopsy.

Pathological Diagnosis

Bone marrow biopsy revealed hypercellular marrow with atypical plasma cells comprising approximately 40% of cellularity. Immunohistochemical staining confirmed these were monoclonal plasma cells producing kappa light chains.

Congo red staining showed apple-green birefringence under polarized light, confirming the presence of amyloid deposits. Mass spectrometry-based proteomics identified the amyloid material as derived from immunoglobulin light chains, specifically AL amyloidosis.

Additional Cardiac Features of Amyloidosis

Repeat echocardiography after the diagnosis showed classic features of cardiac amyloidosis that had evolved from earlier studies:

• Concentric left ventricular hypertrophy
• Granular sparkling appearance of myocardium
• Biatrial enlargement
• Thickened heart valves
• Diastolic dysfunction with restrictive filling pattern
• Pericardial effusion (in some cases)

These findings explained the patient's exercise intolerance, as amyloid infiltration stiffens the heart muscle, impairing its ability to relax and fill properly during exercise.

What This Means for Patients

This case illustrates several important points for patients:

AL amyloidosis is a serious but treatable condition where abnormal plasma cells in bone marrow produce proteins that form amyloid deposits in organs, including the heart. Cardiac involvement typically presents as restrictive cardiomyopathy with:

• Progressive exercise intolerance and shortness of breath
• Low voltage on ECG despite thick heart walls
• Elevated cardiac biomarkers (troponin, NT-proBNP)
• Characteristic imaging findings on echocardiogram and cardiac MRI

Early diagnosis is crucial because available treatments can slow or halt disease progression. The extremely elevated kappa:lambda ratio (1178.68 vs. normal 0.30-1.70) in this case is typical of AL amyloidosis and helps distinguish it from other conditions.

This case is particularly noteworthy because the patient was a high-performance athlete whose symptoms developed insidiously over 17 months. His athletic history initially complicated diagnosis, as some cardiac changes can resemble athlete's heart.

Limitations of This Case

While this case provides valuable insights, several limitations should be noted:

This is a single case report, and findings may not apply to all patients with similar symptoms. The patient's high athletic performance level makes him unusual, and disease presentation may differ in less active individuals.

The diagnosis relied on specialized testing not available at all centers, including advanced cardiac imaging, free light chain assays, and bone marrow biopsy with mass spectrometry. The 17-month delay in diagnosis highlights challenges in recognizing amyloidosis, especially in athletic individuals.

Patient Recommendations

Based on this case, patients should:

1. Seek evaluation for persistent exercise intolerance - especially if you notice a progressive decline in your ability to perform activities that were previously easy
2. Report all symptoms - including seemingly unrelated issues like hoarseness, skin changes, or ligament problems, as these might provide important clues
3. Request cardiac biomarker testing - troponin and NT-proBNP are simple blood tests that can reveal cardiac stress
4. Consider referral to specialists - at centers experienced with complex cardiac cases if initial evaluations are inconclusive
5. Follow up on abnormal findings - even if initial tests are normal, persistent symptoms warrant repeat evaluation

For patients diagnosed with cardiac amyloidosis, current treatments include chemotherapy targeting abnormal plasma cells, stem cell transplantation for eligible patients, and recently developed medications that directly target amyloid deposits.

Frequently Asked Questions

What are the early symptoms of cardiac amyloidosis in athletes?

Early symptoms include progressive shortness of breath during activity, chest pressure, and declining exercise tolerance. In this case, the athlete noticed inability to get a full breath during high-intensity exercise. Other signs like hoarseness, skin changes, or ligament problems may also occur. These symptoms can be mistaken for normal aging or deconditioning, especially in active individuals.

How is cardiac amyloidosis diagnosed?

Diagnosis involves blood tests for cardiac biomarkers (troponin, NT-proBNP) and free light chains, plus imaging like echocardiography and cardiac MRI. A bone marrow biopsy with Congo red staining and mass spectrometry confirms amyloid deposits. In this case, an extremely elevated kappa:lambda ratio (1178.68) strongly suggested AL amyloidosis, which was confirmed by biopsy.

Why does cardiac amyloidosis cause exercise intolerance?

Amyloid deposits stiffen the heart muscle, impairing its ability to relax and fill with blood during exercise. This reduces stroke volume and limits oxygen delivery to muscles. Cardiopulmonary testing in this patient showed severely reduced peak oxygen consumption (59% of predicted) and impaired oxygen pulse augmentation, reflecting the heart's inability to increase output during activity.

What is AL amyloidosis and how does it affect the heart?

AL amyloidosis is a condition where abnormal plasma cells in the bone marrow produce proteins that form amyloid deposits in organs, including the heart. Cardiac involvement causes restrictive cardiomyopathy, making the heart muscle stiff and impairing its ability to relax and fill properly, leading to exercise intolerance and shortness of breath.

What blood tests are used to diagnose cardiac amyloidosis?

Blood tests for cardiac amyloidosis include serum free light chain assays, which measure kappa and lambda light chains and their ratio. In AL amyloidosis, the kappa:lambda ratio is extremely elevated, as seen in this case (1178.68 vs. normal 0.30-1.70). Cardiac biomarkers like troponin and NT-proBNP are also elevated.

What should a patient do if they experience persistent exercise intolerance?

If you experience persistent exercise intolerance, especially a progressive decline in activities that were previously easy, seek evaluation. Report all symptoms, including seemingly unrelated issues like hoarseness or skin changes, and request cardiac biomarker testing. Consider referral to specialists if initial evaluations are inconclusive.

Source Information

Original Article Title: Case 3-2025: A 54-Year-Old Man with Exertional Dyspnea and Chest Pain

Authors: Clyde W. Yancy, M.D., J. Sawalla Guseh II, M.D., Brian G. Ghoshhajra, M.D., Rodney H. Falk, M.D., Andrew J. Yee, M.D., and Bailey M. Hutchison, M.D.

Publication: The New England Journal of Medicine, January 23, 2025; 392:383-94

DOI: 10.1056/NEJMcpc2300900

This patient-friendly article is based on peer-reviewed research from the Massachusetts General Hospital Case Records.