Primary care physicians (PCPs) are often the first to encounter patients with early cardiac amyloidosis, well in advance of when these patients are referred for advanced heart failure care. In individuals with obesity and type 2 diabetes, early symptoms are frequently attributed to cardiometabolic disease alone, allowing amyloid cardiomyopathy to progress undetected until recurrent hospitalizations or advanced cardiac dysfunction force further evaluation.

In fact, among Medicare beneficiaries aged 65 years or older, the incidence of transthyretin cardiac amyloidosis (ATTR-CM) diagnoses rose from about 10.1 per 100,000 person-years in 2010 to 38.9 per 100,000 in 2023, and prevalence climbed from 15.8 per 100,000 to 85.6 per 100,000 in the same period, according to a January 2025 study in the Journal of Cardiac Failure. The study also showed that incidence and prevalence increased in commercially insured populations, with older age groups and men showing the largest gains.

“The rising prevalence of obesity and type 2 diabetes is expanding the HFpEF [heart failure with preserved ejection fraction] population, which increases the absolute number of patients who could have underlying ATTR-CM — especially wild-type ATTR, an important but often under-recognized cause of HFpEF,” said Cynthia A. Kos, DO, an advanced HF cardiologist at the Jersey Shore University Medical Center Advanced Heart Failure Center based in Hackensack, New Jersey. “However, because obesity and diabetes provide convenient alternative explanations for heart failure symptoms, ATTR is frequently missed unless clinicians actively test for it.”

Kos added that because evaluation for amyloidosis routinely includes screening for primary amyloidosis, “more evaluations mean we may identify more cases of both.”

However, before these individuals present at cardiology clinics, they present in primary care with subtle, overlapping complaints: fatigue, exertional intolerance, neuropathy, carpal tunnel syndrome, or “typical” HFpEF attributed to obesity or type 2 diabetes. 

For PCPs, recognizing when these common explanations no longer fully account for a patient’s symptoms can be the difference between early diagnosis and years of missed disease.

When ‘Typical’ Isn’t Typical and Red Flags Not to Ignore

Both Kos and Wahaj Aman, MD, a cardiologist with Memorial Hermann and UTHealth Houston, said the diagnostic challenge for PCPs is not recognizing HFpEF — it’s recognizing when HFpEF no longer fits the expected pattern. In treating patients on a longitudinal basis, pattern recognition across visits is where PCPs can make a big difference in being able to spot changes and irregularities.

“With obesity and type 2 diabetes, many symptoms and signs on EKG or imaging can overlap with amyloidosis,” Aman said. “People are quick to attribute everything to diabetes or obesity, but clinicians should look more deeply.”

HFpEF itself is common in cardiometabolic disease, creating fertile ground for misattribution, Aman said.

Kos recommends heightened suspicion in older adults with HFpEF when cardiac findings seem out of proportion to a patient’s clinical history.

She said particular red flags to look out for are left ventricular hypertrophy that cannot be explained by longstanding hypertension, low-voltage EKGs despite increased wall thickness on imaging, and evidence of conduction disease, including atrial fibrillation, chronotropic incompetence, or the need for a new pacemaker, and that these should prompt reconsideration of the diagnosis.

Signs of autonomic dysfunction, such as orthostatic symptoms, may further signal an underlying infiltrative cardiomyopathy rather than routine HFpEF, according to Kos.

Aman added a couple of classic “tells” to look out for in the early going.

“When the heart muscle is thick, the EKG usually shows high voltage. In amyloidosis, voltage is low despite thickened muscle,” he said. “Also, disproportionately elevated NT-proBNP (N-terminal pro-brain natriuretic peptide) levels — particularly when patients are not overtly volume overloaded — should also raise suspicion,” he said.

Both experts emphasized that amyloidosis is often systemic long before it becomes overtly cardiac, leaving other clues for attentive PCPs. Kos said there are significant orthopedic and neurologic symptoms, for example.

“Bilateral carpal tunnel syndrome, lumbar spinal stenosis, biceps tendon rupture, and rotator cuff or labral tears can precede heart failure or cardiomyopathy symptoms by years,” she said.

Neuropathy deserves special scrutiny when diabetes severity does not match symptoms, according to Aman.

“Patients may have neuropathy even though their A1c or diabetes markers are not high enough to explain it,” he said. He characterized this as well as lightheadedness with position changes, gastrointestinal motility issues, and carpal tunnel syndrome as part of a concerning “constellation of symptoms.”

Amyloid light-chain (AL) amyloidosis presents a bit differently, Kos said. In this rare disease, she emphasized systemic involvement that can include proteinuria, peripheral neuropathy, unexplained hepatomegaly, and physical exam findings such as macroglossia (an oversized tongue) or periorbital purpura (suddenly arising dark bruising around the eyes).

When to Move This Up on Your Checklist

Obesity and diabetes increase the diagnostic noise when keeping an eye out for cardiac amyloidosis, but they don’t define risk, according to these experts.

“Common patient characteristics for ATTR patients include adults, typically greater than 60 years old, male predominance, with unexplained left ventricular hypertrophy out of proportion to hypertensive disease,” Kos said. “(There’s an) initially slow onset of cardiac symptoms, but comorbid orthopedic complaints, particularly bilateral carpal tunnel, should raise a high level of suspicion.”

Kos said that AL amyloidosis may present slightly earlier — often after age 50 — with no sex predilection, and that patients may exhibit a more rapid clinical decline. She said that multiorgan involvement is common in this disease.

“A family history of neuropathy or cardiomyopathy may suggest hereditary variants of either disease,” she said.

Aman summarized the practical takeaway for PCPs.

“People with multiple risk factors whose symptoms seem out of proportion to those risk factors — that is the biggest clue,” he said.

No reported disclosures.