Carpal tunnel syndrome – Pt 2

AMYLOIDOSIS AND THE HEART

Carpal tunnel syndrome (CTS) can be caused by the accumulation and deposition of an abnormal protein (amyloid) in the structures that lie within the carpal tunnel. Amyloidosis is a generic term for a group of diseases in which different, previously normal soluble proteins misfold and aggregate as fibrous deposits (amyloid fibrils) in different tissues, including the transverse carpal ligament which forms the roof of the carpal tunnel. Additionally, amyloid fibrils accumulate in the synovial tissue, the coverings (sheaths) of the tendons within the tunnel, vessel walls of small arteries and veins, and the connective tissue layers surrounding the fibres of the median nerve.

There are several types of amyloidosis, determined by different configurations of the amyloid protein. The focus of this article is on a systemic amyloidosis caused by the deposition of transthyretinamyloid (ATTR). There are two types of ATTR, the wild type (ATTRwt) and the hereditary (inherited) type, which results from a mutation of the TTR gene. A single mutation can increase the probability of TTR misfolding, leading to amyloid deposition in peripheral nerves, heart muscle, gastrointestinal tract and other tissues/organs.

In December 2019, a multi-institution study led by researchers from the University of Pennsylvania revealed that a genetic variant in the transthyretin (TTR) gene, found in four per cent of individuals of African descent, was under-recognised and underdiagnosed, and is a more significant cause of heart failure than previously believed.

They performed DNA sequencing of 9,694 individuals of African and Latino ancestry enrolled in Penn Medicine BioBank (and Mount Sinai BioMeBioBank), identified carriers of the gene (TTRV1221) and then examined longitudinal electronic health record – linked genetic data to determine which of the carriers had evidence of heart failure.

They found that 44 per cent of the TTR variant carriers older than age 50 had heart failure, but only 11 per cent of these individuals had been diagnosed with ATTR-CA. They also observed a thickening of the wall of one of the heart’s chambers (left ventricle), which could be a sign of early subclinical heart failure, even in patients without heart failure.

EARLY WARNING SIGN

In early studies among patients with amyloid deposition in the carpal tunnel, the majority were of the ATTR type. Although bilateral CTS has long been recognised to be a manifestation of another subtype of amyloidosis [light chain (AL) amyloidosis], recent studies have found this disorder to be even more common in transthyretin amyloidosis. Research indicates that patients with TTR amyloidosis may experience CTS symptoms five to 10 years before developing significant cardiac impairment. CTS may therefore be an early warning sign of amyloidosis and cardiac failure – the feared outcome of TTR amyloidosis.

Transthyretin cardiac amyloidosis (ATTR-CA), also known as transthyretin amyloid cardiomyopathy (ATTR-CM), is a progressive, often life-threatening disease which results from the abnormal misfolded deposits in the heart tissue causing it to thicken and stiffen. The symptoms of heart failure can vary from person to person, but some of the most common include fatigue, shortness of breath, irregular heartbeat, swelling of the feet and hands, breathing difficulty when lying, and sudden falls in blood pressure when standing. Sudden cardiac death is a significant risk for individuals with cardiac amyloidosis, often due to abnormal ventricular rhythms.

CTS, especially when bilateral, may serve as a red flag, an early warning sign many years prior to the onset of systemic amyloidosis,and in particular cardiac amyloidosis, providing ample time to screen and monitor for amyloid development. Cardiac amyloidosis was once considered an untreatable disease, unless patients underwent liver or combined heart – liver transplantation. However, in May 2019, the US Food and Drug Administration (FDA) approved a TTR stabiliser, Tafamidis, for this transthyretin mediated cardiac amyloidosis; and in November 2024 and March 2025, the FDA further approved two new drugs (Acoramidis and Vutrisiran), an indication of the urgency for new treatments to stop the production of the TTR protein and slow down the development of amyloidosis.

These drugs have also been approved for the treatment of transthyretin amyloid polyneuropathy (ATTR-PN), a potentially disabling neuropathy caused by the deposition of abnormal amyloid protein in peripheral nerves. The clinical symptoms and signs are heterogeneous and influenced by several factors, including age of onset, penetrance of the mutation, disease duration and geographic origin – factors which may lead to a difficult and delayed diagnosis. Symptoms typically begin with symmetric distal sensory disturbances (burning, tingling, numbness) in the feet (or hands), shooting pain in the legs, progressing to muscle weakness, balance difficulties making it difficult to walk and eventually use of a wheelchair or confinement to bed.

SYMPTOMS

Many healthcare professionals may not be fully aware of ATTR-CA and its symptoms which can overlap with other cardiac conditions. It is often misdiagnosed as hypertensive heart failure and may already be advanced by the time clinical symptoms are noticed and a definitive diagnosis made.

The frequency of V1221 transthyretin mutation in individuals with bilateral CTS may well be higher than four per cent, which raises the question as to whether screening for this mutation in people of African descent should be increased in order to prevent advanced cardiac (and neurologic) disease associated with ATTR. One of the red flags for ATTR diagnosis is the co-existence of a history of CTS and unexplained cardiomyopathy, particularly hypertrophic cardiomyopathy – a condition in which the muscle tissues of the heart become thickened without an obvious cause.

Fortunately, Dr Ernest Madu, senior consultant cardiologist and chairman of the Heart Institute of the Caribbean and Heart Hospital, and his fellow colleagues have partnered with Yale University in a landmark initiative that is reshaping the future of cardiovascular care in Jamaica and the wider Caribbean. One of their key strategic outcomes is the first-ever determination of TTR cardiac amyloidosis burden in Jamaica.

The connection between carpal tunnel syndrome and heart failure is an emerging, important and fascinating one. It remains unclear what the ideal clinical approach should be for a patient with the diagnosis of idiopathic CTS, especially if the patient is male with bilateral involvement or non-dominant hand symptomatology, since these characteristics may indicate a higher probability of ATTR. All physicians who frequently encounter patients with symptoms/signs of carpal tunnel syndrome, i.e. neurologists, orthopaedic surgeons, neurosurgeons, physiatrists and family medicine physicians, should be aware of the association between these two disorders.

Dr Daniel S. Graham, OD, MD, FACP, is a consultant in clinical neurology, diplomate, American Board of Neurology and Fellowship trained in neurophysiology and neuromuscular diseases. He is the medical director of Neurodiagnostics Limited, Centre for Electrodiagnosis of Neurological Disorders.