Heart Ailment Can Be Reversed, Study Shows

In an extraordinary example presented by a team at UCL (University College London) and the Royal Free Hospital, three men who experienced heart failure caused by the buildup of sticky, poisonous proteins are now free of symptoms.

The disease, a kind of amyloidosis that affects the heart, is progressive and has previously been thought to be irreversible, with half of patients dying within four years of diagnosis.

The new study, published as a letter in The New England Journal of Medicine, details the recovery of three men, ages 68, 76, and 82, who were diagnosed with transthyretin cardiac amyloidosis but later recovered. Objective evaluations, such as cardiovascular magnetic resonance (CMR) scans, showed that the buildup of amyloid proteins in the heart had cleared, confirming their own observations of symptoms resolving.Lead author Professor Marianna Fontana (UCL Division of Medicine) said, “We have seen for the first time that the heart can get better with this disease. That has not been known until now and it raises the bar for what might be possible with new treatments.”

The researchers also discovered evidence of an immune response that particularly targeted amyloid in the three guys. Other patients whose conditions proceeded normally did not have amyloid-targeting antibodies.

Senior author Professor Julian Gillmore (UCL Division of Medicine), Head of the UCL Centre for Amyloidosis, based at the Royal Free Hospital, said, “Whether these antibodies caused the patients’ recovery is not conclusively proven. However, our data indicates that this is highly likely and there is potential for such antibodies to be recreated in a lab and used as a therapy. We are currently investigating this further, although this research remains at a preliminary stage.”

Amyloid deposits of a blood protein called transthyretin (TTR) induce transthyretin (ATTR) amyloidosis. It can be inherited or acquired (“wild-type”). ATTR amyloid cardiomyopathy (ATTR-CM) is the accumulation of these protein deposits in the heart.

Current NHS treatments aim to relieve the symptoms of heart failure (such as fatigue, swelling in the legs or abdomen, and shortness of breath with activity), but do not address the amyloid (although a number of “gene-silencing” therapies that reduce TTR protein concentration in the blood and thus slow ongoing amyloid formation are currently being trialed).
Advances in imaging techniques—some of which were pioneered at the UCL Centre for Amyloidosis—has meant substantially more people being diagnosed with the disease than was the case 20 years ago. Previously, a biopsy (tissue obtained from the heart) was required for diagnosis.

The imaging techniques also mean the burden of amyloid on the heart, and consequently the progression of the disease, can be more precisely monitored, making it easier to detect cases where the condition has reversed, rather than merely remaining stable.

The newest study, funded by the Royal Free Charity, began when a 68-year-old man reported that his symptoms were improving. This motivated the research team to examine the medical data of 1,663 ATTR-CM patients. Two further instances were discovered among these patients.

The three men’s recoveries were confirmed via blood tests, several imaging techniques including echocardiography (a type of ultrasound), CMR scans and scintigraphy (a nuclear medicine bone scan), and, for one patient, an assessment of exercise capacity. CMR scans revealed that the heart structure and function had restored to near-normal levels, and the amyloid had almost totally removed.

An examination of the records and assessments for the remaining 1,663 patients revealed that these three individuals were the only ones whose condition had improved.

One of the three males had a cardiac muscle biopsy, which demonstrated an unusual inflammatory response (containing white blood cells known as macrophages) surrounding the amyloid plaques, indicating an immunological response. In 286 samples from individuals whose disease progressed normally, no similar inflammatory response was found.

Further investigation revealed antibodies in the three patients that bind particularly to ATTR amyloid plaques in mouse and human tissue, as well as synthetic ATTR amyloid. There were no such antibodies in the 350 other patients in the sample who had a typical clinical history.

If these antibodies could be harnessed, they could be combined with new therapies being trialed that suppress TTR protein production, enabling clinicians to clear away amyloid as well as preventing further amyloid deposition.

A single intravenous infusion of NTLA-2001, a new gene-editing therapy based on CRISPR/Cas9, is one such promising therapeutic. The trial’s preliminary findings, conducted by Professor Gillmore, suggest that it may be able to halt disease development.

The UCL Centre for Amyloidosis is one of the world’s leading centers for amyloid research. It includes the NHS National Amyloidosis Centre, the only center in the UK specializing in amyloidosis.

Jon Spiers, chief executive of the Royal Free Charity, said, “As an NHS charity, we are proud to be supporting this research. Our priority is to drive early-stage research that brings innovative treatments to patients sooner.”

“This work not only represents a major breakthrough in our understanding of cardiac amyloidosis, but crucially opens up new possibilities for more effective treatment options. It’s a hugely significant development that we welcome on behalf of all patients of the National Amyloidosis Centre and their families, many of whom have contributed to our research funding with their own fundraising efforts.”

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