Low Plasma Transthyretin Linked to Risk of
Heart Failure

Fran Lowry

December 10, 2020

Low plasma transthyretin, also known as prealbumin, is associated with incident heart failure in the general population, new research suggests.

In two prospective, population-based studies done in the Danish general population, individuals with very low concentration of plasma transthyretin (at the 5th percentile or lower) had a 1.4-fold to 1.6-fold increased risk of incident heart failure on long-term follow-up, with men having a higher risk than women.

The data also showed that genetic variants in transthyretin that are associated with reduced tetramer stability were associated with lower transthyretin concentration, and thus, a higher risk of heart failure, and that other genetic variants that were linked to increased tetramer stability were associated with high transthyretin levels and lowest risk of incident heart failure.

The research was published online November 25 in JAMA Cardiology.

"Transthyretin is one of the proteins that can cause amyloidosis, that is, extracellular deposition of amyloid fibrils locally or throughout the body," senior author Anne Tybjærg-Hansen, MD, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, said in an Author Audio Interview podcast. "These deposited fibrils are cytotoxic and they eventually lead to failure of the affected organs."

"Transthyretin amyloidosis with cardiac involvement is the most common phenotype of transthyretin amyloidosis and it is increasingly recognized as an important contributor to heart failure and mortality in older individuals," Tybjærg-Hansen added.

Transthyretin circulates as a tetrameric protein and the tetramers may become unstable and amyloidogenic, either because of mutations in the transthyretin gene or as a result of advancing age.

The genetic mutations are a cause of hereditary transthyretin amyloidosis, which is a rare condition. More commonly, the tetramers can become unstable with age, causing wild type transthyretin amyloidosis.

"So, transthyretin amyloidosis is probably heavily underdiagnosed and also misdiagnosed as other forms of cardiovascular disease. The prevalence in the general population is unknown and there are also currently no biomarkers to inform on future cardiac involvement in initially asymptomatic individuals," Tybjærg-Hansen said.

To test their hypothesis that low plasma transthyretin concentration is linked to heart failure in the general population, the researchers looked at data from the Copenhagen General Population Study (CGPS), which included 9582 individuals (53% women, median age 56 years), and had a median follow-up of 13 years, and the Copenhagen City Heart Study (CCHS), which included 7385 individuals (60.3% women, median age 59 years), with a median follow-up of 22 years.

"The rationale for this basically rests on the assumption that low plasma transthyretin concentration is an in vivo biomarker of transthyretin tetramer instability, which is a prerequisite for the development of both the wild type form of cardiac amyloidosis, and the hereditary form of cardiac amyloidosis," Tybjærg-Hansen said.

In the second part of the study, the researchers looked at whether genetic variants in transthyretin associated with increasing tetramer instability were associated with lower transthyretin concentration and with higher risk of heart failure.

Data were collected from November 2003 to March 2017 in the CGPS, and from November 1991 to June 1994 in the CCHS.

Individuals with low concentration of plasma transthyretin, at the 5th percentile or lower, corresponding to values less than 19.0 mg/dL, had roughly one and a half times the risk of developing heart failure. In the CGPS, the hazard ratio (HR) was 1.6 (95% CI, 1.1 - 2.4). In the CCHS, the HR was 1.4 (95% CI, 1.1 - 1.7). The risk of heart failure was highest in men.

The researchers also found a stepwise association between transthyretin genetic variants, transthyretin levels, and incident heart failure. Variants associated with the lowest transthyretin levels were associated with the highest risk of incident heart failure, and the stabilizing variant T139M was associated with the highest transthyretin levels and lowest risk of incident heart failure.

Writing in an accompanying editorial, Sanjiv J. Shah, MD, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, notes that the findings are compelling for two reasons.

"They provide novel insight into the pathogenesis of heart failure that could be associated with amyloidogenic transthyretin cardiomyopathy (ATTR-CM) in the general population, and they open the possibility that low concentrations of transthyretin may be useful as a test that could alert clinicians to the possibility of a patient being at risk for having overt ATTR-CM, which could lead to confirmatory tests and earlier diagnosis," writes Shah, who is also an associate editor of JAMA Cardiology,.

In an interview with theheart.org | Medscape Cardiology, Shah estimated that somewhere between 3% to 4% of patients with heart failure with preserved ejection fraction have ATTR-CM.

"The current thinking is that it is underdiagnosed and clinicians aren't aware of it, but I think that awareness is increasing. There have been studies that have shown that the diagnosis of transthyretin cardiac amyloidosis, especially the wild type, the form that is not genetically mediated, is going up," Shah said. "The number of diagnoses is going up a lot, but it's a bit unclear whether that has to do with increased recognition or that it is actually happening more commonly, or due to the aging of the population. It's probably around 120,000 individuals in the United States alone."

Also unknown is the cause. "We don’t really know," he said. "We know that men are more affected, we know that aging is a big risk factor, but other than that, we're not really sure why in some people, their transthyretin starts to misfold. The other thing we don't know is why in some of those people amyloid fibrils start to develop and deposit into the heart muscle.

"Also, although I don't think there is any literature on this, one element in the history that seems to be present in many patients with the wild type of transthyretin amyloidosis [is they] either had a job that required heavy physical work or participated in competitive sports at a high level," he added.

There are two theories about potential association, Shah said. "One is that these individuals who are physically active and healthy enough to live to [age] 80 develop ATTR-CM. The other is that there is something about the intense physical stress that does something to the heart that makes it more susceptible to amyloid fibril deposition," he added. "This is just one of the hypotheses. We don't know if it is correct or not, but it's an interesting one."

Currently, the transthyretin stabilizer tafamidis (Vyndamax) is the only US Food and Drug Administration (FDA)-approved drug to treat ATTR-CM.

The drug received expedited approval from the FDA in May 2019 after phase 3 trials showed that it reduces all-cause mortality and cardiovascular hospitalizations and slows decline in quality of life compared with placebo.

The FDA deemed it to be a breakthrough drug for a rare disease, but its huge cost, at $225,000 per year, limits its use.

Other drugs that are used to treat polyneuropathy as a result of hereditary transthyretin amyloidosis (the "TTR silencers"), which are in development for transthyretin cardiac amyloidosis, cost even more — up to $450,000 a year, said Shah.

"We have the potential to improve diagnosis of ATTR-CM with a blood test, but if we can't afford to give the drug to the estimated 120,000 people in the US with this disease, it's not going to do us any good," he said.

The study was sponsored by The Research Fund at Rigshospitalet, Copenhagen University Hospital, Chief Physician Johan Boserup and Lise Boserup’s Fund, Ingeborg and Leo Dannin’s Grant, and Henry Hansen’s and Wife’s Grant and a grant from the Odd Fellow Order. Tybjærg-Hansen has disclosed no relevant financial relationships. Shah reports financial relationships with Pfizer (research grant, consulting fees), Eidos (consulting fees), Ionis (consulting fees) and Prothena (consulting fees).

JAMA Cardiol. Published online November 25, 2020. Abstract, Editorial

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