A new way to prevent cardiac complications in children

Researchers have discovered a new way to treat Kawasaki disease (KD) in children to prevent life-threatening coronary artery damage and heart attacks
.


Wehi-led research has shown that treatment with mTOR inhibitors can prevent coronary artery damage and aneurysm formation, a very frightening complication
of KD.


Importantly, mTOR inhibitors have been shown to be safe and effective in other clinical applications, meaning that the therapy may be rapidly tested
in clinical trials in children with KD.

 

summary  

• Kawasaki disease is the leading cause of acquired heart disease in children

• Existing treatments are effective for most patients with KD, but not all, and those who develop coronary artery damage and aneurysms are at risk of heart attack

• New research provides compelling preclinical evidence that mTOR inhibitors can prevent the progression of coronary artery injury.
  mTOR inhibitors are available and have demonstrated safety and efficacy in other clinical applications

KD mainly affects children under 5 years of age and is the most common cause of
acquired heart disease in children in developed countries.
Up to 300 Australian children are diagnosed with the disease
each year.


The exact cause of KD is unknown, but it is widely believed that common respiratory viral infections, including coronavirus, can cause the disease
.


A major clinical feature of KD is inflammation of blood vessels, particularly the coronary arteries
that supply blood to the heart.


In severe cases, this inflammation causes the coronary arteries to "reshape," leading to narrowing of damaged arteries and aneurysms that weaken the walls of the arteries and swell
like balloons.

 

Risk of heart attack

Severe stenosis and large aneurysms caused by KD can cause potentially fatal damage to the heart and predispose patients to heart attacks
later in life.

 

Professor Ian Wicks, co-head of clinical translation at WEHI, said that even if children with KD survived an aneurysm, their coronary arteries could suffer long-term damage and require treatment
, including surgery.

 

"Preventing coronary artery injury is a top priority for KD treatment," Professor Wicks said
.

 

"Current treatments have been effective in reducing the risk of potentially fatal aneurysms in most children, but we need more options
for children whose KD is resistant to these treatments.
"
 

"The risk of blood clots and heart attack in these children makes it important
for us to find treatments that can prevent coronary artery damage.
"

Dr.
Angus Stock, co-lead author of the study, said the new findings suggest that mTOR inhibitors are able to prevent and treat these adverse changes
in KD patients who develop coronary artery aneurysms.

 

"This is particularly exciting because mTOR inhibitors have been shown to be safe and effective in relevant clinical applications, such as preventing restenosis of arteries after coronary stenting
in adults," he said.

 

The cause of coronary artery damage has been established

The WEHI team first investigated the cellular processes that lead to KD and found that coronary artery remodeling and narrowing are driven
by overactivity of local connective tissue cells called cardiac fibroblasts.


The researchers were able to determine that the source of this abnormal activity is a specialized cell signaling pathway called the rapamycin mechanism target (mTOR).



Analysis of the hearts of patients who died of KD confirmed that mTOR signaling was enhanced or "upregulated"
in fibroblasts of the inflammatory coronary arteries in these children.

 

Dr Stock, Senior Research Officer in WEHI Wicks' lab, explains: "Our study confirms that mTOR proliferates fibroblasts in the coronary arteries, leading to thickening
of the innermost layer of the artery wall.
"

"We then focused on blocking mTOR signaling with rapamycin—the prototype and best-known mTOR inhibitor—as a way to block the proliferation of coronary fibroblasts, thereby preventing aneurysms and coronary artery stenosis
.
" ”
 

The study, published in the journal Arthritis & Rheumatology, shows that in a preclinical model of Kawasaki disease, treatment with rapamycin, also known as sirolimus, can limit fibroblast growth and activity
.


mTOR inhibitors are currently used in adults to treat and prevent coronary artery stenosis and prevent organ rejection after transplantation
.


These drugs can be taken orally, which gives them a clinical advantage
over treatments that must be injected or given intravenously.


Professor Wicks said: "These findings set the stage for clinical trials to evaluate a drug
currently used to prevent coronary artery damage and heart disease in drug-resistant KD patients.


Funding for the study was supported by the UK's National Health Council and World Health Initiative donors Jenny Tatchell and John M.
Courtesy of
T.
Reed Charitable Trusts.


The authors thank and thank the families of the KD patients and the families of organ donors for allowing their tissue samples
to be used in the study.