Nav: Home

Possible treatment breakthrough for the rare disease arrhythmogenic right ventricular cardiomyopathy

September 05, 2019

Arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5) is a fatal genetic disease for which there is unfortunately no cure. Now, scientists at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) and Puerta de Hierro Majadahonda Hospital (Spain) have discovered a possible treatment for this rare disease. The research team, whose findings are published in Circulation, show that strategies to inhibit the kinase GSK3? in mice with the disease reduce fibrosis and improve heart function.

Arrhythmogenic cardiomyopathy can cause sudden cardiac death, especially in young men. Less severely affected men and women with this disease gradually develop heart failure, explained study coordinators Dr Enrique Lara Pezzi, a group leader at the CNIC, and Dr Pablo García-Pavía, director of the Familial Cardiomyopathy Unit in the Cardiology Service at Puerta de Hierro University Hospital, Majadahonda (Madrid).

Arrhythmogenic cardiomyopathy affects an estimated 0.02% to 0.1% of the population, and is therefore classed as a rare disease. ARVC5 is the most aggressive subtype and is caused by a mutation in the TMEM43 gene. The first ARVC5 patients were identified in the island of Newfoundland, Canada, but the disease has since been detected in other regions around the world, including Spain.

The Spanish scientists said that during the early 'hidden' phase of the disease, patients generally show no symptoms, despite already being at risk of arrhythmias and sudden death. Although at early stages the disease predominantly affects the right ventricle, as fibrosis expands it can also impair left ventricular function, and patients develop symptoms and manifestations of heart failure that can require heart transplant.

"Nevertheless, the mechanisms underlying this disease are unknown, and there is currently no cure," said Dr Lara Pezzi. Current treatments are therefore palliative, and the main emphasis is on the prevention of sudden cardiac death by fitting an implantable cardioverter defibrillator (ICD), with subsequent management of heart failure, and possibly heart transplant.

In a clear example of translational research, the groups led by Dr Lara Pezzi and Dr García-Pavía joined forces to find new treatments for this devastating disease that could be used in newly diagnosed patients at Puerta de Hierro hospital. Summarizing the challenge faced by the research team, Dr García-Pavía commented, "We were confronted by a disease about which very little was known and that causes the very early death of several people from the same family."

"We realized that to identify effective treatments we needed to get a better understanding of the disease from its earliest stages. For this, we needed an animal model of the disease that we could study from birth," Dr García-Pavía continued. The two research groups together developed a transgenic mouse line that expresses the mutant version of the human protein TMEM43 and mimics the human disease. The researchers found that the mutant TMEM43 protein activates the protein kinase GSK3?. This leads to the progressive death of heart cells, which are gradually replaced by fibrotic tissue, one of the most characteristic signs of the disease. "After a few months, the hearts of these mice had too few cells to pump blood efficiently, and the heart failure resulted in the death of the animals," explained first author Laura Padrón-Barthe.

The research team tested several possible therapeutic approaches in the mouse model. While treatments directly targeting fibrosis were ineffective, positive results were obtained with two strategies for inhibiting GSK3?, one based on pharmacological inhibition and the other on overexpression of the calcineurin subunit CnAβ1. As Dr Lara Pezzi explained, "both approaches reduced the rate of cardiac cell death, improved cardiac contraction, and prolonged survival."

Nevertheless, the scientists warn that, although the transgenic mouse model mimics human ARVC5, it does not reproduce all disease characteristics. For example, male and female mice are equally affected, whereas the human disease is much more aggressive in men than in women.

Having identified a possible route for effective treatment for the disease in mice, the research team is now working to translate the results to patients. Using the mouse model, the scientists are testing drugs used to treat human heart failure to see if they are effective against ARVC5. The team is also investigating gene therapy strategies that could improve heart function or even cure the disease.
-end-
The study was funded by grants from the Spanish Ministry of Science, Innovation and Universities, the Carlos III Institute of Health, the Community of Madrid regional government, the Spanish Society of Cardiology, and the "Todos somos raros" program of the Isabel Gemio Foundation.

About the CNIC


The Centro Nacional de Investigaciones Cardiovasculares (CNIC), directed by Dr. Valentín Fuster, is dedicated to cardiovascular research and the translation of knowledge gained into real benefits for patients. The CNIC, recognized by the Spanish government as a Severo Ochoa center of excellence, is financed through a pioneering public-private partnership between the government (through the Carlos III Institute of Health) and the Pro-CNIC Foundation, which brings together 12 of the most important Spanish private companies.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (F.S.P.)

Related Heart Failure Articles:

Heart attacks, heart failure, stroke: COVID-19's dangerous cardiovascular complications
A new guide from emergency medicine doctors details the potentially deadly cardiovascular complications COVID-19 can cause.
Autoimmunity-associated heart dilation tied to heart-failure risk in type 1 diabetes
In people with type 1 diabetes without known cardiovascular disease, the presence of autoantibodies against heart muscle proteins was associated with cardiac magnetic resonance (CMR) imaging evidence of increased volume of the left ventricle (the heart's main pumping chamber), increased muscle mass, and reduced pumping function (ejection fraction), features that are associated with higher risk of failure in the general population
Transcendental Meditation prevents abnormal enlargement of the heart, reduces chronic heart failure
A randomized controlled study recently published in the Hypertension issue of Ethnicity & Disease found the Transcendental Meditation (TM) technique helps prevent abnormal enlargement of the heart compared to health education (HE) controls.
Beta blocker use identified as hospitalization risk factor in 'stiff heart' heart failure
A new study links the use of beta-blockers to heart failure hospitalizations among those with the common 'stiff heart' heart failure subtype.
Type 2 diabetes may affect heart structure and increase complications and death among heart failure patients of Asian ethnicity
The combination of heart failure and Type 2 diabetes can lead to structural changes in the heart, poorer quality of life and increased risk of death, according to a multi-country study in Asia.
Preventive drug therapy may increase right-sided heart failure risk in patients who receive heart devices
Patients treated preemptively with drugs to reduce the risk of right-sided heart failure after heart device implantation may experience the opposite effect and develop heart failure and post-operative bleeding more often than patients not receiving the drugs.
How the enzyme lipoxygenase drives heart failure after heart attacks
Heart failure after a heart attack is a global epidemic leading to heart failure pathology.
Novel heart pump shows superior outcomes in advanced heart failure
Severely ill patients with advanced heart failure who received a novel heart pump -- the HeartMate 3 left ventricular assist device (LVAD) -- suffered significantly fewer strokes, pump-related blood clots and bleeding episodes after two years, compared with similar patients who received an older, more established pump, according to research presented at the American College of Cardiology's 68th Annual Scientific Session.
NSAID impairs immune response in heart failure, worsens heart and kidney damage
Non-steroidal anti-inflammatory drugs, or NSAIDs, are widely known as pain-killers and can relieve pain and inflammation.
Heart cell defect identified as possible cause of heart failure in pregnancy
A new Tel Aviv University study reveals that one of the possible primary causes of heart failure in pregnant women is a functional heart cell defect.
More Heart Failure News and Heart Failure Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Making Amends
What makes a true apology? What does it mean to make amends for past mistakes? This hour, TED speakers explore how repairing the wrongs of the past is the first step toward healing for the future. Guests include historian and preservationist Brent Leggs, law professor Martha Minow, librarian Dawn Wacek, and playwright V (formerly Eve Ensler).
Now Playing: Science for the People

#565 The Great Wide Indoors
We're all spending a bit more time indoors this summer than we probably figured. But did you ever stop to think about why the places we live and work as designed the way they are? And how they could be designed better? We're talking with Emily Anthes about her new book "The Great Indoors: The Surprising Science of how Buildings Shape our Behavior, Health and Happiness".
Now Playing: Radiolab

The Third. A TED Talk.
Jad gives a TED talk about his life as a journalist and how Radiolab has evolved over the years. Here's how TED described it:How do you end a story? Host of Radiolab Jad Abumrad tells how his search for an answer led him home to the mountains of Tennessee, where he met an unexpected teacher: Dolly Parton.Jad Nicholas Abumrad is a Lebanese-American radio host, composer and producer. He is the founder of the syndicated public radio program Radiolab, which is broadcast on over 600 radio stations nationwide and is downloaded more than 120 million times a year as a podcast. He also created More Perfect, a podcast that tells the stories behind the Supreme Court's most famous decisions. And most recently, Dolly Parton's America, a nine-episode podcast exploring the life and times of the iconic country music star. Abumrad has received three Peabody Awards and was named a MacArthur Fellow in 2011.