American Heart Month: What Can Squirrels Teach Us About Survival?
Joe Martel was a traveling salesman. He had his first heart attack at the age of 49 while driving on the freeway bringing his 16-year-old daughter home from a party. He was somehow still able to maintain control of his car and drive both of them to the emergency room, but he was never quite the same after that. After his third heart attack, only five years later, one physician wrote in his medical record that he was ‘the greyest man he’d ever seen.’ He died at the age of 59 after suffering a massive coronary in his sleep, only 10 years after his first heart attack. My mother is Joe’s daughter, the same girl he brought home from that party. She had me six years after Joe died and she always regretted that he never got to meet his granddaughter.
My grandfather, Joe Martel, my grandmother and my aunt.
February is American Heart Month. The American Heart Association (AHA) reports that nearly 18.6 million people across the globe died of cardiovascular disease in 2019, the latest year for which worldwide statistics are calculated, which is a 17.1 percent increase over the past decade. 523.2 million cases of cardiovascular disease were reported in 2019, a 26.6 percent increase over 2010 and heart disease is still the number one killer of adults in the U.S. and around the world.
In the search for new therapies, we know that finding people with resistance to disease is a proven path forward. Take the case of PCSK9 inhibitors. In 2005, researchers from the Dallas Heart Study discovered that a subset of Afro-Americans were associated with very low cholesterol levels and markedly reduced incidence of cardiovascular disease.[ref] This built on findings from a researcher in Montreal who linked overactivation of this same gene to increased cholesterol in a French family.[ref] These discoveries have led to two approved therapies (Praluent and Repatha) and many new PCSK9 targeting therapies are in the pipeline, including companies working to permanently disable PCKS9 in humans using CRISPR technology. However, there simply aren’t human populations with naturally evolved disease resistance to many diseases without effective therapies.
Fortunately, the strategy of looking to animals to identify human drug targets is becoming increasingly popular. When it comes to heart research, the 13-lined ground squirrel has been known to survive as many as 25 heart attacks each winter, and humans are 85% identical in the genes responsible for this protection. These are obligate hibernators that have a circannual rhythm, which is an annual hibernation rhythm -- as opposed to humans who, as most of us are aware, have a daily circadian rhythm. These animals hibernate regardless of temperature or food availability.
During the summer the 13-lined ground squirrel’s body temperature is 37C (98.6 F) and their heart rate is around 300 beats per minute (bpm) but in the fall their temperature goes down to just above freezing (4C/39.2F) with a heart rate of 5-10bpm, where they stay for 1-2 weeks before rapidly rewarming to 37C (in interbout arousal (IBA)), where they stay for 12-18 hours and then dropping back down.
This is not easy on the animal’s heart. During this time, their metabolism increases approximately 235-fold and their metabolic demands out-strip blood and oxygen supply, leading to a supply/demand mismatch and a pattern of restricted blood flow and sudden repercussion, very similar to what humans experience during a heart attack or a stroke. Yet the squirrels have only minimal damage and are able to repair what damage their tissues sustain by the end of the hibernation season.
By comparing the genes found in the 13-lined ground squirrel and those in humans, something that was not possible even just 5 years ago, we can now work with new and emerging model systems to find therapies to diseases with high unmet needs, like cardiovascular disease.
And we know this approach works. We have identified new genes that protect the heart and discovered new drugs and shown they work in rodent models of heart attack.
Compounds and genetic targets found to protect the heart. from damage using the Fauna Bio platform. Arrows show areas of damage in untreated animals.
As we take time this February to acknowledge the challenge still facing the millions of people around the world with heart disease, it's important to remember there are new strategies emerging that can help us find new therapies for this and many other diseases without effective therapies.