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Existing Drug Shows Promise For Abnormal Heart Rhythms
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Ruxolitinib, a drug that is already approved by the U.S. Food and Drug Administration (FDA) for treating certain cancers and skin conditions, is effective at inhibiting CaMKII, a protein kinase linked to cardiac arrhythmias.
In a new study published June 21, 2023, in Science Translational Medicine, researchers from Johns Hopkins University and the University of Chicago invented a new reporting technique to monitor activity of CaMKII while screening the effects of nearly 5,000 FDA approved drugs on human cells that expressed the enzyme. The screen identified five previously unknown CaMKII inhibitors; ruxolitinib, which is used to treat cancers of the blood and bone marrow, along with skin conditions like atopic dermatitis and vitiligo, was the most effective.
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Subscribe for FREECaMKII, or Calcium and calmodulin-dependent protein kinase II, is critical to cardiomyocytes, the muscle cells of the heart, where it maintains the balance of calcium. Activation of CaMKII helps facilitate rapid changes in heart activity, such as initiating a fight-or-flight response in the body. Overactivation can lead to impaired heart function and cell death, which can in turn lead to poor heart health outcomes like arrhythmia.
CaMKII is perhaps best known, however, for its role in the brain, where it is believed to play key roles in learning and memory. This has slowed the development of CaMKII inhibitors to treat arrythmia, for fear they could impact cognitive function.
"Finding an FDA approved drug means that millions of people have been taking CaMKII inhibitors, and in the case of ruxolitinib, there are no reported major problems with the brain," said Mark Anderson, MD, PhD, a senior author of the paper and Dean of the Biological Sciences Division and Pritzker School of Medicine, Executive Vice President for Medical Affairs, and Paul and Allene Russell Professor at the University of Chicago. "That should give pharma and biotech companies confidence that they could carry out development of a CaMKII inhibitor program, because the biggest obstacle seems to be surmountable."
This could be a finding that will translate relatively rapidly into people now since it has already been proven to be safe in humans. Mark Anderson, MD, PhD
The research began in Anderson's lab at Johns Hopkins University, where he previously served as the William Osler Professor and Director of the Department of Medicine. Oscar Reyes Gaido, the study's first author and an MD-PhD student in the lab, developed a new tool to measure activity of CaMKII in living cells. He started with a protein called green fluorescent protein (GFP), originally derived from jellyfish, that emits green light. He then engineered the GFP tag to detect CaMKII activation, making a new reporter called CaMKAR (CaMKII Activity Reporter). When this reporter was inserted into human heart cells, it helpfully glowed bright green whenever CaMKII became active, allowing researchers to monitor enzyme activity.
"This biosensor will be very useful for studying how CaMKII activity changes in both healthy and pathological contexts. Existing methods can measure CaMKII activity, but they lack the versatility and resolution to track in real time and with high sensitivity," Reyes Gaido said. "This has been a real obstacle for studying enzyme biology in general, so this gives the field an important new tool."
Using this tool, the researchers conducted a drug repurposing screen to test the effects of 4,475 approved compounds on cultured human cardiomyocytes. This identified five previously unknown CaMKII inhibitors: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. Of the five, ruxolitinib was the most effective at inhibiting CaMKII activity in cell and mouse models of CaMKII-driven arrhythmias. A 10-minute application of the drug was enough to prevent catecholaminergic polymorphic ventricular tachycardia (CPVT), a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. Crucially, the mice treated with ruxolitinib did not show any adverse cognitive effects when they were tested with memory and learning tasks.
Anderson said that new drugs based on ruxolitinib could be used in several ways to treat heart conditions. One would be what he called the "pill in a pocket" scenario. In the early stages of atrial fibrillation, people could take the medication occasionally as symptoms arise. Patients with CPVT are often resistant to standard treatments, and a ruxolitinib-based treatment could provide another option. Finally, there is evidence that inhibiting CaMKII during a heart attack can prevent heart muscle from dying, so emergency responders could potentially administer such a drug as part of standard practice.
"There's been a long search for fundamental pathways that could be targets for therapeutics in arrhythmias," Anderson said. "This could be a finding that will translate relatively rapidly into people now since it's already been proven to be safe in humans."
Reference: Reyes Gaido OE, Pavlaki N, Granger JM, et al. An improved reporter identifies ruxolitinib as a potent and cardioprotective CaMKII inhibitor. Sci Transl Med. 2023;15(701):eabq7839. Doi: 10.1126/scitranslmed.Abq7839
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Dad, 40, Had No Idea He Had 5 Blocked Arteries. A Checkup Prevented A Heart Attack
While on vacation with his wife last year, Peter Sunwoo heard about a healthy acquaintance who had a heart attack at 39 years old. He and a friend had just turned 40, so they decided to get their hearts checked — just in case.
Sunwoo's doctor appointment led to an early discovery of five extremely blocked arteries, and he underwent surgery to repair them before they caused a heart attack. His doctors couldn't point to a specific cause for the blockages, and Sunwoo didn't have any risk factors, so they speculated that it was likely genetic.
"Luckily, I found out just by chance," Sunwoo, 41, of Brooklyn tells TODAY.Com. "I'm an extremely unlucky person for even having this genetic thing, but at the same time, it's being countered with being extremely lucky because my heart is in complete, functional condition."
A check-up reveals an unknown problemFor much of his life, when Sunwoo ran, he felt a tightness in his chest. He thought running was supposed to feel uncomfortable.
"I always thought when you run you would have a chest tightness — that was always a norm for me. I never thought like, 'Oh, this is a symptom,'" Sunwoo says. "I would cycle a lot or swim. ... Running was not my thing."
Then, on a recent cruise with his wife and friends, Sunwoo and his friend thought they should undergo an examination of their heart health, especially because the acquaintance who had a heart attack seemed healthy and fit.
When Sunwoo went for his cardiac stress test, it revealed some abnormalities. Doctors recommended he undergo a CT scan, which showed a high calcium score. According to the American Heart Association, a calcium score gives doctors an understanding of how much calcium is in the arteries. The higher the score, the more severe the blockage is. A cardiologist reinforced the CT findings, locating five blocked arteries.
More than a year ago, Peter Sunwoo transitioned to a mostly plant-based diet. He increased the amount he exercised, too, to lose some weight.Courtesy Peter Sunwoo "Most people will find out (about blocked arteries) after a heart attack," Sunwoo says.
He says that the severity of his blockages made doctors think that something underlying was going on in his body. He was eating fairly healthy and exercised regularly, recently losing about 50 pounds before his heart problems were discovered.
"It can't be lifestyle is what the doctors (were) saying because there's just nothing you could do to possibly get (a calcium score) that high," he says. "I had no symptoms."
Sunwoo met with Dr. John Puskas, chair of cardiovascular surgery at Mount Sinai Morningside, about bypass surgery. Finding his blocked arteries before a heart attack meant that Sunwoo's heart muscle was still at full capacity, and undergoing a bypass would help keep it that way.
"The way Dr. Puskas has described it is my engine is perfectly fine, but the fuel lines are clogged," he says.
To help clear the blockages, Puskas performed bypass surgery on Sunwoo.
'Blockages are silent until they're not'It's common for people with heart disease to be unaware that something's wrong. Sometimes conditions such as high blood pressure or elevated cholesterol cause no symptoms.
"The blockages are silent until they're not," Puskas tells TODAY.Com. "That sounds silly, but the blockages tend to develop that slowly. They develop because of the deposition of calcium and cholesterol in the walls of the arteries that feed the heart, narrowing the pathway down."
Puskas says CT scans of the heart give doctors a good idea about artery blockage.
"Peter's (calcium) score was 1,789. Normal is anything less than 10. So, 1,789 will put him in the highest top 1% or 2% for his age," Puskas explains. "In fact, he had some damage to the pumping function of his heart even without him being unaware, which is a little unusual."
Doctors aren't exactly sure why Sunwoo experienced such severe blockages as a young age.
"He didn't have a lot of other risk factors," Puskas says. "We're left with a bit of a mystery as to why this particular young man developed these blockages to such an extent in all of the arteries of his heart. When we don't have a good thing to point the finger at, we blame the genes."
Sunwoo's chest pain while running was an early sign of heart troubles, which he did not realize. Still, he visited the doctor before anything catastrophic occurred.
"He came early, and he hadn't suffered a big heart attack, and that's terribly important because bypass surgery prevents another heart attack," Puskas says. "It can't undo a heart attack that's already happened."
Puskas preforms bypass surgery differently than many doctors. A heart bypass surgery involves taking a blood vessel — an artery or vein — from another part of the body and connecting it to the heart so blood can go around the blockage, according to the Mayo Clinic.
Traditional bypass surgery involves the use of a heart-lung machine (which takes over the function of the heart and lungs), a thin tube inserted into the heart, draining the heart of blood, clamping the aorta (the largest artery in the body) and an injection of a high potassium solution to stop the heart. But this type of procedure carries some risks, such as stroke or post-surgery cognitive decline.
Puskas does not use a heart-lung machine, nor does he insert the tube or clamp the aorta. What's more, his blood vessel of choice for a bypass is arteries, not the traditional veins, because arteries are better suited for the high-volume flow of the heart, he says.
While Peter Sunwoo "bounced back" after bypass surgery, he still had to take things slowly.Courtesy Peter Sunwoo Veins "gradually wear out," he says, increasing the chances that a young person who gets a bypass using veins will need another one.
"The veins thicken in response to that high pressure, and they eventually occlude. About half of them will be closed 10 years after the operation," Puskas says. "Those arteries will last the rest of (Sunwoo's) life because they're designed for a high-pressure environment. They're designed to do the job they're doing."
A 'journey for something new'After five days in the hospital, Sunwoo returned home. The next day, he walked five blocks. The day after, he walked 10 blocks. The following day, he walked about 3 miles. By the second week, he began working out on his Peleton for a half an hour. A month after surgery, he was in the gym doing cardio. He couldn't swim or lift heavy weights, but he still felt surprised by how he bounced back.
"It was pretty painful, right?" Sunwoo says. "The recovery was way faster than I thought it would be. But at the same time, I'm a lot younger than most patients that do this (procedure)."
It's been more than three months since the surgery, which means he can return to activities, such as lifting or sleeping on his stomach.
"After 12 weeks, they said, 'Your body won't be at 100%, but you can try everything,'" he says.
He has regular follow-up exams with a cardiologist, and for the rest of his life, he will be taking three medications — aspirin to thin his blood, a statin to lower his cholesterol and another to regulate his heart rate.
The year prior to surgery, Sunwoo started exercising more and focusing on a healthy diet to lose some pandemic pounds. He eats a plant-based diet with two servings of fish per week.
Having bypass surgery changed his focus a bit. He's taken up sailing, and he and his family, including his two kids, planted a garden at their place in upstate New York. Balancing work and life has become really important. He signed up for the New York City triathlon and is hiking 350 miles of the Camino de Santiago, a religious pilgrimage in Spain and Portugal.
"There's a lot of things I missed out on," he says. "It's the beginning of the journey for something new."
Heart Scan Calcium Tests Could Save Your Life
The scan can show signs of coronary artery disease. It's quick and painless.
GREENSBORO, N.C. — Heart scan calcium tests are a quick and painless way to check for coronary artery disease.
It's a simple test that can really save your life.
Often times people dealing with with coronary artery issues have no symptoms and the goal of the scan is to detect it before you do notice any problems.
"The calcium we see in the heart is soft, squishy plaque that has aged over time, cholesterol plaque that is old and been there for years and we're able to detect it with this scan," said Dr. Gayatri Acharya, Cone Health Heart & Vascular Medical Director of Cardiac Imaging.
So who exactly should get this test? Patients without symptoms but who may at risk of heart health issues in the future.
"If you've got calcium it pushes me to be more aggressive with your care and medications. If you don't have calcium, maybe we can let you push a little harder on your own with diet and lifestyle," said Dr. Acharya.
The test is very easy. It does not require an IV or any medications before hand.
The CT scan lasts about 60 seconds and then the patient is done. Your doctor will look over your results and talk with you a few days later.
A heart scan is not the only way to diagnose a problem. High blood pressure, diabetes, and high cholesterol that are not controlled can also be signs you may be dealing with coronary artery disease.
If you think a heart scan calcium test may be for you, talk to your primary care provider. It can be scheduled at any time, you do not have to wait for your annual physical.
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