How 30 Years of Heart Surgeries Taught My Dad How to Live
[Editor's Note: This piece is the winner of our 2019 essay contest, which prompted readers to reflect on the question: "How has an advance in science or medicine changed your life?"]
My father did not expect to live past the age of 50. Neither of his parents had done so. And he also knew how he would die: by heart attack, just as his father did.
In July of 1976, he had his first heart attack, days before his 40th birthday.
My dad lived the first 40 years of his life with this knowledge buried in his bones. He started smoking at the age of 12, and was drinking before he was old enough to enlist in the Navy. He had a sarcastic, often cruel, sense of humor that could drive my mother, my sister and me into tears. He was not an easy man to live with, but that was okay by him - he didn't expect to live long.
In July of 1976, he had his first heart attack, days before his 40th birthday. I was 13, and my sister was 11. He needed quadruple bypass surgery. Our small town hospital was not equipped to do this type of surgery; he would have to be transported 40 miles away to a heart center. I understood this journey to mean that my father was seriously ill, and might die in the hospital, away from anyone he knew. And my father knew a lot of people - he was a popular high school English teacher, in a town with only three high schools. He knew generations of students and their parents. Our high school football team did a blood drive in his honor.
During a trip to Disney World in 1974, Dad was suffering from angina the entire time but refused to tell me (left) and my sister, Kris.
Quadruple bypass surgery in 1976 meant that my father's breastbone was cut open by a sternal saw. His ribcage was spread wide. After the bypass surgery, his bones would be pulled back together, and tied in place with wire. The wire would later be pulled out of his body when the bones knitted back together. It would take months before he was fully healed.
Dad was in the hospital for the rest of the summer and into the start of the new school year. Going to visit him was farther than I could ride my bicycle; it meant planning a trip in the car and going onto the interstate. The first time I was allowed to visit him in the ICU, he was lying in bed, and then pushed himself to sit up. The heart monitor he was attached to spiked up and down, and I fainted. I didn't know that heartbeats change when you move; television medical dramas never showed that - I honestly thought that I had driven my father into another heart attack.
Only a few short years after that, my father returned to the big hospital to have his heart checked with a new advance in heart treatment: a CT scan. This would allow doctors to check for clogged arteries and treat them before a fatal heart attack. The procedure identified a dangerous blockage, and my father was admitted immediately. This time, however, there was no need to break bones to get to the problem; my father was home within a month.
During the late 1970's, my father changed none of his habits. He was still smoking, and he continued to drink. But now, he was also taking pills - pills to manage the pain. He would pop a nitroglycerin tablet under his tongue whenever he was experiencing angina (I have a vivid memory of him doing this during my driving lessons), but he never mentioned that he was in pain. Instead, he would snap at one of us, or joke that we were killing him.
I think he finally determined that, if he was going to have these extra decades of life, he wanted to make them count.
Being the kind of guy he was, my father never wanted to talk about his health. Any admission of pain implied that he couldn't handle pain. He would try to "muscle through" his angina, as if his willpower would be stronger than his heart muscle. His efforts would inevitably fail, leaving him angry and ready to lash out at anyone or anything. He would blame one of us as a reason he "had" to take valium or pop a nitro tablet. Dinners often ended in shouts and tears, and my father stalking to the television room with a bottle of red wine.
In the 1980's while I was in college, my father had another heart attack. But now, less than 10 years after his first, medicine had changed: our hometown hospital had the technology to run dye through my father's blood stream, identify the blockages, and do preventative care that involved statins and blood thinners. In one case, the doctors would take blood vessels from my father's legs, and suture them to replace damaged arteries around his heart. New advances in cholesterol medication and treatments for angina could extend my father's life by many years.
My father decided it was time to quit smoking. It was the first significant health step I had ever seen him take. Until then, he treated his heart issues as if they were inevitable, and there was nothing that he could do to change what was happening to him. Quitting smoking was the first sign that my father was beginning to move out of his fatalistic mindset - and the accompanying fatal behaviors that all pointed to an early death.
In 1986, my father turned 50. He had now lived longer than either of his parents. The habits he had learned from them could be changed. He had stopped smoking - what else could he do?
It was a painful decade for all of us. My parents divorced. My sister quit college. I moved to the other side of the country and stopped speaking to my father for almost 10 years. My father remarried, and divorced a second time. I stopped counting the number of times he was in and out of the hospital with heart-related issues.
In the early 1990's, my father reached out to me. I think he finally determined that, if he was going to have these extra decades of life, he wanted to make them count. He traveled across the country to spend a week with me, to meet my friends, and to rebuild his relationship with me. He did the same with my sister. He stopped drinking. He was more forthcoming about his health, and admitted that he was taking an antidepressant. His humor became less cruel and sadistic. He took an active interest in the world. He became part of my life again.
The 1990's was also the decade of angioplasty. My father explained it to me like this: during his next surgery, the doctors would place balloons in his arteries, and inflate them. The balloons would then be removed (or dissolve), leaving the artery open again for blood. He had several of these surgeries over the next decade.
When my father was in his 60's, he danced at with me at my wedding. It was now 10 years past the time he had expected to live, and his life was transformed. He was living with a woman I had known since I was a child, and my wife and I would make regular visits to their home. My father retired from teaching, became an avid gardener, and always had a home project underway. He was a happy man.
Dancing with my father at my wedding in 1998.
Then, in the mid 2000's, my father faced another serious surgery. Years of arterial surgery, angioplasty, and damaged heart muscle were taking their toll. He opted to undergo a life-saving surgery at Cleveland Clinic. By this time, I was living in New York and my sister was living in Arizona. We both traveled to the Midwest to be with him. Dad was unconscious most of the time. We took turns holding his hand in the ICU, encouraging him to regain his will to live, and making outrageous threats if he didn't listen to us.
The nursing staff were wonderful. I remember telling them that my father had never expected to live this long. One of the nurses pointed out that most of the patients in their ward were in their 70's and 80's, and a few were in their 90's. She reminded me that just a decade earlier, most hospitals were unwilling to do the kind of surgery my father had received on patients his age. In the first decade of the 21st century, however, things were different: 90-year-olds could now undergo heart surgery and live another decade. My father was on the "young" side of their patients.
The Cleveland Clinic visit would be the last major heart surgery my father would have. Not that he didn't return to his local hospital a few times after that: he broke his neck -- not once, but twice! -- slipping on ice. And in the 2010's, he began to show signs of dementia, and needed more home care. His partner, who had her own health issues, was not able to provide the level of care my father needed. My sister invited him to move in with her, and in 2015, I traveled with him to Arizona to get him settled in.
After a few months, he accepted home hospice. We turned off his pacemaker when the hospice nurse explained to us that the job of a pacemaker is to literally jolt a patient's heart back into beating. The jolts were happening more and more frequently, causing my Dad additional, unwanted pain.
My father in 2015, a few months before his death.
My father died in February 2016. His body carried the scars and implants of 30 years of cardiac surgeries, from the ugly breastbone scar from the 1970's to scars on his arms and legs from borrowed blood vessels, to the tiny red circles of robotic incisions from the 21st century. The arteries and veins feeding his heart were a patchwork of transplanted leg veins and fragile arterial walls pressed thinner by balloons.
And my father died with no regrets or unfinished business. He died in my sister's home, with his long-time partner by his side. Medical advancements had given him the opportunity to live 30 years longer than he expected. But he was the one who decided how to live those extra years. He was the one who made the years matter.
An Investigational Drug Offers Hope to Patients with a Disabling Neuromuscular Disease
Robert Thomas was a devoted runner, gym goer, and crew member on a sailing team in San Diego when, in his 40s, he noticed that his range of movement was becoming more limited.
He thought he was just getting older, but when he was hiking an uphill trail in Lake Tahoe, he kept tripping over rocks. "I'd never had this happen before," Robert says. "I knew something was wrong but didn't know what it was."
It wasn't until age 50 when he was diagnosed with Charcot-Marie-Tooth disease. The genetic disorder damages the peripheral nerves, which connect the brain and spinal cord to the rest of the body. This network of nerves is responsible for relaying information and signals about sensation, movement, and motor coordination. Over time, the disease causes debilitating muscle weakness and the loss of limb control.
Charcot-Marie-Tooth usually presents itself in childhood or in a person's teens, but in some patients, like Robert, onset can be later in life. Symptoms may include muscle cramping, tingling, or burning. Many patients also have high foot arches or hammer toes — toes that curl from the middle joint instead of pointing forward. Those affected often have difficulty walking and may lose sensation in their lower legs, feet, hands, or forearms. One of the most common rare diseases, it affects around 130,000 people in the United States and 2.8 million worldwide.
Like many people with Charcot-Marie-Tooth, or CMT, Robert wears corrective braces on his legs to help with walking. Now 61, he can't run or sail anymore because of the disease, but he still works out regularly and can hike occasionally. CMT also affects his grip, so he has to use special straps while doing some exercises.
For the past few years, Robert has been participating in a clinical trial for an investigational CMT drug. He takes the liquid formulation every morning and evening using an oral syringe. Scientists are following patients like Robert to learn if their symptoms stabilize or improve while on the drug. Dubbed PXT300, the drug was designed by French biopharmaceutical company Pharnext and is the farthest along in development for CMT. If approved, it would be the first drug for the disease.
Currently, there's no cure for CMT, only supportive treatments like pain medication. Some individuals receive physical and occupational therapy. A drug for CMT could be a game-changer for patients whose quality of life is severely affected by the disease.
Genetic Underpinnings
CMT arises from mutations in genes that are responsible for creating and maintaining the myelin sheath — the insulating layer around nerves. Pharnext's drug is meant to treat patients with CMT1A, the most common form of the disease, which represents about half of CMT cases. Around 5% of those with CMT1A become severely disabled and end up in wheelchairs. People with CMT1A have an extra copy of the gene PMP22, which makes a protein that's needed to maintain the myelin sheath around peripheral nerves.
Typically, an individual inherits one copy of PMP22 from each parent. But a person with CMT1A receives a copy of PMP22 from one parent and two copies from a parent with the disease. This extra copy of the gene results in excess protein production, which damages the cells responsible for preserving and regenerating the myelin sheath, called Schwann cells.
The myelin sheath helps ensure that a signal from the brain gets carried to nerves in the muscles so that a part of the body can carry out a particular action or movement. This sheath is like the insulation on an electrical cord and the action is like a light bulb. If the insulation is fine, the light bulb turns on. But if the insulation is frayed, the light will flicker.
"The same happens to these patients," says David Horn Solomon, CEO of Pharnext. "The signal to their muscle is weak and flickers." Over time, their muscles become weaker and thinner.
The PMP22 gene has proven difficult to target with a drug because it's located in a protected space — the Schwann cells that make up the insulation around nerves. "There's not an easy way to tamp it down," Solomon says.
Another company, Acceleron Pharma of Cambridge, Massachusetts, was developing an injectable CMT drug meant to increase the strength of leg muscles. But the company halted development last year after the experimental drug failed in a mid-stage trial. While the drug led to a statistically significant increase in muscle volume, it didn't translate to improvements in muscle function or quality of life for trial participants.
Made by Design
Pharnext's drug, PXT3003, is a combination of three existing drugs — baclofen, a muscle relaxant; naltrexone, a drug that decreases the desire for alcohol and opioids; and sorbitol, a type of sugar alcohol.
The company designed the drug using its artificial intelligence platform, which screened 20,000 existing drugs to predict combinations that could inhibit the PMP22 gene and thereby lower protein production. The AI system narrowed the search to several hundreds of combinations and Pharnext tested around 75 of them in the lab before landing on baclofen, naltrexone, and sorbitol. Individually, the drugs don't have much effect on the PMP22 gene. But combined, they work to lower how much protein the gene makes.
"How the drug inside the cell reduces expression isn't quite clear yet," says Florian Thomas, director of the Hereditary Neuropathy Center, and founding chair and professor in the department of neurology at Hackensack University Medical Center and Hackensack Meridian School of Medicine in New Jersey (no relation to Robert Thomas, the CMT patient). "By reducing the amount of protein being produced, we hopefully can stabilize the nerves."
In rodents genetically engineered to have the PMP22 gene, the drug reduced protein levels and delayed onset of muscle weakness when given to rats. In another animal study, the drug increased the size of the myelin sheath around nerves in rats.
"Like humans with CMT, one of the problems the animals have is they can't grip things, their grip strength is poor," Solomon says. But when treated with Pharnext's drug, "the grip strength of these animals improves dramatically even over 12 weeks."
Human trials look encouraging, too. But the company ran into a manufacturing issue during a late-stage trial. The drug requires refrigeration, and as a result of temperature changes, crystals formed inside vials containing the high dose of the drug. The study was a double-blind trial, meaning neither the trial participants nor investigators were supposed to know who received the high dose of the drug, who received the low dose, and who received a placebo. In these types of studies, the placebo and experimental drug should look the same so that investigators can't tell them apart. But because only the high dose contained crystals, not the low dose or placebo, regulators said the trial data could be biased.
Pharnext is now conducting a new randomized, double-blind trial to prove that its drug works. The study is recruiting individuals aged 16 through 65 years old with mild to moderate CMT. The company hopes to show that the drug can stop patients' symptoms from worsening, or in the best case scenario, possibly even improve them. The company doesn't think the drug will be able to help people with severe forms of the disease.
"In neurologic disease, you're looking for plasticity, where there's still the possibility of stabilization or reversal," Solomon says. Plasticity refers to the ability of the nervous system to change and adapt in response to stimuli.
Preventing Disability
Allison Moore, a CMT patient and founder and CEO of the Hereditary Neuropathy Foundation, has been following drug development for CMT since she founded the organization in 2001. She says many investigational drugs haven't moved forward because they've shown little success in animals. The fact that Pharnext's drug has made it to a late-stage human trial is promising, she says.
"It's really exciting," Moore says. "There's a chance that if you take the drug early before you're very severe, you'll end up not developing the disease to a level that's super disabling."
CMT has damaged Moore's peroneal nerve, a main nerve in the foot. As a result, she has foot drop, the inability to lift the front part of her foot, and needs to wear leg braces to help her walk. "The idea that you could take this early on and that it could stop progression, that's the hope that we have."
Thomas, the neurologist, says a drug doesn't have to be a cure to have a significant impact on patients. "If I have a CMT patient who's 50 years old, that patient will be more disabled by age 60," he says. "If I can treat that person with a drug, and that person is just as disabled at age 60 as they were at age 50, that's transformative in my mind."
While Robert Thomas says he hasn't noticed a dramatic improvement since he's been on the drug, he does think it's helping. Robert is now in an open-label study, which means he and his health provider are aware that he's receiving the drug.
When the COVID-19 pandemic hit, manufacturing and supply chain disruptions meant that Robert was without the trial drug for two months. When his medication ran out, his legs felt unstable again and walking was harder. "There was a clear distinction between being on and off that medication," he says.
Pharnext's current trial will take about a year and a half to complete. After that, the FDA will decide on whether to approve the drug for CMT patients.
As scientists learn more about the PMP22 gene and the more than 100 other genes that when mutated cause CMT, more precise treatments could be possible. For instance, scientists have used the gene-editing tool CRISPR to correct a CMT-causing mutation in human cells in the lab. The results were published August 16 in the journal Frontiers in Cell and Developmental Biology.
Pharnext is also interested in pursuing genetic treatments for CMT, but in the meantime, repurposed drugs may be the best shot at helping patients until more advanced treatments are available.
"Making Sense of Science" is a monthly podcast that features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This episode is hosted by science and biotech journalist Emily Mullin, summer editor of the award-winning science outlet Leaps.org.