Cardiomyopathy

Making the Connection

By Stacey Mancarella

Illustrations by Yesenia Carrero

illustration of photos of unconnected symptoms

A rare but debilitating condition, hereditary amyloidosis (hATTR) presents as seemingly unrelated illnesses that mask the root cause. But increased awareness and new treatment options bring hope for sufferers of this devastating genetic condition.


We hear of it too often in health care. Even with the most diligent doctors and patients, sometimes figuring out the correct diagnosis of a rare medical condition can be a challenge.

Unexplained weight loss and diarrhea. Shortness of breath during exercise. Carpal tunnel syndrome. Weakness and difficulty balancing that gets progressively worse. Tingling or numbness in the hands and feet. Symptoms like these point to different culprits, bringing patients to a variety of specialists and glimmers of hope as they find potential answers. But treating one symptom doesn’t help the others, and everything gets worse.

This particular collection of ailments, among other symptoms, points to hereditary amyloidosis (hATTR), a devastating genetic disease that, up until recently, was considered untreatable. Dr. Fernanda Wajnsztajn is all too familiar with the plight of her patients who have searched in vain for a diagnosis. A neurologist at the UConn Health neuropathy clinic, Wajnsztajn specializes in peripheral neuropathy, damage or disease of the peripheral nervous system.

“Because some of the symptoms of hereditary amyloidosis are also seen in a variety of diseases, some of my patients went to several doctors for years until hATTR was suspected,” she says. “With a detailed history, we are also able to trace the heritage of patients, and, often, patients realize during the interview that some their relatives also have similar symptoms.”

Now these families have options. New drug treatments have been approved to treat neuropathy, the nerve pain, tingling, or numbness that’s a symptom of this little-known disease, and doctors at UConn Health have assembled a team to tackle hATTR head on.

Interpreting the Evidence

Wajnsztajn has been aware of hATTR since her days at Columbia University, where she was involved in research and clinical trials for hATTR therapies. Only about 50,000 people worldwide are affected by hATTR, “but we suspect that many cases go undiagnosed or misdiagnosed,” Wajnzsztajn says. “Our goal is to reach those people.”

Hereditary amyloidosis is caused by a hereditary mutation of the TTR gene. If one parent carries the gene mutation, offspring have a 50 percent chance of inheriting the disease. Hereditary amyloidosis wreaks havoc on the body by depositing amyloid proteins into organs, most commonly the heart, nerves, and digestive tract. These deposits cause the organs to function improperly, which eventually leads to a myriad of debilitating symptoms.

Even though the gene mutation is present at birth, most patients don’t experience symptoms until well into adulthood. And even once symptoms start, it can take years for a proper diagnosis.

“Hereditary amyloidosis is not a well-known disease. The patient can present with a history of heart problems and receive a diagnosis of polyneuropathy, but if the doctor isn’t familiar with it, they won’t put it together. It’s easy to miss,” Wajnsztajn says.

For example, two of the most common symptoms of hereditary amyloidosis are carpal tunnel and cardiomyopathy, or heart muscle disease. Because these two diseases are seemingly unrelated and treated by different kinds of doctors, hereditary amyloidosis can go undetected. The average delay in diagnosis is four years, and in that time, amyloid is continuously deposited into the affected organs, causing symptoms to worsen.

Even with the new treatments, a timely diagnosis is important as the medications cannot reverse the symptoms but only prevent further protein deposits that cause the condition to worsen. The earlier a patient can be identified and a course of treatment initiated, the slower the disease will progress.

Dr. Fernanda Wajnzsztajn (left) and Dr. Sarah Tabtabai discuss a patient case.

Dr. Fernanda Wajnsztajn (left) and Dr. Sarah Tabtabai discuss a patient case.

Case Closed

UConn Health’s multidisciplinary approach can shorten this delay, giving patients relief sooner and stopping hATTR in its tracks. Cardiologists at the Pat and Jim Calhoun Cardiology Center work hand in hand with neurologists from the peripheral nerve disease clinic to examine a patient’s symptoms, get that crucial neuropathy or polyneuropathy diagnosis, and schedule them for genetic testing to confirm a hATTR diagnosis. Once the diagnosis is confirmed, treatment can begin very quickly, and the deposition of amyloid into the organs is halted within weeks — sometimes within days — thanks to neurologists, cardiologists, neuropathy testing, and an infusion center to administer treatment being all in one place.

Two treatment options currently exist, one that’s infused intravenously every three weeks, the other given by weekly subcutaneous injection. These new treatments work by inhibiting the body’s ability to create the amyloid protein. They reduce the amount of the protein the liver can make by 84 percent, improving the patient’s quality of life. Clinical trials are ongoing, with the hope that such medications can treat other types of amyloidosis as well.

“Before medicines like this came along, there was really no therapy for this particular heart disease. It’s progressive and very debilitating, and the hereditary type, in particular, occurs in younger people,” says Dr. Sarah Tabtabai, cardiologist at the Pat and Jim Calhoun Cardiology Center at UConn Health.

Previously attempted treatments for hATTR symptoms were drastic, sometimes including heart transplants or heart and liver transplants, Tabtabai says. But with the new medications, “patients have had good outcomes with both their neurologic disease and their heart disease, and it sort of keeps things at bay.”

Close collaboration between the departments makes everything go smoothly for patients who have already waited so long for answers, says Wajnsztajn.

“We work very closely with cardiology to obtain the appropriate exams for diagnosis as quickly as possible. Despite being a challenging or daunting diagnosis, our patients feel fortunate that they finally have answers, and we are able to provide the most advanced treatments along with the support necessary,” she says.

Because of the high rate of misdiagnosis, the companies that produce the new medications are currently offering free screenings for patients with suspected hereditary amyloidosis. A patient simply has to schedule the genetic test at UConn Health, and the billing is handled directly through the hospital, creating a streamlined process for the patient.

Early diagnosis of hATTR can also bring awareness to family members who might be afflicted.

“Once a patient is diagnosed with hereditary amyloidosis, we can test blood relatives as well to identify any members of their family who may also have this disease,” Tabtabai says. “The hope is that, down the line, we can offer medications like this sooner, before patients become symptomatic or right at the onset of symptoms so that they fare even better as time goes on.”

Tell-Tale Heart

‘Heart-In-A-Dish’ Sheds Light on Heart Disease Genetics

By Nicole Davis for The Jackson Laboratory for Genomic Medicine
Photography by Peter Morenus

Dr. Travis Hinson holds petri dishes containing beating heart tissue

Dr. J. Travis Hinson is seen holding petri dishes that contain heart cells. Hinson, a joint faculty appointment at UConn Health and The Jackson Laboratory for Genomic Medicine, has pioneered a system to study the genetics of heart failure by recreating beating heart tissue using patients’ stem cells. Photo: Peter Morenus


When a patient shows symptoms of cancer, a biopsy is taken. Scientists study the tissue, examining it under a microscope to determine exactly what’s going on.

But the same can’t be done for heart disease, the leading cause of death among Americans. Until now.

Dr. J. Travis Hinson, a physician-scientist who joined the faculties of UConn Health and The Jackson Laboratory for Genomic Medicine (JAX) in January, uses a novel system he pioneered to study heart tissue.

Hinson engineers heart-like structures with cells containing specific genetic mutations in order to study the genetics of cardiomyopathies, the diseases of the heart muscle that can lead to heart failure and, ultimately, death.

“We basically try to rebuild a little piece of a patient’s heart in a dish,” says Hinson, who developed the technique during his postdoctoral fellowship.
He combines cardiac muscle cells with support cells, such as fibroblasts, and other key factors, including extracellular matrix proteins. Although these tiny, three-dimensional structures do not pump blood, they do contract rhythmically, and their beating strength can be studied.

Making a Difference

Hinson is applauded for his ability to move seamlessly between research, clinical practice, and teaching — the three prongs of an academic medical center’s mission. He’s able to do so, perhaps, because his own career began at the intersection of multiple scientific specialties.

As a University of Pennsylvania undergraduate, Hinson interned at DuPont in New Jersey to explore interests in chemistry and engineering. But he soon realized his passion for science needed a real-word focus. “I wanted to do science that made a difference in people’s health,” he says.

The same summer, he volunteered in the emergency department of a local hospital. Impressed by a cardiologist’s calm and collected manner in a crisis, and gaining interest in the heart, Hinson changed his career trajectory from engineering to medical school.

Hinson and his colleagues can isolate skin or blood cells directly from cardiomyopathy patients and coax them to form heart muscle cells, making it possible to study the biological effects of patients’ own mutations.

Hinson joined the laboratory of Dr. Robert J. Levy, a pediatric cardiologist and researcher at The Children’s Hospital of Philadelphia, working to harness gene therapy techniques to make artificial heart valves and other cardiovascular devices more durable. Through this early foray into biomedical research, Hinson deepened his interest in biomedical science and gained an appreciation of the work of a physician-scientist.

In Dr. Christine Seidman’s lab at Harvard Medical School, Hinson chose to lead a project on Björnstad syndrome, a rare, inherited syndrome characterized by hearing loss and twisted, brittle hair. At the time, little was known about the molecular causes of the disorder, although the genetic culprits were thought to reside within a large swath of chromosome 2. Using genetic mapping techniques and DNA sequencing, Hinson homed in on the precise mutations.

In addition to casting light on disease biology, he glimpsed the power of genomic information. “I was fascinated by the potential for understanding new genes that cause human diseases, and how important that was to society,” Hinson says.

Matters of the Heart

Throughout his medical training, Hinson noticed there were some significant stumbling blocks to gathering a deep knowledge of heart disease, particularly cardiomyopathies.

Cardiac muscle has essentially two paths toward dysfunction and ultimate failure. It can either dilate — become abnormally large and distended — or it can thicken. Both routes severely impair how well the heart performs as a pump. These conditions, known as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), can stem from pre-existing disorders of the heart, such as a previous heart attack or long-standing hypertension, or from DNA mutations.

Fueled by advances in genomics over the last two decades, more than 40 genes have been identified that underlie cardiomyopathy. But unlike diseases such as cystic fibrosis or sickle cell anemia, where it is fairly common for affected individuals from different families to carry the exact same genetic typo, it is exceedingly rare for unrelated patients with cardiomyopathy to share the same mutation. With such a complex genetic architecture, figuring out how the different genes and gene mutations contribute to heart disease has been an enormous challenge.


Dr. Travis Hinson speaks with others in his lab

Above: Dr. J. Travis Hinson gives a tour of his laboratory. Photo: Peter Morenus


Because of this formidable hurdle, drug discovery for the cardiomyopathies has languished. “There really has not been a paradigm-shifting drug developed for heart failure in the last 20 years,” says Hinson. Moreover, the few treatments that do exist are primarily aimed at controlling patients’ symptoms, not slowing or halting their disease.

Hinson aims to improve this picture. With his “heart-in-a-dish” technique, he and his team are now unraveling the effects of genetic mutations on cardiac biology.

The system harnesses multiple recent advances in both stem cell and genome editing technologies. With these capabilities, Hinson and his colleagues can isolate skin or blood cells directly from cardiomyopathy patients and coax them to form heart muscle cells, making it possible to study the biological effects of patients’ own mutations. Moreover, he can correct those mutations, or create additional ones, to further probe how genetic differences influence heart biology.

Part of the allure of Hinson’s approach is that it can be readily applied to study other forms of heart disease. It can also be leveraged for drug discovery, providing a platform to screen and test compounds with therapeutic potential in a wide range of cardiovascular diseases.

In addition to his research lab based at JAX, Hinson continues to practice cardiology at UConn Health. He helps run a specialized clinic focused on genetic forms of heart disease, as well as arrhythmias, connective tissue disorders, and other conditions.

“We have an exciting opportunity to provide clinical services in cardiac genetics in the corridor between New York and Boston,” he says. That means state-of-the-art genetic testing, including gene panels and genome sequencing, as well as genetic counseling for both patients and family members to help inform disease diagnosis and guide treatment. Although there are only a handful of treatments now available, Hinson believes this clinic will be uniquely poised to take advantage of a new generation of personalized treatments that are precisely tailored to patients’ specific gene mutations.

“Travis really is a quintessential physician-scientist,” says Dr. Bruce Liang, dean of UConn School of Medicine and director of the Pat and Jim Calhoun Cardiology Center at UConn Health.

“He has a remarkable ability to link basic science with important clinical problems, and his work holds a great deal of promise for developing new treatments for patients with cardiomyopathy. I wish there were two or three Travis Hinsons.”


Hinson’s beating heart tissue. Provided by Dr. Travis Hinson