cardiology

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.”

Follow-Up – Fall 2018

Research doesn’t stop when we report it. Here is an update on a past UConn Health Journal stories:


Glycogen Storage Disease

Dr. Annabelle Rodriguez-Oquendo, professor of cell biology at the UConn School of Medicine, was recently issued a diagnostic patent to test for a genetic predisposition for an abnormal inflammatory response that causes several life-threatening disorders, like coronary artery disease and chronic inflammatory disease. Lipid Genomics, the start-up Rodriguez-Oquendo founded in 2010, has exclusively licensed the technology from UConn Health. The company is currently in discussion with potential investors to continue commercialization of this product, as well as other therapeutic innovations for HDL-cholesterol dysfunction.

Winter 2015, “Getting to the Heart of the Matter”

Class of 2009 Med Students Return to Practice at UConn Health

Class of 2009 reunite. From left: Dr. Sara Tabtabai, Dr. Ben Ristau, Dr. Todd Falcone, and Dr. Marilyn Katz

From left: Dr. Sara Tabtabai, Dr. Ben Ristau, Dr. Todd Falcone, and Dr. Marilyn Katz


TThe UConn School of Medicine graduating class of 2009 is experiencing a mini-reunion at UConn Health, with five doctors from the class now practicing here.

Dr. Todd Falcone (ear, nose, and throat), Dr. Marilyn Katz (internal medicine), Dr. Ben Ristau (urologic oncology), Dr. Sara Tabtabai (cardiology), and Dr. Rafael Pacheco (radiology) came back with fond memories of their time as UConn medical students.

Katz says she knew the UConn School of Medicine was a match right away. “I loved everyone I met on my interview day — students, faculty, and staff — and canceled all my other interviews once I received my acceptance.”

Falcone joined UConn Health in 2014. “I had an excellent time here, and I credit the School of Medicine for preparing me to match into a competitive residency program and become a competent and caring physician and educator. I do not believe I could have received a better medical school education anywhere else.”

The five physicians say their medical school connections help them deliver better patient care today. “Rafael Pacheco and I were medical interns together as he was doing his prelim year prior to radiology,” Katz shares. “It was great to discuss similar patient cases with him then, and knowing I can call him now to discuss testing is a huge benefit as a primary care physician.”

Protecting Cancer Patients’ Heart Health

Kim Agnes looks at heart

Dr. Agnes Kim, director of the Cardio-Oncology Program at UConn Health, uses new echocardiography strain imaging to detect signs of potential heart problems in cancer patients, before clinical symptoms are evident.


There are currently more than 15 million cancer survivors in the U.S., and that number is expected to grow to 20 million within 10 years. But as more patients survive cancer, the risk of developing cardiovascular health issues from lifesaving chemotherapy and radiation treatments also is increasing.

In an effort to detect cardiac health risks or conditions early, UConn Health has begun tracking cancer patients with an advanced heart imaging test before, during, and after chemotherapy and radiation therapy.

New echocardiography strain imaging allows cardiologists to hunt for early warning signs of heart muscle function changes or damage within the heart tissue. The in-depth strain analysis is powered by traditional ultrasound technology, which uses high-frequency soundwaves to create a sonogram of the pumping heart.

Dr. Agnes Kim, director of the Cardio-Oncology Program at the Pat and Jim Calhoun Cardiology Center at UConn Health, says it’s very important to monitor cancer patients for any signs of cardiac toxicity.

“Echo strain imaging has been compared to a canary in a coal mine,” she says. “We are so grateful that our cancer patients have access to this latest technology so that we can monitor and intervene early if any warning signs are present.”

Studies have shown that confirming any changes in heart muscle strain can help doctors predict whether a patient is at risk for cardiotoxicity and its side effect of future heart failure. A decline in heart strain of 15 percent or more suggests cardiotoxicity, and doctors may prescribe cardio-protective drugs, such as beta-blockers or ACE inhibitors, or modify the patient’s chemotherapy dosage.

Possible cardiotoxicity side effects from chemotherapy medications include a lowering of overall heart muscle function, which can lead to heart failure, formation of blood clots, or an increase in blood pressure. The side effects of radiation therapy also can lead to damaged heart muscle, heart valves, and arteries, or impact the lining of the heart.

Kim launched the Cardio-Oncology Program in 2014 to ensure UConn Health had an integrated program of oncologists and cardiologists, allowing for coordinated care to address the potential risks to heart health that can arise from cancer treatment.

The program also is studying the presence of serum biomarkers in the blood for predicting whether a cancer patient is at high risk for cardiotoxicity, as well as tracking cancer patients’ long-term heart health to analyze the impact of additional clinical care protections.

Lab Notes – Fall 2017

E-Cigarettes Not a Safe Alternative

Using a new low-cost, 3-D-printed testing device, UConn researchers found that e-cigarettes loaded with a nicotine-based liquid are potentially as harmful as unfiltered cigarettes when it comes to causing DNA damage. The researchers also found that vapor from non-nicotine e-cigarettes caused as much potentially cancer-causing DNA damage as filtered cigarettes, possibly due to the many chemical additives present in e-cigarette vapors. Several factors impact the amount of DNA damage e-cigarettes cause, says Karteek Kadimisetty, a postdoctoral researcher in UConn’s chemistry department and the study’s lead author. “I never expected the DNA damage from e-cigarettes to be equal to tobacco cigarettes,” says Kadimisetty. “I ran the controls again. I even diluted the samples. But the trend was still there — something in the e-cigarettes was definitely causing damage to the DNA.” The findings appear in the journal ACS Sensors.

electronic cigarette


New Device Tests Heart Health

finger pricked with a spot of blood (for blood sugar test)

UConn researchers from the Department of Mechanical Engineering have developed a device that can test blood viscosity during a routine office visit. The heart must work harder to pump sticky — high viscosity — blood, and studies have shown thicker blood can indicate cardiac event and stroke risk. UConn associate professor of mechanical engineering George Lykotrafitis and doctoral candidate Kostyantyn Partola have filed a provisional patent on the small electronic device, which requires just a finger prick of blood, gives precise readings in minutes, and costs under $1,000. Currently, physicians must send large blood samples to off-site labs for analysis in a rheometer. “With this information, doctors can suggest simple lifestyle changes on the spot to prevent their patients from having a stroke or heart attack,” says Partola.


The Lack of Black Men in Medicine

Male african-american doctor

Medical school matriculation rates for black males have failed to surpass those from 35 years ago, according to a recent UConn Health analysis of data from the Association of American Medical Colleges. African-American men make up just 2.8 percent of the applicants to medical school. Out of all African-American applicants, only 38 percent are men, and black males who are unsuccessful in their first application are less likely to reapply than their white counterparts, the researchers write in the Journal of Racial and Ethnic Health Disparities. “The absence of Black males in medical school represents an American crisis that threatens efforts to effectively address health disparities and excellence in clinical care,” wrote authors Dr. Cato T. Laurencin and Marsha Murray.


Lifting Spirits Doesn’t Require Many Reps

25KG weight

More physical activity is not necessarily better when it comes to improving your mood, especially if you spend most of your day sitting, UConn and Hartford Hospital researchers found in a recent study. The work, published in the Journal of Health Psychology, found that people who led sedentary lives and engaged in light or moderate activity showed the greatest improvement in overall sense of well-being. Further, the study found no positive or negative association between high-intensity physical activity and subjective well-being, contradicting a widely reported recent study that found high-intensity workouts significantly lowered some people’s sense of well-being.

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

Close at Heart

By Kim Kreiger
Illustration by Yesenia Carrero

Radiation treatment for breast cancer can inadvertently graze the heart, leading to damage and disease years later. UConn doctors are working to change that.

closeatheart


Getting radiation treatment for breast cancer can make you feel vulnerable. Sitting in a machine with radiation pointed directly at your chest, you have to trust that the doctor knows what she’s doing, that the X-rays are aimed right, that the machine is properly calibrated … and then you just sit perfectly still.

But what if you could have some control over the process?

Dr. Robert Dowsett, chief of UConn’s Division of Radiation Oncology, and
colleagues in the Carole and Ray Neag Comprehensive Cancer Center are using a new technique to give breast cancer patients agency in their radiation treatments. And they’re taking better care of the patients’ hearts in the process.

A patient can intentionally increase the heart-chest wall distance by more than a centimeter by controlling her breathing using the Deep Inspiration Breath Hold.

Using the technique, called Deep Inspiration Breath Hold, patients can help control the accuracy and timing of their own radiation dose. The patient takes a breath of specific depth before the radiation machine turns on. Doing this correctly can increase the distance between the heart and the breast by a centimeter or two, lowering the amount of radiation hitting the heart by as much as 50 percent.

Jeryl Dickson, 62, of Manchester, Conn., was one of the first patients at UConn Health to use the technique, from late 2015 through Feb. 2. Her doctors, including Dowsett, prescribed a course of radiation therapy to make sure there were no lingering cancer cells remaining after a lumpectomy removed her breast cancer.

“I practiced deep breathing and breath holds prior to radiation treatment with the radiation oncology staff so I could feel what it would be like,” says Dickson.

Radiation treatment of breast cancer can be very effective, eradicating tumor cells hiding in the chest wall. But breast cancer survivors have a heightened risk of heart disease that shows itself years later. Ironically, the heart disease stems from the radiation that originally saved their lives. Radiation is a type of light, and like visible light, it has a tendency to reflect and scatter. Just as even the sharpest spotlight has blurred edges where it blends into shadow, even the best-aimed medical radiation beam occasionally scatters into tissue outside of the tumor it targets. Sometimes it hits the heart.

Dr. Agnes Kim, director of the Cardio-Oncology Program at UConn Health, analyzes echocardiography images as one way to monitor cancer patients’ risk of heart disease.

Dr. Agnes Kim, director of the Cardio-Oncology Program at UConn Health, analyzes echocardiography images as one way to monitor cancer patients’ risk of heart disease.
Tina Encarnacion/UConn Health Photo

“We worry about heart attacks down the road, 10 to 15 years after radiation treatment of cancer in the chest. We also worry about inflammation on the outside of the heart in the short term. We don’t exactly know how the radiation damages the tissue, but it definitely seems to accelerate damage to blood vessels. It can also cause scarring and fibrosis damage,” says Dowsett.

But the distance between the heart and the chest wall varies from person to person. And a patient can intentionally increase the heart-chest wall distance by controlling her breathing using the Deep Inspiration Breath Hold.

To make the best use of the Deep Inspiration Breath Hold technique, Dowsett and his colleagues at UConn Health combine it with an optical scanning system supplied by C-RAD. The scanning system is essentially a computer with a camera that models the surface of the skin on the patient’s chest. It tracks the patient’s breathing, and coaches her to inhale just the right amount. As the patient, you wear virtual-reality goggles in which you see a bar graph showing your inhalation, with a box at the top. Your goal is to hit the box and then hold your breath for the 20 to 30 seconds it takes to complete the radiation treatment. Some patients can hold their breath that long; others can’t. It doesn’t matter, because if you exhale, or giggle, or cough, the system sees your chest move out of the perfect range and stops the radiation. It won’t restart until you get yourself back in position and inhale to just the right spot again.

“The deep breathing technique was not difficult at all,” says Dickson, “Honestly, I was more focused on my cancer, and heart health never entered my mind. But I am glad I put my trust in my doctors, and I never had any doubts.”

UConn Health is the only hospital using this technology in Central Connecticut. It’s a powerful, precise way to make sure the radiation beam gets the cancer, and to minimize the risk to other organs.

Previously, “the area we treated inevitably ended up being bigger than the target (tumor) itself,” Dowsett says. “Now we’ve expanded this to abdominal targets such as the pancreas and adrenal lesions,” while sparing healthy surrounding organs.

Honor Roll – Winter 2015

For the second consecutive year, UConn Health has received a Gold Award from Get With The Guidelines, an American College of Cardiology and American Heart Association initiative that recognizes hospitals for providing exceptional care to heart-attack victims according to evidence-based guidelines.


UConn Health psychiatrist Dr. Kristina Zdanys was voted onto the Medical and Scientific Advisory Council for the Connecticut Alzheimers Association in June. She will join colleagues Rick Fortinsky and Dr. Lavern Wright, who also sit on the council.


Hartford Magazine’s 2015 list of Best Doctors in Connecticut includes 53 UConn Health faculty members. See the list of cited UConn docs at UConn Today.