What Happens to Young Adults After a First Heart Attack?

Study finds that the vast majority of patients with familial hypercholesterolemia still had elevated cholesterol levels a year later, highlighting an opportunity for more aggressive treatment

Heart attacks among adults younger than 50 years of age are on the rise. In fact, the proportion of very young people has been increasing, rising by 2 percent each year for the last 10 years, according to a team of investigators a Brigham and Women’s Hospital who are focused on studying heart attacks among young adults. The research team is now investigating why, by evaluating both risk factors and outcomes for this population in order to help prevent heart attacks in the first place. In a paper published today in the Journal of the American College of Cardiology, the team reports on the prevalence of familial hypercholesterolemia (FH), a genetic disorder that results in high cholesterol, and outcomes for patients. Investigators have found that nearly one in 10 patients who suffer a first heart attack before age 50 had FH, and many continued having elevated cholesterol levels a year after their first heart attack. Many were not on a statin therapy before their first heart attack, highlighting opportunities for prevention and more aggressive treatment for those at risk.

“One of the challenges of familial hypercholesterolemia is that it is under-recognized and under-treated,” said corresponding author Ron Blankstein, MD, a preventative cardiology specialist and associate director of the Cardiovascular Imaging Program at the Brigham. “Only about half of the FH patients in our study were on a statin therapy before their first heart attack, and many were not treated aggressively following their event. Intervening to lower cholesterol could mean preventing not only subsequent heart attacks but first heart attacks, too.”

Blankstein and colleagues collected data on all patients at the Brigham and Massachusetts General Hospital who had suffered a heart attack before age 50 between 2000 and 2016. Using the Dutch Lipid Clinic (DLC) Network criteria, the team identified those patients with FH and used electronic medical records to determine cardiovascular risk factors as well as what medications the patients had been taking prior to their heart attack and what medications were prescribed at discharge.

Blankstein and colleagues found that nearly 1 in 10 young adults who had suffered a heart attack met the clinical definition for FH. Of those who had elevated LDL cholesterol (greater than or equal to 160 mg/dl), that proportion increased to 4 out of every 10. And among those who had both family history of premature coronary artery disease and high cholesterol, the proportion was 6 in 10. On average, FH patients had LDL cholesterol levels of 180 mg/dl at the time of their heart attack, and 43 percent were not on a statin therapy.

Following their first heart attack, only 49 percent of FH patients were prescribed a high-density statin therapy. One year after their heart attack, most had elevated cholesterol levels, with 43 percent having cholesterol levels greater than 100 mg/dl and 82 percent having cholesterol levels above 70 mg/dl.

Over 11 years of follow-up, 10 percent of FH patients died.

The team notes that the underutilization of high-intensity statin therapy after a first heart attack was not unique to FH patients, and that there are opportunities for more aggressive lipid-lowering therapy for young FH and non-FH patients alike.

“It’s important for both providers and patients to be aware of the real benefit associated with reducing cholesterol. It’s important to do so after a heart attack, but even before, if a patient has risk factors, there’s an important opportunity to avoid heart attacks through aggressive therapy,” said Blankstein. “However, there is also an enormous need to improve other risk factors.  Our team is examining both modifiable risk factors, such as smoking, being overweight, or having an elevated blood pressure, as well as well as non-modifiable factors such as genetics. But in this study, we find clinically defined FH in only 1 in 10 young patients who have had a heart attack. “Other factors beyond FH seem to play a much larger role in explaining why individuals in our study cohort experienced a myocardial infarction at a young age.”

This work was funded in part by Amgen, Inc. via a grant to Brigham and Women’s Hospital. Authors of this work are supported by grants from the National Institutes of Health (5T32HL094301. T32HL007604.). Blankstein has served on the advisory board of Amgen, Inc.; and has received research support from Amgen, Astellas, and Sanofi. Co-authors of this work have been employed by, hold stock in, consulted for, and received grant support from Amgen, AstraZeneca, Merck, Pfizer and other pharmaceutical companies. For a complete listing of disclosures, please visit https://doi.org/10.1016/j.jacc.2019.02.059

Paper cited: Singh A, et al. “Familial Hypercholesterolemia Among Young Adults With Myocardial Infarction” JACC DOI: 10.1016/j.jacc.2019.02.059

What Are the Neurological Side Effects of CAR T-Cell Therapy?

Researchers report complex neural toxicities observed after CAR-T treatment for blood cancers

The recent advent of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the clinical treatment of cancer. Under the umbrella of immunotherapy, CAR T-cell treatment trains and strengthens a patient’s own immune system to attack tumors. Early successes in clinical trials have led to approval of the treatment for recurrent blood cancers, including leukemia and lymphoma.

Despite the therapeutic successes of CAR T-cell therapy, the intervention carries the risk of severe side effects. These include neurotoxicity, which can result in headache, confusion, and delirium, among other neural changes. These debilitating effects remain poorly understood and characterized. A team at Brigham and Women’s Hospital recently cataloged the neurological symptoms of patients who had received CAR T-cell therapy to better understand its neurotoxic side effects. While neurological symptoms were prevalent — 77 percent of patients experienced at least one symptom — they were also temporary. The findings are published in Brain.

“The mechanism underlying CAR T-cell-associated neurotoxicity is unknown and symptoms can be very hard to predict,” said lead author Daniel Rubin, MD, PhD, of the Department of Neurology at the Brigham. “We conducted this study to better define the specific neurologic symptoms experienced by patients after CAR T-cell therapy.”

To define clinical symptoms of CAR-T-associated neurotoxicity, the team conducted an observational cohort study of 100 lymphoma patients admitted to the Dana-Farber/Brigham and Women’s Cancer Center for CAR T-cell therapy between 2015 and 2018. The team evaluated symptoms from the start of CAR T-cell therapy infusion through two months’ post-infusion. In addition, all diagnostic assessments, including laboratory tests and imaging scans, were reviewed.

“We shared a few clinical cases early in the therapies which were very severe and unusual from a neurological standpoint,” said senior author Henrikas Vaitkevicius, MD, of the Department of Neurology. “This sparked an interest to collaborate with oncology and T-cell therapy groups, and allowed us to evaluate the majority of patients prospectively rather than retrospectively.”

Their findings reveal the widespread prevalence of neurological symptoms after starting CAR-T therapy. The most prevalent symptom was encephalopathy, a type of brain disease that causes confusion, but additional symptoms such as headache, tremor, weakness and language dysfunction were also observed. Importantly, most of these effects were reversible, and symptoms almost always resolved over time.

In addition, the researchers observed a unique pattern of activity, or inactivity, in their study. The neurological deficits associated with therapy often originated from areas which appeared metabolically silent. This finding carries important implications for the clinical assessment of neurotoxicity and the use of imaging.

“Despite the common occurrence of neurologic symptoms, imaging studies such as MRI, which serve as a cornerstone of neurologic diagnosis, were almost always normal,” remarked Rubin. “In contrast, diagnostic studies that more directly evaluated neuronal functioning, like EEG and PET scan, could reliably detect and predict neurologic dysfunction.”

As a next step, investigators are building and validating a model for more accurate scoring and diagnosis of CAR T-associated neurotoxicity.

No funding was received towards this work. Co-authors report consulting for Kite, Novartis, Precision Biosciences, Humanigen, Pfizer, Bayer, and Celgene.

Paper cited: Rubin D et al. “Neurological toxicities associated with chimeric antigen receptor T-cell therapy” Brain DOI: 10.1093/brain/awz053