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Strategies to accelerate diagnosis and treatment of rare cardiovascular diseases

February 25, 2021
by Elisabeth Reitman

The current landscape for patients with rare cardiovascular disease has shifted. Using genome sequencing Yale physician-scientists have begun to elucidate the pathophysiology of genetic disorders and develop treatment guidelines and recommendations. With these advanced diagnostic tools, our team of international experts can offer clinical diagnosis, genetic testing, and risk assessment for patients.

Underlying cause of rare diseases

In 2017, the Yale Cardiovascular Genetics Program was one of the first clinical centers to use whole exome sequence analysis to detect novel disease genes. After conducting whole exome sequencing with a group of 200 patients, the research team identified specific mutations that resulted in a more accurate diagnosis of inherited cardiovascular disease. The results were published in Circulation: Genomic and Precision Medicine. According to the authors, “The use of whole exome sequencing has the potential to revolutionize the way we practice medicine by generating large-scale personalized genetic information.”

Arya Mani, MD, director of the cardiovascular genetics program, and his colleagues have identified several genetic mutations linked to rare disorders; more recently CELA2A, a gene responsible for regulating calcium-dependent insulin secretion and sensitivity, has been identified as a promising target for novel therapies. In Nature Genetics, the authors concluded that CELA2A could have a “physiologic role in cellular glucose metabolism.”

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) affects an estimated one in 500 adults. Yale’s well-established program offers comprehensive diagnostic, treatment, education, and research for hypertrophic, dilated, arrhythmogenic, and restrictive cardiomyopathies. Yale is the only program in the state of Connecticut to be listed as a Center of Excellence by the Hypertrophic Cardiomyopathy Association. With the addition of John Stendahl, MD, PhD, a graduate of Yale’s advanced fellowship training, the program is expanding to support patients with hereditary disorders.

With FDA approval pending, mavacamten is poised to become the first disease-specific therapy for obstructive hypertrophic cardiomyopathy. As Daniel Jacoby, MD, director of comprehensive heart failure and cardiomyopathy program, reported on September 12 in The Lancet, the EXPLORER-HCM trial indicated an improvement in exercise capacity and a reduction in left ventricular outflow tract obstruction. Further analysis may also reveal a reduction in left ventricular mass and hypertrophy.

The American College of Cardiology released updated guidelines in 2020 which emphasized personalized approaches regarding decisions around implantable cardioverter-defibrillator placement and exercise guidelines. Two additional clinical trials —MAVA-LTE and VALOR-HCM — are now ongoing to determine the long-term safety and efficacy of this novel treatment.

Cardiac Amyloidosis

Yale serves as the premier institution across southern New England for the evaluation and treatment of cardiac amyloidosis, which is caused when deposits of an abnormal protein called amyloid affect heart function. Cardiac amyloidosis disproportionately affects Caribbean and African-American communities and is a leading cause of heart failure.

Advances in cardiac imaging and the development of targeted therapies including patisiran, inotersen, and tafamidis for transthyretin amyloidosis (ATTR) has led to progress for patients with cardiomyopathy and inherited cardiovascular disease. Edward Miller, MD PhD, director of the clinical nuclear cardiology laboratory, co-authored a review last year with Cesia Gallegos Kattan, MD, which examined the benefits of positron emission tomography (PET) radiotracers to detect cardiac amyloidosis.

“There is unmet and critical need to develop tracers to distinguish between amyloid types and quantify response to treatment,” the authors wrote. To help address this, Jacoby, Miller, and Gallegos Kattan have partnered with Oyere Onuma, MD, MSc, cardiovascular disease prevention specialist, Matthew Burg, PhD, a clinical psychologist, and Kristie Harris, PhD, a postdoctoral associate in cardiovascular medicine, as well as Curt Scharfe MD, PhD, FACMG, and Michael F. Murray MD, FACMG, FACP, from the Department of Genetics.

Ongoing clinical research at Yale can also contribute to future discoveries. The V142I mutation in the ATTR gene is thought to be associated with an increased risk of cardiac amyloidosis. The Yale Cardiovascular Amyloid group has an ongoing partnership with Ernest C. Madu, MD, FACC, from the Heart Institute of the Caribbean in Kingston, Jamaica, to develop methods to screen high-risk patients for amyloidosis as well as a novel community partnership being developed with the Yale Center for Clinical Investigation and the New Haven community to better understand the impact of V142I ATTR locally.

Two additional studies THAOS, a global, multi-center, longitudinal observational survey open to all patients with transthyretin-associated amyloidoses (ATTR), and ATTRIBUTE-CM, a phase 3 randomized clinical trial of AG10 in patients with symptomatic transthyretin amyloid cardiomyopathy, will help develop the next generation of therapeutics.

To learn more about clinical research within the Section of Cardiovascular Medicine, visit Cardiovascular Medicine.

Submitted by Elisabeth Reitman on February 27, 2021