A Breakthrough in Understanding and Diagnosing Congenital Heart Disease

Seth Nickerson, Staff Writer

One in a thousand people are born at risk of sudden death due to an inherited genetic disorder that weakens the muscle cells of the heart, causing lasting damage that is virtually irreparable. Following years of symptom-free disease progression, a single episode of strenuous activity is all it takes to induce an irregular heartbeat, an arrhythmia, and death within minutes. Later this month, researchers at the New York University School of Medicine will publish a groundbreaking collaborative study in the journal Cardiovascular Research that sheds light on longstanding mysteries surrounding this pathological process: Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC).

The investigation, lead by postdoctoral fellow Esperanza Agullo-Pascual, could lead to routine diagnostic tests that determine at birth the likelihood of developing such cardiomyopathies, thus providing ARVC patients with life saving information. Dr. Agullo-Pascual is a member of the laboratory of Mario Delmar of the Leon H Charney Division of Cardiology. Her utilization of advanced super-resolution, single-molecule microscopy and statistical modeling is enabled by close collaboration with the laboratories of Eli Rothenberg and David Fenyö, both of the Department of Biochemistry and Molecular Pharmacology.

Previous decades of research in this field have identified 8 human genes that can carry mutations attributable to 30-40% of known ARVC cases. Most of these genes encode instructions for structural proteins that link individual cardiac muscle cells, known as cardiomyocytes, together to form a chain of contractile muscle tissue, thus allowing the heart to pump blood. The structural proteins are grouped into an intricate cluster, known as the intercalated disc, which resides at the cell-cell junction. Hundreds of these discs collectively act like iron rivets, physically coupling the cardiomyocytes together into a continuous contractile unit. The aforementioned mutations compromise the structural integrity of the intercalated discs, leading to a physical destruction of the heart muscle termed cardiomyopathy.

Each defunct strand of cardiac muscle is methodically cleared out by the immune system. But because the human heart does not have true regenerative capacity, the defective cardiomyocytes are replaced with virtually useless scar tissue and fat. Eventually, this filler material will encompass a large portion of what was once vital cardiac muscle. The walls of the heart then weaken and stretch, leading directly to an increased risk of arrhythmia and sudden death.

People who carry these mutations often develop symptoms in adulthood, such as frequent chest pain and loss of breath. However, many people who ultimately succumb to arrhythmia are symptom free at the time of death. For those who do develop symptoms, a diagnosis can lead to a change of lifestyle and a surgically implanted defibrillator that can shock the heart back into rhythm on demand. But for those who are asymptomatic, including the recent increased incidence specifically in adolescents during recreational sports, there are no preventative measures.

Accumulating post mortem genetic evidence suggests that a large proportion of those without symptoms do not carry any mutations attributable to ARVC or to proteins known to reside within the intercalated disc. Yet, further examination confirms that in these cases, the disease causing protein indeed resides within the intercalated disc. These data point to an entirely unappreciated cause of asymptomatic sudden death from arrhythmia, and cast a light on a gap in the knowledge of disease progression. Further research leading to a cost-effective and reliable diagnostic tool to identify risk factors at an early age is therefore the only path forward.

Shattering the limits of resolution

Dr. Aguillo-Pascal’s study began as an attempt to uncover the structural organization of the intercalated disc. She hypothesized that an organizational glitch, rather than a strictly mechanical failure within the disc, could give rise to the asymptomatic disease. The intercalated disc has been studied for decades with classical biochemistry and microscopy. However, the molecular resolution of these techniques was insufficient for understanding the intricate and detailed architecture that she hoped to achieve.

Enter Eli Rothenberg, an expert in an advanced new technique that combines clever chemistry, particle-wave physics, and custom computation to shatter the limits of resolution under the microscope. Utilizing components including laser illuminated optics and specialized computer code for statistical reconstructions, his group is able to clearly resolve the structural organization of protein complexes by breaking the physical limits of resolution by ~15-fold.

Using Dr. Rothenberg’s super-resolution microscopy methods, Dr. Agullo-Pascual uncovered a completely unexpected property of the intercalated disc. Namely, that it contains not only the previously known structural proteins, but also electrochemical components that were not previously associated with the intercalated disc. These previously unrecognized components regulate the exchange of chemical ions between cells, and their localization with the intercalated disc suggests an intimate relationship between the mechanical and electrochemical properties and functions of cardiomyocytes in the coordinated contraction of cardiac muscle.

Dr. Agullo-Pascual’s discovery of this novel protein architecture links previously unappreciated aspect of cardiovascular physiology to large gaps in knowledge about the causes of ARVC and other cardiomyopathies. Not only will this discovery allow for a more thorough study of the malfunctioning intercalated disc that drives arrhythmia and sudden death, but it also provides a potential new series of genes that may be contributing to ARVC or other congenital heart diseases. Additionally, these findings reconcile a longstanding mystery surrounding the link between the mechanical properties of the intercalated disc and the electrochemical properties of cardiac muscle contraction.

Dr. Aguillo-Pascual envisions a foreseeable future where readily available skin cells from any patient can be coaxed to become cardiomyocytes and structurally analyzed to assess their functionality. Such a technique could be used to diagnose a patient decades before symptoms appear, even in the absence of known mutations. Thanks to the collaborative research performed at the NYU School of Medicine, the future of diagnostic and preventative cardiovascular medicine is quite bright.

Seth Nickerson is a PhD candidate in the department of Biochemistry and Molecular Pharmacology at the NYU School of Medicine. Contact him at: Seth.Nickerson@med.nyu.edu


One comment

  1. This man is so incredibly talented, this Seth Nickerson….. Why pray tell does he not get to have his picture up like the rest of these very bright people?


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