SCD Research at Johns Hopkins

The Johns Hopkins Hospital has a long history in sudden cardiac death research. Dr. Michel Mirowski invented the implantable cardioverter-defibrillator (ICD) while working at Sinai Hospital in Baltimore which is an affiliate of Johns Hopkins. Many of his early papers were written with Dr. Helen Taussig, internationally known for her work with "blue babies" and Myron Weisfeldt who became the Chairman of Medicine at Johns Hopkins Hospital.

Prominent sudden cardiac death research continues to this day, particularly in the area of genetics. Dr. Dan Arking is a geneticist who has achieved wide recognition for his discovery of many genes involved in regulating electrical properties of the heart, including the PR, QRS, and QT intervals. Some of these genes also influence the risk of sudden cardiac death, and characterizing the biological role of these genes is under investigation. Dr. Arking is also using genome-wide association studies (GWAS) to identify specific genetic changes that make an individual more likely to die of sudden cardiac death.

Dr. Marc Halushka is a cardiovascular pathologist who has studied a variety of cardiovascular diseases ranging from aortic aneurysms to sudden cardiac death. Dr. Halushka has taken a technique commonly used in cancer research - the tissue microarray - and has adapted it to cardiovascular research questions. He is now focusing his efforts on using tissue microarrays for sudden cardiac death research.

Research Program of:


Dan Arking Dr. Arking has published extensively on many causes of cardiovascular disease. His more recent focus has been on genetic causes of sudden cardiac death. A complete list of publications can be found here. Learn more about his research at his faculty web page.




GWAS Studies +

GWAS Manhattan Plot The goal of this research is to identify genes and specific genetic changes that influence risk for sudden cardiac death. From the standpoint of preventive care, SCD poses a huge burden since less than 10% of SCD victims survive, and approximately 2/3 of SCD victims do not have clinical symptoms that would warrant preventive intervention. Thus, the use of genetics to identify individuals who are at high risk for SCD is crucial.

Traditional approaches to identify genes have relied upon screening candidate genes or family-based studies in families with rare single-gene forms of disease (S/LQTS, ARVC/D, Brugada syndrome). Given the limited success of these approaches to identify genes contributing to common forms of sudden cardiac death, Dr. Arking has pioneered the use of genome-wide association studies (GWAS), which allow for an unbiased screen of virtually all common genetic variants in the genome. These have directly lead to the identification of at least 2 genes involved in SCD, NOS1AP and BAZ2B. He is currently participating in an international collaboration to increase the available SCD samples for GWAS, which is critical to identifying additional genes.

Dr. Arking is also currently developing improved GWAS methodology, as well as exploring the use of additional genome-scale data, including gene expression directly from hearts obtained at autopsy, to improve the power to both identify SCD risk genes, and understand how modification of these gene products influences risk of SCD.


TMA Studies +

Wolf-Parkinson-White (WPW) is a rare disease in which the electrical conducting system of the heart is abnormal. A normal heart has two "pacemakers" that keep the heart beating synchronously. They are called the sinoatrial (SA) node and the atrioventricular (AV) node. They are usually connected to each other by a single conducting pathway. There are two pathways out of the AV node, which pass through the bundle of His and are called Purkinje fibers. In WPW, there is an accessory pathway, known as the bundle of Kent, that bypasses all or part of the typical AV node conduction system. This can cause the heart to get "confused" as it can recieve different signals on when to beat. This results in a preactivation contraction and can cause tachyarrhythmias (accelerated heartbeats) and a typical appearance on the EKG of a delta wave. In some individuals this can result in sudden cardiac death. Some individuals who have been diagnosed with WPW will actually improve and lose the accessory excitation pathway.

There are a number of different treatments for WPW, which depends on the type of reentrant pathway. Some individuals can stop arrhythmias by coughing, bearing down, or massaging the neck. Some individuals need to undergo radiofrequency ablation, in which the abnormal pathway is destroyed.



Publications

  1. Sotoodehnia N, et al. Common variants in 22 loci are associated with QRS duration and cardiac ventricular conduction. Nat Genet. 2010 Dec;42(12):1068-76.
  2. Wirka RC, et al. A common connexin-40 gene promoter variant affects connexin-40 expression in human atria and is associated with atrial fibrillation. Circ Arrhythm Electrophysiol. 2011 Feb;4(1):87-93.
  3. Lubitz SA, et al. Independent susceptibility markers for atrial fibrillation on chromosome 4q25. Circulation. 2010 Sep 7;122(10):976-84.
  4. Eijgelsheim M, et al. Genome-wide association analysis identifies multiple loci related to resting heart rate. Hum Mol Genet. 2010 Oct 1;19(19):3885-94.
  5. Tomas M, et al. Polymorphisms in the NOS1AP gene modulate QT interval duration and risk of arrhythmias in the long QT syndrome. J Am Coll Cardiol. 2010 Jun 15;55(24):2745-52.
  6. Arking DE, et al. Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. PLoS One. 2010 Mar 25;5(3):e9879
  7. Ellinor PT, et al. Common variants in KCNN3 are associated with lone atrial fibrillation. Nat Genet. 2010 Mar;42(3):240-4.
  8. Pfeufer A, et al. Genome-wide association study of PR interval. Nat Genet. 2010 Feb;42(2):153-9.
  9. Pfeufer A, et al. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet. 2009 Apr;41(4):407-14.
  10. Arking DE, et al. Multiple independent genetic factors at NOS1AP modulate the QT interval in a multi-ethnic population. PLoS One. 2009;4(1):e4333.
  11. Arking DE, et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet. 2006 Jun;38(6):644-51.