Cardiac arrhythmias are a leading cause of morbidity and sudden death, and collectively constitute a substantial public health problem. We are focused on understanding the mechanisms of arrhythmias, identifying individuals at risk, and intervening to improve health outcomes. Our group comprises a large and collaborative multi-disciplinary team focused on improving cardiovascular health by leveraging human genetics, prediction modeling, and clinical trials. Several areas of active investigation include:
Determining the genetic basis of arrhythmias: Using genotyping and sequencing techniques, we aim to determine genetic factors that underlie atrial fibrillation, bradyarrhythmias, and sudden cardiac arrest. We leverage rare disease collections and large-scale biorepositories to perform genetic discovery.
Identifying individuals at risk for arrhythmias and related morbidity: By curating datasets including electronic health record data and imaging data, we study factors associated with onset of cardiovascular disease. We use a variety of conventional and novel statistical methods to inform risk assessment.
Improving treatment of individuals with or at risk for arrhythmias: We seek to determine whether specific interventions will improve outcomes and efficiency of care delivery. We are examining digital technology, including wearables, in large-scale clinical trials to screen for atrial fibrillation.
The goal of our laboratory work is to use genetics to elucidate the molecular basis underlying abnormalities of the heart rhythm and heart function. Much of our recent work has focused atrial fibrillation which is the most common arrhythmia. To identify novel pathways for atrial fibrillation we are using a broad range of techniques including population genetics, electrophysiology, and animal models of arrhythmias.
This work in turn led the establishment of the AFGen Consortium, an international group of investigators studying the genetics of atrial fibrillation. In the ensuing years, we have led large-scale genetic analyses for atrial fibrillation and many other cardiovascular diseases. Our work now spans a wide range of topics centered on cardiovascular disease genetics, mechanisms, single cell sequencing, and therapeutic development.
Our experimental laboratory is developing bench-to-bedside approaches to image and understand in vivo inflammation and thrombogenesis in vascular disease, including atherosclerosis, venous thrombosis, and arteriovenous fistula. Via close collaborations with molecular imaging chemistry, we have developed an array of molecular imaging agents to report on macrophages, fibrin, cathepsin K, VCAM-1, thrombin, and activated factor XIII. Using intravital microscopy, FMT, MRI, or PET-CT we have imaged and quantified these molecular targets in murine models of vascular disease, which have led to new insights into how atheroma, thrombi, and AVF evolve and resolve.
Our major translational focus is the development of intravascular near-infrared fluorescence molecular imaging catheter technology to image inflammation in human coronary arteries and coronary stents, using large animal models. In conjunction with leading engineering groups, we have developed intravascular NIRF-OCT and NIRF-IVUS catheters and systems. The ability to image inflammation at high-resolution could provide new approaches to identify high-risk plaques and high-risk stents.
Clinical research efforts are focused in improving percutaneous coronary intervention success for chronic total occlusions, radial artery catheterization, and improving the treatment of microvascular coronary disease / microvascular angina.
Dr. Jaffer graduated from Stanford University (1990, BS with distinction in Mathematical and Computational Sciences) and received his M.D. and Ph.D. in Biophysics from the University of Pennsylvania School of Medicine in 1996. He was a Howard Hughes Medical Institute-NIH Research Scholar from 1993-1995. Dr. Jaffer completed a residency in internal medicine at the Brigham and Women’s Hospital (1999) and went on to a fellowship in Cardiovascular Medicine at Massachusetts General Hospital (1999-2001). Dr. Jaffer completed a postdoctoral research fellowship in the Center for Molecular Imaging Research at MGH, directed by Professor Ralph Weissleder, M.D. Ph.D. followed by a fellowship year in Interventional Cardiology. In 2003, Dr. Jaffer joined the MGH Cardiology Division as a faculty member. In 2006, he was promoted to Assistant Professor of Medicine at Harvard Medical School. In 2007, Dr. Jaffer was appointed as a Principal Investigator in the Cardiovascular Research Center at MGH. In 2011, he became an affiliated Faculty Member in the MGH Wellman Center for Photomedicine. In 2012, he was promoted to Associate Professor of Medicine at Harvard Medical School. In 2013, he was elected to the American Society for Clinical Investigation.
I received my MD in Siberian State Medical University (Tomsk) and PhD in Institute of Evolutionary Physiology and Biochemistry (St.Petersburg) in Russia. I was postdoctoral fellow in Institute of Environmental Medicine of University of Pennsylvania (laboratories of Drs. D. Buerk, S. Thom and V. Muzykantov) and in CVRC of MGH (laboratory of Dr. P. Huang), where I was promoted to Instructor and Assistant Professor.
My research combines mouse genetics, detailed physiologic and hemodynamic measurements, and animal models of human disease, including stroke, atherosclerosis, and diabetes.
My current work focuses on the role of Akt-eNOS-cGMP axis in cerebrovascular dysfunction. My publications demonstrated that mice that carry specific S1177D mutation in eNOS gene are protected against stroke (Journal of Clinical Investigation, 2007), and that they show less obesity and metabolic abnormalities on high fat diet (Biochemical and Biophysical Research Communications, 2013). We show that unphosphorylatable eNOS impairs vascular reactivity to nitric oxide and is associated with incomplete reperfusion, larger infarct size, and worse metabolic profile, suggesting that S1177 eNOS is protective in ischemic stroke. We have found that increased phosphorylation of eNOS on serine 1177 normalized vascular abnormalities in type 2 diabetic mice and protect them against reperfusion injury (Stroke, 2013).
I demonstrated that sGC alpha 1 deficiency impairs vascular reactivity to nitric oxide and is associated with incomplete reperfusion, larger infarct size, and worse neurological damage, indicating that cGMP generated by sGC alpha1 is protective in ischemic stroke (Stroke 2010). The hydrogen clearance method of absolute cerebral blood flow measurement which I use provides absolute measurements as opposed to relative measurements seen with laser Doppler or other commonly used approaches. It has become more accepted, as comparison of genetically altered mice with control animals requires consideration of baseline physiologic differences. I used the hydrogen clearance technique to assess the state-of-the-art novel method of Doppler optical coherence tomography in cerebrovascular physiology (Journal of Cerebral Blood Flow and Metabolism 2011).
We demonstrated that C-reactive protein, a widely accepted marker of cardiovascular diseases, causes insulin resistance through Fcγ receptor IIB-mediated inhibition of skeletal muscle glucose delivery (Diabetes 2012). I showed that C-reactive protein increases the severity of stroke outcome (International Stroke Conference 2012). This demonstrates that C-reactive protein is not just a marker, but also plays a mechanistic role in cerebrovascular and cardiometabolic diseases, opening the possibility for additional treatment and prevention strategies.
The overall unifying theme behind my work is to apply in vivo physiology and disease models and in vitro vascular reactivity measurements, to genetic models relevant to the NO pathway, such as nNOS, eNOS, iNOS, soluble guanylate cyclase, and C-reactive protein. My work is important because it can lead to the development of new approaches to treat cardiovascular and cerebrovascular disease in the setting of diabetes and metabolic abnormalities.
Dr. Newton-Cheh is a complex trait geneticist and cardiovascular epidemiologist, as well as a practicing cardiologist. His laboratory investigates hypertension, sudden cardiac death and cardiotoxic drug response as manifest in the electrocardiographic QT interval. He has led several international consortia that have identified scores of novel genetic factors contributing to hypertension, myocardial repolarization and sudden cardiac death in work published in Nature Genetics, Nature, with many additional high-impact publications in JAMA and the New England Journal of Medicine. He has received awards from MGH for his highly collaborative science efforts to characterize the role of natriuretic peptides in blood pressure regulation, spanning the Center for Human Genetic Research, the Cardiology Division and the Department of Anesthesia, Critical Care and Pain Medicine.
Dr. Newton-Cheh’s finding of eight genetic loci related to blood pressure was highlighted as one of the ten most important discoveries of 2009 by the American Heart Association. He is currently leveraging the rapid growth of human genetics to identify genetic variants in genes known and previously unknown which underlie cardiac diseases, and to translate these genetic discoveries into an improved understanding of human physiology through clinically-focused research. This important work seeks to define the role of genetics and other factors in predicting patients’ risk of disease and cardiotoxic drug response. He has several ongoing physiological trials in humans to better understand the mechanisms by which common variants contribute to the development of disease.
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