Day 2 :
William Harvey Research Institute & Queen Mary University of London, UK
Time : 09:05-09:40
Professor Mark Caulfield graduated in medicine in 1984 and trained in Clinical Pharmacology at St Bartholomew’s Hospital where he developed a major programme in genetics of blood pressure regulation. In 2002 he became Co-Director of the William Harvey Research Institute at Queen Mary University of London which he grew from 140 to 530 clinicians and scientists and a major worldwide pharmacological centre focused on cardiovascular, inflammation and endocrine research. He was President of the British Hypertension Society and served on the council of the European Society of Hypertension. In 2013 he became an NIHR Senior Investigator and Chief Scientist for the 100,000 Genomes Project.
Statement of the problem: Hypertension is the commonest cardiovascular worldwide with an anticipated 1.5 billion people with high blood pressure by 2025. It arises from a complex interplay between genes and lifestyle. From family studies between 30-50% of the heritability of blood pressure is due genetic influences or gene plus lifestyle. Approximately 8-12% of hypertensives cannot tolerate or are resistant to current therapies. Understanding the genes underpinning blood pressure could identify new biological pathways for innovative therapeutics. In genome wide studies of blood pressure now expanded to more than 1000 gene loci for blood pressure discovered and validated in over 1 million people. Many of these loci identify new biological pathways and some repurposing opportunities for existing therapies used for other disorders. A genetic risk score of all aggregate variants at 1000 loci suggested that in the over 50 year olds these loci cause a potential 10 mm Hg rise in blood pressure. This prompts the question is it tie to translate these findings into the clinic. First a targeted gene chip could identify those at risk in early life and enable lifestyle measures such as exercise a diet rich in fruit and vegetables, maintenance of an ideal body weight and reduced alcohol intake. In addition in mechanistic studies we and others have identified potential therapies acting on the nitric oxide-natriuretic peptide pathway including beetroot juice and c-natriuretic peptide mimetics. We can also now deploy next generation sequencing techniques to diagnose the cause of rare syndromic forms of hypertension and the impact of that will be explored.
1. Warren HR, Evangelou E, Cabrera CP, Gao H, Ren M, Mifsud B, and multiple co-authors then, Caulfield M., Elliott P. Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Nat Genet. 2017 Mar; 49(3):403-415. doi: 10.1038/ng.3768.
2. Georg B. Ehret then multiple co-authors then Mark J. Caulfield, Toby Johnson. Genetic variants from novel pathways influence blood pressure and cardiovascular disease risk. Nature 2011; 478(7367):103-9.
3. Louise V Wain, then multiple authors then Mark J Caulfield, Dabeeru C Rao, Martin D Tobin, Paul Elliott, Cornelia M van Duijn. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nature Genetics 2011 Sep 11; 43(10):1005-11.
4. Newton-Cheh C, then 152 co-authors then Elliott P, Abecasis GR, Caulfield M, Munroe PB. Genome-wide association study identifies eight loci associated with blood pressure. Nature Genetics 2009 May 10. [Epub ahead of print] PubMed PMID: 19430483.
Assistant Professor, Harvard Medical School, USA
Time : 09:40-10:15
Antonis A Armoundas completed his BS in Electrical Engineering from National Technical University of Athens, Athens, Greece, in 1991 and MS in Biomedical Engineering from Boston University, Boston, MA, in 1994. He received PhD in Nuclear Engineering, from the Massachusetts Institute of Technology (MIT), in 1999. He was an American Heart Association sponsored Post-doctoral Fellow at the Division of Molecular Cardiobiology and the Department of Biomedical Engineering at Johns Hopkins University. Now, he is a National Institute of Health supported Principal Investigator at Massachusetts General Hospital and an Assistant Professor at Harvard Medical School, while he maintains an appointment at M.I.T. He has authored more than 80 high-impact peer-reviewed journal articles and book chapters, and he also holds six patents. His
research interests include “Biomedical signal processing, forward and inverse problem solutions, and cellular electrophysiology methods”.
Background: This study investigates the spatio-temporal variability of intracardiac repolarization alternans (RA) and its relationship to arrhythmia susceptibility in a swine acute myocardial ischemia (MI) model.
Methods & Results: We developed a real-time multi-channel repolarization signal acquisition, display and analysis system to record electrocardiographic signals from catheters in the right ventricle, coronary sinus and left ventricle prior to and following circumflex coronary artery balloon occlusion. We found that RA is detectable within 4 minutes following the onset ischemia, and is most prominently seen during the first half of the repolarization interval. We developed a novel, clinically-applicable intracardiac lead system based on a triangular arrangement of leads spanning the right ventricular (RV) and coronary sinus (CS) catheters which provided the highest sensitivity for intracardiac RA detection when compared to any other far-field bipolar sensing configurations (p < 0.0001). The magnitude of RA was used to adjust pacing stimuli delivered during the absolute refractory period (ARP) aimed to reduce RA. We found that the pacing pulse polarity and the phase polarity are sufficient parameters to suppress RA. To calibrate the pacing stimuli, we estimated the required charge to induce one μV [one unit] change in the alternans voltage [and Kscore] on CS and LV leads as 0.05 ± 0.025 [0.32 ± 0.29] and 0.06 ± 0.033 [0.33 ± 0.37] μC, respectively. Using this approach, we demonstrated the ability to suppress spontaneous RA following acute MI. Overall, pacing during the ARP resulted in a significant decrease in alternans
voltage and Kscore and reduced arrhythmia susceptibility (p<0.01).
Conclusion: RA can be reliably detected through a novel triangular RV-CS lead configuration. Electrical stimulation during the ARP can be used to suppress RA, in vivo. Our findings may have important implications in developing methods to prevent the onset of ventricular arrhythmias.
1. Merchant FM and Armoundas A A. Role of substrate and triggers in the genesis of cardiac alternans, from the myocyte to the whole heart: Implications for therapy. Circulation. 2012;125:539-549.
2. Sayadi O, Puppala D, Ishaque N, Doddamani R, Merchant F M, Barrett C, Singh J P, Heist E K, Mela T, Martinez J P, Laguna P and Armoundas A A. A novel method to capture the onset of dynamic electrocardiographic ischemic changes and its implications to arrhythmia susceptibility. J Am Heart Assoc. 2014;3.
3. Sayadi O, Merchant F M, Puppala D, Mela T, Singh J P, Heist E K, Owen C and Armoundas A A. A novel method for determining the phase of t-wave alternans: Diagnostic and therapeutic implications. Circ Arrhythm Electrophysiol. 2013;6:818-826.
4. Merchant F M, Sayadi O, Moazzami K, Puppala D and Armoundas A A. T-wave alternans as an arrhythmic risk stratifier: State of the art. Curr Cardiol Rep. 2013;15:398.
5. Merchant F M, Sayadi O, Puppala D, Moazzami K, Heller V and Armoundas A A. A translational approach to probe the proarrhythmic potential of cardiac alternans: A reversible overture to arrhythmogenesis? Am J Physiol Heart Circ Physiol. 2014;306:H465-474.