Heartbeat Matrix: Accelerating targeted treatments for patients with inherited heart disease

Our work will reshape the care of patients and families with inherited heart diseases, allowing robust diagnosis of abnormal genes, matching patients to a range of new treatments, and transforming lives around the world by fast-tracking not just one potential cure, but many.

We will create an international platform to rapidly diagnose and stratify over 20,000 patients with inherited heart diseases, matching them to novel therapies in a unique clinical trials platform enabling multiple simultaneous evaluations and continuous adaptation. Bringing together patients, industry, scientists, clinicians and policymakers globally, we will transform the lives of people with inherited heart disease around the world, accelerating not just one potential cure but many.


  • University of Birmingham, UK
  • University College London, UK
  • University Hospital Hamburg, GER
  • University of Heidelberg, GER
  • European Molecular Biology Labs EMBL, Heidelberg, GER
  • Broad Institute/Harvard, USA
  • Stanford University, USA
  • John’s Hopkins University, USA
  • Ohio State University, USA
  • Landspitali Reykjavik, IS
  • University of Pavia, I; Spanish Centre for Cardiovascular Research, Madrid, ES
  • University of Amsterdam Medical Center, NL
  • Preventicus GmbH, GER
  • Recombinetics, USA
  • deCODE Genetics, IS
  • Novo Nordisk, DK
  • Audentes Rx, USA
  • Avantea SRL
  • Cardiomyopathy UK
  • ARVC Selbsthilfe
  • Una Famiglia per il Cuore
  • Patients at all sites

Full reference list

  1. Goldraich LA, Stehlik J, Cherikh WS, et al. Duration of corticosteroid use and long-term outcomes after adult heart transplantation: A contemporary analysis of the International Society for Heart and Lung Transplantation Registry. Clin Transplant 2018; 32(8): e13340.
  2. Myerburg RJ, Spooner PM. Opportunities for sudden death prevention: directions for new clinical and basic research. Cardiovascular research 2001; 50(2): 177-85.
  3. Priori SG, Blomstrom-Lundqvist C, Mazzanti A, et al. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J 2015; 36(41): 2793-867.
  4. Kotecha D, Holmes J, Krum H, et al. Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet 2014; 384(9961): 2235-43.
  5. Ziff OJ, Lane DA, Samra M, et al. Safety and efficacy of digoxin: systematic review and meta-analysis of observational and controlled trial data. BMJ 2015; 351: h4451.
  6. Kirchhof P, Sipido KR, Cowie MR, et al. The continuum of personalized cardiovascular medicine: a position paper of the European Society of Cardiology. Eur Heart J 2014; 35(46): 3250-7.
  7. Arnar DO, Palsson R. Precision Medicine and Advancing Clinical Care: Insights From Iceland. JAMA Internal Medicine 2019; 179(2): 139-40.
  8. Arnar DO, Thorvaldsson S, Manolio TA, et al. Familial aggregation of atrial fibrillation in Iceland. European Heart Journal 2006; 27(6): 708-12.
  9. Gudbjartsson DF, Arnar DO, Helgadottir A, et al. Variants conferring risk of atrial fibrillation on chromosome 4q25. Nature 2007; 448(7151): 353-7.
  10. Gudbjartsson DF, Helgason H, Gudjonsson SA, et al. Large-scale whole-genome sequencing of the Icelandic population. Nature genetics 2015; 47(5): 435.
  11. Gudbjartsson DF, Holm H, Gretarsdottir S, et al. A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Nature genetics 2009; 41(8): 876.
  12. Gudbjartsson DF, Holm H, Sulem P, et al. A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation. Eur Heart J 2017; 38(1): 27-34.
  13. Holm H, Gudbjartsson DF, Sulem P, et al. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nature genetics 2011; 43(4): 316.
  14. Roselli C, Chaffin MD, Weng LC, et al. Multi-ethnic genome-wide association study for atrial fibrillation. Nat Genet 2018; 50(9): 1225-33.
  15. Syeda F, Holmes AP, Yu TY, et al. PITX2 modulates atrial membrane potential and reduced PITX2 potentiates the antiarrhythmic effects of sodium-channel blockers. JACC 2016; 68: 59-72; doi: 10.1016/j.jacc.2016.07.766.
  16. Kirchhof P, Kahr PC, Kaese S, et al. PITX2c is expressed in the adult left atrium, and reducing Pitx2c expression promotes atrial fibrillation inducibility and complex changes in gene expression. Circ Cardiovasc Genet 2011; 4(2): 123-33.
  17. Kirchhof P, Breithardt G, Bax J, et al. A roadmap to improve the quality of atrial fibrillation management: proceedings from the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference. Europace 2016; 18(1): 37-50.
  18. Holm H, Gudbjartsson DF, Arnar DO, et al. Several common variants modulate heart rate, PR interval and QRS duration. Nat Genet 2010; 42(2): 117-22.
  19. Prins BP, Mead TJ, Brody JA, et al. Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6. Genome Biol 2018; 19(1): 87.
  20. den Hoed M, Eijgelsheim M, Esko T, et al. Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nat Genet 2013; 45(6): 621-31.
  21. Bezzina CR, Barc J, Mizusawa Y, et al. Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. Nat Genet 2013; 45(9): 1044-9.
  22. Schott JJ, Alshinawi C, Kyndt F, et al. Cardiac conduction defects associate with mutations in SCN5A. Nat Genet 1999; 23(1): 20-1.
  23. Tan HL, Bink-Boelkens MT, Bezzina CR, et al. A sodium-channel mutation causes isolated cardiac conduction disease. Nature 2001; 409(6823): 1043-7.
  24. Bezzina CR, Pazoki R, Bardai A, et al. Genome-wide association study identifies a susceptibility locus at 21q21 for ventricular fibrillation in acute myocardial infarction. Nat Genet 2010; 42(8): 688-91.
  25. Aragam KG, Chaffin M, Levinson RT, et al. Phenotypic Refinement of Heart Failure in a National Biobank Facilitates Genetic Discovery. Circulation 2018.
  26. Sveinbjornsson G, Olafsdottir EF, Thorolfsdottir RB, et al. Variants in NKX2-5 and FLNC Cause Dilated Cardiomyopathy and Sudden Cardiac Death. Circ Genom Precis Med 2018; 11(8): e002151.
  27. Arking DE, Pulit SL, Crotti L, et al. Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization. Nat Genet 2014; 46(8): 826-36.
  28. Holm H, Gudbjartsson DF, Sulem P, et al. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat Genet 2011; 43(4): 316-20.
  29. Thorolfsdottir RB, Sveinbjornsson G, Sulem P, et al. Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation. Commun Biol 2018; 1: 68.
  30. Marsman RF, Barc J, Beekman L, et al. A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular fibrillation in childhood and adolescence. Journal of the American College of Cardiology 2013.
  31. Haas J, Frese KS, Peil B, et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur Heart J 2014.
  32. Elliott PM, Gimeno Blanes JR, Mahon NG, Poloniecki JD, McKenna WJ. Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet 2001; 357(9254): 420-4.
  33. Charron P, Elliott PM, Gimeno JR, et al. The Cardiomyopathy Registry of the EURObservational Research Programme of the European Society of Cardiology: baseline data and contemporary management of adult patients with cardiomyopathies. Eur Heart J 2018; 39(20): 1784-93.
  34. Elliott PM, Brecker SJ, McKenna WJ. Diastolic dysfunction in hypertrophic cardiomyopathy. Eur Heart J 1998; 19(8): 1125-7.
  35. Elliott P, McKenna WJ. Hypertrophic cardiomyopathy. Lancet 2004; 363(9424): 1881-91.
  36. McKenna WJ, Coccolo F, Elliott PM. Genes and disease expression in hypertrophic cardiomyopathy. Lancet 1998; 352(9135): 1162-3.
  37. Parikh VN, Caleshu C, Reuter C, et al. Regional Variation in RBM20 Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy. Circ Heart Fail 2019; 12(3): e005371.
  38. Ritterhoff J, Volkers M, Seitz A, et al. S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction. Mol Ther 2015; 23(8): 1320-30.
  39. Sedaghat-Hamedani F, Haas J, Zhu F, et al. Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy. Eur Heart J 2017; 38(46): 3449-60.
  40. Streckfuss-Bomeke K, Tiburcy M, Fomin A, et al. Severe DCM phenotype of patient harboring RBM20 mutation S635A can be modeled by patient-specific induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol 2017; 113: 9-21.
  41. van den Hoogenhof MMG, Beqqali A, Amin AS, et al. RBM20 Mutations Induce an Arrhythmogenic Dilated Cardiomyopathy Related to Disturbed Calcium Handling. Circulation 2018.
  42. Weber C, Neacsu I, Krautz B, et al. Therapeutic safety of high myocardial expression levels of the molecular inotrope S100A1 in a preclinical heart failure model. Gene Ther 2014; 21(2): 131-8.
  43. Fabritz L, Hoogendijk MG, Scicluna BP, et al. Load-reducing therapy prevents development of arrhythmogenic right ventricular cardiomyopathy in plakoglobin-deficient mice. Journal of the American College of Cardiology 2011; 57(6): 740-50.
  44. James CA, Bhonsale A, Tichnell C, et al. Exercise Increases Age-Related Penetrance and Arrhythmic Risk in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy Associated Desmosomal Mutation Carriers. Journal of the American College of Cardiology 2013.
  45. Dalal D, James C, Devanagondi R, et al. Penetrance of mutations in plakophilin-2 among families with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Journal of the American College of Cardiology 2006; 48(7): 1416-24.
  46. Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 2004; 292(11): 1341-4.
  47. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001; 103(1): 89-95.
  48. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003; 348(19): 1866-74.
  49. Mazzanti A, Maragna R, Vacanti G, et al. Interplay Between Genetic Substrate, QTc Duration, and Arrhythmia Risk in Patients With Long QT Syndrome. Journal of the American College of Cardiology 2018; 71(15): 1663-71.
  50. Rivaud MR, Jansen JA, Postema PG, et al. A common co-morbidity modulates disease expression and treatment efficacy in inherited cardiac sodium channelopathy. Eur Heart J 2018.
  51. Priori SG, Napolitano C, Tiso N, et al. Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 2001; 103(2): 196-200.
  52. Denegri M, Bongianino R, Lodola F, et al. Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age. Circulation 2014; 129(25): 2673-81.
  53. Bongianino R, Denegri M, Mazzanti A, et al. Allele-Specific Silencing of Mutant mRNA Rescues Ultrastructural and Arrhythmic Phenotype in Mice Carriers of the R4496C Mutation in the Ryanodine Receptor Gene (RYR2). Circ Res 2017; 121(5): 525-36.
  54. Wilde AA, Bhuiyan ZA, Crotti L, et al. Left cardiac sympathetic denervation for catecholaminergic polymorphic ventricular tachycardia. N Engl J Med 2008; 358(19): 2024-9.
  55. Backs J, Backs T, Bezprozvannaya S, McKinsey TA, Olson EN. Histone deacetylase 5 acquires calcium/calmodulin-dependent kinase II responsiveness by oligomerization with histone deacetylase 4. Molecular cellular biology 2008; 28(10): 3437-45.
  56. Backs J, Song K, Bezprozvannaya S, Chang S, Olson EN. CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. J Clin Invest 2006; 116(7): 1853-64.
  57. Di Pasquale E, Lodola F, Miragoli M, et al. CaMKII inhibition rectifies arrhythmic phenotype in a patient-specific model of catecholaminergic polymorphic ventricular tachycardia. Cell Death Dis 2013; 4: e843.
  58. Kreusser MM, Lehmann LH, Keranov S, et al. Cardiac CaM Kinase II genes delta and gamma contribute to adverse remodeling but redundantly inhibit calcineurin-induced myocardial hypertrophy. Circulation 2014; 130(15): 1262-73.
  59. Lehmann LH, Jebessa ZH, Kreusser MM, et al. A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. Nature Medicine 2018; 24(1): 62.
  60. Gedicke-Hornung C, Behrens-Gawlik V, Reischmann S, et al. Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice. EMBO Mol Med 2013; 5(7): 1128-45.
  61. Lodola F, Morone D, Denegri M, et al. Adeno-associated virus-mediated CASQ2 delivery rescues phenotypic alterations in a patient-specific model of recessive catecholaminergic polymorphic ventricular tachycardia. Cell Death Dis 2016; 7(10): e2393.
  62. Bongianino R, Priori SG. Gene therapy to treat cardiac arrhythmias. Nat Rev Cardiol 2015; 12(9): 531-46.
  63. Denegri M, Avelino-Cruz JE, Boncompagni S, et al. Viral gene transfer rescues arrhythmogenic phenotype and ultrastructural abnormalities in adult calsequestrin-null mice with inherited arrhythmias. Circ Res 2012; 110(5): 663-8.
  64. Cerrone M, Colombi B, Santoro M, et al. Bidirectional ventricular tachycardia and fibrillation elicited in a knock-in mouse model carrier of a mutation in the cardiac ryanodine receptor. Circ Res 2005; 96(10): e77-82.
  65. Kirchhof P, Fabritz L, Zwiener M, et al. Age- and training-dependent development of arrhythmogenic right ventricular cardiomyopathy in heterozygous plakoglobin-deficient mice. Circulation 2006; 114(17): 1799-806.
  66. Ruan Y, Liu N, Bloise R, Napolitano C, Priori SG. Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. Circulation 2007; 116(10): 1137-44.
  67. Mazzanti A, Maragna R, Faragli A, et al. Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3. Journal of the American College of Cardiology 2016; 67(9): 1053-8.
  68. Dorr M, Nohturfft V, Brasier N, et al. The WATCH AF Trial: SmartWATCHes for Detection of Atrial Fibrillation. JACC Clin Electrophysiol 2019; 5(2): 199-208.
  69. Brasier N, Raichle CJ, Dorr M, et al. Detection of atrial fibrillation with a smartphone camera: first prospective, international, two-centre, clinical validation study (DETECT AF PRO). Europace 2018.
  70. Raichle CJ, Eckstein J, Lapaire O, et al. Performance of a Blood Pressure Smartphone App in Pregnant Women: The iPARR Trial (iPhone App Compared With Standard RR Measurement). Hypertension 2018; 71(6): 1164-9.
  71. Kotecha D, Calvert M, Deeks JJ, et al. A review of rate control in atrial fibrillation, and the rationale and protocol for the RATE-AF trial. BMJ Open 2017; 7(7): e015099.
  72. Shantsila E, Haynes R, Calvert M, et al. IMproved exercise tolerance in patients with PReserved Ejection fraction by Spironolactone on myocardial fibrosiS in Atrial Fibrillation rationale and design of the IMPRESS-AF randomised controlled trial. BMJ Open 2016; 6(10): e012241.
  73. Anker SD, Agewall S, Borggrefe M, et al. The importance of patient-reported outcomes: a call for their comprehensive integration in cardiovascular clinical trials. Eur Heart J 2014; 35(30): 2001-9.
  74. Calvert M, Blazeby J, Altman DG, et al. Reporting of patient-reported outcomes in randomized trials: the CONSORT PRO extension. JAMA 2013; 309(8): 814-22.
  75. Calvert M, Kyte D, Price G, Valderas JM, Hjollund NH. Maximising the impact of patient reported outcome assessment for patients and society. BMJ 2019; 364: k5267.
  76. Middleton G, Crack LR, Popat S, et al. The National Lung Matrix Trial: translating the biology of stratification in advanced non-small-cell lung cancer. Ann Oncol 2015; 26(12): 2464-9.
  77. Brauch KM, Karst ML, Herron KJ, et al. Mutations in ribonucleic acid binding protein gene cause familial dilated cardiomyopathy. Journal of the American College of Cardiology 2009; 54(10): 930-41.
  78. Maatz H, Jens M, Liss M, et al. RNA-binding protein RBM20 represses splicing to orchestrate cardiac pre-mRNA processing. J Clin Invest 2014; 124(8): 3419-30.
  79. Wehrens XH, Lehnart SE, Huang F, et al. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell 2003; 113(7): 829-40.
  80. Priori SG, Napolitano C, Memmi M, et al. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia. Circulation 2002; 106(1): 69-74.
  81. Liu B, Walton SD, Ho HT, et al. Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin-Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia. J Am Heart Assoc 2018; 7(10).
  82. Vecchietti S, Grandi E, Severi S, et al. In silico assessment of Y1795C and Y1795H SCN5A mutations: implication for inherited arrhythmogenic syndromes. Am J Physiol Heart Circ Physiol 2007; 292(1): H56-65.
  83. Fabritz L, Kirchhof P, Franz MR, et al. Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in hearts of SCN5A ð-KPQ (LQT3) mice. Cardiovascular research 2003; 57(4): 1085-93.
  84. Lemoine MD, Duverger JE, Naud P, et al. Arrhythmogenic left atrial cellular electrophysiology in a murine genetic long QT syndrome model. Cardiovascular research 2011; 92(1): 67-74.
  85. Bhonsale A, Groeneweg JA, James CA, et al. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur Heart J 2015; 36(14): 847-55.
  86. Mazzanti A, Ng K, Faragli A, et al. Arrhythmogenic Right Ventricular Cardiomyopathy: Clinical Course and Predictors of Arrhythmic Risk. Journal of the American College of Cardiology 2016; 68(23): 2540-50.
  87. Cerrone M, Montnach J, Lin X, et al. Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm. Nat Commun 2017; 8(1): 106.
  88. Mearini G, Stimpel D, Geertz B, et al. Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice. Nat Commun 2014; 5: 5515.
  89. Sawant AC, Te Riele AS, Tichnell C, et al. Safety of American Heart Association-recommended minimum exercise for desmosomal mutation carriers. Heart Rhythm 2015.
  90. Sawant AC, Bhonsale A, te Riele AS, et al. Exercise has a disproportionate role in the pathogenesis of arrhythmogenic right ventricular dysplasia/cardiomyopathy in patients without desmosomal mutations. J Am Heart Assoc 2014; 3(6): e001471.
  91. Fabritz L, Fortmuller L, Yu TY, Paul M, Kirchhof P. Can preload-reducing therapy prevent disease progression in arrhythmogenic right ventricular cardiomyopathy? Experimental evidence and concept for a clinical trial. Prog Biophys Mol Biol 2012; 110(2-3): 340-6.