title: Identification of genetic markers for treatment success in heart failure patients: insight from cardiac resynchronization therapy.
abstract: BACKGROUND
  Cardiac resynchronization therapy (CRT) can improve ventricular size, shape, and mass and reduce mitral regurgitation by reverse remodeling of the failing ventricle. About 30% of patients do not respond to this therapy for unknown reasons. In this study, we aimed at the identification and classification of CRT responder by the use of genetic variants and clinical parameters.
  
  
  RESULTS
  Of 1421 CRT patients, 207 subjects were consecutively selected, and CRT responder and nonresponder were matched for their baseline parameters before CRT. Treatment success of CRT was defined as a decrease in left ventricular end-systolic volume >15% at follow-up echocardiography compared with left ventricular end-systolic volume at baseline. All other changes classified the patient as CRT nonresponder. A genetic association study was performed, which identified 4 genetic variants to be associated with the CRT responder phenotype at the allelic (P<0.035) and genotypic (P<0.031) level: rs3766031 (ATPIB1), rs5443 (GNB3), rs5522 (NR3C2), and rs7325635 (TNFSF11). Machine learning algorithms were used for the classification of CRT patients into responder and nonresponder status, including combinations of the identified genetic variants and clinical parameters.
  
  
  CONCLUSIONS
  We demonstrated that rule induction algorithms can successfully be applied for the classification of heart failure patients in CRT responder and nonresponder status using clinical and genetic parameters. Our analysis included information on alleles and genotypes of 4 genetic loci, rs3766031 (ATPIB1), rs5443 (GNB3), rs5522 (NR3C2), and rs7325635 (TNFSF11), pathophysiologically associated with remodeling of the failing ventricle.
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati). Boris.Schmitz@UKmuenster.de.
authors.forename: Boris
authors.initials: B
authors.lastname: Schmitz
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Renata
authors.initials: R
authors.lastname: De Maria
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Dimitris
authors.initials: D
authors.lastname: Gatsios
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Theodora
authors.initials: T
authors.lastname: Chrysanthakopoulou
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Maurizio
authors.initials: M
authors.lastname: Landolina
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Maurizio
authors.initials: M
authors.lastname: Gasparini
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Jonica
authors.initials: J
authors.lastname: Campolo
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Marina
authors.initials: M
authors.lastname: Parolini
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Antonio
authors.initials: A
authors.lastname: Sanzo
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Paola
authors.initials: P
authors.lastname: Galimberti
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Michele
authors.initials: M
authors.lastname: Bianchi
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Malte
authors.initials: M
authors.lastname: Lenders
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Eva
authors.initials: E
authors.lastname: Brand
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Oberdan
authors.initials: O
authors.lastname: Parodi
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Maurizio
authors.initials: M
authors.lastname: Lunati
authors.affiliation: From the Institute of Sports Medicine, Molecular Genetics of Cardiovascular Disease (B.S., S.-M.B.) and Internal Medicine D, Department of Nephrology, Hypertension and Rheumatology (B.S., M. Lenders, E.B.), University Hospital Münster, Münster, Germany; Cardiothoracic and Vascular Department, CNR Institute of Clinical Physiology, Niguarda Ca' Granda Hospital, Milan, Italy (R.D.M., J.C., M.P., O.P.); University of Ioannina, Department of Biomedical Research, Ioannina University Campus (D.G.); Neuron Energy Solutions G.P., Science & Technology Park of Epirus, Ioannina, Greece (T.C.); Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia (M. Landolina, A.S.); Department of Cardiology, Humanitas Research Hospital IRCCS, Rozzano-Milan (M.G., P.G.); and Cardiothoracic and Vascular Department, Niguarda Ca' Granda Hospital, Milan, Italy (M.B., M. Lunati).
authors.forename: Stefan-Martin
authors.initials: SM
authors.lastname: Brand
mesh_terms: D000368:Aged; D019540:Area Under Curve; D058406:Cardiac Resynchronization Therapy; D016022:Case-Control Studies; D053503:Epithelial Sodium Channels / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics*; D005838:Genotype; D006333:Heart Failure / Q000145:classification / Q000235:genetics* / Q000628:therapy; D006352:Heart Ventricles / Q000503:physiopathology; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D053245:RANK Ligand / Q000235:genetics; D012372:ROC Curve; D018161:Receptors, Mineralocorticoid / Q000235:genetics; D012307:Risk Factors; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics; D014463:Ultrasonography; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging
chemical_list: C503551:ATP1B1 protein, human; D053503:Epithelial Sodium Channels; C000595803:GNB3 protein, human; D005819:Genetic Markers; C561839:NR3C2 protein, human; D053245:RANK Ligand; D018161:Receptors, Mineralocorticoid; C507045:SCNN1A protein, human; C507052:SCNN1G protein, human; C505688:TNFSF11 protein, human; D020962:Heterotrimeric GTP-Binding Proteins; D000254:Sodium-Potassium-Exchanging ATPase
keywords: artificial intelligence; cardiac resynchronization therapy; cardiovascular disease; data mining; heart failure; risk factors