Myocardial remodeling as a complex trait- focus on cardiac specific troponin I and T

Cardiovascular disease is among the leading cause of death in the Western world. Given the increasing prevalence of elderly subjects in the population, the number of patients with cardiovascular disease will increase, and heart failure, in particular, will become a major health problem. Heart failure is caused by several etiologies and leads to systemic and pulmonary congestion with the patient experiencing fatigue and breathlessness. Developments in the therapy for heart failure after myocardial infarction have improved the outcome for this patient' groups. In contrast, no therapy is available to improve survival in heart failure caused by hypertension, which is the predominant type of heart failure in patients over the age of 70 years. The importance of increased left ventricular mass and remodeling (i.e. altered myocardial structure and function) for heart failure development and mortality have been explored in large community-acquired cohorts. Risk factors for left ventricular remodeling include hypertension and diabetes mellitus, but currently less information is available regarding the genetic susceptibility to develop left ventricular remodeling. The current proposal aims to assess the influence of cardiac troponin I and T in the development of myocardial remodeling. To this end, we have assessed troponin levels in approximately 3500 subjects included in the Akershus Cardiac Examination (ACE) 1950 Study. We have also performed exome sequencing (analysis of expressed genes in a genome) on all study subjects, investigating possible genetic susceptibility associated with the development of left ventricular remodeling. The ACE 1950 Study is a large community-based study of subjects born in the year 1950 with residence in Akershus County, Norway. All the participants of the ACE 1950 Study have been subjected to extensive cardiovascular phenotyping, including cardiac echocardiography. A selected group of study participants have also been examined by cardiac MRI, enabling detailed studies on cardiac structure and function. The project combines state-of-the-art molecular biology and genetics with innovative imaging, additionally aiming to examine mechanisms of left ventricular remodeling on the cellular level. Results from the current project have identified cardiac troponins as early predictors of heart failure development, and subjects with high concentrations of cardiac troponin have increased left ventricular mass and low-grade reductions in cardiac function.

Prosjektet har etablert en unik forskningsdatabase som integrerer hjertespesifikke biomarkører, avansert bildediagnostikk og genetiske analyser. Arbeid fra prosjektet vil kunne gi ny innsikt i sammenhengene mellom genetiske sårbarheter og tidligere stadier av hjertesykdom, som kan gi økt forståelse av utvikling av hjertesykdom på befolkningsnivå. Prosjektet vil kunne danne grunnlag for persontilpasset medisin, som integrerer etablerte risikofaktorer for hjertesykdom (som eksempelvis høyt blodtrykk og diabetes) med genetiske og bildediagnostiske verktøy. Mange av metodene benyttet i prosjektet er også tilgjengelig for implementering i større skala, som igjen muliggjør kommersialisering av metoder til allmenn bruk. Resultatene fra prosjektet viser at hjertespesifikke troponiner er assosiert med fortykket hjertemuskel og lavgradig reduksjon i hjertefunksjon. Slik informasjon kan videre benyttes til å forutsi hvem som står i fare for å utvikle symptomgivende hjertesykdom som hjertesvikt.

The proposal represents an ambitious but realistic project to enhance the understanding of hs-troponin measurements in subclinical and stable CVD. hs-troponins are the most promising biomarkers for population screening for CVD, and the large Norwegian community-based Akershus Cardiac Examination (ACE) 1950 Study (ClinicalTrials.gov Identifier: NCT01555411) will form the basis for this project. The ACE 1950 Study is perfectly suited to answer the proposed research question as it will permit exploration in a large community-based cohort of the association between protein and genetic variance in troponin I and T expression and LV remodeling. Currently, ~2000 subjects have been included in the ACE 1950 Study and we expect recruitment to be finalized by the end of 2014 with approximately 3700 participants included (65% of the total cohort). For this project participants with history of, or evidence of prior CVD or renal failure will be excluded, which will leave us with approximately 3500 subjects for WP #1-3. Our group has proven expertise in the use of the hs-troponin assays and CVs for these assays have been published for our laboratory. The recent recruitment of the group of Professor Hilde Nilsen, previously at the Biotechnology Centre, to Akershus University Hospital ensures that the consortium will have extensive knowledge regarding next generation sequencing and epigenetic studies. Professor Nilsen is the head the Clinical Molecular Laboratory, Akershus University Hospital and gene sequencing, chromatin immunoprecipitation and ChIP-sequencing, and in vitro experiments will be performed in her laboratory. The Clinical Molecular Laboratory, Akershus University Hospital also has knowledge regarding bioinformatics and biostatistics as outlined in WP #3. LGE and T1-weighted cardiac MRI imaging will be performed in collaboration with Siri L. Heck, consultant radiologist and responsible for cardiac MRI at Akershus University Hospital.