Biomarkers of fibrosis for arrhythmia risk stratification; Challenging arrhythmias in heart failure by reducing fibrosis and increasing cell-to-cell coupling.
01 / 2009 - 13 / 2012
Congestive heart failure (CHF) is an important public health problem, with a lifetime risk of about 20% in both men and women. Although heart failure is defined by reduced pump function, about half of CHF patients die suddenly due to ventricular tachyarrhythmias, caused by abnormal repolarisation and conduction. Reduced gap junction and/or sodium channel expression (up to 50% in CHF patients) and increased collagen expression (fibrosis) (5-fold increase in CHF patients) are likely candidates for abnormal conduction related arrhythmias in CHF. In NHS projects M96.001, 2003B128, 2003B195 and 2005B170 we have elucidated, using genetically modified mice, pressure overloaded mice, and CHF patient biopsies, that heterogeneously reduced electrical coupling by gap junctions combined with increased fibrosis are the key determinants for arrhythmogeneity in CHF. Furthermore, we have shown that chronic suppression of the renin-angiotensin-aldosteron system (RAAS) is able to reduce fibrosis related arrhythmias in senescent wildtype mice. Our previous findings point at reduced electrical coupling and increased fibrosis as prime suspects for arrhythmogeneity and prime targets for anti arrhythmogenic therapy. Secondly, because cardiac fibrosis is associated with cardiac dysfunction and arrhythmogeneity, we hypothesise that early quantitative detection of fibrosis may play an important role in the treatment and prognosis of individual patients suffering from HF. Since cardiac biopsies demand invasive approaches which only give very local information, non-invasive techniques that provide global information, such as biomarkers of fibrosis, might be much more beneficial. This application embraces two hypotheses: 1. Serum levels of collagen propeptides directly correlate to the amount of myocardial collagen content and are individual risk indicators for cardiac arrhythmogeneity. 2.Reduction of fibrosis and restoration of normal electrical coupling in the failing heart will reduce arrhythmogenic vulnerability. We will exploit our mouse model of long standing (16wk) pressure overload (transverse aortic constriction, TAC), in which mice develop heart failure and are highly vulnerable to arrhythmias. TAC mice will be studied at week 2, 4, 6, 8, 10, 12, 14 and 16 to monitor the development of the arrhythmogenic substrate (Collagen deposition and Cx43 remodeling). Furthermore, blood samples will be taken to estimate collagen turnover using the serum biomarkers PICP, PIIICP, PINP and PIIINP, which are the C- and N-terminal propeptides of procollagen type I and III, respectively. These experiments will define the feasibility of these biomarkers as individual risk stratifiers for arrhythmogeneity. Parallelly, we will pursue two anti arrhythmic strategies in increasingly higher levels of complexity, starting with cultured cardiac slices up to intact TAC mice: 1. To reduce the amount of fibrosis by treatment with inhibitors of the Renin Angiotensin Aldosterone System (RAAS) or procollagen gene silencing. 2. To increase electrical coupling by adenoviral overexpression of Cx43. These results will determine the feasibility of anti-arrhythmic therapies by normalizing the substrate in patients with heart failure. Objectives "To evaluate the predictive value of blood born biomarkers of collagen turnover in the prediction of arrhythmogeneity in heart failure. "To correlate the development of reactive and replacement fibrosis and Cx43 remodeling in a mouse model of heart failure with arrhythmias "To establish whether chronic treatment with RAAS-inhibitors is able to reduce fibrosis and arrhythmias in pressure overloaded mice. "To determine the anti-arrhythmic effect of improvement of electrical coupling by upregulation of Cx43. Relevance for cardiovascular diseases Increased interstitial collagen deposition and reduced gap junction expression is associated with the pathologic and arrhythmogenic heart. The current strategy to treat patients is not focused on the substrate of the arrhythmias, and currently most patients receive an implantable cardiac defibrillator. In addition, a number of patients with an ICD require alternative treatment because of frequent electrical shocks. This project explores the possibilities to ameliorate the substrate, thereby increasing the electrical stability of the heart. Keywords arrhythmia - collagen - conduction - heart failure