Predictors of outcome in heart failure with normal ejection fraction

Background: Heart failure patients with normal left ventricular ejection fraction (HFNEF) face an adverse outcome. The aim of the present study is to identify factors that determine prognosis. Based upon the hypothesis that obliteration and loss of myocardial microvessels leads into myocardial fibrosis and heart failure, a series of pathobiological, hemodynamic and demographic parameters will be investigated. Specific aims: 1. To recruit consecutive patients with an echocardiographic and hemodynamic diagnosis of HFNEF 2. To perform myocardial biopsy for quantification of myocardial fibrosis and correlation with the number of microvessels 3. To perform cardiac magnetic resonance imaging (CMR) in order to quantify right ventricular function, left ventricular hypertrophy and fibrosis. 4. To draw blood in order to correlate serum levels of markers of fibrogenesis with histological and CMR degree of fibrosis. In case of a prognostic impact of cardiac fibrosis, serum markers of fibrogenesis could confer usefulness as biomarkers of disease. Study design: In this single-center study, 350 patients with HFNEF will be followed prospectively over at least one year. Pathobiological, hemodynamic and demographic parameters will be tested as potential predictors of outcome. Study endpoints: The primary outcome measure will be a combined endpoint consisting of hospitalization due to clinical worsening or death. Further endpoints will be changes in exercise capacity as measured by the 6-minute walk test, time to clinical worsening and death. Inclusion criteria: Written informed consent, diagnosis of HFNEF (LVEF > 50 %, LVEDVI < 97ml/m2 ), NYHA > 1 Exclusion criteria: inability or unwillingness to perform any of the diagnostic tests or to participate in follow-up visits, left ventricular ejection fraction =50%, significant valvular disease, congenital heart disease, left ventricular diastolic dysfunction in the absence of symptoms or signs of heart failure, GFR < 30 ml/min, pregnancy.

Heart failure with preserved ejection fraction (HFpEF) is a common disease amongst the elderly population and affects mostly women. In HFpEF, a variety of predisposing factors cause an increase in cardiac fibrosis, which causes stiffness of the heart and leads to an elevation of cardiac filling pressures. These patients present with signs and symptoms of heart failure, such as breathlessness, decreased exercise capacity and fluid retention. Even though it is a frequent disease, not much is known about the pathophysiology and risk factors in these patients. To learn more about HFpEF and its prognosis we created a clinical registry. To date, this registry includes the data of 376 patients, including clinical, laboratory, imaging parameters and hemodynamic parameters. Additional procedures were performed in a subset of patients, e.g. cardiac biopsy for the quantification of fibrosis. Due to the thorough clinical work-up, data collection and analysis, we have presented the following results: - Parameters including symptom severity, exercise capacity, fluid overload, increased pulmonary pressures and right heart dysfunction predict poor prognosis in patients with HFpEF - HFpEF patients with additional pulmonary vascular disease present with lower blood oxygen saturation and show worse prognosis than patients with elevated pulmonary pressures due to mere backwards transmission of left ventricular filling pressures. - In HFpEF, fibrosis can be quantified non-invasively without cardiac biopsy samples by contrast magnetic resonance imaging. - Among our total HFpEF population, more than 50% of patients died of right heart failure. Previously, the modes of death in these patients were not known. These findings can increase the understanding of this disease and aid clinicians treating these patients in their clinical decisions. Of note, we also found incidental cases of patients with cardiac amyloid deposits due to biopsies performed as part of this registry. We have become a national referral centre for cardiac amyloidosis (CA) and have diagnosed 150 patients so far.