INVITED REVIEW Future strategies for the treatment of diastolic heart failure YAIR FELD 1 , SHAY DUBI 2,* , YOTAM REISNER 3 , EHUD SCHWAMMENTHAL 4 & AMIR ELAMI 5 1 GeneGrafts Limited, Haifa, Israel, 2 Sackler Faculty of Medicine, Tel Aviv University, Israel, 3 Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel, 4 Cardiac Rehabilitation Institute, Sheba Medical Center (Tel Aviv University), Tel Hashomer, Israel, and 5 Hadassah University Hospital, Jerusalem, Israel Abstract It is estimated that 30% to 50% of heart failure patients have preserved systolic left ventricular (LV) function, often referred to as diastolic heart failure (DHF). Mortality is high in this patient population, and morbidity and rate of hospitalization are similar to those of patients with systolic heart failure. The management of patients with diastolic heart failure is essentially empirical, limited, and disappointing. New drugs, devices, and gene therapy based treatment options are currently under investigation. In this review, future strategies for the treatment of diastolic heart failure are discussed. Key Words: Diastolic heart failure, diastolic dysfunction, device, gene therapy, cell therapy Introduction The term diastolic heart failure (DHF) generally refers to the clinical syndrome of heart failure associated with a preserved left ventricular ejection fraction (EF), in the absence of major valvular disease (1). Forty percent of incident CHF cases and 50–60% of prevalent CHF cases occur in the setting of preserved systolic function (2). Mortality rate among patients with DHF is considered lower than in systolic heart failure (3). Some challenge this notion, showing that the natural history of patients with DHF may not be different from that of patients with systolic heart failure (2,4). The morbidity and rate of hospitalization are similar to those of patients with systolic heart failure (3,4). Due to its higher prevalence in the elderly population, the incidence of DHF is expected to rise with the increased aging of the western world population. The fundamental problem in diastolic heart failure is the inability of the left ventricle to accommodate blood volume during diastole at normal filling pressures (5,6). Two basic types of diastolic abnorma- lities may be present: impaired ventricular relaxation (which primarily affects early diastole), and increased myocardial stiffness (which primarily affects late diastole) (7–9). The rate and extent of the active relaxation may influence LV suction during the early filling phase (10). Both abnormalities lead to elevation of diastolic pressures. In DHF patients, a relatively small increase in central blood volume or an increase in venous tone, arterial stiffness, or both, can cause a substantial increase in left atrial and pulmonary venous pressures and may result in exercise intolerance (11,12) and acute pulmonary edema (13,14). The mechanisms underlying abnormalities in diastolic function can be divided into factors intrinsic to the myocardium itself and factors that are extrinsic to the myocardium (15). Myocardial factors can additionally be divided to cellular and extracellular. Cellular factors include impaired cal- cium homeostasis leading to abnormalities in both active relaxation and passive stiffness, changes in sarcomeric proteins isotypes, such as titin, which acts as a viscoelastic spring that gains potential energy during systole and provides a recoiling force to restore the myocardium to its resting length during diastole (16). Since relaxation is an energy- consuming process, any abnormalities in cellular energy supply and utilization can lead to impaired relaxation (15). Extracellular factors include changes in structures and quantity of the extracellular matrix, i.e. fibrosis, that lead to increased myocar- dial stiffness (17). There is limited data on neuro- humoral markers in DHF patients other than natriuretic peptides (NPs). This probably reflects the fact that DHF has only recently been Correspondence: Yair Feld, GeneGrafts Limited, Building No. 30, MATAM – Advanced Technology Center, Haifa 31905, Israel. Fax: +972-4- 8501246; E-mail: feld@genegrafts.com *This work was performed in partial fulfillment of the requirements for a Ph.D. degree of Shay Dubi. Acute Cardiac Care. 2006; 8: 13–20 ISSN 1748-2941 print/ISSN 1748-295X online # 2006 Taylor & Francis DOI: 10.1080/14628840600548988