Preclinical Diastolic Dysfunction (PDD) has been broadly defined as subjects with left ventricular diastolic dysfunction, without the diagnosis of congestive heart failure (HF), and with normal systolic function. PDD is an entity which remains poorly understood, yet has definite clinical significance. Although few original studies have focused on PDD, it has been shown that PDD is prevalent, and that there is a clear progression from PDD to symptomatic heart failure including dyspnea, edema, and fatigue. In diabetic patients and patients with coronary artery disease or hypertension, it has been shown that patients with PDD have a significantly higher risk of progression to heart failure and death compared to patients without PDD. Because of these findings and the increasing prevalence of the heart failure epidemic, it is clear that an understanding of PDD is essential to decreasing patients’ morbidity and mortality. This review will focus on what is known concerning preclinical diastolic dysfunction, including definitions, staging, epidemiology, pathophysiology, and the natural history of the disease. In addition, given the paucity of trials focused on PDD treatment, studies targeting risk factors associated with the development of PDD and therapeutic trials for heart failure with preserved ejection fraction will be reviewed.
BACKGROUND The Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE AHF) trial found that as compared to placebo, neither low-dose dopamine (2 ug/kg/min) nor low-dose nesiritide (0.005 µg/kg/min without bolus) enhanced decongestion or preserved renal function in AHF patients with renal dysfunction. However, there may be differential responses to vasoactive agents in AHF patients with reduced versus preserved ejection fraction (EF). This post-hoc analysis examined potential interaction between treatment effect and EF group (EF ≤ 40% vs > 40%) on the ROSE AHF endpoints. METHODS AND RESULTS ROSE AHF enrolled AHF patients (n=360; any EF) with renal dysfunction. The co-primary endpoints were cumulative urine volume and the change in serum cystatin-C from over 72 hours. The effect of dopamine (interaction p=0.001) and nesiritide (interaction p=0.039) on urine volume varied by EF group. In HFrEF, urine volume was higher with active treatment versus placebo whereas in HFpEF, urine volume was lower with active treatment. The effect of dopamine and nesiritide on weight change, sodium excretion and incidence of AHF treatment failure also varied and in a similar manner by EF group (interaction p<0.05 for all). There was no interaction between either vasoactive treatment’s effect and EF group on change in cystatin-C. Compared to placebo, dopamine was associated with improved clinical outcomes in HFrEF and worse clinical outcomes in HFpEF. With nesiritide, there were no differences in clinical outcomes as compared to placebo in both HFrEF and HFpEF. CONCLUSIONS In this post-hoc analysis of ROSE AHF, the response to vasoactive therapies differed in patients with HFrEF and HFpEF. Investigation of AHF therapies should assess the potential for differential responses in AHF with preserved versus reduced EF. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01132846.
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