041 - Influence of Local Renal Versus Systemic RAAS Activation on Loop Diuretic Response and Clinical Outcomes in Heart Failure

Abstract

Introduction: The renin-angiotensin-aldosterone-system (RAAS) is universally recognized as a critical pathophysiologic axis in heart failure (HF). Notably, RAAS activation causes both progression of cardiac and renal dysfunction and is a major driver of renal sodium retention. However, the RAAS system has paracrine as well as endocrine effects and tissue RAAS activity has been shown in many situations to have limited correlation with circulating levels. Urinary renin and urinary angiotensinogen have been shown to correlate well with renal RAAS activity at the tissue level. Our goal was to determine the relative importance of renal versus systemic RAAS activation on renal and cardiac function in addition to survival in a well phenotyped contemporary HF population. Hypothesis: We expect to see cardiorenal parameters correlate differently with local versus systemic RAAS activation. Methods: Heart failure outpatients in the Yale Transition Care Center treated with loop diuretics were prospectively studied. Diuretic efficiency (DE) was defined as total sodium excreted per doubling of the diuretic dose. Total renin and angiotensinogen were determined in plasma and urine using the Meso Scale Discovery (MSD) platform (Meso Scale diagnostics, Gaithersburg, MD, USA). Urine renin and angiotensinogen were indexed to urinary creatinine to account for dilution. Results: In total 164 patients were studied. Cardiac parameters: Ejection fraction correlated with plasma renin (r=-0.17, P = .03) but not urinary renin levels (P = .23). Systolic blood pressure correlated with plasma renin (r=-0.21, P = .007) and plasma angiotensinogen (r = 0.23, P = .003), but did not correlate with urinary markers (P > .58 for both). Renal parameters: eGFR was not correlated with plasma angiotensinogen and only weakly correlated with plasma renin (r = 0.2, P = .01). However, the correlation between urinary RAAS markers and eGFR was substantially stronger (urinary angiotensinogen r=-0.47, P < .0001, urinary renin r=-0.30, P = .001). DE was also more strongly correlated to urinary renin (r=-0.41, P < .0001) than plasma renin (r=-0.29, P < .001) and urinary angiotensinogen (r=-0.29, P = .001) than plasma angiotensinogen (r=-0.17, P = .046). Outcomes: A plasma renin above the median (HR = 4.3, 95% CI 2.1–9.1, P < .0001) or plasma angiotensinogen above the median (HR = 2.1, 95% CI 1.1–4.0, P = .021) were both strongly associated with mortality. However, there was no association between the urinary markers and survival (P > .10 for both). Conclusion: Both systemic and renal RAAS activation appear to be important parameters in HF. However, cardio-renal metrics such as diuretic responsiveness and renal function are more closely related to renal RAAS activity whereas left ventricular function, blood pressure and survival are more strongly linked to plasma RAAS activation