LAUSR

Introduction: Although frequently used in heart failure (HF), long-term furosemide exacerbates HF in a swine model. This paradoxical phenomenon may reflect furosemide-induced alterations in signaling proteins of the extracellular matrix (ECM) to increase fibrosis. Examination of the ECM may clarify how treatments like furosemide enhance the progression of HF. Hypothesis: The administration of furosemide increased inflammation and fibrosis of the heart, leading to accelerated HF deterioration in a swine model. Methods: After Institutional Animal Care and Use Committee (IACUC) approval, Yorkshire swine (N=10, 5 = furosemide, 5 = saline) were paced 3 to 5 weeks at 200 beats per minute to induce HF (left ventricular fractional shortening <16% on echocardiogram). Animals were treated with furosemide (1 mg/kg intramuscularly) or saline. Western Blot and histology with Masson’s trichrome stain were performed on transmural LV myocardium to quantify critical determinants of fibrosis. ANOVA with Tukey HSD correction and descriptive statistics were performed using SPSS with significance by α of 0.05; mean ± SEM. Results: The overall increase in ECM fibrosis in HF was clearly demonstrated on Masson’s trichrome histology associated with significant, uniform increase in signaling pathways leading to fibrosis associated with furosemide use. SMAD 2-HF Furosemide to Control (p<.05): HF Furosemide 0.266 ±.05, HF Saline 0.183±.02, Control 0.163±.01 ERK-all (p<.05): HF Furosemide 0.312±.02, HF Saline 0.209±.01,Control 0.149±.01 GDF-15-HF Furosemide to Control (p<.05): HF Furosemide 0.095 ±.00, HF Saline 0.073±.01, Control 0.062±.01 MMP-14-all (p<.05): HF Furosemide 0.451±.02, HF Saline 0.374±.03,Control 0.231±.02 TIMP-1-all (p<.05): HF Furosemide 0.184±.01, HF Saline 0.0135±.03,Control 0.033±.01 PAI-1-all (p<.05): HF Furosemide 0.105±.01, HF Saline 0.046±.01,Control 0.043±.00 Conclusions: Histologic and biochemical analysis showed worsening HF in furosemide-treated paced swine was associated with consistent increases in fibrosis and indices of adverse ECM remodeling. The diuretic intended to reduce water retention during HF appeared to enhance myocardial fibrosis, paradoxically accelerating pathological processes responsible for HF.