Despite being the cornerstone of decongestive therapy in heart failure (HF), loop diuretics are paradoxically one of the least well-studied classes of HF medications and substantial differences exist between members of the class. Compared to furosemide, torsemide has 1) superior bioavailability and absorption, 2) significantly longer half-life and 3) potential broad spectrum ?anti-aldosterone? effects. These theoretical advantages of torsemide, in part, motivated the NIH funded 6000 participant TRANSFORM-HF study, which will definitively establish the value of torsemide on hard outcomes. At first glance, the above differences would imply a self- evident superiority of torsemide. However, it is also known that severe within-dose diuretic resistance occurs in healthy subjects administered torsemide during its long half-life; indeed, animal studies have demonstrated massive adverse structural remodeling of the distal tubule with prolonged loop diuretic exposure. We have recently demonstrated that distal tubular compensation is in fact the dominant mechanism of loop diuretic resistance in human HF and pharmacokinetic defects are relegated to a minor role. Additionally, while there may be in vitro anti-aldosterone effects, it is unclear if this translates into clinically relevant effects in HF patients on contemporary medical therapy. Lastly, furosemide also has unique properties such as promiscuous antagonism of sodium channels proximal and distal to the loop of Henle and a paradoxical improvement in relative potency with progressive renal dysfunction. As such, with currently available data, a biologically plausible case for superiority or inferiority of torsemide can be made. The overarching goal of this proposal is to rigorously characterize candidate mechanisms by which torsemide may influence outcome within the TRANSFORM-HF population. To achieve this goal, we propose a three center, 150 patient mechanistic sub study of TRANSFORM-HF which will query a detailed set of mechanistic parameters both at randomization and again at 30 days to answer the following questions: 1) What are the net effects of known and unknown differences between torsemide and furosemide on the ultimate target of diuretic therapy- volume status? We will address this by evaluating changes in gold standard body fluid space measurements (plasma volume, extra cellular water, total body water). 2) Are there clinically relevant pleiotropic anti-aldosterone effects of torsemide? We will address this with functional and structural readouts of tissue level aldosterone activity; potassium excretion and urinary exosomal levels of the aldosterone regulated protein ?ENaC. 3) Does torsemide, with its long half-life, result in adverse structural remodeling of the kidney and redistribution of intra- renal sodium handling? We will address this by evaluating structural changes with urinary exosomal levels of the distal tubular transporter NCC and functionally by evaluating changes in endogenous lithium clearance, a well-established in vivo metric of regional tubular sodium handling.

Public Health Relevance

Diuretic medications are used to treat fluid retention in patients with heart failure, however it is unclear which medication is best. The TRANSFORM-HF trial will determine if torsemide is superior to furosemide in preventing death, but it will not provide information if one of the medications is better at removing fluid than the other. The current grant proposal will measure parameters such as body fluid levels to allow us to understand differences between these drugs that may contribute to different effects on survival.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ketema, Fassil
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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