Abstract Body: Dysregulated cardiac metabolism has long been thought to contribute to heart failure (HF) progression, but many of the pathways involved remain incompletely understood. Polyamine metabolism is one such pathway. Polyamines, including spermidine (SPD), regulate essential cellular processes, but cardiac polyamine metabolism remains understudied in normal physiology and even more so in HF. Here, we identify a previously unrecognized dysregulation of this pathway in HF that is marked by SPD accumulation despite impaired synthesis capacity.

We performed targeted metabolomic and transcriptomic analyses of explanted human hearts from patients with end-stage dilated cardiomyopathy (DCM), compared with nonfailing donor hearts. Levels of S-adenosylmethionine (SAM), an obligate substrate for SPD synthesis, were reduced in DCM hearts (p<0.0001), and the expression of S-adenosylmethionine decarboxylase 1, a rate-limiting enzyme in SPD synthesis, was likewise decreased (p<0.0001). Intriguingly, despite evidence of impaired synthesis, SPD levels were elevated in human DCM hearts (p<0.01).

To mechanistically investigate this metabolic shift, we quantitatively mapped cardiac SPD flux. In vivo steady-state isotope infusion studies showed that the heart primarily maintains its SPD pool via import. Complementary in vitro isotope tracing in neonatal rat ventricular myocytes showed that cardiomyocytes preferentially import SPD when extracellular supply is available but synthesize ~50% of their SPD pool when extracellular supply is limited. We next asked whether impairing SPD synthesis via low SAM availability could recapitulate the elevated SPD levels seen in human DCM hearts. In a genetic DCM mouse model with cardiac-specific deletion of SAM synthase, SAM levels were reduced, SPD synthesis was impaired, and cardiac SPD levels were elevated (p<0.001). In addition, the catabolic metabolite N¹-acetylspermidine was increased (p<0.001), suggesting that SPD accumulation in HF may arise from increased import rather than reduced catabolism.

Although polyamines are essential for maintaining cellular homeostasis, high intracellular polyamine levels can be cytotoxic. Ongoing studies are testing whether enhanced SPD import is sufficient to cause cardiac dysfunction and whether blocking SPD import can rescue cardiac function in HF. Together, these studies aim to quantify the dynamics of cardiac polyamine metabolism and elucidate its role in HF pathophysiology.