Abstract Body: Background and Hypothesis: While there is substantial literature on how heart failure exacerbates non-healing ulcers like Stage-4 pressure ulcers (Stage-4 PUs), how non-healing leg ulcers modulate cardiac stress or function is unclear. We hypothesized that Stage-4 PUs on leg would trigger cardiac dysfunction in healthy individuals and suppression of inflammatory mediators like Tumor Necrosis Factor-α (TNFα) via localized needle-free micromist carrying TNFα silencer RNA (siTNFα) delivered to Stage-4 PUs would render cardioprotection.
Methods: Stage-4 PUs were induced in young (6-months) and aged (>20-months) Wistar rats (N=71). Obesity was induced by high fact diet feeding (N=29). PU was induced on left hindlimb by 8-hour-long 1000 mmHg pressure application after leg paralysis by botulinum toxin A (Botox) injection. Cardiac parameters were assessed by echocardiography, deep muscle damage at PU site by ultrasound, and PU healing by daily imaging, survival and morbidity scores. DMTD-micromist therapy (600μL of saline or 1μMolar Silencer Select siRNAs [scrambled: siSCR] or siTNFα]) of PUs was performed using Droplette Micromist Technology Device (DMTD) twice weekly. Circulating cardiac troponin I (cTn1) and NT-proBNP were measured as indices of myocardial injury and cardiac stress.
Results: Stage-4 PUs developed on all rats and deep muscle damage at the PU site was confirmed by Vevo2100 muscle ultrasound. Morbidity and mortality increased with obesity and aging (p<0.05). In young healthy male rats, PU caused increase in E/E′ from baseline by day 7 (p=0.03), day 15 and day 21 (p=0.007) while this response was delayed until day 21 (p=0.03) in female rats indicating sex differences in Stage-4 PU-induced heart disease. siTNFα therapy expedited PU healing and reduced deep muscle damage (p<0.05) in all rats, suppressed cTn1 (p=0.051) and resulted in 100% survival through day 48, compared to 0% survival by day 30 in aged rats treated with saline or siScr. In young obese rats, siTNFα therapy reduced NT-proBNP (p=0.052).
Conclusions: Stage-4 PU induces new-onset cardiac dysfunction in healthy rats while localized siTNFα therapy of PU mitigated cardiac stress and improved survival highlighting crosstalk between Stage-4 PU and the heart.