Background: Heart disease is the leading cause of death in the United States, and salt-sensitive (SS) hypertension (HTN) is a major driver of cardiovascular pathology. Understanding the cardiac mechanisms underlying SS HTN remains a critical need. One key mechanism regulating cardiac function is the molecular clock, which controls circadian physiology in a tissue-specific manner. PERIOD1 (PER1) is a transcription factor and one of the key components of the core clock mechanism. Loss of PER1 drives HTN in rodent models, and its expression is downregulated in the hearts of patients with cardiomyopathy and heart failure. Previously, we demonstrated that male Dahl SS PER1 knockout (KO) rats fed a high salt (HS) diet develop exacerbated SS HTN compared with control Dahl SS rats. This was associated with a disrupted circadian rhythm of heart rate. However, the impact of PER1 KO on in vivo cardiac function is undetermined.Hypothesis: Given that HS diet caused HTN and loss of HR rhythm in PER1 KO, we hypothesized that exacerbated cardiac dysfunction would become evident in male KO rats on HS diet. Methods: Male PER1 KO and Dahl SS rats (N=6) were maintained on NS (0.4% NaCl) diet followed by HS (4% NaCl) diet for 14 days. Echocardiography was performed under anesthesia using the Vevo F2 Ultrasound System at 2 PM on a weekly basis. Images were acquired in M-mode and B-mode and analyzed using VevoLab. Statistical comparisons were performed using mixed effects ANOVA. Results: Contrary to our hypothesis, male PER1 KO rats on NS diet had significantly decreased stroke volume (KO=197 ul, SS=239 ul; p=0.012), ejection fraction (KO=64%, SS=78%; p=0.0377), fractional shortening (KO=33%, SS=48%; p=0.0486), and cardiac output (KO=61 mL/min, SS=81 mL/min; p=0.0149). On HS diet, both groups demonstrated significantly increased heart rate at week 1 and 2. There were significant effects of genotype (p=0.0433) and diet (p=0.0186), with a trend towards interaction (p=0.0576) for stroke volume, with SS rats showing a reduction with HS diet that is blunted in KO rats. There were no effects of diet on fractional shortening, ejection fraction, or cardiac output. Conclusions: Loss of PER1 in SS HTN is associated with cardiac dysfunction in male rats, including circadian disruption of heart rate and cardiac fibrosis. However, these data indicate that this dysfunction is driven by pathology occurring prior to exposure to HS diet. At baseline, loss of PER1 impedes cardiac function under NS conditions, which may sensitize KO to further pathology when placed on HS diet. Individuals with decreased PER1 expression due to circadian disruption could demonstrate cardiac dysfunction even before the development of HTN. This presents a potential window of opportunity to target the molecular clock to prevent or attenuate SS HTN. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Eikenberry et al. (Fri,) studied this question.