bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2025.04.25.650549

Mechanical unloading coupled with coronary reperfusion reduces fibrosis and stimulates cardiomyocyte proliferation after myocardial infarction

Bello, S. O.·Singh, C.·Perbellini, F.·Punjabi, P. P.·Terracciano, C. M.
View original source ↗Export metadata ↓

Abstract

IntroductionPercutaneous left ventricular assist devices (pLVADs) have become essential tools during coronary reperfusion in high risk PCI. Significant reduction in infarct propagation is observed when mechanical unloading is coupled with reperfusion, but little is known of the effect this reduction in wall stress and extracellular matrix with pLVADs have on the hearts regenerative capacity. ObjectiveThis study investigates the effect coronary reperfusion coupled with mechanical unloading has on myocardial fibrosis, and the impact these changes in extracellular matrix have on the hearts regenerative potential. MethodsMI was induced by coronary artery ligation in Lewis rats. Hearts underwent permanent coronary ligation (AMI) or were reperfused after 90 minutes (AMI/R). In each group, hearts were either loaded (AMI-L or AMI/R-L) or unloaded (AMI-U or AMI/R-U). In the unloaded subgroup, the infarcted hearts were explanted after 90 minutes and transplanted into the abdomen of healthy recipients via heterotopic abdominal heart-lung transplantation. The recipients heart acted as control. Hearts were analysed on day 7. Results30 hearts were studied. In the permanent ligation group, fibrosis increased in both the loaded and unloaded hearts with no significant rise in cardiomyocyte proliferation. After coronary reperfusion, there was a decrease in fibrosis with mechanical unloading and cardiomyocyte proliferation rose significantly (AMI/R-L vs AMI/R-U p= 0.0001). Cardiomyocyte proliferative rate in the loaded and unloaded hearts was 0.6%, and 3.7% respectively after permanent ligation, and 0.5%, and 10.4% respectively after coronary reperfusion. ConclusionThese data show that coronary reperfusion coupled with mechanical unloading reduces myocardial fibrosis and upregulates cardiomyocyte proliferation after myocardial infarction. TRANSLATIONAL PERSPECTIVEThis study demonstrates that the adult hearts intrinsic regenerative capacity is significantly augmented when coronary reperfusion is coupled with mechanical unloading after MI in an animal model. This finding has significant translational implications for myocardial self- repair and recovery especially in ischaemic cardiomyopathy. The investigation of cardiomyocyte proliferative response should be included in current ongoing trials such as the PROTECT IV, RECOVER IV, and IMPACT trials, all currently investigating clinical outcomes when mechanical unloading is coupled with coronary reperfusion after MI.

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Bello, S. O., Singh, C., Perbellini, F., Punjabi, P. P., Terracciano, C. M.. 2025-04-28. Mechanical unloading coupled with coronary reperfusion reduces fibrosis and stimulates cardiomyocyte proliferation after myocardial infarction. https://doi.org/10.1101/2025.04.25.650549

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Cholinergic impairment in the dorsal motor nucleus of the vagus during experimental Alzheimer's disease

Cholinergic neurons in the dorsal motor nucleus of the vagus (DMN) in the brainstem are a key source of efferent vagus nerve fibers that regulate vital functions, including heart rate and inflammation. Whether the integrity of DMN cholinergic neurons is affected during Alzheimer's disease (AD) remains unknown. Here, in female and male mice with experimental AD (5xFAD), which exhibit age-dependent memory impairment, basal forebrain cholinergic neurodegeneration, and microglial alterations, we observe a reduction in cholinergic neuron density in the DMN at 6 and 10 months of age. Furthermore, while an important physiological function of DMN cholinergic signaling, such as suppression of heart rate, is preserved in control mice upon electrical DMN stimulation, the extent of suppression diminishes with age in both female and male 5xFAD mice. In addition, while electrical DMN stimulation lowers pro-inflammatory cytokine levels in control mice subjected to endotoxemia, this anti-inflammatory effect is diminished with age in 5xFAD mice, with females showing earlier dysfunction at 6 months. These results reveal previously unrecognized age-dependent cholinergic deficits in the DMN and disrupted brain - to - periphery vagus nerve circuits in experimental AD. These findings advance our understanding of AD mechanisms and are of interest for the development of conceptually novel therapies.

physiology↗
bioRxiv2026

Ketogenic diet is protective during endotoxin-induced lung injury through the elevation of BHB

Acute respiratory distress syndrome (ARDS) is marked by severe pulmonary edema and concomitant hypoxia, affecting hundreds of thousands of people a year, especially those in critical care conditions or suffering from septic shock. Previous studies have implicated that the ketogenic diet, a high-fat and low-carbohydrate diet, modulates inflammatory responses. However, the impact of the ketogenic diet on septic ARDS outcomes is unknown. Here, we demonstrated that mice on a ketogenic diet showed strikingly reduced lung injury and inflammation compared to those on a control diet during a murine model of endotoxin-induced lung injury, induced by intratracheal lipopolysaccharide (LPS) injection. Immune mass cytometry studies on lung tissue indicated that the ketogenic diet reduces immune cell infiltration. Treating mice with beta-hydroxybutyrate (BHB), the primary metabolite of ketogenesis, after the onset of ARDS reduced pulmonary edema and lung inflammation, as well as NF-kB activity, suggesting strong therapeutic potential. By multiplex analysis in bronchial alveolar lavage fluid, we observed that the ketogenic diet or BHB administration attenuates the chemotaxis and activation of immune cells. Altogether, our findings reveal that the ketogenic diet provides lung protection during endotoxin-induced lung injury through BHB.

physiology↗
bioRxiv2026

Efficacy of postmenopausal estrogen replacement in SIV-infected female macaques on antiretroviral therapy.

The success of modern antiretroviral therapy (ART) has increased the life expectancy of people living with HIV to levels approaching that of uninfected individuals. For women living with HIV (WLWH), this means that more will survive to undergo menopause and experience the consequences of decreased ovarian hormone levels, particularly estrogen (E2). The recent change in federal guidance for use of postmenopausal hormone therapy is increasing demand for both E2-alone and E2+progestogen formulations to control adverse symptoms of menopause. The consequences and efficacy of hormone therapy in WLWH are thus an important issue for WLWH and their healthcare providers. The role of E2 replacement in postmenopausal WLWH is a significant issue because of its potential effects on control the viral reservoir and its demonstrated beneficial metabolic effects in uninfected postmenopausal women. To address these questions, we employed a novel nonhuman primate model of postmenopausal WLWH undergoing E2 replacement. Reproductively competent female rhesus macaques were infected with simian immunodeficiency virus (SIV) and then subjected to a daily ART regimen. After complete suppression of plasma viremia, all animals were ovariectomized (OVX) and then implanted with Silastic capsules containing either cholesterol vehicle or sufficient E2 to restore pre-OVX plasma levels. Plasma and cell-associated viral dynamics, immune responses, body composition, systemic and tissue-specific metabolic parameters, cytokine profiles, and parameters of bone health were followed longitudinally from baseline through 34 weeks of E2 deficiency or replacement. We found that E2 status did not significantly affect plasma or tissue viral dynamics or overall metabolic homeostasis. However, E2 replacement exerted beneficial effects on several aspects of bone health in spite of a chronic inflammatory state that persisted following effective ART suppression of the SIV reservoir. Our findings suggest that hormone therapy, specifically E2 replacement, offers benefit to WLWH, particularly with respect to bone loss.

physiology↗