Therapeutic strategies aiming at the reduction of the antiplatelet intensity should not overlook the ischemic risk in patients with coronary syndromes.

De-escalation of dual antiplatelet therapy (DAPT) is gaining traction as a strategy to reduce bleeding risks while ensuring ischemic outcomes. Undiscriminating de-escalation, notably in patients with high ischemic risk, might expose them to major adverse cardiac events. Platelet function and genetic tests are emerging tools to guide de-escalation, but both present specific drawbacks. Recent meta-analyses have aimed to consolidate the findings of individual trials to provide clearer insights. Yet, limitations remain for patients with concomitant high bleeding and ischemic risks. These high-risk patients are frequently underrepresented in clinical trials, and, therefore, currently available guidelines lack evidence-based recommendations for this subset. While DAPT de-escalation strategies hold promise, the choice of approach, whether clinically or assay-guided, remains complex and should be individualized.

One-Month Versus Three-Month Dual-Antiplatelet Therapy in High Bleeding Risk Patients With Chronic Kidney Disease.

Shortening the duration of dual-antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) was shown to be effective and safe in patients at high bleeding risk (HBR). We aimed to investigate the effect of 1 versus 3-month DAPT on outcomes after drug-eluting stent in HBR patients with or without chronic kidney disease (CKD). Data from 3 prospective single-arm studies (XIENCE Short DAPT Program) enrolling HBR patients after successful coronary implantation of cobalt-chromium everolimus-eluting stent (XIENCE, Abbott) were analyzed. Subjects were eligible for DAPT discontinuation at 1 or 3 months if free from ischemic events. The primary end point was all-cause death or any myocardial infarction. The key secondary end point was Bleeding Academic Research Consortium Type 2 to 5 bleeding. Outcomes were assessed from 1 to 12 months after PCI. CKD was defined as baseline creatinine clearance <60 ml/min. Of 3,286 patients, 1,432 (43.6%) had CKD. One-month versus 3-month DAPT was associated with a similar 12-month risk of the primary outcome irrespective of CKD status (CKD: 9.5% vs 10.9%, adjusted hazard ratio 0.86, 95% confidence interval 0.60 to 1.22; no-CKD: 6.6% vs 5.6%, adjusted hazard ratio 1.15, 95% confidence interval 0.77 to 1.73; p interaction 0.299). Bleeding Academic Research Consortium 2 to 5 bleeding rates were numerically but not significantly lower with 1-month versus 3-month DAPT in both CKD (9.9% vs 12%) and no-CKD (6.4% vs 9.0%) patients. In conclusion, in HBR patients, 1-month versus 3-month DAPT was associated with a similar risk of ischemic complications and a trend toward fewer bleeding events at 12 months after PCI, irrespective of CKD status.

Effects of Subchronic Buspirone Treatment on Depressive Profile in Socially Isolated Rats: Implication of Early Life Experience on 5-HT1A Receptor-Related Depression.

The heterogeneity of etiology may serve as a crucial factor in the challenges of treatment, including the low response rate and the delay in establishing therapeutic effect. In the present study, we examined whether social experience since early life is one of the etiologies, with the involvement of the 5-HT1A receptors, and explored the potentially therapeutic action of the subchronic administration of buspirone, a partial 5-HT1A agonist. Rats were isolation reared (IR) since their weaning, and the depressive profile indexed by the forced-swim test (FST) was examined in adulthood. Nonspecific locomotor activity was used for the IR validation. Buspirone administration (1 mg/kg/day) was introduced for 14 days (week 9-11). The immobility score of the FST was examined before and after the buspirone administration. Tissue levels of serotonin (5-HT) and its metabolite 5-HIAA were measured in the hippocampus, the amygdala, and the prefrontal cortex. Efflux levels of 5-HT, dopamine (DA), and norepinephrine (NE) were detected in the hippocampus by brain dialysis. Finally, the full 5-HT1A agonist 8-OH-DPAT (0.5 mg/kg) was acutely administered in both behavioral testing and the dialysis experiment. Our results showed (i) increased immobility time in the FST for the IR rats as compared to the social controls, which could not be reversed by the buspirone administration; (ii) IR-induced FST immobility in rats receiving buspirone was corrected by the 8-OH-DPAT; and (iii) IR-induced reduction in hippocampal 5-HT levels can be reversed by the buspirone administration. Our data indicated the 5-HT1A receptor-linked early life social experience as one of the mechanisms of later life depressive mood.

Variability patterns in dual antiplatelet therapy following endovascular repair of intracranial aneurysms: Insight into regimen heterogeneity and the need for a consensus.

This comprehensive review delves into the evolving field of neurointervention for intracranial aneurysms, exploring the critical adjunct of Dual Antiplatelet Therapy (DAPT) to endovascular coiling, stent-assisted coiling (SAC), flow-diversion stents, and flow-disruption (intrasaccular) devices. Despite growing evidence supporting the success of DAPT in reducing thromboembolic events, the lack of consensus on optimal regimens, doses, and duration is evident. Factors contributing to this variability include genetic polymorphisms affecting treatment response and ongoing debates regarding the clinical significance of hemorrhagic complications associated with DAPT. This review analyzes pre- and post-procedural antiplatelet usage across various interventions. The imperative lies in ongoing research to define optimal DAPT durations, ensuring a nuanced approach to the delicate balance between thrombosis and hemorrhage in intracranial aneurysm management.

Efficacy and Safety of P2Y12 monotherapy vs standard DAPT in patients undergoing percutaneous coronary intervention: meta-analysis of randomized trials.

BACKGROUND: Debates persist regarding the optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in coronary artery disease (CAD). Recent trials have introduced a novel approach involving P2Y12 inhibitor monotherapy with ticagrelor or clopidogrel, after a short DAPT. However, the effectiveness and safety of this strategy remains to be established. We aimed to perform a meta-analysis comparing monotherapy with P2Y12 inhibitors versus standard DAPT in patients undergoing PCI at 12 months. METHODS: Multiple databases were searched. Six RCTs with a total of 24877 patients were included. The primary endpoint was all-cause mortality at 12 months of follow-up. The secondary endpoints were cardiovascular mortality, myocardial infarction, probable or definite stent thrombosis, stroke events, and major bleeding. The study is registered with PROSPERO (CRD42024499529). RESULTS: Monotherapy with P2Y12 inhibitor ticagrelor significantly reduced both allcause mortality (HR 0.71, 95 CI [0.55-0.91], P = 0.007) and cardiovascular mortality (HR 0.66, 95% CI [0.49-0.89], P = 0.006) compared to standard DAPT. In contrast, clopidogrel monotherapy did not demonstrate a similar reduction. The decrease in mortality associated with ticagrelor was primarily due to a lower risk of major bleeding (HR 0.56, 95% CI [0.43-0.72], P < 0.001), while the risk of myocardial infarction (MI) remained unchanged (HR 0.90, 95% CI [0.73-1.11], P = 0.32). The risk of stroke was found to be similar across treatments. CONCLUSIONS: In comparison to standard DAPT, P2Y12 inhibitor monotherapy with ticagrelor may lead to a reduced mortality. The clinical benefits are driven by a reduction of bleeding risk without ischemic risk trade-off.

On the relationship between various anticoagulants and robot-assisted radical prostatectomy: a single-surgeon serial analysis.

Prostate cancer patients often have other health conditions and take anticoagulants. It was believed that surgery under anticoagulants could worsen surgical results. This study aims to explore the safety of robot-assisted prostatectomy in anticoagulated patients, without any exclusion criteria. The study included 500 patients who underwent RARP by a single surgeon between April 2019 and August 2022. Patients were divided into two groups: Group 1, consisting of 376 men (75.2%), did not receive any anticoagulation, while Group 2, with 124 patients (24.8%), received different forms of anticoagulation. Then, the anticoagulation group was divided into 4 subgroups according to their definite anticoagulation: the aspirin 15.6%, new oral anticoagulants (NOAC) 5.4%, Vitamin K antagonist (VKA) 2%, and dual-antiplatelet therapy (DAPT) 1.8% subgroup. Postoperative complications and readmission rates were compared between the two study groups and subgroups. Patients in the combined group 2 were older and they also carried more comorbidities compared to men in group 1 (p = 0.03, p = 0.001).The study groups had similar oncological results, with 40.4% of patients having locally advanced cancers. Catheter days were longer in the anticoagulation group (4.5 vs 4 days, p = 0.001). No significant differences were observed between study groups for overall, minor, and major complications (p = 0.160, 0.100, and 0.915, respectively). In addition, readmissions were low (5.6%) and similar between the study groups (p = 0.635). Under cautious management, RARP under diverse anticoagulation regimes is safe and has comparable results to men with no medications. Further prospective studies must be conducted to confirm our findings.

Successful Endoscopic Retrograde Appendicitis Therapy Following a Recent ST-Elevation Myocardial Infarction.

Acute appendicitis is one of the most common abdominal surgical emergencies. A laparoscopic or open appendectomy has traditionally been the gold standard. Antibiotic therapy has recently been found to be noninferior. The treatment of acute uncomplicated appendicitis remains a challenge, especially in the presence of an appendicolith. We present a case of a 59-year-old man with recent ST-elevation myocardial infarction who underwent successful endoscopic retrograde appendicitis therapy.

Inhibition of Notch1 signal promotes brain recovery by modulating glial activity after stroke.

BACKGROUND: Notch1 signaling inhibiton with N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester] (DAPT) treatment could promote brain recovery and the intervention effect is different between striatum (STR) and cortex (CTX), which might be accounted for different changes of glial activities, but the in-depth mechanism is still unknown. The purpose of this study was to identify whether DAPT could modulate microglial subtype shifts and astroglial-endfeet aquaporin-4 (AQP4) mediated waste solute drainage. METHODS: Sprague-Dawley rats (n=10) were subjected to 90min of middle cerebral artery occlusion (MCAO) and were treated with DAPT (n=5) or act as control with no treatment (n=5). Two groups of rats underwent MRI scans at 24h and 4 week, and sacrificed at 4 week after stroke for immunofluorescence (IF). RESULTS: Compared with control rats, MRI data showed structural recovery in ipsilateral STR but not CTX. And IF showed decreased pro-inflammatory M1 microglia and increased anti-inflammatory M2 microglia in striatal lesion core and peri-lesions of STR, CTX. Meanwhile, IF showed decreased AQP4 polarity in ischemic brain tissue, however, AQP4 polarity in striatal peri-lesions of DAPT treated rats was higher than that in control rats but shows no difference in cortical peri-lesions between control and treated rats. CONCLUSIONS: The present study indicated that DAPT could promote protective microglia subtype shift and striatal astrocyte mediated waste solute drainage, that the later might be the major contributor of waste solute metabolism and one of the accounts for discrepant recovery of STR and CTX.

STENOSIS: Long-term single versus dual antiplatelet therapy in patients with ischaemic stroke due to intracranial atherosclerotic disease - a randomised trial.

Rationale: Intracranial atherosclerotic disease (ICAD) is a pathological process that causes progressive stenosis and cerebral hypoperfusion, leading to stroke occurrence and recurrence around the world. The exact duration of dual antiplatelet therapy (DAPT) for ICAD is unclear in view of long-term risk of bleeding complications. Aim: The current study aims to study the efficacy and safety of long-term DAPT (up to 12 months) in patients with ICAD. Sample size: Using 80% power and an alpha error of 5 %, presuming a 10%-15% drop-out rate, a total of 2200 patients will be recruited for the study. Methodology: This is a prospective, randomised, double-blind, placebo controlled trial. Study outcomes: The primary outcomes include recurrent ischaemic stroke (IS) or transient ischaemic attack and any intracranial haemorrhage (ICH), major or minor systemic bleeding at the end of 12 months. Secondary outcomes include composite of any stroke, myocardial infarction or death at the end of 12 months. The safety outcomes include any ICH, major or minor bleeding as defined using GUSTO (Global Use of Streptokinase and tPA for occluded Coronary Arteries) classification at the end of 12 months and 1 month after completion of the drug treatment phase. Discussion: The study will provide level I evidence on the duration of DAPT among patients with IS due to ICAD of more than or equal to 50%.

PRECISE-DAPT, ARC-HBR, or Simplified Clinical Evaluation for the Prediction of Major Bleeding After Percutaneous Coronary Intervention in older Patients.

Older patients have been remarkably underrepresented in bleeding risk cohorts. Thus, the PRECISE-DAPT (Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy) and Academic Research Consortium for High Bleeding Risk (ARC-HBR) scores are not validated in older adults. Therefore, we sought to evaluate the PRECISE-DAPT and ARC-HBR scores in an exclusively older population and assess the prognostic value of a truly simplified clinical evaluation (SCE), consisting of only 3 binary clinical variables (hemoglobin <11 g/100 ml, previous bleeding, and anticipated use of anticoagulants). This is a retrospective analysis of the prospective single-center older-HCD registry. Consecutive patients aged ≥75 years who underwent percutaneous coronary intervention from 2012 to 2019 were included. The primary end point was postdischarge bleeding at 12 months of follow-up, defined according to the Bleeding Academic Research Consortium 3 or 5 criteria. A total of 693 patients with a mean age of 81 (±4.4) years were included in the study and 60 patients (6.8%) met the primary end point. The PRECISE-DAPT and ARC-HBR scores did not significantly predict postdischarge bleeding in the Cox regression models (hazard ratio 1.65 [0.78 to 3.42] and 1.46 [0.72 to 4.24], respectively), whereas the SCE outperformed both scores (hazard ratio 2.47, 1.34 to 4.49). All 3 scores exhibited a moderate discriminatory potential, as determined by a receiver-operating characteristic curve analysis (areas under the curve 0.601, 0.621, and 0.616, respectively), with no significant differences between them. The SCE showed an Integrated Discrimination Improvement of 0.25, p = 0.02 (SCE vs ARC-HBR) and 0.24, p = 0.01 (SCE vs PRECISE-DAPT), with an Net Reclassification Improvement of 6.54%, p = 0.37 and 7.12%, p = 0.43, respectively. In conclusion, the PRECISE-DAPT score and ARC-HBR criteria showed insufficient predictive value in older adults. A truly SCE consisting of 3 easily accessible variables not only provides equal discriminatory potential but also demonstrates superior predictive value, as determined by Cox regression models. This makes it a highly appealing tool for risk stratification, pending its evaluation in larger prospective studies.

[Acute coronary syndrome: diagnosis and treatment].

INTRODUCTION: In Switzerland, about 20 000 people experience an acute coronary syndrome (ACS) event each year. Acute coronary syndromes comprise ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), and unstable angina. The diagnosis is made based on the clinical presentation, a rise in cardiac biomarkers, and ischemic ECG changes. In patients with acute STEMI, urgent coronary angiography with primary percutaneous coronary intervention (PCI) to open the occluded artery is indicated. In patients with NSTEMI and unstable angina, the timing of coronary angiography and PCI is based on the clinical presentation and on a comprehensive and individualized risk stratification. Optimal secondary prevention and aggressive cardiovascular risk factor control are important following the acute event. Keywords.

The predictive value of PRECISE-DAPT score for long-term mortality in patients with acute coronary syndrome complicated by cardiogenic shock.

BACKGROUND: Besides its primary clinical utility in predicting bleeding risk in patients with acute coronary syndrome (ACS), the PRECISE-DAPT (Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Anti-Platelet Therapy) score may also be useful for predicting long-term mortality in ACS patients presenting with cardiogenic shock (CS) since several studies have reported an association between the score and certain cardiovascular conditions or events. The aim of the present study was to evaluate the utility of the PRECISE-DAPT score for predicting the long-term all-cause mortality in patients (n = 293) with ACS presenting with CS. METHODS: The PRECISE-DAPT score was calculated for each patient who survived in hospital, and the association with long-term mortality was studied. Median follow-up time was 2.7 years. The performance of the final model was determined with measurements of its discriminative power (Harrell's and Uno's C indices and time-dependent area under the receiver operating characteristic curve [AUC]) and predictive accuracy (coefficient of determination [R2] and likelihood ratio χ2). Hazard ratios (HRs) were used to assess the relationship between the variables of the model and long-term all-cause death. RESULTS: All-cause death occurred in 197 patients (67%). There was a positive association between the PRECISE-DAPT score (change from 17 to 38 was associated with an HR of 2.42 [95% CI: 1.59-3.68], R2 = 0.209, time-dependent AUC = 0.69) and the risk of death such that in the adjusted survival curve, the risk of mortality increased as the PRECISE-DAPT score increased. CONCLUSION: The PRECISE-DAPT score may be a useful easy-to-use tool for predicting long-term mortality in patients with ACS complicated by CS.

Gamma-Secretase Inhibitors Downregulate the Profibrotic NOTCH Signaling Pathway in Recessive Dystrophic Epidermolysis Bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare skin fragility disorder caused by mutations in COL7A1. RDEB is hallmarked by trauma-induced unremitting blistering, chronic wounds with inflammation, and progressive fibrosis, leading to severe disease complications. There is currently no cure for RDEB-associated fibrosis. Our previous studies and increasing evidence highlighted the profibrotic role of NOTCH pathway in different skin disorders, including RDEB. In this study, we further investigated the role of NOTCH signaling in RDEB pathogenesis and explored the effects of its inhibition by γ-secretase inhibitors DAPT and PF-03084014 (nirogacestat). Our analyses demonstrated that JAG1 and cleaved NOTCH1 are upregulated in primary RDEB fibroblasts (ie, RDEB-derived fibroblasts) compared with controls, and their protein levels are further increased by TGF-ß1 stimulation. Functional assays unveiled the involvement of JAG1/NOTCH1 axis in RDEB fibrosis and demonstrated that its blockade counteracts a variety of fibrotic traits. In particular, RDEB-derived fibroblasts treated with PF-03084014 showed (i) a significant reduction of contractility, (ii) a diminished secretion of TGF-ß1 and collagens, and (iii) the downregulation of several fibrotic proteins. Although less marked than PF-03084014-treated cells, RDEB-derived fibroblasts exhibited a reduction of fibrotic traits also upon DAPT treatment. This study provides potential therapeutic strategies to antagonize RDEB fibrosis onset and progression.

Analysis of Determinants for Suture-mediated Closure Device Failure During EVAR Procedures.

OBJECTIVE: Endovascular aortic repair (EVAR) for elective and emergency infrarenal aortic pathologies is the primary approach for treatment nowadays. During such procedure, the suture-mediated closure device (SMCD) (Perclose ProGlideTM, Abbott Laboratories, Chicago, IL, USA) is commonly used. This study aimed to identify potential contributors for SMCD failure in a patient cohort of elective and emergency EVAR. METHODS: Archived medical records from patients who underwent EVAR for aortic pathologies in elective and emergency setting at the University Hospital Düsseldorf, Germany were included. Patient's co-morbidities, access vessel morphologies and hemostasis-related blood parameters were evaluated on their association with SMCD failure applying different statistical methods. RESULTS: A total of 71 patients (139 femoral accesses) was included. The mean age was 73.5 ± 8.4 years. Overall SMCD failure rate was 4.3%, 4.1% for elective and 5.9% for emergency cases, respectively. Total procedure time was longer for the SMCD failure group (323 ± 117.8 min vs 171 ± 43.7 min). The calcification status of the common femoral artery (CFA), the diameter of the aortic bifurcation, and dual anti-platelet therapy (DAPT) on the medication plan prior to the procedure were associated with SMCD failure. Univariate binary logistic regression analysis nominated several potentially relevant predictors for SMCD failure who underwent subsequent multivariable binary logistic regression analysis. Here, DAPT on the medication plan was identified as being promising in predicting SMCD failure (OR 30.5), while anterior plaque formation in the CFA maintained as only statistically relevant determinant (OR 44.9). CONCLUSIONS: This study confirms the CFA calcification status to be associated with SMCD failure. Although discontinued prior to endovascular treatment, DAPT was also found to be associated with SMCD failure. Our results may advocate to perform obligatory platelet testing prior to EVAR to maximize patient safety.

Short duration of dual antiplatelet therapy following complex percutaneous coronary intervention: A systematic review and meta-analysis.

INTRODUCTION AND AIM: The optimal composition and duration of antiplatelet therapy after complex percutaneous coronary intervention (PCI) remains unclear. We conducted a meta-analysis to compare 1-3 months of dual antiplatelet therapy (DAPT) followed by monotherapy vs. 12 months of DAPT. METHOD: MEDLINE/PubMed, EMBASE, and Cochrane Central Register of Controlled Trials were queried for studies comparing 1-3 months of DAPT followed by monotherapy vs. 12 months of DAPT in the outcomes of complex PCI from inception through January 2023. Outcomes of interest included major bleeding, all-cause mortality, cardiovascular mortality, myocardial infarction (MI), stent thrombosis, target vessel revascularization, and stroke. RESULTS: Compared to 12 months, 1-3 months of dual antiplatelet therapy had a weak association with less major bleeding (OR 0.67; 95 % CI, 0.44-1.00; p = 0.05; I2 = 28 %). There were no significant differences between the shorter and longer antiplatelet therapy in terms of all-cause mortality (OR 0.83; 95 % CI, 0.59-1.16; p = 0.21; I2 = 17 %), cardiovascular mortality (OR 0.87; 95 % CI, 0.53-0.42; p = 0.50; I2 = 0), MI (OR 0.97; 95 % CI, 0.69-1.35; p = 0.82; I2 = 32 %), stent thrombosis (OR 1.17, 95 % CI, 0.77-1.76; p = 0.38; I2 = 0 %), target vessel revascularization (OR 1.05, 95 % CI, 0.58-1.89; p = 0.82; I2 = 64 %), or stroke (OR 1.10, 95 % CI, 0.55-2.17; p = 0.37; I2 = 7 %);. CONCLUSION: Among patients undergoing complex PCI, DAPT for 1-3 months may be associated with less major bleeding but similar rates of cardiovascular events (death, MI, stroke, stent thrombosis, and revascularization) compared to DAPT for 12 months.

Bleeding in acute coronary syndrome: from definitions, incidence, and prognosis to prevention and management.

INTRODUCTION: In patients with acute coronary syndrome (ACS), the ischemic benefit of antithrombotic treatment is counterbalanced by the risk of bleeding. The recognition that bleeding events have prognostic implications (i.e. mortality) similar to recurrent ischemic events led to the development of treatment regimens aimed at balancing both ischemic and bleeding risks. AREAS COVERED: This review aims at describing definitions, incidence, and prognosis related to bleeding events in ACS patients as well as bleeding-avoidance strategies for their prevention and management of bleeding complications. EXPERT OPINION: Management of ACS patients has witnessed remarkable progress after the shift in focusing on the trade-off between ischemia and bleeding. Efforts in standardizing bleeding definitions will allow for better defining the prognostic impact of different types of bleeding events and enable to identify the high-bleeding risk patient. Such efforts will allow to balance the trade-off between the thrombotic and bleeding risk of the individual patient translating into better downward diagnostic and therapeutic decision-making. Novel strategies aiming at maximizing the safety and efficacy of antithrombotic regimens as well as the development of novel antithrombotic drugs and reversal agents and technological advances will allow for optimization of bleeding-avoidance strategies and management of bleeding complications.

Drugs targeting TGF-ß/Notch interaction attenuate hypertrophic scar formation by optic atrophy 1-mediated mitochondrial fusion.

Hypertrophic scar (HS) formation is a cutaneous fibroproliferative disease that occurs after skin injuries and results in severe functional and esthetic disability. To date, few drugs have shown satisfactory outcomes for the treatment of HS formation. Transforming growth factor-beta (TGF-ß)/Notch interaction via small mothers against decapentaplegic 3 (Smad3) could facilitate HS formation; therefore, targeting TGF-ß/ Notch interaction via Smad3 is a potential therapeutic strategy to attenuate HS formation. In addition, optic atrophy 1 (OPA1)-mediated mitochondrial fusion contributes to fibroblast proliferation, and TGF-ß/Smad3 axis and the Notch1 pathway facilitate OPA1-mediated mitochondrial fusion. Thus, the aim of this study was to investigate whether drugs targeting TGF-ß/Notch interaction via Smad3 suppressed fibroblast proliferation to attenuate HS formation through OPA1-mediated mitochondrial fusion. We found that the TGF-ß pathway, Notch pathway, and TGF-ß/Notch interaction via Smad3 were inhibited by pirfenidone, the gamma- secretase inhibitor DAPT, and SIS3 in human keloid fibroblasts (HKF) and an HS rat model, respectively. Protein interaction was detected by co-immunoprecipitation, and mitochondrial morphology was determined by electron microscopy. Our results indicated that pirfenidone, DAPT, and SIS3 suppressed the proliferation of HKFs and attenuated HS formation in the HS rat model by inhibiting TGF-ß/Notch interaction via Smad3. Moreover, pirfenidone, DAPT, and SIS3 hindered OPA1-mediated mitochondrial fusion through inhibiting TGF-ß/Notch interaction, thereby suppressing the proliferation of HS fibroblasts and HS formation. In summary, these findings investigating the effects of drugs targeting TGF-ß/Notch interaction on HS formation might lead to novel drugs for the treatment of HS formation.