Role of Aortic Stiffness in Predicting Response to Phosphodiesterase-5 Inhibitors in the Treatment of Erectile Dysfunction. / Papel da Rigidez Aórtica na Previsão da Resposta aos Inibidores da Fosfodiesterase-5 no Tratamento da Disfunção Erétil.

BACKGROUND: It is known that aortic stiffness (AS) increases in patients with erectile dysfunction (ED). Phosphodiesterase type-5 (PDE-5) enzyme inhibitors are used in the treatment of ED, and patients' responses to this treatment may vary. OBJECTIVES: We aimed to investigate the role of AS in predicting the response of patients planned to take PDE-5 enzyme inhibitors due to ED. METHODS: A total of 96 male patients with ED were included in the study. The International Index of Erectile Function (IIEF) questionnaire was used to evaluate the presence and severity of ED and the response to treatment. Transthoracic echocardiography was used to evaluate AS. RESULTS: There was a statistically significant difference between the aortic strain and aortic distensibility values of the study groups (p<0.001). The delta IIEF score had a high level of positive correlation with aortic strain (p<0.01, r=0.758) and a moderate level of positive correlation with aortic distensibility (p<0.01, r=0.574). CONCLUSION: We determined that in patients with ED, aortic strain and aortic distensibility measured non-invasively using transthoracic echocardiography are important parameters in predicting patients' response to PDE-5 inhibitor therapy.

FUNDAMENTO: Sabe-se que a rigidez aórtica (RA) aumenta em pacientes com disfunção erétil (DE). Os inibidores da enzima fosfodiesterase tipo 5 (PDE-5) são usados no tratamento da DE, e as respostas dos pacientes a esse tratamento podem variar. OBJETIVOS: Nosso objetivo foi investigar o papel da RA na previsão da resposta de pacientes planejados para tomar inibidores da enzima PDE-5 devido à DE. MÉTODOS: Um total de 96 pacientes do sexo masculino com DE foram incluídos no estudo. O questionário do Índice Internacional de Função Erétil (IIEF) foi utilizado para avaliar a presença e gravidade da DE e a resposta ao tratamento. A ecocardiografia transtorácica foi utilizada para avaliar RA. RESULTADOS: Houve diferença estatisticamente significativa entre os valores de deformação aórtica e distensibilidade aórtica dos grupos de estudo (p<0,001). O escore delta IIEF apresentou alto nível de correlação positiva com a deformação aórtica (p<0,01, r=0,758) e um nível moderado de correlação positiva com a distensibilidade aórtica (p<0,01, r=0,574). CONCLUSÃO: Determinamos que em pacientes com DE, a deformação aórtica e a distensibilidade aórtica medidas de forma não invasiva por meio de ecocardiografia transtorácica são parâmetros importantes na previsão da resposta dos pacientes à terapia com inibidores da PDE-5.

Prescription, offer and access to medications for erectile dysfunction: a paradox in public health? / Prescrição, oferta e acesso aos medicamentos para disfunção erétil: um paradoxo na saúde pública?

This is an opinion-based article that aims to reflect on the antagonism established between the National Policy of Integral Attention to Men's Health (PNAISH) with specific focus on ED (Erectile Dysfunction), directed to access to medication. It is well-known that PNAISH presents objectives that go beyond sexual and reproductive health, especially, even after 13 years of its publication, since there was no incorporation of medications to treat ED within the SUS. This article was developed based on the scenario observed in the daily care of patients who undergo treatment in the Men's Health Outpatient Service of a High-Complexity Hospital. According to this perspective, it is important to emphasize, that the prescription of medications within the SUS should faithfully follow the Rename; as recommended by Decree 7,508, observing the Resolution SS-83 of 2015, in the state of São Paulo. This establishes that the cost of dispensing medications not included in the SUS pharmaceutical assistance protocols, through judicialization, prescribed by a physician in the state health network, may be funded by the institution to which this physician is affiliated.

Trata-se de um artigo embasado em opinião que procura refletir sobre o antagonismo estabelecido entre a Política Nacional de Atenção Integral à Saúde do Homem (PNAISH) com o recorte específico para DE (Disfunção Erétil) direcionado ao acesso de medicamentos. É notório que a PNAISH apresenta objetivos que vão além da saúde sexual e reprodutiva, sobretudo, mesmo após 13 anos de sua publicação, não houve incorporação de medicamentos para tratar DE no âmbito SUS. O artigo foi desenvolvido com base no cenário observado no dia a dia de atendimento aos pacientes que recebem cuidados no Serviço Ambulatorial da Saúde Masculina de um Hospital de Alta Complexidade. Isto por constatar a dificuldade dos médicos em prescreverem medicamentos para DE, por ausência de padronização no contexto SUS. Importante ressaltar, nesta perspectiva, que a prescrição de medicamentos no âmbito SUS deve seguir fidedignamente a Rename; conforme preconiza o Decreto 7.508 e, se atentar à Resolução SS-83 de 2015, vigente no estado de São Paulo. Ela estabelece que o custo da dispensação de medicamentos não contemplados na Rename, por meio da judicialização, prescritos por médico da rede estadual de saúde, poderá ser custeado pela instituição ao qual este esteja vinculado.

Efficacy of resveratrol in male urogenital tract dysfunctions: an evaluation of pre-clinical data.

Resveratrol is a polyphenol found naturally in fruits and plants. Recently, studies in humans and animal models have suggested beneficial properties of this polyphenol, such as improvements to metabolic and lipid profiles, along with antioxidant, anti-inflammatory and anti-proliferative effects. In the urogenital tract (UGT), resveratrol has also been tested clinically and experimentally as a therapeutic drug in several diseases; however, the translational efficacy of resveratrol, especially in UGT, is still a matter of debate. In the present review, we address the pre-clinical efficacy of resveratrol in UGT-related dysfunctions, focusing on lower urinary tract symptoms, non-cancerous prostatic disease (benign prostatic hyperplasia and prostatitis) and erectile dysfunction. In vitro studies indicate that resveratrol reduces inflammatory markers and oxidative stress, and improves endothelial function in UGT organs and cells isolated from humans and animals. Despite displaying low oral bioavailability, in vivo administration of resveratrol largely improves erectile dysfunction, benign prostatic hyperplasia, prostatitis and voiding impairments, as evidenced in different animal models. Resveratrol also acts as a microbiota modulator, which may explain some of its beneficial effects in vivo. In contrast to the large amount of pre-clinical data, there are insufficient clinical trials to establish resveratrol treatment efficacy in human UGT-related diseases. In summary, we provide an overview of the in vivo and in vitro efficacy of resveratrol in animal and human UGT dysfunctions, which may support future clinical trials.

Inhibition of multidrug resistance proteins by MK571 restored the erectile function in obese mice through cGMP accumulation.

BACKGROUND: Intracellular levels of cyclic nucleotides can also be controlled by the action of multidrug resistance protein types 4 (MRP4) and 5 (MRP5). To date, no studies evaluated the role of their inhibition in an animal model of erectile dysfunction (ED). OBJECTIVES: To evaluate the effect of a 2-week treatment with MK571, an inhibitor of the efflux of cyclic nucleotides in the ED of obese mice. MATERIALS AND METHODS: Mice were divided in three groups: (i) lean, (ii) obese, and (iii) obese + MK571. The corpus cavernosum (CC) were isolated, and concentration-response curves to acetylcholine (ACh), sodium nitroprusside (SNP), and tadalafil in addition to electrical field stimulation (EFS) were carried out in phenylephrine pre-contracted tissues. Expression of ABCC4 and ABCC5, intracellular levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), the protein levels for pVASPSer157 and pVASPSer239 , and the intracavernous pressure (ICP) were also determined. The intracellular and extracellular (supernatant) ratios in CC from obese and lean stimulated with a cGMP-increasing substance (BAY 58-2667) in the absence and presence of MK571 (20 µM, 30 min) were also assessed. RESULTS: The treatment with MK571 completely reversed the lower relaxing responses induced by EFS, ACh, SNP, and tadalafil observed in obese mice CC in comparison with untreated obese mice. Cyclic GMP and p-VASPSer239 expression were significantly reduced in CC from obese groups. MK571 promoted a sixfold increase in cGMP without interfering in the protein expression of p-VASPSer239 . Neither the cAMP levels nor p-VASPSer157 were altered in MK571-treated animals. The ICP was ∼50% lower in obese than in the lean mice; however, the treatment with MK571 fully reversed this response. Expressions of ABCC4 and ABCC5 were not different between groups. The intra/extracellular ratio of cGMP was similar in CC from obese and lean mice stimulated with BAY 58-2667. CONCLUSIONS: The MRPs inhibition by MK571 favored the accumulation of cGMP in the smooth muscle cells, thus improving the smooth muscle relaxation and the erectile function in obese mice.

Supplementation with Spirulina platensis Prevents Damage to Rat Erections in a Model of Erectile Dysfunction Promoted by Hypercaloric Diet-Induced Obesity.

Erectile dysfunction (ED) is the inability to achieve and/or maintain a penile erection sufficient for sexual satisfaction. Currently, many patients do not respond to the pharmacotherapy. The effects of a supplementation with Spirulina platensis, were evaluated in a model of ED induced by hypercaloric diet consumption. Wistar rats were divided into groups fed with standard diet (SD) or hypercaloric diet (HD) and supplemented with this alga at doses of 25, 50 or 100 mg/kg. Experimental adiposity parameters and erectile function were analyzed. In SD groups, Spirulina platensis reduced food intake, final body mass and adiposity index, and increased the total antioxidant capacity (TAC) of adipose tissue. However, no change was observed in erectile function. In the HD group, without Spirulina supplementation, a decrease in food intake was observed, in addition to an increase of final body mass, weight gain, adipose reserves, and adiposity index. Additionally, reduction in the number and increase in the latency of penile erection and adipose malondialdehyde levels, as well as a reduction in TCA was noted. Furthermore, cavernous contractility was increased, and the relaxing response was decreased. Interestingly, these deleterious effects were prevented by the algae at doses of 25, 50 and/or 100 mg/kg. Therefore, the supplementation with S. platensis prevents damages associated to a hypercaloric diet consumption and emerges as an adjuvant the prevention of ED.

Trends in treatments for erectile dysfunction in Chile between 2010 and 2020 with special focus on penile prostheses.

OBJECTIVES: Evidence regarding demand trends for erectile dysfunction (ED) treatments are scarce in South America. This study aims to evaluate trends in ED treatments in Chile over a 10-year period (2010- 2020) and estimate the potential number of candidates for penile prosthesis. MATERIALS AND METHODS: Sales trends of pharmacological treatments and penile prosthesis were obtained from market studies. The potential number of candidates for penile prosthesis implantation was calculated by crossing epidemiological data with previously reported ED prevalence, proportion of sexually active men, percentage of men seeking medical assistance for ED, and the proportion of patients who are non-responders to ED oral drug therapies Results: In the 10-year studied period, the Chilean male population older than 50 years increased 34.7%, with an average annual variation (AAV) of 3.4%. For the same period, the sales of oral drug therapies for ED increased by 71.3% (AAV 6.2%), the sales of intracavernosal vasoactive agents (ICVA) decreased by 0.4% (AAV -0.2%), and penile prosthesis sales increased by 113% (AAV 6.7%). We estimated that only 0.05% of sexually active men older than 50 years old with ED who sought medical assistance finally had a penile prosthesis implanted to manage their condition. CONCLUSIONS: Demand for ED oral drug therapies significantly increased in Chile during the last decade, while ICVA remained stable. The annual rate of penile prosthesis implantation increased. However, the gap between the potential penile prosthesis candidates and the actual number of devices implanted is suspected to remain extremely high.

Phytochemical Screening by LC-ESI-MS/MS and Effect of the Ethyl Acetate Fraction from Leaves and Stems of Jatropha macrantha Müll Arg. on Ketamine-Induced Erectile Dysfunction in Rats.

Jatropha macrantha Müll Arg. L is also known as "huanarpo macho" and used in the Peruvian traditional medicine as an aphrodisiac and erectile dysfunction (ED). The aim of this study was to determine the phytochemical constituents in leaves and stems ethyl acetate fraction (LEAF and SEAF) of J. macrantha and to compare the antioxidant activity and the ameliorative effect on ketamine-induced erectile dysfunction in rats. The phytochemical constituents were determined by LC-ESI-MS/MS, the total phenolic compounds and total flavonoids (TPC and TF) by Folin-Ciocalteu and aluminum chloride, respectively. The antioxidant activity was determined by DPPH, ABTS, and FRAP assays. Experimental groups were divided as follows: I: negative control; II: positive control (ketamine at 50 mg/ kg/d); III: sildenafil 5 mg/kg; IV, V, VI: LEAF at 25, 50 and 100 mg/kg, respectively, and VII, VIII, IX: SEAF at 25, 50, and 100 mg/kg, respectively. The phytochemical analysis revealed the presence mainly of coumarins, flavonoids, phenolic acids, and terpenes. TPC of LEAF and SEAF were 359 ± 5.21 mg GAE/g and 306 ± 1.93 mg GAE/g, respectively; TF in LEAF and SEAF were 23.7 ± 0.80 mg EQ/g, and 101 ± 1.42 mg EQ/g, respectively. The DPPH, ABTS, FRAP in SEAF were 647 ± 3.27; 668 ± 2.30; and 575 ± 2.86 µmol TE/g, respectively, whilst LEAF showed 796 ± 3.15; 679 ± 0.85; and 806 ± 3.42 µmol TE/g, respectively. Regarding sexual behavior, LEAF showed a better effect in mount frequency, intromission frequency, ejaculation frequency, mount latency, intromission latency, ejaculatory latency, and post ejaculatory latency than SEAF. As conclusion, LEAF of J. macrantha at 50 mg/kg showed a better effect on sexual behavior in male rats with erectile dysfunction than SEAF but not higher than sildenafil.

Efficacy and safety of oral phosphodiesterase 5 inhibitors for erectile dysfunction: a network meta-analysis and multicriteria decision analysis.

PURPOSE: To quantitatively assess the benefit-risk ratio on the efficacy and safety of all phosphodiesterase type 5 inhibitors (PDE5i) in men with erectile dysfunction. METHODS: A systematic review with network meta-analysis, surface under the cumulative ranking analysis and stochastic multicriteria acceptability analyses were performed. Searches were conducted in Pubmed, Scopus, Web of Science without limits for time-frame or language. Randomized controlled trials evaluating the efficacy or safety of any PDE5i compared to a placebo or to other PDE5i in males with erectile disfunction were included. RESULTS: Overall, 184 articles representing 179 randomized controlled trials (50,620 patients) were included. All PDE5i were significantly more efficient than placebo. Sildenafil 25 mg was statistically superior to all interventions in enhancing IIEF (with a 98% probability of being the most effective treatment), followed by sildenafil 50 mg (80% of probability). Taladafil 10 mg and 20 mg also presented good profiles (73% and 76%, respectively). Avanafil and lodenafil were less effective interventions. Mirodenafil 150 mg was the treatment that caused more adverse events, especially flushing and headaches. Sildenafil 100 mg was more related to visual disorders, while vardenafil and udenafil were more prone to cause nasal congestion. CONCLUSION: Sildenafil at low doses and tadalafil should be the first therapeutic options. Avanafil, lodenafil and mirodenafil use are hardly justified given the lack of expressive efficacy or high rates of adverse events.

Effects of chronic type 5 phosphodiesterase inhibition on penile microvascular reactivity in hypertensive patients with erectile dysfunction: a randomized crossover placebo-controlled trial.

This randomized crossover and placebo-controlled trial evaluated the effects of daily use of sildenafil citrate (SIL, 1-month 50 mg twice daily) on penile and systemic endothelial microvascular function in hypertensive patients presenting with erectile dysfunction. The effects of SIL on arterial pressure were evaluated using ambulatory blood pressure monitoring (ABPM). Fifty patients diagnosed with primary arterial hypertension and erectile dysfunction (aged 57.4 ± 5.6 years), recruited in a tertiary public hospital, were treated with SIL (50 mg twice daily) or placebo (PLA) for two 30-day periods with a 30-day washout between them. Laser speckle contrast imaging coupled with acetylcholine skin iontophoresis was used to evaluate penile and systemic (forearm) cutaneous microvascular reactivity. SIL treatment increased penile basal microvascular flow (P = 0.002) and maximal endothelial-dependent peak response to skin iontophoresis of acetylcholine (ACh, P = 0.006). The area under the curve of microvascular vasodilation induced by ACh was also significantly increased (P = 0.02). Lastly, SIL treatment did not modify systemic microvascular reactivity. Twenty-four-hour ABPM (P = 0.0002) and daytime (P = 0.002) and nighttime (P = 0.001) mean diastolic blood pressure values were significantly reduced after SIL treatment. The scores of the Simplified International Index of Erectile Function (P < 0.0001) and the number of patients with positive responses to Sexual Encounter Profile question 3 (P < 0.0001) also increased after SIL treatment. Penile endothelium-dependent microvascular reactivity improved after continuous use of sildenafil in hypertensive patients with erectile dysfunction; the treatment also reduced blood pressure, suggesting that, in addition to improving erectile function, daily use of sildenafil could improve blood pressure control.

Pharmacological treatment and inappropriate prescriptions for patients with erectile dysfunction.

Background Erectile dysfunction is associated with old age, some morbidities and the use of certain medications. Objective To identify the treatments and drugs related to worsening sexual activity in patients with erectile dysfunction. Setting Patients diagnosed with erectile dysfunction during 2018. Methods This cross-sectional study of a population database identified all drug prescriptions of patients with erectile dysfunction during 2018. Main outcome measure The identification of other comorbidities and potentially inappropriate drugs that could worsen erectile dysfunction. Results A total of 2999 patients with erectile dysfunction (mean age 59.6 ± 12.1 years) were identified. A total of 88.2% received pharmacological treatment for erectile dysfunction, mainly tadalafil (70.5%). A total of 47.6% of all patients received at least one medication associated with worsening erectile dysfunction, especially hydrochlorothiazide (17.0%), metoprolol (7.9%) and sertraline (6.7%). Residing in Cali (OR 1.86; 95% CI 1.52-22.27) or Bucaramanga (OR 2.23; 95% CI 1.39-33.58), having 3 or more chronic comorbidities (OR 1.52; 95% CI 1.04-2.24) and presenting psychiatric (OR 5.5; 95% CI 3.70-8.17), cardiovascular (OR 3.48; 95% CI 2.79-4.33), genitourinary (OR 1.31; 95% CI 1.05-1.64) pathologies or chronic kidney failure (OR 1.84; 95% CI 1.18-2.21) elevated the probability of receiving these prescriptions. Conclusions The pharmacological treatment of erectile dysfunction was in accordance with the recommendations of clinical practice guidelines, but the high proportion of potentially inappropriate prescriptions makes it necessary to promote educational and pharmacovigilance strategies that improve the prescription habits of physicians involved in caring for this group of patients.

Guanosine, a guanine-based nucleoside relaxed isolated corpus cavernosum from mice through cGMP accumulation.

In corpus cavernosum (CC), guanosine triphosphate (GTP) is converted into cyclic guanosine monophosphate (cGMP) to induce erection. The action of cGMP is terminated by phosphodiesterases and efflux transporters, which pump cGMP out of the cell. The nucleotides, GTP, and cGMP were detected in the extracellular space, and their hydrolysis lead to the formation of intermediate products, among them guanosine. Therefore, our study aims to pharmacologically characterize the effect of guanosine in isolated CC from mice. The penis was isolated and functional and biochemical analyses were carried out. The guanine-based nucleotides GTP, guanosine diphosphate, guanosine monophosphate, and cGMP relaxed mice corpus cavernosum, but the relaxation (90.7 ± 12.5%) induced by guanosine (0.000001-1 mM) was greater than that of the nucleotides (~ 45%, P < 0.05). Guanosine-induced relaxation was not altered in the presence of adenosine type 2A and 2B receptor antagonists. No augment was observed in the intracellular levels of cyclic adenosine monophosphate in tissues stimulated with guanosine. Inhibitors of nitric oxide synthase (L-NAME, 100 µM) and soluble guanylate cyclase (ODQ, 10 µM) produced a significant reduction in guanosine-induced relaxation in all concentrations studied, while in the presence of tadalafil (300 nM), a significant increase was observed. Pre-incubation of guanosine (100 µM) produced a 6.6-leftward shift in tadalafil-induced relaxation. The intracellular levels of cGMP were greater when CC was stimulated with guanosine. Inhibitors of ecto-nucleotidases and xanthine oxidase did not interfere in the response induced by guanosine. In conclusion, our study shows that guanosine relaxes mice CC and opens the possibility to test its role in models of erectile dysfunction.

State-of-the-art pharmacotherapy for autonomic dysfunction in Parkinson's disease.

Introduction: Autonomic dysfunction is one of the most frequent and disabling non-motor symptoms of Parkinson's disease (PD). It includes, among others, orthostatic hypotension (OH), sialorrhea, constipation, erectile dysfunction (ED), urinary dysfunction, and diaphoresis. They are usually under-recognized and suboptimally managed.Areas covered: Recommended treatments for dysautonomias are summarized with a description of the mechanism of action and observed results. The pathophysiology of each disorder is reviewed to pinpoint possible therapeutic targets. Drugs approved for treating dysautonomia in the general population along with those under development for PD-related dysautonomia are also reviewed. Finally, the key elements of each symptom that should be addressed in clinical trials' design are considered.Expert opinion: Midodrine, droxidopa, fludrocortisone, and domperidone may be used for OH treatment. Sialorrhea can be managed with botulin toxin injections and oral glycopyrrolate. Erectile dysfunction can benefit from sildenafil treatment, as urinary dysfunction can from solifenacin. Macrogol, lubiprostone, and probiotics might be effective in treating constipation. Further research is needed to determine adequate treatment for diaphoresis in PD patients. Multidisciplinary management of motor and non-motor symptoms in PD is the best approach for dysautonomias in PD.

Treatment with nitrite prevents reactive oxygen species generation in the corpora cavernosa and restores intracavernosal pressure in hypertensive rats.

Hypertension is a risk factor for erectile dysfunction (ED) and both conditions are associated with oxidative stress. Given that nitrite is described to display antioxidant effects, we hypothesized that treatment with nitrite would exert antioxidant effects attenuating both reactive oxygen species (ROS) generation in the corpora cavernosa (CC) and ED induced by hypertension. Two kidney, one clip (2K1C) hypertension was induced in male Wistar rats. Treatment with sodium nitrite (15 mg/kg/day, p.o., gavage) was initiated two weeks after surgery to induce hypertension and maintained for four weeks. Nitrite abrogated both the decrease in intracavernosal pressure and endothelial dysfunction of the CC induced by hypertension. Treatment with nitrite decreased hypertension-induced ROS generation in the CC assessed in situ using the fluorescent dye dihidroethidium (DHE) and with the lucigenin assay. Western immunoblotting analysis revealed that nitrite prevented the increase in Nox1 expression in the CC from 2K1C rats. Decreased concentrations of hydrogen peroxide (H2O2) were found in the CC from hypertensive rats and treatment with nitrite prevented this response. Treatment with nitrite increased the fluorescence of DAF-2DA in the CC from sham-operated rats and restored nitric oxide (NO) levels in the CC from 2K1C rats. In summary, we found novel evidence that nitrite reversed the decrease in intracavernosal pressure induced by 2K1C hypertension. This response was partially attributed to the antioxidant effect of nitrite that blunted ROS generation and endothelial dysfunction in the CC. In addition, nitrite-derived NO may have promoted direct protective actions against hypertension-induced CC dysfunction.

IcarisideII facilitates the differentiation of ADSCs to SCs via let-7i/STAT3 axis to preserve erectile function.

BACKGROUND: IcarisideII (ICAII) could promote the differentiation of adipose tissue-derived stem cells (ADSCs) to Schwann cells (SCs), leading to improvement of erectile function (EF) and providing a realistic therapeutic option for the treatment of erectile dysfunction (ED). However, the underlying molecular mechanisms of ADSCs and ICAII in this process remain largely unclear. METHODS: ADSCs were treated with different concentrations of ICAII. Cell proliferation was determined by MTT assay. qRT-PCR and western blot were performed to detect expressions of SCs markers, signal transducer and activator of transcription-3 (STAT3), and microRNA-let-7i (let-7i). Luciferase reporter assay was conducted to verify the regulatory relationship between let-7i and STAT3. The detection of intracavernosal pressure (ICP) and the ratio of ICP/mean arterial pressure (MAP) were used to evaluate the EF in bilateral cavernous nerve injury (BCNI) rat models. RESULTS: ICAII promoted cell proliferation of ADSCs in a dose-dependent manner. The mRNA and protein levels of SCs markers were increased by ICAII treatment in a dose-dependent manner in ADSCs. Moreover, let-7i was significantly decreased in ICAII-treated ADSCs and upregulation of let-7i attenuated ICAII-induced promotion of SCs markers. In addition, STAT3 was a direct target of let-7i and upregulated in ICAII-treated ADSCs. Interestingly, overexpression of STAT3 abated the let-7i-mediated inhibition effect on differentiation of ADSCs to SCs and rescued the ICAII-mediated promotion effect on it. Besides, combination treatment of ADSCs and ICAII preserved the EF of BCNI rat models, which was undermined by let-7i overexpression. CONCLUSION: ICAII was effective for preserving EF by promoting the differentiation of ADSCs to SCs via modulating let-7i/STAT3 pathway.