Vasodilator Drugs Research Articles

Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold

TRP channels are important pharmacological targets in physiopathology. TRPV2 plays distinct roles in cardiac and neuromuscular function, immunity, and metabolism, and is associated with pathologies like muscular dystrophy and cancer. However, TRPV2 pharmacology is unspecific and scarce at best. Using in silico similarity-based chemoinformatics we obtained a set of 270 potential hits for TRPV2 categorized into families based on chemical nature and similarity. Docking the compounds on available rat TRPV2 structures allowed the clustering of drug families in specific ligand binding sites. Starting from a probenecid docking pose in the piperlongumine binding site and using a Gaussian accelerated molecular dynamics approach we have assigned a putative probenecid binding site. In parallel, we measured the EC50 of 7 probenecid derivatives on TRPV2 expressed in Pichia pastoris using a novel medium-throughput Ca2+ influx assay in yeast membranes together with an unbiased and unsupervised data analysis method. We found that 4-(piperidine-1-sulfonyl)-benzoic acid had a better EC50 than probenecid, which is one of the most specific TRPV2 agonists to date. Exploring the TRPV2-dependent anti-hypertensive potential in vivo, we found that 4-(piperidine-1-sulfonyl)-benzoic acid shows a sex-biased vasodilator effect producing larger vascular relaxations in female mice. Overall, this study expands the pharmacological toolbox for TRPV2, a widely expressed membrane protein and orphan drug target.

Soluplus-Stabilized Nimodipine-Entrapped Spanlastic Formulations Prepared with Edge Activator (Tween20): Comparative Physicochemical Evaluation.

Nimodipine (ND) is a vasodilator drug that is used for acute subarachnoid hemorrhage. It has a predominant hydrophobic property, causing low solubility and low bioavailability. Spanlastics are elastic nanovesicular systems based on non-ionic surfactants and edge activators as major components. The goal of this work is to formulate ND as spanlastic nanovesicles to improve the drug's bioavailability. Spanlastic formulations containing ND were prepared by using the ethanol injection method. The composition of the ND formulation includes Span60 as a nonionic surfactant and Tween 20 as edge activators in different ratios. Stabilizers like Soluplus are used in some formulations and then compared with other formulations without that stabilizer. The evaluation study involved Vesicle Size (VS), PolyDispersity Index (PDI), and Entrapment Efficiency (%EE). Then, the optimized formula was subjected to an in vitro release study and zeta potential, additionally comparing the optimized formula with the formula without soluplus in the same concentration in Scanning Electron Microscopy (SEM), solubility study, Deformability Index (DI), and stability study. The results indicated a significant shift in some evaluation criteria and a non-significant change in other characterizations, including the difference in polymer ratio, sonication time, and the existence of a stabilizer. The best formula, F27, was found to have VS, PDI, %EE, and zeta potential of 125.7±0.29 nm, 0.4744±0.002, and 85.43±0.17% and -20.01 ± 0.89 mV, respectively. The photomicrographs of the prepared spanlastic revealed a more uniform and spherical spanlastic, indicating a greater capacity for continuous release. With the addition of Soluplus, the formula became more stable in one month and had a higher deformability index. A significant shift was observed in both VS and PDI. As the stabilizer concentration increases, VS and PDI will decrease. The non-significant shift was noted in the %EE with the presence of a stabilizer. Soluplus has the ability to spontaneously self-assemble into spherical particles. Additionally, PEG 6000, as a component of Soluplus's structure, has a tendency to form strong or tightly bound bilayers and prevent aggregation and formulation of large vesicles. This study explains the accessibility of the formulation of ND as spanlastic nanovesicles by using the ethanol injection method. This spanlastic formulation contains non-ionic surfactants and edge activators (Span 40 and Tween 20) in varying ratios. To get a stable formula, Soluplus is added to prevent the development of crystals and agglomeration.

Controlled Release of a Vasodilator Drug through Membrane-controlled Transdermal Systems: Development, Characterization, and Ex-vivo Evaluation

Controlled Release of a Vasodilator Drug through Membrane-controlled Transdermal Systems: Development, Characterization, and Ex-vivo Evaluation

Rehabilitation report of 2 cases of spinal cord ischemic injury after intra-aortic repair.

Spinal cord ischemia injury is a serious complication after intra-aortic surgery, with a low incidence but high disability rate. However, patients often do not receive comprehensive treatment in the early stages of the disease. Therefore, active neurological intervention is needed to protect and prevent spinal cord ischemia during and after surgery. In this paper, rehabilitation program and imaging data of 2 cases with spinal cord ischemic injury are presented and discussed regarding causes, prevention and acute treatment with this disease, which could be referred by clinicians. Case report 1: A 69-year-old male patient underwent aortic arch aneurysm and thoracic endovascular aortic repair (coated stent) was performed under general anesthesia. Complete paralysis of both lower limbs, constipation, and urinary retention occurred after surgery and was subsequently referred to our rehabilitation department. Case report 2: A man aged 41 years experienced sudden chest pain with no dizziness or headache. Weakness of both lower limbs gradually appeared over 30 minutes with subsequent loss of consciousness. He was diagnosed with aortic dissection and underwent aortic stent implantation. Inpatient rehabilitation began systematically 3 months after discharge. The 2 patients were diagnosed with paraplegia and spinal cord ischemic injury. The patients received strength and transfer training, sensory input, health mission, and activities of daily living. Patient 1 returned home without assistive devices and patient 2 returned home with wheelchair. Perioperative spinal cord protection is directly related to postoperative quality of life. Once the symptoms of spinal cord ischemic injury occur, cerebrospinal fluid drainage should be performed as soon as possible to increase mean arterial pressure. At the same time, methylprednisolone, ganglioside, anticoagulation, vasodilator drugs, and symptomatic supportive treatments are required. Intercostal artery and subclavian artery are reconstructed if necessary. Symptom stability flags referral to commence rehabilitation. Repetitive functional training is necessary to help patients return to the family and society as soon as possible.

Vascular Reactivity during Cardiopulmonary Bypass in Patients at Punjab Institute of Cardiology and Shalamar Hospital Lahore, Pakistan

Background: The operative treatment of cardiac diseases remains associated with systemic inflammation and a suboptimal outcome in many patients. These inflammatory changes are manifested by systemic hypotension, myocardial failure, increased vascular permeability and consequent dysfunction of organs such as the lungs, gut and brain. In general terms, sympathetic innervations of the small arteries and arterioles allows vasoconstriction, thereby increasing resistance to blood flow, whereas innervations of the large arteries and veins decreases the volume in these vessels, resulting in the redistribution of blood volume. This study was conducted to determine the effect of vasodilator drugs on duration of vasodilatation in patients undergoing coronary artery bypass grafting (CABG) with Cardiopulmonary bypass (CPB).Methods: We evaluated prospectively the effect of vasodilator medications before CABG surgery on hemodynamic variables and use of vasoactive drugs. We studied 30 patients with good left ventricular function allocated randomly to continue vasodilator drugs before cardiac surgery. Arterial pressure, Cardiac output, systemic vascular resistance and use of vasoactive drugs were recorded during anaesthesia, perioperative and in the early postoperative period.Results: Patients who using vasodilator drugs before cardiac surgery had not significant relationship between vasodilator drugs and vessels reactivity (vasoconstriction & vasodilatation). However, these patients required more vasodilator drugs to control hypertension after CPB and in the early postoperative period.Conclusion: There was no difference in hypotension at the onset of CPB or in the use of vasodilator drugs before cardiac surgery. We conclude that vasodilator drugs before cardiac surgery did not have sufficient effect to be recommended routinely.

Vinpocetine increases the microsporicidal effect of albendazole on Encephalitozoon intestinalis.

Microsporidia are obligate, intracellular, spore-forming eukaryotic fungi that infect humans and animals. In the treatment of disseminated microsporidiosis albendazole is the choice of drug. In recent years, antiparasitic activity of phosphodiesterase (PDE) enzyme inhibitors has been demonstrated against parasites and fungi, however, there is no information on microsporidia. Vinpocetine is currently used as a cerebral vasodilator drug and also as a dietary supplement to improve cognitive functions. Vinpocetine inhibits PDE1, so we aimed to investigate whether vinpocetine alone or in combination with albendazole has any effect on the spore load of Encephalitozoon intestinalis (E. intestinalis)-infected HEK293 cells. After determining the noncytotoxic concentrations of vinpocetine and albendazole on the host cell by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, HEK293 cells were infected with E. intestinalis spores. Then, two different concentrations of vinpocetine, albendazole, and a combination of both drugs were applied to the cells with an interval of 72 h for 15 days. Spore load of the cells was analyzed by real-time PCR. After the last treatment, spore Deoxyribonucleic Acid (DNA) load was significantly reduced only in the group treated with 14ng/ml albendazole. It was not different from control in groups treated with 7ng/ml albendazole and 4-20 µM vinpocetine. However, the combination of vinpocetine significantly increased the effect of albendazole at both concentrations. To our knowledge, this is the first study to investigate the microsporicidal activity of vinpocetine as well as its combinations with albendazole. However, further studies are needed to investigate the mechanism of action and also confirm in vivo conditions.

Nitroglycerin versus milrinone for low central venous pressure in patients undergoing laparoscopic hepatectomy: a double-blinded randomized controlled trial

BackgroundConventional anesthesia used to reduce central venous pressure (CVP) during hepatectomy includes fluid restriction and vasodilator drugs, which can lead to a reduction in blood perfusion in vital organs and may counteract the benefits of low blood loss. In this study, we hypothesized that milrinone is feasible and effective in controlling low CVP (LCVP) during laparoscopic hepatectomy (LH). Compared with conventional anesthesia such as nitroglycerin, milrinone is beneficial in terms of intraoperative blood loss, surgical environment, hemodynamic stability, and patients’ recovery.MethodsIn total, 68 patients undergoing LH under LCVP were randomly divided into the milrinone group (n = 34) and the nitroglycerin group (n = 34). Milrinone was infused with a loading dose of 10 µg/kg followed by a maintenance dose of 0.2–0.5 µg/kg/min and nitroglycerin was administered at a rate of 0.2–0.5 µg/kg/min until the liver lesions were removed. The characteristics of patients, surgery, intraoperative vital signs, blood loss, the condition of the surgical field, the dosage of norepinephrine, perioperative laboratory data, and postoperative complications were compared between groups. Blood loss during LH was considered the primary outcome.ResultsBlood loss during hepatectomy and total blood loss were significantly lower in the milrinone group compared with those in the nitroglycerin group (P < 0.05). Both the nitroglycerin group and milrinone group exerted similar CVP (P > 0.05). Nevertheless, the milrinone group had better surgical field grading during liver resection (P < 0.05) and also exhibited higher cardiac index and cardiac output during the surgery (P < 0.05). Significant differences were also found in terms of fluids administered during hepatectomy, urine volume during hepatectomy, total urine volume, and norepinephrine dosage used in the surgery between the two groups. The two groups showed a similar incidence of postoperative complications (P > 0.05).ConclusionOur findings indicate that the intraoperative infusion of milrinone can help in maintaining an LCVP and hemodynamic stability during LH while reducing intraoperative blood loss and providing a better surgical field compared with nitroglycerin.Trial registrationChiCTR2200056891,first registered on 22/02/2022.

Enhancing Urological Cancer Treatment: Leveraging Vasodilator Synergistic Potential with 5-FU for Improved Therapeutic Outcomes.

Backgroud: This study investigates the potential of vasodilator drugs as additive therapy in the treatment of urological cancers, particularly in combination with the antineoplastic agent 5-fluorouracil (5-FU). Methods: The study evaluated the cytotoxic effects of sildenafil, tezosentan and levosimendan alone and in combination with 5-FU on urological cancer cell lines. The assessment included MTT assays, colony formation assays and wound healing assays to determine cell viability, proliferative capacity, and migratory behavior, respectively. Results: Sildenafil and tezosentan showed limited cytotoxic effects, while levosimendan demonstrated moderate anticancer activity. The combination of levosimendan and 5-FU exhibited an additive interaction, enhancing cytotoxicity against cancer cells while sparing normal cells. Levosimendan also inhibited cell migration and proliferation, potentially through mechanisms involving the modulation of cAMP levels and nitric oxide production. Conclusions: The findings suggest that levosimendan can be used in conjunction with 5-FU to reduce the required dose of 5-FU, thereby minimizing side effects without compromising therapeutic efficacy. This study offers a new perspective for enhancing therapeutic outcomes in patients with urological cancers.

Microfluidic formulation of diazoxide-loaded solid lipid nanoparticles as a Novel approach for Friedreich's ataxia treatment

Friedreich ataxia (FRDA) is a hereditary autosomal recessive disorder characterized by frataxin deficiency, impacting mitochondrial function and causing oxidative damage. Diazoxide (DZX), a vasodilating drug used in the management of systemic hypertension, has shown promise in preclinical models but faces challenges in crossing the blood-brain barrier and potential toxicity at higher doses. This study aimed to create solid lipid nanoparticles (SLNs) loaded with DZX by microfluidic technique to improve blood-brain barrier (BBB) penetration and reduce side effects. Employing an in vitro BBB model, SLN-DZX demonstrated enhanced permeability compared to plain DZX. Cell viability assays carried out on FRDA fibroblast cells indicated enhanced viability with 1 μM SLN-DZX. Cellular uptake studies confirmed SLN internalization in FRDA fibroblasts, and subsequent treatment with SLN-DZX significantly reduced both total and mitochondrial ROS levels compared to control and empty SLN-treated cells. These findings suggest SLN-DZX as a potential therapeutic approach for FRDA, mitigating oxidative stress with improved BBB penetration and reduced toxicity.

Analysis of online prescription patterns in Chinese patients with sequelae of cerebral infarction: a real-world study

Cerebral infarction (CI) is a common cerebrovascular disease worldwide, and the burden caused by the sequelae of CI has increased significantly. However, current treatment guidelines lack standardized recommendations for pharmacotherapy of sequelae of CI. This retrospective study collected and analyzed 1.98 million prescriptions concerning sequelae of CI from patients admitted to Zhiyun Health Internet Hospital in 2022. The mean age of patients was 66.2 ± 11.4 years, and 52.40% were male. 79.73% had one or more comorbidities. For treatment, the prescriptions of 1-, 2- and ≥ 3-drug accounted for 64.55%, 23.77% and 11.68% respectively. Chinese patent medicine (CPM) prescriptions, western medicine (WM) prescriptions, and CPM and WM combined (CPM + WM) prescriptions accounted for 53.81%, 27.33%, and 18.86% respectively. In CPM prescriptions, the most frequently prescribed medications were Salvia miltiorrhiza (34.81%), Ginkgo biloba (24.96%), Panax notoginseng (20.67%), Gastrodia (7.15%) and Ligusticum Wallichii (4.90%). For WM prescriptions, the most commonly prescribed agents were anti-hypertensive (32.82%), anti-thrombotic (16.06%), vasodilator (15.70%), anti-dementia (10.88%), and lipid-lowering (9.58%) drugs. Among CPM + WM prescriptions, 72.61% had CPM/WM = 1, 21.20% had CPM/WM < 1, and 6.19% had CPM/WM > 1. This research utilized real-world data extracted from internet hospitals in China to present valuable evidence of online prescription patterns among patients experiencing sequelae of CI.

Prescribing beta-blockers to patients after acute myocardial infarction

In the treatment of patients with acute coronary syndrome in the pre-reperfusion era, one of the first-line drugs was beta-blockers. Now the management strategy of such patients has changed significantly. The results of these studies confirm the important role of beta-blockers in the therapy of patients who have undergone ACS in the era of reperfusion therapy. Beta-blocker therapy may be beneficial because of a potential reduction in the risk of all-cause death. The choice of vasodilatory drugs can provide benefits and additionally prevent the occurrence of complications.

Efficacy of topical minoxidil in enhancing beard growth in a group of transgender assigned female at birth individuals on gender affirming hormone therapy

PurposeTestosterone therapy represents the cornerstone of gender affirming hormone therapy (GAHT) among t-AFAB (transgender Assigned Female At Birth) people. Minoxidil is a vasodilator drug approved for topical use for the treatment of androgenetic alopecia. The aim of the present study was to evaluate the efficacy of topical minoxidil in enhancing beard growth in a group of t-AFAB people on GAHT.MethodsSixteen t-AFAB individuals with an incomplete beard development, on GAHT for at least 6 months, were enrolled. Topical minoxidil was applied to the interested facial areas. Before starting (T0), after 3 (T3) and 6 (T6) months, we evaluated facial hair growth using the Ferriman-Gallwey modified score (FGm).ResultsSubjects were 26 (2.7) years old and on GAHT for 18.5 [15–54] months; using a paired match evaluation, a statistically significant facial hair growth was observed over time, in particular at T6 (median upper lip FGm 3.5 [3–4] vs 2 [1–2] at T0 and chin FGm 4 [3.25–4] vs 1 [1–2] at T0; p ≤ 0.002). Comparing the minoxidil group with a control group (n = 16) matched for age and BMI who developed a full-grown beard only with GAHT, a logistic multivariable analysis identified hirsutism before GAHT was independently positively associated with the development of a full beard [OR 15.22 (95% CI 1.46–158.82); p = 0.023].ConclusionsThis is the first study demonstrating the efficacy of topical minoxidil in enhancing facial hair growth among t-AFAB people on GAHT. Further studies will be necessary to assess whether the obtained improvements will persist after discontinuing the medication.

Systemic tolerance of intravenous milrinone administration for cerebral vasospasm secondary to non-traumatic subarachnoid hemorrhage

PurposeDelayed cerebral ischemia (DCI) is a severe subarachnoid hemorrhage (SAH) complication, closely related to cerebral vasospasm (CVS). CVS treatment frequently comprises intravenous milrinone, an inotropic and vasodilatory drug. Our objective is to describe milrinone's hemodynamic, respiratory and renal effects when administrated as treatment for CVS. MethodsRetrospective single-center observational study of patients receiving intravenous milrinone for CVS with systemic hemodynamics, oxygenation, renal disorders monitoring. We described these parameters' evolution before and after milrinone initiation (day – 1, baseline, day 1 and day 2), studied treatment cessation causes and assessed neurological outcome at 3–6 months. ResultsNinety-one patients were included. Milrinone initiation led to cardiac output increase (4.5 L/min [3.4–5.2] at baseline vs 6.6 L/min [5.2–7.7] at day 2, p < 0.001), Mean Arterial Pressure decrease (101 mmHg [94–110] at baseline vs 95 mmHg [85–102] at day 2, p = 0.001) norepinephrine treatment requirement increase (32% of patients before milrinone start vs 58% at day 1, p = 0.002) and slight PaO2/FiO2 ratio deterioration (401 [333–406] at baseline vs 348 [307–357] at day 2, p = 0.016). Milrinone was interrupted in 8% of patients. 55% had a favorable outcome. ConclusionIntravenous milrinone for CVS treatment seems associated with significant impact on systemic hemodynamics leading sometimes to treatment discontinuation.

Allergic Acute Coronary Syndrome: A Case Report and Literature Review

Introduction: Kounis Syndrome was first described in 1991 by Kounis and Zavras as “the concurrence of chest pain during an allergic reaction, accompanied by clinical laboratory findings of classical angina pectoris caused by inflammatory mediators released during the allergic insult” [1].&#x0D; The mechanism of Kounis Syndrome most likely involves the release of cytokines through mast-cell degranulation, which leads to coronary vasospasm and atheromatous plaque erosion or rupture following the allergic reaction to an allergen.[2]&#x0D; The treatment is specific to acute coronary syndrome and anaphylaxis, with the added complication that the drugs used, while indicated in each of the two disorders separately, may present contradictions when administered jointly in one patient.[3]&#x0D; The purpose of this review is to briefly revise the existing literature regarding its overlooked diagnosis and contradictory joint management of anaphylaxis and acute coronary syndrome.&#x0D; We will conduct a brief review of the current literature on Kounis Syndrome while describing a suspected case of a female patient presented with both anaphylaxis symptoms and angina pectoris.&#x0D; Conclusions: Kounis syndrome is defined as the co-incidental occurrence of an acute coronary syndrome with hypersensitivity reactions following an allergic reaction. Treatment of allergic reactions may be sufficient in type I KS. In contrast, coronary intervention is needed in the other two types, accompanied by vasodilator drugs, including nitrates and calcium antagonists, each of which may have contradictory effects.

Hesperetin Relaxes Depolarizing Contraction in Human Umbilical Vein by Inhibiting L-Type Ca2+ Channel.

To study hesperetin-induced vasorelaxation after depolarizing contraction in human umbilical veins (HUVs) to elucidate the role of L-type Ca2+ channel (LTCC) and related signaling pathway. Isometric tension recording was performed in HUV rings pre-contracted with K+. Hesperetin relaxing mechanism was investigated using a LTCC opener (BayK8644) and blockers of cyclic nucleotides and phosphodiesterases (PDEs). Whole-cell patch-clamping in A7r5 cells, a rat vascular smooth muscle cell line, was performed to study the effect of hesperetin on LTCC current. After depolarizing precontraction, hesperetin induced HUV relaxation concentration-dependently and endothelium-independently; 1 mmol/L hesperetin reduced denuded HUV ring tension by 68.7% ± 4.3% compared to matching vehicle, osmolality, and time controls (P<0.0001). Importantly, hesperetin competitively inhibited BayK8644-induced contraction, shifting the half maximal effective concentration of BayK8644 response from 1.08 nmol/L [95% confidence interval (CI) 0.49-2.40] in vehicle control to 11.30 nmol/L (95% CI 5.45-23.41) in hesperetin (P=0.0001). Moreover, hesperetin elicited further vasorelaxation in denuded HUV rings pretreated with inhibitors of soluble guanylyl cyclase, adenylyl cyclase, PDE3, PDE4, and PDE5 (P<0.01), while rings pretreated with PDE1 inhibitors could not be relaxed by hesperetin (P>0.05). However, simultaneously applying inhibitors of soluble guanylyl cyclase and adenylyl cyclase could not inhibit hesperetin's effect (P>0.05). In whole-cell patch-clamping, hesperetin rapidly decreased LTCC current in A7r5 cells to 66.7% ± 5.8% (P=0.0104). Hesperetin diminishes depolarizing contraction of human vascular smooth muscle through inhibition of LTCC, and not cyclic nucleotides nor PDEs. Our evidence supports direct LTCC interaction and provides additional basis for the use of hesperetin and its precursor hesperidin as vasodilators and may lead to future vasodilator drug development as a treatment alternative for cardiovascular diseases.

Advancements in preventing post-contrast acute kidney injury in EVAR: clinical strategies and future directions.

Abdominal Aortic Aneurysm (AAA) represents a signif i cant global health issue with a high risk of rupture, resulting in substantial mortality rates. Endovascular Aneurysm Repair (EVAR) has emerged as the preferred treatment method due to its minimally invasive nature. However, the procedure carries a risk of acute kidney injury (AKI), particularly post-contrast acute kidney injury (PC-AKI), which can adversely af f ect patient outcomes. This review examines the incidence, pathophysiology, and prevention strategies for PC-AKI in the context of EVAR. It synthesizes current research on the mechanisms underlying PC-AKI, such as renal vasoconstriction, oxidative stress, and tubular toxicity. The ef f ectiveness of various preventive measures, including pre-procedural hydration, use of low-osmolality contrast agents, and alternative imaging techniques, is evaluated. Additionally, the review explores patient-specif i c risk factors and the potential of novel pharmacologic interventions. The incidence of PC-AKI in EVAR varies based on procedural complexity and patient-specif i c factors like preexisting renal insuf f i ciency, diabetes, and hypertension. Preventive strategies such as intravenous hydration and the use of less nephrotoxic contrast agents have shown ef f ectiveness. Advances in imaging technology and innovative pharmacologic interventions, including antioxidants and vasodilatory drugs, present promising approaches to reducing the risk of PC-AKI. Ef f ective management of PC-AKI in EVAR necessitates a comprehensive and multifaceted approach that considers both procedural and patient-specif i c factors. Future research should aim to standardize diagnostic criteria, ref i ne preventive strategies, and explore novel therapies. Enhanced understanding of PC-AKI pathophysiology and personalized preventive measures can improve patient safety and outcomes in EVAR procedures.

Patient phenotype profiling using echocardiography and natriuretic peptides to personalise heart failure therapy.

Heart failure (HF) is a progressive condition with a clinical picture resulting from reduced cardiac output (CO) and/or elevated left ventricular (LV) filling pressures (LVFP). The original Diamond-Forrester classification, based on haemodynamic data reflecting CO and pulmonary congestion, was introduced to grade severity, manage, and risk stratify advanced HF patients, providing evidence that survival progressively worsened for those classified as warm/dry, cold/dry, warm/wet, and cold/wet. Invasive haemodynamic evaluation in critically ill patients has been replaced by non-invasive haemodynamicphenotype profiling using echocardiography. Decreased CO is not infrequent among ambulatory HF patients with reduced ejection fraction, ranging from 23 to 45%. The Diamond-Forrester classification may be used in combination with the evaluation of natriuretic peptides (NPs) in ambulatory HF patients to pursue the goal of early identification of those at high risk of adverse events and personalise therapy to antagonise neurohormonal systems, reduce congestion, and preserve tissue/renal perfusion. The most benefit of the Guideline-directed medical treatment is to be expected in stable patients with the warm/dry profile, who more often respond with LV reverse remodelling, while more selective individualised treatments guided by echocardiography and NPs are necessary for patients with persisting congestion and/or tissue/renal hypoperfusion(cold/dry, warm/wet, and cold/wet phenotypes) to achieve stabilizationandto avoid further neurohormonal activation, as a result of inappropriate use of vasodilating or negative chronotropic drugs, thuspursuing the therapeutic objectives. Therefore, tracking the haemodynamic status over time by clinical, imaging, and laboratory indicators helps implement therapy by individualising drug regimens and interventionsaccording to patients'phenotypes even in an ambulatory setting.

Evaluation of retinal microvascular network in patients with systemic sclerosis: An optical cohorence tomography angiography study

PurposeTo investigate the long-term effect of systemic sclerosis on the optic disk and retinal capillary network and to see whether the drugs used in the treatment of SSc affected optical coherence tomography angiography (OCTA) parameters. Materials and MethodsThis cross-sectional case-control study included 40 systemic sclerosis patients and 40 healthy individuals. We included only one eye of each patient in the study. Macular layers and angiography scanning were performed with a Zeiss Cirrus 5000 OCTA system. Such values as macular thickness, retinal nerve fiber layer (RNFL), ganglion cell inner plexiform layer (GC-IPL) were obtained. For central vessel and perfusion density (VD, PD), central 6 mm were obtained and were evaluated by dividing it into 3 groups as inner, outer, and full. The FAZ was evaluated through 3 parameters: area, perimeter, circularity index. ResultsStatistically significant difference was found between the groups in terms of the mean and foveal macular thickness values (p=0.008, p=0.033). Significant differences were also found between the two groups in terms of the VD and PD parameters in all regions except for 1 mm center (p<0.05). There were no significant differences in RNFL and GC-IPL values between two groups. Also, a positive correlation was observed between parapapillary perfusion density values and RNFL and GC-IPL thicknesses in SSc group. When the subgroups were compared in terms of vasodilator drug use, the subgroup using vasodilators was seen to have higher mean RNFL and inferior RNFL thicknesses (p=0.045 and p=0.035, respectively). In addition, there was a significant positive correlation between parapapillary VD and RNFL values in the SSc subgroup treated with vasodilators. ConclusionsThe results of this study demonstrate microvascular loss in individuals with systemic sclerosis, compared with healthy subjects. Also, it has been determined that OCTA is an important test for screening retinal and optic disk microvascular changes over time in cases of systemic sclerosis and may be used to evaluate the response to vasodilator drugs used in the treatment of SSc disease.

Sildenafil for congenital heart diseases induced pulmonary hypertension, a meta-analysis of randomized controlled trials

BackgroundSildenafil was first prescribed for angina pectoris and then for erectile dysfunction from its effects on vascular smooth muscle relaxation and vasodilatation. Recently, sildenafil has been proposed for congenital heart diseases induced pulmonary hypertension, which constitutes a huge burden on children's health and can attribute to fatal complications due to presence of unoxygenated blood in the systemic circulation. Therefore, our meta-analysis aims to further investigate the safety and efficacy of sildenafil on children population.MethodsWe searched the following electronic databases: PubMed, Cochrane CENTRAL, WOS, Embase, and Scopus from inception to April 20th, 2022. Randomized controlled trials that assess the efficacy of using sildenafil in comparison to a placebo or any other vasodilator drug were eligible for inclusion. The inverse variance method was used to pool study effect estimates using the random effect model. Effect sizes are provided in the form of mean difference (MD) with 95% confidence intervals (CI).ResultsOur study included 14 studies with (n = 849 children) with a mean age of 7.9 months old. Sildenafil showed a statistically significant decrease over placebo in mean and systolic pulmonary artery pressure (PAP) with MD -7.42 (95%CI [-13.13, -1.71], P = 0.01) and -8.02 (95%CI [-11.16, -4.88], P < 0.0001), respectively. Sildenafil revealed a decrease in mean aortic pressure and pulmonary artery/aortic pressure ratio over placebo with MD -0.34 (95%CI [-2.42, 1.73], P = 0.75) and MD -0.10 (95%CI [-0.11, -0.09], P < 0.00001), respectively. Regarding post corrective operations parameters, sildenafil had a statistically significant lower mechanical ventilation time, intensive care unit stay, and hospital stay over placebo with MD -19.43 (95%CI [-31.04, -7.81], s = 0.001), MD -34.85 (95%CI [-50.84, -18.87], P < 0.00001), and MD -41.87 (95%CI [-79.41, -4.33], P = 0.03), respectively. Nevertheless, no difference in mortality rates between sildenafil and placebo with OR 0.25 (95%CI 0.05, 1.30], P = 0.10) or tadalafil with OR 1 (95%CI 0.06, 17.12], P = 1).ConclusionSildenafil is a well-tolerated treatment in congenital heart diseases induced pulmonary hypertension, as it has proven its efficacy not only in lowering both PAP mean and systolic but also in reducing the ventilation time, intensive care unit and hospital stay with no difference observed regarding mortality rates.

Vinpocetine alleviates intestinal ischemia/reperfusion injury and enhances M2 macrophage polarization in rats: Role of SIRT1/SOCS3/STAT3 signaling pathway

Vinpocetine (Vinpo) is a neuroprotective vasodilator drug. It is an effective therapeutic agent for a variety of cerebrovascular and cognitive disorders. However, its potential protective efficacy on intestinal ischemia/reperfusion (I/R) injury remains elusive. The present study aimed to investigate the effect of Vinpo on intestinal I/R injury and to explore its modulatory effect on sirtuin (SIRT1)/ Suppressor of cytokine signaling (SOCS3)/ Signal Transducer and Activator of Transcription (STAT3) signaling. Twenty-four male Wistar albino rats were randomly allocated into four groups. G1 (sham): rats were subjected to surgical stress without I/R, GII (I/R): rats were subjected to 60 min/2-h I/R, GIII (Vinpo + I/R): rats were pre-treated with Vinpo (20 mg/kg/day, P.O. daily) for 2 weeks before intestinal I/R; GIV (EX527 + Vinpo + I/R): rats received both Vinpo (20 mg/kg/day, P.O.) and EX527 (5 mg/kg, once every 2 days, i.p) for 2 weeks before intestinal I/R. The current results showed that Vinpo improved the intestinal histopathological picture, enhanced M1 to M2 macrophage polarization and alleviated the I/R-induced increase in interleukins (IL-6, IL-1β), tumor necrosis factor (TNF-α), inducible nitric oxide synthase (i-NOS), and nitric oxide (NO). Additionally, Vinpo pretreatment upregulated SIRT1 mRNA expression/protein level and SOCS3 mRNA expression while downregulating P-STAT3 immunoreactivity. The effects of Vinpo were attenuated by the SIRT1 inhibitor EX527. We concluded that Vinpo ameliorated the intestinal I/R injury and enhanced M2 anti-inflammatory macrophage polarization through modulation of SIRT1/SOCS3/STAT3/i-NOS cascade.