Cardioprotective Agent Research Articles

Sodium-glucose co-transporter-2 inhibitors : a potential cardioprotective agent?

Abstract Background Sodium-glucose co-transporter-2 inhibitors (SGLT2i) are one of the cornerstones in the treatment of patients with heart failure (HF) , regardless the ejection fraction (EF) or the presence of diabetes mellitus (DM). Other types of medications used in the treatment of heart failure , like angiotensin converting enzyme inhibitors (ACEi) or beta-blockers (BB) have shown some degree of cardioprotection in high risk patients receiving cardiotoxic chemotherapy, but data on SGLT2i are very limited. Purpose To examine the possible differences in the development of anthracycline cardiotoxicity in diabetic patients receiving SGLT2i compared to those who don’t. Methods We retrospectively analysed the data from the oncological as well as hematological patients of our hospital. Group 1 (SGLT2) included patients with cancer who received anthracycline treatment and diabetes on treatment with SGLT2i. Group 2 (control) included patients with cancer who received anthracycline treatment and diabetes but with treatment other than SGLT2i. We recorded the basic demographic parameters, the development of cardiotoxicity (heart failure incidence, heart failure admissions, new cardiomyopathy [>10% decline in ejection fraction to <50%], and clinically significant arrhythmias) as well as the abnormal levels of troponin I (tnI) and natriuretic peptides (NTproBNP). Results Age, sex, ethnicity, cancer type, cancer stage, and other cardiac risk factors were similar between groups. The mean duration of the follow up was 2 years. In the SLT2 group were included 86 patients and in the control group 97. The rates of the cardiotoxicity events were recorded as follow : (SGLT2 vs control) Heart failure (7.4% vs 31.9%, p<0.01), heart failure admissions (3.4% vs 12.3%, p<0.05), new cardiomyopathy (6.1% vs 27.2%, p<0.05), arrhythmias (2.7% vs 24.3%, p<0.01), abnormal tnI levels (4.2% vs 14.7% , p< 0.01), abnormal NTproBNP levels (6.4% vs 30.9%, p<0.01) Conclusions SGLT2 inhibitors were associated with lower rate of cardiac events among patients with cancer and DM who were treated with anthracyclines. Further studies are needed in order to test the possible cardioprotective effects of SGLT2 inhibitors in patients at high cardiac risk treated with anthracyclines.

Cardioprotective strategies in the management of chemotherapy-induced cardiotoxicity: Current approaches and future directions

Background: Chemotherapy-induced cardiotoxicity (CIC) is a significant challenge in cancer treatment, leading to heart failure and myocardial infarction. With rising cancer survival rates, the long-term cardiovascular health of survivors has gained importance. While several cardioprotective medications have been studied to mitigate chemotherapy’s harmful effects on the heart, more research is needed to confirm their effectiveness and optimal use. Methodology: This review synthesizes evidence on cardioprotective drugs in managing CIC. We conducted a comprehensive literature search of peer-reviewed articles, clinical trials, and meta-analyses published between January 2000 and May 2024. Studies were selected based on relevance, quality, and focus on mechanisms, efficacy, and clinical outcomes of cardioprotective agents such as beta-blockers, ACE inhibitors, ARBs, statins, and dexrazoxane. Results and Discussion: Cardioprotective medications show potential in alleviating the impact of chemotherapy on heart function. Beta-blockers and ACE inhibitors effectively reduce heart failure incidence and improve cardiac outcomes. Statins, with their anti-inflammatory and antioxidative properties, and dexrazoxane, which reduces anthracycline-induced cardiotoxicity, also show promise. However, variability in study designs, patient groups, and chemotherapy treatments complicates the establishment of standardized treatment protocols. Conclusion: Cardioprotective drugs hold significant promise in managing CIC and improving cardiac outcomes for cancer patients. Current evidence supports the efficacy of beta-blockers, ACE inhibitors, statins, and dexrazoxane. Further research is needed to establish standardized protocols, evaluate long-term safety, and optimize treatment timing. Integrating cardioprotective strategies into oncological care can enhance the quality of life and prognosis for cancer survivors.

Tetra aniline-based polymers ameliorate BPA-induced cardiotoxicity in Sprague Dawley rats, in silico and in vivo analysis

AimsBisphenol A (BPA), xenoestrogen, is an environmental toxicant, that generates oxidative stress leading to cardiotoxicity. The oxidative stress can be neutralized by natural and synthetic antioxidants. The present study elucidates the highly selective antioxidative potential of synthetic tetra aniline polymers Es-37 and L-37 against Bisphenol A-induced cardiac cellular impairments and the role of miRNA-15a-5p in the regulation of different apoptotic proteins. Materials and methodsThe molecular docking of L-37 and Es-37 with three proteins (p53, Cytochrome c, and Bcl-2) were performed. The dose of 1 mg/kg BW of BPA, 1 mg/kg BW Es-37 and L-37 and 50 mg/kg BW N-acetyl cysteine (NAC) was administered to Sprague Dawley rats. The miRNA and target gene expression were confirmed by qRt-PCR and Immunoblotting. Key findingsIn our results, BPA administration significantly elevated the reactive oxygen species (ROS), p53, cytochrome c, and particularly miRNA-15a-5p expression; however: these changes were notably reversed by Es-37 and L-37 treatment. Additionally, molecular docking of synthetic polymers validated that L-37 has a greater binding affinity with the target proteins compared to Es-37, with the highest binding values reported for the enzymatic protein cytochrome c. SignificanceThese results suggest that both synthetic polymers Es-37 and L-37 have the potential to scavenge free radicals, boost-up antioxidant enzyme activities, and avert (BPA-induced) toxicity, thus, may serve as cardioprotective agents. Moreover, this study first time proposes that miRNA-15a-5p overexpression is associated with oxidative stress and coincides with BPA induced cardiotoxicity, thus may serve as potential therapeutic target in future.

Role of polypill in cardiovascular prevention and treatment.

Cardiovascular diseases (CVD) remain the leading cause of mortality globally and require innovative strategies for effective prevention and treatment. The polypill concept, which integrates multiple cardioprotective agents into a single dosage form, has emerged as a promising approach to improve adherence and simplify the management of cardiovascular risk factors. We review clinical trials and observational studies evaluating the impact of the polypill on reducing the incidence of major cardiovascular events (MACEs), its influence on medication adherence, and its potential to fill treatment gaps in diverse populations. Also of note are the pharmacoeconomic implications of the widespread use of the polypill, particularly in low- and middle-income countries where the burden of cardiovascular disease is increasing. Although the polypill demonstrates a favorable profile in improving therapeutic compliance and reducing cardiovascular risk factors, debates persist regarding its efficacy compared to individualized treatment regimens. This review summarizes the current evidence on the efficacy, safety, and cost-effectiveness of the polypill in CVD primary and secondary prevention. Furthermore, potential challenges in implementing the polypill strategy include tailoring the components to patient-specific risk profiles and the need for robust evidence from large-scale randomized controlled trials to substantiate its long-term benefits.

Alda-1 attenuation of binge alcohol-caused atrial arrhythmias through a novel mechanism of suppressed c-Jun N-terminal Kinase-2 activity

Holiday Heart Syndrome (HHS) is caused by excessive binge alcohol consumption, and atrial fibrillation (AF) is the most common arrhythmia among HHS patients. AF is associated with substantial morbidity and mortality, making its prevention and treatment of high clinical interest. This study defines the anti-AF action of Alda-1 (an established cardioprotective agent) and the underlying mechanisms of the action in our well-characterized HHS and cellular models. We found that Alda-1 effectively eliminated binge alcohol-evoked Ca2+ triggered activities (Ca2+ waves, prolonged Ca2+ transient diastolic decay) and arrhythmia inducibility in intact mouse atria. We then demonstrated that alcohol impaired human RyR2 channels (isolated from organ donors' hearts). The functional role of alcohol-caused RyR2 channel dysfunction in Ca2+ triggered arrhythmic activities was evidenced in a unique transgenic mouse model with a loss-of-function mutation (RyR2E4872Q+/−). Alda-1 is known to activate aldehyde dehydrogenase 2 (ALDH2), a key enzyme in alcohol detoxification. However, we found an increased level of ALDH2 and a preserved normal balance of pro- vs anti-apoptotic signaling in binge alcohol exposed hearts and H9c2 differentiated myocytes, which suggests that the link of alcohol-ALDH2-apoptosis is unlikely to be a key factor leading to binge alcohol-evoked arrhythmogenicity. We have previously reported that binge alcohol-activated stress response kinase JNK2 causatively drives Ca2+-triggered atrial arrhythmogenicity. Here, we found that JNK2-specific inhibition in either isolated human RyR2 channels or intact mouse atria abolished alcohol-evoked RyR2 channel dysfunction and Ca2+ triggered arrhythmic activities, suggesting a strong alcohol-JNK2-RyR2 interaction in atrial arrhythmogenicity. Furthermore, we revealed, for the first time, that Alda-1 suppresses JNK2 (but not JNK1) enzyme activity independently of ALDH2, which in turn alleviates binge alcohol-evoked Ca2+ triggered atrial arrhythmogenesis. Our findings provide novel mechanistic insights into the anti-arrhythmic action of Alda-1 and suggest that Alda-1 represents a potential preventative agent for AF management for HHS patients.

Carvacrol-conjugated 3-Hydroxybenzoic Acids: Design, Synthesis, cardioprotective potential against doxorubicin-induced Cardiotoxicity, and ADMET study

Carvacrol (CA) is a phenolic monoterpene renowned for its diverse pharmacological benefits, particularly its cardioprotective effects. Concurrently, phenolic acids have also demonstrated promise in mitigating drug-induced cardiotoxicity. Focusing on combating doxorubicin-induced cardiotoxicity (DIC), the research aims to synthesize novel cardioprotective agents by combining CA with 3-hydroxybenzoic acid (3HA). Doxorubicin, an anticancer drug, poses cardiovascular risks as its adverse effect, prompting the exploration of hybrid compounds. Various linker molecules, including alkyl and acyl with different carbon lengths, were investigated to understand their impact on bioactivity. In vitro testing on the DOX-induced H9c2 cell death model revealed the effectiveness of a CA conjugate in preserving cardiomyocyte viability. In silico analysis highlighted favorable drug-like properties and low toxicity of the conjugate. This study sheds light on molecular hybridization’s potential in developing cardioprotective agents, emphasizing CA’s pivotal role in combating DIC.

The cardiac toxicity of PAMAM dendrimer drug delivery systems can be attenuated with the adjunct use of cardioprotective agents.

Polyamidoamine (PAMAM) dendrimer nanoparticles are efficient drug delivery vectors with potential clinical applications in nanomedicine. However, PAMAMs can compromise heart function, and strategies to mitigate cardiotoxicity would be beneficial. In this study, we investigated whether the adjunct use of three key cardioprotective agents could prevent the cardiac injury induced by a seventh-generation cationic PAMAM dendrimer (G7). Isolated rat hearts were subjected to ischemia and reperfusion (I/R) injury in the presence or absence of G7 or the cardioprotective agents Losartan, Epidermal Growth Factor (EGF), or S-nitroso-N-acetylpenicillamine (SNAP). I/R injury significantly compromised cardiac function, in terms of left ventricular hemodynamics, contractility, and vascular dynamics, which were markedly improved (p<0.05) by the administration of Losartan, EGF, or SNAP alone, confirming their cardioprotective effects. The administration of G7 significantly worsened cardiac function recovery following I/R(p<0.05). G7-induced impairments in cardiac and vascular dynamics were significantly improved by co-administration of Losartan, EGF, or SNAP. Treatment with G7 also significantly increased cardiac enzyme levels and infarct size, both of which were markedly reduced upon co-infusion of Losartan, EGF, or SNAP (p<0.05). Thus, G7 deteriorates the recovery of cardiac function in isolated hearts subjected to I/R injury, which can be rescued by co-administration of Losartan, EGF, or SNAP. These findings enhance our understanding of the nanotoxicology of PAMAM dendrimers in the mammalian heart and suggest that the adjunct use of cardioprotective agents is an effective strategy for mitigating the cardiotoxicity of these dendrimers and potentially other drug delivery systems.

Ferroptosis-induced Cardiotoxicity and Antitumor Drugs.

The induction of regulated cell death ferroptosis in tumors is emerging as an intriguing strategy for cancer treatment. Numerous antitumor drugs (e.g., doxorubicin, etoposide, tyrosine kinase inhibitors, trastuzumab, arsenic trioxide, 5-fluorouracil) induce ferroptosis. Although this mechanism of action is interesting for fighting tumors, the clinical use of drugs that induce ferroptosis is hampered by cardiotoxicity. Besides in cancer cells, ferroptosis induced by chemotherapeutics can occur in cardiomyocytes, and this feature represents an important drawback of antitumor therapy. This inconvenience has been tackled by developing less or no cardiotoxic antitumor drugs or by discovering cardioprotective agents (e.g., berberine, propofol, fisetin, salidroside, melatonin, epigallocatechin- 3gallate, resveratrol) to use in combination with conventional chemotherapeutics. This review briefly summarizes the molecular mechanisms of ferroptosis and describes the ferroptosis dependent mechanisms responsible for cardiac toxicity developed by cancer- suffering patients following the administration of some chemotherapeutics. Additionally, the pharmacological strategies very recently proposed for potentially preventing this inconvenience are considered.

Heart Failure Mortality in Chronic Kidney Disease: The Fatal Crossover

Real-world mortality data regarding heart failure in patients with comorbid chronic kidney disease remains limited, especially following the advent of advanced heart failure therapies. Using the CDC WONDER database, we included patients ≥ 25 years old who died primarily from heart failure (2011-2020) with comorbid chronic kidney disease. We calculated age-adjusted mortality rates (AAMR) per 100,000 individuals. We determined the trends over time by estimating the annual percent change (APC) using the Joinpoint regression program. There were 82,454 heart failure deaths with comorbid chronic kidney disease. The AAMR increased from 2.34 (95% CI, 2.28- 2.41) in 2011 to 4.79 (95% CI, 4.71- 4.88) in 2020. During the study period, Heart failure deaths among patients with comorbid chronic kidney disease increased by 149.0% compared to 59.9% in those without. Men had higher AAMR than women (3.92 [95% CI, 3.88- 3.96] vs. 2.96 [95% CI, 2.93- 2.99]). African American patients had the highest AAMR (5.85 [95% CI, 5.75- 5.96]). The Midwest region had the highest AAMR (3.83 [95% CI, 3.78- 3.89]). The AAMR was higher in the rural areas than in the urban regions (3.77 [95% CI, 3.71- 3.83] vs. 3.23 [95% CI, 3.20- 3.25]). Most patients died in hospices or nursing homes (29,000, 35.2%). Our study showed a significant increase in heart failure AAMR in patients with comorbid chronic kidney disease in recent eras. Further effort is needed to optimize cardioprotective agents for this population and to address demographic discrepancies at the policy level.

Can Alpha-Pinene Prevent Methotrexate-Induced Cardiac and Hepatic Damage?

The effects of alpha-pinene (AP), a monoterpenoid, known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, on methotrexate (MTX)-induced cardiac and hepatic damage were investigated in this study. Male Sprague-Dawley rats were divided into Control, Vehicle, AP, MTX, and AP+MTX groups (n=7). AP (50 mg/kg/day, 14 days) was applied subcutaneously in the AP and AP+MTX groups. MTX (20 mg/kg) was injected three days before sacrification. Serum CK-MB, troponin T, ALT, and AST levels, as well as cardiac and hepatic MDA, GSH, caspase-3, and p53 levels, were measured by ELISA. Histological changes in tissues were evaluated by scoring in terms of tissue damage and cellular degeneration parameters after hematoxylin-eosin staining. MTX caused significant increase in serum CK-MB, troponin T, ALT, and AST levels, hepatic and cardiac lipid peroxidation, GSH depletion, and caspase-3 level. However, tissue levels of p53 did not change significantly. MTX-induced histological deterioration was observed in both tissues. These MTX-induced changes were significantly reduced in the AP+MTX group. Present results show that MTX-induced cardiac and hepatic damage is prevented by AP pretreatment. This protection can be attributed to the antioxidant and anti-apoptotic properties of AP. Considering the importance of MTX in cancer treatment, AP appears to have highly promising potential as a cardioprotective and hepatoprotective agent in anti-tumoral therapy.

The role of doxorubicin in the formation of cardiotoxicity is a consensus statement. Part II. Cardiotoxicity of doxorubicin unrelated to myocytes and cardioprotection strategy (review)

Introduction. The use of doxorubicin in clinical practice has shown cumulative and dose-dependent toxic effects on cardiomyocytes, leading to an increase of mortality risk among patients with cancer and as a resulting to restrictions in the indications for its use.Text. A dangerous adverse reaction of doxorubicin is cardiomyopathy, leading to congestive heart failure. Cardiotoxicity is based on at least several pathophysiological mechanisms (described in more detail in the first part of the review), leading to damage to cardiomyocytes as a result of oxidative stress with the formation of free radicals, dysfunction of mitochondria, autophagy, release of nitric oxide and inflammatory mediators, as well as changes in gene expression and proteins leading to apoptosis. The current (second) part of the review provides detailed information on the actual understanding of the pathophysiological mechanisms underlying the described cardiotoxicity, the effect of doxorubicin on other heart cells. The use of cardioprotective strategies will reduce the severity and likelihood of developing cardiotoxicity. This article describes strategies based on reducing the maximum cumulative dose, changing the speed of doxorubicin administration, using pegylated liposomal formulations and cardioprotective agents, as well as exercise.Conclusion. Despite the huge number of scientific papers devoted to various aspects of cardiotoxicity of doxorubicin, its prevention and treatment, this issue requires more careful study and development of more advanced methods of early diagnosis, prevention and more effective therapy the complication.

Incidence of new onset type 2 diabetes in adults living with obesity treated with tirzepatide or semaglutide: real world evidence from an international retrospective cohort study

Tirzepatide, a novel dual agonist of glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), has demonstrated greater magnitude of weight loss compared to semaglutide in a phase 3 clinical trial. However, the effect of tirzepatide on incidence of type 2 diabetes (T2D) in individuals with overweight and obesity, and the effect on major adverse cardiovascular outcomes in individuals with pre-existing T2D, remains unknown. We performed a retrospective cohort study of anonymised electronic medical records using the TriNetX network (TriNetX LLC, Cambridge, MA, USA) a global federated database. The data used in this study was collected on 5th June 2024. Two cohorts of individuals were generated: 1) without pre-existing T2D and, 2) with T2D. We adopted an active comparator new user design on new initiations of either tirzepatide or semaglutide therapy. Analysis began from the index event which was defined as individuals on respective therapy for 6 months only. Analysis of outcomes was conducted off-drug, in individuals without a pre-existing history of the disease of interest. Individuals were followed up for 12 months post the index event. Primary outcome for cohort 1 was incidence of T2D, and for cohort 2 was composite: all-cause mortality, cerebral infarction, acute coronary syndrome, and heart failure. Secondary outcomes for cohort 1 were change in HbA1c and body weight and for cohort 2: incidence of micro- and macrovascular complications, suicidal ideation and/or attempt, and all-cause mortality. We propensity score matched (1:1) for potential confounders: baseline demographics, socioeconomic circumstances, HbA1c, weight, relevant co-morbidities, and anti-obesity, hypoglycaemic and cardioprotective agents. The study population without T2D consisted of 13,846 individuals, equally split between tirzepatide and semaglutide users. Tirzepatide was associated with both lower risk for incident T2D (HR 0.73, 95% CI 0.58-0.92, p<0.001) and greater weight loss (-7.7kg, [95% CI-6.8,-8.5kg], p<0.001), compared to semaglutide (-4.8kg, [95% CI-3.9,-5.6kg], p<0.001). In individuals with pre-existing T2D (n=8446), tirzepatide was associated with lower risk of the composite outcome (HR 0.54, 95% CI 0.38-0.76, p<0.001), cerebral infarction (HR 0.45, 95% CI 0.24-0.84, p=0.010) and all-cause mortality (HR 0.33, 95% CI 0.15-0.73, p=0.004) compared to semaglutide. Tirzepatide is associated with significantly reduced risk of developing T2D and major adverse cardiovascular events in individuals living with obesity and T2D respectively. Randomised controlled trials investigating the utility of dual incretin agonists in the primary prevention of T2D and cardiovascular disease in higher risk populations are now required. Nil.

Cardioprotective effect of Robinin ameliorates Endoplasmic Reticulum Stress and Apoptosis in H9c2 cells.

Robinin is one of the glycosyloxyflavones that has been less explored for its therapeutic application, especially in the field of CVD. Herein, we explored the cardioprotective efficacy of Robinin by using H2O2 and Doxorubicin (DOX) - treated H9c2 cells as an in vitro model. H2O2 and DOX treatment resulted in severe cellular damage to the cardiomyocytes, which was followed by apoptosis. Apoptosis and nuclear morphology were analysed through Hoechst 33342 and AO/EB staining. qPCR was employed to detect the expression of apoptosis as well as ERS-related markers. Reactive oxygen species (ROS) generation was observed using DCFH-DA staining and FACS analysis. Signaling pathways involved were analysed using Western blot. Robinin pre-treatment considerably decreased the apoptotic rate by boosting the endogenous anti-oxidative activity and lowering the activity of Malonaldehyde and Lactate dehydrogenase enzyme. Robinin also inhibited the generation of ROS. Robinin reduced the expression of ERS-associated genes and proteins, thereby decreasing apoptosis-related proteins. Upon comparing the cardioprotective effect of Robinin with a known cardioprotective agent Dexrazoxane (DEX) it was revealed that DEX has more cardioprotective effect against DOX than H2O2-induced stress, while Robinin showed a significant protective effect against both H2O2 and DOX induced stress.

Efficacy of Nicorandil in Preventing Myocardial Injury and Cardiovascular Outcomes in Patients Undergoing Percutaneous Coronary Intervention (PCI): A Systematic Review and Meta-Analysis.

Percutaneous coronary intervention (PCI) is a common procedure for treating coronary artery disease, but it carries a risk of periprocedural myocardial injury (PMI). This meta-analysis evaluated the efficacy of nicorandil, a hybrid compound with nitrate-like and potassium channel-opening properties, in preventing PMI during PCI. A comprehensive literature search identified 14 studies involving 1,762 patients, with 882 receiving nicorandil and 880 in the control group. The analysis revealed that nicorandil significantly reduced the incidence of PMI (RR: 0.73, 95% CI: 0.61-0.86) and major adverse cardiovascular events (MACE) (RR: 0.76, 95% CI: 0.58-0.99) compared to the control group. Nicorandil's cardioprotective effects are attributed to its ability to improve coronary blood flow, precondition the myocardium, and reduce oxidative stress and inflammation. These findings suggest that nicorandil could be a valuable adjunctive therapy during PCI, potentially improving patient outcomes. However, the study had limitations, including variations in drug administration methods and a lack of individual-level data for subgroup analysis. Future research should focus on optimizing dosing regimens and administration timing and comparing nicorandil's effectiveness with other cardioprotective agents.

Freeze-drying cycle optimization of an amorphous solid dispersion of resveratrol

Resveratrol (RES) has demonstrated advantages as anti-cancer, anti-inflammatory, blood sugar-lowering agent and as cardioprotective agent, among others. Despite RES therapeutic advantages its use in pharmaceutical applications is limited by its low oral bioavailability, mainly due to its poor water solubility. Formulation of poorly water-soluble compound as solid dispersion (SD) converts a crystalline into a more soluble in water amorphous drug. Lyophilization or freeze-drying is a process in which water, an organic solvent, or a co-solvent system is frozen, followed by its removal from the sample, initially by sublimation (primary drying) and then by desorption (secondary drying). This study aimed the development and optimization of a bulk freeze-drying cycle by critical process parameters assessment in each phase to prepare a RES third-generation SD, containing Eudragit E PO as hydrophilic polymer at 1:2 ratio, and Gelucire 44/14 as surfactant at 16 % (w/w) to RES, using a tert-butanol (TBA)/Acetate buffer pH 4.5 (75:25) co-solvent system. A RES third-generation SD with good appearance, not cracked, collapsed, or melted was prepared by an optimized and robust bulk lyophilization process. A physicochemical characterization confirmed the conversion of RES to the amorphous state in the SD and formulation stability after 1 month at 40 °C/75 % RH. Increased solubility and higher dissolution rate compared with pure RES were also obtained.

Adjunctive therapy with an oral H2S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction.

Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S donor in two preclinical models of cardiometabolic HFpEF was investigated. Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H2S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8 weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols. SGLT2i treatment improved E/e' ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end-diastolic function (E/e' ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow-up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology. SGLT2i monotherapy remediated pathological complications exhibited by two well-established HFpEF models. Adjunctive H2S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow-up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.

Dehydroandrographolide ameliorates doxorubicin-mediated cardiotoxicity by regulating autophagy through the mTOR-TFEB pathway

The clinical application of doxorubicin (DOX) was limited by the serious cardiotoxicity. The traditional Chinese medicine Andrographis paniculata and its principal active component (Dehydroandrographolide, DA) have been well known for their diverse cardiovascular protective effects. However, the effects of DA on DOX-induced cardiotoxicity (DIC) were still unknown. In this study, we evaluated the effects and revealed the potential mechanisms of DA on DIC both in vivo and in vitro. The effects of DA on DIC were systematically assessed by echocardiography and histological assays. Western blot and flow cytometry were used to measure apoptosis of cardiomyocytes. Transmission electron microscopy and StubRFP-SensGFP-LC3 lentivirus were further used to assay autophagic flux. Our results showed that DA administration significantly improved cardiac function and attenuated DOX-induced cardiomyocyte apoptosis. Mechanically, DA restored autophagic flux and lysosome functions via inhibiting DOX-induced mTOR signal pathway activation and increasing the translocation of TFEB to the nucleus. However, activation of mTOR or knockdown of TFEB significantly inhibited the protective effects of DA against DIC by impacting lysosomal functions and autophagic flux. In conclusion, our results revealed that DA might be a potential cardioprotective agent against DIC.

Efficacy of Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists for Weight Loss Management in Non-Diabetic Patients.

The rising prevalence of obesity has led to a poor quality of life affecting millions worldwide. The lack of a healthy diet and exercise intervention are the major risk factors leading to obesity, as well as genetics. Obesity can lead to type 2 diabetes mellitus. However, there are many people who are obese and do not have an established diagnosis of diabetes but want to reduce their body weight to improve their quality of life. This review aims to discuss the efficacy of the diabetic pharmacologic agents, glucagon-like peptide-1 (GLP-1) receptor agonists, on body weight. The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 2020 and includes a comprehensive search strategy. The articles gathered are from the last five to 10 years. The articles are collected from distinguished databases such as PubMed, Google Scholar, ResearchGate, and Science Direct. Of the 698 studies identified based on the screening methods, 22 were assessed for eligibility and 10 studies were included in the final review. The findings of this systematic reviewprovide a bigger picture of the efficacy and safety of glucagon-like peptide receptor agonist agents. The review thoroughly discusses the risk factors for obesity and provides a treatment strategy that can be utilized in clinical practice in the future. The review concludes that glucagon-like peptideagents act as pharmacologic treatments for reduction in body weight and also serve as cardioprotective agents.

Role of GLP-1 Receptor Agonist in Diabetic Cardio-renal Disorder: Recent Updates of Clinical and Pre-clinical Evidence.

Cardiovascular complications and renal disease is the growing cause of mortality in patients with diabetes. The subversive complications of diabetes such as hyperglycemia, hyperlipidemia and insulin resistance lead to an increase in the risk of myocardial infarction (MI), stroke, heart failure (HF) as well as chronic kidney disease (CKD). Among the commercially available anti-hyperglycemic agents, incretin-based medications appear to be safe and effective in the treatment of type 2 diabetes mellitus (T2DM) and associated cardiovascular and renal disease. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to be fruitful in reducing HbA1c, blood glucose, lipid profile, and body weight in diabetic patients. Several preclinical and clinical studies revealed the safety, efficacy, and preventive advantages of GLP-1RAs against diabetes- induced cardiovascular and kidney disease. Data from cardio-renal outcome trials had highlighted that GLP-1RAs protected people with established CKD from significant cardiovascular disease, lowered the likelihood of hospitalization for heart failure (HHF), and lowered all-cause mortality. They also had a positive effect on people with end-stage renal disease (ESRD) and CKD. Beside clinical outcomes, GLP-1RAs reduced oxidative stress, inflammation, fibrosis, and improved lipid profile pre-clinically in diabetic models of cardiomyopathy and nephropathy that demonstrated the cardio-protective and reno-protective effect of GLP-1RAs. In this review, we have focused on the recent clinical and preclinical outcomes of GLP-1RAs as cardio-protective and reno-protective agents as GLP-1RAs medications have been demonstrated to be more effective in treating T2DM and diabetes-induced cardiovascular and renal disease than currently available treatments in clinics, without inducing hypoglycemia or weight gain.

A REVIEW ON THE CHEMICAL-INDUCED EXPERIMENTAL MODEL OF CARDIOTOXICITY

Drug-induced cardiotoxicity is a major concern during drug development, prompting the need for reliable experimental models to thoroughly assess potential cardioprotective drugs. The review delves into the intricacies of various models for drug-induced cardiotoxicity in experimental animals, with a specific focus on streptozotocin, isoprenaline, and antineoplastic drugs like cisplatin, doxorubicin, and 5-fluorouracil in rats and mice. Streptozotocin-induced cardiotoxicity is characterized by oxidative stress, inflammation, and mitochondrial dysfunction, resulting in myocardial damage and impaired cardiac function. Preclinical studies employing streptozotocin-induced cardiotoxicity models have revealed crucial pathways related to diabetic cardiomyopathy, aiding the evaluation of potential cardioprotective interventions. Isoprenaline, a beta-adrenergic agonist, is known for inducing acute myocardial injury resembling cardiac ischemia and heart failure in animals. Its mechanism involves overstimulation of beta-adrenergic receptors, calcium overload, oxidative stress, and apoptosis. Isoprenaline-induced models have offered insights into acute myocardial injury pathophysiology and facilitated the screening of cardioprotective agents against Myocardial Infarction (MI) and injury. Antineoplastic drugs, such as cisplatin, doxorubicin, and 5-fluorouracil, are linked to significant cardiotoxic effects, including cardiomyopathy and heart failure. Animal models have revealed dose-dependent cardiomyopathy, shedding light on underlying mechanisms like oxidative stress, Deoxyribonucleic Acid (DNA) damage, and mitochondrial dysfunction. The article aims to consolidate the current understanding of the pathophysiology and mechanisms behind drug-induced cardiac damage. Additionally, it underscores the importance of using animal models in preclinical evaluations to assess drug safety and efficacy and to develop potential cardioprotective therapies.