Cardioprotective Agent Research Articles

The molecular mechanism involved in cardioprotection by the dietary flavonoid fisetin as an agonist of PPAR-γ in a murine model of myocardial infarction

The methodology exploring the cardioprotective potential of the flavonoid Fisetin through its ability to modulate PPAR-γ was unraveled in the present study. Computational modelling through molecular docking based binding study of interactions between Fiestin and PPAR-γ revealed the potential role of Fisetin as an agonist of PPAR-γ. A murine model of cardiac ischemia-reperfusion injury was used to explore this further. Male Wistar Rats were randomly assigned to five groups. Fisetin (20 mg/kg; p. o) was administered for 28 days. Ischemia was induced for 45 min on the 29th day followed by 60 min of reperfusion. Fisetin pretreatment upregulated the expression of PPAR-γ in heart tissue significantly Cardioprotection was assessed by measurement of hemodynamic parameters, infarct size, ELISA for oxidative stress, immunohistochemistry and TUNEL assay for apoptosis, and western blot analysis for MAPK proteins and inflammation. PPAR-γ activation by fisetin led to significantly reduced infarct size, suppression of oxidative stress, reduction of cardiac injury markers, alleviation of inflammation, and inhibition of apoptosis The MAPK-based molecular mechanism showed a rise in a key prosurvival kinase, ERK1/ERK2 and suppression of JNK and p38 proteins. The aforementioned beneficial findings of fisetin were reversed on the administration of a specific antagonist of PPAR-γ. In conclusion, through our experiments, we have proved that fisetin protects the heart against ischemia-reperfusion injury and the evident cardioprotection is PPAR-γ dependant. In conclusion, our study has revealed a prime mechanism involved in the cardioprotective effects of fisetin. Hence, Fisetin may be evaluated in further clinical studies as a cardioprotective agent in patients undergoing reperfusion interventions.

Potential Cardio-Protective Agents: A Resveratrol Review (2000-2019).

With a 2030 projection of 23.6 million deaths per year, the prevalence and severity of cardiovascular disease are astoundingly high. Thus, there is a definitive need for the identification of novel compounds with the potential to prevent or treat the disease and associated states. Moreover, there is also an ever-increasing need for drug delivery systems (DDS) that cope with poor and ranging physiochemical properties of therapeutic compounds to achieve the clinical effect. The usage of resveratrol (RES) is a growing area of interest with innumerate pieces of research, evidencing the drug's efficacy. This drug is, however, marred; its notably poor physiochemical properties (namely poor water solubility) limit its use for oral drug delivery. RES analogues, however, potentially possess superior physiochemical characteristics offering a remedy for the aforementioned drawback. However, particulate based DDS are equally able to offer property amelioration and targeting. This review offers an extensive examination into the role of RES as a potential cardioprotective agent. The prevalence and suitability of associated analogues and the role of nanotechnology in overcoming physicochemical boundaries, particularly through the development of nanoparticulate formulations, will be discussed in detail.

Design, Synthesis, and Structure-Activity Relationships of Indoline-Based Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-Like 2 (Keap1-Nrf2) Protein-Protein Interaction Inhibitors.

The Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) pathway is the major defending mechanism against oxidative stresses, and directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has been an attractive strategy to target oxidative stress-related diseases, including cardiovascular diseases. Here, we describe the design, synthesis, and structure-activity relationships (SARs) of indoline-based compounds as potent Keap1-Nrf2 PPI inhibitors. Comprehensive SAR analysis and thermodynamics-guided optimization identified 19a as the most potent inhibitor in this series, with an IC50 of 22 nM in a competitive fluorescence polarization assay. Further evaluation indicated the proper drug-like properties of 19a. Compound 19a dose-dependently upregulated genes and protein level of Nrf2 as well as its downstream markers and showed protective effects against lipopolysaccharide-induced injury in both H9c2 cardiac cells and mouse models. Collectively, we reported here a novel indoline-based Keap1-Nrf2 PPI inhibitor as a potential cardioprotective agent.

The effect of trimethazidine on mortality in an experimental acute pancreatitis model1.

Acute pancreatitis has a high morbidty and mortality. Its physiopathogenesis has not been enlightened up to the present. This study aims to investigate trimetazidine (antiischemic, antioxidant and cardioprotective agent) 's effects on the acute pancreatitis. In this study, four aqual groups are formed with 43 female Spraque-dawley type rats weighed between230-300 gr (mean 265 gr). 0.9% NaCl is injected intraperitoneally after laparotomy to the Group 1 (n=6). Group 2 (n=6) is control group that without any intervention. Acute pancreatitis is formed in Group 3 (n=16) via injection of Na-taurokolat in the common bile duct. Group 4 (n=15) is being formed pancreatitis and treated with Trimetazidine. In group 4 Trimetazidine 10 mg/kg/day drugs were given, 30 minutes, 24 and 72 hours after formation of acute pancreatitis, in three equal doses by orogastric way. In all groups, the rats have been laparatomised 72 hours later under general anesthesia and pancreas tissues has been extracted and studied histopathologically. Amylase, lipase, lactate dehydrogenase, aspartate transaminase, alanine tranaminase levels in the rats serum and superoxide dismutase, catalase, glutathione, malondialdehyde, nitric oxide, protein carbonyl, glutathione peroxidase levels in the rats tissue also have been looked up. Serum and tissue findings and histopathologically examination of the pancreas tissues show significant decrease in the treatment group compare to study group. Trimetazidine protects pancreas tissue and decreases the mortality by significantly lowering the biochemical and histopathological changes in the early stages of acute pancreatitis.

Thymoquinone attenuates doxorubicin-cardiotoxicity in rats.

Contrary to the fact that doxorubicin is a powerful chemotherapeutic agent for the treatment of neoplastic diseases, cardiotoxicity is too important to be ignored. Thymoquinone serves as a powerful free radical scavenger. In the study, the effects of thymoquinone against doxorubicin-cardiotoxicity will be evaluated. Forty rats were divided into five groups. Group I: control group (n = 8); group II: olive oil group (n = 8); group III: thymoquinone group (n = 8); given 10 mg/kg thymoquinone intraperitoneally per day throughout the experiment; group IV: doxorubicin group (n = 8); injected with a single dose of 15 mg/kg ip doxorubicin on the 7th day of the experiment; group V: doxorubicin + thymoquinone group (n = 8); administered with 10 mg/kg thymoquinone per day during the experiment and 15 mg/kg doxorubicin ip on the 7th day. The experiment was planned for 14 days. Immunohistochemically, heat shock protein (HSP) 70 and HSP90, glucose-regulated protein 78 (GRP78), caspase-3 were stained. We made terminal deoxynucleotidyl transferase dUTP nick end labeling for apoptotic evaluation. Total oxidant status (TOS) levels and total antioxidant status (TAS) were measured in the heart tissue. Atrial natriuretic peptide (ANP) and pro-B type natriuretic peptide (proBNP) were evaluated. In the study, HSP70, HSP90, GRP78, and caspase-3 levels increased in group IV. TOS and TAS levels were significant compared to group I. Doxorubicin significantly increased ANP and NT-proBNP levels. Thymoquinone revealed significant differences in these values. Thymoquinone can be an important cardioprotective agent against doxorubicin-cardiotoxicity.

Characterization of astragaloside I-IV based on the separation of HPTLC from Pleurotus ostreatus cultivated with Astragalus.

In this study, total saponins were extracted from Pleurotus ostreatus cultivated with Astragalus as one of organic culture substrates. High Performance Thin Layer Chromatography (HPTLC) assay showed total saponins could be separated effectively, and four kinds of spots were identified as AG I, AG II, AG III, and AG IV, respectively. FTIR spectra based on HPTLC separation assay showed the saponin characteristic groups including -OH, C-H, C=O, and the glycoside linkaged to sapogenin group C-O-C, suggesting the four kinds of spots belonged to cycloartane-type triterpene saponins. The primary mass spectra of precursor ion (HPTLC-ESI-MS) assay further proved the main composition of four kinds of spots was AG I-IV, respectively. Physical properties, including the detection of specific rotation and melting point, revealed the separation of high-purity saponin monomer by HPTLC. HPTLC-dual wavelength spectrodensitometric method detection showed that content of astragaloside I-IV was ranged from 0.2 to 0.5mg/g, and the total astragalosides contents attained to 1.397mg/g, indicating P. ostreatus could bioaccumulate astragalosides from Astragalus. These results demonstrated the characterization of astragalosides based on the separation of HPTLC was effective, and supported to consider astragalosides-enriched P. ostreatus as functional edible fungus for food and medical applications. PRACTICAL APPLICATION: Currently, the consumption of enriched foods has become common and continues to increase due to urgent demanding for foods with high nutritional value. Pleurotus ostreatus is a functional edible fungus, which not only can produce secondary metabolites, but can enrich bioactive ingredients. Astragalosides have a wide range of biological activities, especially currently being tested as cardioprotective agent. In this study, P. ostreatus was cultivated through adding Astragalus into culture substrates, which realized massive enrichment of astragalosides. Astragalosides-enriched P. ostreatus as functional edible fungus could be extensively used in food and medical areas, especially for the prevention of cardiovascular diseases.

Association of Genetic Variants at TRPC6 With Chemotherapy-Related Heart Failure

Background: Our previous GWAS identified genetic variants at six novel loci that were associated with a decline in left ventricular ejection fraction (LVEF), p < 1 × 10−5 in 1,191 early breast cancer patients from the N9831 clinical trial of chemotherapy plus trastuzumab. In this study we sought replication of these loci.Methods: We tested the top loci from the GWAS for association with chemotherapy-related heart failure (CRHF) using 26 CRHF cases from N9831 and 984 patients from the Mayo Clinic Biobank which included CRHF cases (N = 12) and control groups of patients treated with anthracycline +/– trastuzumab without HF (N = 282) and patients with HF that were never treated with anthracycline or trastuzumab (N = 690). We further examined associated loci in the context of gene expression and rare coding variants using a TWAS approach in heart left ventricle and Sanger sequencing, respectively. Doxorubicin-induced apoptosis and cardiomyopathy was modeled in human iPSC-derived cardiomyocytes and endothelial cells and a mouse model, respectively, that were pre-treated with GsMTx-4, an inhibitor of TRPC6.Results: TRPC6 5′ flanking variant rs57242572-T was significantly more frequent in cases compared to controls, p = 0.031, and rs61918162-T showed a trend for association, p = 0.065. The rs61918162 T-allele was associated with higher TRPC6 expression in the heart left ventricle. We identified a single TRPC6 rare missense variant (rs767086724, N338S, prevalence 0.0025% in GnomAD) in one of 38 patients (2.6%) with CRHF. Pre-treatment of cardiomyocytes and endothelial cells with GsMTx4 significantly reduced doxorubicin-induced apoptosis. Similarly, mice treated with GsMTx4 had significantly improved doxorubicin-induced cardiac dysfunction.Conclusions: Genetic variants that are associated with increased TRPC6 expression in the heart and rare TRPC6 missense variants may be clinically useful as risk factors for CRHF. GsMTx-4 may be a cardioprotective agent in patients with TRPC6 risk variants. Replication of the genetic associations in larger well-characterized samples and functional studies are required.

Methyl Palmitate: the Naturally Occurring Cardioprotective Agent

Cardioprotective agents are compounds that provide heart protection and decrease cardiotoxicity incidence. Cardiotoxicity is a serious condition that results in diminishing the heart's ability to pump blood throughout the body and can be developed into heart failure. Oxidative stress is an important pathogenic event in cardiotoxicity where the generated reactive oxygen species (ROS) cause myocardial cellular destruction. Moreover, apoptosis, fibrosis, and inflammatory cascades play major roles in cardiotoxicity pathogenesis. Recently, much attention has been paid to the cardioprotective effects of natural products. Methyl palmitate (MP) is a naturally occurring methyl ester that can be also synthesized. This review article aimed to elucidate the potential cardioprotective effects of MP as well as the underlying possible mechanisms. Indeed, MP showed effective cytoprotective roles in various experimental models. In this regard, MP showed potent antioxidant activity which was proven by the decreased production of oxidative stress markers and the increased activity of the endogenous antioxidant enzymes. It also exhibited anti-inflammatory activity which was evidenced by the reduced expression of the pro-inflammatory cytokines and the elevated expression of the anti-inflammatory cytokines. Moreover, MP showed anti-apoptotic activity evidenced by the elevated anti-apoptotic protein expression and the mitigated pro-apoptotic protein expression. Besides, further studies proved the anti-fibrotic and vasodilatation activities of MP. Thus, MP could provide major cardioprotective activities through its antioxidant, anti-inflammatory, anti-apoptotic, anti-fibrotic, and vasodilatation properties.

A possible underlying mechanism behind the cardioprotective efficacy of tangeretin on isoproterenol triggered cardiotoxicity via modulating PI3K/Akt signaling pathway in a rat model.

This study was aimed to examine the possible underlying cardioprotective efficacy of tangeretin (TAN) in rats exposed to isoproterenol (ISP). Forty male SD rats were separated into four equal groups as the control group, ISP (myocardial infarction; MI group) group rats which were injected intraperitoneally (ip) with 85mg/kg of ISP. Treatment TAN groups (TAN 50 and TAN 100) rats were orally pretreated with TAN (50 or 100mg/kg) for 28days before ISP exposure. Pretreatment with TAN (50/100) significantly reduced (p<.05/0.01) the infarct size, levels of inflammatory markers, cardiac marker enzymes, apoptotic markers along with improved antioxidants. Histo-morphological results also well-supported the results of the above biochemical parameters by displaying normal myofibrillar arrangement in TAN pretreated rats. Moreover, the protein expressions of pPI3K and pAkt were considerably elevated in rats administered with TAN. Collectively, TAN pretreatment (especially TAN 100) display better cardioprotective activity against ISP-induced MI rats. PRACTICAL APPLICATIONS: Tangeretin (TAN) has been reported to exhibit an array of biological functions including cardioprotective, hepatoprotective, and renoprotective activities. However, the in-depth mechanism is still lacking, which results in this study. Our results indicate that TAN could effectively reduce cardiac infarct size, inflammatory markers, oxidative stress, apoptotic markers, by modulating (upregulating) the protein expressions of the PI3K/Akt signaling pathway. Thus, demonstrating that TAN could be a strong contender for developing a cardioprotective agent and can recommend along with conventional cardioprotective drugs for abolishing MI-related complications/symptoms. Nevertheless, further human studies are needed to confirm the above suggestion.

Nano-Encapsulation of Coenzyme Q10 in Secondary and Tertiary Nano-Emulsions for Enhanced Cardioprotection and Hepatoprotection in Human Cardiomyocytes and Hepatocytes During Exposure to Anthracyclines and Trastuzumab.

IntroductionCoenzymeQ10 (CoQ10) is a well-known antioxidant and anti-inflammatory agent with cardioprotective properties. However, clinical trials based on its oral administration have failed to provide significant effect on cardiac functionality. The main limitation of CoQ10 is based on its very low oral bioavailability and instability that limit dramatically its effects as a cardioprotective agent. Herein, we loaded CoQ10 in high bioavailable nano-emulsions (NEs) coated with chitosan or chitosan and hyaluronic acid in order to improve its performance.MethodsWe tested cardioprotective and hepatoprotective effects of CoQ10-loaded nano-carriers against Doxorubicin and Trastuzumab toxicities in cardiomyocytes and liver cells through analysis of cell viability, lipid peroxidation, expression of leukotrienes, p65/NF-kB and pro-inflammatory cytokines involved in anticancer-induced cardio and hepatotoxicity.ResultsNano-carriers showed high stability and loading ability and increased cell viability both in hepatocytes and cardiomyocytes during anticancer treatments. We observed that these effects are mediated by the inhibition of lipid peroxidation and reduction of the inflammation. CoQ10-loaded nano-emulsions showed also strong anti-inflammatory effects reducing leukotriene B4 and p65/NF-κB expression and Interleukin 1β and 6 production during anticancer treatments.DiscussionAnthracyclines and Human epidermal growth factor receptor (HER2) inhibitors have shown significant anticancer effects in clinical practice but their use is characterized by cardiotoxicity and hepatotoxicity. Nano-carriers loaded with CoQ10 showed cardio and hepatoprotective properties mediated by reduction of oxidative damages and pro-inflammatory mediators. These results set the stage for preclinical studies of cardio and hepatoprotection in HER2+ breast cancer-bearing mice treated with Doxorubicin and Trastuzumab.

Neuregulin‑1, a microvascular endothelial‑derived protein, protects against myocardial ischemia‑reperfusion injury (Review).

As regards acute myocardial infarction, great success has been achieved in therapies that reduce the effects of myocardial ischemic injury, while few interventions have achieved satisfactory outcomes for myocardial ischemia‑reperfusion (IR) injury. Thus, new research is urgently required to achieve breakthroughs in promising treatments. Neuregulin‑1 (NRG‑1), which is an endothelium‑derived protein and the ligand of ErbB receptors, exerts cardioprotective effects and is rapidly upregulated during IR. NRG‑1/ErbB activates several downstream signaling pathways in response to myocardial IR injury. Previous studies have revealed the protective effects of NRG‑1 during heart failure, and numerous experiments have explored the mechanisms underlying the NRG‑1‑induced cardioprotective effects against myocardial IR injury. In the present review, the progress made in the research of NRG‑1 as a cardioprotective agent during IR and related conditionings is summarized. Furthermore, the potential benefits of NRG‑1 against myocardial IR injury are listed with the prospective use of NRG‑1 in clinical applications.

Hydrogen sulfide alleviates oxidative stress injury and reduces apoptosis induced by MPP+ in Parkinson’s disease cell model

Hydrogen sulfide (H2S), an endogenously produced gas, is a cardioprotective agent against neurotoxin-induced neurodegeneration in Parkinson's disease (PD). However, the roles of H2S in 1-methyl-4-phenylpyridinium ion (MPP+)-treated SH-SY5Y cells with the involvement of reactive oxygen species-nitric oxide (ROS-NO) signaling pathway in PD remain unclear. For this study, a MPP+-treated SH-SY5Y cell model was established to explore the regulatory role of H2S in oxidative stress injury and cell apoptosis. With the cell viability, apoptosis, cytotoxicity, levels of reactive oxygen species (ROS) and nitric oxide (NO), mitochondrial transmembrane potential (Δψm), contents of oxidative stress injury-related markers (glutathione, superoxide dismutase, malondialdehyde), levels of apoptosis-related proteins (Caspase 3, Bax, Bcl-2) and inducible nitric oxide synthase (iNOS) determined, this study demonstrated that NaHS (an H2S donor) treatment could alleviated the reduction of cell viability and cytotoxicity, cell apoptosis, Δψm loss, contents of ROS and NO, and oxidative stress injury induced by MPP+. The present study showed that H2S may protect SH-SY5Y cells from MPP+-induced injury in PD cell model via the inhibition of ROS-NO signaling pathway and provide insight into the potential of H2S for PD therapy.

The Role of Estrogen Receptors in Cardiovascular Disease.

Cardiovascular Diseases (CVDs) are the leading cause of death globally. More than 17 million people die worldwide from CVD per year. There is considerable evidence suggesting that estrogen modulates cardiovascular physiology and function in both health and disease, and that it could potentially serve as a cardioprotective agent. The effects of estrogen on cardiovascular function are mediated by nuclear and membrane estrogen receptors (ERs), including estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G-protein-coupled ER (GPR30 or GPER). Receptor binding in turn confers pleiotropic effects through both genomic and non-genomic signaling to maintain cardiovascular homeostasis. Each ER has been implicated in multiple pre-clinical cardiovascular disease models. This review will discuss current reports on the underlying molecular mechanisms of the ERs in regulating vascular pathology, with a special emphasis on hypertension, pulmonary hypertension, and atherosclerosis, as well as in regulating cardiac pathology, with a particular emphasis on ischemia/reperfusion injury, heart failure with reduced ejection fraction, and heart failure with preserved ejection fraction.

Investigation on protective effect of Terminalia bellirica (Roxb.) against drugs induced cardiotoxicity in wistar albino rats

Ethnopharmacological relevanceVarious traditional texts like Ayurveda and Materia Medica profoundly mentioned the ethnopharmacological use of Terminalia bellirica fruit for its protective effect on heart and various other vital organs. Hence the present research was focussed to scientifically prove the effect of T. bellirica in support of its traditionally claimed use as cardioprotective agent. Aim the studyThe aim and objective of the present study was to investigate the protective effect of T. bellirica (Roxb.) against drugs viz. Doxorubicin (DOX) and Isoproterenol (ISO) induced cardiotoxicity in wistar albino rats. Material and methodsCardiotoxicity was induced using DOX (15 mg/kg, i.p.) and ISO (85 mg/kg s.c.) models. Methanolic extract of T. bellirica (METB) was subjected to rats in two different doses (low dose of 250 mg/kg p.o.; and high dose of 500 mg/kg p.o.) for the purpose of investigation of various biochemical markers present in cardiac tissue as well as in blood serum, in order to assess the improvement in drugs induced cardiotoxicity. Also, the histopathological study was carried out in terms of ultrastructural changes occurred in the myocardium during drugs induced cardiomyopathy, to ensure the proposed cardioprotective effect of METB. ResultBiochemical investigation of cardiac tissue using METB showed significant decrease in CK-MB (creatine kinase-muscle/brain) activity and MDA (malondialdehyde) levels and increase in GSH (reduced glutathione) levels. It also increased the activity of SOD (superoxide dismutase) and CAT (catalase). In serum, METB increased the levels of oxidative stress markers like ALP (alkaline phosphatase), UA (uric acid), ALT (alanine transferase), and AST (aspartate transaminase) near to their normal values as in control group. The use of METB also decreased the levels of total cholesterol and TGs (triglycerides) in serum and significantly increased HDL (high density lipoprotein) levels. Treatment with METB also proved a considerable restoration in histopathological findings of myocardium. ConclusionIn the present study it was concluded that T. bellirica fruit has profound potential for the treatment of drugs induced cardiotoxicity suggesting the consumption of T. bellirica for cardiac benefits during routine treatment of cardiotoxicity.

Role of sodium tetraborate as a cardioprotective or competitive agent: Modulation of hypertrophic intracellular signals

Boron is an essential trace element in cellular metabolism; however, the molecular mechanism of boron in the heart is unclear. In this study, we examined the effect of sodium tetraborate (as boron source) as a possible protective agent or competitive inhibitor of cardiac hypertrophy in an in vitro murine model.We evaluated different previously reported sodium tetraborate concentrations and it was found that 13 μM improves viability without affecting the cellular structure.We demonstrated that cardiomyocytes pretreated with sodium tetraborate prevents cellular damage induced by isoproterenol (cardioprotective effect) by increasing proliferation rate and inhibiting apoptosis. In addition, the reduction of the expression of the α1AR and β1AR adrenergic receptors as well as Erk1/2 was notable. Consequently, the expression of the early response genes c-myc, c-fos and c-jun was delayed. Also, the expression of GATA-4, NFAT, NKx2.5 and myogenin transcription factors involved in sarcomere synthesis declined. In contrast, cardiomyocytes, when treated simultaneously with sodium tetraborate and isoproterenol, did not increase their size (cytoplasmic gain), but an increase in apoptosis levels was observed; therefore, the proliferation rate was reduced. Although the mRNA levels of α1AR and β1AR as well as Erk1/2 and Akt1 were low at 24 h, their expression increased to 48 h. Notably, the mRNA of expression levels of c-myc, c-fos and c-jun were lower than those determined in the control, while the transcription factors GATA-4, MEF2c, Nkx2.5, NFAT and CDk9 were determined in most cells.These results suggest that pretreatment with sodium tetraborate in cardiomyocytes inhibits the hypertrophic effect. However, sodium tetraborate attenuates isoproterenol induced hypertrophy damage in cardiomyocytes when these two compounds are added simultaneously.

P1588CAN L-CARNITINE SUPPLEMENTATION IMPROVE CARDIOPULMONARY FUNCTION? A RANDOMIZED CONTROLLED TRIAL IN HEMODIALYSIS PATIENTS

Abstract Background and Aims It is well known that L-Carnitine is a cardioprotective agent, which balances cardiac energy metabolism, by promoting mitochondrial β-oxidation and facilitating transport of long chain fatty acids into the mitochondrial matrix. It has been shown that L-Carnitine level in plasma and tissue is lower in hemodialysis patients and they may lose the benefits of this substance. As far as our knowledge, the effect of L-Carnitine on cardiopulmonary function has not been evaluated by ergospirometry up to now. The aim of this randomized clinical trial was to assess the effects of L-carnitine supplementation on cardiopulmonary Function in hemodialysis patients through ergospirometry. Method This randomized clinical trial was conducted on 46 chronic hemodialysis patients. The patients were divided into two groups. In both groups ergospirometry parameters (VE Max, VO2-Max, VCO2 Max, AT, VE/VCO2 Slope) were recorded for a 3-month period. During this period, one group received L-Carnitine at doses of 2 gr/day orally and the other group received only placebo. After three months, all of the mentioned parameters were rechecked and statistical analysis performed by SPSS software. Results Only CRP was different between the two groups increasing in placebo group significantly after 3 months (P = 0.018). No significant difference was detected in Cardiopulmonary factors. In terms of ergospirometry factors, PET-CO2 was the only parameter significantly increased in the treatment group (P = 0.026). Conclusion The present results indicate that L-Carnitine can improve cardiopulmonary function among hemodialysis patients.

Ex vivo and in vivo studies of Viola tricolor Linn. as potential cardio protective and hypotensive agent: Inhibition of voltage-gated Ca++ ion channels.

Viola tricolor Linn. is used as cardio-protective and anti-hypertensive agent in traditional medicine. Current study objective was to evaluate cardio-protective and hypotensive effects of Viola tricolor L. in vitro and in vivo studies. Viola tricolor L. crude extract (Vt.Cr) and its fractions (Aqueous and organic) were tested at rabbit atria and aorta coupled to Power Lab Data Acquisition System for cardio depressant and vasorelaxant effects in vitro whereas in vivo Blood Pressure was checked by invasive method in normotensive ketamine-diazepam anesthetized rats. Isoproterenol was employed for acute myocardial infarction (AMI) and left ventricular hypertrophy (LVH) development and cardioprotective effects of Vt.Cr were evaluated hemodynamically and histopathologically. Vt.Cr and its fractions decreased heart rate and contractile force in paired atria and relaxed Phenylephrine (1µM) and K+ (80mM) stimulated contractions in aorta possibly mediated through Voltage dependent L-type calcium channels blockage supported by in vivo hypotensive action. In LVH, Vt.Cr lowered Angiotensin Converting Enzymes and renin, increased cyclic Guanosine Monophosphate and nitric oxide levels, decreased cardiomyocytes size and fibrosis attributed to Gallic acid as detected by High Performance Liquid Chromatography. Partial positive results were seen hemodynamically and histologically in AMI Viola tricolor L. showed vasorelaxant, cardio-relaxant, hypotensive, and cardio protective effect validating traditional practice in cardiovascular disorders.

Unravelling the Biology of Adult Cardiac Stem Cell-Derived Exosomes to Foster Endogenous Cardiac Regeneration and Repair.

Cardiac remuscularization has been the stated goal of the field of regenerative cardiology since its inception. Along with the refreshment of lost and dysfunctional cardiac muscle cells, the field of cell therapy has expanded in scope encompassing also the potential of the injected cells as cardioprotective and cardio-reparative agents for cardiovascular diseases. The latter has been the result of the findings that cell therapies so far tested in clinical trials exert their beneficial effects through paracrine mechanisms acting on the endogenous myocardial reparative/regenerative potential. The endogenous regenerative potential of the adult heart is still highly debated. While it has been widely accepted that adult cardiomyocytes (CMs) are renewed throughout life either in response to wear and tear and after injury, the rate and origin of this phenomenon are yet to be clarified. The adult heart harbors resident cardiac/stem progenitor cells (CSCs/CPCs), whose discovery and characterization were initially sufficient to explain CM renewal in response to physiological and pathological stresses, when also considering that adult CMs are terminally differentiated cells. The role of CSCs in CM formation in the adult heart has been however questioned by some recent genetic fate map studies, which have been proved to have serious limitations. Nevertheless, uncontested evidence shows that clonal CSCs are effective transplantable regenerative agents either for their direct myogenic differentiation and for their paracrine effects in the allogeneic setting. In particular, the paracrine potential of CSCs has been the focus of the recent investigation, whereby CSC-derived exosomes appear to harbor relevant regenerative and reparative signals underlying the beneficial effects of CSC transplantation. This review focuses on recent advances in our knowledge about the biological role of exosomes in heart tissue homeostasis and repair with the idea to use them as tools for new therapeutic biotechnologies for “cell-less” effective cardiac regeneration approaches.

The role of cardio-protective agents in cardio-preservation in breast cancer patients receiving Anthracyclines ± Trastuzumab: a Meta-analysis of clinical studies.

Breast cancer patients often receive cardiotoxic drugs such as anthracyclines (ANT) and Trastuzumab. Numerous trials have tested angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and beta-blockers (BB) as monotherapy or in combination to reprogram cardiac function dynamics in these patients, but no clear conclusions have been reached thus far, due to evident heterogeneity in the design of clinical studies. This PRISMA-guided systematic review and meta-analysis assessed a pooled effect estimate of the potential benefit/harm of ACEi/ARB/BB in breast cancer patients treated with ANT ± Trastuzumab. The protocol was registered on the PROSPERO database. Electronic databases (PubMed, Cochrane Central, Scopus, Web of Science) were searched from inception until February 2019. Twenty-two prospective studies comprising of 2,302 participants were included in the meta-analysis. The 16 studies testing the protective effects of ACEi/ARB/BB after immediate completion of chemotherapy showed a significant lower difference in the mean change of left ventricular ejection fraction (LVEF) in patiens receiving cardio-protective drugs as compared to controls, with a standardized mean difference [SMD = -2.36 (95% CI: -3.23 to -1.49), p < 0.00001] favoring the protective role of these drugs. LVEF was evaluated after 6 months after completion of chemotherapy in 3 studies, where ACEi/ARB/BB persistently showed cardio-protective effects as compared to controls [SMD = -6.54 (95% CI: -10.74 to -2.34), p = 0.002]. After 1 year from completion of chemotherapy, ACEi/ARB/BB preserved beneficial effects on LVEF vs control [SMD = -5.37 (95% CI: -9.31 to -1.43), p = 0.008]. The effect of ACEi/ARB/BB on end-systolic volume (ESV) and end-diastolic volume (EDV) were evaluated immediately after chemotherapy completion and after 1 year. No significant protective effect was apparent. On the other hand, end-diastolic diameter (EDD) was significantly spared in the ACEi/ARB/BB group vs control after chemotherapy completion [SMD = -1.11 (95% CI: -1.88 to -0.35), p = 0.004]. Heart failure as a clinical endpoint was assessed in 11 trials. The incidence of heart failure was significantly lower in the ACEi/ARB/BB group as compared to control [Odds ratio = 0.12 (95% CI: 0.03 to 0.45), p = 0.002]. ACEi/ARB/BB may act as cardioprotective agents in breast cancer patients who undergo ANT ± Trastuzumab. More studies are required to better assess the magnitude of the cardiotoxicity hazards of ANT ± Trastuzumab, with more precise assessment of the effect of ACEi/ARB/BB on cardio-protection.

Design and synthesis of novel SCM-198 analogs as cardioprotective agents: Structure-activity relationship studies and biological evaluations

SCM-198 (Leonurine) has attracted great attention due to its cardioprotective effects in myocardial infarction (MI). However, no systematic modifications and structure-activity relationship (SAR) studies could be traced so far. In this study, 35 analogs of SCM-198 were designed, synthesized and their cardioprotective effects were evaluated. The cell viability assay on cardiomyocyte cell line H9c2 challenged with H2O2 showed that several analogs exhibited more potent cytoprotective effects than SCM-198 at 1 μM and 10 μM concentrations. LDH release level in cells treated with 1 μM 14o was comparable with cells treated with 10 μM SCM-198. Results of Bcl-2 expression and caspase-3 activation accordingly indicated higher protective activity of 14o than SCM-198. Moreover, in a mouse model of MI, the mice pretreated with 14o had much lower infarct size compared with that of SCM-198. The mechanism study suggested that 14o improved cardiac morphology and reduced apoptosis of cardiomyocytes in the border zone of infarction, as proved by H&E and TUNEL staining.