Cardioprotective Molecules Research Articles

Management of Hypertension in Patients with Type 2 Diabetes Mellitus: Indian Guideline 2024 by Association of Physicians of India and Indian College of Physicians.

In India and the Southeast Asian population, hypertension and type 2 diabetes mellitus (T2DM) are the leading lifestyle-related diseases, responsible for a majority burden of morbidity and mortality. Multiple population-spanning studies have revealed the staggering prevalence of both diseases in India, and the prevalence of both will only increase further due to factors such as an aging population, rapid urbanization, increased obesity, and sedentary lifestyles. More than 50 percent of hypertensive patients in India are also diagnosed with T2DM, and a detailed management protocol for the same is required, especially when a major portion of the disease is managed at the primary care level. The Association of Physicians of India (API) guidelines for the management of hypertension in patients with T2DM have been formulated based on consultation with leading physicians, cardiologists, diabetologists, and endocrinologists of India and Southeast Asia, keeping in mind the challenges faced by the patients in these countries and the appropriate management protocols that will be beneficial. While standard office-based blood pressure (BP) measurement forms the cornerstone of hypertension diagnosis and demands a uniform methodology to be followed, home blood pressure monitoring (HBPM) is recommended for long-term follow-up with validated devices. Ambulatory blood pressure monitoring (ABPM) offers comprehensive insights crucial for cardiovascular (CV) risk stratification. The complications of diabetic hypertension can span from increased CV risk, heart failure (HF), and renal dysfunction, and nonpharmacological and pharmacological management should be aimed toward not only control of the BP values but also protecting the end organs. While nonpharmacological measures include a focus on nutrition and diet, they also focus on approaches to weight loss, including a novel section covering the benefits of yoga. The guideline also focuses on a novel section of factors influencing CV risk, especially in the Indian population. For the pharmacological management, the guidelines address each of the categories of antihypertensive drugs, emphasizing the significance of combination therapies in the management of diabetic hypertension. In line with leading global guidelines for the management of hypertension in T2DM, for diabetic patients who often struggle with BP management and carry a high CV risk, the recommended dual combination antihypertensive therapy is particularly crucial and should be considered as first-line management therapy. While angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) play a highly beneficial role in the management of diabetic hypertension, a combination of ACEi or ARB with dihydropyridine calcium channel blockers (DHP-CCBs) is recommended to reduce the risk of complications and enhance patient adherence. To achieve the target of effective BP control and end-organ protection, it is beneficial and recommended to include newer CCBs (e.g., cilnidipine) in the management protocol in combination with ACEi/ARBs. Combination therapy including ARBs and DHP-CCBs should be preferred over β-blockers and thiazides. Among the CCBs, cilnidipine, a novel molecule, is a more effective and safer option for diabetic hypertensive patients in India. β-blockers should be used if there is a history of myocardial infarction (MI), HF, coronary artery disease (CAD), or stable angina along with the initial hypertensive regimen. The guideline also focuses on the novel reno- and cardioprotective molecules such as finerenone and sodium-glucose cotransporter 2 inhibitors (SGLT2i) and their benefits in the management of diabetic hypertension.

Donor Heart Preservation: Current Knowledge and the New Era of Machine Perfusion

Heart transplantation remains the conventional treatment in end-stage heart failure, with static cold storage (SCS) being the standard technique used for donor preservation. Nevertheless, prolonged cold ischemic storage is associated with the increased risk of early graft dysfunction attributed to residual ischemia, reperfusion, and rewarming damage. In addition, the demand for the use of marginal grafts requires the development of new methods for organ preservation and repair. In this review, we focus on current knowledge and novel methods of donor preservation in heart transplantation. Hypothermic or normothermic machine perfusion may be a promising novel method of donor preservation based on the administration of cardioprotective agents. Machine perfusion seems to be comparable to cold cardioplegia regarding donor preservation and allows potential repair treatments to be employed and the assessment of graft function before implantation. It is also a promising platform for using marginal organs and increasing donor pool. New pharmacological cardiac repair treatments, as well as cardioprotective interventions have emerged and could allow for the optimization of this modality, making it more practical and cost-effective for the real world of transplantation. Recently, the use of triiodothyronine during normothermic perfusion has shown a favorable profile on cardiac function and microvascular dysfunction, likely by suppressing pro-apoptotic signaling and increasing the expression of cardioprotective molecules.

Antidiabetic Molecule Efficacy in Patients with Type 2 Diabetes Mellitus-A Real-Life Clinical Practice Study.

In this paper, we aim to evaluate the efficacy of antidiabetic cardioprotective molecules such as Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) and Glucagon-like Peptide 1 Receptor Agonists (GLP-1 RAs) when used with other glucose-lowering drugs, lipid-lowering, and blood pressure (BP)-lowering drugs in a real-life setting. A retrospective, observational study on 477 patients admitted consecutively in 2019 to the outpatient clinic of a tertiary care unit for Diabetes Mellitus was conducted. Body mass index (BMI), blood pressure (BP) (both systolic and diastolic), and metabolic parameters, as well as A1c hemoglobin, fasting glycaemia and lipid profile, including total cholesterol (C), HDL-C, LDL-C and triglycerides), were evaluated at baseline and two follow-up visits were scheduled (6 months and 12 months) in order to assess the antidiabetic medication efficacy. Both SGLT-2i and GLP-1 RAs were efficient in terms of weight control reflected by BMI; metabolic control suggested by fasting glycaemia and A1c; and the diastolic component of BP control when comparing the data from the 6 and 12-month visits to the baseline, and when comparing the 12-month visit to the 6-month visit. Moreover, when comparing SGLT-2i and GLP-1 RAs with metformin, there are efficacy data for SGLT-2i at baseline in terms of BMI, fasting glycaemia, and HbA1c. In this retrospective study, both classes of cardioprotective molecules, when used in conjunction with other glucose-lowering, antihypertensive, and lipid-lowering medications, appeared to be efficient in a real-life setting for the management of T2DM.

Estrogen downregulates CD73/adenosine axis hyperactivity via adaptive modulation PI3K/Akt signaling to prevent myocarditis and arrhythmias during chronic catecholamines stress

BackgroundDuring myocardial damage, the sex hormone estrogen and CD73, the main enzyme that converts AMP into adenosine, are cardioprotective molecules. However, it is unclear how these two molecules work together to provide cardioprotection. The current study aimed to elucidate the interaction between estrogen and CD73 under chronic stress.MethodsOvariectomy and SHAM operations were done on FVB wild-type (WT) female mice. Two weeks after the operation, the mice were treated with daily isoproterenol (10 mg/kg/day) injections for 14 days. The effect of E2 on relevant cardiac injury biomarkers (BNP, ANP), myocardial morphology (cardiomyocyte surface area), electrocardiography, CD73 protein expression and activity, and macrophage (CD86 + and CD206 +) infiltrations were assessed. In vitro, H9C2 cells were treated with 1 nM of estrogen and 10 mM APCP (CD73 inhibitor α, β-methylene adenosine-5'-diphosphate), 10 µM isoproterenol and 20 µm LY294002 (PI3K inhibitor) for 24 h and western blot was done to elucidate the mechanism behind the effect of estrogen on the CD73/adenosine axis.ResultsEstrogen deficiency during chronic catecholamine stress caused myocardial injury, thereby triggering the hyperactivity of the CD73/adenosine axis, which aggravated myocarditis, adverse remodeling, and arrhythmias. However, estrogen normalizes CD73/Adenosine axis via the upregulation of PI3K/Akt pathways to prevent adverse outcomes during stress. In vivo results showed that the inhibition of PI3K significantly decreased PI3K/Akt pathways while upregulating the CD73/adenosine axis and apoptosis.ConclusionEstrogen’s pleiotropy cardioprotection mechanism during stress includes its normalization of the CD73/Adenosine axis via the PI3K/Akt pathway.9z1eijmQFGaVTY6LcoepL6Video

A Comprehensive Review of the Pleiotropic Effects of Ticagrelor.

This review summarizes the findings of preclinical studies evaluating the pleiotropic effects of ticagrelor. These include attenuation of ischemia-reperfusion injury (IRI), inflammation, adverse cardiac remodeling, and atherosclerosis. In doing so, it aims to provide novel insights into ticagrelor's mechanisms and benefits over other P2Y12 inhibitors. It also generates viable hypotheses for the results of seminal clinical trials assessing ticagrelor use in acute and chronic coronary syndromes. A comprehensive review of the preclinical literature demonstrates that ticagrelor protects against IRI in the setting of both an acute myocardial infarction (MI), and when MI occurs while on chronic treatment. Maintenance therapy with ticagrelor also likely mitigates adverse inflammation, cardiac remodeling, and atherosclerosis, while improving stem cell recruitment. These effects are probably mediated by ticagrelor's ability to increase local interstitial adenosine levels which activate downstream cardio-protective molecules. Attenuation and augmentation of these pleiotropic effects by high-dose aspirin and caffeine, and statins respectively may help explain variable outcomes in PLATO and subsequent randomized controlled trials (RCTs). Most RCTs and meta-analyses have not evaluated the pleiotropic effects of ticagrelor. We need further studies comparing cardiovascular outcomes in patients treated with ticagrelor versus other P2Y12 inhibitors that are mindful of the unique pleiotropic advantages afforded by ticagrelor, as well as possible interactions with other therapies (e.g., aspirin, statins, caffeine).

Phenotypic screen with deep learning finds cardioprotective molecules.

Phenotypic screen with deep learning finds cardioprotective molecules.

Identification of metabolic pathways underlying FGF1 and CHIR99021-mediated cardioprotection

SummaryAcute myocardial infarction is a leading cause of death worldwide. We have previously identified two cardioprotective molecules — FGF1 and CHIR99021— that confer cardioprotection in mouse and pig models of acute myocardial infarction. Here, we aimed to determine if improved myocardial metabolism contributes to this cardioprotection. Nanofibers loaded with FGF1 and CHIR99021 were intramyocardially injected to ischemic myocardium of adult mice immediately following surgically induced myocardial infarction. Animals were euthanized 3 and 7 days later. Our data suggested that FGF1/CHIR99021 nanofibers enhanced the heart’s capacity to utilize glycolysis as an energy source and reduced the accumulation of branched-chain amino acids in ischemic myocardium. The impact of FGF1/CHIR99021 on metabolism was more obvious in the first three days post myocardial infarction. Taken together, these findings suggest that FGF1/CHIR99021 protects the heart against ischemic injury via improving myocardial metabolism which may be exploited for treatment of acute myocardial infarction in humans.

AAV9-mediated functional screening for cardioprotective cytokines in Coxsackievirus-B3-induced myocarditis

Viral myocarditis (VM) is an important cause of heart failure (HF) in children and adults. However, the molecular determinants involved in cardiac inflammation and cardiomyocyte necrosis remain poorly characterized, and cardioprotective molecules are currently missing. Here, we applied an in vivo method based on the functional selection (FunSel) of cardioprotective factors using AAV vectors for the unbiased identification of novel immunomodulatory molecules in a Coxsackievirus B3 (CVB3)-induced myocarditis mouse model. Two consecutive rounds of in vivo FunSel using an expression library of 60 cytokines were sufficient to identify five cardioprotective factors (IL9, IL3, IL4, IL13, IL15). The screening also revealed three cytokines (IL18, IL17b, and CCL11) that were counter-selected and likely to exert a detrimental effect. The pooled overexpression of the five most enriched cytokines using AAV9 vectors decreased inflammation and reduced cardiac dilatation, persisting at 1 month after treatment. Individual overexpression of IL9, the top ranking in our functional selection, markedly reduced cardiac inflammation and injury, concomitant with an increase of anti-inflammatory Th2-cells and a reduction of pro-inflammatory Th17- and Th22-cells at 14 days post-infection. AAV9-mediated FunSel cardiac screening identified IL9 and other four cytokines (IL3, IL4, IL13, and IL15) as cardioprotective factors in CVB3-induced VM in mice.

Pharmacological assessment of zebrafish-based cardiotoxicity models

Cardiotoxicity remains the most common reason for failure during drug development. Recently, the zebrafish (Danio rerio) model has emerged for the evaluation of drug-dependent cardiotoxicity and for the identification of cardioprotective molecules. However, it remains unknown how closely the zebrafish-based results may be translated to humans. To tackle this issue, we established embryonic zebrafish models of doxorubicin-, adrenaline- and terfenadine-induced cardiotoxicity with unified dosing regimen which eventually enabled head-to-head comparison of the drugs. Subsequently, we determined whether human cardioprotective medications – dexrazoxane, metoprolol, carvedilol and valsartan – are able to manage heart dysfunction in zebrafish. Our results indicated that doxorubicin, adrenaline and terfenadine elicited overt signs of cardiotoxicity in fish, and we further showed that the blockade of the renin-angiotensin system and, to a lesser extent, β-adrenergic system, ameliorated the heart disease in zebrafish. From the drug development standpoint, our work opens the possibility to determine the cardiovascular properties of tested compounds using the rapid and affordable zebrafish model.

Abstract 10526: Surface Located Adiponectin On Adipocytes-derived Exosomes Mediates Adipocytes/cardiomyocytes Communication And Contributes To Cardioprotection

Introduction and Hypothesis: Increasing evidence emphasizes the roles of adipocyte-cardiomyocyte (ADp-CM) communication plays in health and diabetes. We recently reported that diabetes switched ADp-derived Exosomes (ADp-Exo) from carrying cardioprotective molecules to delivering cardiotoxic molecules to CM. However, the molecular mechanisms mediating ADp-Exo cardioprotection and its alteration by diabetes remain unknown. Methods and Results: ADp-Exo was isolated from epididymal white adipocytes of WT mice. Western Blot demonstrated high level of adiponectin (APN), a potent cardioprotective adipokine, present in ADp-Exo. More interestingly, APN was detected on the surface of ADp-Exo by flow cytometry using Exo-flow kit (System Biosciences). To determine whether surface-located APN on ADp-Exo protect heart, WT ADp-Exo were intramyocardially injected. Mice were subjected to 90 minutes coronary occlusion, followed by 4 weeks of reperfusion. Cardiac function was evaluated by echocardiograph weekly. WT ADp-Exo significantly reduced MI/R injury in vivo , as evidenced by improved LVEF, radial and longitudinal myocardial Strain and SR (vs vehicle group, p<0.05). Importantly, pre-incubation of ADp-Exo with an APN neutralization antibody blocked ADp-Exo cardioprotection. To determine the role of CM AdipoR1, ex vivo and in vitro experiments were performed. WT ADp-Exo activated AdipoR1 pathway (increased phosphorylation of ACC, ERK and AMPK) in CM and protected against cell injury and death (MTT and LDH assay). However, surface APN blocked WT ADp-Exo or APN -/- ADp-Exo failed to active this signaling and protection. WT ADp-Exo failed to activate cell salvage kinases in AdipoR1 -/- CM. Finally, overexpression of GRK2, a pathogenic molecule that we reported to cause AdipoR1 S205 phosphorylation, blocked WT ADp-Exo cardioprotection. AAV9-mediated overexpression of a phosphorylation resistant AdipoR1 (AdipoR1 S205A ) restored ADp-Exo protective action. Conclusions: We demonstrate for the first time that ADp-Exo surface located APN mediates ADp-CM communication via CM AdipoR1 pathway, promoting cardioprotection. This protective system is blocked by GRK2-induced AdipoR1 phosphorylation in diabetic heart, promoting MI/R injury.

Excess ischemic tachyarrhythmias trigger protection against myocardial infarction in hypertensive rats.

Increased level of C-reactive protein (CRP) is a risk factor for cardiovascular diseases, including myocardial infarction and hypertension. Here, we analyzed the effects of CRP overexpression on cardiac susceptibility to ischemia/reperfusion (I/R) injury in adult spontaneously hypertensive rats (SHR) expressing human CRP transgene (SHR-CRP). Using an in vivo model of coronary artery occlusion, we found that transgenic expression of CRP predisposed SHR-CRP to repeated and prolonged ventricular tachyarrhythmias. Excessive ischemic arrhythmias in SHR-CRP led to a significant reduction in infarct size (IS) compared with SHR. The proarrhythmic phenotype in SHR-CRP was associated with altered heart and plasma eicosanoids, myocardial composition of fatty acids (FAs) in phospholipids, and autonomic nervous system imbalance before ischemia. To explain unexpected IS-limiting effect in SHR-CRP, we performed metabolomic analysis of plasma before and after ischemia. We also determined cardiac ischemic tolerance in hearts subjected to remote ischemic perconditioning (RIPer) and in hearts ex vivo. Acute ischemia in SHR-CRP markedly increased plasma levels of multiple potent cardioprotective molecules that could reduce IS at reperfusion. RIPer provided IS-limiting effect in SHR that was comparable with myocardial infarction observed in naïve SHR-CRP. In hearts ex vivo, IS did not differ between the strains, suggesting that extra-cardiac factors play a crucial role in protection. Our study shows that transgenic expression of human CRP predisposes SHR-CRP to excess ischemic ventricular tachyarrhythmias associated with a drop of pump function that triggers myocardial salvage against lethal I/R injury likely mediated by protective substances released to blood from hypoxic organs and tissue at reperfusion.

Cytotoxic and inflammatory effects induced by secretome from epicardial adipose tissue of diabetic patients in human cardiomyocytes are partly reverted by HDL and APOJ

Background and Aims: Diabetic patients have high incidence of cardiovascular disease, which is associated with increased volume and functional alterations of epicardial adipose tissue (EAT). We aimed to study the inflammatory and cytotoxic effects induced by EAT from diabetic patients on cardiomyocytes, and the counteracting effect of two cardioprotective molecules: HDL and apolipoprotein J (apoJ).

Cardiac Exosomes in Ischemic Heart Disease- A Narrative Review.

Ischemic heart disease (IHD) is the primary cause of death globally. IHD is associated with the disruption of blood supply to the heart muscles, which often results in myocardial infarction (MI) that further may progress to heart failure (HF). Exosomes are a subgroup of extracellular vesicles that can be secreted by virtually all types of cells, including cardiomyocytes, cardiac fibroblasts, endothelial cells, and stem and progenitor cells. Exosomes represent an important means of cell–cell communication through the transport of proteins, coding and non-coding RNA, and other bioactive molecules. Several studies show that exosomes play an important role in the progression of IHD, including endothelial dysfunction, the development of arterial atherosclerosis, ischemic reperfusion injury, and HF development. Recently, promising data have been shown that designates exosomes as carriers of cardioprotective molecules that enhance the survival of recipient cells undergoing ischemia. In this review, we summarize the functional involvement of exosomes regarding IHD. We also highlight the cardioprotective effects of native and bioengineered exosomes to IHD, as well as the possibility of using exosomes as natural biomarkers of cardiovascular diseases. Lastly, we discuss the opportunities and challenges that need to be addressed before exosomes can be used in clinical applications.

The Predictive Value of 2D Myocardial Strain for Epirubicin-Induced Cardiotoxicity.

Introduction Although epirubicin has significantly improved outcome in breast cancer (BC) patients, it is responsible for myocardial dysfunction that affects patients' quality of life. The use of 2D global longitudinal strain (GLS) has been reported to detect early myocardial dysfunction. The aim of this study was to evaluate how GLS changes can predict cardiotoxicity. Methods We conducted a prospective study from March 2018 to March 2020 on 66 patients with no cardiovascular risk factors, who presented with BC and received epirubicin. We measured left ventricular ejection fraction (LVEF) and GLS before chemotherapy, at three months (T3), and at 12 months (T12) from the last epirubicin infusion. Chemotherapy-Related-Cardiac-Dysfunction (CTRCD) was defined as a decrease of 10% in LVEF to a value below 53% according to ASE and EACI 2014 expert consensus. Results The mean age at diagnosis was 47 ± 9 years old. At baseline, median LVEF was 70% and median GLS was −21%. Shortly after chemotherapy completion, two patients presented with symptomatic heart failure while asymptomatic CTRCD was revealed in three other patients at T12. Three months after the last epirubicin infusion, median LVEF was 65%, median GLS was −19%, and median GLS variation was 5%. However, in patients who presented with subsequent CTRCD, median GLS at T3 was −16% and median GLS variation was 19% (p=0.002 and p < 0.001, respectively, when compared to patients who did not develop cardiotoxicity). Persistent GLS decrease at T3 was an independent predictor of CTRCD at T12. Age and left-sided thoracic irradiation did not increase the risk of cardiotoxicity in our study while the cumulative dose of epirubicin significantly affected cardiologic findings (p=0.001). Conclusion This was the first North African study that assesses the value of measuring GLS to early detect cardiotoxicity. Patients whose GLS remained decreased after 3 months from anthracyclines-base chemotherapy had an increased risk for developing subsequent CTRCD. Further studies with larger sample size are warranted to identify the best cardioprotective molecules to be initiated in these patients before LVEF declines.

Identification of novel cardioprotective molecules for anti-cancer combination therapy

Do an improvement in cancer treatments, cancer survivors can develop treatment-related cardiotoxicity. The aim of this project is to identify new compounds able to protect the cardiomyocytes from cell death to avoid cardiotoxicity. A screening of 1.600 compounds (Prestwick and CEA Saclay libraries) was performed to identify potential cardioprotective compounds by methylene-blue cell survival assay. For this, a necrosis model induced by H 2 O 2 and an apoptosis model induced by camptothecin were developped. The screening allowed us to identify 21 molecules able to increase cell survival (> average + 3 standard deviation (SD)). Then, these molecules were validated as cardioprotective using permeability membrane tests: lactate deshydrogenasse (LDH) colorimetric assay and Propidium Iodid fluorescence assay. Mechanisms involved in the cardioprotective effect of the identified molecules are being investigated. Western-blots were performed in order to verify our hypothesis for autophagy activation. We showed that some of the 21 compounds tested increased LC3-II, a protein marker of autophagy. Rapamycin, known as autophagy activator trough inhibition of mTOR was used as positive control. Indeed, it has been shown that under stress condition, autophagy is activated, promoting cell survival by releasing energy substrates via degradation of the cellular components and by eliminating defective or damaged organelles. In addition, we verified that the molecules do not induce cancer cells proliferation during 48h using 3 cancer cell lines, e.g. A549, HepG2 and HeLa, which is crucial in the perspective of drug development. Among the 21 molecules identified, we chose to focus only on 5 more potent molecules to pursue the project. In order to complete the study on autophagy pathway, we plan to perform transcriptomic studies by RNA-seq method.

Injectable Hydrogels for Cardiac Tissue Engineering.

In light of the limited efficacy of current treatments for cardiac regeneration, tissue engineering approaches have been explored for their potential to provide mechanical support to injured cardiac tissues, deliver cardio-protective molecules, and improve cell-based therapeutic techniques. Injectable hydrogels are a particularly appealing system as they hold promise as a minimally invasive therapeutic approach. Moreover, injectable acellular alginate-based hydrogels have been tested clinically in patients with myocardial infarction (MI) and show preservation of the left ventricular (LV) indices and left ventricular ejection fraction (LVEF). This review provides an overview of recent developments that have occurred in the design and engineering of various injectable hydrogel systems for cardiac tissue engineering efforts, including a comparison of natural versus synthetic systems with emphasis on the ideal characteristics for biomimetic cardiac materials.

Mechanisms Involved in Secondary Cardiac Dysfunction in Animal Models of Trauma and Hemorrhagic Shock

Clinical evidence reveals the existence of a trauma-induced secondary cardiac injury (TISCI) that is associated with poor patient outcomes. The mechanisms leading to TISCI in injured patients are uncertain. Conversely, animal models of trauma hemorrhage have repeatedly demonstrated significant cardiac dysfunction following injury, and highlighted mechanisms through which this might occur. The aim of this review was to provide an overview of the animal studies describing TISCI and its pathophysiology.Basic science models of trauma show evidence of innate immune system activation via Toll-like receptors, the exact protagonists of which remain unclear. Shortly following trauma and hemorrhage, cardiomyocytes upregulate gene regulatory protein and inflammatory molecule expression including nuclear factor kappa beta, tumor necrosis factor alpha, and interleukin-6. This is associated with expression of membrane bound adhesion molecules and chemokines leading to marked myocardial leukocyte infiltration. This cell activation and infiltration is linked to a rise in enzymes that cause oxidative and nitrative stress and subsequent protein misfolding within cardiomyocytes. Such protein damage may lead to reduced contractility and myocyte apoptosis. Other molecules have been identified as cardioprotective following injury. These include p38 mitogen-activated protein kinases and heat shock proteins.The balance between increasing damaging mediators and a reduction in cardio-protective molecules appears to define myocardial function following trauma. Exogenous therapeutics have been trialled in rodents with promising abilities to favorably alter this balance, and subsequently lead to improved cardiac function.

Abstract 463: Elevated Oxidative Stress and Reduction of Hydrogen Sulfide (H 2 S) and Nitric Oxide (NO) in HIV Patients: Possible Role in Cardiovascular (CV) Disease

Background: HIV attacks the immune system and weakens the ability to fight infections/disease. HIV infection confers approximately two-fold higher risk of cardiac events compared with the general population. ADMA, high-sensitivity CRP (hs-CRP) and IL-6 are well-characterized biomarkers of cardiac events. H 2 S and NO exert potent antioxidant properties and are cardioprotective. The present study was undertaken to determine the levels of H 2 S, NO, and CV disease biomarkers in HIV patients. Methods: Plasma from both HIV patients and normal subjects were used for all assays. Oxidative stress was determined by analyzing the levels of advanced oxidation protein products and H 2 O 2 . Antioxidant levels were determined by measuring the levels of trolox equivalent capacity. ADMA, hs-CRP, and IL-6 were determined by using ELISA. The levels of H 2 S/sulfane sulfur and nitrite were determined in plasma by using gas chromatography and HPLC, respectively. Results: We observed a marked induction in the levels of oxidative stress and decreased antioxidant status in the plasma of HIV patients as compared with the controls. CV risk factors levels such as ADMA, hs-CRP, and IL-6 were significantly increased in the plasma of HIV patients. Significant reduction in the levels of both nitrite and H 2 S/sulfane sulfur were observed in the plasma of HIV patients as compared with controls. Conclusion: Our data demonstrate significant increases in oxidative stress and CV disease biomarkers in conjunction with decreased bioavailability of H 2 S and NO in HIV patients. Diminished levels of these two cardioprotective gaseous signaling molecules may be involved in the pathogenesis of CV disease in the setting of HIV.

Degradable acetalated dextran microparticles for tunable release of an engineered hepatocyte growth factor fragment.

Injectable biomaterials are promising as new therapies to treat myocardial infarction (MI). One useful property of biomaterials is the ability to protect and sustain release of therapeutic payloads. In order to create a platform for optimizing the release rate of cardioprotective molecules we utilized the tunable degradation of acetalated dextran (AcDex). We created microparticles with three distinct degradation profiles and showed that the consequent protein release profiles could be modulated within the infarcted heart. This enabled us to determine how delivery rate impacted the efficacy of a model therapeutic, an engineered hepatocyte growth factor fragment (HGF-f). Our results showed that the cardioprotective efficacy of HGF-f was optimal when delivered over three days post-intramyocardial injection, yielding the largest arterioles, fewest apoptotic cardiomyocytes bordering the infarct and the smallest infarcts compared to empty particle treatment four weeks after injection. This work demonstrates the potential of using AcDex particles as a delivery platform to optimize the time frame for delivering therapeutic proteins to the heart.

Electrical stimulation to optimize cardioprotective exosomes from cardiac stem cells

Injured or ischemic cardiac tissue has limited intrinsic capacity for regeneration. While stem cell transplantation is a promising approach to stimulating cardiac repair, its success in humans has thus far been limited. Harnessing the therapeutic benefits of stem cells requires a better understanding of their mechanisms of action and methods to optimize their function. Cardiac stem cells (CSC) represent a particularly effective cellular source for cardiac repair, and pre-conditioning CSC with electrical stimulation (EleS) was demonstrated to further enhance their function, although the mechanisms are unknown. Recent studies suggest that transplanted stem cells primarily exert their effects through communicating with endogenous tissues via the release of exosomes containing cardioprotective molecules such as miRNAs, which upon uptake by recipient cells may stimulate survival, proliferation, and angiogenesis. Exosomes are also effective therapeutic agents in isolation and may provide a feasible alternative to stem cell transplantation. We hypothesize that EleS enhances CSC-mediated cardiac repair through its beneficial effects on production of cardioprotective exosomes. Moreover, we hypothesize that the beneficial effects of biventricular pacing in patients with heart failure may in part result from EleS-induced preconditioning of endogenous CSC to promote cardiac repair. With future research, our hypothesis may provide applications to optimize stem cell therapy and augment current pacing protocols, which may significantly advance the treatment of patients with heart disease.