Endothelial progenitor cells in cardiovascular diseases

Endothelial dysfunction has been associated with the development of atherosclerosis and cardiovascular diseases. Adult endothelial progenitor cells(EPCs) are derived from hematopoietic stem cells and are capable of forming new blood vessels through a process of vas-culogenesis. There are studies which report correlations between circulating EPCs and cardiovascular risk fac-tors. There are also studies on how pharmacotherapies may influence levels of circulating EPCs. In this review, we discuss the potential role of endothelial progenitor cells as both diagnostic and prognostic biomarkers. In addition, we look at the interaction between cardio-vascular pharmacotherapies and endothelial progenitor cells. We also discuss how EPCs can be used directly and indirectly as a therapeutic agent. Finally, we evalu-ate the challenges facing EPC research and how these may be overcome.

Stem cell therapies in cardiac diseases: Current status and future possibilities

Cardiovascular diseases represent the world’s leading cause of death. In thisheterogeneous group of diseases, ischemic cardiomyopathies are the mostdevastating and prevalent, estimated to cause 17.9 million deaths per year.Despite all biomedical efforts, there are no effective treatments that can replacethe myocytes lost during an ischemic event or progression of the disease to heartfailure. In this context, cell therapy is an emerging therapeutic alternative to treatcardiovascular diseases by cell administration, aimed at cardiac regeneration andrepair. In this review, we will cover more than 30 years of cell therapy in cardiology,presenting the main milestones and drawbacks in the field and signalingfuture challenges and perspectives. The outcomes of cardiac cell therapies arediscussed in three distinct aspects: The search for remuscularization byreplacement of lost cells by exogenous adult cells, the endogenous stem cell era,which pursued the isolation of a progenitor with the ability to induce heart repair,and the utilization of pluripotent stem cells as a rich and reliable source ofcardiomyocytes. Acellular therapies using cell derivatives, such as microvesiclesand exosomes, are presented as a promising cell-free therapeutic alternative.

Novel lipid-modifying therapies addressing unmet needs in cardiovascular disease

Cardiovascular disease(CVD)remains a major cause of morbidity and mortality worldwide.Currently,it is well established that dyslipidemia is one of the major risk factors leading to the development of atherosclerosis and CVD.Statins remain the standard-of-care in the treatment of hypercholesterolemia and their use has significantly reduced cardiovascular morbidity and mortality.In addition,recent advances in lipid-modifying therapies,such as the development of proprotein convertase subtilisin/kexin type 9 inhibitors,have further improved cardiovascular outcomes in patients with hypercholesterolemia.However,despite significant progress in the treatment of dyslipidemia,there is still considerable residual risk of recurring cardiovascular events.Furthermore,in some cases,an effective therapy for the identified primary cause of a specific dyslipidemia has not been found up to date.Thus,a number of novel pharmacological interventions are under early human trials,targeting different molecular pathways of lipid formation,regulation and metabolism.This editorial aims to discuss the current clinical and scientific data on new promising lipidmodifying therapies addressing unmet needs in CVD,which may prove beneficial in the near future.

Ultrasound:The Potential Power for Cardiovascular Disease Therapy

Ultrasound can be considered a mechanical wave for both clinical diagnostic and therapeutic purposes on the basis of its good penetrability and directivity while spreading in solid organs or tissues without any ionizing radiation.As a powerful form of energy,ultrasound,is used for deep-tissue therapy with different sonication parameters.The feasibility of minimally invasive or noninvasive acoustic treatment of a variety of diseases,such as hypertension,arrhythmia,hypertrophic cardiomyopathy,and myocardial infraction,is being explored in animal experiments and clinical trials.In this review,we summarize the biomedical effects of acoustic intervention in experimental and clinical studies,current challenges,and the potential of ultrasound for cardiovascular disease therapy.

Potential role of intermittent fasting on decreasing cardiovascular disease in human immunodeficiency virus patients receiving antiretroviral therapy

Cardiovascular disease(CVD)has become one of the commonest causes of comorbidity and mortality among People living with human immunodeficiency virus(HIV)(PLWH)on antiretroviral therapy(ART).Nearly 50%of PLWH are likely to have an increased risk of developing CVD,including coronary heart disease,cerebrovascular disease,peripheral artery disease and aortic atherosclerosis.Aside from the common risk factors,HIV infection itself and side effects of antiretroviral therapy contribute to the pathophysiology of this entity.Potential non-pharmacological therapies are currently being tested worldwide for this purpose,including eating patterns such as Intermittent fasting(IF).IF is a widespread practice gaining high level of interest in the scientific community due to its potential benefits such as improvement in serum lipids and lipoproteins,blood pressure(BP),platelet-derived growth factor AB,systemic inflammation,and carotid artery intima-media thickness among others cardiovascular benefits.This review will focus on exploring the potential role of intermittent fasting as a non-pharmacological and cost-effective strategy in decreasing the burden of cardiovascular diseases among HIV patients on ART due to its intrinsic properties improving the main cardiovascular risk factors and modulating inflammatory pathways related to endothelial dysfunction,lipid peroxidation and aging.Intermittent fasting regimens need to be tested in clinical trials as an important,cost-effective,and revolutionary coadjutant of ART in the fight against the increased prevalence of cardiovascular disease in PLWH.

Antioxidants,inflammation and cardiovascular disease

Multiple factors are involved in the etiology of cardiovascular disease(CVD). Pathological changes occur in a variety of cell types long before symptoms become apparent and diagnosis is made. Dysregulation of physiological functions are associated with the activation of immune cells,leading to local and finally systemic inflammation that is characterized by production of high levels of reactive oxygen species(ROS). Patients suffering from inflammatory diseases often present with diminished levels of antioxidants either due to insufficient dietary intake or,and even more likely,due to increased demand in situations of overwhelming ROS production by activated immune effector cells like macrophages. Antioxidants are suggested to beneficially interfere with diseases-related oxidative stress,however the interplay of endogenous and exogenous antioxidants with the overall redox system is complex. Moreover,molecular mechanisms underlying oxidative stress in CVD are not fully elucidated. Metabolic dybalances are suggested to play a major role in disease onset and progression. Several central signalingpathways involved in the regulation of immunological,metabolic and endothelial function are regulated in a redox-sensitive manner. During cellular immune response,interferon γ-dependent pathways are activated such as tryptophan breakdown by the enzyme indoleamine 2,3-dioxygenase(IDO) in monocyte-derived macrophages,fibroblasts,endothelial and epithelial cells. Neopterin,a marker of oxidative stress and immune activation is produced by GTP-cyclohydrolase Ⅰ in macrophages and dendritic cells. Nitric oxide synthase(NOS) is induced in several cell types to generate nitric oxide(NO). NO,despite its low reactivity,is a potent antioxidant involved in the regulation of the vasomotor tone and of immunomodulatory signaling pathways. NO inhibits the expression and function of IDO. Function of NOS requires the cofactor tetrahydrobiopterin(BH4),which is produced in humans primarily by fibroblasts and endothelial cells. Highly toxic peroxynitrite(ONOO-) is formed solely in the presence of superoxide anion(O2-). Neopterin and kynurenine to tryptophan ratio(Kyn/Trp),as an estimate of IDO enzyme activity,are robust markers of immune activation in vitro and in vivo. Both these diagnostic parameters are able to predict cardiovascular and overall mortality in patients at risk. Likewise,a significant association exists between increase of neopterin concentrations and Kyn/Trp ratio values and the lowering of plasma levels of vitamin-C,-E and-B. Vitamin-B deficiency is usually accompanied by increased plasma homoycsteine. Additional determination of NO metabolites,BH4 and plasma antioxidants in patients with CVD and related clinical settings can be helpful to improve the understanding of redox-regulation in health and disease and might provide a rationale for potential antioxidant therapies in CVD.

Clinical Effects of Hydrogen Administration: From Animal and Human Diseases to Exercise Medicine

Here we review the literature on the effects of molecular hydrogen (H2) on normal human subjects and patients with a variety of diagnoses, such as metabolic, rheumatic, cardiovascular and neurodegenerative and other diseases, infections and physical and radiation damage as well as effects on aging and exercise. Although the effects of H2 have been studied in multiple animal models of human disease, such studies will not be reviewed in depth here. H2 can be administered as a gas, in saline implants or infusions, as topical solutions or baths or by drinking H2-enriched water. This latter method is the easiest and least costly method of administration. There are no safety issues with hydrogen;it has been used for years in gas mixtures for deep diving and in numerous clinical trials without adverse events, and there are no warnings in the literature of its toxicity or long-term exposure effects. Molecular hydrogen has proven useful and convenient as a novel antioxidant and modifier of gene expression in many conditions where oxidative stress and changes in gene expression result in cellular damage.

Adverse effects of androgen deprivation therapy in men with prostate cancer： a focus on metabolic and cardiovascular complications

Prostate cancer （PCa） is the most common malignancy in men. Prostate being an androgen responsive tissue, androgen deprivation therapy （ADT） is used in the management of locally advanced （improves survival） and metastatic （improves pain and quality of life） PCa. Over the past two decades, the use of ADT has significantly increased as it is also being used in patients with localized disease and those experiencing biochemical recurrences, though without any evidence of survival advantage. Hypogonadism resulting from ADT is associated with decreased muscle mass and strength, increased fat mass, sexual dysfunction, vasomotor symptoms, decreased quality of life, anemia and bone loss. Insulin resistance, diabetes and cardiovascular disease have recently been added to the list of these complications. As the majority of men with PCa die of conditions other than their primary malignancy, recognition and management of these adverse effects is paramount. Here we review data evaluating metabolic and cardiovascular complications of ADT.

Therapies for patients with coexisting heart failure with reduced ejection fraction and non-alcoholic fatty liver disease

Heart failure with reduced ejection fraction(HFrEF)and nonalcoholic fatty liver disease(NAFLD)are two common comorbidities that share similar pathophysiological mechanisms.There is a growing interest in the potential of targeted therapies to improve outcomes in patients with coexisting HFrEF and NAFLD.This manuscript reviews current and potential therapies for patients with coexisting HFrEF and NAFLD.Pharmacological therapies,including angiotensinconverting enzyme inhibitors/angiotensin receptor blockers,mineralocorticoids receptor antagonist,and sodium-glucose cotransporter-2 inhibitors,have been shown to reduce fibrosis and fat deposits in the liver.However,there are currently no data showing the beneficial effects of sacubitril/valsartan,ivabradine,hydralazine,isosorbide nitrates,digoxin,or beta blockers on NAFLD in patients with HFrEF.This study highlights the importance of considering HFrEF and NAFLD when developing treatment plans for patients with these comorbidities.Further research is needed in patients with coexisting HFrEF and NAFLD,with an emphasis on novel therapies and the importance of a multidisciplinary approach for managing these complex comorbidities.

Progress in Chimeric Vector and Chimeric Gene Based Cardiovascular Gene Therapy

Gene therapy for cardiovascular diseases has developed from preliminary animal experiments to clinical trials. However, vectors and target genes used currently in gene therapy are mainly focused on viral, nonviral vector and single target gene or monogene. Each vector system has a series of advantages and limitations. Chimeric vectors which combine the advantages of viral and nonviral vector, chimeric target genes which combine two or more target genes and novel gene delivery modes are being developed. In this article, we summarized the progress in chimeric vectors and chimeric genes based cardiovascular gene therapy, which including proliferative or occlusive vascular diseases such as atheroslerosis and restenosis, hypertonic vascular disease such as hypertension and cardiac diseases such as myocardium ischemia, dilated cardiomyopathy and heart failure, even heart transplantation. The development of chimeric vector, chimeric gene and their cardiovascular gene therapy is promising.

The role of Interleukin-1 family in cardiovascular disease and its research progress

The interleukin-1 family is a group of important cytokines that play a key regulatory role in the immune and inflammatory response(including infectious and non-bacterial injuries).Nowadays,the interleukin-1 family mainly includes 11 cytokines and has multiple roles in the pathology and physiology of inflammation.Moreover,accumulating number of research show that the interleukin-1 family and its receptors are involved in the occurrence and development of cardiovascular diseases.Therefore,we show here the review involving hotspots of the interleukin-1 family in the process of inflammation and its target therapy in cardiovascular diseases,including atherosclerosis,myocardial infarction and heart failure.

Proprotein convertase subtilisin/kexin type 9 inhibitors in peripheral artery disease:A review of efficacy,safety,and outcomes

Peripheral artery disease(PAD)is a common condition characterized by atherosclerosis in the peripheral arteries,associated with concomitant coronary and cerebrovascular diseases.Proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors are a class of drugs that have shown potential in hypercholesterolemic patients.This review focuses on the efficacy,safety,and clinical outcomes of PCSK9 inhibitors in PAD based on the literature indexed by PubMed.Trials such as FOURIER and ODYSSEY demonstrate the efficacy of evolocumab and alirocumab in reducing cardiovascular events,offering a potential treatment option for PAD patients.Safety evaluations from trials show few adverse events,most of which are injection-site reactions,indicating the overall safety profile of PCSK9 inhibitors.Clinical outcomes show a reduction in cardiovascular events,ischemic strokes,and major adverse limb events.However,despite these positive findings,PCSK9 inhibitors are still underutilized in clinical practice,possibly due to a lack of awareness among care providers and cost concerns.Further research is needed to establish the long-term effects and cost-effectiveness of PCSK9 inhibitors in PAD patients.

Prevention of Coronary Heart Disease: A Translational Clinical Challenge

Introduction: Atherosclerotic cardiovascular disease is a dysmetabolic medical condition resulting in the #1 cause of morbidity and mortality in the United States. Coronary Artery Calcium (CAC) CT non-invasively identifies atherosclerosis in asymptomatic individuals. This translational study tested the hypothesis that clinically overtcardiovascular disease can be prevented in asymptomatic individuals in a medical clinic. Methods: Two hundred and six asymptomatic adults requested a CAC scan to identify subclinical heart disease. Individuals with a positive CAC score > 1 (n = 125) were prescribed targeted medical therapy to reverse their atherosclerosis. The goal was to achieve an LDL Cholesterol (LDL-C) ≤ 60 mg/dl. One hundred and ten individuals reached this goal (67 male, 43 female) receiving 10 mg/d of rosuvastatin and 10 mg/d of ezetimibe plus a low cholesterol diet. Other fifteen individuals with positive CAC scores did not achieve this LDL-C goal. Results: In the group following medical therapy and achieving an LDL-C ≤ 60 mg/dl, no cardiovascular events were observed during a maximum observation period of 5 years (mean observation time = 3.6 years). Based on previously published CVD outcome data in individuals with similar CAC scores, 12.6 cardiovascular events were expected. Two of fifteen individuals with positive CAC scores not following medical therapy had a cardiovascular event. None of the 81 individuals with a zero score had a cardiovascular event during follow-up. No adverse effects of therapy occurred. Conclusion: In a medical clinic, adult population with positive CAC scores and an LDL-C ≤ 60 mg/dl, targeted medical therapy prevented overt cardiovascular disease. These results should encourage other physicians to aggressively treat atherosclerotic cardiovascular disease in their clinic populations.

Recent advances in CRISPR-based genome editing technology and its applications in cardiovascular research

The rapid development of genome editing technology has brought major breakthroughs in the fields of life science and medicine. In recent years, the clustered regularly interspaced short palindromic repeats(CRISPR)-based genome editing toolbox has been greatly expanded, not only with emerging CRISPR-associated protein(Cas) nucleases, but also novel applications through combination with diverse effectors. Recently, transposon-associated programmable RNA-guided genome editing systems have been uncovered, adding myriads of potential new tools to the genome editing toolbox. CRISPR-based genome editing technology has also revolutionized cardiovascular research. Here we first summarize the advances involving newly identified Cas orthologs, engineered variants and novel genome editing systems, and then discuss the applications of the CRISPR-Cas systems in precise genome editing, such as base editing and prime editing. We also highlight recent progress in cardiovascular research using CRISPR-based genome editing technologies, including the generation of genetically modified in vitro and animal models of cardiovascular diseases(CVD) as well as the applications in treating different types of CVD. Finally, the current limitations and future prospects of genome editing technologies are discussed.

Gene editing therapy ready for cardiovascular diseases: opportunities, challenges, and perspectives

Gene editing nucleases(GENs),represented by CRISPR/Cas9,have become major tools in biomedical research and offer potential cures for many human diseases.Gene editing therapy(GETx)studies in animal models targeting genes such as proprotein convertase subtilisin/kexin type 9(PCSK9),apolipoprotein C3(APOC3),angiopoietin Like 3(ANGPTL3)and inducible degrader of the low-density lipoprotein receptor(IDOL)have demonstrated the benefits and advantages of GETx in managing atherosclerosis.Here we present our views on this brand new therapeutic option for cardiovascular diseases(CVD).

Reirradiation of recurrent breast cancer with proton beam therapy:A case report and literature review

BACKGROUND Locoregional recurrence of breast cancer is challenging for clinicians,due to the various former treatments patients have undergone.However,treatment of the recurrence with systemic therapy and subsequent reirradiation of chest wall is accompanied by increased toxicities,particularly radiation-induced cardiovascular disease.Reirradiation by proton beam therapy(PBT)enables superior preservation of adjacent organs at risk as well as concurrent dose escalation for delivery to the gross tumor.This technology is expected to improve the overall outcome of recurrent breast cancer.CASE SUMMARY A 47-year-old female presented with an extensive locoregional recurrence at 10 yr after primary treatment of a luminal A breast cancer.Because of tumor progression despite having undergone bilateral ovarectomy and systemic therapy,the patient was treated with PBT BE total dose of 64.40 Gy to each gross tumor and 56.00 Gy to the upper mediastinal and retrosternal lymphatics including the entire sternum in 28 fractions.Follow-up computed tomography showed a partial remission,without evidence of newly emerging metastasis.At 19 mo after the PBT,the patient developed a radiation-induced pericardial disease and pleural effusions with clinical burden of dyspnea,which were successfully treated by drainage and corticosteroid.Cytological analysis of the puncture fluid showed no malignancy,and the subsequent computed tomography scan indicated stable disease as well as significantly decreased pericardial and pleural effusions.The patient remains free of progression to date.CONCLUSION PBT was a safe and effective method of reirradiation for locoregionally recurrent breast cancer in our patient.

The hippo kinases MST1/2 in cardiovascular and metabolic diseases:A promising therapeutic target option for pharmacotherapy

Cardiovascular diseases(CVDs)and metabolic disorders are major components of noncommunicable diseases,causing an enormous health and economic burden worldwide.There are common risk factors and developmental mechanisms among them,indicating the far-reaching significance in exploring the corresponding therapeutic targets.MST1/2 kinases are well-established proapoptotic effectors that also bidirectionally regulate autophagic activity.Recent studies have demonstrated that MST1/2 influence the outcome of cardiovascular and metabolic diseases by regulating immune inflammation.In addition,drug development against them is in full swing.In this review,we mainly describe the roles and mechanisms of MST1/2 in apoptosis and autophagy in cardiovascular and metabolic events as well as emphasis on the existing evidence for their involvement in immune inflammation.Moreover,we summarize the latest progress of pharmacotherapy targeting MST1/2 and propose a new mode of drug combination therapy,which may be beneficial to seek more effective strategies to prevent and treat CVDs and metabolic disorders.

Preventing Heart Disease via Coronary Artery Calcium Scoring to Make a Definitive Diagnosis of Atherosclerosis

Purpose: Cardiovascular disease is the number one cause of death in the Western world. The purpose of this manuscript is to compare the benefits and deficiencies of coronary artery calcium scanning versus computer generated risk equations in identifying atherosclerotic cardiovascular disease. These two approaches provide significantly different cardiovascular risk assessments and often lead to therapeutic differences in recommendations from the physician to the patient. Methods: Pertinent medical literature is reviewed concerning both risk assessment approaches (i.e., coronary artery scanning and computer generated risk equations). The strengths and weaknesses of both approaches are discussed, and recommendations are provided based upon available data. Results: Cardiovascular risk equations are simple and readily obtained at no charge by physicians. However, their drawbacks are several, including non-applicability to specific populations, disagreements among different cardiovascular society risk equations, wide ranges of risk outputs (e.g., intermediate 10-year risk is between 5% and 20%), inability to definitively identify coronary artery plaques, and lack of definitive anatomical coronary disease. Alternatively, coronary artery calcium scanning costs approximately $100/scan (if not covered by insurance), requires time and effort by the patient, and exposes the patient to a minimal amount of radiation. However, coronary calcium scanning identifies specific atherosclerotic coronary disease and provides additional information about the anatomical location (i.e., coronary artery) of the atherosclerotic plaque. Conclusion: Based on the published literature, coronary artery calcium scanning is the preferred approach for identifying atherosclerotic cardiovascular disease. Although there are minor drawbacks, overall it provides superior clinical information compared with computer generated risk equations.

有高血压脑出血史的患者冠状动脉介入术标准双抗治疗预后影响因素分析

目的:心脏支架置入术后要求使用双重抗血小板治疗(dual antiplatelet therapy DAPT),而脑出血后使用抗血小板治疗仍然存在争议。本研究旨在评估有高血压脑出血病史者,对使用双重抗血小板(双抗)治疗的经皮冠状动脉介入(percutaneous coronary intervention PCI)术后患者预后的影响。方法:本研究为观察性临床研究,纳入有高血压脑出血病史的PCI患者128例作为观察组,有高血压但无脑出血病史的PCI患者153例作为对照者。所有患者在PCI术后均服用阿司匹林100mg和氯吡格雷75mg治疗,随访时间为12~48个月。疗效结局为主要不良心脑血管病事件,安全性结局为再发脑出血和主要出血。结果:共随访到228例患者,其中观察组102例,对照组126例。既往脑出血病史(HR:1.998,95%CI:1.164~3.415,P=0.012)和冠心病病史(HR:2.664,95%CI:1.388~5.111,P=0.003)是导致高血压的PCI患者,双抗治疗下主要不良心脑血管病事件的危险因素。既往脑出血病史并未增加高血压的PCI患者,双抗治疗下再发脑出血(HR:2.292,95%CI:0.368~14.254,P=0.199)和主要出血的风险(HR:1.467,95%CI:0.475~4.536,P=0.506)。结论:脑出血病史和冠心病病史,是高血压的PCI患者双抗治疗下主要不良心脑血管病事件的危险因素。脑出血病史的高血压患者,PCI术后,在标准双抗治疗下,再发脑出血和主要出血的风险未增加,但明显增加主要不良心脑血管病事件的风险,需予以关注。

1例糖尿病合并心血管疾病患者的药物治疗管理

目的 为糖尿病合并心血管疾病患者的药物治疗管理(MTM)提供参考。方法 1例63岁男性糖尿病患者行冠状动脉介入术后因每日上午出现一过性头痛到我院神经内科就诊,并被推荐到药学门诊。药学门诊药师分析后认为,患者出现的头痛症状、严重便秘和高尿酸血症很可能与其所用药物有关;进一步发现患者血压、心率、血糖和血脂等动脉粥样硬化性心血管疾病影响因素均未达标。药师通过药学问诊与药品不良反应的判断、用药评估、药物重整、用药宣教和药学随访等为患者提供MTM服务。结果 药师经过13周15次的MTM服务,重整优化了药物治疗方案,停用了引起药品不良反应的药物单硝酸异山梨酯缓释片、硝苯地平控释片和吲达帕胺片,使患者用药品种数由15种调减至7种。患者头痛症状消失,严重便秘症状明显改善,血尿酸降至正常范围;血压、心率、空腹血糖、糖化血红蛋白、低密度脂蛋白胆固醇和尿酸等动脉粥样硬化性心血管疾病影响因素分别由MTM服务前的>140/90 mmHg(1 mmHg=0.133 kPa)、70~80次/min、7.71 mmol/L、7.2%、2.13 mmol/L和494μmol/L降至MTM服务后的<130/80 mmHg、55~60次/min、6.22 mmol/L、6.3%、1.55 mmol/L和348μmol/L。结论 药师为患者提供MTM服务,可提高患者生活质量和治疗效果,降低用药风险,提升医院药物合理应用水平和临床药学服务能力。