ABSTRACT
BACKGROUND: Compound Danshen dripping pills (CDDP), a traditional Chinese medicine, has had an extensive application in the treatment of angina pectoris (AP) in China. However, research on the bioactive ingredients and underlying mechanisms of CDDP in AP remains unclear. OBJECTIVE: In the present study, we explored the major chemical components and potential molecular mechanisms linked to the anti-angina effects of CDDP through the application of network pharmacology and molecular docking. METHODS: The potential targets of active ingredients in CDDP were sourced from the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and the Swiss Target Prediction Database (STPD). Additionally, targets related to angina pectoris (AP) were retrieved from various databases, including Gene Cards, DisGeNET, Dis Genet, the Drug Bank database (DBD), and the Therapeutic Target Database (TDD). Protein- protein interaction networks were also established, and core targets were identified based on their topological significance. GO enrichment analysis and KEGG pathway analysis were conducted using the R software. Interactions between active ingredients and potential targets selected through the above process were investigated through molecular docking. RESULTS: Seventy-six active ingredients were selected with the following criteria: OB ≥ 30%, DL ≥ 0.18. 383 targets of CDDP and 1488 targets on AP were gathered, respectively. Afterwards, 194 common targets of CDDP and anti-AP targets were defined, of which 12 were core targets. GO enrichment analysis indicated that CDDP acted on AP by response to lipopolysaccharide, regulating the reactive oxygen species and metal ion metabolism, and epithelial cell proliferation. In addition, KEGG enrichment analysis indicated that the signaling pathways were notably enriched in lipid and atherosclerosis, fluid shear stress and atherosclerosis, IL-17 signaling pathway, EGFR tyrosine kinase inhibitor resistance, PI3K-Akt signaling pathway, and TNF signaling pathway. Moreover, the molecular docking manifested excellent binding capacity between the active ingredients and targets on AP. CONCLUSION: This study comprehensively illustrated the bioactive, potential targets, and molecular mechanisms of CDDP against AP, offering fresh perspectives into the molecular mechanisms of CDDP in preventing and treating AP.
Subject(s)
Angina Pectoris , Drugs, Chinese Herbal , Molecular Docking Simulation , Network Pharmacology , Salvia miltiorrhiza , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/chemistry , Humans , Salvia miltiorrhiza/chemistry , Angina Pectoris/drug therapy , Angina Pectoris/metabolism , Medicine, Chinese Traditional , Camphanes , Panax notoginsengABSTRACT
BACKGROUND: Humanin is an endogenous mitochondria-derived peptide that plays critical roles in oxidative stress, inflammation and CAD. In this study, we measured the levels of circulating humanin, markers of oxidative stress and inflammation in patients with unstable angina and MI and studied the relationship between these parameters and major adverse cardiac events (MACE). METHODS: A total of 327 subjects were recruited from the inpatient department at First Hospital of Jilin University and divided into 3 groups [control, angina and myocardial infarction (MI)] based on the clinical data and the results of the angiography. Serum humanin and thiobarbituric acid reactive substances (TBARS) were measured at the time of initial admission. The hospitalization data and MACE of all patients were collected. RESULTS: Circulating humanin levels were lower in the angina group compared to controls [124.22⯱â¯63.02 vs. 157.77⯱â¯99.93â¯pg/ml, pâ¯<â¯0.05] and even lower in MI patients [67.17⯱â¯24.35â¯pg/ml, pâ¯<â¯0.05 vs controls] and oxidative stress marker were higher in MI patients compared to the control and angina groups [12.94⯱â¯4.55 vs. 8.26⯱â¯1.66 vs. 9.06⯱â¯2.47 umol/ml, pâ¯<â¯0.05]. Lower circulating humanin levels was an independent risk factor of MI patients. Circulating humanin levels could be used to predict MACE in angina group. CONCLUSIONS: Lower circulating humanin levels was an independent risk factor for CAD, and a potential prognostic marker for mild CAD. GENERAL SIGNIFICANCE: Humanin may become a new index for the diagnosis and treatment of CAD.
Subject(s)
Coronary Artery Disease/metabolism , Intracellular Signaling Peptides and Proteins/analysis , Adult , Angina Pectoris/metabolism , Angina Pectoris/physiopathology , Biomarkers/blood , Coronary Artery Disease/blood , Female , Heart , Humans , Inflammation/metabolism , Intracellular Signaling Peptides and Proteins/blood , Intracellular Signaling Peptides and Proteins/metabolism , Male , Middle Aged , Mitochondria , Myocardial Infarction/metabolism , Oxidative Stress/physiology , Prognosis , Risk FactorsABSTRACT
Angina pectoris is cardiac pain that is a common clinical symptom often resulting from myocardial ischemia. Spinal cord stimulation (SCS) is effective in treating refractory angina pectoris, but its underlying mechanisms have not been fully elucidated. The spinal dorsal horn is the first region of the central nervous system that receives nociceptive information; it is also the target of SCS. In the spinal cord, glial (astrocytes and microglia) activation is involved in the initiation and persistence of chronic pain. Thus, the present study investigated the possible cardiac painrelieving effects of SCS on spinal dorsal horn glia in chronic myocardial ischemia (CMI). CMI was established by left anterior descending artery ligation surgery, which induced significant spontaneous/ongoing cardiac pain behaviors, as measured using the open field test in rats. SCS effectively improved such behaviors as shown by open field and conditioned place preference tests in CMI model rats. SCS suppressed CMIinduced spinal dorsal horn microglial activation, with downregulation of ionized calciumbinding adaptor protein1 expression. Moreover, SCS inhibited CMIinduced spinal expression of phosphorylatedp38 MAPK, which was specifically colocalized with the spinal dorsal horn microglia rather than astrocytes and neurons. Furthermore, SCS could depress spinal neuroinflammation by suppressing CMIinduced IL1ß and TNFα release. Intrathecal administration of minocycline, a microglial inhibitor, alleviated the cardiac pain behaviors in CMI model rats. In addition, the injection of fractalkine (microgliaactivating factor) partially reversed the SCSproduced analgesic effects on CMIinduced cardiac pain. These results indicated that the therapeutic mechanism of SCS on CMI may occur partially through the inhibition of spinal microglial p38 MAPK pathway activation. The present study identified a novel mechanism underlying the SCSproduced analgesic effects on chronic cardiac pain.
Subject(s)
Angina Pectoris/metabolism , Calcium-Binding Proteins/metabolism , Cytokines/metabolism , Microfilament Proteins/metabolism , Microglia/metabolism , Myocardial Ischemia/metabolism , Spinal Cord Stimulation , p38 Mitogen-Activated Protein Kinases/metabolism , Angina Pectoris/therapy , Animals , Astrocytes/metabolism , Chronic Disease/therapy , Disease Models, Animal , Gene Expression Regulation , Male , Myocardial Ischemia/therapy , Neuroinflammatory Diseases/metabolism , Rats , Rats, Sprague-Dawley , Spinal Cord Dorsal Horn/metabolismABSTRACT
Extracorporeal shockwave myocardial revascularization (ESMR) is a therapy for refractory angina pectoris. Our aim was to assess the efficacy and safety of ESMR in the management of patients with stable coronary artery disease (CAD) and heart failure as well as its effects on inflammation and angiogenesis. In this single-arm prospective trial, we included 48 patients with CAD, myocardial ischemia assessed by radionuclide imaging, echocardiographic evidence of left ventricular systolic dysfunction and without revascularization options. Changes in angina grading score, myocardial perfusion, left ventricular ejection fraction, and six-minute walk test after ESMR therapy were used for efficacy assessment. Changes of inflammation and angiogenesis biomarkers were also evaluated. ESMR therapy was performed using a commercially available cardiac shockwave generator system (Cardiospec; Medispec). After 9 weeks of ESMR therapy, a significant improvement was found regarding the initial angina class, severity of ischemia, left ventricular ejection fraction, and six-minute walk test in most patients. No deleterious side effects after treatment were detected. Regarding biomarkers, endothelial progenitor cells and angiopoietin-3 were significantly increased whereas IL-18 and TGF-ß were significantly decreased after ESMR in the total group. Notably, VEGF, IL-1ß, and lipoxin A4 levels were significantly increased only in patients with myocardial ischemia improvement. In conclusion, ESMR therapy is safe and effective in most but not all patients with CAD and heart failure. ESMR is associated with increased markers of angiogenesis and decreased markers of inflammation. Myocardial ischemia improvement after ESMR is associated with increased markers of angiogenesis and pro-resolving mediators.
Subject(s)
Angina Pectoris/therapy , Coronary Artery Disease/therapy , Extracorporeal Shockwave Therapy/methods , Heart Failure/physiopathology , Myocardial Revascularization/methods , Ventricular Dysfunction, Left/physiopathology , Aged , Angina Pectoris/complications , Angina Pectoris/diagnostic imaging , Angina Pectoris/metabolism , Angiopoietin-Like Protein 1 , Angiopoietin-like Proteins/metabolism , Coronary Artery Disease/complications , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/metabolism , Cytokines/metabolism , Endothelial Progenitor Cells , Female , Heart Failure/complications , Heart Failure/metabolism , Humans , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Lipoxins/metabolism , Male , Middle Aged , Myocardial Perfusion Imaging , Prospective Studies , Severity of Illness Index , Stroke Volume , Transforming Growth Factor beta/metabolism , Treatment Outcome , Vascular Endothelial Growth Factor A/metabolism , Ventricular Dysfunction, Left/complications , Ventricular Dysfunction, Left/metabolism , Walk TestABSTRACT
In recent times cardiovascular diseases (CVDs) are the leading cause of mortality universally, caused more or less 17.7 million casualties with 45% of all illnesses (except communicable ones) in 2015 as per World Health Organization (WHO). According to American National Center for Health Statistics, cardiac disorders are costliest. Moreover, health care expenditures related to cardiac disorders are anticipated to exceed than diabetes and Alzheimer's. Straining of reactive oxygen species with diminished neutralization & inflammation critically adds to atherosclerosis and also proceed to other cardiovascular diseases such as cardiac remodeling and myocardial infarction (MI). In the past few years, researchers revealed multiple drug targets from animal studies and evaluated them in the therapeutics of cardiac disorders, which offered exciting clues for novel therapeutic strategies. Although, only few newer agents approved clinically and actual approaches for treatment are lagging behind. Several novel drugs found effective for the treatment of hypertension, congestive heart failure, cardiac arrhythmia and angina pectoris. Detailed mechanism of action, basic and clinical pharmacology of all novel drugs has been discussed in this review.
Subject(s)
Cardiovascular Diseases/physiopathology , Cardiovascular Diseases/therapy , Inflammation , Angina Pectoris/metabolism , Animals , Antihypertensive Agents , Arrhythmias, Cardiac/metabolism , Cardiology/trends , Cardiovascular Diseases/metabolism , Catecholamines/metabolism , Female , Heart Diseases , Heart Failure/drug therapy , Humans , Hypertension/drug therapy , Ligands , Male , Myocardial Infarction/drug therapy , Renin-Angiotensin System , Risk Factors , SmokingABSTRACT
PURPOSE: Systemic inflammation and coronary microvascular dysfunction (CMD) may be causal drivers of heart failure with preserved ejection fraction (HFpEF). We tested the hypothesis that subclinical inflammation is associated with non-endothelial dependent CMD and diastolic dysfunction. METHODS: In a cross-sectional study of 336 women with angina but no flow limiting coronary artery stenosis (180 with diabetes) and 95 asymptomatic controls, blood samples were analysed for 90 biomarkers of which 34 were part of inflammatory pathways. CMD was assessed as coronary flow velocity reserve (CFVR) by transthoracic Doppler echocardiography and defined as CFVR<2.5. We used E/e' as an indicator of diastolic function in age-adjusted linear regressions to assess correlations between biomarkers, CFVR and diastolic function. RESULTS: CMD was found in 59% of participants whereas only 4% fulfilled strict criteria for diastolic dysfunction. Thirty-five biomarkers, 17 of them inflammatory, were negatively correlated with CFVR and 25, 15 inflammatory, were positively correlated with E/e'. A total of 13 biomarkers, 9 inflammatory, were associated with both CFVR and E/e'. CFVR and E/e' were only correlated in the subgroup of patients with CMD and signs of increased filling pressure (E/e'>10) (p = 0.012). CONCLUSION: This is the first study to link a large number of mainly inflammatory biomarkers to both CMD and E/e', thus confirming a role of inflammation in both conditions. However, despite a high prevalence of CMD, few patients had diastolic dysfunction and the data do not support a major pathophysiologic role of non-endothelial dependent CMD in diastolic dysfunction.
Subject(s)
Angina Pectoris/epidemiology , Coronary Circulation , Coronary Vessels/physiopathology , Diastole , Inflammation/physiopathology , Stroke Volume , Adult , Aged , Aged, 80 and over , Angina Pectoris/etiology , Angina Pectoris/metabolism , Angina Pectoris/pathology , Biomarkers/metabolism , Case-Control Studies , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Inflammation/metabolism , Inflammation Mediators/metabolism , Male , Middle Aged , PrognosisABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Kuanxiong aerosol has been reported to be an effective and safe clinical treatment for angina pectoris (AP). AIM OF THE STUDY: To explore the potential pharmacological mechanism of Kuanxiong aerosol by combined methods of network pharmacology prediction and experimental verification. MATERIALS AND METHODS: Networks of Kuanxiong aerosol-associated targets and AP-related genes were constructed through STRING database. Potential targets and pathway enrichment analysis related to the therapeutic efficacy of Kuanxiong aerosol were identified using Cytoscape and Database for Annotation, Visualization and Integrated Discovery (DAVID). To explore the mechanism of action of Kuanxiong aerosol, its in vitro effects on myocardial hypoxia, inflammatory cytokines, and oxidative injury, and its in vivo pharmacological effects on myocardial ischemia and cardiac fibrosis were studied in rat models. RESULTS: Network pharmacology analysis revealed that the potential targets mainly include the Fas ligand (FASLG), interleukin 4 (IL4), and catalase (CAT), which mediated the processes of apoptosis, and cellular responses to hypoxia, lipopolysaccharide (LPS), reactive oxygen species (ROS), and mechanical stimulus. Multiple pathways, such as the hypoxia-inducible factor 1 (HIF1) and tumor necrosis factor (TNF) pathways were found to be closely related to the pharmacological protective mechanism of Kuanxiong aerosol against AP. In addition, Kuanxiong aerosol suppressed the hypoxia, LPS, and hydrogen peroxide (H2O2)-induced injuries of H9c2 cardiomyocytes through the regulation of HIF1A, suppressed expression of IL6 and TNF, and antioxidant property. In the rat model of myocardial ischemia, Kuanxiong aerosol was found to lower the creatine kinase (CK), creatine kinase-myocardial band (CK-MB), and lactate dehydrogenase (LDH) levels, without altering the hemodynamic function. Kuanxiong aerosol was capable of attenuating cardiac fibrosis and improving cardiac function in a cardiac fibrosis rat model. CONCLUSIONS: This study revealed that the pharmacological mechanisms of Kuanxiong aerosol for AP therapy were related to anti-myocardial ischemia, anti-inflammation, and anti-oxidation via a non-hemodynamic manner, indicating that Kuanxiong aerosol is a preferable drug clinically for AP treatment due to its both preventive and protective effects.
Subject(s)
Angina Pectoris/drug therapy , Cardiovascular Agents/pharmacology , Myocytes, Cardiac/drug effects , Oils, Volatile/pharmacology , Systems Biology , Administration, Sublingual , Aerosols , Angina Pectoris/genetics , Angina Pectoris/metabolism , Angina Pectoris/pathology , Animals , Cardiovascular Agents/administration & dosage , Cell Line , Databases, Genetic , Disease Models, Animal , Drug Combinations , Gene Expression Regulation , Gene Regulatory Networks , Male , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Oils, Volatile/administration & dosage , Protein Interaction Maps , Rats, Wistar , Signal TransductionABSTRACT
The role of NT-proBNP and hs-cTnT levels in predicting heart failure (HF) and cardiovascular disease (CVD) events in persons with prediabetes (pre-DM) and diabetes mellitus (DM) is not well-established. We examined the individual and combined relations of N-terminal natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) levels among asymptomatic adults with pre-DM and DM with the development of incident HF and CVD events. 5,584 participants with biomarker measures aged 45 to 84 years were included from the Multi-Ethnic Study of Atherosclerosis, of which 4,090 were normoglycemic, 799 had pre-DM, and 695 had DM at baseline and were followed for 12.4 ± 3.8 years. In those with DM, HF incidence rates per 1,000 person-years ranged from 3.2 to 39.4 across quartiles of NT-proBNP and 0.6 to 18.2 for hs-cTnT, respectively. Corresponding values for CVD incidence per 1,000 person-years ranged from 13.7 to 39.4 for NT-proBNP and 13.2 to 35.4 for hs-cTnT. Multivariate adjusted HRs were highest when both NT-proBNP and hs-cTnT were above versus below the median in those with pre-DM/DM (16.7 for incident HF and 2.1 for CVD events, both p <0.01). In conclusion, the combination of both biomarkers to traditional risk factors in participants who were normoglycemic or with pre-DM or DM improved risk prediction for both incident HF and total CVD events in an ethnically diverse population.
Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Type 2/metabolism , Heart Failure/metabolism , Myocardial Ischemia/metabolism , Natriuretic Peptide, Brain/metabolism , Peptide Fragments/metabolism , Prediabetic State/metabolism , Stroke/metabolism , Troponin T/metabolism , Aged , Aged, 80 and over , Angina Pectoris/epidemiology , Angina Pectoris/metabolism , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/metabolism , Coronary Disease/metabolism , Coronary Disease/mortality , Female , Heart Failure/epidemiology , Humans , Male , Middle Aged , Myocardial Infarction/epidemiology , Myocardial Infarction/metabolism , Myocardial Ischemia/epidemiology , Myocardial Ischemia/mortality , Risk Assessment , Stroke/epidemiology , Stroke/mortality , United States/epidemiologyABSTRACT
Despite optimal combination of guideline-directed anti-ischemic therapies and myocardial revascularization, a substantial proportion of patients with stable coronary artery disease continues to experience disabling symptoms and is often referred as "no-option." The appraisal of the pathways linking ischemia to symptom perception indicates a complex model of heart-brain interactions in the generation of the subjective anginal experience and inspired novel approaches that may be clinically effective in alleviating the angina burden of this population. Conversely, the prevailing ischemia-centered view of angina, with the focus on traditional myocardial revascularization as the sole option to address ischemia on top of medical therapy, hinders the experimental characterization and broad-scale clinical implementation of strongly needed therapeutic options. The interventionist, often the first physician to establish the diagnosis of refractory angina pectoris (RAP) following coronary angiography, should be aware of the numerous emerging technologies with the potential to improve quality of life in the growing population of RAP patients. This review describes the current landscape and the future perspectives on nonpharmacological treatment technologies for patients with RAP, with a view on the underlying physiopathological rationale and current clinical evidence.
Subject(s)
Angina Pectoris/therapy , Coronary Artery Disease/therapy , Counterpulsation , Electric Stimulation Therapy , Extracorporeal Shockwave Therapy , Genetic Therapy , Heart/innervation , Laser Therapy , Stem Cell Transplantation , Angina Pectoris/genetics , Angina Pectoris/metabolism , Angina Pectoris/physiopathology , Animals , Brain/metabolism , Brain/physiopathology , Coronary Artery Disease/genetics , Coronary Artery Disease/metabolism , Coronary Artery Disease/physiopathology , Coronary Circulation , Counterpulsation/adverse effects , Electric Stimulation Therapy/adverse effects , Energy Metabolism , Extracorporeal Shockwave Therapy/adverse effects , Genetic Therapy/adverse effects , Humans , Laser Therapy/adverse effects , Myocardium/metabolism , Stem Cell Transplantation/adverse effects , Treatment OutcomeSubject(s)
Angina Pectoris/drug therapy , Brain Infarction/complications , Drugs, Chinese Herbal/administration & dosage , Lipid Metabolism/drug effects , Administration, Oral , Administration, Topical , Aged , Angina Pectoris/blood , Angina Pectoris/etiology , Angina Pectoris/metabolism , Brain Infarction/metabolism , Cholesterol, HDL/blood , Cholesterol, HDL/metabolism , Cholesterol, LDL/blood , Cholesterol, LDL/metabolism , Double-Blind Method , Drugs, Chinese Herbal/adverse effects , Female , Humans , Male , Middle Aged , Prospective Studies , Treatment Outcome , Triglycerides/blood , Triglycerides/metabolismSubject(s)
Angina Pectoris/diagnostic imaging , Health Status , Myocardial Ischemia/diagnostic imaging , Myocardial Perfusion Imaging/methods , Myocardial Revascularization/methods , Positron-Emission Tomography/methods , Aged , Angina Pectoris/epidemiology , Angina Pectoris/metabolism , Cohort Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myocardial Ischemia/epidemiology , Myocardial Ischemia/metabolismABSTRACT
Fibroblast growth factor 21 (FGF21) is a metabolic hormone having anti-oxidative and anti-hypertrophic effects. However, the regulation of FGF21 expression during acute myocardial infarction (AMI) remains unclear. We tested blood samples from 50 patients with AMI and 43 patients with stable angina pectoris (sAP) for FGF21, fatty acid binding protein 4 (FABP4), a protein secreted from adipocytes in response to adrenergic lipolytic signal, and total and individual fatty acids. Compared with sAP patients, AMI patients had higher serum FGF21 levels on admission, which were significantly correlated with peak FABP4 and saturated fatty acids (SFAs) but not with peak levels of cardiac troponin T. In mice, myocardial ischemia rapidly induced FGF21 production by the heart, which accompanied activation of AMP-activated protein kinase (AMPK)-dependent pathway. Like AICAR, an activator of AMPK, catecholamines (norepinephrine and isoproterenol) and SFAs (palmitate and stearate) significantly increased FGF21 production and release by cardiac myocytes via AMPK activation. Recombinant FGF21 induced its own expression as well as members of down-stream targets of AMPK involved in metabolic homeostasis and mitochondrial biogenesis in cardiac myocytes. These findings suggest that adrenergic overdrive and resultant adipose tissue lipolysis induce cardiac AMPK-FGF21 feed-forward loop that potentially provides cardioprotection against ischemic damage.
Subject(s)
AMP-Activated Protein Kinases/metabolism , Adrenergic Agents/metabolism , Fibroblast Growth Factors/metabolism , Lipolysis , Myocardial Infarction/metabolism , Aged , Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/pharmacology , Angina Pectoris/blood , Angina Pectoris/metabolism , Animals , Catecholamines/metabolism , Disease Models, Animal , Fatty Acid-Binding Proteins/blood , Fatty Acids/blood , Female , Fibroblast Growth Factors/blood , Humans , Male , Multivariate Analysis , Myocardial Infarction/blood , Myocardium/metabolism , Myocardium/pathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Recombinant Proteins/pharmacology , Ribonucleotides/pharmacology , Time Factors , Troponin T/bloodABSTRACT
Obstructive disease of the epicardial coronary arteries is the main cause of angina. However, a number of patients with anginal symptoms have normal coronaries or non-obstructive coronary artery disease (CAD) despite electrocardiographic evidence of ischaemia during stress testing. In addition to limited microvascular vasodilator capacity, the coronary microcirculation of these patients is particularly sensitive to vasoconstrictor stimuli, in a condition known as microvascular angina. This review briefly summarizes the determinants and control of coronary blood flow (CBF) and myocardial perfusion. It subsequently analyses the mechanisms responsible for transient myocardial ischaemia: obstructive CAD, coronary spasm and coronary microvascular dysfunction in the absence of epicardial coronary lesions, and variable combinations of structural anomalies, impaired endothelium-dependent and/or -independent vasodilation, and enhanced perception of pain. Lastly, we exemplify mechanism of angina during tachycardia. Distal to a coronary stenosis, coronary dilator reserve is already recruited and can be nearly exhausted at rest distal to a severe stenosis. Increased heart rate reduces the duration of diastole and thus CBF when metabolic vasodilation is no longer able to increase CBF. The increase in myocardial oxygen consumption and resulting metabolic vasodilation in adjacent myocardium without stenotic coronary arteries further acts to divert blood flow away from the post-stenotic coronary vascular bed through collaterals.
Subject(s)
Angina Pectoris/physiopathology , Coronary Circulation , Heart Rate , Microcirculation , Myocardial Ischemia/physiopathology , Angina Pectoris/diagnosis , Angina Pectoris/metabolism , Animals , Collateral Circulation , Energy Metabolism , Humans , Myocardial Ischemia/diagnosis , Myocardial Ischemia/metabolism , Myocardium/metabolism , Oxygen ConsumptionABSTRACT
Silent angina is a critical phenomenon in the clinic and is more commonly associated with women patients suffering from myocardial ischemia. Its underlying cause remains mysterious in medicine. With our recent discovery of female-specific Ah-type baroreceptor neurons (BRNs), we hypothesize that cardiac analgesia is due to the direct activation of Ah-type BRNs by elevated levels of circulating serotonin (5-HT) myocardial infarction (MI) patients. Electromyography and the tail-flick reflex were assessed in control and MI-model rats to evaluate 5-HT-mediated BP regulation as well as peripheral and cardiac nociception. 5-HT or a 5-HT receptor agonist was microinjected into the nodose ganglion to confirm the involvement of the afferent pathway of the baroreflex arc. An inward current was observed in identified BRNs by applying a whole-cell patch-clamp technique in conjunction with qRT-PCR to verify the afferent-specific action of 5-HT and the expression of 5-HT receptors. Although the tail-flick reflex and mean arterial pressure were dramatically reduced in female MI rats with elevated serum 5-HT, intrapericardial capsaicin-evoked muscular discharges were significantly inhibited in comparing with those of males, which were mimicked by microinjection of 5-HT or SR57227A into the nodose. Ah-type BRNs displayed robust inward currents at lower concentrations of 5-HT than the C-type or the A-type, with significantly increased expression and cellular distribution of 5-HT3AR but not 5-HT3BR compared to the A- and C-types. Activation of 5-HT3AR in Ah-type BRNs by 5-HT contributes significantly to cardiac analgesia, which may suggest the pathogenic condition that silent angina occurs mainly in female patients.
Subject(s)
Angina Pectoris/metabolism , Blood Pressure/physiology , Myocardial Infarction/metabolism , Nociception/physiology , Pressoreceptors/metabolism , Serotonin/metabolism , Animals , Baroreflex/drug effects , Blood Pressure/drug effects , Disease Models, Animal , Neurons/drug effects , Neurons/metabolism , Nodose Ganglion/drug effects , Nodose Ganglion/metabolism , Rats , Receptors, Serotonin/metabolism , Serotonin/pharmacology , Serotonin Receptor Agonists/pharmacologyABSTRACT
BACKGROUND AND PURPOSE: Tanshinol borneol ester (DBZ) is a novel synthetic compound derived from Dantonic® , a botanical drug approved in 26 countries outside the United States for angina pectoris and currently undergoing FDA Phase III clinical trial. Here, we investigated the angiogenic effects of (S)-DBZ and (R)-DBZ isomers in vitro and in vivo. EXPERIMENTAL APPROACH: A network pharmacology approach was used to predict molecular targets of DBZ. The effects of DBZ isomers on proliferation, migration, and tube formation of human endothelial cells were assessed. For in vivo approaches, the transgenic Tg (vegfr2:GFP) zebrafish and C57BL/6 mouse Matrigel plug models were used. ELISA and western blots were used to quantitate the release and expression of relevant target molecules and signalling pathways. KEY RESULTS: DBZ produced a biphasic modulation on proliferation and migration of three types of human endothelial cells. Both DBZ isomers induced tube formation in Matrigel assay and a 12-day co-culture model in vitro. Moreover, DBZ promoted Matrigel neovascularization in mice and partially reversed the vascular disruption in zebrafish induced by PTK787. Mechanistically, DBZ enhanced the cellular levels of VEGF, VEGFR2, and MMP-9, as well as activating Akt and MAPK signalling in endothelial cells. Selective inhibition of PI3K and MEK significantly attenuated its angiogenic effects. CONCLUSIONS AND IMPLICATIONS: These data reveal, for the first time, that DBZ promotes multiple key steps of angiogenesis, at least in part through Akt and MAPK signalling pathways, and suggest it may be potentially developed further for treating myocardial infarction and other cardiovascular diseases.
Subject(s)
Angina Pectoris/drug therapy , Camphanes/pharmacology , Lactates/pharmacology , Small Molecule Libraries/pharmacology , Angina Pectoris/metabolism , Animals , Camphanes/chemical synthesis , Camphanes/chemistry , Cell Movement/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Coculture Techniques , Dose-Response Relationship, Drug , Drug Compounding , Humans , Lactates/chemical synthesis , Lactates/chemistry , Male , Mice , Mice, Inbred C57BL , Mitogen-Activated Protein Kinase Kinases/metabolism , Molecular Structure , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Stereoisomerism , Structure-Activity Relationship , Wound Healing/drug effects , ZebrafishABSTRACT
BACKGROUND: Previous studies have demonstrated that intramyocardial human CD34+ cells may relieve symptoms and improve clinical outcomes in chronic refractory angina unresponsive to optimal medical therapy or not amenable to revascularization. METHODS: We performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the impact of human CD34+ cells compared with placebo in chronic refractory angina. Primary efficacy outcomes in our analysis were angina frequency and exercise time. Primary safety outcomes included major adverse cardiovascular events such as myocardial infarction (MI), stroke and death. RESULTS: Three eligible randomized trials including 269 patients (placeboâ¯=â¯90, CD34+â¯=â¯179) were included. Dose of auto-CD34+ cells ranged from 5â¯×â¯104 to 5â¯×â¯105â¯cells/kg. Follow-up ranged from 6 to 24â¯months. In a pooled analysis, administration of CD34+ cells decreased the risk of all-cause mortality [OR 0.24, 95% CI (0.08-0.73), pâ¯=â¯0.01], reduced angina frequency [mean difference -2.91, 95% CI (-4.57 to -1.25), pâ¯=â¯0.0006] and improved exercise time [mean difference 58.62â¯s, 95% CI (21.19 to 96.06), pâ¯=â¯0.02] compared with control group. However, there was no significant difference in the risk of myocardial infarction (MI) and stroke between groups. CONCLUSION: In a meta-analysis, intra-myocardial CD34+ cell therapy was superior to placebo in improving risk of all - cause mortality, angina frequency with an increase in exercise time, without a significant increase in adverse events. This analysis supports further trials of CD34+ cell therapy for ischemic heart disease.
Subject(s)
Angina Pectoris/surgery , Antigens, CD34/metabolism , Neovascularization, Physiologic , Stem Cell Transplantation , Stem Cells/metabolism , Angina Pectoris/metabolism , Angina Pectoris/mortality , Angina Pectoris/physiopathology , Exercise Tolerance , Health Status , Humans , Randomized Controlled Trials as Topic , Recovery of Function , Risk Factors , Stem Cell Transplantation/adverse effects , Stem Cell Transplantation/mortality , Time Factors , Transplantation, Autologous , Treatment OutcomeABSTRACT
BACKGROUND: Recent evidence indicates a pivotal role for fetuin B, one of the cystatin superfamily of cysteine protease inhibitors, in the pathogenesis of metabolic diseases. This study investigated whether serum fetuin B levels are associated with the presence of coronary artery disease. METHODS: Serum fetuin B levels were assessed in 87 patients with coronary artery disease (41 with acute coronary syndromes and 46 with stable angina pectoris) and 87 healthy controls using an enzyme-linked immunosorbent assay. The association of serum fetuin B levels with cardiac risk factors was analyzed. RESULTS: Serum fetuin B levels were significantly higher in patients with coronary artery disease than those in healthy controls (90.7 ± 32.1 vs. 110.0 ± 32.7 µg/ml, P < 0.001), extremely elevated in group with acute coronary syndromes (115.0 ± 35.2 µg/ml). Pearson correlation analysis showed that serum fetuin B levels were positively associated with the levels of total cholesterol (r = 0.276, P < 0.001), low-density lipoprotein cholesterol (r = 0.363, P < 0.001), and fasting blood glucose (r = 0.159, P < 0.05). In addition, multiple logistic regression analyses revealed that fetuin B was independently associated with the presence of coronary artery disease (OR, 1.019; 95% CI, 1.009 to 1.029; P < 0.001) and acute coronary syndromes (OR, 1.017; 95% CI, 1.006 to 1.028; P < 0.01). CONCLUSIONS: Our data revealed that high fetuin B levels are associated with the presence of coronary artery disease and acute coronary syndromes, and that fetuin B may serve as a potential biomarker for coronary artery disease.
Subject(s)
Coronary Artery Disease/blood , Fetuin-B/analysis , Acute Coronary Syndrome/blood , Aged , Aged, 80 and over , Angina Pectoris/metabolism , Biomarkers/blood , Blood Glucose/metabolism , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, LDL/blood , Female , Humans , Male , Middle Aged , ROC Curve , Risk FactorsABSTRACT
BACKGROUND: We explored the impact of glycemic variability on the occurrence of periprocedural myocardial infarction and major adverse cardiovascular events (MACE) after coronary intervention in patients with stable angina pectoris (SAP) at 6months follow-up. METHODS: From May 2015 to April 2016, a total of 746 patients with SAP were divided to high glycemic variability group (H group) (n=261) and low glycemic variability group (L group) (n=485). The primary end point was incidence of periprocedural myocardial infarction and MACE at 6months follow-up. RESULTS: The occurrence of periprocedural myocardial infarction occurred in 18.8% of patients in H group and in 12.4% in L group (P=0.03). The incidence of MACE at 6months follow-up was 9.6% in H group and 4.5% in L group (P=0.01). Multivariable analysis suggested that high glycemic variability conferred a 53% risk increment of 6months follow-up MACE (odds ratio 2.13, 95% confidence interval 1.85-5.38; P=0.01). CONCLUSIONS: The trial shows that higher blood glucose variability was correlated with higher incidence of periprocedural myocardial infarction and MACE at 6months follow-up.
Subject(s)
Angina Pectoris/metabolism , Blood Glucose/metabolism , Myocardial Infarction/metabolism , Myocardial Infarction/surgery , Percutaneous Coronary Intervention/adverse effects , Aged , Angina Pectoris/drug therapy , Angina Pectoris/surgery , Female , Follow-Up Studies , Glucose Tolerance Test , Humans , Male , Middle Aged , Multivariate Analysis , Myocardial Infarction/drug therapy , Odds Ratio , Prospective StudiesABSTRACT
The study was carried out in 126 patients with stable angina pectoris, who underwent elective coronary artery stenting with drug-eluting stents and follow-up angiography within 6-12 months thereafter. Five significant risk factors of restenosis were identified by binary comparisons of different variables. The logistic regression equation that included the level of CD45-positive platelets, diabetes, small vessel stenting, number of simultaneously implanted stents in one patient, and lesion length demonstrates the highest level of prediction of in-stent restenosis (OR=22.8; p<0.001). ROC-analysis demonstrated high prognostic value of the logit model (area under ROC curve 0.87, p<0.001). The data suggest that a close relationship exists between the development of restenosis and the level of circulating CD45+ platelets.
Subject(s)
Angina Pectoris/pathology , Blood Platelets/pathology , Constriction, Pathologic/pathology , Coronary Disease/pathology , Drug-Eluting Stents/adverse effects , Adult , Aged , Angina Pectoris/metabolism , Angina Pectoris/surgery , Blood Platelets/metabolism , Constriction, Pathologic/diagnostic imaging , Constriction, Pathologic/etiology , Coronary Angiography , Coronary Disease/metabolism , Coronary Disease/surgery , Coronary Vessels/metabolism , Coronary Vessels/pathology , Coronary Vessels/surgery , Diabetes Mellitus/physiopathology , Female , Gene Expression , Humans , Leukocyte Common Antigens/genetics , Leukocyte Common Antigens/metabolism , Male , Middle Aged , ROC Curve , Risk FactorsABSTRACT
The present study was aimed to develope a proliposomal formulation to decrease the hepatic first-pass metabolism of protocatechualdehyde (PD), followed by pellet coating to modify the drug release for angina chronotherapy. PD proliposomes were prepared by depositing PD-phospholipid complex on mannitol powders to improve the drug encapsulation. Afterwards, the PD proliposomes were prepared into pellet cores via extrusion-spheronization using 10% κ-carrageenan as pelletization aid prior to the development of PD sustained-release pellets (PD-SRPs). Eudragit® NE 30D was chosen as coating material and the desired drug release profile of PD-SRPs was calculated for formulation optimization by deconvolution based on the circadian rhythm of variant angina. A high similarity factor (f2=85.72) was achieved when the coating weight was 30% and the sustained release behavior also prevented the destruction of liposomes by gastric fluids. Pharmacokinetic studies revealed a basically consistent trend between the actual and the predicted plasma concentration-time curve with absolute percent errors (%PE) of concentrations <10% in 2-12h. Meanwhile, a relative bioavailability of 200% was achieved compared with pure PD. Therefore, the development of proliposomes-based PD-SRPs was an effective strategy to provide both improved oral bioavailability and desired drug plasma concentration-time course for angina chronotherapy.