Project description:Cardiovascular disease remains the leading global cause of death, and the number of patients with coronary artery disease (CAD) and exhausted therapeutic options (i.e., percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG) and medical treatment) is on the rise. Therefore, the evaluation of new therapeutic approaches to offer an alternative treatment strategy for these patients is necessary. A promising research field is the promotion of the coronary collateral circulation, an arterio-arterial network able to prevent or reduce myocardial ischemia in CAD. This review summarizes the basic principles of the human coronary collateral circulation, its extracardiac anastomoses as well as the different therapeutic approaches, especially that of stimulating the extracardiac collateral circulation via permanent occlusion of the internal mammary arteries.
Project description:The factors affecting cardioprotective collateral circulation are still incompletely understood. Recently, characteristics, such as CpG methylation of cell-free DNA (cfDNA), have been reported as markers with clinical utility. The aim of this study was to evaluate whether cfDNA methylation patterns are associated with the grade of coronary collateral circulation (CCC). In this case-control study, clinical and angiographic data were obtained from 143 patients (mean age, 58 years, male 71%) with chronic total coronary occlusion. Enzymatic methyl-sequencing (EM-seq) libraries were prepared using the cfDNA extracted from the plasma. Data were processed to obtain the average methylation fraction (AMF) tables of genomic regions from which blacklisted regions were removed. Unsupervised analysis of the obtained AMF values showed that some of the changes in methylation were due to CCC. Through random forest preparation process, 256 differentially methylated region (DMR) candidates showing strong association with CCC were selected. A random forest classifier was then constructed, and the area under the curve of the receiver operating characteristic curve indicated an appropriate predictive function for CCC. Finally, 20 DMRs were identified to have significantly different AMF values between the good and poor CCC groups. Particularly, the good CCC group exhibited hypomethylated DMRs. Pathway analysis revealed five pathways, including TGF-beta signaling, to be associated with good CCC. These data have demonstrated that differential hypomethylation was identified in dozens of cfDNA regions in patients with good CCC. Our results support the clinical utility of noninvasively obtained epigenetic signatures for predicting collateral circulation in patients with vascular diseases.
Project description:Arteriogenesis as a way to restore blood flow after arterial occlusion has been under investigation for the treatment of coronary artery disease (CAD) for decades. Therapeutic approaches so far have included delivery of cytokines and growth factors as well as mechanical stimulation such as external counterpulsation. As knowledge on the mechanisms of arteriogenesis expanded, new therapeutic approaches have emerged. This review summarizes recent attempts to stimulate the growth of the coronary vasculature and discusses their potential in clinical application. This article also delivers an overview of current studies and trials on coronary arteriogenesis.
Project description:Objective: Patients with well-developed coronary collateral circulation (CC) usually have low mortality, improved cardiac function, and reduced infarct size. Currently, there is conflicting evidence on the association between traditional cardiovascular risk factors (diabetes, hypertension, and smoking habit) and CC. Design: We performed a meta-analysis of case-control studies to better understand such associations. Data Sources: We searched the MEDINE, EMBASE, and Science Citation Index databases to identify relevant studies. Eligibility Criteria for Selecting Studies: Case control studies reporting data on risk factors (smoking habit, hypertension, and diabetes mellites) in comparing cases between poor CC and well-developed CC groups. Well-developed CC was the primary outcome of this meta-analysis Data Extraction and Synthesis: Relevant data were extracted by two independent investigators. We derived pooled odds ratios (ORs) with random effects models. We performed quality assessments, publication bias, and sensitivity analysis to ensure the reliability of our results. Results: In total, 18 studies that had 4,746 enrolled patients were analyzed. Our results showed that hypertension and smoking habit did not (OR = 0.94, 95% CI: 0.75-1.17, p = 0.564 and OR = 1.00, 95% CI: 0.84-1.18, p = 0.970, respectively), and diabetes did (OR = 0.50, 95% CI: 0.38-0.67, p = 0.00001) affect the development of CC. Conclusion: Unlike hypertension and smoking habit, diabetes was associated with poor CC formation. Trial Registration Number: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=87821, identifier: CRD42018087821.
Project description:Background The mechanism through which high-density lipoprotein (HDL) induces cardioprotection is not completely understood. We evaluated the correlation between cholesterol efflux capacity (CEC), a functional parameter of HDL, and coronary collateral circulation (CCC). We additionally investigated whether A1BP (apoA1-binding protein) concentration correlates with CEC and CCC. Methods and Results In this case-control study, clinical and angiographic data were collected from 226 patients (mean age, 58 years; male, 72%) with chronic total coronary occlusion. CEC was assessed using a radioisotope and J774 cells, and human A1BP concentration was measured using enzyme-linked immunosorbent assay. Differences between the good and poor CCC groups were compared, and associations between CEC, A1BP, and other variables were evaluated. Predictors of CCC were identified by multivariable logistic regression analysis. The CEC was higher in the good than in the poor CCC group (22.0±4.6% versus 20.2±4.7%; P=0.009). In multivariable analyses including age, sex, HDL-cholesterol levels, age (odds ratio [OR], 0.96; P=0.003), and CEC (OR, 1.10; P=0.004) were identified as the independent predictors of good CCC. These relationships remained significant after additional adjustment for diabetes mellitus, acute coronary syndrome, and Gensini score. The A1BP levels were not significantly correlated with CCC (300 pg/mL and 283 pg/mL in the good CCC and poor CCC groups, respectively, P=0.25) or CEC. Conclusions The relationship between higher CEC and good CCC indicates that well-functioning HDL may contribute to CCC and may be cardioprotective; this suggests that a specific function of HDL can have biological and clinical consequences.
Project description:Following an arterial occlusion outward remodeling of pre-existent inter-connecting arterioles occurs by proliferation of vascular smooth muscle and endothelial cells. This is initiated by deformation of the endothelial cells through increased pulsatile fluid shear stress (FSS) caused by the steep pressure gradient between the high pre-occlusive and the very low post-occlusive pressure regions that are interconnected by collateral vessels. Shear stress leads to the activation and expression of all NOS isoforms and NO production, followed by endothelial VEGF secretion, which induces MCP-1 synthesis in endothelium and in the smooth muscle of the media. This leads to attraction and activation of monocytes and T-cells into the adventitial space (peripheral collateral vessels) or attachment of these cells to the endothelium (coronary collaterals). Mononuclear cells produce proteases and growth factors to digest the extra-cellular scaffold and allow motility and provide space for the new cells. They also produce NO from iNOS, which is essential for arteriogenesis. The bulk of new tissue production is carried by the smooth muscles of the media, which transform their phenotype from a contractile into a synthetic and proliferative one. Important roles are played by actin binding proteins like ABRA, cofilin, and thymosin beta 4 which determine actin polymerization and maturation. Integrins and connexins are markedly up-regulated. A key role in this concerted action which leads to a 2-to-20 fold increase in vascular diameter, depending on species size (mouse versus human) are the transcription factors AP-1, egr-1, carp, ets, by the Rho pathway and by the Mitogen Activated Kinases ERK-1 and -2. In spite of the enormous increase in tissue mass (up to 50-fold) the degree of functional restoration of blood flow capacity is incomplete and ends at 30% of maximal conductance (coronary) and 40% in the vascular periphery. The process of arteriogenesis can be drastically stimulated by increases in FSS (arterio-venous fistulas) and can be completely blocked by inhibition of NO production, by pharmacological blockade of VEGF-A and by the inhibition of the Rho-pathway. Pharmacological stimulation of arteriogenesis, important for the treatment of arterial occlusive diseases, seems feasible with NO donors.
Project description:The coronary arteries have been regarded as end arteries for decades. However, there are functionally relevant anastomotic vessels, known as collateral arteries, which interconnect epicardial coronary arteries. These vessels provide an alternative source of blood supply to the myocardium in cases of occlusive coronary artery disease. The relevance of these collateral arteries is a matter of ongoing debate, but increasing evidence indicates a relevant protective role in patients with coronary artery disease. The collateral circulation can be assessed by different methods; the gold standard involves intracoronary pressure measurements. While the first clinical trials to therapeutically induce growth of collateral arteries have been unavailing, recent pilot studies using external counterpulsation or growth factors such as granulocyte colony stimulating factor (G-CSF) have shown promising results.
Project description:Premenopausal women and intact female rodents sustain smaller cerebral infarctions than males. Several sex-dependent differences have been identified as potential contributors, but many questions remain unanswered. Mice exhibit wide variation in native collateral number and diameter (collateral extent) that is dependent on differences in genetic background, aging, and other comorbidities and that contributes to their also-wide differences in infarct volume. Likewise, variation in infarct volume correlates with differences in collateral-dependent blood flow in patients with acute ischemic stroke. We examined whether extent of pial collateral arterioles and posterior communicating collateral arteries (PComAs) differ depending on sex in young, aged, obese, hypertensive, and genetically different mice. We combined new data with meta-analysis of our previously published data. Females of C57BL/6J (B6) and BALB/cByJ (BC) strains sustained smaller infarctions than males after permanent MCA occlusion. This protection was unchanged in BC mice after introgression of the B6 allele of Dce1, the major genetic determinant of variation in pial collaterals among mouse strains. Consistent with this, collateral extent in these and other strains did not differ with sex. Extent of PComAs and primary cerebral arteries also did not vary with sex. No dimorphism was evident for loss of pial collateral number and/or diameter (collateral rarefaction) caused by aging, obesity, and hypertension, nor for collateral remodeling after pMCAO. However, rarefaction was greater in females with long-standing hypertension. We conclude that smaller infarct volume in female mice is not due to greater collateral extent, greater remodeling, or less rarefaction caused by aging, obesity, or hypertension.
Project description:We read with interest the article entitled "Circulating microRNAs characterizing patients with insufficient coronary collateral artery function" which was recently published in the PLOS ONE journal. It was demonstrated for the first time that specific circulating microRNAs (miRNAs) can distinguish patients with sufficient from those with insufficient coronary collateral circulation. Circulating miRNAs in the plasma of patients with stable CAD and chronic CTO could provide information with regard to the coronary collateral artery capacity. However, several aspects need to be taken into consideration before the use of miRNAs in the clinical practice. A risk model that would incorporate risk factors for cardiovascular disease and miRNAs could prove to be very useful. Although an association between the levels of miRNAs and the collateral artery capacity appears promising, it still does not confirm any causal role for miRNAs. Therefore, large clinical studies in populations with CTO are warranted to evaluate this finding.
Project description:Background and aimsTo investigate the disparities in coronary collateral circulation (CCC) and peripheral serum metabolites among patients presenting with chronic total occlusion (CTO) of the coronary arteries, a non-targeted metabolic approach was employed.MethodsA cohort of 22 patients diagnosed with CTO of coronary arteries in the context of coronary heart disease (CHD) was selected for blood sample collection from CCC and peripheral arteries. The patients were categorized into two groups, namely CTO-C and CTO-P. The Waters UPLC I-Class Plus is combined with the Q Exactive high-resolution mass spectrometer for metabolite separation and detection. The acquired raw data from mass spectrometry is subsequently imported into Compound Discoverer 3.2 software for comprehensive analysis, which seamlessly integrates the BGI Metabolome Database (BMDB), mzCloud database, and ChemSpider online database. Subsequently, the identified differential metabolites were subjected to a metabolic pathway enrichment analysis, as documented in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.ResultsA total of 403 differential metabolites were identified in CCC and peripheral serum samples from patients with CTO of coronary arteries in CHD. Compared to the CTO-P group, the CTO-C group exhibited decreased levels of metabolites such as Testosterone, dehydroepiandrosterone (DHA), deoxyacetone, while demonstrating increased levels of metabolites including Progesterone, androstanone, l-threonine. The biosynthesis pathway of steroid hormones emerges as the key metabolic pathway significantly associated with differential metabolites.ConclusionsThrough metabolomics analysis, distinct differences in the CCC and peripheral serum metabolites have been identified among patients with CTO of coronary artery. Notably, a significant association between the steroid hormone biosynthesis pathway and CCC has been observed.