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1.  Influence of high-density lipoprotein cholesterol on coronary collateral formation in a population with significant coronary artery disease 
BMC Research Notes  2013;6:105.
Coronary collateral circulation plays an important role in protecting myocardium from ischemia and reducing cardiovascular events. Low High-density lipoprotein cholesterol (HDL-C) level is a strong risk factor for coronary artery disease (CAD) and is associated with poor cardiovascular outcome. It was recently reported to be associated with poor coronary collateral development in Turkish population. Hence, we investigated the influence of HDL-C on coronary collateral formation in Chinese population.
We evaluated 970 consecutive patients undergoing coronary angiography, and 501 patients with significant coronary artery disease (SCAD) were finally analyzed. The collateral scoring system developed by Rentrop was used to classify patient groups as those with poor or good collaterals.
The patients with poor collaterals had fewer diseased vessels (1.97 ± 0.84 vs 2.47 ± 0.68, p < 0.001) and lower diffuse score (2.65 ± 1.63 vs 3.76 ± 1.78, p < 0.001). There was no significant difference in HDL-C and other variables between good and poor collaterals. Multivariate analysis showed only number of diseased vessels (odd ratio 0.411, p < 0.001) was a significant predictor of poor collateral development.
The extent of CAD severity but not HDL-C level was the most powerful predictor of coronary collateral formation in our Chinese population with SCAD.
PMCID: PMC3606844  PMID: 23510196
Coronary artery disease; Coronary collateral circulation; High-density lipoprotein cholesterol
2.  Coronary Collateral Circulation in Patients of Coronary Ectasia with Significant Coronary Artery Disease 
PLoS ONE  2014;9(1):e87001.
Patients with coronary ectasia (CE) usually have coexisting coronary stenosis resulting in myoischemia. Coronary collateral plays an important role in protecting myocardium from ischemia and reducing cardiovascular events. However, limited studies investigate the role of CE in coronary collaterals development.
We evaluated 1020 consecutive patients undergoing coronary angiography and 552 patients with significant coronary artery disease (SCAD), defined as diameter stenosis more than 70%, were finally analyzed. CE is defined as the ectatic diameter 1.5 times larger than adjacent reference segment. Rentrop collateral score was used to classify patients into poor (grades 0 and 1) or good (grades 2 and 3) collateral group.
73 patients (13.2%) had CE lesions which were most located in the right coronary artery (53.4%). Patients with CE had a lower incidence of diabetes (43.8% vs 30.1%, p = 0.03), higher body mass index (25.4±3.5 vs 26.7±4.6, p = 0.027) and poorer coronary collateral (58.2% vs 71.2%, p = 0.040). Patients with poor collateral (n = 331) had a higher incidence of CE (15.7% vs 9.5%, p = 0.040) and fewer diseased vessels numbers (1.96±0.84 vs 2.48±0.69, p<0.001). Multivariate analysis showed diabetes (odd ratio (OR) 0.630, p = 0.026), CE (OR = 0.544, p = 0.048), and number of diseased vessels (OR = 2.488, p<0.001) were significant predictors of coronary collaterals development.
The presence of CE was associated with poorer coronary collateral development in patients with SCAD.
PMCID: PMC3903606  PMID: 24475209
3.  Clinical and angiographic features associated with coronary collateralization in stable angina patients with chronic total occlusion 
Objective: Coronary collateral circulation is an alternative source of blood supply to myocardium in the presence of advanced coronary artery disease. We sought to determine which clinical and angiographic variables are associated with collateral development in patients with stable angina and chronic total coronary occlusion. Methods: Demographic variables, biochemical measurements, and angiographic findings were collected from 478 patients with stable angina and chronic total coronary occlusion. The presence and extent of collaterals supplying the distal aspect of a total coronary occlusion from the contra-lateral vessel were graded from 0 to 3 according to the Rentrop scoring system. Results: Low (Rentrop score of 0 or 1) and high (Rentrop score of 2 or 3) coronary collateralizations were detected in 186 and 292 patients, respectively. Despite similar age, cigarette smoking, and medical treatment, patients with low collateralization were female in a higher proportion and less hypertensive, and had higher rates of type 2 diabetes and dyslipidemia than those with high collateralization (for all comparisons, P<0.05). In addition, patients with low collateralization exhibited more single-vessel disease, less right coronary artery occlusion, more impaired renal function, and higher serum levels of high-sensitivity C-reactive protein (hsCRP) compared with those with high collateralization. Multivariate analysis revealed that age of ≥65 years, female gender, diabetes, no history of hypertension, dyslipidemia, moderate to severe renal dysfunction, single-vessel disease, and elevated hsCRP levels were independently associated with low coronary collateralization. Conclusions: Coronary collateralization was reduced in almost 40% of stable angina patients with chronic total occlusion, which was related to clinical and angiographic factors. The impact of coronary collateralization on outcomes after revascularization needs further investigation.
PMCID: PMC3735970  PMID: 23897789
Stable angina; Coronary collateral circulation; Risk factors; Angiography; Chronic total coronary occlusion
4.  Observed Influence of Nitroglycerine on Myocardial Perfusion Scintigraphy in Patients with Multiple Vessel Coronary Artery Disease and Well-Developed Collaterals 
The objective of this scientific work was to evaluate the extent and severity of perfusion abnormalities on myocardial perfusion scintigraphy (MPS) at rest and with sublingual nitroglycerine, in relation to the presence and anatomical location of collaterals demonstrated by selective coronary angiography (SCA). Twenty-eight patients with unstable angina underwent selective coronary angiography. Eighteen of them were diagnosed with myocardial infarction (MI) 2–15 days prior to examination. Presence or absence of collaterals was noted, with anatomical depiction of donor and recipient arteries as well as evaluation of degree of collateral flow. As an inclusion criterion, collateral flow had to be grade 2 (partial epicardial filling of the occluded artery) or 3 (complete epicardial filling of the occluded artery) in accordance with the Rentrop collateral flow classification. Flow was noted as follows: Complete antegrade (CA), complete retrograde (CR), partial antegrade (PA), and partial retrograde (PR). Myocardial perfusion scintigraphy using Tc-99m Sestamibi at rest and after sublingual administration of nitroglycerine was performed according to a 2-day protocol. Perfusion abnormalities, which were quantified using the 20-segments model and visual 5-point system (0, normal perfusion; 4, absent perfusion), were analyzed according to donor's and recipient's territories, as well as territories with limited or without collateral flow (PA/PR, grade 0–1 flow). A total of 84 arteries were analyzed, with stenosis in 79 of them. Arteries were divided into three groups: Donors (group I), recipients (group II), and arteries with limited or without collaterals (group III). In group I, there were 28 donor arteries, with mean severity of stenosis 71.3 ± 0.65%. In group II, there were 36 recipient arteries and mean severity of stenosis was 94.8 ± 0.26%. In group III, there were 20 arteries, and all of them had either no or poorly developed collaterals (mean severity of stenosis 60.4 ± 2%). In 3 cases, 2 donor arteries gave collaterals to 1 recipient artery, while in 11 cases, a single donor artery gave collaterals to 2 recipient arteries, and in 11 cases there was 1 donor to 1 recipient artery. A total of 1120 MPS segments were analyzed (560 at rest and 560 after nitroglycerine). The number of segments in groups I, II, and III were 204, 242, and 144, respectively. Mean number of segments per donor artery was 7.2 ± 0.7, mean number of segments per recipient artery was 7.0 ± 0.3, and mean number of segments in the territory of arteries without collaterals was 5.5 ± 0.5. In the territory of donor arteries, the mean number of segments with normal, decreased, and absent perfusion at rest was 1.6 ± 0.07, 5.67 ± 0.07, and 0.6 ± 0.03, respectively. After nitroglycerine administration, the mean number of above-mentioned segments was 1.2 ± 0.07, 6.07 ± 0.06, and 2.3 ± 0.06, respectively. There was no significant difference in the mean number of segments with normal and decreased perfusion at rest and after nitroglycerine administration (P = 0.4). However, the increase of mean segments with absent perfusion that appeared after nitroglycerine administration in donor arteries was statistically significant in comparison to MPS at rest (P < 0.0001). In the territory of recipient arteries, there was statistically significant increase in the mean number of segments with normal perfusion from 0.5 ± 0.02 at rest to 2.7 ± 0.06 with nitroglycerine (P < 0.0001), decrease in mean number of segments with decreased perfusion from 6.5 ± 0.06 at rest to 4.19 ± 0.06 with nitroglycerine (P < 0.0001), and decrease in the mean number of segments with absent perfusion from 2.3 ± 0.06 to 0.7 ± 0.03 (P = 0.003). In Group III, there was increase in mean segments with normal perfusion from 2.4 ± 0.5 to 3.2 ± 0.5, decrease in mean segments with decreased perfusion from 3.15 ± 0.5 to 2.35 ± 0.5, and absent tracer uptake from 1.1 ± 0.5 to 0.45 ± 0.3. However, these changes were not statistically significant (P = 0.3, P = 0.4, and P = 0.2, respectively). There was also statistically significant improvement of perfusion in the recipient territories from mean severity score at rest of 2.67 ± 0.08 to 1.6 ± 0.09 with nitroglycerine (P < 0.0001), in territories of poorly collateralized arteries from mean severity score at rest of 1.5 ± 0.14 to 0.8 ± 0.12 with nitroglycerine (P < 0.0008), as well as significant deterioration of myocardial perfusion in donor artery territories from mean severity score at rest of 1.7 ± 0.06 to 2.4 ± 0.06 with nitroglycerine (P  < 0.0001). Based on the results of the study, we concluded that nitroglycerine administration in patients with multiple vessel coronary artery disease and well-developed collaterals can reduce myocardial perfusion to the areas supplied by donor arteries, even resulting in apparent absent perfusion, probably due to “steal syndrome,” although these arteries were less stenosed angiographically and deemed viable on MPS at rest. It appears that MPS in patients on nitroglycerine medication may result in an inappropriate decision by interventionists and surgeons to forgo revascularization. Hence, in cases where large and severe perfusion abnormalities are noted, MPS should be repeated after omitting nitrates.
PMCID: PMC3555395  PMID: 23372438
Collaterals; myocardial perfusion scintigraphy; nitroglycerine; selective coronary angiography; unstable angina
5.  Association of increased serum glycated albumin levels with low coronary collateralization in type 2 diabetic patients with stable angina and chronic total occlusion 
We investigated whether serum glycated albumin (GA) levels are related to coronary collateralization in type 2 diabetic patients with chronic total occlusion.
Blood levels of GA and glycosylated hemoglobin (HbA1c) were determined in 317 diabetic and 117 non-diabetic patients with stable angina and angiographic total occlusion of at least one major coronary artery. The degree of collaterals supplying the distal aspect of a total occlusion from the contra-lateral vessel was graded as low (Rentrop score of 0 or 1) or high collateralization (Rentrop score of 2 or 3).
For diabetic patients, GA (21.2 ± 6.5% vs. 18.7 ± 5.6%, P < 0.001) but not HbA1c levels (7.0 ± 1.1% vs. 6.8 ± 1.3%, P = 0.27) was significantly elevated in low collateralization than in high collateralization group, and correlated inversely with Rentrop score (Spearmen’s r = -0.28, P < 0.001; Spearmen’s r = -0.10, P = 0.09, respectively). There was a trend towards a larger area under the curve of GA compared with that of HbA1c for detecting the presence of low collateralization (0.64 vs. 0.58, P = 0.15). In non-diabetic patients, both GA and HbA1c levels did not significantly differ regardless the status of coronary collateralization. In multivariable analysis, female gender, age > 65 years, smoke, non-hypertension, duration of diabetes > 10 years, metabolic syndrome, eGFR < 90 ml/min/1.73 m2, and GA > 18.3% were independently determinants for low collateralization in diabetic patients.
Increased GA levels in serum are associated with impaired collateral growth in type 2 diabetic patients with stable angina and chronic total occlusion.
PMCID: PMC4225762  PMID: 24209601
Glycated albumin; Coronary collateralization; Diabetes
6.  The relation between endothelial dependent flow mediated dilation of the brachial artery and coronary collateral development – a cross sectional study 
Endothelial dysfunction is thought to be a potential mechanism for the decreased presence of coronary collaterals. The aim of the study was to investigate the association between systemic endothelial function and the extent of coronary collaterals.
We investigated the association between endothelial function assessed via flow mediated dilation (FMD) of the brachial artery following reactive hyperemia and the extent of coronary collaterals graded from 0 to 3 according to Rentrop classification in a cohort of 171 consecutive patients who had high grade coronary stenosis or occlusion on their angiograms.
Mean age was 61 years and 75% were males. Of the 171 patients 88 (51%) had well developed collaterals (grades of 2 or 3) whereas 83 (49%) had impaired collateral development (grades of 0 or 1). Patients with poor collaterals were significantly more likely to have diabetes (p = 0.001), but less likely to have used statins (p = 0.083). FMD measurements were not significantly different among good and poor collateral groups (11.5 ± 5.6 vs. 10.4 ± 6.2% respectively, p = 0.214). Nitroglycerin mediated dilation was also similar (13.4 ± 5.9 vs. 12.8 ± 6.5%, p = 0.521).
No significant association was found between the extent of angiographically visible coronary collaterals and systemic endothelial function assessed by FMD of the brachial artery.
PMCID: PMC2702291  PMID: 19527494
7.  Plasma Chemokine Levels Are Associated with the Presence and Extent of Angiographic Coronary Collaterals in Chronic Ischemic Heart Disease 
PLoS ONE  2011;6(6):e21174.
In patients with chronic ischemic heart disease (IHD), the presence and extent of spontaneously visible coronary collaterals are powerful determinants of clinical outcome. There is marked heterogeneity in the recruitment of coronary collaterals amongst patients with similar degrees of coronary artery stenoses, but the biological basis of this heterogeneity is not known. Chemokines are potent mediators of vascular remodeling in diverse biological settings. Their role in coronary collateralization has not been investigated. We sought to determine whether plasma levels of angiogenic and angiostatic chemokines are associated with of the presence and extent of coronary collaterals in patients with chronic IHD.
Methodology/Principal Findings
We measured plasma concentrations of angiogenic and angiostatic chemokine ligands in 156 consecutive subjects undergoing coronary angiography with at least one ≥90% coronary stenosis and determined the presence and extent of spontaneously visible coronary collaterals using the Rentrop scoring system. Eighty-eight subjects (56%) had evidence of coronary collaterals. In a multivariable regression model, the concentration of the angiogenic ligands CXCL5, CXCL8 and CXCL12, hyperlipidemia, and an occluded artery were associated with the presence of collaterals; conversely, the concentration of the angiostatic ligand CXCL11, interferon-γ, hypertension and diabetes were associated with the absence of collaterals (ROC area 0.91). When analyzed according to extent of collateralization, higher Rentrop scores were significantly associated with increased concentration of the angiogenic ligand CXCL1 (p<0.0001), and decreased concentrations of angiostatic ligands CXCL9 (p<0.0001), CXCL10 (p = 0.002), and CXCL11 (p = 0.0002), and interferon-γ (p = 0.0004).
Plasma chemokine concentrations are associated with the presence and extent of spontaneously visible coronary artery collaterals and may be mechanistically involved in their recruitment.
PMCID: PMC3120847  PMID: 21731663
8.  Hematological parameters and coronary collateral circulation in patients with stable coronary artery disease 
Although hematological parameters have been associated with prognosis in patients with various cardiovascular diseases, their relationship with coronary collateral (CC) circulation in patients with stable coronary artery disease (CAD) is unknown.
To investigate the relationship between hematological parameters and CC vessel development in patients with stable CAD.
A total of 96 patients who underwent coronary angiography were retrospectively enrolled. All study participants had at least one occluded major coronary artery. Development of CCs was classified using the method of Rentrop. Rentrop grades of 0 and 1 indicate poor CCs, whereas grades 2 and 3 indicate good CCs. Hematological parameters, including mean platelet volume (MPV) and neutrophil/lymphocyte (N/L) ratio, were measured. Multivariate logistic regression analysis was performed to identify independent variables.
The MPV and N/L ratio were significantly higher in the poor CC group compared with the good CC group. Negative correlations were found in the analyses comparing Rentrop score with MPV and N/L ratio (r=−0.274; P=0.012 and r=−0.339; P=0.001, respectively). In multivariate analysis, the N/L ratio was independently related to CC circulation (OR 0.762 [95% CI 0.587 to 0.988]; P=0.04).
The results suggest that N/L ratio and MPV are associated with poor CCs, and a high N/L ratio is a significant predictor of poor CC development in patients with stable CAD.
PMCID: PMC3716494  PMID: 24294041
Coronary collateral circulation; Hematological parameters; Mean platelet volume; Neutrophil/lymphocyte ratio
9.  Metabolic syndrome and collateral vessel formation in patients with documented occluded coronary arteries: association with hyperglycaemia, insulin-resistance, adiponectin and plasminogen activator inhibitor-1 
European Heart Journal  2009;30(7):840-849.
The metabolic syndrome (MS) is associated with an increased cardiovascular risk. Patients with the MS have endothelial dysfunction, decreased circulating adiponectin, and a high expression of angiogenic inhibitors such as plasminogen activator inhibitor-1 (PAI-1). We hypothesized that such patients, in the event of a coronary occlusion, might exhibit a less developed collateral circulation.
Methods and results
Three hundred and eighty-seven consecutive patients with at least one coronary occlusion of a major coronary vessel at diagnostic angiography were prospectively enrolled. Collateral development was graded with validated angiographic methods. The MS was defined according to the ATP-III definition. Fasting glucose, adiponectin, insulin concentrations, and PAI-1 were measured at the time of angiography. MS was associated with less developed collateral vessels (P = 0.005). In multivariable analysis adjusting for potential confounding factors including the duration of coronary occlusion (P = 0.0001), fasting glycaemia (P = 0.0007), low adiponectin concentration (P = 0.01), insulin-resistance (HOMA-IR; P = 0.01), high circulating PAI-1 concentration (P = 0.01), and hypertension (P = 0.008) were independently associated with poor coronary collateral vessel development.
This study shows that in patients with coronary occlusion, collateral circulation is impaired in patients with the MS. This association is partly related to fasting glycaemia and to key parameters linked to insulin resistance.
PMCID: PMC2663725  PMID: 19164335
Angiogenesis; Collateral circulation; Coronary disease; Diabetes mellitus; Fibrinolysis; Insulin
10.  Risk Models to Predict Chronic Kidney Disease and Its Progression: A Systematic Review 
PLoS Medicine  2012;9(11):e1001344.
A systematic review of risk prediction models conducted by Justin Echouffo-Tcheugui and Andre Kengne examines the evidence base for prediction of chronic kidney disease risk and its progression, and suitability of such models for clinical use.
Chronic kidney disease (CKD) is common, and associated with increased risk of cardiovascular disease and end-stage renal disease, which are potentially preventable through early identification and treatment of individuals at risk. Although risk factors for occurrence and progression of CKD have been identified, their utility for CKD risk stratification through prediction models remains unclear. We critically assessed risk models to predict CKD and its progression, and evaluated their suitability for clinical use.
Methods and Findings
We systematically searched MEDLINE and Embase (1 January 1980 to 20 June 2012). Dual review was conducted to identify studies that reported on the development, validation, or impact assessment of a model constructed to predict the occurrence/presence of CKD or progression to advanced stages. Data were extracted on study characteristics, risk predictors, discrimination, calibration, and reclassification performance of models, as well as validation and impact analyses. We included 26 publications reporting on 30 CKD occurrence prediction risk scores and 17 CKD progression prediction risk scores. The vast majority of CKD risk models had acceptable-to-good discriminatory performance (area under the receiver operating characteristic curve>0.70) in the derivation sample. Calibration was less commonly assessed, but overall was found to be acceptable. Only eight CKD occurrence and five CKD progression risk models have been externally validated, displaying modest-to-acceptable discrimination. Whether novel biomarkers of CKD (circulatory or genetic) can improve prediction largely remains unclear, and impact studies of CKD prediction models have not yet been conducted. Limitations of risk models include the lack of ethnic diversity in derivation samples, and the scarcity of validation studies. The review is limited by the lack of an agreed-on system for rating prediction models, and the difficulty of assessing publication bias.
The development and clinical application of renal risk scores is in its infancy; however, the discriminatory performance of existing tools is acceptable. The effect of using these models in practice is still to be explored.
Please see later in the article for the Editors' Summary
Editors' Summary
Chronic kidney disease (CKD)—the gradual loss of kidney function—is increasingly common worldwide. In the US, for example, about 26 million adults have CKD, and millions more are at risk of developing the condition. Throughout life, small structures called nephrons inside the kidneys filter waste products and excess water from the blood to make urine. If the nephrons stop working because of injury or disease, the rate of blood filtration decreases, and dangerous amounts of waste products such as creatinine build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet and ankles, puffiness around the eyes, and frequent urination, especially at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes, both of which cause CKD, and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place.
Why Was This Study Done?
CKD is associated with an increased risk of end-stage renal disease, which is treated with dialysis or by kidney transplantation (renal replacement therapies), and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD, but most people present with advanced disease. Early identification would be particularly useful in developing countries, where renal replacement therapies are not readily available and resources for treating cardiovascular problems are limited. One way to identify people at risk of a disease is to use a “risk model.” Risk models are constructed by testing the ability of different combinations of risk factors that are associated with a specific disease to identify those individuals in a “derivation sample” who have the disease. The model is then validated on an independent group of people. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the researchers critically assess the ability of existing CKD risk models to predict the occurrence of CKD and its progression, and evaluate their suitability for clinical use.
What Did the Researchers Do and Find?
The researchers identified 26 publications reporting on 30 risk models for CKD occurrence and 17 risk models for CKD progression that met their predefined criteria. The risk factors most commonly included in these models were age, sex, body mass index, diabetes status, systolic blood pressure, serum creatinine, protein in the urine, and serum albumin or total protein. Nearly all the models had acceptable-to-good discriminatory performance (a measure of how well a model separates people who have a disease from people who do not have the disease) in the derivation sample. Not all the models had been calibrated (assessed for whether the average predicted risk within a group matched the proportion that actually developed the disease), but in those that had been assessed calibration was good. Only eight CKD occurrence and five CKD progression risk models had been externally validated; discrimination in the validation samples was modest-to-acceptable. Finally, very few studies had assessed whether adding extra variables to CKD risk models (for example, genetic markers) improved prediction, and none had assessed the impact of adopting CKD risk models on the clinical care and outcomes of patients.
What Do These Findings Mean?
These findings suggest that the development and clinical application of CKD risk models is still in its infancy. Specifically, these findings indicate that the existing models need to be better calibrated and need to be externally validated in different populations (most of the models were tested only in predominantly white populations) before they are incorporated into guidelines. The impact of their use on clinical outcomes also needs to be assessed before their widespread use is recommended. Such research is worthwhile, however, because of the potential public health and clinical applications of well-designed risk models for CKD. Such models could be used to identify segments of the population that would benefit most from screening for CKD, for example. Moreover, risk communication to patients could motivate them to adopt a healthy lifestyle and to adhere to prescribed medications, and the use of models for predicting CKD progression could help clinicians tailor disease-modifying therapies to individual patient needs.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Maarten Taal
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease, including some personal stories
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease (in English and Spanish)
The not-for-profit UK National Kidney Federation support and information for patients with kidney disease and for their carers, including a selection of patient experiences of kidney disease
World Kidney Day, a joint initiative between the International Society of Nephrology and the International Federation of Kidney Foundations, aims to raise awareness about kidneys and kidney disease
PMCID: PMC3502517  PMID: 23185136
11.  Does rich coronary collateral circulation distal to chronically occluded left anterior descending artery compete with graft flow? 
In coronary artery bypass grafting (CABG), graft flow distal to a mild stenosis can compete with relatively preserved native flow through the stenosis and the competition can result in graft stenosis. In chronic total occlusion (CTO), coronary collateral circulation, which is essential to maintain myocardial viability distal to CTO, varies in extent among patients and the extent can be scored by Rentrop grade in coronary angiography. We investigated whether rich collateral circulation distal to CTO competes with distally anastomosed graft flow in association with Rentrop grade.
Of 666 patients who underwent CABG from January 2001 to December 2012, 70 patients whose left internal thoracic artery (ITA) was grafted distal to CTO in the left anterior descending artery (LAD) were divided into three groups: Poor collaterals (Rentrop grades 0 and 1, Group P, n = 22), Moderate collaterals (grade 2, Group M, n = 23) and Rich collaterals (grade 3, Group R, n = 25). The intraoperative measurements of mean graft flow (MGF) and pulsatility index (PI) of left ITA grafts, early graft patency and long-term clinical outcomes were compared.
The MGF and PI of left ITA grafts differed significantly among the three groups (P = 0.025 and P = 0.046, respectively). Lower Rentrop grade was associated with preferable results of higher MGF and lower PI. The graft flow pattern in Group P showed a significantly higher MGF (P = 0.020) and lower PI (P = 0.041) than those in Group R. All early postoperative coronary angiograms showed patent left ITA grafts. Serial echocardiographic evaluations, survival rates and cardiac event-free rates were comparable with the follow-up of 5.00 ± 3.11 years.
Rich collateral circulation distal to CTO in LADs can potentially compete with graft flow, although the competition seems not to affect clinical outcomes probably due to the regression of collaterals surmounted by the graft flow. Rentrop grade is shown to certainly reflect the degree of collateral haemodynamic circulation distal to CTO and especially important to evaluate intraoperative graft flow appropriately, considering the possible phenomenon of graft flow competition.
PMCID: PMC3829484  PMID: 23959772
Collateral circulation; Coronary artery bypass grafting; Coronary circulation; Coronary occlusion; Pulse wave analysis
12.  Serial Plasma Levels of Angiogenic Factors in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention 
Korean Circulation Journal  2012;42(7):464-470.
Background and Objectives
Patients with acute myocardial infarction show varying degrees of collateral development. However, the relationships between angiogenic factors and degree of collaterals are not well known.
Subjects and Methods
Fifty-nine patients (mean age, 59±10 years) with ST-segment elevation myocardial infarction (STEMI) underwent primary percutaneous coronary intervention (PCI). Patients were divided into one of 2 groups: group I (Rentrop collateral grade 0/1, n=34) or group II (grade 2/3, n=25). Plasma levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sFlt-1), angiopoietin (Ang)-2, and soluble Tie-2 at baseline, 24 and 48 hours after PCI were measured.
There were fewer diabetic patients and higher incidence of previous angina and multi-vessel disease in group II. Group II had a lower left ventricular ejection fraction and a trend toward longer pain-to-balloon time. Plasma levels of Ang-2, sFlt-1 were elevated prior to primary PCI and decreased after PCI, whereas plasma level of VEGF was relatively low initially, however rose after PCI. sTie-2 levels showed no significant interval change in group I, but decreased over time in group II. VEGF, sFlt-1, and Tie-2 levels did not differ between the groups at each time point. However, plasma levels of Ang-2 were higher in group I than in group II at baseline and at 48 hours.
Presence of collaterals in STEMI patients undergoing primary PCI was associated with lesser rise in Ang-2 plasma level. VEGF showed a delayed response to acute ischemia compared to Ang-2. Clinical implications of our findings need to be investigated in further studies.
PMCID: PMC3409395  PMID: 22870080
Myocardial infarction; Angiogenesis modulating agents; Vascular endothelial growth factor; Angiopoietin-2
13.  Functional significance of coronary collateral circulation during dynamic exercise evaluated by thallium-201 myocardial scintigraphy. 
British Heart Journal  1980;43(1):47-55.
Sixty-five patients with angiographically documented coronary artery disease were investigated by thallium-201 (201Tl) scintigraphy to determine the role of the collateral circulation during dynamic exercise. Fifty-three patients had complete proximal occlusion of at least one major coronary artery. One patient had total occlusion of all three major coronary arteries. Sixty-four collateral channels were identified, graded, and compared with corresponding regions of the myocardial scintigram. Tracer uptake was also graded and classified as various degrees of protection from ischaemia. A significant correlation between good collaterals with complete protection and poor or absent collaterals with no protection was noted. Seventeen patients (20 occluded vessels) had total coronary occlusion without myocardial infarction. Collaterals conferred protection in 9/15 occlusions whereas no protection was seen in five occlusions without collaterals. There was no difference in the protective role of homocoronary and heterocoronary collateral vessels. Hypertrophy of the first septal left anterior descending perforator conferred significant protection from ischaemia in contrast to bridging collaterals and ghosting. During exercise the right coronary bed is preferentially protected from ischaemia, in contrast to the left anterior descending territory. This probably reflects the direction of a transmural flow gradient between left and right ventricles during exercise.
PMCID: PMC482241  PMID: 7356862
14.  Association of Non-alcoholic Fatty Liver Disease with Chronic Kidney Disease: A Systematic Review and Meta-analysis 
PLoS Medicine  2014;11(7):e1001680.
In a systematic review and meta-analysis, Giovanni Musso and colleagues examine the association between non-alcoholic fatty liver disease and chronic kidney disease.
Please see later in the article for the Editors' Summary
Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.
Methods and Findings
English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.
The presence and severity of NAFLD are associated with an increased risk and severity of CKD.
Please see later in the article for the Editors' Summary
Editors' Summary
Chronic kidney disease (CKD)—the gradual loss of kidney function—is becoming increasingly common. In the US, for example, more than 10% of the adult population (about 26 million people) and more than 25% of individuals older than 65 years have CKD. Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. CKD gradually destroys the kidneys' filtration units, the rate of blood filtration decreases, and dangerous amounts of waste products build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, particularly at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes (two risk factors for CKD), and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place.
Why Was This Study Done?
CKD is associated with an increased risk of end-stage renal (kidney) disease and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD. Because early recognition of CKD has the potential to reduce its health-related burden, the search is on for new modifiable risk factors for CKD. One possible new risk factor is non-alcoholic fatty liver disease (NAFLD), which, like CKD is becoming increasingly common. Healthy livers contain little or no fat but, in the US, 30% of the general adult population and up to 70% of patients who are obese or have diabetes have some degree of NAFLD, which ranges in severity from simple fatty liver (steatosis), through non-alcoholic steatohepatitis (NASH), to NASH with fibrosis (scarring of the liver) and finally cirrhosis (extensive scarring). In this systematic review and meta-analysis, the researchers investigate whether NAFLD is a risk factor for CKD by looking for an association between the two conditions. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 33 studies that assessed NAFLD and CKD in nearly 64,000 participants, including 20 cross-sectional studies in which participants were assessed for NAFLD and CKD at a single time point and 13 longitudinal studies in which participants were assessed for NAFLD and then followed up to see whether they subsequently developed CKD. Meta-analysis of the data from the cross-sectional studies indicated that NAFLD was associated with a 2-fold increased risk of prevalent (pre-existing) CKD (an odds ratio [OR]of 2.12; an OR indicates the chance that an outcome will occur given a particular exposure, compared to the chance of the outcome occurring in the absence of that exposure). Meta-analysis of data from the longitudinal studies indicated that NAFLD was associated with a nearly 2-fold increased risk of incident (new) CKD (a hazard ratio [HR] of 1.79; an HR indicates often a particular event happens in one group compared to how often it happens in another group, over time). NASH was associated with a higher prevalence and incidence of CKD than simple steatosis. Similarly, advanced fibrosis was associated with a higher prevalence and incidence of CKD than non-advanced fibrosis.
What Do These Findings Mean?
These findings suggest that NAFLD is associated with an increased prevalence and incidence of CKD and that increased severity of liver disease is associated with an increased risk and severity of CKD. Because these associations persist after allowing for established risk factors for CKD, these findings identify NAFLD as an independent CKD risk factor. Certain aspects of the studies included in this meta-analysis (for example, only a few studies used biopsies to diagnose NAFLD; most used less sensitive tests that may have misclassified some individuals with NAFLD as normal) and the methods used in the meta-analysis may limit the accuracy of these findings. Nevertheless, these findings suggest that individuals with NAFLD should be screened for CKD even in the absence of other risk factors for the disease, and that better treatment of NAFLD may help to prevent CKD.
Additional Information
Please access these websites via the online version of this summary at
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Digestive Diseases Information Clearinghouse provides information about non-alcoholic liver disease
The US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease, including some personal stories, and information on non-alcoholic fatty liver disease
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease (in English and Spanish)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers
The British Liver Trust, a not-for-profit organization, provides information about non-alcoholic fatty liver disease, including a patient story
PMCID: PMC4106719  PMID: 25050550
15.  Effect and Mechanism of Thrombospondin-1 on the Angiogenesis Potential in Human Endothelial Progenitor Cells: An In Vitro Study 
PLoS ONE  2014;9(2):e88213.
Coronary collateral circulation plays a protective role in patients with coronary artery disease (CAD). We investigated whether thrombospondin-1(TSP-1) has an inhibitory effect on angiogenesis potential in endothelial progenitor cells(EPCs) and tested whether TSP-1 are altered in plasma of patients who had chronic total occlusion (CTO) in at least one coronary artery and with different collateral stages(according to Rentrop grading system).
Methods and Results
We isolated early and late EPCs from human cord blood and investigated a dose-dependent effect of TSP-1 on their angiogenesis potential by Matrigel angiogenesis assay. We found that TSP-1 (5 µg/ml) inhibited early EPCs incorporation into tubules after pretreatment for 1, 6 and 12 hours, respectively (83.3±11.9 versus 50.0±10.1 per field for 1 hour,161.7±12.6 versus 124.0±14.4 for 6 hours, 118.3±12.6 versus 68.0±20.1 for 12 hours, p<0.05). TSP-1 also inhibited late EPCs tubule formation at 1 µg/ml (6653.4±422.0 µm/HPFversus 5552.8±136.0 µm/HPF, p<0.05), and the inhibition was further enhanced at 5 µg/ml (6653.4±422.0 µm/HPF versus 2118.6±915.0 µm/HPF p<0.01). To explore the mechanism involved, a small interfering RNA was used. In vitro, CD47 siRNA significantly attenuated TSP-1's inhibition of angiogenesis on late EPCs and similar results were obtained after functional blocking by anti-CD47 antibody. Then we investigated pathways downstream of CD47 and found TSP-1 regulated VEGF-induced VEGFR2 phosphorylation via CD47. Furthermore, we examined plasma TSP-1 levels in patients with CTO who developed different stages of collaterals and found a paradoxical higher level of TSP-1 in patients with good collaterals compared with bad ones (612.9±554.0 ng/ml versus 224.4±132.4 ng/ml, p<0.05).
TSP-1 inhibited angiogenesis potential of early and late EPCs in vitro. This inhibition may be regulated by TSP-1's interaction with CD47, resulting in down regulation of VEGFR2 phosphorylation. In patients with CTO, there may be a self-adjustment mechanism in bad collaterals which is shown as low level of angiogenesis inhibitor TSP-1, and thus favoring collateral formation.
PMCID: PMC3914943  PMID: 24505433
16.  Effects of Previously Well-Developed Collateral Vessels on Left Internal Mammary Artery Graft Flow after Bypass Surgery 
Texas Heart Institute Journal  2005;32(1):35-42.
Transthoracic Doppler ultrasonography can assess left internal mammary artery patency and flow after coronary artery bypass grafting. We aimed to show, by transthoracic Doppler ultrasonography, the early effects upon left internal mammary artery graft flow of preoperative collateral vessels supplying the left anterior descending artery.
Thirty-four consecutive patients undergoing coronary artery bypass were prospectively enrolled: 19 patients with collateral vessels supplying the left anterior descending were compared with 15 patients without collaterals. After bypass, end-diastolic velocity, mean velocity, flow volume, and ejection fraction were significantly greater, and the resistivity index was lower in patients with collateral vessels. The changes in velocities, volume, resistivity index, and pulsatility index were also found to be greater in patients with collateral vessels than in those without collaterals. Collateral vessels were the only factor affecting the changes in end-diastolic volume, mean velocity, flow volume, and resistivity index in multivariate analysis. Three factors affected postoperative left ventricular ejection fraction: collateral vessels, preoperative ejection fraction, and changes in left internal mammary flow volume.
We conclude that patients with well-developed collaterals to the left anterior descending have better flow in the left internal mammary graft and more significant improvement in left ventricular function after coronary bypass. The flow volume of the mammary graft and the improvement of ventricular systolic functions after coronary bypass might be presumed with the presence of grade 2 or 3 preoperative collateral vessels.
PMCID: PMC555819  PMID: 15902819
Blood flow velocity; collateral circulation; coronary artery bypass; coronary vessels/ultrasonography; echocardiography, Doppler; hemodynamic processes; internal mammary-coronary artery anastomosis; mammary arteries/ultrasonography; vascular patency
17.  Importance of angina for development of collateral circulation. 
British Heart Journal  1987;57(2):139-143.
The extent of collateral circulation in 46 patients who had intracoronary thrombolysis within six hours of the onset of acute myocardial infarction was evaluated. Patients who had had a previous myocardial infarction (4 cases) or who had spontaneously recanalized infarct related coronary arteries (5 cases) were excluded from the analysis. Collateral development was graded during coronary cineangiography according to the extent of opacification of the collateral and epicardial arteries distal to the site of occlusion (collateral index 0 to 3). Angina was considered to be present before myocardial infarction if it had occurred more than one week before acute myocardial infarction. Collateral channels were visible in only two of 19 patients without angina before infarction and nine of the 18 patients with angina before infarction. The prevalence of angina and the collateral index were not significantly influenced by the extent of coronary vessel disease. It is concluded that myocardial ischaemia is important in promoting collateral development in man as well as in laboratory animals.
PMCID: PMC1277094  PMID: 3814448
18.  Relation of coronary collateral circulation with epicardial fat volume in patients with stable coronary artery disease 
To investigated the relationship between epicardial fat volume (EFV) and coronary collateral circulation (CCC) in patients with stable coronary artery disease (CAD).
The study population consisted of 152 consecutive patients with CAD who underwent coronary angiography and were found to have at least 95% significiant lesion in at least one major coronary artery. EFV was assessed utilizing 64-multislice computed tomography. The patients were classifield into impaired CCC group (Group 1, Rentrop grades 0−1, n = 58), or adequate CCC (Group 2, Rentrop grades 2−3, n = 94).
The EFV values were significantly higher in paitients with adequate CCC than in those with impaired CCC. In multivariate logistic regression analysis, EFV (OR = 1.059; 95% CI: 1.035−1.085; P = 0.001); and presence of angina were independent predictors of adequate CCC. In receiver-operating characteristic curve analysis, the EFV value > 106.5 mL yielded an area under the curve value of 0.84, with the test sensitivity of 49.3%, and with 98.3% specifity.
High EFV, and the presence of angina independently predict adequate CCC in patients with stable coronary artery disease. This association offers new diagnostic opportinities to assess collateral flow by conventional ultrasound techniques.
PMCID: PMC3888916  PMID: 24454327
Epicardial adipose tissue; Coronary artery disease; Angına; Collateral circulation
19.  Influence of diabetes mellitus on coronary collateral flow: an answer to an old controversy 
Heart  2005;91(10):1289-1293.
Objectives: To determine the influence of diabetes mellitus on coronary collateral flow by accurate means of collateral flow measurement in a large population with variable degrees of coronary artery disease.
Methods: 200 patients (mean (SD) age 64 (9) years; 100 diabetic and 100 non-diabetic) were enrolled in the study. Coronary collateral flow was assessed in 174 stenotic and in 26 angiographically normal vessels with a pressure guidewire (n  =  131), Doppler guidewire (n  =  36), or both (n  =  33) to calculate pressure or flow velocity derived collateral flow index (CFI). Diabetic patients were perfectly matched with a non-diabetic control group for clinical, haemodynamic, and angiographic parameters.
Results: CFI did not differ between the diabetic and the non-diabetic patients (0.21 (0.12) v 0.19 (0.13), not significant). Likewise, CFI did not differ when only angiographically normal vessels (0.20 (0.09) v 0.15 (0.08), not significant) or chronic total coronary occlusions (0.30 (0.14) v 0.30 (0.17), not significant) were compared. Fewer patients in the diabetic group tended to have angina pectoris during the one minute vessel occlusion (60 diabetic v 69 non-diabetic patients, p  =  0.15).
Conclusion: Quantitatively measured coronary CFI did not differ between diabetic and non-diabetic patients with stable coronary artery disease.
PMCID: PMC1769134  PMID: 16162618
collateral circulation; diabetes mellitus; angiogenesis; collateral flow index
20.  Washout collaterometry: a new method of assessing collaterals using angiographic contrast clearance during coronary occlusion 
Heart  2001;86(5):540-546.
OBJECTIVE—To investigate the hypothesis that the time to washout of radiographic contrast medium trapped distal to an occluded collateral receiving vessel is inversely related to collateral flow, and that this provides an accurate method for characterising coronary collaterals.
METHODS—An intracoronary pressure derived collateral flow index was determined in 54 patients undergoing percutaneous transluminal coronary balloon angioplasty (PTCA). The study group was subdivided according to whether the collateral vessels were sufficient (n = 17) or insufficient (n = 37) to prevent ECG signs of myocardial ischaemia during PTCA. Washout collaterometry—an angiographic washout method—was carried out simultaneously; after injection of radiographic contrast medium into the collateral receiving vessel followed immediately by vascular occlusion, the number of heart beats was counted until approximately half the length of the epicardial vessel was cleared of contrast.
RESULTS—The collateral flow index was higher (0.28 (0.09) v 0.12 (0.07); p < 0.0001) and the contrast washout time shorter (8.0 (2.9) v 17.5 (6.7) heart beats; p < 0.0001) in patients with sufficient versus insufficient collaterals. There was an inverse correlation between contrast washout time and collateral flow index (r = 0.72, p < 0.0001). Washout of contrast distal to the occluded vessel within 11 heart beats correctly determined sufficient and insufficient collaterals with 88% sensitivity and 81% specificity.
CONCLUSIONS—Washout collaterometry is a new radiographic contrast washout method based on the inverse relation between collateral flow and the time to clearance of radiographic dye injected into the ipsilateral vessel during PTCA. It appears to be an accurate method of characterising coronary collateral vessels.

Keywords: coronary artery disease; collateral circulation; coronary angiography
PMCID: PMC1729956  PMID: 11602548
21.  The Role of Vitamin D Deficiency and Vitamin D Receptor Genotypes on the Degree of Collateralization in Patients with Suspected Coronary Artery Disease 
BioMed Research International  2014;2014:304250.
We determined the association of vitamin D deficiency and the FokI polymorphism of the vitamin D receptor (VDR) gene in 760 patients who underwent angiography due to suspected coronary artery disease (CAD). Angiography and the Rentrop scoring system were used to classify the severity of CAD in each patient and to grade the extent of collateral development, respectively. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the FokI VDR gene polymorphism. The prevalence of severe vitamin D deficiency (serum 25(OH)D < 10 ng/mL) was significantly higher in patients with at least one stenotic coronary artery compared to those without any stenotic coronary arteries. Severe vitamin D deficiency was not independently associated with collateralization, but it was significantly associated with the VDR genotypes. In turn, VDR genotype was independently associated with the degree of collateralization; the Rentrop scores were the highest in FF, intermediate in Ff, and the lowest in the ff genotype. The results show that FokI polymorphism is independently associated with collateralization. Additionally, vitamin D deficiency is more prevalent in patients with CAD that may result from FokI polymorphism. Therefore, maintaining a normal vitamin D status should be a high priority for patients with CAD.
PMCID: PMC3963370  PMID: 24729966
22.  Hemodynamic Determinants of Perivascular Collateral Development in Swine Renal Artery Stenosis 
American Journal of Hypertension  2013;26(2):209-217.
Renal artery stenosis (RAS) resulting in reduced renal blood flow (RBF) is a common cause of secondary hypertension and deterioration of renal function, which may lead to end-stage renal disease. Recruitment and formation of periarterial collateral vessels may serve to bypass RAS and restore distal blood supply. We hypothesized that development of collaterals around RAS may preserve kidney function.
Collateral formation index (CI) was assessed using multidetector computed tomography as fractional vascular volume surrounding the stenosis in 31 pigs with unilateral RAS. Single kidney RBF and glomerular filtration rate (GFR) were also measured.
Of 25 pigs that developed significant stenosis (≥65%), 8 demonstrated minor collateral development (CI < 0.3), and 17 showed major collateral development (CI ≥ 0.3). The degree of RAS was significantly higher in pigs with major collaterals compared with pigs with minor collaterals, and poststenotic kidney cortical volume, perfusion, RBF, and GFR were significantly lower. In a subset of pigs matched for the degree of RAS, RBF and GFR remained lower in pigs with major collaterals.
We conclude that collaterals develop in animals with significant RAS in proportion to its severity and might be triggered by distal injury, such as decreases in cortical volume and perfusion. However, development of collaterals was unable to confer measurable benefits for stenotic kidney function distal to severe RAS.
PMCID: PMC3626039  PMID: 23382405
blood pressure; collateral circulation; computed tomography; hypertension; renal artery stenosis; renal function.
23.  Renal Function and Risk of Coronary Heart Disease in General Populations: New Prospective Study and Systematic Review 
PLoS Medicine  2007;4(9):e270.
End-stage chronic kidney disease is associated with striking excesses of cardiovascular mortality, but it is uncertain to what extent renal function is related to risk of subsequent coronary heart disease (CHD) in apparently healthy adults. This study aims to quantify the association of markers of renal function with CHD risk in essentially general populations.
Methods and Findings
Estimated glomerular filtration rate (eGFR) was calculated using standard prediction equations based on serum creatinine measurements made in 2,007 patients diagnosed with nonfatal myocardial infarction or coronary death during follow-up and in 3,869 people without CHD in the Reykjavik population-based cohort of 18,569 individuals. There were small and nonsignificant odds ratios (ORs) for CHD risk over most of the range in eGFR, except in the lowest category of the lowest fifth (corresponding to values of <60 ml/min/1.73m2), in which the OR was 1.33 (95% confidence interval 1.01–1.75) after adjustment for several established cardiovascular risk factors. Findings from the Reykjavik study were reinforced by a meta-analysis of six previous reports (identified in electronic and other databases) involving a total of 4,720 incident CHD cases (including Reykjavik), which yielded a combined risk ratio of 1.41 (95% confidence interval 1.19–1.68) in individuals with baseline eGFR less than 60 ml/min/1.73m2 compared with those with higher values.
Although there are no strong associations between lower-than-average eGFR and CHD risk in apparently healthy adults over most of the range in renal function, there may be a moderate increase in CHD risk associated with very low eGFR (i.e., renal dysfunction) in the general population. These findings could have implications for the further understanding of CHD and targeting cardioprotective interventions.
John Danesh and colleagues conclude there may be a moderate increase in risk of coronary heart disease associated with very low estimated glomerular filtration rate.
Editors' Summary
Coronary heart disease (CHD), the leading cause of death in most Western countries, is a “cardiovascular” disease—literally a disorder affecting the heart and/or blood vessels. In CHD, the blood vessels that supply the heart become increasingly narrow. Eventually, the flow of blood to the heart slows or stops, causing chest pains (angina), breathlessness, and heart attacks. Many factors increase the risk of developing CHD and other cardiovascular diseases, including high blood pressure, high blood levels of cholesterol (a type of fat), or being overweight. Individuals can reduce their chances of developing cardiovascular disease by taking drugs to reduce their blood pressure or cholesterol levels or by making lifestyle changes (so-called cardioprotective interventions). Another important risk factor for cardiovascular disease is end-stage chronic kidney disease (CKD), a condition in which the kidneys stop working. (In healthy people, the kidneys remove waste products and excess fluid from the body.) People with end-stage CKD (which is treated by dialysis) have about a five times higher risk of dying from cardiovascular disease compared with healthy people.
Why Was This Study Done?
End-stage CKD is preceded by a gradual loss of kidney function. There is a clear association between non-dialysis–dependent CKD and the incidence of cardiovascular events (such as heart attacks) in people who already have signs of cardiovascular disease. But are people with slightly dysfunctional kidneys (often because of increasing age) but without any obvious cardiovascular disease at greater risk of developing cardiovascular diseases than people with fully functional kidneys? If the answer is yes, it might be possible to reduce CHD deaths by minimizing the exposure of people with CKD to other risk factors for cardiovascular disease. In this study, the researchers have taken two approaches to answer this question. In a population-based study, they have examined whether there is any association in healthy adults between kidney function measured at the start of the study and incident CHD (the first occurrence of CHD) over subsequent years. In addition, they have systematically searched the published literature for similar studies and combined the results of these studies using statistical methods, a so-called “meta-analysis.”
What Did the Researchers Do and Find?
Between 1967 and 1991, nearly 19,000 middle-aged men and women without a history of heart attacks living in Reykjavik, Iceland, enrolled in a prospective study of cardiovascular disease. Baseline blood samples were taken at enrollment and the participants' health monitored for 20 years on average. The researchers identified 2,007 participants who suffered a nonfatal heart attack or died of CHD during follow-up and 3,869 who remained disease free. They then calculated the estimated glomerular filtration rate (eGFR; a measure of kidney function) for each participant from baseline creatinine measurements (creatinine is a muscle waste product). There was no association between lower-than-average eGFRs and the risk of developing CHD over most of the range of eGFR values. However, people whose eGFR was below approximately 60 units had about a 40% higher risk of developing CHD after allowing for established cardiovascular risk factors than individuals with higher eGFRs. This finding was confirmed by the meta-analysis of six previous studies, which included a further 2,700 incident CHD cases.
What Do These Findings Mean?
These findings indicate that people with an eGFR below about 60 units (the cut-off used to define CKD) may have an increased risk of developing CHD. They also indicate a nonliner association between kidney function and CHD risk. That is, any association with CHD became evident only when the eGFR dropped below about 60 units. These findings need confirming in different ethnic groups and by using more accurate methods to measure eGFRs. Nevertheless, they suggest that improving kidney function across the board is unlikely to have much effect on the overall incidence of CHD. Instead, they suggest that targeting cardioprotective interventions at the one in ten adults in Western countries whose eGFR is below 60 units might be a good way to reduce the burden of CHD.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia pages on coronary heart disease, chronic kidney failure, and end-stage kidney disease (in English and Spanish).
Information for patients and carers from the American Heart Association on all aspects of heart disease, including prevention of CHD
Information from the British Heart Foundation on heart disease and on keeping the heart healthy
Information on chronic kidney disease from the US National Kidney Foundation, and the US National Kidney and Urologic Diseases Information Clearing House (in English and Spanish)
Information on chronic kidney disease from the UK National Kidney Foundation
PMCID: PMC1961630  PMID: 17803353
24.  Dual-Phase CT Collateral Score: A Predictor of Clinical Outcome in Patients with Acute Ischemic Stroke 
PLoS ONE  2014;9(9):e107379.
Background and Purpose
The presence of good collaterals on CT angiography (CTA) is a well-known predictor for favorable outcome in acute ischemic stroke. Recently, multiphase CT has been introduced as a more accurate method in assessing collaterals. The aim of this study was to assess the ability of dual-phase CT to evaluate collateral status and predict clinical outcome.
Forty-three patients who underwent both dual-phase CT and transfemoral cerebral angiography (TFCA) for occluded intracranial internal carotid artery (ICA) and/or middle cerebral artery (M1 segment) were recruited from a prospectively collected database. The collateral status on dual-phase CT was graded by using a 4-point scale: grade 0 = no collaterals; 1 = some collaterals with persistence of some defects; 2 = slow but complete collaterals; and 3 = fast and complete collaterals. Univariate and multivariate analysis were performed to define the independent predictors for favorable outcome at 3 months.
Dual-phase CT collateral status (ρ = 0.744) showed higher correlation with TFCA collateral status than CTA collateral status (ρ = 0.596) and substantial interobserver agreement (weighted κ = 0.776). In the univariate analysis, age, history of hypertension, collateral scores on CTA, dual-phase CT, and TFCA, occlusion in intracranial ICA, final infarct volume, and symptomatic hemorrhage were significantly associated with outcome. Among them, only the dual-phase CT collateral score was an independent predictor for favorable outcome (OR = 26.342 (2.788–248.864); P = 0.004) in the multivariate analysis.
The collateral status on dual-phase CT can be a useful predictor for clinical outcome in acute stroke patients, especially when advanced CT techniques are not available in emergent situations.
PMCID: PMC4161414  PMID: 25210853
25.  Role of Statin in Atrial Fibrillation-Related Stroke: An Angiographic Study for Collateral Flow 
Currently, intensive lipid lowering is recommended in patients with atherosclerotic ischemic stroke or transient ischemic attack. However, the role of statin in cardioembolic stroke is unclear. We investigated the association of statin with pretreatment collateral status in cardioembolic stroke.
A collaborative study from two stroke centers in distinct geographic regions included consecutive patients with acute middle cerebral artery (MCA) infarction due to atrial fibrillation (AF) who underwent cerebral angiography. The relationship between pretreatment collateral grade and the use/dose of statin at stroke onset was assessed. The angiographic collateral grade was evaluated according to the ASITN/SIR Collateral Flow Grading System.
Ninety-eight patients (76 statin-naïve, 22 statin users) were included. Compared with statin-naïve patients, statin users were older and more frequently had hypertension, hyperlipidemia and coronary heart disease. Excellent collaterals (grade 3–4) were more frequently observed in statin users (11 patients, 50%) than in statin-naïve patients (21 patients, 27.6%; p = 0.049). The use of atorvastatin 10 mg equivalent or higher doses of statin was associated with excellent collaterals (p for trend = 0.025). In multiple regression analysis, prestroke statin use was independently associated with excellent collaterals (odds ratio, 7.841; 95% confidence interval, CI, 1.96–31.363; p = 0.004).
Premorbid use of statin in AF patients is associated with excellent collateral flow. Although most statin trials excluded patients with cardioembolic stroke, our data suggests the possibility that statin may be beneficial in AF-related stroke.
PMCID: PMC4157914  PMID: 24457535
Atrial fibrillation; Collateral flow; Stroke; Statin; Arteriogenesis

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