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1.  Correlation between the severity of coronary artery lesions and levels of estrogen, hs-CRP and MMP-9 
The aim of this study was to investigate the correlation between the severity of coronary artery lesions in patients with acute coronary syndromes (ACS) and levels of estrogen, high-sensitivity C-reactive protein (hs-CRP) and matrix metalloproteinase-9 (MMP-9). A total of 65 patients with ACS, 33 patients with stable angina pectoris (SAP) and 36 healthy controls were randomly enrolled. Patients with ACS were subdivided into two groups: Acute myocardial infarction (AMI; n=30) and unstable angina pectoris (UAP; n=35). Serum levels of estrogen, hs-CRP and MMP-9 were detected in the four groups of subjects. Serum estrogen levels in patients with AMI, UAP and SAP were significantly lower than those in the control group (P<0.05). Estrogen levels were also significantly different among the AMI, UAP and SAP groups (P<0.05), with a progressive increase across the three respective groups. Compared with healthy subjects, patients with AMI had the highest levels of hs-CRP and MMP-9, followed in descending order by those with UAP and SAP (P<0.05). Levels of hs-CRP and MMP-9 were also significantly different among the AMI, UAP and SAP groups (P<0.05). Serum estrogen levels were negatively correlated with hs-CRP and MMP-9 levels (r=−0.6634 and −0.6878, respectively; both P<0.05). hs-CRP and MMP-9 levels correlated positively (r=0.7208, P<0.05). The number of stenosed coronary vessels was negatively correlated with estrogen levels (r=−0.6467, P<0.05), and positively correlated with hs-CRP and MMP-9 levels (r=0.6519 and 0.6835, respectively; both P<0.05). In conclusion, serum estrogen, hs-CRP and MMP-9 levels were significantly correlated with the severity of coronary artery lesions. There was also a significant correlation between serum estrogen, hs-CRP and MMP-9 levels. These data indicate that serum estrogen, hs-CRP and MMP-9 have the potential to be used as biomarkers for evaluating the severity of coronary artery lesions and the stability of coronary artery plaques.
PMCID: PMC3991495  PMID: 24940407
estrogen; high-sensitivity C-reactive protein; matrix metalloproteinase-9; acute coronary syndrome
2.  Colocalisation of intraplaque C reactive protein, complement, oxidised low density lipoprotein, and macrophages in stable and unstable angina and acute myocardial infarction 
Journal of Clinical Pathology  2006;59(2):196-201.
C reactive protein (CRP), an important serum marker of atherosclerotic vascular disease, has recently been reported to be active inside human atherosclerotic plaques.
To investigate the simultaneous presence of macrophages, CRP, membrane attack complex C5b–9 (MAC), and oxidised low density lipoprotein (oxLDL) in atherectomy specimens from patients with different coronary syndromes.
In total, 54 patients with stable angina (SA; n = 21), unstable angina (UA; n = 15), and myocardial infarction (MI; n = 18) underwent directional coronary atherectomy for coronary lesions. Cryostat sections of atherosclerotic plaques were immunohistochemically stained with monoclonal antibodies: anti‐CD68 (macrophages), anti‐5G4 (CRP), aE11 (MAC), and 12E7 (oxLDL). Immunopositive areas were evaluated in relation to fibrous and neointima tissues, atheroma, and media. Quantitative analysis was performed using image cytometry with systematic random sampling (percentage immunopositive/total tissue area).
Macrophages, CRP, MAC, and oxLDL were simultaneously present in a higher proportion of fibrous tissue and atheroma of atherectomy specimens from patients with UA and MI compared with SA (p<0.05). Quantitative analysis showed significantly higher mean percentages of macrophages in plaques from patients with MI (44%) than UA (30%; p<0.01) and SA (20%; p<0.001). Significantly higher mean percentages of CRP were also seen in MI (25%) and UA (25%) compared with SA (12%; p<0.05).
The presence of CRP, complement, and oxLDL in a high proportion of plaque tissue from patients with unstable coronary artery disease implies that these surrogate markers have important proinflammatory effects inside atherosclerotic plaques. This may increase vulnerability to plaque rupture and thrombosis, with subsequent clinical sequelae.
PMCID: PMC1860312  PMID: 16443738
acute coronary syndromes; atherosclerosis; plaque inflammation; C reactive protein
3.  Evaluation of serum neopterin, high-sensitivity C-reactive protein and thiobarbituric acid reactive substances in Egyptian patients with acute coronary syndromes 
The present study evaluated serum neopterin, high-sensitivity C-reactive protein (hs-CRP) and thiobarbituric acid reactive substances (TBARS) in Egyptian patients with acute coronary artery disease. Thirty-six patients with unstable angina aged (mean ± SD) 61.3±9.4 years, 29 patients with myocardial infarction aged 58.2±8.7 years and 24 sex- and age-matched control subjects were included in the study. Neopterin levels were significantly higher in patients with myocardial infarction and those with unstable angina than in the healthy control group (P<0.001). The serum level of neopterin in the control group (median [range]) was 3.25 nmol/L (1.25 nmol/L to 5.4 nmol/L), whereas in patients with unstable angina and those with myocardial infarction, neopterin levels were 10.4 nmol/L (3.5 nmol/L to 15.2 nmol/L) and 12.6 nmol/L (3.25 nmol/L to 17.8 nmol/L), respectively. Levels of hs-CRP and TBARS were also significantly higher in patients with unstable angina and those with myocardial infarction than in the healthy control group (P<0.01). The medians (ranges) of hs-CRP were 4.8 mg/L (2.5 mg/L to 9.9 mg/L), 12.0 mg/L (4.6 mg/L to 31.0 mg/L) and 12.3 mg/L (7.5 mg/L to 32.1 mg/L) in the control group, patients with unstable angina and those with myocardial infarction, respectively. The means ± SD of TBARS in the control group, patients with unstable angina and those with myocardial infarction were 0.64±0.17 μmol/L, 1.17±0.31 μmol/L and 1.17±0.49 μmol/L, respectively. TBARS positively correlated with hs-CRP and neopterin levels. Furthermore, when both patients and controls were classified according to their smoking status, significantly higher levels of neopterin and TBARS were found in the smokers of each subgroup than in the nonsmokers.
In conclusion, the present study found a higher level of neopterin, hs-CRP and TBARS in patients with coronary artery disease. Serum neopterin and hs-CRP positively correlated with the level of TBARS. The authors suggest that triggering factors (eg, smoking, high cholesterol, elevated body mass index or raised blood pressure) may lead to increased oxidative stress, which induces an inflammatory insult leading to higher levels of inflammatory markers such as neopterin and hs-CRP.
PMCID: PMC2716238  PMID: 19641675
CAD; hs-CRP; Neopterin; Oxidative stress; TBARS
4.  Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease 
PLoS Medicine  2010;7(6):e1000286.
In a systematic review and meta-analysis of 83 prognostic studies of C-reactive protein in coronary disease, Hemingway and colleagues find substantial biases, preventing them from drawing clear conclusions relating to the use of this marker in clinical practice.
Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease.
Methods and Findings
We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time.
The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66).
Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research.
Please see later in the article for the Editors' Summary
Editors' Summary
Coronary artery disease is the leading cause of death among adults in developed countries. With age, fatty deposits called atherosclerotic plaques coat the walls of the arteries, the vessels that carry blood to the body's organs. Because they narrow the arteries, atherosclerotic plaques restrict blood flow. If plaques form in the arteries that feed the heart, the result is coronary artery disease, the symptoms of which include shortness of breath and chest pains (angina). If these symptoms only occur during exertion, the condition is called stable coronary artery disease. Coronary artery disease can cause potentially fatal heart attacks (myocardial infarctions). A heart attack occurs when a plaque ruptures and a blood clot completely blocks the artery, thereby killing part of the heart. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), diabetes, and being overweight are risk factors for coronary artery disease. Treatments for the condition include lifestyle changes and medications that lower blood pressure and blood cholesterol. Narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Clinicians can predict whether a patient with coronary artery disease is likely to have a heart attack by considering their risk factors. They then use this “prognosis” to help them manage the patient. To provide further help for clinicians, researchers are trying to identify prognostic biomarkers (molecules whose blood levels indicate how a disease might develop) for coronary artery disease. However, before a biomarker can be used clinically, it must be properly validated and there are concerns that there is insufficient high quality evidence to validate many biomarkers. In this systematic review and meta-analysis, the researchers ask whether the evidence for an association between blood levels of C-reactive protein (CRP, an inflammatory protein) and subsequent fatal and nonfatal events affecting the heart and circulation (cardiovascular events) among patients with stable coronary artery disease supports the routine measurement of CRP as recommended in clinical practice guidelines. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies that investigated the association between CRP levels measured in people with coronary artery disease and subsequent cardiovascular events. Their examination of these studies revealed numerous reporting and publication short-comings. For example, none of the studies reported a prespecified statistical analysis protocol, yet analyses should be prespecified to avoid the choice of analytical method biasing the study's results. Furthermore, on average, the studies only reported seven of the 17 recommended items in the REMARK reporting guidelines, which were designed to improve the reporting quality of tumor biomarker prognostic studies. The meta-analysis revealed that patients with a CRP level in the top third of the distribution were nearly twice as likely to have a cardiovascular event as patients with a CRP in the bottom third of the distribution (a relative risk of 1.97). However, the outcomes varied considerably between studies (heterogeneity) and there was strong evidence for publication bias—most published studies were small and smaller studies were more likely to report higher relative risks. Adjustment for publication bias reduced the relative risk associated with high CRP levels to 1.19. Finally, nearly all the studies failed to calculate whether CRP measurements discriminated between patients likely and unlikely to have a subsequent cardiovascular event.
What Do These Findings Mean?
These findings suggest that, because of multiple types of reporting and publication bias, the size of the association between CRP levels and prognosis among patients with stable coronary artery disease is extremely uncertain. They also suggest that CRP measurements are unlikely to add anything to the prognostic discrimination achieved by considering blood pressure and other standard clinical factors among this patient group. Thus, the researchers suggest, the recommendation that CRP measurements should be used in the management of patients with stable coronary artery disease ought to be removed from clinical practice guidelines. More generally, these findings increase concerns about the quality of research into prognostic biomarkers and highlight areas that need to be changed, the most fundamental of which is the need to preregister studies on prognostic biomarkers and their analytic protocols.
Additional Information
Please access these Web sites via the online version of this summary at
The MedlinePlus Encyclopedia has pages on coronary artery disease and C-reactive protein (in English and Spanish)
MedlinePlus provides links to other sources of information on heart disease
The American Heart Association provides information for patients and caregivers on all aspects of cardiovascular disease, including information on the role of C-reactive protein in heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
Wikipedia has pages on biomarkers and on C-reactive protein (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The EQUATOR network is a resource center for good reporting of health research studies
PMCID: PMC2879408  PMID: 20532236
5.  Risk stratification in unstable angina and non-Q wave myocardial infarction using soluble cell adhesion molecules 
Heart  2001;85(6):623-627.
OBJECTIVE—To assess prospectively the prognostic value of soluble cellular adhesion molecules (CAMs) in patients with unstable angina and non-Q wave myocardial infarction and to compare their prognostic accuracy with that of C reactive protein (CRP).
DESIGN AND SETTING—Prospective observational study of patients presenting acutely with unstable angina and non-Q wave myocardial infarction to a single south Dublin hospital.
METHODS—Patients with Braunwald IIIA unstable angina and non-Q wave myocardial infarction had serum samples taken at presentation before initiation of antithrombotic treatment and were followed for six months. The primary end point was the occurrence of major adverse cardiovascular events (recurrent unstable angina, non-fatal myocardial infarction, and cardiovascular death) at six months. Concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble endothelial selectin, and soluble platelet selectin were measured using an enzyme linked immunosorbent assay technique. CRP was measured with an immunophelometric assay.
RESULTS—91 patients (73 men and 18 women, mean (SD) age 61 (11) years) were studied; 27 patients (30%) had major adverse cardiac events during the six months of follow up. Concentration of CRP were significantly raised in patients who had an ischaemic event (mean (SEM) 11.5 (6.4) mg/l v 5.4 (2.5) mg/l, p < 0.001). Concentrations of sVCAM-1 were also significantly raised in the ischaemic event group (979 (30) ng/ml v 729 (22) ng/ml, p < 0.001). Both sVCAM-1 and CRP concentrations correlated strongly with the occurrence of an adverse event. The sensitivity of CRP > 3 mg/l and sVCAM-1 > 780 ng/ml for predicting future events was > 90%. There was no difference in concentrations of sICAM-1, soluble endothelin selectin, or soluble platelet selectin between event and non-event groups.
CONCLUSION—Raised concentrations of sVCAM-1 and CRP are predictive of an increased risk of major adverse cardiovascular events six months after presentation with unstable angina and non-Q wave myocardial infarction. These findings suggest that the intensity of the vascular inflammatory process at the time of presentation is a determinant of clinical outcome in unstable coronary artery disease. 

Keywords: cell adhesion molecules; risk stratification; unstable angina
PMCID: PMC1729754  PMID: 11359739
6.  Coronary artery compliance and adaptive vessel remodelling in patients with stable and unstable coronary artery disease 
Heart  2000;84(3):314-319.
OBJECTIVE—To test the hypothesis that patients with unstable coronary syndromes show accentuated compensatory vessel enlargement compared with patients with stable angina, and that this may in part be related to increased coronary artery distensibility.
DESIGN AND PATIENTS—In 23 patients with unstable coronary syndromes (10 with non-Q wave myocardial infarction and 13 with unstable angina), the culprit lesion was investigated by intravascular ultrasound before intervention. The vessel cross sectional area (VA), lumen area (LA), and plaque area (VA minus LA) were measured at end diastole and end systole at the lesion site and at the proximal and distal reference segments. Similar measurements were made in 23 patients with stable angina admitted during the same period and matched for age, sex, and target vessel. Calculations were made of remodelling index (VA at lesion site ÷ VA at reference site), distensibility index ([(ΔA/A)/ΔP] × 103, where ΔA is the luminal area change in systole and diastole and ΔP the difference in systolic and diastolic blood pressure measured at the tip of the guiding catheter during a cardiac cycle), and stiffness index β ([ln(Psys/Pdias)]/(ΔD/D), where Psys is systolic pressure, Pdias is diastolic pressure, and ΔD is the difference between systolic and diastolic lumen diameters). Positive remodelling was defined as when the VA at the lesion was > 1.05 times larger than at the proximal reference site, and negative remodelling when the VA at the lesion was < 0.95 of the reference site.
RESULTS—Mean (SD) LA at the lesion site was similar in both groups (4.03 (1.8) v 4.01 (1.93) mm2), while plaque area was larger in the unstable group (13.29 (4.04) v 8.34 (3.6) mm2, p < 0.001). Remodelling index was greater in the unstable group (1.14 (0.18) v 0.83 (0.15), p < 0.001). Positive remodelling was observed in 15 patients in the unstable group (65%) but in only two (9%) in the stable group (p < 0.001). Negative remodelling occurred only in two patients with unstable symptoms (9%) but in 17 (74%) with stable symptoms. At the proximal reference segment, the difference in LA between systole and diastole was 0.99 (0.66) mm2 in the unstable group and 0.39 (0.3) mm2 in the stable group (p < 0.001), and the calculated coronary artery distensibility was 3.09 (2.69) and 0.94 (0.83) per mm Hg in unstable and stable patients, respectively (p < 0.001). The stiffness index β was lower in patients with unstable angina (1.95 (0.94) v 3.1 (0.96), p < 0.001).
CONCLUSIONS—Compensatory vessel enlargement occurs to a greater degree in patients with unstable than with stable coronary syndromes, and is associated with increased coronary artery distensibility.

Keywords: coronary artery disease; remodelling; compliance; angina pectoris
PMCID: PMC1760936  PMID: 10956298
7.  Coronary artery disease: arterial remodelling and clinical presentation 
Heart  1999;82(4):461-464.
OBJECTIVE—To investigate the hypothesis that in coronary artery disease large plaques in compensatorily enlarged segments are associated with acute coronary syndromes, whereas smaller plaques in shrunken segments are associated with stable angina pectoris.
METHODS—Patients selected for percutaneous transluminal coronary angioplasty (PTCA) were divided into two groups, one with stable angina pectoris (stable group, n = 37) and one with unstable angina or postmyocardial infarction angina of the infarct related artery (unstable group, n = 32). In both groups, remodelling at the culprit lesion site was determined by intravascular ultrasound before the intervention. Remodelling was calculated as relative vessel area: [vessel area culprit lesion site ÷ mean vessel area of both proximal and distal reference sites] × 100%. Compensatory enlargement was defined as remodelling of ⩾ 105%, whereas shrinkage was defined as remodelling of ⩽ 95%.
RESULTS—In the unstable group, the vessel area at the culprit lesion site was larger than in the stable group, at mean (SD) 18.1 (5.3) v 14.6 (5.4) mm2 (p = 0.008). Lumen areas were similar. Consequently, plaque area and percentage remodelling were larger in the unstable group than in the stable group: mean (SD) 14.8 (4.8) v 11.6 (4.9) mm2 (p = 0.009) and 112 (31)% v 95 (17)% (p = 0.005), respectively. Significantly more culprit lesion sites were classified as shrunken in the stable group (21/37) than in the unstable group (8/32; p = 0.014). On the other hand, more lesion sites were classified as enlarged in the unstable group (16/23) than in the stable group (8/37; p = 0.022).
CONCLUSIONS—In patients selected for PTCA, the mode of remodelling is related to clinical presentation.

Keywords: atherosclerosis; coronary disease; remodelling; intravascular ultrasound
PMCID: PMC1760264  PMID: 10490561
8.  Intracoronary Multi-link stents: experience in 218 patients using aspirin alone 
Heart  1998;80(5):499-504.
Objectives—To assess procedural outcome, complications, and clinical follow up in 218 patients who underwent treatment with 297 Multi-link (Guidant) stents implanted without the use of intravascular ultrasound (IVUS) or quantitative coronary angiography (QCA), and using aspirin alone as antiplatelet therapy.
Methods—The case records and angiograms were reviewed and the patients were contacted by telephone to determine their symptoms and any adverse events at follow up. Data were analysed using Fisher's exact test. 
Results—Of the 218 patients included in the study, 45 had multivessel intracoronary intervention, and 55 had unstable angina. The mean (SD) length of hospital stay following the procedure was 2.0 (2.1) days. There were two early deaths at less than 30 days, and two deaths during follow up at more than 100 days. Ten patients suffered complications during the first 30 days: four had subacute stent thrombosis, of whom two died and two were treated successfully with coronary artery bypass grafting; five had a non-Q wave myocardial infarction; and one had a femoral false aneurysm. Patient outcome was analysed according to stent diameter (3.0 mm or less, or 3.5 mm or more) and by angina status (stable or unstable). In patients in whom at least one stent was 3.0 mm diameter, four of 86 patients suffered acute stent occlusion, whereas in the 132 patients in whom all stents were at least 3.5 mm diameter there were no cases of stent occlusion (p = 0.02). In the unstable angina group two of 55 patients suffered acute stent occlusion compared to two of 163 patients in the stable angina group (NS). In patients with unstable angina and at least one stent of 3.0 mm diameter, the acute occlusion rate was 7.1% (two of 28 patients). Three of the four patients with stent occlusion had undergone complex procedures. Twenty eight patients were restudied for recurrent symptoms during the follow up period. Of these, eight patients had restenosis within their stent. In seven of these patients the stent size was 3.0 mm diameter, and in the remaining patient the stent size was 4.0 mm diameter. Three of the 28 patients restudied had developed new disease remote from the stented site, and 17 had patent stents and no significant other coronary lesion. 
Conclusions—This study suggests that coronary intervention using the Multi-link stent is safe and effective using aspirin alone, without IVUS or QCA, when stent diameter is greater than 3.0 mm. All cases of stent occlusion in this series occurred in patients in whom at least one stent was 3.0 mm diameter, with stent occlusion being higher in patients with unstable angina compared to those with stable angina. Additional antiplatelet therapy may be beneficial in those patients in whom Multi-link stent diameter is less than 3.5 mm, particularly in those with unstable angina, but is not necessary for patients receiving Multi-link stents of 3.5 mm diameter or greater.

 Keywords: intracoronary Multi-link stents;  aspirin;  stent occlusion
PMCID: PMC1728838  PMID: 9930052
9.  Clinically stable angina pectoris is not necessarily associated with histologically stable atherosclerotic plaques. 
Heart  1996;76(4):312-316.
OBJECTIVE: To investigate the extent of plaque inflammation in culprit lesions of patients with chronic stable angina. DESIGN: Retrospective study. SETTING: Amsterdam reference centre. SUBJECTS: 89 consecutive patients who underwent directional coronary atherectomy, 58 of whom met the following inclusion criteria: chronic stable angina (Canadian Cardiovascular Society classification 1-3 (group 1, n = 28)); unstable angina (Braunwald class II (group 2, n = 18)); unstable angina (Braunwald class III (group 3, n = 12)). INTERVENTIONS: Directional atherectomy in patients with angina pectoris. MAIN OUTCOME MEASURES: Tissue areas of culprit lesions occupied by inflammatory cells and smooth muscle cells related to clinically defined ischaemic syndrome. RESULTS: Areas (% of total surface area (mean (SEM)) rich in smooth muscle cells were larger in patients with chronic stable angina (group 1, 51.2 (20.9)) than in those with unstable angina (group 2, 42.1 (20.5); group 3, 29.5 (19.4)) (1 v 2 and 2 v 3, NS; 1 v 3, P < 0.004). Macrophage rich areas were significantly smaller in patients with stable angina (group 1, 21.8 (11.9)) than in those with unstable angina (group 2, 31.5 (14.6); group 3, 46.4 (16.7)) (1 v 2, P < 0.02; 2 v 3, P < 0.02; 1 v 3, P < 0.001). Mean numbers of T cells per mm2 were as follows: group 1, 17 (9.4); group 2, 25 (15.9); group 3, 41 (30.6) (1 v 2, P 0.04; 2 v 3, P 0.07; 1 v 3, P < 0.001). Areas with HLA-DR positive cells showed the same pattern as macrophages and T cells and were smaller in stable (29.9 (12.4)) than in unstable angina (group 2, 40.4 (17.6); group 3, 52.4 (12.0)) (1 v 2, P < 0.02; 2 v 3, P < 0.05; 1 v 3, P < 0.001). CONCLUSION: The inverse relation between the extent of inflammatory activity in plaque tissues of culprit lesions and the clinical stability of the ischaemic syndrome supports the concept that reduction of inflammation favours plaque stabilisation. At the same time, the considerable overlap between groups indicates that patients with clinically stable angina do not all have histologically stable plaques.
PMCID: PMC484541  PMID: 8983676
10.  Acute and convalescent changes in plasma homocysteine concentrations in acute coronary syndromes 
Heart  2001;85(4):380-384.
BACKGROUND—Raised plasma homocysteine is a risk factor for coronary artery disease. Patients with myocardial infarction or unstable angina show greater activation of coagulation, greater troponin release, and a worse outcome.
OBJECTIVE—To examine variations in plasma homocysteine concentration in relation to C reactive protein (CRP) in patients presenting with acute coronary syndromes.
METHODS—Consecutive patients presenting with acute myocardial infarction (22) and unstable angina pectoris (12) were studied. Plasma samples were obtained on admission (before clinical intervention), on days 2, 7, and 28, and again six months after admission. Plasma homocysteine, assayed by high performance liquid chromatography, and CRP were both determined at the same time points. Changes were assessed by analysis of variance.
RESULTS—CRP concentrations showed a classical rise on day 2, followed by a gradual decline to normal values taken at six months from admission in both myocardial infarction (p < 0.0001) and unstable angina (p = 0.02). Homocysteine concentrations in myocardial infarction (median, 25th to 75th interquartile range) were: 11.9 (10.7 to 12.6), 11.5 (9.1 to 13.4), 12.1 (11.4 to 14.1), 12.4 (11.1 to 14.4), and 12.1 (11.2 to 14.0) µmol/l, for days 1, 2, 7, 28, and 180, respectively (p = 0.02). Significant differences were observed only between day 2 and day 7 (p < 0.05). The final homocysteine measurement was not different from the admission level. Homocysteine concentrations in unstable angina did not differ between admission and convalescence (12.5 (9.1 to 14.5) µmol/l and 12.3 (7.7 to 14.9) µmol/l, respectively).
CONCLUSIONS—Plasma homocysteine concentrations are minimally influenced by acute phase variations with reliable measurements obtained on admission in patients with myocardial infarction and unstable angina.

Keywords: myocardial infarction; unstable angina; homocysteine; sample timing
PMCID: PMC1729690  PMID: 11250957
11.  Plasma osteopontin levels are elevated in non-ST-segment elevation acute coronary syndromes. 
BACKGROUND: The regions of ruptured atherosclerotic plaques have numerous macrophages. Osteopontin that modulates macrophage function has been shown in atherosclerotic plaques. We aimed to study the plasma levels of osteopontin in patients with unstable angina or non-ST-seg ment elevation myocardial infarction (NSTEMI) and the rela tionship between osteopontin and the extent of the coronary artery disease (CAD). METHODS: We studied 65 patients with unstable angina or NSTEMI, 25 patients with stable angina and 18 patients as the control group. The extent of coronary artery stenosis was determined by the number of vessels with >50% stenosis. Plasma osteopontin concentrations were measured from the blood samples that were drawn immediately after admission to the emergency department in unstable angina/NSTEMI patients and before the coronary angiograph in the stable angina and control groups. RESULTS: The plasma osteopontin concentration was (495 118 ng/ml) significantly higher in the patients with unstable angina/NSTEMI compared to the stable angina group (319 106 ng/ml) and control group (125+/-54 ng/ml) (p=0.0001 The plasma osteopontin levels were lower in the patients with stable angina pectoris who had one-vessel disease compared to those with two-vessel disease (p=0.01). How ever, in the unstable angina/NSTEMI group, the plasma osteopontin levels were statistically not different among the patients with one-vessel, and two-vessel and three-vessel disease (p=NS). There was no correlation between the plasma osteopontin levels and the extent of coronary stenosis. CONCLUSIONS: The plasma osteopontin levels are elevatedin patients with unstable angina/NSTEMI, but there appears to be no correlation with the extent of CAD. These results ma suggest that osteopontin may have a role in the pathobiology of ACS.
PMCID: PMC2569782  PMID: 17128682
12.  Patients with acute coronary syndromes express enhanced CD40 ligand/CD154 on platelets 
Heart  2001;86(6):649-655.
OBJECTIVE—To investigate whether CD40L/CD154 on platelets and soluble CD40L/CD154 may play a role in the inflammatory process of acute coronary syndromes.
DESIGN AND SETTING—Observational study in a university hospital.
PATIENTS—15 patients with acute myocardial infarction, 25 patients with unstable angina, 15 patients with stable angina, and 12 controls.
MAIN OUTCOME MEASURES—CD40L/CD154 on platelets, P-selectin/CD62P on platelets, soluble CD40L/CD154 serum concentrations.
RESULTS—Mean (SD) CD40L/CD154 expression on platelets was 6.2 (2.8) MFI (mean fluorescence intensity) in the infarct group, 11 (3.3) MFI in the unstable angina group (p < 0.001 v infarction), 3.6 (0.9) MFI in the stable angina group (p < 0.01 v infarction; p < 0.001 v unstable angina), and 3.2 (1.0) MFI in the controls (p < 0.01 v infarction; p < 0.001 v unstable angina; NS v stable angina). Soluble CD40L/CD154 concentration was 5.2 (1.1) ng/ml in the infarct group, 4.2 (0.7) ng/ml in the unstable angina group (p < 0.001 v infarction), 2.9 (1.0) ng/ml in stable angina group (p < 0.001 v infarction and unstable angina), and 3.0 (0.5) ng/ml in the controls (p < 0.001 v infarction and unstable angina; NS v stable angina). At a six months follow up, there was lower expression of CD40L/CD154 on platelets in patients with unstable angina (12.3 (3.6) v 3.8 (1.2) MFI, p < 0.0001) and acute myocardial infarction (6.2 (2.8) v 3.5 (0.8) MFI, p < 0.01) compared with their admission values six months earlier. Patients with unstable angina who needed redo coronary angioplasty (PTCA) or who had recurrence of angina were characterised by increased CD40L/CD154 expression on platelets compared with the remainder of the study group (recurrence of angina: 12.7 (3.2) v 9.7 (1.6) MFI, p < 0.05; re-do PTCA: 14.3 (4.2) v 10.3 (2.1) MFI, p < 0.05).
CONCLUSIONS—Both CD40L/CD154 on platelets and soluble CD40L/CD154 are raised in patients with unstable angina and myocardial infarction. These findings suggest that CD40-CD40L/CD154 interactions may play a pathogenic role in triggering and propagation of acute coronary syndromes.

Keywords: acute coronary syndromes; unstable angina; CD40L/CD154; platelets
PMCID: PMC1730016  PMID: 11711459
13.  Histological patterns of atherosclerotic plaques in unstable angina patients vary according to clinical presentation 
Heart  1998;80(1):19-22.
Background—Unstable angina is a heterogeneous clinical syndrome. The diverse clinical presentations of unstable angina may reflect different pathogenic mechanisms within the plaque.
Objective—To investigate the cellular constituents of culprit coronary atheromatous plaques in patients with stable angina pectoris and patients with diverse clinical presentations of unstable angina.
Methods—48 patients who underwent coronary atherectomy for management of ischaemic heart disease: 23 had stable angina and 25 had unstable angina. Of the latter, 11 patients were classified as Braunwald's IIB and 14 as Braunwald's IIIB unstable angina. The presence of thrombus, cholesterol clefts, and smooth muscle cell proliferation was assessed in atherectomy samples using standard histological techniques. Monoclonal antibodies were used to identify smooth muscle cells and macrophages within atherosclerotic plaque fragments.
Results—Fresh thrombus was more frequently found in patients with Braunwald's IIIB unstable angina (64%) than in patients with stable angina (22%) or IIB unstable angina (27%) (p < 0.0006). A pattern of smooth muscle cell proliferation ("accelerated progression pattern") was observed which was also associated with coronary thrombus. This pattern was present in 30% of patients with stable angina, 64% of patients with IIIB unstable angina, and in all patients (100%) with IIB unstable angina. Atherosclerotic plaques with thrombus, cholesterol clefts, and macrophages were more common in patients with unstable angina than in stable angina patients.
Conclusion—The presence of a specific smooth muscle cell proliferation (accelerated progression) pattern in patients with unstable angina, particularly in those with Braunwald's IIB unstable angina, suggests that episodic plaque disruption and subsequent healing may be an important mechanism underlying angina symptoms in these patients.

 Keywords: angina pectoris;  atherosclerosis;  unstable angina;  accelerated progression pattern
PMCID: PMC1728764  PMID: 9764053
14.  Analysis of C-Reactive Protein and Biochemical Parameters in Pericardial Fluid 
Yonsei Medical Journal  2006;47(3):372-376.
This study was designed to examine the relationship between pericardial fluid and plasma CRP levels, and to alterations in other biochemical parameters in patients undergoing Coronary Artery Bypass Grafting (CABG). The study group consisted of 96 Coronary Artery Disease (CAD) patients who were referred to our clinic for a CABG procedure and from whom sufficient amount of pericardial fluid could be collected. The patients were classified into 3 groups: Stable Angina Pectoris (SAP) (n = 27), Unstable Angina Pectoris (USAP) (n = 36), and Post-Myocardial Infarction (PMI) (n = 33). Levels of CRP, glucose, albumin, total protein, Creatine Kinase (CK), Creatine Kinase-MB (CK-MB), and Lactate Dehydrogenase (LDH) were determined in pericardial fluid samples and in simultaneously collected blood samples from radial artery. The pericardial CRP and LDH levels in the PMI group were higher than in the SAP (p = 0.015 and p = 0.000, respectively) and USAP (p = 0.011, p = 0.047) groups. Serum CRP levels in USAP (p = 0.014) and PMI (p = 0.000) groups were higher than those in the SAP group. Pericardial albumin levels in the PMI group were higher than in the USAP group (p = 0.038). In all groups, the pericardial fluid/serum protein ratio was > 0.5, the LDL ratio was > 0.6, and pericardial fluid LDH concentrations were > 300 mg/dl. CRP level of pericardial fluid was significantly higher in the PMI group than in other groups. However, pericardial fluid LDH levels were higher than blood LDH levels in this group and were also higher than pericardial fluid LDH levels of other groups.
PMCID: PMC2688157  PMID: 16807987
Pericardial fluid; CRP; pericardial CK-MB; pericardial LDH
15.  Diagnostic accuracy of dual-source CT angiography and coronary risk stratification 
The aim of this study was to evaluate the diagnostic accuracy of dual-source computed tomography (DSCT) in coronary artery disease, and to test the possibility of using this technique for coronary risk stratification.
With the advent of DSCT, it is possible to image coronary plaque noninvasively. However, the accuracy of this method in terms of sensitivity and specificity has not been determined. Furthermore, noninvasive determination of plaque composition and plaque burden may be important for improving coronary risk stratification.
Forty-six patients with known coronary artery disease underwent DSCT quantitative coronary angiography (QCA), and intravascular ultrasound (IVUS) were included in the study. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of DSCT was calculated against QCA and IVUS. Plaque analysis software in a DSCT workstation was used to detect plaque characteristics associated with the Hounsfield unit (Hu) value compared with IVUS. Coronary artery plaques were classified into three types of lesions based on DSCT, and the relationship between different coronary lesions and clinical diagnosis was determined.
DSCT angiography was performed in 46 patients, and a diagnostic-quality CT image was obtained in 44 patients. Coronary angiography was performed in 138 vessels and IVUS in 102 vessels of all 46 patients. Sensitivity, specificity, PPV, and NPV of DSCT compared with QCA was 100%, 98%, 92%, and 100%, respectively. The same corresponding index of DSCT compared with IVUS was 100%, 99%, 95%, and 100%, respectively. Quantitative coronary stenosis analysis revealed a good correlation between DSCT and QCA (r = 0.85, P < 0.05, 95% confidence interval [CI] 0.60–0.87). There was also a good correlation between DSCT and IVUS (r = 0.81, P < 0.05, 95% CI 0.56–0.82). In comparison with IVUS, DSCT predicted plaque characteristics more accurately. The coefficient correlation (r) of luminal cross-sectional area and external elastic membrane cross-sectional area between DSCT and IVUS was 0.82 (P < 0.01, CI 0.67–0.89) and 0.78 (P < 0.01, CI 0.67–0.86), respectively. Three different types of plaque were identified on IVUS. Fatty plaque had a 45 ± 14 Hu value, fibrous plaque 90 ± 20, and calcified plaque 530 ± 185, respectively, on DSCT. The relationship between clinical diagnosis and coronary plaque on DSCT indicated that lesions in patients with unstable angina pectoris or ST elevation myocardial infarction were mainly discrete soft plaques, but there was no significant difference in the distributive characteristics of the lesions in patients with non-ST elevation myocardial infarction and stable angina pectoris patients.
DSCT is a noninvasive tool that allows accurate evaluation of plaque characteristics, diagnosis of coronary artery disease, and stratification of coronary risk according to different coronary plaque type.
PMCID: PMC2964946  PMID: 21057578
dual-source computed tomography; quantitative coronary angiography; intravascular ultrasound; risk stratification
16.  Prognostic value of the high-mobility group box-1 in young patients with chest pain 
ARYA Atherosclerosis  2014;10(3):154-158.
Atherosclerosis is accepted as an inflammatory disease. Evidence suggests that inflammation evoked by injury plays a pathogenic role in all stages of atherosclerosis. This study aimed to investigate whether the high-mobility group box-1 (HMGB1) a proinflammatory cytokine/nuclear protein, which is derived from both injured endothelium and activated macrophages/monocytes, could contribute to the progression of atherosclerosis and other cardiovascular diseases.
This study was designed as case-control. A total of 135 patients who referred to the hospital due to angina pectoris had the diagnosis of unstable angina and were candidates of angiography were recruited in this study. Forty patients who had coronary artery disease confirmed by angiography were considered as case group and control group consists of 40 persons who had no plaque, and 55 persons were excluded according to the exclusion criteria. At first, a questionnaire was filled for each patient including demographic factors and their medical history. Then a blood sample was taken to assess the level of HMGB1. Data were analyzed using SPSS, Student’s independent t-test, and chi-square tests.
The mean plasma level of HMGB1 in the case group was 27.1 ± 2.9 ng/ml, while it was 19.6 ± 1.9 ng/ml in control groups (P = 0.03). The odds ratio for coronary artery plaque associated with high (> 15.03 ng/ml) levels of HMGB1 was 2.50 (95% confidence interval, 1.02-6.17, P = 0.03).
Increased plasma HMGB1 concentration may be associated with an increased risk of coronary atherosclerosis.
PMCID: PMC4144380  PMID: 25161686
High-Mobility Group Box-1; Coronary Artery Diseases; Inflammation; Biomarkers
17.  Enhanced External Counterpulsation (EECP) 
Executive Summary
To assess the effectiveness, and cost effectiveness of EECP in patients with severe anginal symptoms, secondary to chronic coronary disease, who are unresponsive to exhaustive pharmacotherapy and not candidates for surgical/percutaneous revascularization procedures (e.g., angioplasty, coronary bypass surgery).
To assess the effectiveness, and cost effectiveness of EECP in patients with heart failure.
Clinical Need
Angina is a clinical syndrome characterized by discomfort in the chest, jaw, shoulder, back or arm. Angina usually occurs in patients with coronary artery disease (CAD) involving ≥1 large epicardial artery. However it can also occur in people with valvular heart disease, hypertrophic cardiomyopathy, and uncontrolled hypertension.
Conventional approaches to restoring the balance between oxygen supply and demand focus on the disruption of the underlying disease through: drug therapy (β blockers, calcium channel blockers, nitrates, antiplatelet agents, ACE inhibitors, statins); life-style modifications (smoking cessation, weight loss); or revascularization techniques such as coronary artery bypass graft surgery (CABG) or percutaneous coronary interventions (PCI). (1) Limitations of each of these approaches include: adverse drug effects, procedure-related mortality and morbidity, restenosis after PCI, and time dependent graft attrition after CABG. Furthermore, an increasing number of patients are not appropriate candidates for standard revascularization options, due to co-morbid conditions (HF, peripheral vascular disease), poor distal coronary artery targets, and patient preference. The morbidity and mortality associated with repeat surgical revascularization procedures are significantly higher, and often excludes these patients from consideration for further revascularizations. (2)
Patients with CAD who have chronic ischemic symptoms that are unresponsive to both conventional medical therapy and revascularization techniques have refractory angina pectoris. It has been estimated that greater than 100,000 patients each year in the US may be diagnosed as having this condition. (3) Patients with refractory angina have marked limitation of ordinary physical activity or are unable to perform any ordinary physical activity without discomfort (CCS functional class III/IV). Also, there must be some objective evidence of ischemia as demonstrated by exercise treadmill testing, stress imaging studies or coronary physiologic studies. (1)
Dejongste et al. (4)estimated that the prevalence of chronic refractory angina is about 100,000 patients in the United States. This would correspond to approximately 3,800 (100,000 x 3.8% [Ontario is approximately 3.8% of the population of the United States]) patients in Ontario having chronic refractory angina.
Heart Failure
Heart failure results from any structural or functional cardiac disorder that impairs the ability of the heart to act as a pump.
A recent study (5) revealed 28,702 patients were hospitalized for first-time HF in Ontario between April 1994 and March 1997. Women comprised 51% of the cohort. Eighty-five percent were aged 65 years or older, and 58% were aged 75 years or older.
Patients with chronic HF experience shortness of breath, a limited capacity for exercise, high rates of hospitalization and rehospitalization, and die prematurely. (6) The New York Heart Association (NYHA) has provided a commonly used functional classification for the severity of HF (7):
Class I: No limitation of physical activity. No symptoms with ordinary exertion.
Class II: Slight limitations of physical activity. Ordinary activity causes symptoms.
Class III: Marked limitation of physical activity. Less than ordinary activity causes symptoms. Asymptomatic at rest.
Class IV: Inability to carry out any physical activity without discomfort. Symptoms at rest.
The National Heart, Lung, and Blood Institute (7) estimates that 35% of patients with HF are in functional NYHA class I; 35% are in class II; 25%, class III; and 5%, class IV. Surveys (8) suggest that from 5% to 15% of patients with HF have persistent severe symptoms, and that the remainder of patients with HF is evenly divided between those with mild and moderately severe symptoms.
To date, the diagnosis and management of chronic HF has concentrated on patients with the clinical syndrome of HF accompanied by severe left ventricular systolic dysfunction. Major changes in treatment have resulted from a better understanding of the pathophysiology of HF and the results of large clinical trials. Treatment for chronic HF includes lifestyle management, drugs, cardiac surgery, or implantable pacemakers and defibrillators. Despite pharmacologic advances, which include diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone, and digoxin, many patients remain symptomatic on maximally tolerated doses. (6)
The Technology
Patients are typically treated by a trained technician in a medically supervised environment for 1 hour daily for a total of 35 hours over 7 weeks. The procedure involves sequential inflation and deflation of compressible cuffs wrapped around the patient’s calves, lower thighs and upper thighs. In addition to 3 sets of cuffs, the patient has finger plethysmogram and electrocardiogram (ECG) attachments that are connected to a control and display console.
External counterpulsation was used in the United States to treat cardiogenic shock after acute myocardial infarction. (9;10) More recently, an enhanced version namely “enhanced external counterpulsation” (EECP) was introduced as a noninvasive procedure for outpatient treatment of patients with severe, uncontrollable cardiac ischemia. EECP is said to increase coronary perfusion pressure and reduce the myocardial oxygen demand. Currently, EECP is not applicable for all patients with refractory angina pectoris. For example, many patients are considered ineligible for therapy due to co-morbidities, including those with severe pulmonary vascular disease, deep vein thrombosis, phlebitis and irregular heart rhythms, and heart failure. (1)
Very recently, investigation began into EECP as an adjunctive treatment for patients with HF. Anecdotal reports suggested that EECP may benefit patients with coronary disease and left ventricular dysfunction. The safety and effectiveness of EECP in patients with symptomatic heart failure and coronary disease and its role in patients with nonischemic heart failure secondary to LV dysfunction is unclear. Furthermore, the safety and effectiveness of EECP in the different stages of HF and whether it is only for patients who are refractive to pharmacotherapy is unknown.
2003 Health Technology Assessment by the Medical Advisory Secretariat
The Medical Advisory Secretariat health technology assessment (originally published in February 2003) reported on the effectiveness of EECP for patients with angina and HF. The report concluded that there was insufficient evidence to support the use of EECP in patients with refractory stable CCS III/IV angina as well as insufficient evidence to support the use of EECP in patients with HF.
Review Strategy
The aim of this literature review was to assess the effectiveness, safety, and cost effectiveness of EECP for the treatment of refractory stable CCS III/IV angina or HF.
The standard search strategy used by the Medical Advisory Secretariat was used. This included a search of all international health technology assessments as well as a search of the medical literature from December 2002 to March 2006.
A modification of the GRADE approach (11) was used to make judgments about the quality of evidence and strength of recommendations systematically and explicitly. GRADE provides a framework for structured reflection and can help to ensure that appropriate judgments are made. GRADE takes into account a study’s design, quality, consistency, and directness in judging the quality of evidence for each outcome. The balance between benefits and harms, quality of evidence, applicability, and the certainty of the baseline risks are considered in judgments about the strength of recommendations.
Summary of Findings
The Cochrane and INAHTA databases yielded 3 HTAs or systematic reviews on EECP treatment (Blue Cross Blue Shield Technology Evaluation Center [BCBS TEC], ECRI, and the Centers for Medicare and Medicaid Services [CMS]). A search of Medline and Embase December 2005 – March 2006 (after the literature search cutoff from the most recent HTA) was conducted using key words enhanced external counterpulsation, EECP, angina, myocardial ischemia, congestive heart failure. This search produced 1 study which met the inclusion criteria. This level 4a study was inferior in quality to the RCT which formed the basis of the 2003 Medical Advisory Secretariat recommendation.
BCBS reviewed the evidence through November 2005 to determine if EECP improves health outcomes for refractory chronic stable angina pectoris or chronic stable HF. (12) BCBS concluded that the available evidence is not sufficient to permit conclusions of the effect of EECP on health outcomes. Both controlled trials had methodologic flaws (MUST EECP and MUST EECP quality of life studies). The case series and observational studies for both indications while suggestive of a treatment benefit from EECP have shortcomings as well.
On March 20 2006, CMS posted their proposed coverage decision memorandum for external counterpulsation therapy. (13) Overall, CMS stated that the evidence is not adequate to conclude that external counterpulsation therapy is reasonable and necessary for:
Canadian Cardiovascular Society Classification (CCSC) II angina
Heart failure
NYHA class II/III stable HF symptoms with an EF≤35%
NYHA class II/III stable HF symptoms with an EF≤40%
NYHA class IV HF
Acute HF
Cardiogenic shock
Acute MI
In January 2005, ECRI (14) stated that there was insufficient evidence available to draw conclusions about the long-term effectiveness of EECP, with respect to morbidity, survival, or quality of life, for any coronary indication (refractory angina, congestive heart failure, cardiogenic shock and acute MI).
GRADE Quality of the Studies
According to the GRADE Working Group criteria, the quality of the trials was examined (Table 1). (11)
Quality refers to the criteria such as the adequacy of allocation concealment, blinding and followup.
Consistency refers to the similarity of estimates of effect across studies. If there is important unexplained inconsistency in the results, our confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect and the significance of the differences guide the decision about whether important inconsistency exists.
Directness refers to the extent to which the people interventions and outcome measures are similar to those of interest. For example, there may be uncertainty about the directness of the evidence if the people of interest are older, sicker or have more comorbidity than those in the studies.
As stated by the GRADE Working Group, the following definitions were used in grading the quality of the evidence. (11)
GRADE Quality of Studies
Economic Analysis - Literature Review
No economic analysis of EECP was identified in the published literature.
Estimated Prevalence of Angina in Ontario
3,800 patients with chronic refractory angina:
The number of patients with chronic refractory angina in the US is estimated to be approximately 100,000 (4), this corresponds to about 3,800 patients in Ontario (3.8% × 100,000) with refractory angina.
3,800 patients × $7,000 Cdn (approximate cost for a full course of therapy) ~ $26.6M Cdn.
Estimated Prevalence of Heart Failure in Ontario
23,700 patients EF ≤ 0.35:
This estimate is from an expert (personal communication) at the Institute for Clinical Evaluative Sciences (ICES), where they examined a sample of echocardiography studies drawn from a diagnostic lab in 2001. They found that the prevalence of EF ≤ 0.35 was 8.3%, and if generalized to all patients undergoing echocardiography, there would be 23,700 patients.
23,700 patients with EF ≤35% × $7,000 Cdn ~ $166 M Cdn.
There is insufficient evidence to support the effectiveness and safety of EECP treatment for patients with refractory stable CCS III-IV angina or HF.
As per the GRADE Working Group, overall recommendations consider 4 main factors. (11)
The tradeoffs, taking into account the estimated size of the effect for the main outcome, the confidence limits around those estimates and the relative value placed on the outcome.
The quality of the evidence.
Translation of the evidence into practice in a specific setting, taking into consideration important factors that could be expected to modify the size of the expected effects such as proximity to a hospital or availability of necessary expertise.
Uncertainty about the baseline risk for the population of interest.
The GRADE Working Group also recommends that incremental costs of healthcare alternatives should be considered explicitly alongside the expected health benefits and harms. (11) Recommendations rely on judgments about the value of the incremental health benefits in relation to the incremental costs. The last column in Table 2 is the overall trade-off between benefits and harms and incorporates any risk/uncertainty.
For angina and heart failure, the overall GRADE and strength of the recommendations is “weak” – the quality of the evidence is “low” (uncertainties due to methodological limitations in the study design in terms of study quality and directness), and the corresponding risk/uncertainty is increased due to a budget impact of approximately $26.6 M Cdn or $166 M Cdn respectively while the cost-effectiveness of EECP is unknown and difficult to estimate considering that there are no high quality studies of effectiveness.
Overall GRADE and Strength of Recommendation (Including Uncertainty)
PMCID: PMC3379533  PMID: 23074496
18.  Arterial remodelling of native human coronary arteries in patients with unstable angina pectoris: a prospective intravascular ultrasound study 
Heart  1999;82(1):68-74.
OBJECTIVE—To investigate the use of intravascular ultrasound (IVUS) in detecting the presence of arterial remodelling in patients with unstable angina.
DESIGN—Prospective case study.
PATIENTS—60 of 95 consecutively admitted patients with unstable angina (41 male, 19 female), mean (SD) age 61.2 (8.1) years.
INTERVENTIONS—Qualitative and quantitative coronary angiography and IVUS.
MAIN OUTCOME MEASURES—Adaptive or constrictive remodelling (AR, CR) was considered present when the cross sectional area of the external elastic membrane at the lesion site was larger than the proximal cross sectional area or smaller than the distal cross sectional area, respectively.
RESULTS—22 of the 60 patients (37%) showed AR and 14 (23%) showed CR. No remodelling was seen in 24 patients (group NR). The plaque contained more thrombus and plaque rupture in group AR than in groups CR and NR (thrombus: 91% v 50% and 67%, respectively, p = 0.023; rupture: 73% v 29% and 42%, p = 0.020). AR was associated with a larger plaque cross sectional area (12.6 (SD 4.6) mm2 v 10.8 (6.3) and 9.2 (3.7) mm2, p = 0.001) and larger external elastic membrane cross sectional area (16.5 (5.8) mm2 v 13.2 (5.2) and 14.4 (3.6) mm2, p = 0.01 in group AR v groups CR and NR, respectively), while the plaque burden was larger in groups AR (74.9 (9.1)%) and CR (72.4 (16.6)%) than in group NR (66.2 (18.1)%, p = 0.005).
CONCLUSIONS—IVUS is capable of detecting adaptive and constrictive remodelling of target lesions and its relation to plaque morphology in unstable angina.

Keywords: unstable angina; intravascular ultrasound; arterial remodelling; angiography
PMCID: PMC1729084  PMID: 10377312
19.  A significant correlation between C - reactive protein levels in blood monocytes derived macrophages versus content in carotid atherosclerotic lesions 
Atherosclerosis is a complex disease involving different cell types, including macrophages that play a major role in the inflammatory events occurring in atherogenesis. C-Reactive Protein (CRP) is a sensitive systemic marker of inflammation and was identified as a biomarker of cardiovascular diseases. Histological studies demonstrate CRP presence in human atherosclerotic lesions, and we have previously shown that macrophages express CRP mRNA. CRP could be locally secreted in the atherosclerotic lesion by arterial macrophages and local regulation of CRP could affect its pro-atherogenic effects. Moreover, human blood derived macrophages (HMDM) expression of CRP could reflect atherosclerotic lesion secretion of CRP.
Ten type 2 diabetic patients and ten non-diabetic patients scheduled to undergo carotid endarterectomy were enrolled in this study, and their blood samples were used for serum CRP, lipid determination, and for preparation of HMDM further analyzed for their CRP mRNA expression and CRP content. Carotid lesions obtained from the patients were analyzed for their CRP and interleukin 6 (IL-6) content by immunohistochemistry.
Lesions from diabetic patients showed substantially higher CRP levels by 62% (p = 0.05) than lesions from non diabetic patients, and CRP staining that co-localized with arterial macrophages. CRP carotid lesion levels positively correlated with CRP mRNA expression (r2 = 0.661) and with CRP content (r2 = 0.611) in the patient’s HMDM.
Diabetes up-regulated carotid plaques CRP levels and CRP measurements in HMDM could reflect atherosclerotic lesion macrophages secretion of CRP. Understanding the regulation of locally produced macrophage CRP in the arterial wall during atherogenesis could be of major importance in identifying the underlying mechanisms of inflammatory response pathways during atherogenesis.
PMCID: PMC3944991  PMID: 24588988
C-reactive protein; Atherosclerosis; Macrophages; Inflammation
20.  Clinical presentation and functional prognosis in syndrome X. 
British Heart Journal  1993;70(4):346-351.
OBJECTIVES--To assess the effect of clinical presentation on functional prognosis in patients with syndrome X. DESIGN--A prospective study. Patients with syndrome X presenting with unstable angina and stable angina were followed up with a questionnaire to examine their functional state. PATIENTS--41 patients with syndrome X and unstable angina and 41 patients with syndrome X and stable angina. Syndrome X was defined as typical anginal chest pain, a positive exercise test, and normal coronary angiogram. SETTING--Regional cardiothoracic centre. RESULTS--The mean follow up time was 36 (range 20-51) months for the unstable angina group and 35 (range 19-51) months for the stable angina group. No patient was lost to follow up in either group. At follow up 28 patients in the unstable angina group were pain free compared with 15 patients in the stable angina group (p = 0.008). Seven patients in the unstable angina group had further hospital admission with chest pain after the cardiac catheterisation compared wtih 12 patients in the stable angina group (NS). Seven patients in the unstable angina group believed that they had heart disease compared with 27 in the stable angina group (p < 0.001). 26 patients in the unstable angina group but only eight patients in the stable angina group were unlimited in their physical activity (p < 0.001). 12 patients in the unstable angina group compared with 27 patients in the stable angina group were unable to work normally because of chest pain (p < 0.001). The mean (SD) duration of symptoms before cardiac catheterisation was 7.9 (4.7) months in the unstable angina group and 13.4 (5.6) months in the stable angina group (p < 0.001). 10 patients in the unstable angina group and 24 patients in the stable angina group still attended hospital outpatient clinics because of chest pain (p = 0.004). 16 patients in the unstable angina group and 29 patients in the stable angina group were still taking regular antianginal medication (p < 0.001). CONCLUSIONS--Patients with syndrome X who present with unstable angina have a significantly better functional prognosis than those presenting with symptoms of stable angina. This may reflect differences in underlying pathophysiological mechanisms.
PMCID: PMC1025330  PMID: 8217443
21.  Increased serum neopterin: a marker of coronary artery disease activity in women 
Heart  2000;83(3):346-350.
OBJECTIVE—To assess whether neopterin concentrations in women with unstable angina differ from those in women with chronic stable angina.
DESIGN—Prospective cohort study.
SETTING—University hospital in south west London.
PATIENTS—114 consecutive women with angina were studied: 82 had chronic stable angina (typical exertional chest pain, positive exercise ECG testing, and/or abnormal myocardial scintigraphy; symptoms stable for at least three months), and 32 had unstable angina (Braunwald class III). All patients with chronic stable angina (100%) and 18 with unstable angina (56.3%) underwent digital coronary angiography; neopterin concentrations were determined using a commercially available immunoassay.
MAIN OUTCOME MEASURES—Major clinical events during one year follow up were readmission with Braunwald's class IIIb unstable angina, non-fatal myocardial infarction, and cardiac death.
RESULTS—Major events occurred in 12 women with chronic stable angina (14.6%) and nine women with unstable angina (28.1%). Mean (range) neopterin concentrations were significantly higher in women with unstable angina than in those with chronic stable angina (7.6 (5.1-11.5) nmol/l v 5.9 (4.4-7.5) nmol/l; p = 0.003), even after adjustment for variables which were significantly different on univariate analysis. In women with chronic stable angina, baseline neopterin concentrations were higher in those with cardiac events than in those without events (7.1 (5.9-9.1) nmol/l v 5.7 (3.9-7.3 nmol/l); p = 0.010), even after adjustment for variables with significant differences between both groups on univariate analysis.
CONCLUSIONS—On average, women with unstable angina had significantly higher neopterin concentrations than women with chronic stable angina. Women with chronic stable angina with events during follow up had higher neopterin concentrations than those without events. Neopterin concentrations were similar in patients with unstable angina and women with chronic stable angina who developed events. Neopterin concentrations may therefore be a marker of risk in women with coronary artery disease.

Keywords: neopterin; women; coronary artery disease
PMCID: PMC1729345  PMID: 10677418
22.  Importance of thrombosis and thrombolysis in silent ischaemia: comparison of patients with acute myocardial infarction and unstable angina. 
British Heart Journal  1994;71(2):151-155.
OBJECTIVE--To investigate whether plaque rupture and thrombosis have a role in silent ischaemia as well as in unstable angina. DESIGN--Prospective analysis of the results of haemostatic diagnostic tests at the moment of developing silent ischaemia at rest. SETTING--Coronary care unit. PATIENTS--22 patients with acute myocardial infarction, 12 patients with symptomatic angina (unstable angina), and 10 normal volunteers (control group). INTERVENTIONS--Continuous cardiac monitoring detected 15 asymptomatic episodes (silent ischaemia) in 6 patients with unstable angina. Blood samples were obtained at admission and when an asymptomatic alteration was detected and 10 minutes later. MAIN OUTCOME MEASURES--Comparisons of concentrations of tissue plasminogen activator, urokinase type plasminogen activator, tissue plasminogen activator inhibitor-1, cross-linked fibrin degradation products, von Willebrand factor, and thrombin-antithrombin III complexes in patients and controls at admission; same comparisons in patients with silent ischaemia at the start of an episode and 10 minutes later. RESULTS--Tissue plasminogen activator concentrations were raised at admission in patients with acute myocardial infarction (mean (SD) 14.2 (6) ng/ml) and in patients with unstable angina (10.1 (2.5) ng/ml) in comparison with controls (5.1 (2.7) ng/ml, p < 0.01 and < 0.05 respectively). There was no differences between the two groups of patients, however. Similar results were observed at the start of a silent ischaemic episode (9.8 (1.9) ng/ml) and 10 minutes later (10.5 (2.9) ng/ml) compared with controls (p < 0.05). Tissue plasminogen activator inhibitor-1 concentrations were raised in patients with acute myocardial infarction (45.1 (15) ng/ml) compared with volunteers (20.6 (16) ng/ml, p < 0.01). In patients with silent ischaemia tissue plasminogen activator inhibitor-1 concentrations were slightly but not significantly increased. Concentrations of cross-linked fibrin degradation products (D dimer) increased during unstable angina (2150 (350) ng/ml) and silent ischaemia (2270 (450) ng/ml) compared with the concentrations in volunteers (340 (80) ng/ml) and patients with acute myocardial infarction (310 (120) ng/ml; p < 0.01). CONCLUSIONS--The results suggest that thrombosis mediates the pathophysiological mechanisms of silent ischaemia and unstable angina.
PMCID: PMC483635  PMID: 8130023
23.  Evidence for oxidative stress in unstable angina 
British Heart Journal  1992;68(5):454-457.
Objective—To determine whether unstable angina, which is characterised by recurring episodes of myocardial ischaemia and reperfusion, is associated with oxidative stress (that is, where there is an imbalance between oxidants, such as free radicals, which are in excess and antioxidants).
Design—Between group comparison of patients with unstable angina, stable angina, and healthy controls.
Setting—The coronary care unit and cardiac investigation ward of a regional cardiology centre.
Patients—Twenty five consecutive patients admitted to the coronary care unit with unstable angina. Twenty five consecutive patients admitted to the cardiac investigation ward (patients with stable angina undergoing coronary angiography) were used as control for the presence of [ill], drug treatment, and smoking habit. Thirty eight healthy controls (hospital staff and patients admitted for minor surgical procedures who were otherwise healthy) were also studied.
Main outcome
measures—Thiobarbituric acid related substances (TBARS) in plasma and plasma reduced thiol (PSH) as indicators of oxidative damage to lipids and proteins respectively were measured. Coronary angiography was performed in all patients with stable angina and roughly half of those with unstable angina.
Results—Mean (SEM) plasma TBARS in unstable angina and stable angina were 9·95 (0·36) nmol/ml and 9·14 (0·28) nmol/ml respectively (p = 0·08). Mean plasma TBARS in healthy controls were 8·09 (0·21) nmol/ml (p < 0·05 compared with both angina groups). Mean (SEM) PSH concentration in unstable angina was 4·21 (9) nmol/ml and in stable angina was 4·85 (9) nmol/ml (p < 0·05). Mean PSH in healthy controls was 5·64 (8) nmol/ml (p < 0·001 compared with both angina groups). The extent of coronary artery disease, use of medication, and smoking habit were not significantly different between the angina groups.
Conclusions—Biochemical indicators of oxidative stress are more abnormal in unstable than stable angina. This is in keeping with experimental evidence that episodes of ischaemia and reperfusion lead to generation of free radicals and toxic oxygen species and depression of endogenous antioxidant activity. The clinical significance of this finding remains to be determined, although, experimentally, free radicals and toxic oxygen species have adverse effects on myocardial contractile function, myocardial electrical stability, endothelial mediated vasodilatation, and coagulation.
PMCID: PMC1025186  PMID: 1467028
24.  Contraindications for Percutaneous Transluminal Coronary Angioplasty in Treatment of Unstable Angina Pectoris 
Texas Heart Institute Journal  1988;15(3):152-154.
In recent years, the indications for percutaneous transluminal coronary angioplasty have expanded to include multivessel disease, unstable angina pectoris, stenosis of coronary bypass grafts, and recent total coronary occlusion. To evaluate our experience in using percutaneous transluminal coronary angioplasty to treat unstable angina, we reviewed the records of the patients who underwent this procedure at our hospital between January 1983 and December 1986.
Of the 689 patients who underwent balloon angioplasty during the study period, 454 had stable angina and 235 had unstable angina; of the latter group, 34 (14.5%) required emergency coronary artery bypass grafting after balloon angioplasty failed. This outcome was associated with 2 risk factors: previous myocardial infarction and triple-vessel disease.
Our data suggest that, in cases of unstable angina pectoris, percutaneous transluminal coronary angioplasty should be reserved for patients with single-vessel disease and no evidence of previous myocardial infarction. They also lend credence to the conclusion that the disease process in unstable angina is different from that in stable angina, and that therapy should be directed towards reducing platelet aggregation and correcting global ischemia, rather than towards balloon angioplasty of “culprit lesions.” (Texas Heart Institute Journal 1988;15:152-154)
PMCID: PMC324817  PMID: 15227244
Angioplasty, transluminal; angina, unstable; aortocoronary bypass; myocardial infarction; ischemia, global; multivessel disease
25.  Coronary angioplasty in unstable angina and stable angina: a comparison of success and complications. 
British Heart Journal  1988;60(5):367-372.
One hundred and five patients with unstable angina and 175 with chronic stable angina were treated by primary percutaneous transluminal coronary angioplasty. Patients with unstable angina had had symptoms for a shorter time and were more likely to have angiographically complex lesions and lesions less than 10 mm in length than patients with chronic stable angina. Other baseline variables were not significantly different in the two groups. The overall primary success rate was similar in both groups (87% v 86%). Nine of the 14 unsuccessful procedures in those with unstable angina and nine of the 24 unsuccessful procedures in those with stable angina were the result of acute occlusion. These results led to a 9% frequency of procedure related myocardial infarction in patients with unstable angina and a 5% rate in those with stable angina (NS). The procedure related infarct rate tended to be higher in patients with unstable angina who had coronary angioplasty soon after an episode of unstable angina (mean 10 days) than in those in whom it was delayed (mean 35 days) (12% v 3%) (NS). In patients with unstable angina who had had a previous myocardial infarction procedure related infarction was significantly more common (18%) than in patients with no previous myocardial infarction (3%). The difference between those with and without previous infarction was also significant in patients with stable angina (10% v 3%).
PMCID: PMC1216592  PMID: 2974297

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