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1.  Effect of nitroglycerin and dipyridamole on regional left ventricular blood flow during coronary artery occlusion. 
Journal of Clinical Investigation  1976;58(6):1287-1296.
Coronary vasodilators have been variously reported to increase, decrease, or have no effect upon blood flow to ischemic myocardium. Consequently, the effects of two different types of dilators, nitroglycerin (TNG) and dipyridamole, were studied with radioactive microspheres in open-chested dogs after coronary artery ligation. Given as a bolus i.v. injection 0.4 mg TNG resulted in an increase in blood flow to nonischemic areas of myocardium and a preservation of flow to ischemic regions, despite a fall in blood pressure. 5 min later blood pressure and nonischemic flow were back to base line, and a small selective increase in flow to ischemic myocardium was found (0.15-0.18 ml/min per g, P less than 0.05). During an 0.2 mg/min infusion of TNG, and also after 1 mg/kg i.v. dipyridamole, ischemic flow was maintained in the face of a 20-30% reduction in blood pressure. In this setting, nonischemic flow was unchanged during TNG and doubled after dipyridamole. With the addition of methoxamine in both dilator groups, blood pressure returned to base line while flow to ischemic areas increased above base-line values (TNG, 0.16-0.20 ml/min per g, P less than 0.01; dipyridamole, 0.18-0.31 ml/min per g, P less than 0.05). Epicardial ST segment elevations increased during TNG infusion and were unchanged after dipyridamole, but with addition of methoxamine, ST segments became less elevated in both drug groups, concomitant with the observed increase in collateral blood flow. These data indicate that both types of coronary vasodilators, when used in conjunction with methoxamine to support blood pressure, reduce collateral resistance, increase collateral flow, and reduce epicardial ST-segment elevations.
PMCID: PMC333300  PMID: 825534
2.  The Effects of Nitroglycerin on Coronary Collaterals and Myocardial Contractility 
Journal of Clinical Investigation  1973;52(11):2836-2847.
Nitroglycerin (TNG) causes a prolonged dilatation of coronary collaterals. To demonstrate a functional significance of this dilatation we measured the effect of TNG on myocardial contractile force in dogs 2½-4 wk after the left anterior descending coronary artery (LAD) had been embolized in closed-chest animals. Development of collaterals was documented by angiography. Via a left thoracotomy the main left coronary artery (LCA) and LAD distal to the embolized plug were cannulated. Coronary flow and perfusion pressure were recorded. Contractile force was measured with gauges sutured to epicardial areas supplied by the left circumflex coronary artery (LCf) and occluded LAD. Coronary perfusion pressure in the LCA was gradually decreased until the contractile force recorded by the LAD gauge diminished while the LCf gauge was unaffected. Under these conditions, with coronary perfusion pressure held constant with the aid of a Starling resistance, TNG (18 μg) injected into the LCA increased peripheral LAD pressure by 3-12 mm Hg and contractile force in the LAD region by 36% (range 20-90%), returning it to near-normal levels, while having minimal effect in the LCf area. These changes persisted for 5 min. When LCf and LAD areas were both ischemic, intracoronary TNG had minimal effect on peripheral LAD pressure and contractile force. Thus, TNG causes prolonged dilatation of coronary collaterals and presumed increased collateral flow with subsequent enhancement of myocardial contractile force in ischemic areas. This effect is seen only when ischemia is limited to an area supplied by the collaterals. When the whole heart is ischemic, collaterals are unresponsive to TNG, suggesting that these collaterals dilate fully when the regions from which they originate become ischemic.
PMCID: PMC302551  PMID: 4201267
3.  Ergonovine stress echocardiography: Recent experience and safety in our centre 
World Journal of Cardiology  2010;2(12):437-442.
AIM: To study recent experience and safety of ergonovine stress echocardiography in our centre.
METHODS: In this study we collected the clinical variables of patients referred since 2002 for ergonovine stress echocardiography, in addition to indications, the results of this test, complications, blood pressure and heart rate values during the test and the number and results of tests requested before this technique.
RESULTS: We performed 40 tests in 38 patients, 2 tests were carried out to verify therapy efficacy. The prevalence of classic cardiovascular risk factors was low and the most frequent indication was chest pain (57.5%). Coronary angiography was performed in 32 patients, and showed normal coronary arteries in 27 patients and non-significant stenosis in 5 cases. In 16 patients, coronary angiography was carried out after a positive or inconclusive ischemia test. Another 6 patients had a normal stress test (5 exercise electrocardiography tests and 1 nuclear imaging test). Of the 40 ergonovine stress echocardiography tests, 6 were positive (4 in the right coronary artery territory and 2 in the circumflex coronary artery territory), all of them by echocardiographic criteria, and by electrocardiographic criteria in only 3 (50%). The presence of non-significant coronary artery stenosis was more frequent in patients with positive ergonovine stress echocardiography (50% vs 6%, P = 0.038), and were related to ischemic territory. During the maximum stress stage, there was a higher systolic (130.26 ± 19.17 mmHg vs 136.58 ± 27.27 mmHg, 95% CI: -12.77 to 0.14 mmHg, P = 0.055) and diastolic blood pressure (77.89 ± 13.49 mmHg vs 83.95 ± 15.73 mmHg, 95% CI: -10.41 to -1.69 mmHg, P = 0.008) than at the baseline stage, and the same was registered with heart rate (73 ± 10.96 beats/min vs 79.79 ± 11.72 beats/min, 95% CI: -9.46 to -4.11 beats/min, P < 0.01). Nevertheless, there were only 2 hypertensive reactions during the last stage, which did not force a premature end to the test, without sustained tachy or bradyarrhythmias, and the technique was well tolerated in 58% of cases. A unique complication (2.5%) of this test was a prolonged vasospasm with a slight increase in necrosis biomarkers, however, this was without repercussion.
CONCLUSION: Ergonovine stress echocardiography can be performed with safety, is well tolerated in the majority of cases, and is useful for determining the ischemia mechanism in selected cases.
PMCID: PMC3011139  PMID: 21191545
Coronary angiography; Ergonovine; Myocardial ischaemia; Stress echocardiography; Vasospasm
4.  Percutaneous coronary intervention delays pacemaker implantation in coronary artery disease patients with established bradyarrhythmias 
Pacemakers have long been used to assist the heart under pathological conditions, and they are the first choice in the treatment of systematic bradyarrhythmias. However, the effect of percutaneous coronary intervention (PCI) in patients with coronary artery disease as well as bradyarrhythmias remains unknown.
In the present study, 42 patients with chest pain and/or abnormal stress test results were surveyed. Before coronary angiography, patients underwent complete examination, including a 24 h dynamic electrocardiogram, which was used to diagnose bradyarrhythmias that were not suitable for pacemaker implantation due to a lack of arrhythmia-related symptoms. All patients underwent PCI but did not undergo pacemaker implantation. Forty-one patients with chest pain and/or abnormal stress test results, as well as symptom-free bradyarrhythmias, were selected as the control group. All of the patients in the control group were committed to treatments without PCI.
During a mean (±SD) of 3.3±0.5 years of follow-up (range 2.5 to 4.5 years), 24 of 42 patients who received PCI underwent pacemaker implantation for arrhythmia-related symptoms, eight were shown by Holter monitoring to have worsened but still exhibited no symptoms, and the remainder did not show any changes according to the examinations performed. In the control group, 31 patients underwent pacemaker implantation for arrhythmia-related symptoms, eight were shown by Holter monitoring to have worsened but still exhibited no symptoms, and two did not show any changes according to the examinations performed. Nevertheless, the rates of pacemaker implantation each year (from the first to the third year) between the two groups were 7.1% versus 39.0% (P=0.001); 33.3% versus 63.4% (P=0.006); and 57.1% versus 75.6%, (P=0.075), respectively.
The present study found that PCI delayed the demand for pacemaker implantation among coronary artery disease patients.
PMCID: PMC3716496  PMID: 24294031
Pacemaker; Percutaneous coronary intervention; Sinus node diseases
5.  Evaluation of coronary microvascular function in patients with vasospastic angina 
AIM: To investigate endothelium-dependent and -independent coronary microvascular functions in patients with vasospastic angina (VSA).
METHODS: Thirty-six patients with VSA (30 men and 6 women; mean age, 58 years) were enrolled in this study. VSA was defined as ≥ 90% narrowing of the epicardial coronary arteries on angiography performed during a spasm provocation test, presence of chest pain, and/or ST-segment deviation on an electrocardiogram (ECG). Patients (n = 36) with negative spasm provocation test results and those matched for age and sex were enrolled as a control group (nonVSA group). Low-dose acetylcholine (ACh; 3 μg/min) was infused into the left coronary ostium for 2 min during the spasm provocation test. Following the spasm provocation test, nitroglycerin (0.2 mg) was administered intracoronally. Coronary blood flow (was calculated from quantitative angiography and Doppler flow velocity measurements, and the coronary flow reserve was calculated as the ratio of coronary flow velocity after injection of adenosine triphosphate (20 μg) to the baseline value. Changes in the coronary artery diameter in response to ACh and nitroglycerin infusion were expressed as percentage changes from baseline measurements.
RESULTS: Body mass index was significantly lower in the VSA group than in the nonVSA group. The frequency of conventional coronary risk factors and the rate of statin use were similar between the 2 groups. The left ventricular ejection fraction as evaluated by echocardiography was similar between the 2 groups. The duration of angina was 9 ± 2 mo. The results of blood chemistry analysis were similar between the 2 groups. Low-dose ACh did not cause coronary spasms. The change in coronary artery diameter in response to ACh was lower in the VSA group (-1.4% ± 9.3%) than in the nonVSA group (3.1% ± 6.5%, P < 0.05), whereas nitroglycerin-induced coronary artery dilatation and coronary blood flow increase in response to ACh or coronary flow reserve did not differ significantly between the 2 groups.
CONCLUSION: These findings suggest that microvascular coronary function may be preserved despite endothelial dysfunction of the epicardial coronary arteries in patients with VSA.
PMCID: PMC3565162  PMID: 23390571
Coronary spasm; Endothelial function; Acetylcholine
6.  Intravascular Ultrasound to Guide Percutaneous Coronary Interventions 
Executive Summary
The objective of this health technology policy assessment was to determine the effectiveness and cost-effectiveness of using intravascular ultrasound (IVUS) as an adjunctive imaging tool to coronary angiography for guiding percutaneous coronary interventions.
Intravascular Ultrasound
Intravascular ultrasound is a procedure that uses high frequency sound waves to acquire 3-dimensional images from the lumen of a blood vessel. The equipment for performing IVUS consists of a percutaneous transducer catheter and a console for reconstructing images. IVUS has been used to study the structure of the arterial wall and nature of atherosclerotic plaques, and obtain measurements of the vessel lumen. Its role in guiding stent placement is also being investigated. IVUS is presently not an insured health service in Ontario.
Clinical Need
Coronary artery disease accounts for approximately 55% of cardiovascular deaths, the leading cause of death in Canada. In Ontario, the annual mortality rate due to ischemic heart disease was 141.8 per 100,000 population between 1995 and 1997. Percutaneous coronary intervention (PCI), a less invasive approach to treating coronary artery disease, is used more frequently than coronary bypass surgery in Ontario. The number of percutaneous coronary intervention procedures funded by the Ontario Ministry of Health and Long-term Care is expected to increase from approximately 17, 780 in 2004/2005 to 22,355 in 2006/2007 (an increase of 26%), with about 95% requiring the placement of one or more stents. Restenosis following percutaneous coronary interventions involving bare metal stents occurs in 15% to 30% of the cases, mainly because of smooth muscle proliferation and migration, and production of extracellular matrix. In-stent restenosis has been linked to suboptimal stent expansion and inadequate lesion coverage, while stent thrombosis has been attributed to incomplete stent-to-vessel wall apposition. Since coronary angiography (the imaging tool used to guide stent placement) has been shown to be inaccurate in assessing optimal stent placement, and IVUS can provide better views of the vessel lumen, the clinical utility of IVUS as an imaging tool adjunctive to coronary angiography in coronary intervention procedures has been explored in clinical studies.
A systematic review was conducted to answer the following questions:
What are the procedure-related complications associated with IVUS?
Does IVUS used in conjunction with angiography to guide percutaneous interventions improve patient outcomes compared to angiographic guidance without IVUS?
Who would benefit most in terms of clinical outcomes from the use of IVUS adjunctive to coronary angiography in guiding PCIs?
What is the effectiveness of IVUS guidance in the context of drug-eluting stents?
What is the cost-effectiveness ratio and budget impact of adjunctive IVUS in PCIs in Ontario?
A systematic search of databases OVID MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) database for the period beginning in May 2001 until the day of the search, November 4, 2005 yielded 2 systematic reviews, 1 meta-analysis, 6 randomized controlled trials, and 2 non-randomized studies on left main coronary arteries. The quality of the studies ranged from moderate to high. These reports were combined with reports from a previous systematic review for analysis. In addition to qualitative synthesis, pooled analyses of data from randomized controlled studies using a random effect model in the Cochrane Review Manager 4.2 software were conducted when possible.
Findings of Literature Review & Analysis
Intravascular ultrasound appears to be a safe tool when used in coronary interventions. Periprocedural complications associated with the use of IVUS in coronary interventions ranged from 0.5% in the largest study to 4%. Coronary rupture was reported in 1 study (1/54). Other complications included prolonged spasms of the artery after stenting, dissection, and femoral aneurysm.
Based on pooled analyses of data from randomized controlled studies, the use of intravascular ultrasound adjunctive to coronary intervention in percutaneous coronary interventions using bare metal stents yielded the following findings:
For lesions predominantly at low risk of restenosis:
There were no significant differences in preintervention angiographic minimal lumen diameter between the IVUS-guided and angiography-guided groups.
IVUS guidance resulted in a significantly larger mean postintervention angiographic minimal lumen diameter (weighted mean difference of 0.11 mm, P = .0003) compared to angiographic guidance alone.
The benefit in angiographic minimal lumen diameter from IVUS guidance was not maintained at 6-month follow-up, when no significant difference in angiographic minimal lumen diameter could be detected between the two arms (weighted mean difference 0.08, P = .13).
There were no statistically significant differences in angiographic binary restenosis rates between IVUS-guidance and no IVUS guidance (Odds ratio [OR] 0.87 in favour of IVUS, 95% Confidence Interval [CI] [0.64–1.18], P = 0.37).
IVUS guidance resulted in a reduction in the odds of target lesion revascularization (repeat percutaneous coronary intervention or coronary bypass graft) compared to angiographic guidance alone. The reduction was statistically significant at a follow-up period of 6 months to 1 year, and at a follow-up period of 18 month to 2 years (OR 0.52 in favour of IVUS, 95% CI [0.33–0.81], P = .004).
Total revascularization rate (either target lesion or target vessel revascularization) was significantly lower for IVUS-guided patients at 18 months to 2.5 years after intervention (OR 0.43 in favour of IVUS, 95% CI [0.29–0.63], p < .0001).
There were no statistically significant differences in the odds of death (OR 1.36 in favour of no IVUS, P =0.65) or myocardial infarction (OR 0.95 in favour of IVUS, P = 0.93) between IVUS-guidance and angiographic guidance alone at up to 2.5 years of follow-up
The odds of having a major cardiac event (defined as death, myocardial infarction, and target lesion or target vessel revascularization) were significantly lower for patients with IVUS guidance compared to angiographic guidance alone during follow-up periods of up to 2.5 years (OR 0.53, 95% CI [0.36–0.78], P = 0.001). Since there were no significant reductions in the odds of death or myocardial infarction, the reduction in the odds of combined events reflected mainly the reduction in revascularization rates.
For lesions at High Risk of Restenosis:
There is evidence from one small, randomized controlled trial (n=150) that IVUS-guided percutaneous coronary intervention in long de novo lesions (>20 mm) of native coronary arteries resulted in statistically significant larger minimal lumen Diameter, and statistically significant lower 6-month angiographic binary restenosis rate. Target vessel revascularization rate and the rate of combined events were also significantly reduced at 12 months.
A small subgroup analysis of a randomized controlled trial reported no benefit in clinical or angiographic outcomes for IVUS-guided percutaneous coronary interventions in patients with diabetes compared to those guided by angiography. However, due to the nature and size of the analysis, no firm conclusions could be reached.
Based on 2 small, prospective, non-randomized controlled studies, IVUS guidance in percutaneous coronary interventions of left main coronary lesions using bare metal stents or drug-eluting stents did not result in any benefits in angiographic or clinical outcomes. These findings need to be confirmed.
Interventions Using Drug-Eluting Stents
There is presently no evidence on whether the addition of IVUS guidance during the implantation of drug-eluting stents would reduce incomplete stent apposition, or improve the angiographic or clinical outcomes of patients.
Ontario-Based Economic Analysis
Cost-effectiveness analysis showed that PCIs using IVUS guidance would likely be less costly and more effective than PCIs without IVUS guidance. The upfront cost of adjunctive use of IVUS in PCIs ranged from $1.56 million at 6% uptake to $13.04 million at 50% uptake. Taking into consideration cost avoidance from reduction in revascularization associated with the use of IVUS, a net saving of $0.63 million to $5.2 million is expected. However, since it is uncertain whether the reduction in revascularization rate resulting from the use of IVUS can be generalized to clinical settings in Ontario, further analysis on the budget impact and cost-effectiveness need to be conducted once Ontario-specific revascularization rates are verified.
Factors to be Considered in the Ontario Context
Applicability of Findings to Ontario
The interim analysis of an Ontario field evaluation that compared drug-eluting stents to bare metal stents showed that the revascularization rates in low-risk patients with bare metal stents were much lower in Ontario compared to rates reported in randomized controlled trials (7.2% vs >17 %). Even though IVUS is presently not routinely used in the stenting of low-risk patients in Ontario, the revascularization rates in these patients in Ontario were shown to be lower than those reported for the IVUS groups reported in published studies. Based on this information and previous findings from the Ontario field evaluation on stenting, it is uncertain whether the reduction in revascularization rates from IVUS guidance can be generalized to Ontario. In light of the above findings, it is advisable to validate the reported benefits of IVUS guidance in percutaneous coronary interventions involving bare metal stents in the Ontario context.
Licensing Status
As of January 16, 2006, Health Canada has licensed 10 intravascular ultrasound imaging systems/catheters for transluminal intervention procedures, most as class 4 medical devices.
Current Funding
IVUS is presently not an insured procedure under the Ontario Health Insurance Plan and there are no professional fees for this procedure. All costs related to the use of IVUS are covered within hospitals’ global budgets. A single use IVUS catheter costs approximately $900CDN and the procedure adds approximately 20 minutes to 30 minutes to a percutaneous coronary intervention procedure.
According to an expert consultant, current use of IVUS in coronary interventions in Ontario is probably limited to high-risk cases such as interventions in long lesions, small vessels, and bifurcated lesions for which images from coronary angiography are indeterminate. It was estimated that IVUS is being used in about 6% of all percutaneous coronary interventions at a large Ontario cardiac centre.
Expert Opinion
IVUS greatly enhances the cardiac interventionists’ ability to visualize and assess high-risk lesions such as long lesions, narrow lesions, and bifurcated lesions that may have indeterminate angiographic images. Information from IVUS in these cases facilitates the choice of the most appropriate approach for the intervention.
The use of adjunctive IVUS in PCIs using bare metal stents in lesions predominantly at low risk for restenosis had no significant impact on survival, myocardial infarction, or angiographic restenosis rates up to 2.5 years after intervention.
The use of IVUS adjunctive to coronary angiography in percutaneous coronary interventions using bare metal stents in lesions predominantly at low risk for restenosis significantly reduced the target lesion and target vessel revascularization at a follow-up period of 18 months to 2.5 years.
One small study suggests that adjunctive IVUS in PCIs using bare metal stents in long lesions (>20 mm) significantly improved the 6-month angiographic restenosis rate and one-year target lesion revascularization rate. These results need to be confirmed with large randomized controlled trials.
Based on information from the Ontario field evaluation on stenting, it is uncertain whether the reduction in revascularization rate resulting from the use of IVUS in the placement of bare metal stents can be generalized to clinical settings in Ontario.
There is presently insufficient evidence available to determine the impact of adjunctive IVUS in percutaneous interventions in high-risk lesions (other than long lesions) or in PCIs using drug-eluting stents.
PMCID: PMC3379536  PMID: 23074482
7.  Effect of Heparin Administration during Coronary Angiography on Vascular or Peripheral Complications: A Single-Blind Randomized Controlled Clinical Trial 
Background: Coronary angiography consists of the selective injection of contrast agents in coronary arteries. Optimal strategy for heparin administration during coronary angiography has yet to be determined. We assessed the effect of heparin administration during coronary angiography on vascular, hemorrhagic, and ischemic complications.
Methods: Five hundred candiates for diagnostic coronary angiography (femoral approach) were randomly divided into case (intravenous Heparin [2000-3000 units]) and control (placebo) groups. Assessment included vascular complications like groin hematoma, retroperitoneal hematoma, pseudoaneurysm, active hemorrhage, cerebral ischemia, and clot formation in the catheter or the sheath during angiography. Information was obtained about the patients’ age, sex, and hypertension and diabetes mellitus history. Patients with severe peripheral vascular disease, aortic stenosis, history of coagulopathy, and angiography over 30 minutes were excluded.
Results: Nine patients from each group were excluded. The remaining 482 patients included 285 (59.1%) men and 197 (40.9%) women. In the case group (n=241), 7 (2.9%) patients experienced active hemorrhage at the site of angiographic puncture, 2 (0.83%) developed groin hematoma, and 8 (3.32%) experienced clot formation during angiography, while the corresponding figures for the control group (n=241) were 3 (1.24%), 2 (083%), and 13 (5.39%), respectively. No significant differences were found in hemorrhagic, ischemic, and vascular complications between the two groups.
Conclusion: Heparin administration during coronary angiography had no effect on clot formation as well as hemorrhagic, ischemic, and vascular complications in our patients.
Trial Registration Number: IRCT201202199080N1
PMCID: PMC3838984  PMID: 24293786
Coronary angiography; Heparin; Hemorrhage; Iran
8.  Multi-Detector Computed Tomography Angiography for Coronary Artery Disease 
Executive Summary
Computed tomography (CT) scanning continues to be an important modality for the diagnosis of injury and disease, most notably for indications of the head and abdomen. (1) According to a recent report published by the Canadian Institutes of Health Information, (1) there were about 10.3 scanners per million people in Canada as of January 2004. Ontario had the fewest number of CT scanners per million compared to the other provinces (8 CT scanners per million). The wait time for CT in Ontario of 5 weeks approaches the Canadian median of 6 weeks.
This health technology and policy appraisal systematically reviews the published literature on multidetector CT (MDCT) angiography as a diagnostic tool for the newest indication for CT, coronary artery disease (CAD), and will apply the results of the review to current health care practices in Ontario. This review does not evaluate MDCT to detect coronary calcification without contrast medium for CAD screening purposes.
The Technology
Compared with conventional CT scanning, MDCT can provide smaller pieces of information and can cover a larger area faster. (2) Advancing MDCT technology (8, 16, 32, 64 slice systems) is capable of producing more images in less time. For general CT scanning, this faster capability can reduce the time that patients must stay still during the procedure, thereby reducing potential movement artefact. However, the additional clinical utility of images obtained from faster scanners compared to the images obtained from conventional CT scanners for current CT indications (i.e., non-moving body parts) is not known.
There are suggestions that the new fast scanners can reduce wait times for general CT. MDCT angiography that utilizes a contrast medium, has been proposed as a minimally invasive replacement to coronary angiography to detect coronary artery disease. MDCT may take between 15 to 45 minutes; coronary angiography may take up to 1 hour.
Although 16-slice and 32-slice CT scanners have been available for a few years, 64-slice CT scanners were released only at the end of 2004.
Review Strategy
There are many proven, evidence-based indications for conventional CT. It is not clear how MDCT will add to the clinical utility and management of patients for established CT indications. Therefore, because cardiac imaging, specifically MDCT angiography, is a new indication for CT, this literature review focused on the safety, effectiveness, and cost-effectiveness of MDCT angiography compared with coronary angiography in the diagnosis and management of people with CAD.
This review asked the following questions:
Is the most recent MDCT angiography effective in the imaging of the coronary arteries compared with conventional angiography to correctly diagnose of significant (> 50% lumen reduction) CAD?
What is the utility of MDCT angiography in the management and treatment of patients with CAD?
How does MDCT angiography in the management and treatment of patients with CAD affect longterm outcomes?
The published literature from January 2003 to January 31, 2005 was searched for articles that focused on the detection of coronary artery disease using 16-slice CT or faster, compared with coronary angiography. The search yielded 138 articles; however, 125 were excluded because they did not meet the inclusion criteria (comparison with coronary angiography, diagnostic accuracy measures calculated, and a sample size of 20 or more). As screening for CAD is not advised, studies that utilized MDCT for this purpose or studies that utilized MDCT without contrast media were also excluded. Overall, 13 studies were included in this review.
Summary of Findings
The published literature focused on 16-slice CT angiography for the detection of CAD. Two abstracts that were presented at the 2005 European Congress of Radiology meeting in Vienna compared 64-slice CT angiography with coronary angiography.
The 13 studies focussing on 16-slice CT angiography were stratified into 2 groups: Group 1 included 9 studies that focused on the detection of CAD in symptomatic patients, and Group 2 included 4 studies that examined the use of 16-slice CT angiography to detect disease progression after cardiac interventions. The 2 abstracts on 64-slice CT angiography were presented separately, but were not critically appraised due to the lack of information provided in the abstracts.
16-Slice Computed Tomography Angiography
The STARD initiative to evaluate the reporting quality of studies that focus on diagnostic tests was used. Overall the studies were relatively small (fewer than 100 people), and only about one-half recruited consecutive patients. Most studies reported inclusion criteria, but 5 did not report exclusion criteria. In these 5, the patients were highly selected; therefore, how representative they are of the general population of people with suspicion if CAD or those with disease progression after cardiac intervention is questionable. In most studies, patients were either already taking, or were given, β-blockers to reduce their heart rates to improve image quality sufficiently. Only 6 of the 13 studies reported interobserver reliability quantitatively. The studies typically assessed the quality of the images obtained from 16-slice CT angiography, excluded those of poor quality, and compared the rest with the gold standard, coronary angiography. This practice necessarily inflated the diagnostic accuracy measures. Only 3 studies reported confidence intervals around their measures.
Evaluation of the studies in Group 1 reported variable sensitivity, from just over 60% to 96%, but a more stable specificity, at more than 95%. The false positive rate ranged from 5% to 8%, but the false negative rate was at best under 10% and at worst about 30%. This means that up to one-third of patients who have disease may be missed. These patients may therefore progress to a more severe level of disease and require more invasive procedures. The calculated positive and negative likelihood ratios across the studies suggested that 16-slice CT angiography may be useful to detect disease, but it is not useful to rule out disease. The prevalence of disease, measured by conventional coronoary angiography, was from 50% to 80% across the studies in this review. Overall, 16-slice CT angiography may be useful, but there is no conclusive evidence to suggest that it is equivalent to or better than coronary angiography to detect CAD in symptomatic patients.
In the 4 studies in Group 2, sensitivity and specificity were both reported at more than 95% (except for 1 that reported sensitivity of about 80%). The positive and negative likelihood ratios suggested that the test might be useful to detect disease progression in patients who had cardiac interventions. However, 2 of the 4 studies recruited patients who had been asymptomatic since their intervention. As many of the patients studied were not symptomatic, the relevance of performing MDCT angiography in the patient population may be in question.
64-Slice Computed Tomography Angiography
An analysis from the interim results based on 2 abstracts revealed that 64-slice CT angiography was insufficient compared to coronary angiography and may not be better than 16-slice CT angiography to detect CAD.
Cardiac imaging is a relatively new indication for CT. A systematic review of the literature was performed from 2003 to January 2005 to determine the effectiveness of MDCT angiography (16-slice and 64-slice) compared to coronary angiography to detect CAD. At the time of this report, there was no published literature on 64-slice CT for any indications.
Based on this review, the Medical Advisory Secretariat concluded that there is insufficient evidence to suggest that 16-slice or 64-slice CT angiography is equal to or better than coronary angiography to diagnose CAD in people with symptoms or to detect disease progression in patients who had previous cardiac interventions. An analysis of the evidence suggested that in investigating suspicion of CAD, a substantial number of patients would be missed. This means that these people would not be appropriately treated. These patients might progress to more severe disease and possibly more adverse events. Overall, the clinical utility of MDCT in patient management and long-term outcomes is unknown.
Based on the current evidence, it is unlikely that CT angiography will replace coronary angiography completely, but will probably be used adjunctively with other cardiac diagnostic tests until more definitive evidence is published.
If multi-slice CT scanners are used for coronary angiography in Ontario, access to the current compliment of CT scanners will necessarily increase wait times for general CT scanning. It is unlikely that these newer-generation scanners will improve patient throughput, despite the claim that they are faster.
Screening for CAD in asymptomatic patients and who have no history of ischemic heart disease using any modality is not advised, based on the World Health Organization criteria for screening. Therefore, this review did not examine the use of multi-slice CT for this purpose.
PMCID: PMC3382628  PMID: 23074474
9.  Clinical and procedural predictors of no-reflow in patients with acute myocardial infarction after primary percutaneous coronary intervention 
The treatment of acute myocardial infarction (AMI) is thought to restore antegrade blood flow in the infarct-related artery (IRA) and minimize ischemic damage to the myocardium as soon as possible. The present study aimed to identify possible clinical predictors for no-reflow in patients with AMI after primary percutaneous coronary intervention (PCI).
A total of 312 consecutive patients with AMI who had been treated from January 2008 to December 2010 at the Cardiology Department of East Hospital, Tongji University School of Medicine were enrolled in this study. Inclusion criteria were: (i) patients underwent successfully primary PCI within 12 hours after the appearance of symptoms; or (ii) patients with ischemic chest pain for more than 12 hours after a successful primary PCI within 24 hours after appearance of symptoms. Exculsion criteria were: (i) coronary artery spasm; (ii) diameter stenosis of the culprit lesion was <50% and coronary blood flow was normal; (iii) patients with severe left main coronary or multivessel disease, who had to require emergency revascularization. According to thrombolysis in myocardial infarction (TIMI), the patients were divided into a reflow group and a no-reflow group. The clinical data, angiography findings and surgical data were compared between the two groups. Univariate and multivariate logistic regressions were used to determine the predictors for no-reflow.
Fifty-four (17.3%) of the patients developed NR phenomenon after primary PCI. Univariate analysis showed that age, time from onset to reperfusion, systolic blood pressure (SBP) on admission, Killip class of myocardial infarction, intra-aortic balloon pump (IABP) use before primary PCI, TIMI flow grade before primary PCI, type of occlusion, thrombus burden on baseline angiography, target lesion length, reference luminal diameter and method of reperfusion were correlated with no-reflow (P<0.05 for all). Multiple logistic regression analysis identified that age >65 years [OR=1.470, 95% confidence interval (CI) 1.460–1.490, P=0.007], long time from onset to reperfusion >6 hours (OR=1.270, 95%CI 1.160–1.400, P=0.001), low SBP on admission <100 mmHg (OR=1.910, 95%CI 1.018–3.896, P=0.004), IABP use before PCI (OR= 1.949, 95%CI 1.168–3.253, P=0.011), low (≤1) TIMI flow grade before primary PCI (OR=1.100, 95%CI 1.080–1.250, P<0.001), high thrombus burden (OR=1.600, 95%CI 1.470–2.760, P=0.030), and long target lesion (OR=1.948, 95%CI 1.908–1.990, P=0.019) on angiography were independent predictors of no-reflow.
The occurrence of no-reflow after primary PCI for acute myocardial infarction can predict clinical, angiographic and procedural features.
PMCID: PMC4129879  PMID: 25215156
Acute myocardial infarction; No-reflow phenomenon; Percutaneous coronary intervention; Thrombus
10.  Assessment of endothelium: Dependent vasodilation with a non-invasive method in patients with preeclampsia compared to normotensive pregnant women 
To assess the endothelial function via noninvasive method, in pregnant women with preeclampsia compared to to normotensive pregnant women.
Materials and Methods:
Brachial artery diameter was measured via ultrasound, in 28 women with preeclampcia in case group and normotensive pregnant women in control group, at rest, after inflation of sphygmomanometer cuff up to 250-300 mmHg, immediately after deflation of the cuff, 60-90 minutes later and 5 min after administration of sublingual trinitroglycerin (TNG). Results of these measurements as well as demographic characteristics of participants in both groups were recorded in special forms. Data were analyzed via Statistical Package for Social Sciences (SPSS) version 16, using t-test and repeated measures analysis of variance (ANOVA). P-value < 0.05 was considered statistically significant. The results were presented as mean ± standard deviation (SD).
The mean of brachial artery diameter at rest in the case and control groups was 4.49 ± 0.39 and 4.08 ± 0.38 mm, respectively (P = 0.1). Also the results showed that the brachial artery diameter, immediately after deflation of the cuff, was 4.84 ± 0.4 and 4.37 ± 0.30 mm in the case and control groups (P < 0.001), respectively. The mean brachial artery diameter, 60-90 s after deflation of the cuff, was 4.82 ± 0.41 and 4.42 ± 0.38 mm in the case and control groups (P < 0.00), respectively. The brachial artery diameter, 5 min after sublingual NO administration, was 4.95 ± 0.6 and 4.40 ± 0.45 mm in case and control groups (P < 0.001), respectively. Applying of repeated measures ANOVA showed that the mean difference between case and control groups was statistically significant (P < 0.001).
Current study concluded that there is no difference in endothelium-dependent vasodilation between women with preeclampsia and pregnant women with normal blood pressure.
PMCID: PMC3999604  PMID: 24778672
Brachial artery diameter; endothelium-dependent vasodilation; Endothelium-dependent vasodilation-Preeclampsia-Nitric oxide (NO); NO; normotensive; preeclampsia
11.  Stenting for Peripheral Artery Disease of the Lower Extremities 
Executive Summary
In January 2010, the Medical Advisory Secretariat received an application from University Health Network to provide an evidentiary platform on stenting as a treatment management for peripheral artery disease. The purpose of this health technology assessment is to examine the effectiveness of primary stenting as a treatment management for peripheral artery disease of the lower extremities.
Clinical Need: Condition and Target Population
Peripheral artery disease (PAD) is a progressive disease occurring as a result of plaque accumulation (atherosclerosis) in the arterial system that carries blood to the extremities (arms and legs) as well as vital organs. The vessels that are most affected by PAD are the arteries of the lower extremities, the aorta, the visceral arterial branches, the carotid arteries and the arteries of the upper limbs. In the lower extremities, PAD affects three major arterial segments i) aortic-iliac, ii) femoro-popliteal (FP) and iii) infra-popliteal (primarily tibial) arteries. The disease is commonly classified clinically as asymptomatic claudication, rest pain and critical ischemia.
Although the prevalence of PAD in Canada is not known, it is estimated that 800,000 Canadians have PAD. The 2007 Trans Atlantic Intersociety Consensus (TASC) II Working Group for the Management of Peripheral Disease estimated that the prevalence of PAD in Europe and North America to be 27 million, of whom 88,000 are hospitalizations involving lower extremities. A higher prevalence of PAD among elderly individuals has been reported to range from 12% to 29%. The National Health and Nutrition Examination Survey (NHANES) estimated that the prevalence of PAD is 14.5% among individuals 70 years of age and over.
Modifiable and non-modifiable risk factors associated with PAD include advanced age, male gender, family history, smoking, diabetes, hypertension and hyperlipidemia. PAD is a strong predictor of myocardial infarction (MI), stroke and cardiovascular death. Annually, approximately 10% of ischemic cardiovascular and cerebrovascular events can be attributed to the progression of PAD. Compared with patients without PAD, the 10-year risk of all-cause mortality is 3-fold higher in patients with PAD with 4-5 times greater risk of dying from cardiovascular event. The risk of coronary heart disease is 6 times greater and increases 15-fold in patients with advanced or severe PAD. Among subjects with diabetes, the risk of PAD is often severe and associated with extensive arterial calcification. In these patients the risk of PAD increases two to four fold. The results of the Canadian public survey of knowledge of PAD demonstrated that Canadians are unaware of the morbidity and mortality associated with PAD. Despite its prevalence and cardiovascular risk implications, only 25% of PAD patients are undergoing treatment.
The diagnosis of PAD is difficult as most patients remain asymptomatic for many years. Symptoms do not present until there is at least 50% narrowing of an artery. In the general population, only 10% of persons with PAD have classic symptoms of claudication, 40% do not complain of leg pain, while the remaining 50% have a variety of leg symptoms different from classic claudication. The severity of symptoms depends on the degree of stenosis. The need to intervene is more urgent in patients with limb threatening ischemia as manifested by night pain, rest pain, ischemic ulcers or gangrene. Without successful revascularization those with critical ischemia have a limb loss (amputation) rate of 80-90% in one year.
Diagnosis of PAD is generally non-invasive and can be performed in the physician offices or on an outpatient basis in a hospital. Most common diagnostic procedure include: 1) Ankle Brachial Index (ABI), a ratio of the blood pressure readings between the highest ankle pressure and the highest brachial (arm) pressure; and 2) Doppler ultrasonography, a diagnostic imaging procedure that uses a combination of ultrasound and wave form recordings to evaluate arterial flow in blood vessels. The value of the ABI can provide an assessment of the severity of the disease. Other non invasive imaging techniques include: Computed Tomography (CT) and Magnetic Resonance Angiography (MRA). Definitive diagnosis of PAD can be made by an invasive catheter based angiography procedure which shows the roadmap of the arteries, depicting the exact location and length of the stenosis / occlusion. Angiography is the standard method against which all other imaging procedures are compared for accuracy.
More than 70% of the patients diagnosed with PAD remain stable or improve with conservative management of pharmacologic agents and life style modifications. Significant PAD symptoms are well known to negatively influence an individual quality of life. For those who do not improve, revascularization methods either invasive or non-invasive can be used to restore peripheral circulation.
Technology Under Review
A Stent is a wire mesh “scaffold” that is permanently implanted in the artery to keep the artery open and can be combined with angioplasty to treat PAD. There are two types of stents: i) balloon-expandable and ii) self expandable stents and are available in varying length. The former uses an angioplasty balloon to expand and set the stent within the arterial segment. Recently, drug-eluting stents have been developed and these types of stents release small amounts of medication intended to reduce neointimal hyperplasia, which can cause re-stenosis at the stent site. Endovascular stenting avoids the problem of early elastic recoil, residual stenosis and flow limiting dissection after balloon angioplasty.
Research Questions
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting more effective than percutaneous transluminal angioplasty (PTA) in improving patency?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting provide immediate success compared to PTA?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting associated with less complications compared to PTA?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting compared to PTA reduce the rate of re-intervention?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion) is primary stenting more effective than PTA in improving clinical and hemodynamic success?
Are drug eluting stents more effective than bare stents in improving patency, reducing rates of re-interventions or complications?
Research Methods
Literature Search
A literature search was performed on February 2, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA). Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language full-reports from 1950 to January Week 3, 2010
Comparative randomized controlled trials (RCTs), systematic reviews and meta-analyses of RCTs
Proven diagnosis of PAD of the lower extremities in all patients.
Adult patients at least 18 years of age.
Stent as at least one treatment arm.
Patency, re-stenosis, re-intervention, technical success, hemodynamic (ABI) and clinical improvement and complications as at least an outcome.
Exclusion Criteria
Non-randomized studies
Observational studies (cohort or retrospective studies) and case report
Feasibility studies
Studies that have evaluated stent but not as a primary intervention
Outcomes of Interest
The primary outcome measure was patency. Secondary measures included technical success, re-intervention, complications, hemodynamic (ankle brachial pressure index, treadmill walking distance) and clinical success or improvement according to Rutherford scale. It was anticipated, a priori, that there would be substantial differences among trials regarding the method of examination and definitions of patency or re-stenosis. Where studies reported only re-stenosis rates, patency rates were calculated as 1 minus re-stenosis rates.
Statistical Analysis
Odds ratios (for binary outcomes) or mean difference (for continuous outcomes) with 95% confidence intervals (CI) were calculated for each endpoint. An intention to treat principle (ITT) was used, with the total number of patients randomized to each study arm as the denominator for each proportion. Sensitivity analysis was performed using per protocol approach. A pooled odds ratio (POR) or mean difference for each endpoint was then calculated for all trials reporting that endpoint using a fixed effects model. PORs were calculated for comparisons of primary stenting versus PTA or other alternative procedures. Level of significance was set at alpha=0.05. Homogeneity was assessed using the chi-square test, I2 and by visual inspection of forest plots. If heterogeneity was encountered within groups (P < 0.10), a random effects model was used. All statistical analyses were performed using RevMan 5. Where sufficient data were available, these analyses were repeated within subgroups of patients defined by time of outcome assessment to evaluate sustainability of treatment benefit. Results were pooled based on the diseased artery and stent type.
Summary of Findings
Balloon-expandable stents vs PTA in superficial femoral artery disease
Based on a moderate quality of evidence, there is no significant difference in patency between primary stenting using balloon-expandable bare metal stents and PTA at 6, 12 and 24 months in patients with superficial femoral artery disease. The pooled OR for patency and their corresponding 95% CI are: 6 months 1.26 (0.74, 2.13); 12 months 0.95 (0.66, 1.38); and 24 months 0.72 (0.34. 1.55).
There is no significant difference in clinical improvement, re-interventions, peri and post operative complications, mortality and amputations between primary stenting using balloon-expandable bare stents and PTA in patients with superficial femoral artery. The pooled OR and their corresponding 95% CI are clinical improvement 0.85 (0.50, 1.42); ankle brachial index 0.01 (-0.02, 0.04) re-intervention 0.83 (0.26, 2.65); complications 0.73 (0.43, 1.22); all cause mortality 1.08 (0.59, 1.97) and amputation rates 0.41 (0.14, 1.18).
Self-expandable stents vs PTA in superficial femoral artery disease
Based on a moderate quality of evidence, primary stenting using self-expandable bare metal stents is associated with significant improvement in patency at 6, 12 and 24 months in patients with superficial femoral artery disease. The pooled OR for patency and their corresponding 95% CI are: 6 months 2.35 (1.06, 5.23); 12 months 1.54 (1.01, 2.35); and 24 months 2.18 (1.00. 4.78). However, the benefit of primary stenting is not observed for clinical improvement, re-interventions, peri and post operative complications, mortality and amputation in patients with superficial femoral artery disease. The pooled OR and their corresponding 95% CI are clinical improvement 0.61 (0.37, 1.01); ankle brachial index 0.01 (-0.06, 0.08) re-intervention 0.60 (0.36, 1.02); complications 1.60 (0.53, 4.85); all cause mortality 3.84 (0.74, 19.22) and amputation rates 1.96 (0.20, 18.86).
Balloon expandable stents vs PTA in iliac artery occlusive disease
Based on moderate quality of evidence, despite immediate technical success, 12.23 (7.17, 20.88), primary stenting is not associated with significant improvement in patency, clinical status, treadmill walking distance and reduction in re-intervention, complications, cardiovascular events, all cause mortality, QoL and amputation rates in patients with intermittent claudication caused by iliac artery occlusive disease. The pooled OR and their corresponding 95% CI are: patency 1.03 (0.56, 1.87); clinical improvement 1.08 (0.60, 1.94); walking distance 3.00 (12.96, 18.96); re-intervention 1.16 (0.71, 1.90); complications 0.56 (0.20, 1.53); all cause mortality 0.89 (0.47, 1.71); QoL 0.40 (-4.42, 5.52); cardiovascular event 1.16 (0.56, 2.40) and amputation rates 0.37 (0.11, 1.23). To date no RCTs are available evaluating self-expandable stents in the common or external iliac artery stenosis or occlusion.
Drug-eluting stent vs balloon-expandable bare metal stents in crural arteries
Based on a very low quality of evidence, at 6 months of follow-up, sirolimus drug-eluting stents are associated with a reduction in target vessel revascularization and re-stenosis rates in patients with atherosclerotic lesions of crural (tibial) arteries compared with balloon-expandable bare metal stent. The OR and their corresponding 95% CI are: re-stenosis 0.09 (0.03, 0.28) and TVR 0.15 (0.05, 0.47) in patients with atherosclerotic lesions of the crural arteries at 6 months follow-up. Both types of stents offer similar immediate success. Limitations of this study include: short follow-up period, small sample and no assessment of mortality as an outcome. Further research is needed to confirm its effect and safety.
PMCID: PMC3377569  PMID: 23074395
12.  Significant Response to Lower Acetylcholine Dose Is Associated with Worse Clinical and Angiographic Characteristics in Patients with Vasospastic Angina 
Korean Circulation Journal  2013;43(7):468-473.
Background and Objectives
The intracoronary injection of acetylcholine (Ach) has been shown to induce coronary spasms in patients with variant angina. Clinical significance and angiographic characteristics of patients with a significant response to lower Ach dosages are as-yet non-clarified compared with patients responding to higher Ach doses.
Subjects and Methods
A total of 3034 consecutive patients underwent coronary angiography with Ach provocation tests from January 2004 to August 2010. Ach was injected in incremental doses of 20, 50, 100 µg into the left coronary artery. Significant coronary artery spasm was defined as focal or diffuse severe transient luminal narrowing (>70%) with/without chest pain or ST-T change on the electrocardiogram (ECG). We compared the clinical and angiographic characteristics of patients who responded to a lower Ach dose (20 or 50 µg, n=556) to those that responded to a higher Ach dose (100 µg, n=860).
The baseline clinical and procedural characteristics are well balanced between the two groups, except diabetes was higher in the lower Ach dose group and there were differences in medication history. After adjusting for confounding factors, the lower Ach dose group showed more frequent temporary ST elevation and atrioventricular block on the ECG. Furthermore, the group of patients who responded to the lower Ach dose was associated with a higher incidence of baseline and severe spasm than those who responded to a higher Ach dose.
Patients with a significant response to a lower Ach dose were associated with more frequent ST elevation, baseline spasm, and more severe spasm compared with those who responded to a higher Ach dose, suggesting more intensive medical therapy with close clinical follow-up is required for those patients.
PMCID: PMC3744734  PMID: 23964293
Angina pectoris, variant; Acetylcholine
13.  Effects of a Multimodal Preparation Package on Vital Signs of Patients Waiting for Coronary Angiography 
Nursing and Midwifery Studies  2014;3(1):e17518.
Patients waiting for coronary angiography are often anxious and worried, experiencing considerable emotional problems before the procedure, which can result in an increase in blood pressure (BP), heart rate, respiratory rate and the myocardial oxygen demand. Such maladaptive responses may not only increase the patients need for sedative drugs, but also could increase the length of post angiography hospitalization. Therefore, it is important to implement some supportive actions to decrease the patients’ anxiety and to stabilize their vital signs before coronary angiography.
This study aimed to investigate the effects of a multimodal preparation package on vital signs of patients undergoing coronary angiography.
Patients and Methods:
A matched trial was conducted on 66 patients waiting for coronary angiography. Patients were assigned in intervention (n = 33) and control (n = 33) groups. A multimodal preparation package was implemented in intervention group, two hours before angiography. The data collection instrument consisted of questions on demographic characteristics and a table for recording the patients’ vital signs including systolic BP (SBP) and diastolic BP (DBP), heart rate, respiratory rate and body temperature. Vital signs were measured three times, the day before angiography, 30 minutes before and 30 minutes after the angiography, using a thermometer and a monitoring device. Data analysis was performed using the Kolmogo-Smirnov test, t test and Mann-Whitney U test.
From the total number of 66 patients, the 63.3% were male and married. No significant differences were observed between the mean of SBP and DBP and also the heart rate in the intervention and control groups, on the day before angiography. However, the mean SBP and DBP and heart rate of the intervention group were significantly lower compared to the control group, both 30 minutes before and 30 minutes after angiography. The intervention did not significantly change the respiration rate and temperature in the intervention group.
The study showed that preparation package was effective in decreasing SBP and DBP, as well as heart rate. Therefore, using multimodal comprehensive preparation packages, such as the package used in the present report, is suggested.
PMCID: PMC4228516  PMID: 25414893
Coronary Angiography; Patient Education; Vital Signs
14.  Impact of hypertension on coronary artery spasm as assessed with intracoronary acetylcholine provocation test 
Journal of Human Hypertension  2009;24(2):77-85.
Both hypertension and coronary artery spasm (CAS) are associated with endothelial dysfunction. Thus, a higher incidence of CAS is expected in hypertensive patients. We evaluated the impact of hypertension on CAS with intracoronary acetylcholine (ACh) provocation test. A total of 986 patients (685 hypertensive patients vs 301 normotensive patients) who underwent coronary angiography with ACh provocation test were enrolled. ACh was injected into the left coronary artery in incremental doses of 20, 50 and 100 μg min−1. Significant CAS was defined as a transient >70% luminal narrowing with concurrent chest pain and/or ST-segment changes. Although the incidences of significant ACh-induced CAS were similar between hypertensive and normotensive patients (35.8 vs 39.2%, P=0.303), multivariate logistic analysis showed that hypertension was negatively associated with ACh-induced CAS (odds ratio: 0.70, 95% confidence interval: 0.51–0.94, P=0.020). The angiographic characteristics of ACh-induced CAS were similar between these two groups. Subgroup analysis regarding the impact of the status of blood pressure control on CAS showed that hypertensive patients with controlled blood pressure had a significantly higher incidence of CAS than those with uncontrolled blood pressure (45.2 vs 27.9%, P<0.001), and that uncontrolled blood pressure was negatively associated with ACh-induced CAS (odds ratio: 0.56, 95% confidence interval: 0.40–0.79, P=0.001). In conclusion, despite the expected endothelial dysfunction, hypertension and uncontrolled blood pressure are negatively associated with CAS, suggesting that the mechanisms and risk factors of CAS may be significantly different from those of coronary artery disease.
PMCID: PMC3011093  PMID: 19458625
acetylcholine; coronary artery spasm; blood pressure control
15.  The Effect of Elevated Body Mass Index on Ischemic Heart Disease Risk: Causal Estimates from a Mendelian Randomisation Approach 
PLoS Medicine  2012;9(5):e1001212.
A Mendelian randomization analysis conducted by Børge G. Nordestgaard and colleagues using data from observational studies supports a causal relationship between body mass index and risk for ischemic heart disease.
Adiposity, assessed as elevated body mass index (BMI), is associated with increased risk of ischemic heart disease (IHD); however, whether this is causal is unknown. We tested the hypothesis that positive observational associations between BMI and IHD are causal.
Methods and Findings
In 75,627 individuals taken from two population-based and one case-control study in Copenhagen, we measured BMI, ascertained 11,056 IHD events, and genotyped FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238). Using genotypes as a combined allele score in instrumental variable analyses, the causal odds ratio (OR) between BMI and IHD was estimated and compared with observational estimates. The allele score-BMI and the allele score-IHD associations used to estimate the causal OR were also calculated individually. In observational analyses the OR for IHD was 1.26 (95% CI 1.19–1.34) for every 4 kg/m2 increase in BMI. A one-unit allele score increase associated with a 0.28 kg/m2 (95 CI% 0.20–0.36) increase in BMI and an OR for IHD of 1.03 (95% CI 1.01–1.05) (corresponding to an average 1.68 kg/m2 BMI increase and 18% increase in the odds of IHD for those carrying all six BMI increasing alleles). In instrumental variable analysis using the same allele score the causal IHD OR for a 4 kg/m2 increase in BMI was 1.52 (95% CI 1.12–2.05).
For every 4 kg/m2 increase in BMI, observational estimates suggested a 26% increase in odds for IHD while causal estimates suggested a 52% increase. These data add evidence to support a causal link between increased BMI and IHD risk, though the mechanism may ultimately be through intermediate factors like hypertension, dyslipidemia, and type 2 diabetes. This work has important policy implications for public health, given the continuous nature of the BMI-IHD association and the modifiable nature of BMI. This analysis demonstrates the value of observational studies and their ability to provide unbiased results through inclusion of genetic data avoiding confounding, reverse causation, and bias.
Please see later in the article for the Editors' Summary
Editors' Summary
Ischemic heart disease (IHD; also known as coronary heart disease) is the leading cause of death among adults in developed countries. In the US alone, IHD kills nearly half a million people every year. With age, fatty deposits (atherosclerotic plaques) build up in the walls of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. The resultant reduction in the heart's blood supply causes shortness of breath, angina (chest pains that are usually relieved by rest), and potentially fatal heart attacks (myocardial infarctions). Risk factors for IHD include smoking, high blood pressure (hypertension), abnormal amounts of cholesterol and other fat in the blood (dyslipidemia), type 2 diabetes, and being overweight or obese (having excess body fat). Treatments for IHD include lifestyle changes (for example, losing weight) and medications that lower blood pressure and blood cholesterol levels. The narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Prospective observational studies have shown an association between a high body mass index (BMI, a measure of body fat that is calculated by dividing a person's weight in kilograms by their height in meters squared; a BMI greater than 30 kg/m2 indicates obesity) and an increased risk of IHD. Observational studies, which ask whether people who are exposed to a suspected risk factor develop a specific disease more often than people who are not exposed to the risk factor, cannot prove, however, that changes in BMI/adiposity cause IHD. Obese individuals may share other characteristics that cause both IHD and obesity (confounding) or, rather than obesity causing IHD, IHD may cause obesity (reverse causation). Here, the researchers use “Mendelian randomization” to examine whether elevations in BMI across the lifecourse have a causal impact on IHD risk. Three common genetic variants—FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238)—which have the largest single genetic variant associations with BMI were used in this study. Given that gene variants are inherited essentially randomly with respect to conventional confounding factors and are not subject reverse causation, use of these as instruments (or proxy measures) for variation in BMI as a risk factor (as opposed to measuring BMI directly) allows researchers to comment on whether obesity is causally involved in IHD.
What Did the Researchers Do and Find?
The researchers analyzed data from two population-based studies in which adults were physically examined and answered a lifestyle questionnaire before being followed to see how many developed IDH. They also analyzed data from a case-control study on IDH (in a case-control study, people with a disease are matched with similar people without the disease and the occurrence of risk factors in the patients and controls is compared). Overall, the researchers measured the BMI of 75,627 white individuals, among whom 11,056 already had IDH or developed it, and determined which of the BMI-increasing genetic variants each participant carried. On the basis of the observational data, every 4 kg/m2 increase in BMI increased the odds of IDH by 26% (an odds ratio of 1.26). Using a score derived from the combination of the three genetic variants, the researchers confirmed an association between each BMI increasing allele and both BMI (as expected) and IHD (0.28 kg/m2 and an odds ratio for IHD of 1.03, respectively). On average, compared to people carrying no BMI-increasing gene variants, people carrying six BMI-increasing gene variants had a 1.68 kg/m2 increase in BMI and an 18% increase in IHD risk. To extend this and to essentially reassess the original, observational, relationship between BMI and IHD risk, an “instrumental variable analysis” was used to examine the causal effect of a lifetime change in BMI on the risk of IDH. In this, it was found that for every 4 kg/m2 increase in BMI increased the odds of IDH by 52%.
What Do These Findings Mean?
These findings support a causal link between increased BMI and IDH risk, although it may be that BMI affects IDH through intermediate factors such as hypertension, dyslipidemia, and diabetes. The findings also show that observational studies into the impact of elevated BMI on IHD risk were consistent with this, but also that the inclusion of genetic data increases the value of observational studies by making it possible to avoid issues such as confounding and reverse causation. Finally, these findings and those of recent, observational studies have important implications for public-health policy because they show that the association between BMI (which is modifiable by lifestyle changes) and IHD is continuous. That is, any increase in BMI increases the risk of IHD; there is no threshold below which a BMI increase has no effect on IDH risk. Thus, public-health policies that aim to reduce BMI by even moderate levels could substantially reduce the occurrence of IDH in populations.
Additional Information
Please access these Web sites via the online version of this summary at
The American Heart Association provides information about IHD and tips on keeping the heart healthy, including weight management; it also provides personal stories about IHD
The UK National Health Service Choices website provides information about IHD, including information on prevention and personal stories about IHD
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
The US National Heart Lung and Blood Institute also provides information on IHD (in English and Spanish)
MedlinePlus provides links to many other sources of information on IHD (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC3341326  PMID: 22563304
16.  Eutectic Mixture of Local Anesthesia Cream Can Reduce Both the Radial Pain and Sympathetic Response During Transradial Coronary Angiography 
Korean Circulation Journal  2011;41(12):726-732.
Background and Objectives
adial artery spasm is one of the most common complications of transradial coronary angiography (TRA): the radial artery is prone to cathecholamine-induced contraction and radial pain during TRA could increase the sympathetic tone. The object of this study was to evaluate whether the eutectic mixture of local anesthesia (EMLA) cream, in addition to lidocaine infiltration, could reduce the sympathetic response by reducing radial pain during TRA.
Subjects and Methods
Seventy-six patients were randomized 1 : 1 to either EMLA or control groups. Radial pain was measured by the visual analogue scale (VAS) and the verbal rating scale (VRS-4). Sympathetic response, including systolic (SBP) and diastolic blood pressure (DBP), pulse rate (PR), stroke volume (SV) and total peripheral resistance (TPR), was measured by photoplethysmography.
Radial pain measured during lidocaine infiltration was significantly lower in the EMLA group (VAS: 3.1 vs. 4.0, p=0.04; VRS-4: 2.0 vs. 2.2, p=0.03) and the sympathetic response was significantly blunted in the EMLA group from baseline to lidocaine infiltration (ΔSBP, mm Hg: 5 vs. 13, p<0.01; ΔDBP, mm Hg: 2 vs. 7, p=0.03; ΔPR, beat/min: 2 vs. 8, p<0.01, ΔSV, mL: 3 vs. 21, p<0.01; ΔTPR, mm Hg · L/min: 1.0 vs. 5.9, p<0.01).
In patients undergoing TRA, the EMLA cream, in addition to lidocaine infiltration, effectively reduces the radial pain and thereby the sympathetic response, during lidocaine infiltration.
PMCID: PMC3257456  PMID: 22259603
Anesthesia, local; Coronary angiography; Radial artery
17.  Stress Echocardiography with Contrast for the Diagnosis of Coronary Artery Disease 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease (CAD), an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies for the diagnosis of CAD. Evidence-based analyses have been prepared for each of these five imaging modalities: cardiac magnetic resonance imaging, single photon emission computed tomography, 64-slice computed tomographic angiography, stress echocardiography, and stress echocardiography with contrast. For each technology, an economic analysis was also completed (where appropriate). A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series is made up of the following reports, which can be publicly accessed at the MAS website at: or at
Single Photon Emission Computed Tomography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography with Contrast for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Cardiac Magnetic Resonance Imaging for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Pease note that two related evidence-based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website:
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: an Evidence-Based Analysis
The Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled:
The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [Internet]. Available from:
The objective of this report is to compare echocardiography (ECHO) performed with microsphere contrast agents (contrast echocardiography) to ECHO performed without contrast and to single photon emission computed tomography (SPECT).
Contrast ECHO
Contrast agents for ECHO have been available since the technology was first introduced in the 1990s. Composed of tiny ‘microbubbles’ of an inert gas encapsulated within a lipid, protein, or polymer coat, these agents act to scatter incident ultrasound waves at the gas/liquid interface to increase the strength of a returning ECHO signal. When injected into a patient’s arm, they are transported throughout even the smallest capillaries to greatly enhance the blood pool signal, which would otherwise appear black on conventional two dimensional ECHO. The enhanced signal then helps cardiologists to determine what parts of the patient’s heart muscle are poorly perfused.
The first commercially available microsphere contrast agent was Albunex, which received approval by the Food and Drug Administration in the United States in 1994. This original microsphere agent was limited by its rapid gas volume loss which caused a decline in the ultrasound signal. It worked well in the right chambers of the heart, but dissolved when passing through the pulmonary capillaries and so was unable to provide contrast in the left side. Second generation agents employed different gases that prolonged the life of the microbubbles within the circulation and increased the reproducibility of results.
Today, the most common use for contrast ECHO is to enhance the definition of the left ventricular (LV) endocardial border for cases of LV opacification. The aim of contrast ECHO is to provide better quantification of LV volume and assessment of LV wall motion than ECHO alone. The newest area of development in the research of contrast ECHO is myocardial perfusion assessment, also known as myocardial contrast ECHO. Theoretically, since myocardial ischemia and infarction affect both perfusion and contractility (wall motion), contrast ECHO could be an ideal non-invasive imaging test as it could assess both perfusion and contractility, simultaneously and in real time.
Notably, critically ill patients on ventilators and those with lung problems are more likely to generate poor or ‘suboptimal’ echocardiograms than other patients, as are obese patients and those who’ve undergone recent chest operations. Contrast agents can potentially be used in 10% to 15% of all studies and in approximately 33% of stress tests due to from such suboptimal echocardiograms. Stress can be induced either pharmaceutically (e.g., through dobutamine, dipyrimidamole, adenosine) or with exercise. Generally, contrast agents are used more in pharmaceutical stress echocardiograms than in exercise stress echocardiograms.
Evidence-Based Analysis
This MAS analysis sought to address the following research questions:
Is contrast ECHO more effective than 99-technetium SPECT in terms its ability to detect CAD?
What is the effectiveness of contrast ECHO in assessing patients with suboptimal echocardiograms?
Is contrast ECHO safe compared to other cardiac imaging modalities?
Is contrast ECHO cost-effective compared to other cardiac imaging modalities?
Literature Search
Literature searches were performed on June 22, 2009 and July 27, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until June 30, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria; full-text articles were obtained. Reference lists were also examined for any relevant studies not identified through the search.
Inclusion Criteria
Systematic reviews, meta-analyses, randomized controlled trials, prospective observational studies, retrospective analyses
Minimum sample size of 20 enrolled patients (human only)
The contrast agent used in the study must be licensed by Health Canada
Comparison to reference standard (coronary angiography for the diagnosis of coronary artery disease)
Reporting accuracy data on individual patients (rather than accuracy data stratified by segments of the heart)
English language
Exclusion Criteria
Non-systematic reviews, case reports
Grey literature (e.g. conference abstracts)
Outcomes of Interest
Accuracy outcomes (sensitivity, specificity, positive predictive value, negative predictive value)
Adverse events
Summary of Findings
Twenty-three observational studies were identified that assessed the diagnostic accuracy of contrast ECHO for the diagnosis of CAD. All of these studies used stress ECHO with contrast. In addition, nine retrospective chart reviews were identified, which assessed the safety of contrast ECHO at rest or stress. Based on the results of these studies the following conclusions were made:
Stress ECHO with contrast has a higher diagnostic accuracy in the diagnosis of CAD than stress ECHO (without contrast).
Stress ECHO with contrast seems to have a similar diagnostic accuracy to 99 technetium SPECT.
The addition of contrast to ECHO in patients with suboptimal ECHO results significantly improves interpretability of the results.
There is not a statistically significantly higher mortality rate in patients who receive contrast compared to those who do not.
PMCID: PMC3377574  PMID: 23074387
18.  Chest pain in women: clinical, investigative, and prognostic features. 
BMJ : British Medical Journal  1994;308(6933):883-886.
OBJECTIVE--To characterise clinical, investigative, and prognostic features of women referred with chest pain who subsequently underwent coronary angiography. DESIGN--Analysis of all women with angina referred to one consultant during 1987-91 who subsequently underwent coronary angiography, with follow up to present day. SETTING--Cardiothoracic centre. SUBJECTS--Women with normal coronary arteries; women with coronary artery disease shown on angiography; men with coronary artery disease matched for age; men referred with chest pain during the same period subsequently found to have normal coronary arteries. MAIN OUTCOME MEASURES--Risk factor analysis; results of exercise testing and coronary angiography; intervention; morbidity and mortality. RESULTS--Women comprised 23% (202/886) of patients referred with chest pain who subsequently underwent angiography. 83/202 women had normal coronary angiograms compared with 55/684 men (41% v 8%, P < 0.01). Diabetes mellitus was the only risk factor more frequently encountered in women with coronary artery disease (P = 0.001). The specificity and positive predictive value of exercise testing before angiography were significantly lower in women than men (71% v 93%, P < 0.001 and 76% v 95%, P < 0.001, respectively). Revascularisation procedures were as common in women with coronary artery disease as in men (81 (68%) v 70 (59%)), and there was no difference in event rate during follow up. Many patients with normal coronary arteries, irrespective of sex, had symptoms during follow up (61 (73%) women, 36 (65%) men) and continued to take antianginal drugs (27 (33%) women, 14 (28%) men); 14 (17%) women and six (11%) men required hospital readmission for severe symptoms. CONCLUSIONS--In this series, although women comprised the minority of patients referred with chest pain, a diagnosis of normal coronary arteries was five times more common in women than men. Risk factor analysis and exercise testing were of limited value in predicting coronary artery disease in women. There was no sex bias regarding revascularisation procedures, and outcome was similar. A diagnosis of non-cardiac chest pain in patients with normal coronary arteries was of little benefit to the patient with regard to morbidity.
PMCID: PMC2539855  PMID: 8173366
19.  Silent myocardial infarction in women with type II diabetes mellitus and microalbuminuria 
The aim of this study was to investigate whether asymptomatic women with diabetes mellitus (DM) without previous history of ischemic heart disease (IHD) and normal electrocardiogram (ECG) have suffered silent myocardial infarction (MI).
The study population consisted of 64-years old women with DM and albuminuria (n = 15) and aged- and body mass index-matched controls (n = 16). The patients were selected after screening of 240 women with previously known or unknown DM. The individuals with previous history of IHD and ECG suggesting the presence of IHD were excluded. All subjects were investigated with magnetic resonance imaging (MRI).
MRI investigation has revealed the presence of subendocardial MI in the two DM women (13%). No MI was detected in the control group. MR coronary angiography detected the presence of significant stenosis in the proximal segment of left anterior descending (LAD) coronary artery in one DM woman. This patient developed unstable angina 1 week after the MRI investigation. The conventional angiography has confirmed the presence of significant stenosis in LAD demanding invasive revascularization by percutaneous coronary angioplasty. No difference was found in indices of left ventricular (LV) systolic function while diastolic function was disturbed in the DM group. There was a tendency for increased LV mass in the DM group. No difference was found in the LV volumes.
Clinically significant proportion of the women with DM and albuminuria without previous history of IHD have had silent MI. MRI screening of these high risk female patient is valuable diagnostic tool which may increase diagnostic accuracy and improve prognosis in DM patients with IHD.
PMCID: PMC2621377  PMID: 19209251
asymptomatic; diabetes mellitus; ischemic heart disease; silent myocardial infarction
20.  Contrast media for left ventricular angiography. A comparison between Cardio-Conray and iopamidol. 
British Heart Journal  1984;51(4):427-430.
Forty consecutive patients with coronary artery disease undergoing left ventricular angiography took part in a randomised double blind trial comparing a conventional contrast medium sodium meglumine iothalamate (Cardio-Conray) with the low osmolar agent iopamidol. Iopamidol produced a smaller rise in heart rate and a smaller fall in left ventricular systolic pressure, but the changes in left ventricular and diastolic pressure and maximum rate of change of pressure (dP/dt max) were not different. The numbers of extrasystoles per minute for five minutes after ventriculography were similar in both groups except for the first 15 seconds, when the number of extrasystoles was increased in the iopamidol group. The frequency and magnitude of symptoms (heat, angina, headache, nausea) were significantly different in two groups. Iopamidol caused less haemodynamic disturbance than Cardio-Conray, although the improvement is small and offers no advantage in reducing symptoms or extrasystoles.
PMCID: PMC481525  PMID: 6200129
21.  Effects of streptokinase on reflow in rescue percutaneous coronary intervention 
ARYA Atherosclerosis  2013;9(1):22-28.
Primary percutaneous coronary intervention (PPCI) is the preferred treatment method for ST elevation myocardial infarction (STEMI). However, the required equipments are not available in all hospitals. Thus, due to shortage of time, some patients receive thrombolysis therapy first. Patients with chest pain and/or persistent ST segment elevation will then undergo rescue percutaneous coronary intervention (PCI). The present study evaluated and compared the frequency of no-reflow phenomenon and 24-hour complications after PCI among patients who underwent PPCI or rescue PCI.
This cross-sectional study assessed no-reflow phenomenon, 24-hour complications, and thrombolysis in myocardial infarction (TIMI) flow in patients admitted to Chamran Hospital (Isfahan, Iran) with a diagnosis of STEMI during March-September, 2011. Subjects underwent PPCI if they had received eptifibatide. Rescue PCI was performed if patients had chest pain and/or persistent ST segment elevation despite receiving streptokinase (SK). Demographic characteristics, history of diseases, medicine, angiography findings, PCI type, and complications during the first 24 hours following PCI were collected. Data was then analyzed by Student’s t-test, chi-square test, and logistic regression analysis.
A total number of 143 individuals, including 67 PPCI cases (46.9%) and 76 cases of rescue PCI (53.1%), were evaluated. The mean age of the participants was 58.92 ± 11.16 years old. Females constituted 18.2% (n = 26) of the whole population. No-reflow phenomenon was observed in 51 subjects (37.1%). Although 9 patients (6.3%) died during the first 24 hours after PCI, neither the crude nor the model adjusted for age and gender revealed significant relations between rescue PCI and death or no-reflow phenomenon. Rescue PCI and no-reflow phenomenon were not significantly correlated even after adjustments for age, gender, history of diabetes, hypertension, hyperlipidemia, coronary artery disease, smoking, platelets number, myocardial infarction level, the extent of stenosis, and the involved artery.
According to the present study, although SK is more effective than eptifibatide in resolution of thrombosis and clots, rescue PCI did not differ from PPCI in terms of the incidence of no-reflow phenomenon or short-term complications.
PMCID: PMC3653257  PMID: 23696756
Primary Percutaneous Coronary Intervention; Rescue Percutaneous Coronary Intervention; No-Reflow Phenomenon
22.  Coronary Balloon Angioplasty in a Severe Takotsubo Syndrome 
Mædica  2013;8(3):265-268.
We reported a patient with Takotsubo syndrome, with severe symptoms, prolonged angina with hemodynamic compromise, in the context of severe coronary artery spasm, without response to full medical treatment, which was successfully managed with coronary balloon angioplasty. A 49-year old woman was admitted with chest pain, ECG changes and elevated myocardial necrosis markers suggestive for acute coronary syndrome. First coronary angiography revealed normal epicardial arteries and typical left ventricular apical ballooning, strongly suggestive for Takotsubo syndrome. Forty-eight hours later, with standard medical treatment, patient developed again severe angina with hemodynamic consequences. Second angiography showed total occlusive spasm of one coronary artery, without response to full medical treatment. Coronary balloon angioplasty was performed with final good result. Two month later, angiography revealed normal coronary arteries and normal ventricular shape. The patient is currently asymptomatic.
As far as we know, no other examples of similar cases were published in medical literature. Therefore, interventional treatment can be taken into consideration for some particular types of patients with Takotsubo syndrome, non-responsive to medical treatment; despite of balloon angioplasty or stenting of coronary vasospasm is not a standard of care.
PMCID: PMC3869116  PMID: 24371496
Takotsubo syndrome; balloon angioplasty; coronary artery spasm
23.  Effects of streptokinase in patients presenting within 6 hours of prolonged chest pain with ST segment depression. 
British Heart Journal  1995;73(6):500-505.
BACKGROUND--The effects of streptokinase on the occurrence of a combined clinical outcome in patients presenting with recent chest pain and ST depression were investigated in view of the role of thrombus in the pathogenesis of acute ischaemic syndromes. METHODS--112 patients aged < or = 75 years presenting within 6 h of the last episode of ischaemic chest pain of least 20 min duration with > or = 1 mm ST depression were randomised in a double blind manner to receive either streptokinase 1.5 million units over 30 min (n = 57) or placebo (n = 55). The primary end point was the combination of death, frequency of myocardial infarction (defined as peak creatine kinase > 600 U/ml), need for angiography because of uncontrollable ischaemia, and an exercise test within 35 days showing > or = 1 mm ST depression at < or = 6 min. The secondary end points were safety, frequency of chest pain, readmission with myocardial infarction or unstable angina, or need for revascularisation between 35 days and 1 year. The severity of ST depression on presentation was analysed with respect to clinical outcome. RESULTS--The frequency of the combined hierarchical end point of death, myocardial infarction, early angiography, and a positive exercise test was 82% (47 of 57 patients) with streptokinase and 75% (41 of 55 patients) with placebo. There were four deaths, two in each group. 27 patients (47%) receiving streptokinase and 22 (40%) receiving placebo developed myocardial infarction. 11 patients (eight streptokinase and three placebo) required coronary arteriography and subsequent revascularisation because of angina uncontrolled by medical treatment. 44 patients (22 in each group) had a positive exercise test. There were three further cardiac deaths (one streptokinase, two placebo), and three noncardiac deaths within 1 year. A conservative approach to intervention was adopted and over a period of 1 year 29 patients (26%) (13 streptokinase and 16 placebo) underwent revascularisation procedures. Three patients (two streptokinase and one placebo) required transfusion. ST depression > or = 3 mm had 90% specificity but only 60% positive predictive value for myocardial infarction at presentation (P = 0.008, stepwise logistic regression). ST depression > or = 2 mm was predictive of death, late development of myocardial infarction, or a need for angiography (P = 0.02). CONCLUSION--Patients presenting with ischaemic chest pain and ST depression frequently develop myocardial infarction. Severe ST depression is predictive of an adverse outcome. The 35 day (3.6% cardiac and total) and 1 year mortality (8.9% total, 6.3% cardiac) are low with conservative management and expeditious revascularisation. Streptokinase treatment within 6 h of the last episode of pain does not seem to be beneficial.
PMCID: PMC483908  PMID: 7626346
24.  Anti-leishmanial Effects of Trinitroglycerin in BALB/C Mice Infected with Leishmania major via Nitric Oxide Pathway 
This study investigated whether trinitroglycerine (TNG) as nitric oxide (NO) releasing agent had anti-leishmanial effects and mediated pathology in BALB/c mice infected with Leishmania major. Cutaneous leishmaniasis (CL), a zoonotic infection caused by leishmania protozoa is still one of the health problems in the world and in Iran. NO is involved in host immune responses against intracellular L. major, and leishmania killing by macrophages is mediated by this substance. Moreover, application of CL treatment with NO-donors has been recently indicated. In our study, TNG was used for its ability to increase NO and to modify CL infection in mice, in order to evaluate NO effects on lesion size and formation, parasite proliferation inside macrophages, amastigote visceralization in target organs, and NO induction in plasma and organ suspensions. Data obtained in this study indicated that TNG increased plasma and liver-NO, reduced lesion sizes, removed amastigotes from lesions, livers, spleens, and lymph nodes, declined proliferation of amastigotes, hepatomegaly, and increased survival rate. However, TNG reduced spleen-NO and had no significant effects on spelenomegaly. The results show that TNG therapy reduced leishmaniasis and pathology in association with raised NO levels. TNG had some antiparasitic activity by reduction of positive smears from lesions, livers, spleens, and lymph nodes, which could emphasize the role of TNG to inhibit visceralization of L. major in target organs.
PMCID: PMC2688791  PMID: 19488416
Leishmania major; BALB/c mouse; nitric oxide; trinitroglycerin; Iran
25.  Effect of the radiographic contrast material iopamidol on hemostasis: an observational study in thirty cardiac patients 
Background: In vitro studies have shown that nonionic radiographic contrast material may induce the generation of thrombin in blood, whereas ionic contrast agents, such as iohexol, do not. However, knowledge of the effects of contrast material on coagulation and fibrinolytic systems in vivo is limited.
Objective: This study was designed to assess the effects of the nonionic radiographic contrast material iopamidol on hemostasis in patients undergoing coronary angiography or cardiac catheterization.
Methods: Patients aged ≥18 years with chest pain and/or dyspnea who underwent coronary angiography or cardiac catheterization with intra-arterial contrast material were assessed for hemostasis. Blood samples were drawn before and 3 minutes after injection of iopamidol. Complete blood count and coagulation profile (bleeding time, clotting time, clot retraction time, euglobulin lysis time [ELT], prothrombin and partial thromboplastin times, coagulation factor I [CFI] level, and platelet factor 3 [PF-3] availability) were assessed. The natural coagulation inhibitors protein C, protein S, and antithrombin III (AT-III) also were measured.
Results: Thirty patients (7 males, 23 females; mean [SD] age, 51.3 [20.2] years; range, 17–79 years) were included in this single-center study. All hematologic variables (hemoglobin, white blood cell count, and platelet count) decreased significantly (P<0.001, P<0.001, and P<0.05, respectively) after administration of iopamidol but remained within normal limits. Mean levels of protein C, protein S, and AT-III did not change significantly after administration of iopamidol. Bleeding time was not changed significantly, and PF-3 availability was prolonged in both groups, but the changes were not statistically significant.
Conclusions: In this study population, although hemostasis remained grossly intact after injection of nonionic contrast material, the coagulation system may have been affected by the accelerated consumption of CFI and platelets. The affected variables were platelets, clot retraction time, ELT, and natural coagulation inhibitors (protein C, protein S, and AT-III). Although the natural coagulation inhibitors remained within the normal range, the correlations were found significant. These changes in hemostasis affected the vascular phase. If the vascular compartment, especially the endothelium, remained intact, the infusion of nonionic agents in low concentrations might be safe for angiography and other procedures; however, more studies are needed.
PMCID: PMC4053030  PMID: 24944396
iopamidol; contrast material; hemostasis; natural coagulation inhibitors

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