COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial.

This article published in Cell J (Yakhteh), Vol 20, No 2, Jul-Sep 2018, on pages 267-277, four affiliations (1, 4, 5, and 10) were changed based on authors request.

COMPARE CPM-RMI Trial: Intramyocardial Transplantation of Autologous Bone Marrow-Derived CD133+ Cells and MNCs during CABG in Patients with Recent MI: A Phase II/III, Multicenter, Placebo-Controlled, Randomized, Double-Blind Clinical Trial.

OBJECTIVES: The regenerative potential of bone marrow-derived mononuclear cells (MNCs) and CD133+ stem cells in the heart varies in terms of their pro-angiogenic effects. This phase II/III, multicenter and double-blind trial is designed to compare the functional effects of intramyocardial autologous transplantation of both cell types and placebo in patients with recent myocardial infarction (RMI) post-coronary artery bypass graft. MATERIALS AND METHODS: This was a phase II/III, randomized, double-blind, placebo-controlled trial COMPARE CPM-RMI (CD133, Placebo, MNCs - recent myocardial infarction) conducted in accordance with the Declaration of Helsinki that assessed the safety and efficacy of CD133 and MNCs compared to placebo in patients with RMI. We randomly assigned 77 eligible RMI patients selected from 5 hospitals to receive CD133+ cells, MNC, or a placebo. Patients underwent gated single photon emission computed tomography assessments at 6 and 18 months post-intramyocardial transplantation. We tested the normally distributed efficacy outcomes with a mixed analysis of variance model that used the entire data set of baseline and between-group comparisons as well as within subject (time) and group×time interaction terms. RESULTS: There were no related serious adverse events reported. The intramyocardial transplantation of both cell types increased left ventricular ejection fraction by 9% [95% confidence intervals (CI): 2.14% to 15.78%, P=0.01] and improved decreased systolic wall thickening by -3.7 (95% CI: -7.07 to -0.42, P=0.03). The CD133 group showed significantly decreased non-viable segments by 75% (P=0.001) compared to the placebo and 60% (P=0.01) compared to the MNC group. We observed this improvement at both the 6- and 18-month time points. CONCLUSIONS: Intramyocardial injections of CD133+ cells or MNCs appeared to be safe and efficient with superiority of CD133+ cells for patients with RMI. Although the sample size precluded a definitive statement about clinical outcomes, these results have provided the basis for larger studies to confirm definitive evidence about the efficacy of these cell types (Registration Number: NCT01167751).

Stress analysis of fracture of atherosclerotic plaques: crack propagation modeling.

Traditionally, the degree of luminal obstruction has been used to assess the vulnerability of atherosclerotic plaques. However, recent studies have revealed that other factors such as plaque morphology, material properties of lesion components and blood pressure may contribute to the fracture of atherosclerotic plaques. The aim of this study was to investigate the mechanism of fracture of atherosclerotic plaques based on the mechanical stress distribution and fatigue analysis by means of numerical simulation. Realistic models of type V plaques were reconstructed based on histological images. Finite element method was used to determine mechanical stress distribution within the plaque. Assuming that crack propagation initiated at the sites of stress concentration, crack propagation due to pulsatile blood pressure was modeled. Results showed that crack propagation considerably changed the stress field within the plaque and in some cases led to initiation of secondary cracks. The lipid pool stiffness affected the location of crack formation and the rate and direction of crack propagation. Moreover, increasing the mean or pulse pressure decreased the number of cycles to rupture. It is suggested that crack propagation analysis can lead to a better recognition of factors involved in plaque rupture and more accurate determination of vulnerable plaques.

A Semi-Experimental Study to Assess Whether the Current Recommended Protocol for Treating Vitamin D Deficiency is Enough?

BACKGROUND: Urbanization and diet change have increased the prevalence of Vitamin D deficiency. Unfortunately, none of the suggested treatments is widely accepted. OBJECTIVES: Therefore, we evaluated the most used and suggested protocol for treating Vitamin D deficiency in Percutaneous coronary intervention (PCI) candidate patients referred to our hospital in a short-term clinical trial. PATIENTS AND METHODS: All patients with coronary artery disease, referred to our hospital and candidates for PCI (drug eluted stents) were included. Deficient patients were randomly assigned to treatment (Vitamin D3 pearls of 50,000 IU; one per week for 10 weeks then one pearl every month for maintenance) and non-treatment groups. Vitamin D was measured after nine months. RESULTS: After initial evaluation, 116 cases were found to be deficient, and were divided into two equal groups of 58. No significant difference was found between the normal, treated and non-treated groups regarding age and gender. Thirty-two out of 58 (55.1%) subjects were vitamin D deficient and reached normal levels by taking supplements and seven out of 58 (12%) were deficient and reached normal levels without taking supplements, with the difference being significant (P < 0.001). CONCLUSIONS: The used protocol is not enough for treating Vitamin D deficiency. Furthermore, the protocol should be revised according to baseline Vitamin D classification.

Glycemic control in type 2 diabetes mellitus prevents coronary arterial wall infection.

BACKGROUND: Diabetes mellitus (DM) is a very well-known risk factor for development of atherosclerosis, and it has been hypothesized that poor glycemic control and hyperglycemia plays a major role in this process. In the current study, we aimed to evaluate the associates of poor glycemic control in Iranian patients who have already undergone coronary artery bypass grafting (CABG), with especial focus on the inhabitation of infectious agents within the coronary arterial wall. METHODS: In January 2010, 52 consecutive patients with type 2 DM who undergone CABG at the Department of Cardiovascular Surgery of Baqiyatallah University of Medical Sciences (Tehran, Iran) were included into this cross-sectional study and biopsy specimens from their coronary plaques were taken and analyzed by polymerase chain reaction (PCR) methods for detecting Helicobacter species, cytomegalovirus (CMV) and Chlamydia pneumoniae, and their potential relation to the glycemic control status in these patients. RESULTS: Compared to that in diabetic patients with mean fasting blood sugar (FBS) levels FBS < 126, atherosclerotic lesions in type 2 diabetic patients with poor glycemic control (FBS > 126) were significantly more likely to be positive for CMV PCR test (41% vs. 9%, respectively; P = 0.05). In laboratorial test results, mean triglyceride level was significantly higher among patients of poor glycemic control (168 ± 89 vs. 222 ± 125 mg/dl, respectively; P = 0.033). Hypertension was also significantly more prevalent in this population (73% vs. 36%, respectively; P = 0.034). CONCLUSION: Type 2 diabetic patients with poor glycemic control can be at higher risk for developing CMV infection in their coronary arterial wall, which can promote atherosclerosis formation process in this patient population. According to the findings of this study, we recommend better control of serum glucose levels in type 2 diabetic patients to prevent formation/progression of atherosclerosis.

Estimation of maximum intraventricular pressure: a three-dimensional fluid-structure interaction model.

BACKGROUND: The aim of this study was to propose a method to estimate the maximum pressure in the left ventricle (MPLV) for a healthy subject, based on cardiac outputs measured by echo-Doppler (non-invasive) and catheterization (invasive) techniques at rest and during exercise. METHODS: Blood flow through aortic valve was measured by Doppler flow echocardiography. Aortic valve geometry was calculated by echocardiographic imaging. A Fluid-structure Interaction (FSI) simulation was performed, using an Arbitrary Lagrangian-Eulerian (ALE) mesh. Boundary conditions were defined as pressure loads on ventricular and aortic sides during ejection phase. The FSI simulation was used to determine a numerical relationship between the cardiac output to aortic diastolic and left ventricular pressures. This relationship enabled the prediction of pressure loads from cardiac outputs measured by invasive and non-invasive clinical methods. RESULTS: Ventricular systolic pressure peak was calculated from cardiac output of Doppler, Fick oximetric and Thermodilution methods leading to a 22%, 18% and 24% increment throughout exercise, respectively. The mean gradients obtained from curves of ventricular systolic pressure based on Doppler, Fick oximetric and Thermodilution methods were 0.48, 0.41 and 0.56 mmHg/heart rate, respectively. Predicted Fick-MPLV differed by 4.7%, Thermodilution-MPLV by 30% and Doppler-MPLV by 12%, when compared to clinical reports. CONCLUSIONS: Preliminary results from one subject show results that are in the range of literature values. The method needs to be validated by further testing, including independent measurements of intraventricular pressure. Since flow depends on the pressure loads, measuring more accurate intraventricular pressures helps to understand the cardiac flow dynamics for better clinical diagnosis. Furthermore, the method is non-invasive, safe, cheap and more practical. As clinical Fick-measured values have been known to be more accurate, our Fick-based prediction could be the most applicable.

Chlamydia pneumoniae in the atherosclerotic plaques of coronary artery disease patients.

An association between Chlamydia pneumoniae (C. pneumoniae) and cardiovascular disease has been demonstrated. In this study, we aimed to study this potential relationship in 105 Iranian patients. Coronary artery specimens from 105 Iranian patients undergoing CABG were analyzed by PCR method for C. pneumoniae. Serological evaluation for C. pneumoniae IgG and IgM was performed using ELISA. 53 specimens from mamillary artery were also investigated. C. pneumoniae PCR test result was positive for 23 (21.9%) of patients with coronary artery atherosclerosis, but none of the specimens from the mamillary artery was positive for C. pneumoniae when it was evaluated by the PCR (P<0.001). Coronary artery disease patients with and without a history of unstable angina or myocardial infarction were comparable in C. pneumoniae PCR test positive rates (P=0.618). Relevance of IgG and IgM positivity were also studied by correlating it to the study parameters, but no difference was found. CRP was significantly higher in the IgM positive group (P<0.001). A significant proportion of coronary atherosclerotic plaques are infected with C. pneumoniae while no infection was found in the normal mamillary artery specimens. No association was found between acute coronary syndromes and serological and PCR positivity. Further prospective randomized controlled studies with large patient population are needed to confirm our findings.

Cytomegalovirus localization in atherosclerotic plaques is associated with acute coronary syndromes: report of 105 patients.

It has been shown that cytomegalovirus (CMV) is present in coronary atherosclerotic plaques, but the clinical relevance of this presence remains to be elucidated. In this study we sought to examine CMV infection in atherosclerosis patients defined by different methods and to identify the clinical significance of CMV replication in the atherosclerotic plaques. The study included 105 consecutive patients who were admitted to our department and underwent coronary artery bypass grafting (CABG) surgical interventions. Coronary atherosclerotic specimens as well as 53 specimens from the mamillary artery of these same patients were analyzed. Enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) methods were used for evaluations. The CMV PCR test result was positive for 28 (26.7%) of patients with coronary artery atherosclerosis. After adjusting for other risk factors, coronary artery disease patients with a history of acute coronary syndrome were more likely to be positive for CMV PCR test (P=0.027; odds ratio: 4.2; 95% CI: 1.18-15.0). They were also more likely to have a positive family history for cardiovascular diseases (CVD). This study confirms previous evidence about the replication of CMV virus in the atherosclerotic plaques of coronary arteries and brings clinical significance to this observation by showing a higher prevalence of acute coronary syndromes in those patients with CMV-infected plaques. Our study also suggests a familial vulnerability to CMV replication in the coronary artery walls.

Helicobacter species in the atherosclerotic plaques of patients with coronary artery disease.

INTRODUCTION: Several epidemiological studies have proposed an association between Helicobacter pylori infection and coronary artery disease. In the current study, we aimed to evaluate the prevalence and relevance of H. pylori infection, using polymerase chain reaction (PCR) methods, in the coronary arterial wall of Iranian patients who have already undergone coronary bypass grafting (CABG). METHODS: A total of 105 consecutive patients who underwent CABG at the Department of Cardiovascular Surgery of Baqiyatallah University of Medical Sciences were included in the study, and biopsy specimens from their coronary plaques were taken and analyzed using the PCR methods for detecting Helicobacter species (H Spp.). Fifty-three specimens from biopsies of the left internal mamillary artery in the same patients were also collected and tested. RESULTS: H. Spp. PCR test result was positive for 31 (29.5%) specimens from coronary artery atherosclerotic plaques. Serologic test results also showed 25 (23.8%) positive cases for H. pylrori immunoglobulin A (IgA) and 56 (53.3%) positive for anti-H. pylori immunoglobulin G. None of the specimens from the mamillary artery were positive for H Spp. genome when it was evaluated using PCR (P<.0001). Patients with positive test result for H. pylori IgA were significantly more likely to have higher total cholesterol and low-density lipoprotein (LDL) levels than IgA-negative patients. CONCLUSION: H Spp. infection replication in the coronary arterial wall is associated with atherosclerotic plaque formation. Seropositivity for H. pylori IgA may also enhance blood values of total cholesterol and LDL in these patients.

A novel scoring system for identifying high-risk patients undergoing carotid stenting.

BACKGROUND/OBJECTIVE: In patients with severe concurrent coronary and carotid artery disease, two different treatment strategies may be used: simultaneous endarterectomy and coronary bypass surgery, and carotid stenting with delayed coronary bypass surgery after a few weeks. To evaluate the safety and efficacy of carotid stenting with delayed coronary bypass surgery after a few weeks in patients referred to Tehran Heart Center, Tehran, Iran and to determine the independent predictors that may be used to identify the appropriate treatment plan for such patients. METHODS: This prospective study was performed from December 2003 through October 2004. Symptomatic patients with >60% stenosis and asymptomatic patients with >80% stenosis were included in this study. The risks and benefits of carotid stenting were explained. Patients were excluded from the study if any of the following was applicable: age > or =85 years, history of a major stroke within the last week, pregnancy, intracranial tumor or arteriovenous malformation, severely disabled as a result of stroke or dementia, and intracranial stenosis that exceeded the severity of the extracranial stenosis. Thirty consecutive patients who underwent carotid stenting were enrolled in this study. RESULTS: The mean +/- SD age of patients was 66.3 +/- 8 years. The procedural success rate was 96.7%. During a mean +/- SD follow-up period of 5.6 +/- 3.2 months, 4 (17%) deaths occurred; none of which were attributed to a neurologic causes. Moreover, 1 (3%) patient developed a minor nonfatal stroke with transient cognitive disorder. Most of patients (80%) with major complications acquired a score of > or =26. CONCLUSION: To reduce the rate of carotid stenting complications in high-risk patients with heart disease, to optimize the patient selections, and to determine the best treatment strategy, based on the clinical and lesion characteristics of patients, we proposed a new scoring system.

An experience with angioplasty and stenting of carotid artery stenosis with embolic protection devices.

BACKGROUND: Carotid artery stenting has recently been recommended as an alternative to carotid endarterectomy by some clinicians. OBJECTIVE: To evaluate success rate, as well as in-hospital and 30-day adverse events in our first experience in Iran for carotid artery stenting with protection devices. METHODS: From December 2003 through July 2004, we performed 12 consecutive (9 males and 3 females) carotid artery stenting procedures. The patients had a mean age of 62 (range: 46 - 78) years. Indications for carotid artery stenting included primary lesions in all patients, stenosis > or =50% in symptomatic, and stenosis > or =80% in asymptomatic patients. RESULTS: Carotid artery stenting was technically successful in all 12 patients. The mean +/- SD severity of stenosis before carotid artery stenting was 85 +/- 14% as compared with 15 +/- 10% after the procedure. No periprocedural death occurred. No in-hospital or 30-day minor or major stroke/death was observed. CONCLUSION: Percutaneous stenting of the carotid artery stenosis, when a cerebral protection device is used, is feasible and effective but not without technical difficulties and potential complications. We, therefore, recommend carotid artery stenting for patients who are at high risk for undergoing carotid endarterectomy. Nevertheless, a long-learning curve may be needed for anyone who wishes to start this technique.