FFR-Guided Complete or Culprit-Only PCI in Patients with Myocardial Infarction.

BACKGROUND: The benefit of fractional flow reserve (FFR)-guided complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease remains unclear. METHODS: In this multinational, registry-based, randomized trial, we assigned patients with STEMI or very-high-risk non-STEMI (NSTEMI) and multivessel disease who were undergoing primary percutaneous coronary intervention (PCI) of the culprit lesion to receive either FFR-guided complete revascularization of nonculprit lesions or no further revascularization. The primary outcome was a composite of death from any cause, myocardial infarction, or unplanned revascularization. The two key secondary outcomes were a composite of death from any cause or myocardial infarction and unplanned revascularization. RESULTS: A total of 1542 patients underwent randomization, with 764 assigned to receive FFR-guided complete revascularization and 778 assigned to receive culprit-lesion-only PCI. At a median follow-up of 4.8 years (interquartile range, 4.3 to 5.2), a primary-outcome event had occurred in 145 patients (19.0%) in the complete-revascularization group and in 159 patients (20.4%) in the culprit-lesion-only group (hazard ratio, 0.93; 95% confidence interval [CI], 0.74 to 1.17; P = 0.53). With respect to the secondary outcomes, no apparent between-group differences were observed in the composite of death from any cause or myocardial infarction (hazard ratio, 1.12; 95% CI, 0.87 to 1.44) or unplanned revascularization (hazard ratio, 0.76; 95% CI, 0.56 to 1.04). There were no apparent between-group differences in safety outcomes. CONCLUSIONS: Among patients with STEMI or very-high-risk NSTEMI and multivessel coronary artery disease, FFR-guided complete revascularization was not shown to result in a lower risk of a composite of death from any cause, myocardial infarction, or unplanned revascularization than culprit-lesion-only PCI at 4.8 years. (Funded by the Swedish Research Council and others; FULL REVASC ClinicalTrials.gov number, NCT02862119.).

OCT or Angiography Guidance for PCI in Complex Bifurcation Lesions.

BACKGROUND: Imaging-guided percutaneous coronary intervention (PCI) is associated with better clinical outcomes than angiography-guided PCI. Whether routine optical coherence tomography (OCT) guidance in PCI of lesions involving coronary-artery branch points (bifurcations) improves clinical outcomes as compared with angiographic guidance is uncertain. METHODS: We conducted a multicenter, randomized, open-label trial at 38 centers in Europe. Patients with a clinical indication for PCI and a complex bifurcation lesion identified by means of coronary angiography were randomly assigned in a 1:1 ratio to OCT-guided PCI or angiography-guided PCI. The primary end point was a composite of major adverse cardiac events (MACE), defined as death from a cardiac cause, target-lesion myocardial infarction, or ischemia-driven target-lesion revascularization at a median follow-up of 2 years. RESULTS: We assigned 1201 patients to OCT-guided PCI (600 patients) or angiography-guided PCI (601 patients). A total of 111 patients (18.5%) in the OCT-guided PCI group and 116 (19.3%) in the angiography-guided PCI group had a bifurcation lesion involving the left main coronary artery. At 2 years, a primary end-point event had occurred in 59 patients (10.1%) in the OCT-guided PCI group and in 83 patients (14.1%) in the angiography-guided PCI group (hazard ratio, 0.70; 95% confidence interval, 0.50 to 0.98; P = 0.035). Procedure-related complications occurred in 41 patients (6.8%) in the OCT-guided PCI group and 34 patients (5.7%) in the angiography-guided PCI group. CONCLUSIONS: Among patients with complex coronary-artery bifurcation lesions, OCT-guided PCI was associated with a lower incidence of MACE at 2 years than angiography-guided PCI. (Funded by Abbott Vascular and others; OCTOBER ClinicalTrials.gov number, NCT03171311.).

The role of endothelial shear stress, shear stress gradient, and plaque topography in plaque erosion.

BACKGROUND AND AIMS: Plaque erosion is a common underlying cause of acute coronary syndromes. The role of endothelial shear stress (ESS) and endothelial shear stress gradient (ESSG) in plaque erosion remains unknown. We aimed to determine the role of ESS metrics and maximum plaque slope steepness in plaques with erosion versus stable plaques. METHODS: This analysis included 46 patients/plaques from TOTAL and COMPLETE trials and Brigham and Women's Hospital's database who underwent angiography and OCT. Plaques were divided into those with erosion (n = 24) and matched stable coronary plaques (n = 22). Angiographic views were used to generate a 3-D arterial reconstruction, with centerlines merged from angiography and OCT pullback. Local ESS metrics were assessed by computational fluid dynamics. Among plaque erosions, the up- and down-slope (Δ lumen area/frame) was calculated for each culprit plaque. RESULTS: Compared with stable plaque controls, plaques with an erosion were associated with higher max ESS (8.3 ± 4.8 vs. 5.0 ± 1.9 Pa, p = 0.02) and max ESSG any direction (9.2 ± 7.5 vs. 4.3 ± 3.11 Pa/mm, p = 0.005). Proximal erosion was associated with a steeper plaque upslope while distal erosion with a steeper plaque downslope. Max ESS and Max ESSG any direction were independent factors in the development of plaque erosion (OR 1.32, 95%CI 1.06-1.65, p = 0.014; OR 1.22, 95% CI 1.03-1.45, p = 0.009, respectively). CONCLUSIONS: In plaques with similar luminal stenosis, plaque erosion was strongly associated with higher ESS, ESS gradients, and plaque slope as compared with stable plaques. These data support that ESS and slope metrics play a key role in the development of plaque erosion and may help prognosticate individual plaques at risk for future erosion.

International randomized trial on the effect of revascularization or optimal medical therapy of chronic total coronary occlusions with myocardial ischemia - ISCHEMIA-CTO trial - rationale and design.

BACKGROUND: Chronic total occlusions (CTO) are frequent among patients with coronary artery disease. Revascularization with percutaneous coronary intervention (PCI) is safe and feasible in experienced hands. However, randomized data are needed to demonstrate symptomatic as well as prognostic effect of CTO-PCI compared to optimal medical therapy alone. METHODS: This trial aims to evaluate the effect of CTO PCI in patients with a CTO lesion and target vessel diameter ≥ 2.5 mm, and myocardial ischemia in the relevant territory. First, all patients are subjected to optimal medical therapy (OMT) for at least for 3 months and non-CTO lesions are managed according to guidelines. Subsequently, prior to randomization myocardial ischemia and quality of life (Seattle Questionnaire (SAQ)) is assessed. Patients are divided into two cohorts based on their SAQ score and randomized to either OMT alone or OMT and CTO-PCI. Cohort A is defined as Low- or asymptomatic patients with a quality-of-life score > 60 and/or CCS class < 2, and more than 10 % ischemia in the left ventricle (LV). Cohort B is symptomatic patients with a quality-of-life score < 60 or CCS class angina > 1 and at least ischemia in 5% of the LV. The primary end-point in cohort A is a composite of major adverse cardiac and cerebral events, hospitalization for heart failure and malignant ventricular arrhythmias. The primary endpoint in cohort B is difference in quality of life 6 months after randomization. IMPLICATIONS: This trial is designed to investigate if CTO-PCI improves QoL and MACCE. Both positive and negative outcome of the trial will affect future guidelines and recommendations on how to treat patients with CTO.

Routine revascularization with percutaneous coronary intervention in patients with coronary artery disease undergoing transcatheter aortic valve implantation - the third nordic aortic valve intervention trial - NOTION-3.

BACKGROUND: Coronary artery disease (CAD) frequently coexists with severe aortic valve stenosis (AS) in patients planned for transcatheter aortic valve implantation (TAVI). How to manage CAD in this patient population is still an unresolved question. In particular, it is still not known whether fractional flow reserve (FFR) guided revascularization with percutaneous coronary intervention (PCI) is superior to medical treatment for CAD in terms of clinical outcomes. STUDY DESIGN: The third Nordic Aortic Valve Intervention (NOTION-3) Trial is an open-label investigator-initiated, multicenter multinational trial planned to randomize 452 patients with severe AS and significant CAD to either FFR-guided PCI or medical treatment, in addition to TAVI. Patients are eligible for the study in the presence of at least 1 significant PCI-eligible coronary stenosis. A significant stenosis is defined as either FFR ≤0.80 and/or diameter stenosis >90%. The primary end point is a composite of first occurring all-cause mortality, myocardial infarction, or urgent revascularization (PCI or coronary artery bypass graft performed during unplanned hospital admission) until the last included patient have been followed for 1 year after the TAVI. SUMMARY: NOTION-3 is a multicenter, multinational randomized trial aiming at comparing FFR-guided revascularization vs medical treatment of CAD in patients with severe AS planned for TAVI.

In vivo morphologic comparison of saphenous vein grafts and native coronary arteries following non-ST elevation myocardial infarction.

OBJECTIVE: This study aimed to assess the pathophysiological differences between saphenous vein grafts (SVG) and native coronary arteries (NCA) following presentation with non-ST elevated myocardial infarction (NSTEMI). BACKGROUND: There is accelerated pathogenesis of de novo coronary disease in harvested SVG following coronary artery bypass (CABG) surgery, which contributes to both early and late graft failure, and is also causal in adverse outcomes following vein graft PCI. However in vivo assessment, with OCT imaging, comparing the differences between vein grafts and NCAs has not previously been performed. METHODS: We performed a retrospective, observational, analysis in patients who underwent PCI with adjunctive OCT imaging following presentation with NSTEMI, where the infarct-related artery (IRA) was either in an SVG or NCA. RESULTS: A total of 1550 OCT segments was analysed from thirty patients with a mean age of 66.3 (±9.0) years were included. The mean graft age of 13.9 (±5.6) years in the SVG group. OCT imaging showed that the SVG group had evidence of increased lipid pool burden (lipid pool quadrants, 2.1 vs 2.7; p = 0.021), with a reduced fibro-atheroma cap-thickness in the SVG group (45.0 µm vs 38.5 µm; p = 0.05) and increased burden of calcification (calcified lesion length = 0.4 mm vs 1.8 mm; p = 0.007; calcified quadrants = 0.2 vs 0.9; p = 0.001; arc of superficial calcium deposits = 11.6° vs 50.9°; p = 0.007) when compared to NCA. CONCLUSION: This OCT study has demonstrated that vein grafts have a uniquely atherogenic environment which leads to the development of calcified, lipogenic, thin-capped fibro-atheroma's, which may be pivotal in the increased, acute and chronic graft failure rate, and may underpin the increased adverse outcomes following vein graft PCI.

Comparison of visual assessment and computer image analysis of intracoronary thrombus type by optical coherence tomography.

BACKGROUND: Analysis of intracoronary thrombus type by optical coherence tomography (OCT) imaging is highly subjective. We aimed to compare a newly developed image analysis method to subjective visual classification of thrombus type identified by OCT. METHODS: Thirty patients with acute ST elevation myocardial infarction were included. Thrombus type visually classified by two independent readers was compared with analysis using QCU-CMS software. RESULTS: Repeatability of the computer-based measurements was good. By using a ROC, area under curve values for discrimination of white and red thrombi were 0.92 (95% confidence intervals (CI) 0.83-1.00) for median attenuation, 0.96 (95% CI 0.89-1.00) for mean backscatter and 0.96 (95% CI 0.89-1.00) for mean grayscale intensity. Median attenuation of 0.57 mm-1 (sensitivity 100%, specificity 71%), mean backscatter of 5.35 (sensitivity 92%, specificity 94%) and mean grayscale intensity of 120.1 (sensitivity 85%, specificity 100%) were identified as the best cut-off values to differentiate between red and white thrombi. CONCLUSIONS: Attenuation, backscatter and grayscale intensity of thrombi in OCT images differentiated red and white thrombi with high sensitivity and specificity. Measurement of these continuous parameters can be used as a less user-dependent method to characterize in vivo thrombi. The clinical significance of these findings needs to be tested in further studies.

Rational and design of the European randomized Optical Coherence Tomography Optimized Bifurcation Event Reduction Trial (OCTOBER).

Background: Percutaneous coronary intervention in complex bifurcation lesions is prone to suboptimal implantation results and is associated with increased risk of subsequent clinical events. Angiographic ambiguity is high during bifurcation stenting, but it is unknown if procedural guidance by intravascular optical coherence tomography (OCT) improves clinical outcome. Methods and Design: OCTOBER is a randomized, investigator-initiated, multicenter trial aimed to show superiority of OCT-guided stent implantation compared to standard angiographic-guided implantation in bifurcation lesions. The primary outcome measure is a 2-year composite end point of cardiac death, target lesion myocardial infarction, and ischemia-driven target lesion revascularization. The calculated sample size is 1,200 patients in total, and allocation is 1:1. Eligible patients have stable or unstable angina pectoris or stabilized non­ST elevation myocardial infarction, and a coronary bifurcation lesion with significant main vessel stenosis and more than 50 % stenosis in a side branch with a reference diameter ≥2.5mm. Treatment is performed by the provisional side branch stenting technique or 2-stent techniques, and the systematic OCT guiding protocol is aimed to evaluate (1) plaque preparation, (2) lesion length, (3) segmental reference sizes, (4) lesion coverage, (5) stent expansion, (6) malapposition, (7) wire positions, and (8) ostial results. Implications: A positive outcome of the OCTOBER trial may establish OCT as a routine tool for optimization of complex percutaneous coronary intervention, whereas a negative result would indicate that OCT remains a tool for ad hoc evaluation in selected cases.

Permanent work disability in patients ≤50 years old after percutaneous coronary intervention and coronary artery bypass grafting (the CRAGS study).

Background: The aim of this study was to investigate the incidence of permanent working disability (PWD) in young patients after percutaneous or surgical coronary revascularization. Methods and Results: The study included 1035 consecutive patients ≤50 years old who underwent coronary revascularization [910 and 125 patients in percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) groups, respectively] between 2002 and 2012 at 4 Finnish hospitals. The median follow-up time was 41 months. The overall incidence of PWD was higher after CABG compared to PCI (at 5 years, 34.8 vs. 14.7%, P < 0.001). Freedom from PWD in the general population aged 45 was 97.2% at 4 years follow-up. Median time to grant disability pension was 11.6 months after CABG and 24.4 months after PCI (P = 0.018). Reasons for PWD were classified as cardiac (35.3 vs. 36.9%), psychiatric (14.7 vs. 14.6%), and musculoskeletal (14.7 vs. 15.5%) in patients undergoing CABG vs. PCI. Overall freedom from PWD was higher in patients without major adverse cardiac and cerebrovascular event (MACCE) (at 5 years, 85.6 vs. 71.9%, P < 0.001). Nevertheless, rate of PWD was high also in patients without MACCE and patients with preserved ejection fraction during follow-up. Conclusions: Although coronary revascularization confers good overall survival in young patients, PWD is common especially after CABG and mostly for cardiac reasons even without occurrence of MACCE. Supportive measures to preserve occupational health are warranted concomitantly with coronary revascularization at all levels of health care.

Culprit plaque morphology in STEMI - an optical coherence tomography study: insights from the TOTAL-OCT substudy.

AIMS: Our aim was to compare stenosis severity and plaque content between STEMI culprit lesions with intact fibrous cap (IFC) and those with plaque rupture (PR) in a prospective study. METHODS AND RESULTS: We evaluated 93 patients undergoing OCT and thrombectomy as part of a prospective substudy of the TOTAL (ThrOmbecTomy versus PCI ALone) trial. Culprit lesion morphology was assessable by OCT in 70/93 (75.3%). IFC was found in 31 (44.3%), PR in 34 (48.6%) and calcified nodule in five (7.1%) patients. Following thrombectomy, OCT demonstrated similar lumen area stenosis in IFC (79.3%) and PR (79.6%) (p=0.88). Lumen area stenosis <50% was observed in none of the patients with PR and in one patient with IFC. IFC had fewer quadrants with lipid plaque as compared to PR (28.16±15.02 vs. 39.12±14.23, p=0.004). However, in both lesion types, lipid was the predominant plaque type (83.9 vs. 63.7% of diseased quadrants). CONCLUSIONS: In a prospective study of STEMI patients treated with thrombectomy, mild residual stenoses were uncommon in IFC lesions. Although lipid content was lower than in PR lesions, lipid composed the majority of the diseased segments in IFC.

[Percutaneous treatment of coronary chronic total occlusions]. / Sepelvaltimon kroonisen totaalitukoksen perkutaaninen hoito.

Chronic total occlusions (CTOs) are frequently detected on diagnostic coronary angiograms. For the selection of patients for CTO percutaneous coronary intervention, factors such as the level of symptoms, level of myocardial viability and extent of ischemia must be taken into account. Remarkable progress has been achieved in the success of complex CTO procedures during the past decade. In addition to antegrade wire escalation strategy, subintimal passage of the guidewire with or without dissection and re-entry techniques and retrograde techniques can be utilized. After successful wiring of the lesion, balloon angioplasty and stenting comparable to a non-CTO lesion are performed.

Optical Coherence Tomography-Guided Percutaneous Coronary Intervention in ST-Segment-Elevation Myocardial Infarction: A Prospective Propensity-Matched Cohort of the Thrombectomy Versus Percutaneous Coronary Intervention Alone Trial.

BACKGROUND: Patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment-elevation myocardial infarction are at increased risk for adverse events. It is unclear if image guidance by optical coherence tomography (OCT) can improve outcomes in these patients. We compared OCT-guided versus angiography-guided primary PCI for ST-segment-elevation myocardial infarction among patients in the Thrombectomy Versus PCI Alone (TOTAL) trial. METHODS AND RESULTS: Among 10 732 patients enrolled in the TOTAL trial, OCT was used for PCI guidance as a part of a prospective substudy in 214 patients. Using 2:1 propensity matching, we identified 428 patients in the trial who had PCI performed with angiography guidance alone. The primary outcome was a composite of cardiovascular death, myocardial infarction, stent thrombosis, and target-vessel revascularization at 1 year. Secondary outcomes included final in-stent angiographic minimum lumen diameter, procedure time, and contrast dose. The final in-stent angiographic minimum lumen diameter was 2.99±0.48 mm in the OCT-guided group versus 2.79±0.47 mm in the angiography-guided group (P<0.0001). OCT- and angiography-guided PCI had a median (interquartile range) procedure time of 58 (47, 71) minute versus 38 (28, 52) minute (P<0.0001) and total contrast dose of 239.7±81.1 mL versus 193.3±78.6 mL (P<0.0001). The primary outcome was observed in 7.5% of the OCT-guided group versus 9.8% of the angiography-guided group (hazard ratio, 0.76; 95% confidence interval, 0.43-1.34; P=0.34). CONCLUSIONS: OCT-guided primary PCI for ST-segment-elevation myocardial infarction was associated with a larger final in-stent minimum lumen diameter. There was no significant difference in clinical outcomes at 1 year; however, the study was underpowered to detect a treatment effect. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01149044.

Complete recovery of the right ventricle from a large intramyocardial hematoma complicating percutaneous coronary intervention.

Right ventricular (RV) intramyocardial hematoma is a potentially life-threatening condition that can complicate percutaneous coronary intervention (PCI). Natural course of RV hematoma and long-term recovery of the affected myocardium have not been described. We present a case of a 70-year-old male with large RV hematoma caused by distal guidewire perforation during PCI of the right coronary artery. Baseline multimodality imaging, serial echocardiography, and long-term follow-up using cardiac magnetic resonance (CMR) imaging were used to investigate the natural course of this rare condition. Despite its massive initial appearance, the hematoma was successfully managed conservatively. Serial echocardiographic examination showed slow gradual resorption of the hematoma. Follow-up CMR performed at 12 months was strikingly normal, showing no late gadolinium enhancement of the RV myocardium indicating lack of significant fibrotic scarring at the site of hematoma resorption. .

Culprit lesion thrombus burden after manual thrombectomy or percutaneous coronary intervention-alone in ST-segment elevation myocardial infarction: the optical coherence tomography sub-study of the TOTAL (ThrOmbecTomy versus PCI ALone) trial.

AIMS: Manual thrombectomy has been proposed as a strategy to reduce thrombus burden during primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI). However, the effectiveness of manual thrombectomy in reducing thrombus burden is uncertain. In this substudy of the TOTAL (ThrOmbecTomy versus PCI ALone) trial, we compared the thrombus burden at the culprit lesion using optical coherence tomography (OCT) in patients treated with thrombectomy vs. PCI-alone. METHODS AND RESULTS: The TOTAL trial (N = 10 732) was an international, multicentre, randomized trial of thrombectomy (using the Export catheter, Medtronic Cardiovascular, Santa Rosa, CA, USA) in STEMI patients treated with primary PCI. The OCT substudy prospectively enrolled 214 patients from 13 sites in 5 countries. Optical coherence tomography was performed immediately after thrombectomy or PCI-alone and then repeated after stent deployment. Thrombus quantification was performed by an independent core laboratory blinded to treatment assignment. The primary outcome of pre-stent thrombus burden as a percentage of segment analysed was 2.36% (95% CI: 1.73-3.22) in the thrombectomy group and 2.88% (95% CI: 2.12-3.90) in the PCI-alone group (P = 0.373). Absolute pre-stent thrombus volume was not different (2.99 vs. 3.74 mm(3), P = 0.329). Other secondary outcomes of pre-stent quadrants of thrombus, post-stent atherothrombotic burden, and post-stent atherothrombotic volume were not different between groups. CONCLUSION: Manual thrombectomy did not reduce pre-stent thrombus burden at the culprit lesion compared with PCI-alone. Both strategies were associated with low thrombus burden at the lesion site after the initial intervention to restore flow.

Feasibility and repeatability of optical coherence tomography measurements of pre-stent thrombus burden in patients with STEMI treated with primary PCI.

AIMS: Intracoronary thrombus is disrupted by stent deployment and confounded by the development of intrastent plaque prolapse. This study aims at investigating the feasibility and repeatability of thrombus quantification prior to stent implantation using optical coherence tomography (OCT) in ST-segment elevation myocardial infarction (STEMI) patients. METHODS AND RESULTS: Patients were enrolled in an OCT substudy of the TOTAL trial (a randomized trial of routine aspiration ThrOmbecTomy with PCI vs. PCI ALone in patients with STEMI undergoing primary PCI) of aspiration thrombectomy or percutaneous coronary intervention (PCI) alone in primary PCI (PPCI) of STEMI. Using OCT, thrombus burden (TB) and other measures of pre- and post-stent atherothrombus were analysed over the arterial segment defined by the final stent length. Feasibility was 86.2% (25/29 patients) for both pre- and post-stent OCT imaging. Altogether, 8111 OCT cross-sections were analysed. In Bland-Altman analyses of inter-observer variation (n = 25), the mean pre-stent TB was 8.76% for Observer 1 and 8.97% for Observer 2 (limits of agreement -2.6 to 2.2%). In Bland-Altman analyses of intra-observer variation (n = 15), the mean pre-stent TB was 8.06% for the first and 7.35% for the second round of analysis by Observer 1 (limits of agreement -1.72 to 3.15%). There was a good correlation between pre-stent TB and pre-stent quadrants with thrombus/mm (r = 0.97), but only modest correlation between pre-stent TB and post-stent atherothrombotic burden (ATB; r = 0.54). CONCLUSIONS: Measurement of pre-stent TB by OCT during the PPCI of STEMI is feasible and highly repeatable. Pre-stent TB is only modestly correlated with post-stent ATB, which indicates that pre-stent measurements might be of additional value when assessing the TB in STEMI.

Multiple pulmonary arteriovenous malformations presenting as an acute myocardial infarction.

Pulmonary arteriovenous malformations are rare, mostly asymptomatic vascular anomalies. These malformations cause direct right to left shunting of unoxygenated blood, resulting chronically in cyanosis, dyspnea, and exercise intolerance. The serious complications reported earlier have mainly been neurologic, for example, cerebrovascular accidents and brain abscesses and are most likely caused by paradoxical embolism. Detection of pulmonary arteriovenous malformations is challenging, and the emergency department personnel play an essential role. Once suspected, the diagnosis can be made promptly using standard imaging techniques and appropriate treatment may prevent serious complications. In this report, we describe a case of a 41-year-old man with acute anterior myocardial infarction, unexpectedly caused by emboli from pulmonary arteriovenous malformations. This rare etiology of acute myocardial infarction should be taken into consideration especially in cases with atypical presentation.

Expression of sterol regulatory element-binding transcription factor (SREBF) 2 and SREBF cleavage-activating protein (SCAP) in human atheroma and the association of their allelic variants with sudden cardiac death.

BACKGROUND: Disturbed cellular cholesterol homeostasis may lead to accumulation of cholesterol in human atheroma plaques. Cellular cholesterol homeostasis is controlled by the sterol regulatory element-binding transcription factor 2 (SREBF-2) and the SREBF cleavage-activating protein (SCAP). We investigated whole genome expression in a series of human atherosclerotic samples from different vascular territories and studied whether the non-synonymous coding variants in the interacting domains of two genes, SREBF-2 1784G>C (rs2228314) and SCAP 2386A>G, are related to the progression of coronary atherosclerosis and the risk of pre-hospital sudden cardiac death (SCD). METHODS: Whole genome expression profiling was completed in twenty vascular samples from carotid, aortic and femoral atherosclerotic plaques and six control samples from internal mammary arteries. Three hundred sudden pre-hospital deaths of middle-aged (33-69 years) Caucasian Finnish men were subjected to detailed autopsy in the Helsinki Sudden Death Study. Coronary narrowing and areas of coronary wall covered with fatty streaks or fibrotic, calcified or complicated lesions were measured and related to the SREBF-2 and SCAP genotypes. RESULTS: Whole genome expression profiling showed a significant (p = 0.02) down-regulation of SREBF-2 in atherosclerotic carotid plaques (types IV-V), but not in the aorta or femoral arteries (p = NS for both), as compared with the histologically confirmed non-atherosclerotic tissues. In logistic regression analysis, a significant interaction between the SREBF-2 1784G>C and the SCAP 2386A>G genotype was observed on the risk of SCD (p = 0.046). Men with the SREBF-2 C allele and the SCAP G allele had a significantly increased risk of SCD (OR 2.68, 95% CI 1.07-6.71), compared to SCAP AA homologous subjects carrying the SREBF-2 C allele. Furthermore, similar trends for having complicated lesions and for the occurrence of thrombosis were found, although the results were not statistically significant. CONCLUSION: The results suggest that the allelic variants (SREBF-2 1784G>C and SCAP 2386A>G) in the cholesterol homeostasis regulating SREBF-SCAP pathway may contribute to SCD in early middle-aged men.

Myeloperoxidase gene variation as a determinant of atherosclerosis progression in the abdominal and thoracic aorta: an autopsy study.

Myeloperoxidase (MPO) is an enzyme that transforms low-density lipoprotein into atherogenic particles. The MPO gene has a promoter polymorphism at position -463, which affects gene transcription and leads to high- (G/G) and low-expression (A/A, A/G) genotypes. To determine if these genotypes are associated with the severity of atherosclerosis, we performed an autopsy study of 300 men aged 33 to 69 years (Helsinki Sudden Death Study). We examined the percentage area of fatty streaks and fibrotic, calcified, and complicated lesions using computer-assisted planimetry. The MPO genotypes were determined by PCR. There were significant interactions of MPO genotype with the mean area of fibrotic (p < 0.01) and calcified (p < 0.05) lesions in the abdominal aorta and in fibrotic lesions in the thoracic aorta (p = 0.003). In the abdominal aorta, men < 53 years with low-expression genotypes had on average a 38.6% larger area of fibrotic lesions and a 43.8% larger area of calcified lesions than did the subjects with the G/G genotype. This association weakened with advancing age. Among men < 53 years, the MPO genotype was an independent predictor of fibrotic (p = 0.037) and calcified (p = 0.001) lesion area in the abdominal aorta after adjustment for age, body mass index, diabetes, hypertension, and smoking. MPO gene variation may modify the extent of advanced atherosclerotic lesions in the human aorta in early middle age.

Association of the endothelial nitric oxide synthase gene polymorphism with risk of coronary artery disease and myocardial infarction in middle-aged men.

Nitric oxide (NO), formed by endothelial constitutive nitric oxide synthase (eNOS) maintains endothelium-dependent vasodilatation and also mediates antithrombotic actions. The eNOS gene harbours a common polymorphism in intron 4 (4a/b), and some clinical studies have suggested an association of the rare a-allele with coronary artery disease (CAD) and myocardial infarction (MI). However, contradictory results have also been reported. We studied associations of eNOS polymorphism with CAD and MI in two prospective autopsy series comprising altogether 700 Caucasian Finnish men, who died suddenly. In ANCOVA, no significant differences in areas of atherosclerotic lesions and coronary stenosis percentages were found between men carrying the a-allele (ba+aa) compared with those homozygous for the b-allele. Subjects with the a-allele had significantly lower risk of MI (odds ratio 0.44, 95% confidence interval 0.25-0.77, P=0.004) compared with those carrying the bb genotype. Men with the a-allele also tended to have coronary thrombosis less often (odds ratio 0.43, 95% confidence interval 0.18-1.01, P=0.055). The eNOS gene 4a/b polymorphism was not associated with the extent of coronary atherosclerosis, but the a-allele of the variant seems to protect to some degree against the development of MI.