Association between lipid fractions and age of first myocardial infarction.

OBJECTIVE: Dyslipidemia is a major cause of early coronary heart disease (CHD). Low-density-lipoprotein cholesterol (LDL-C), remnant cholesterol (remnant-C) and high-density lipoprotein cholesterol (HDL-C) have all been shown to be associated with risk of CHD. We aimed to compare the association of these lipid fractions with age at first myocardial infarction(MI). Design. Multicenter study of consecutive patients hospitalized with a first MI. Linear regression models were used to assess the independent association of LDL-C, remnant-C and HDL-C with age at first MI. Results. The study included 1744 patients. In univariate analyses, LDL-C, remnant-C, and HDL-C were all significantly associated with age at first MI. However, in multivariate analyses only LDL-C [-2.5 years (95%CI: -3.1 to -1.8) per 1 SD increase] and to a lesser extent remnant-C [-0.9 years (95% CI: -1.5 to -0.3)] continued to be associated with age of MI, while HDL-C [0.5 years (95%CI: -0.2 to 1.2)] was not. Conclusions. LDL-C is the lipid fraction strongest associated with younger age of presentation of first MI. These results support the importance of controlling and treating LDL-C in prevention of premature MI.

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association.

Animal studies are a foundation for defining mechanisms of atherosclerosis and potential targets of drugs to prevent lesion development or reverse the disease. In the current literature, it is common to see contradictions of outcomes in animal studies from different research groups, leading to the paucity of extrapolations of experimental findings into understanding the human disease. The purpose of this statement is to provide guidelines for development and execution of experimental design and interpretation in animal studies. Recommendations include the following: (1) animal model selection, with commentary on the fidelity of mimicking facets of the human disease; (2) experimental design and its impact on the interpretation of data; and (3) standard methods to enhance accuracy of measurements and characterization of atherosclerotic lesions.

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association.

Animal studies are a foundation for defining mechanisms of atherosclerosis and potential targets of drugs to prevent lesion development or reverse the disease. In the current literature, it is common to see contradictions of outcomes in animal studies from different research groups, leading to the paucity of extrapolations of experimental findings into understanding the human disease. The purpose of this statement is to provide guidelines for development and execution of experimental design and interpretation in animal studies. Recommendations include the following: (1) animal model selection, with commentary on the fidelity of mimicking facets of the human disease; (2) experimental design and its impact on the interpretation of data; and (3) standard methods to enhance accuracy of measurements and characterization of atherosclerotic lesions.

ACC/AHA guidelines superior to ESC/EAS guidelines for primary prevention with statins in non-diabetic Europeans: the Copenhagen General Population Study.

AIM: We compared the 2013 American College of Cardiology/American Heart Association (ACC/AHA) and the 2016 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on prevention of atherosclerotic cardiovascular disease (ASCVD) using different risk prediction models [US Pooled Cohort Equations (US-PCE for any ASCVD) and European Systematic COronary Risk Evaluation system (European-SCORE for fatal ASCVD)] and different statin eligibility criteria. METHODS AND RESULTS: We examined 44 889 individuals aged 40-75 recruited in 2003-09 in the Copenhagen General Population Study, all free of ASCVD, diabetes, and statin use at baseline. We detected 2217 any ASCVD events and 199 fatal ASCVD events through 2014. The predicted-to-observed event ratio was 1.2 using US-PCE for any ASCVD and 5.0 using European-SCORE for fatal ASCVD. The US-PCE, but not the European-SCORE, was well-calibrated around decision thresholds for statin therapy. For a Class I recommendation, 42% of individuals qualified for statins using the ACC/AHA guidelines vs. 6% with the ESC/EAS guidelines. Using ACC/AHA- vs. ESC/EAS-defined statin eligibility led to a substantial gain in sensitivity (+62% for any ASCVD and +76% for fatal ASCVD) with a smaller loss in specificity (-35% for any ASCVD and -36% for fatal ASCVD). Similar differences between the ACC/AHA and ESC/EAS guidelines were found for men and women separately, and for Class IIa recommendations. The sensitivity and specificity of a US-PCE risk of 5% were similar to those of a European-SCORE risk of 1.4%, whereas a US-PCE risk of 7.5% was similar to a European-SCORE risk of 2.4%. CONCLUSIONS: The ACC/AHA guidelines were superior to the ESC/EAS guidelines for primary prevention of ASCVD, that is, for accurately assigning statin therapy to those who would benefit.

Inducing Persistent Flow Disturbances Accelerates Atherogenesis and Promotes Thin Cap Fibroatheroma Development in D374Y-PCSK9 Hypercholesterolemic Minipigs.

BACKGROUND: Although disturbed flow is thought to play a central role in the development of advanced coronary atherosclerotic plaques, no causal relationship has been established. We evaluated whether inducing disturbed flow would cause the development of advanced coronary plaques, including thin cap fibroatheroma. METHODS AND RESULTS: D374Y-PCSK9 hypercholesterolemic minipigs (n=5) were instrumented with an intracoronary shear-modifying stent (SMS). Frequency-domain optical coherence tomography was obtained at baseline, immediately poststent, 19 weeks, and 34 weeks, and used to compute shear stress metrics of disturbed flow. At 34 weeks, plaque type was assessed within serially collected histological sections and coregistered to the distribution of each shear metric. The SMS caused a flow-limiting stenosis, and blood flow exiting the SMS caused regions of increased shear stress on the outer curvature and large regions of low and multidirectional shear stress on the inner curvature of the vessel. As a result, plaque burden was ≈3-fold higher downstream of the SMS than both upstream of the SMS and in the control artery (P<0.001). Advanced plaques were also primarily observed downstream of the SMS, in locations initially exposed to both low (P<0.002) and multidirectional (P<0.002) shear stress. Thin cap fibroatheroma regions demonstrated significantly lower shear stress that persisted over the duration of the study in comparison with other plaque types (P<0.005). CONCLUSIONS: These data support a causal role for lowered and multidirectional shear stress in the initiation of advanced coronary atherosclerotic plaques. Persistently lowered shear stress appears to be the principal flow disturbance needed for the formation of thin cap fibroatheroma.

Statin use and cardiovascular risk factors in diabetic patients developing a first myocardial infarction.

BACKGROUND: The risk for a first myocardial infarction (MI) in people with diabetes has been shown to be as high as the risk for a new MI in non-diabetic patients with a prior MI. Consequently, risk-reducing statin therapy is recommended for nearly all patients with diabetes 40 years of age or older, regardless of cholesterol level. The purpose of this study was to assess the recommended and real-life use of statins for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in diabetic patients who develop ASCVD. METHODS: In a cross-sectional multicenter study of consecutive patients without previous ASCVD hospitalized with a first MI in 2010-2012, we obtained information on diabetic status, statin use, and cardiovascular risk factors prior to MI. RESULTS: The study population consisted of 1622 patients with first MI (63 % men), 228 of whom had known diabetes before MI. All but three of the diabetic patients were ≥40 years of age. Diabetic patients were older (70 vs 68, p = 0.006), were more often women (43 vs 36 %, p = 0.05) and had a higher prevalence of statin use (47 vs 11 %, p < 0.001) compared with non-diabetic patients. Despite a high risk factor burden, the majority (53 %) of patients with known diabetes was not treated with statins before MI, and there was no relationship between the number of high-risk markers and statin use. Nearly all diabetic patients not treated with statins before first MI had at least one marker of very high cardiovascular risk, including hypertension (71 %), current smoking (37 %), and nephropathy (33 %). CONCLUSIONS: Primary prevention with statins had been initiated in less than half of diabetic patients destined for a first MI, despite the presence of one or more markers of very high cardiovascular risk in nearly all. These results highlight an urgent need for optimizing statin therapy and global risk factor control in diabetic patients.

Mechanisms of plaque formation and rupture.

Atherosclerosis causes clinical disease through luminal narrowing or by precipitating thrombi that obstruct blood flow to the heart (coronary heart disease), brain (ischemic stroke), or lower extremities (peripheral vascular disease). The most common of these manifestations is coronary heart disease, including stable angina pectoris and the acute coronary syndromes. Atherosclerosis is a lipoprotein-driven disease that leads to plaque formation at specific sites of the arterial tree through intimal inflammation, necrosis, fibrosis, and calcification. After decades of indolent progression, such plaques may suddenly cause life-threatening coronary thrombosis presenting as an acute coronary syndrome. Most often, the culprit morphology is plaque rupture with exposure of highly thrombogenic, red cell-rich necrotic core material. The permissive structural requirement for this to occur is an extremely thin fibrous cap, and thus, ruptures occur mainly among lesions defined as thin-cap fibroatheromas. Also common are thrombi forming on lesions without rupture (plaque erosion), most often on pathological intimal thickening or fibroatheromas. However, the mechanisms involved in plaque erosion remain largely unknown, although coronary spasm is suspected. The calcified nodule has been suggested as a rare cause of coronary thrombosis in highly calcified and tortious arteries in older individuals. To characterize the severity and prognosis of plaques, several terms are used. Plaque burden denotes the extent of disease, whereas plaque activity is an ambiguous term, which may refer to one of several processes that characterize progression. Plaque vulnerability describes the short-term risk of precipitating symptomatic thrombosis. In this review, we discuss mechanisms of atherosclerotic plaque initiation and progression; how plaques suddenly precipitate life-threatening thrombi; and the concepts of plaque burden, activity, and vulnerability.

Statin use prior to first myocardial infarction in contemporary patients: Inefficient and not gender equitable.

OBJECTIVES: Guidelines recommend initiating primary prevention with statins to those at highest cardiovascular risk. We assessed the gender-specific implementation and effectiveness of this risk-guided approach. METHODS: We identified 1399 consecutive patients without known cardiovascular disease or diabetes hospitalized with a first myocardial infarction (MI) in Denmark. Statin use before MI was assessed, and cardiovascular risk was calculated using SCORE (Systematic COronary Risk Evaluation). RESULTS: Among patients with first MI, 36% were women. Compared with men, they were older (mean 72 vs. 65years) but had a lower estimated risk (median 3.4% vs. 6.7%, SCORE high-risk model in the statin-naïve patients). Statin therapy had been initiated in 12% of women and 10% of men prior to MI. After adding 1.5mmol/L to the total cholesterol concentration of those already on statins, the estimated pre-treatment risk was much lower in women than men (median 3.8% vs. 9.2%, SCORE high-risk model), and only 29% of women would have passed the risk-based treatment threshold defined by the European guidelines (SCORE ≥5%). Estimated risk and statin use correlated directly in men but not in women. Only ~5% of first MI are prevented by the current use of statins in people without diabetes. CONCLUSION: In people destined for a first MI, statin therapy is uncommon and prevents few events. Lower-risk women receive as much statins as higher risk men. This gender disparity and inefficient targeting of statins to those at highest risk indicate that risk scoring is not widely used in routine clinical practice in Denmark.

The high-density lipoprotein-adjusted SCORE model worsens SCORE-based risk classification in a contemporary population of 30,824 Europeans: the Copenhagen General Population Study.

AIMS: Recent European guidelines recommend to include high-density lipoprotein (HDL) cholesterol in risk assessment for primary prevention of cardiovascular disease (CVD), using a SCORE-based risk model (SCORE-HDL). We compared the predictive performance of SCORE-HDL with SCORE in an independent, contemporary, 'low-risk' European population, focusing on ability to identify those in need of intensified CVD prevention. METHODS AND RESULTS: Between 2003 and 2008, 46,092 individuals without CVD, diabetes, or statin use were enrolled in the Copenhagen General Population Study (CGPS). During a mean of 6.8 years of follow-up, 339 individuals died of CVD. In the SCORE target population (age 40-65; n = 30,824), fewer individuals were at baseline categorized as high risk (≥5% 10-year risk of fatal CVD) using SCORE-HDL compared with SCORE (10 vs. 17% in men, 1 vs. 3% in women). SCORE-HDL did not improve discrimination of future fatal CVD, compared with SCORE, but decreased the detection rate (sensitivity) of the 5% high-risk threshold from 42 to 26%, yielding a negative net reclassification index (NRI) of -12%. Importantly, using SCORE-HDL, the sensitivity was zero among women. Both SCORE and SCORE-HDL overestimated risk of fatal CVD. In well-calibrated models developed from the CGPS, HDL did not improve discrimination or NRI. Lowering the decision threshold from 5 to 1% led to progressive gain in NRI for both CVD mortality and morbidity. CONCLUSION: SCORE-HDL did not improve discrimination compared with SCORE, but deteriorated risk classification based on NRI. Future guidelines should consider lower decision thresholds and prioritize CVD morbidity and people above age 65.

Diabetes with poor glycaemic control does not promote atherosclerosis in genetically modified hypercholesterolaemic minipigs.

AIMS/HYPOTHESIS: Diabetes is associated with an increased risk of atherosclerotic cardiovascular disease, but whether there is a direct and independent role for impaired glucose control in atherogenesis remains uncertain. We investigated whether diabetes with poor glycaemic control would accelerate atherogenesis in a novel pig model of atherosclerosis, the D374Y-PCSK9(+) transgenic minipig. METHODS: Nineteen minipigs were fed a cholesterol-enriched, high-fat diet; ten of these pigs were injected with streptozotocin to generate a model of diabetes. Restricted feeding was implemented to control the pigs' weight gain and cholesterol intake. After 49 weeks of high-fat feeding, the major arteries were harvested for a detailed analysis of the plaque burden and histological plaque type. RESULTS: Stable hyperglycaemia was achieved in the diabetic minipigs, while the plasma total and LDL-cholesterol and creatinine levels were unaffected. Diabetes failed to increase atherosclerosis in any of the vessels examined. The plaque burden in the aorta and right coronary artery was comparable between the groups, and was even reduced in the left anterior descending (LAD) coronary and iliofemoral arteries in the diabetic pigs compared with the controls. The distribution of plaque types and the collagen and macrophage contents were similar between the groups, except for a reduced infiltration of macrophages in the LAD arteries of the diabetic pigs. CONCLUSIONS/INTERPRETATION: Poorly controlled diabetes with no alterations in plasma cholesterol or creatinine concentrations did not augment the plaque burden or promote the development of more advanced lesions in this large-animal model of human-like atherosclerosis. This is consistent with clinical studies in patients with type 1 diabetes, indicating that hyperglycaemia per se is not an independent promoter of atherosclerotic disease, but that other diabetes-associated risk factors are important.

Non-coronary atherosclerosis.

During the last decades, the clinical and research interest in atherosclerosis has been mostly focused on coronary arteries. After the publications of the European Society Guidelines and AHA/ACC Guidelines on Peripheral artery diseases, and of the Registry REduction in Atherothrombosis for Continued Health Registry, there has been an increased interest in atherosclerosis of the lower extremity arteries and its presence in multifocal disease. However, awareness in the general population and the medical community of non-coronary artery diseases, and of its major prognostic implications remain relatively low. The aim of this general review stemming out of an ESC Working Group on Peripheral Circulation meeting in 2011 is to enhance awareness of this complex disease highlighting the importance of the involvement of atherosclerosis at different levels with respect to clinical presentation, diagnosis, and co-existence of the disease in the distinct arterial territories. We also emphasize the need of an interdisciplinary approach to face the broad and complex spectrum of multifocal disease, and try to propose a series of tentative recommendations and measures to be implemented in non-coronary atherosclerosis.

Update on acute coronary syndromes: the pathologists' view.

Although mortality rates from coronary heart disease in the western countries have declined in the last few decades, morbidity caused by this disease is increasing and a substantial number of patients still suffer acute coronary syndrome (ACS) and sudden cardiac death. Acute coronary syndrome occurs as a result of myocardial ischaemia and its manifestations include acute myocardial infarction and unstable angina. Culprit plaque morphology in these patients varies from thrombosis with or without coronary occlusion to sudden narrowing of the lumen from intraplaque haemorrhage. The coronary artery plaque morphologies primarily responsible for thrombosis are plaque rupture, and plaque erosion, with plaque rupture being the most common cause of acute myocardial infarction, especially in men. Autopsy data demonstrate that women <50 years of age more frequently have erosion, whereas in older women, the frequency of rupture increases with each decade. Ruptured plaques are associated with positive (expansive) remodelling and characterized by a large necrotic core and a thin fibrous cap that is disrupted and infiltrated by foamy macrophages. Plaque erosion lesions are often negatively remodelled with the plaque itself being rich in smooth muscle cells and proteoglycans with minimal to absence of inflammation. Plaque haemorrhage may expand the plaque rapidly, leading to the development of unstable angina. Plaque haemorrhage may occur from plaque rupture (fissure) or from neovascularization (angiogenesis). Atherosclerosis is now recognized as an inflammatory disease with macrophages and T-lymphocytes playing a dominant role. Recently at least two subtypes of macrophages have been identified. M1 is a pro-inflammatory macrophage while M2 seems to play a role in dampening inflammation and promoting tissue repair. A third type of macrophage, termed by us as haemoglobin associated macrophage or M(Hb) which is observed at site of haemorrhage also can be demonstrated in human atherosclerosis. In order to further our understanding of the specific biological events which trigger plaque instability and as well as to monitor the effects of novel anti-atherosclerotic therapies newer imaging modalities in vivo are needed.

Ultrahigh-field DCE-MRI of angiogenesis in a novel angiogenesis mouse model.

PURPOSE: To be able to screen and identify potential candidate agents for noninvasive imaging of diseases involving angiogenesis, a standardized in vivo angiogenesis model is needed. Angiogenesis is a common feature of many pathological conditions and has become an important target for diagnosis and treatment, with many noninvasive imaging agents emerging. MATERIALS AND METHODS: Uniform scaffolds consisting of porous and flexible polycaprolactone were implanted subcutaneously in mice and studied after 1 to 6 weeks to describe the time course of angiogenesis. The model was characterized by histology and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Microscopic examination revealed progressive ingrowth of new vessels from the periphery, leading to a fully vascularized scaffold within 6 weeks. Blood flow through the new vessels, assessed by DCE-MRI, revealed peripheral vascularization corresponding to 12.3% (SD 6.1%) of scaffold area at week 1 and a more uniform and complete distribution of vessels corresponding to 84.1% (SD 16.2%) of scaffold area at week 4. CONCLUSION: In agreement with microscopic examination, noninvasive DCE-MRI visualized progressive development of new vessels in a novel and standardized murine angiogenesis model, making this model suitable for screening angiogenesis-related drugs and contrast agents.

Flanking recipient vasculature, not circulating progenitor cells, contributes to endothelium and smooth muscle in murine allograft vasculopathy.

OBJECTIVE: The prevailing view assumes that circulating endothelial and smooth muscle progenitor cells participate in allograft vasculopathy (AV), although the seminal studies in the field were not designed to distinguish between circulating and migrating cells of recipient origin. We developed a double-transplantation technique to overcome this problem and reinvestigated the origin of endothelial cells (ECs) and smooth muscle cells (SMCs) in murine AV. METHODS AND RESULTS: Carotid artery segments from BALB/c mice were allografted to apolipoprotein E(-/-) B6 mice with or without a "flanking" isograft interpositioned between the allograft and the recipient artery. Either recipient mice or interpositioned isografts expressed enhanced green fluorescent protein, and consequently, cells migrating into the allograft from the flanking vasculature could easily be tracked and distinguished from recruited circulating cells. Without immunosuppression, allograft donor cells vanished as expected, and AV developed by replacement and accumulation of ECs and SMCs of recipient origin. The double transplantation models revealed that all ECs and SMCs in AV had migrated into the allograft from the flanking vasculature without any contribution from putative progenitor cells in the blood. CONCLUSIONS: Migrating cells from the flanking vasculature, not circulating progenitor cells, are the source of recipient-derived ECs and SMCs in murine AV.

Genetic susceptibility of the arterial wall is an important determinant of atherosclerosis in C57BL/6 and FVB/N mouse strains.

OBJECTIVE: How genetic variations among inbred mouse strains translate into differences in atherosclerosis susceptibility is of significant interest for the development of new therapeutic strategies. The objective of the present study was to examine whether genetically controlled arterial wall properties influence atherosclerosis susceptibility in FVB/N (FVB) and C57BL/6 (B6) apolipoprotein E knockout (apoE(-/-)) mouse strains. METHODS AND RESULTS: Common carotid artery segments from B6 apoE(-/-), F1 apoE(-/-), and FVB apoE(-/-) mice were transplanted to hybrid F1 apoE(-/-) mice, which can accept grafts from both parental strains without adaptive immune responses. The mice were fed a high-fat diet, and atherosclerosis was induced in the transplanted artery segments by placement of a perivascular constrictive collar. Artery segments from B6 apoE(-/-) mice developed much larger atherosclerotic lesions than artery segments from FVB or F1 apoE(-/-) mice. No differences in aortic arch atherosclerosis of the recipient mice were observed between groups. CONCLUSIONS: Genetically controlled factors acting at the level of the arterial wall are important determinants of atherosclerosis susceptibility in FVB apoE(-/-) and B6 apoE(-/-) mice.

Oversized vein grafts develop advanced atherosclerosis in hypercholesterolemic minipigs.

BACKGROUND: Accelerated atherosclerosis is the main cause of late aortocoronary vein graft failure. We aimed to develop a large animal model for the study of pathogenesis and treatment of vein graft atherosclerosis. METHODS: An autologous reversed jugular vein graft was inserted end-to-end into the transected common carotid artery of ten hypercholesteroemic minipigs. The vein grafts were investigated 12-14 weeks later with ultrasound and angiograpy in vivo and microscopy post mortem. RESULTS: One minipig died during follow up (patent vein graft at autopsy), and one vein graft thrombosed early. In the remaining eight patent vein grafts, the mean (standard deviation) intima-media thickness was 712 µm (276 µm) versus 204 µm (74 µm) in the contralateral control internal jugular veins (P < .01). Advanced atherosclerotic plaques were found in three of four oversized vein grafts (diameter of graft > diameter of artery). No plaques were found in four non-oversized vein grafts (P < .05). CONCLUSIONS: Our model of jugular vein graft in the common carotid artery of hypercholesterolemic minipigs displayed the components of human vein graft disease, i.e. thrombosis, intimal hyperplasia, and atherosclerosis. Advanced atherosclerosis, the main cause of late failure of human aortocoronary vein grafts was only seen in oversized grafts. This finding suggests that oversized vein grafts may have detrimental effects on patient outcome.

Spatial orientation of cross-sectional images of coronary arteries: point of view in intracoronary imaging.

BACKGROUND: In studies where cross-sectional images of coronary arteries obtained with different imaging modalities are compared, the importance of correct co-localization and matching of images along the coronary artery longitudinal axis is obvious. However, it appears neglected that correct spatial orientation of the cross-sectional plane may not be obtainable just by rotating the images to ensure co-localization of identifiable landmarks such as sidebranches. A cross-section has two sides, one facing proximally and the other distally, and pairs of images reconstructed corresponding to these opposite points of view are mirror images of each other and not superimposable. This may be difficult if not impossible to recognize and unrecognized it will give rise to flawed results in the development and validation of imaging technologies aimed at plaque characterization (tissue mapping). We determined the imagined point of view for three commercially available intracoronary imaging systems used by invasive cardiologists and illustrate its importance in imaging modality validation. METHODS AND RESULTS: We made an asymmetric phantom and investigated it with two different intravascular ultrasound (IVUS) systems and one optical coherence tomography (OCT) system. The asymmetry of the phantom allowed determination of the spatial orientation of the cross-sectional images. On all tested systems, an observer should imagine herself/himself standing proximal to the cross-section when looking at the intravascular images. CONCLUSIONS: The tested intracoronary imaging modalities displayed cross-sectional images with a spatial orientation corresponding to a proximal point of view. Knowledge of the spatial orientation is mandatory when comparing and validating different imaging modalities aimed at plaque characterization.