Progression Of Plaque Burden Research Articles

Subclinical Atherosclerosis Progression in Low-Risk, Middle-Aged Adults: Carotid Leads Femoral in IMT Increase but Not in Plaque Formation.

Clinical data, risk factors, carotid/femoral intima-media thickness (IMT), and plaque presence were analyzed. Cardiovascular risk factors and scores increased significantly at follow-up. Both carotid and femoral mean IMT increased (p < 0.001). While plaque prevalence rose and was similar in both arteries (carotid: 4.8% to 17.9%, femoral: 3.6% to 17.7%, p < 0.001 for both), the progression of plaque burden was greater in femorals. Notably, the carotid mean IMT demonstrated a faster yearly progression rate compared to the mean femoral IMT. The prevalence of pathological nomogram-based mean IMT right or left was higher in the carotids (52.9% to 78.8%, p < 0.001) compared to femorals (23.2% to 44.7%, p < 0.001), with a significant increase at the end of follow-up in both territories. This study demonstrates significant subclinical atherosclerosis progression in low-risk, middle-aged adults over 5 years. Carotid arteries showed a faster progression rate of mean IMT and a higher prevalence of pathological nomogram-based mean IMT compared to the femoral arteries. However, plaque burden was similar in both territories, with greater progression in femorals. Identifying carotid and femoral atherosclerosis burden may be a valuable tool for risk stratification in this population.

Development and Validation of CCTA-based Radiomics Signature for Predicting Coronary Plaques With Rapid Progression.

Rapid plaque progression (RPP) is associated with a higher risk of acute coronary syndromes compared with gradual plaque progression. We aimed to develop and validate a coronary computed tomography angiography (CCTA)-based radiomics signature (RS) of plaques for predicting RPP. A total of 214 patients who underwent serial CCTA examinations from 2 tertiary hospitals (development group, 137 patients with 164 lesions; validation group, 77 patients with 101 lesions) were retrospectively enrolled. Conventional CCTA-defined morphological parameters (eg, high-risk plaque characteristics and plaque burden) and radiomics features of plaques were analyzed. RPP was defined as an annual progression of plaque burden ≥1.0% on lesion-level at follow-up CCTA. RS was built to predict RPP using XGBoost method. RS significantly outperformed morphological parameters for predicting RPP in both the development group (area under the receiver operating characteristic curve, 0.82 versus 0.74; P=0.04) and validation group (area under the receiver operating characteristic curve, 0.81 versus 0.69; P=0.04). Multivariable analysis identified RS (odds ratio, 2.35 [95% CI, 1.32-4.46]; P=0.005) as an independent predictor of subsequent RPP in the validation group after adjustment of morphological confounders. Unlike unchanged RS in the non-RPP group, RS increased significantly in the RPP group at follow-up in the whole dataset (P<0.001). The proposed CCTA-based RS had a better discriminative value to identify plaques at risk of rapid progression compared with conventional morphological plaque parameters. These data suggest the promising utility of radiomics for predicting RPP in a low-risk group on CCTA.

The impact of baseline calcified plaque volume on coronary rapid plaque progression by serial coronary computed tomography angiography in patients with type 2 diabetes

Objectives Patients with type 2 diabetes mellitus (T2DM) are susceptible to coronary artery disease (CAD), and coronary outcomes in these patients are heterogeneous. However, the impact of coronary plaque compositions on rapid plaque progression (RPP) in patients with T2DM has rarely been reported. This study aimed to investigate the association of coronary plaque compositions with rapid lesion volume progression in patients with T2DM. Materials and Methods A total of 159 subjects (aged 62.51 ± 10.3 years, 68.6% were male) who underwent serial coronary computed tomography angiography (CCTA) with type 2 diabetic status were enrolled. Annual change of plaque volume (PV) (mm3/year) was defined as PV change divided by inter-scan period. RPP was defined as the progression of plaque burden (PV divided by vessel volume multiplied by 100) ≥0.59%/year. Plaque components were compared between RPP and no RPP groups. Then all patients were divided into 3 groups according to the baseline calcified plaque volume tertiles. The outcome was whether RPP occurred. Results The median inter-scan period was 2.09 (range 1.41–3.33) years. The overall incidence of RPP was 61.0%. The calcified plaque volume decreased significantly in the RPP group as compared to the no RPP group. The risk of RPP (odds ratio [OR] 0.39; 95% confidence interval [CI]: 0.17-0.88; p = 0.024) was reduced in tertiles III as compared to that in tertiles I even after adjustment for baseline variables (OR 0.21; 95% CI: 0.07–0.63; p = 0.005). Moreover, adding the calcified plaque volume significantly raised the predictive value for the RPP (0.370, p = 0.030, and 0.059, p = 0.025, NRI, and IDI respectively) as compared to traditional factors. Conclusion The baseline calcified plaque volume is an independent protective factor for the rapid progression of coronary atherosclerosis in patients with T2DM.

Temporal changes in plaque characteristics after treatment and their relationship with stroke recurrence: a quantitative study using magnetic resonance imaging.

BackgroundIntracranial atherosclerotic disease (ICAD) is the major cause of ischemic stroke. Despite aggressive medical therapy, around 15% of patients with ICAD experience recurrence. The aim of the present study was to evaluate the temporal changes in intracranial arteriosclerotic plaques after medical treatment based on vessel wall magnetic resonance imaging (VWMRI) and to explore their relationship with stroke recurrence.MethodsA total of 67 symptomatic patients with ICAD who underwent initial and follow-up VWMRI were recruited into this retrospective cohort study. Stroke recurrence was defined as an ipsilateral stroke symptom after the initial attack. The clinical characteristics and plaque features, including stenosis ratio (measured based on luminal diameter or area), plaque thickness, plaque burden (PB), enhancement ratio (ER), and enhancement grade, were evaluated and compared between the initial and follow-up examinations. Changes in plaque characteristics were compared between patients with or without recurrence by univariable analyses. Multivariable regression was performed to investigate imaging markers for recurrent stroke.ResultsThe median interval between baseline and follow-up VWMRI was 334 days. A total of 13 cases (19.4%) experienced a stroke recurrence. After treatment, significant decreases in the stenosis ratio (area), PB, and ER were observed in cases without recurrence (all P<0.05), while no significant difference in plaque features was found for cases with recurrence. Univariable analyses showed that changes in stenosis ratio (area), plaque thickness, PB, and ER were significantly different between patients with and without recurrence (all P<0.05). Multivariable regression indicated that PB change was the only significant marker associated with stroke recurrence [odds ratio (OR) =1.112 per 1% increase, 95% confidence interval (CI): 1.010 to 1.224, P=0.031].ConclusionsPatients with arteriosclerotic plaques who benefit from medical treatment show obvious decreases in stenosis (area), PB, and ER. The progression of PB may serve as an independent marker for predicting stroke recurrence.

Computational modeling of atherosclerotic plaque progression in carotid lesions with moderate degree of stenosis.

Carotid atherosclerotic plaque growth leads to the progressive luminal stenosis of the vessel, which may erode or rupture causing thromboembolism and cerebral infarction, manifested as stroke. Carotid atherosclerosis is considered the major cause of ischemic stroke in Europe and thus new imaging-based computational tools that can improve risk stratification and management of carotid artery disease patients are needed. In this work, we present a new computational approach for modeling atherosclerotic plaque progression in real patient-carotid lesions, with moderate to severe degree of stenosis (>50%). The model incorporates for the first time, the baseline 3D geometry of the plaque tissue components (e.g. Lipid Core) identified by MR imaging, in which the major biological processes of atherosclerosis are simulated in time. The simulated plaque tissue production results in the inward remodeling of the vessel wall promoting luminal stenosis which in turn predicts the region of the actual stenosis progression observed at the follow-up visit. The model aims to support clinical decision making, by identifying regions prone to plaque formation, predict carotid stenosis and plaque burden progression, and provide advice on the optimal time for patient follow-up screening.

Progression of Plaque Burden of Intracranial Atherosclerotic Plaque Predicts Recurrent Stroke/Transient Ischemic Attack: A Pilot Follow‐Up Study Using Higher‐Resolution MRI

BackgroundPatients with intracranial atherosclerotic disease (ICAD) have a high frequency of stroke recurrence. However, there has been little investigation into the prognostic value of higher‐resolution magnetic resonance imaging (HR‐MRI).PurposeTo investigate the use of intracranial atherosclerotic plaques features in predicting risk of recurrent cerebrovascular ischemic events using HR‐MRI.Study TypeProspective.PopulationFifty‐eight patients with acute/subacute stroke (N = 46) or transient ischemic attack (N = 12).Field Strength/SequenceA 3.0 T, 3D time‐of‐flight gradient echo sequence and T1‐ and T2‐weighted fast spin echo sequences with 0.31 x 0.39 mm2 in‐plane resolution, twice (with >3 months between scans) following the initial event.AssessmentPatients were also followed clinically for recurrent ischemic events for up to 48 months or until a subsequent event occurred. The degree of stenosis, plaque burden (PB), minimal lumen area (MLA), and contrast enhancement ratio were assessed at each scanning session and the percentage change of each over time was calculated.Statistical TestsUnivariable and multivariable Cox regression analyses were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for predicting recurrent events.ResultsThe mean time interval between baseline and follow‐up MRI scans was 6.2 ± 4.1 months. After the second MRI scan, 20.7% of patients (N = 12) had experienced ipsilateral recurrent TIA/stroke within 10.9 ± 9.2 months. Univariable analyses showed that baseline triglyceride, percentage change of PB, and progression of PB were significantly associated with recurrent events (all P < 0.05). Multivariable Cox regression indicated that progression of PB (HR, 6.293; 95% CI, 1.620–24.444; P < 0.05) was a significant independent imaging feature for recurrent ischemic events.Data ConclusionProgression of PB was independently associated with recurrent ischemic cerebrovascular events. HR‐MRI may help risk stratification of patients at risk of recurrent stroke.Level of Evidence2Technical EfficacyStage 4

Coronary plaque natural history displays significant longitudinal heterogeneity along the length of individual coronary plaques

Abstract Background The natural history of plaque growth is, among other systemic risk factors, related to the blood flow induced local shear stress. Especially at regions of low shear stress plaques are initiated. Upon plaque encroachment into the lumen, plaques will be exposed to high shear stress. Interestingly, it has been observed that individual plaques are very heterogeneous regarding the local shear stress exposure and remodeling patterns along the plaque length. However no information is available on the spatial heterogeneity of temporal changes in plaques burden. We studied the longitudinal spatial heterogeneity of plaque burden progression, regression, quiescence in human coronary plaques. Methods 591 coronary arteries from 302 patients with coronary artery disease who presented with an acute coronary syndrome from the PREDICTION study were investigated for local plaque progression, regression, quiescence patterns after 6–10 months follow up. Arterial geometry was derived from angiography/IVUS-based vascular profiling and reported in 3 mm segments. Plaques were defined as &amp;gt;3 consecutive segments with maximal wall thickness&amp;gt;0.5 mm. Plaque progression was defined as &amp;gt;5% increase, regression as &amp;lt;−5% decrease, and quiescence as no change in plaque burden (plaque area/ total vessel area * 100%). Logistic mixed model regression analysis was performed with plaque progression features as outcome and plaque length as independent variable with vessel as random factor to account for clustering of the data. Results 5658 3mm-segments of 661 plaques were analyzed. Plaque burden changes over time ranged from −22% to +20%, with an average of −0.4%±4% which was not significant different from 0. Among all plaques, 56% showed segments with plaque progression of more than 5%, 60% with plaque regression (&amp;lt;−5%) and 96% of the plaques had segments that did not change over time (quiescence). On average, 17% of the plaque length displayed plaque progression, 20% regression and 63% was quiescent. The presence and number of features (progression, regression, quiescence) within the plaque were significantly related to the plaque length (figure). Conclusion Plaques are very heterogeneous in plaque progression patterns. Most of the plaques show within the plaque length simultaneously more than one plaque progression feature (segments that do not change in plaque burden, segments that regress or progress). The number of observed plaque progression features was related to the plaque length. Funding Acknowledgement Type of funding source: None

The association between anthropometric measures of adiposity and the progression of carotid atherosclerosis

BackgroundFew reports are available on the contribution of general and abdominal obesity to the progression of carotid atherosclerosis in late adulthood. This study investigated the impact of four simple anthropometric measures of general and abdominal obesity on the progression of carotid atherosclerosis and the extent to which the association between adiposity and the progression of plaque burden is mediated by cardiometabolic markers.MethodsFour thousand three hundred forty-five adults (median age 60) from the population-based Tromsø Study were followed over 7 years from the first carotid ultrasound screening to the next. The progression of carotid atherosclerosis was measured in three ways: incidence of plaques in previously plaque-free participants; change in the number of plaques; and total plaque area (TPA). We used generalised linear models to investigate the association between each adiposity measure – body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) – and each outcome. Models were adjusted for potential confounders (age, sex, smoking, education, physical activity). The pathways through which any associations observed might operate were investigated by further adjusting for cardiometabolic mediators (systolic blood pressure, cholesterol, and HbA1c).ResultsThere was little evidence that adiposity was related to the formation of new plaques during follow-up. However, abdominal adiposity was associated with TPA progression. WHtR showed the largest effect size (mean change in TPA per one standard deviation (SD) increase in WHtR of 0.665 mm2, 95% confidence interval 0.198, 1.133) while BMI showed the smallest. Effect sizes were substantially reduced after the adjustment for potential mediators.ConclusionsAbdominal obesity indirectly measured with WC seems more strongly associated with the progression of TPA than general obesity. These associations appear to be largely mediated by known cardiometabolic markers.

The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability.

The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

Combined non-invasive assessment of endothelial shear stress and molecular imaging of inflammation for the prediction of inflamed plaque in hyperlipidaemic rabbit aortas.

To evaluate the incremental value of low endothelial shear stress (ESS) combined with high-resolution magnetic resonance imaging (MRI)- and computed tomography angiography (CTA)-based imaging for the prediction of inflamed plaque. Twelve hereditary hyperlipidaemic rabbits underwent quantitative analysis of plaque in the thoracic aorta with 256-slice CTA and USPIO-enhanced (ultra-small superparamagnetic nanoparticles, P904) 1.5-T MRI at baseline and at 6-month follow-up. Computational fluid dynamics using CTA-based 3D reconstruction of thoracic aortas identified the ESS patterns in the convex and concave curvature subsegments of interest. Subsegments with low baseline ESS exhibited significant increase in wall thickness and plaque inflammation by MRI, in non-calcified plaque burden by CTA, and developed increased plaque size, lipid and inflammatory cell accumulation (high-risk plaque features) at follow-up by histopathology. Multiple regression analysis identified baseline ESS and inflammation by MRI to be independent predictors of plaque progression, while receiver operating curve analysis revealed baseline ESS alone or in combination with inflammation by MRI as the strongest predictor for augmented plaque burden and inflammation (low ESS at baseline: AUC = 0.84, P < 0.001; low ESS and inflammation by molecular MRI at baseline: AUC = 0.89, P < 0.001). Low ESS predicts progression of plaque burden and inflammation as assessed by non-invasive USPIO-enhanced MRI. Combined non-invasive assessment of ESS and imaging of inflammation may serve to predict plaque with high-risk features.

HDL and CER-001 Inverse-Dose Dependent Inhibition of Atherosclerotic Plaque Formation in apoE-/- Mice: Evidence of ABCA1 Down-Regulation.

ObjectiveCER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3).Methods and ResultsCER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse “flow cessation model,” in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively.ConclusionsThese data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression.

Prediction of High-Risk Plaque Development and Plaque Progression With the Carotid Atherosclerosis Score

The goal of this prospective study was to evaluate the carotid atherosclerosis score (CAS) for predicting the development of high-risk plaque features and plaque burden progression. Previous studies have shown that carotid intraplaque hemorrhage (IPH) and a disrupted luminal surface (DLS), as identified by using magnetic resonance imaging, are associated with greater risk for cerebrovascular events. On the basis of data from a large cross-sectional study, a scoring system was developed to determine which plaque features are associated with the presence of IPH and DLS. However, the predictive value of CAS has not been previously tested in a prospective, longitudinal study. A total of 120 asymptomatic subjects with 50% to 79% carotid stenosis underwent carotid magnetic resonance imaging scans at baseline and 3 years thereafter. Presence of IPH and DLS, wall volume, maximum wall thickness, and maximum percent lipid-rich necrotic core area were measured at both time-points. Baseline CAS values were calculated on the basis of previously published criteria. Of the 73 subjects without IPH or DLS at baseline, 9 (12%) developed 1 or both of these features during follow-up. There was a significant increasing trend between CAS and the development of new DLS (p < 0.001) and with plaque burden progression (p= 0.03) but not with the development of new IPH (p= 0.3). Percent carotid stenosis was not significantly associated with new DLS (p= 0.2), new IPH (p= 0.1), or plaque progression (p= 0.6). CAS was found to have a significant increasing relationship with incident DLS andplaque progression in this prospective study. CAS can potentially provide improved risk stratificationbeyond luminal stenosis.

Quantification of carotid vessel wall and plaque thickness change using 3D ultrasound images

Quantitative measurements of carotid plaque burden progression or regression are important in monitoring patients and in evaluation of new treatment options. 3D ultrasound (US) has been used to monitor the progression or regression of carotid artery plaques. This paper reports on the development and application of a method used to analyze changes in carotid plaque morphology from 3D US. The technique used is evaluated using manual segmentations of the arterial wall and lumen from 3D US images acquired in two imaging sessions. To reduce the effect of segmentation variability, segmentation was performed five times each for the wall and lumen. The mean wall and lumen surfaces, computed from this set of five segmentations, were matched on a point-by-point basis, and the distance between each pair of corresponding points served as an estimate of the combined thickness of the plaque, intima, and media (vessel-wall-plus-plaque thickness or VWT). The VWT maps associated with the first and the second US images were compared and the differences of VWT were obtained at each vertex. The 3D VWT and VWT-Change maps may provide important information for evaluating the location of plaque progression in relation to the localized disturbances of flow pattern, such as oscillatory shear, and regression in response to medical treatments.

Abstract 1391: Atherogenic Dyslipidemia Predicts Accelerated Progression of Atherosclerosis in Patients with Coronary Artery Disease

Background: Atherogenic dyslipidemia (AD) is characterized by the combination of elevated serum triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C) and small-dense low-density lipoprotein cholesterol (LDL-C) and has emerged as a powerful risk factor of coronary disease. The effect of AD on the progression of plaque burden remains incompletely defined. This analysis aimed to determine the impact of AD on measures of atherosclerotic progression in patients receiving intensive lipid lowering therapy. Methods: 910 patients with angiographic coronary artery disease treated with atorvastatin to a goal LDL-C of 100 ± 15mg/dl received torcetrapib or placebo. Atheroma burden was determined by intravascular ultrasound performed at baseline and following 24 months of treatment. Baseline and changes in atheroma burden were investigated in patients stratified according to the presence or absence of an AD phenotype (HDL-C &lt; 45 mg/dL for men and &lt; 50mg/dL for women, triglycerides 150 – 600mg/dL and LDL-C &lt; 160mg/dL) Results: 20.4% of patients met the criteria for AD. Patients with AD were younger (55.5 v 58 years, p=0.003), had higher body mass index (30.9 v 29.3 kg/m2, p&lt;0.001) and were more likely to fit the definition of the metabolic syndrome (93 v 30.3%, p&lt;0.001). Accelerated progression of percent atheroma volume (PAV, +0.76 v +0.01%, p=0.001) and total atheroma volume (TAV, −4.75 v −7.18 mm3, p=0.022) was observed in patients with AD. Patients with AD were less likely to undergo substantial regression (reduction in PAV &gt;5%, 12.9% v 24.2%, p=0.001) and more likely to undergo substantial progression (increase in PAV &gt;5%, 34.9% v 23.2%, p=0.001) No differences were observed between treatment groups with regard to changes in PAV (0.59 v 0.99%, p=0.727) or TAV (−5.7 v −3.8 mm3, p=0.461) in patients with AD. On multivariate analysis, the presence of atherogenic dyslipidemia was an independent predictor of increase in PAV (p=0.004) and TAV (p=0.045). Conclusions: Despite aggressive lipid lowering therapy, AD is an independent predictor of accelerated progression of atherosclerosis. With a rise in the prevalence of obesity and its metabolic complications there is an increasing need to intensively modify factors that place these patients at high risk.

Smoking-Induced Vascular Disease

Polycyclic aromatic hydrocarbons (PAHs) are recognized widely as potential environmental procarcinogens and have attracted their share of attention from both funding agencies and scientists interested in biomedical research. Curiously, their potential relevance to cardiovascular disease, rather than cancer, has stirred less emotion. This imbalance of attention is reflected also in society’s response to that most intimate form of self-pollution with PAHs (and much else), cigarette smoking. While the States have chosen to allocate varying proportions of their Tobacco Settlements to research, cancer tends to dominate the agenda. Yet, tobacco-related cardiovascular disease yields an even more striking burden on the public health than cancer. It has been estimated that cardiovascular morbidity and mortality are increased 4-fold in smokers and by one third in passive smokers.1 One might think that such daunting figures would prompt advocacy groups, such as the American Heart Association, to lobby vigorously at the State level for an appropriate allocation of the Tobacco Settlements to cardiovascular research. Our understanding of the mechanisms by which smoking mediates cardiovascular injury and the factors that determine interindividual susceptibility to smoking-induced tissue injury is remarkably limited. In this issue of Circulation Research , Kerzee and Ramos2 draw our attention to a mechanism of potential relevance to acceleration of atherogenesis by PAHs, including those in cigarette smoke. The aryl hydrocarbon receptor (Ahr) is a member of the family of basic helix loop helix proteins (bHLHs) that contain PAS domains. This family includes proteins related to differentiation, such as MyoD, the response to hypoxia, such as Hif1α, and circadian rhythms, such as CLOCK, …