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Background and hypothesisThe recently introduced Bayesian quantile regression (BQR) machine-learning method enables comprehensive analyzing the relationship among complex clinical variables. We analyzed the relationship between multiple cardiovascular (CV) risk factors and different stages of coronary artery disease (CAD) using the BQR model in a vessel-specific manner.MethodsFrom the data of 1,463 patients obtained from the PARADIGM (NCT02803411) registry, we analyzed the lumen diameter stenosis (DS) of the three vessels: left anterior descending (LAD), left circumflex (LCx), and right coronary artery (RCA). Two models for predicting DS and DS changes were developed. Baseline CV risk factors, symptoms, and laboratory test results were used as the inputs. The conditional 10%, 25%, 50%, 75%, and 90% quantile functions of the maximum DS and DS change of the three vessels were estimated using the BQR model.ResultsThe 90th percentiles of the DS of the three vessels and their maximum DS change were 41%-50% and 5.6%-7.3%, respectively. Typical anginal symptoms were associated with the highest quantile (90%) of DS in the LAD; diabetes with higher quantiles (75% and 90%) of DS in the LCx; dyslipidemia with the highest quantile (90%) of DS in the RCA; and shortness of breath showed some association with the LCx and RCA. Interestingly, High-density lipoprotein cholesterol showed a dynamic association along DS change in the per-patient analysis.ConclusionsThis study demonstrates the clinical utility of the BQR model for evaluating the comprehensive relationship between risk factors and baseline-grade CAD and its progression.

Aims To investigate the impact of statins on plaque progression according to high-risk coronary atherosclerotic plaque (HRP) features and to identify predictive factors for rapid plaque progression in mild coronary artery disease (CAD) using serial coronary computed tomography angiography (CCTA). Methods and results We analyzed mild stenosis (25–49%) CAD, totaling 1432 lesions from 613 patients (mean age, 62.2 years, 63.9% male) and who underwent serial CCTA at a ≥2 year inter-scan interval using the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging (NCT02803411) registry. The median inter-scan period was 3.5 ± 1.4 years; plaques were quantitatively assessed for annualized percent atheroma volume (PAV) and compositional plaque volume changes according to HRP features, and the rapid plaque progression was defined by the ≥90th percentile annual PAV. In mild stenotic lesions with ≥2 HRPs, statin therapy showed a 37% reduction in annual PAV (0.97 ± 2.02 vs. 1.55 ± 2.22, P = 0.038) with decreased necrotic core volume and increased dense calcium volume compared to non-statin recipient mild lesions. The key factors for rapid plaque progression were ≥2 HRPs [hazard ratio (HR), 1.89; 95% confidence interval (CI), 1.02–3.49; P = 0.042], current smoking (HR, 1.69; 95% CI 1.09–2.57; P = 0.017), and diabetes (HR, 1.55; 95% CI, 1.07–2.22; P = 0.020). Conclusion In mild CAD, statin treatment reduced plaque progression, particularly in lesions with a higher number of HRP features, which was also a strong predictor of rapid plaque progression. Therefore, aggressive statin therapy might be needed even in mild CAD with higher HRPs. Clinical trial registration ClinicalTrials.gov NCT02803411

Aims The magnitude of alterations in which coronary arteries remodel and narrow over time is not well understood. We aimed to examine changes in coronary arterial remodelling and luminal narrowing by three-dimensional (3D) metrics from serial coronary computed tomography angiography (CCTA). Methods and results From a multicentre registry of patients with suspected coronary artery disease who underwent clinically indicated serial CCTA (median interscan interval = 3.3 years), we quantitatively measured coronary plaque, vessel, and lumen volumes on both scans. Primary outcome was the per-segment change in coronary vessel and lumen volume from a change in plaque volume, focusing on arterial remodelling. Multivariate generalized estimating equations including statins were calculated comparing associations between groups of baseline percent atheroma volume (PAV) and location within the coronary artery tree. From 1245 patients (mean age 61 ± 9 years, 39% women), a total of 5721 segments were analysed. For each 1.00 mm3 increase in plaque volume, the vessel volume increased by 0.71 mm3 [95% confidence interval (CI) 0.63 to 0.79 mm3, P < 0.001] with a corresponding reduction in lumen volume by 0.29 mm3 (95% CI −0.37 to −0.21 mm3, P < 0.001). Serial 3D arterial remodelling and luminal narrowing was similar in segments with low and high baseline PAV (P ≥ 0.496). No differences were observed between left main and non-left main segments, proximal and distal segments and side branch and non-side branch segments (P ≥ 0.281). Conclusions Over time, atherosclerotic coronary plaque reveals prominent outward arterial remodelling that co-occurs with modest luminal narrowing. These findings provide additional insight into the compensatory mechanisms involved in the progression of coronary atherosclerosis.

BACKGROUND The association between the change in vessel inflammation, as quantified by perivascular adipose tissue (PVAT) density, and the progression of coronary atherosclerosis remains to be determined.OBJECTIVES The purpose of this study was to explore the association between the change in PVAT density and the progression of total and compositional plaque volume (PV). METHODS Patients were selected from a prospective multinational registry. Patients who underwent serial coronary computed tomography angiography studies with $2-year intervals and were scanned with the same tube voltage at baseline and follow-up were included. Total and compositional PV and PVAT density at baseline and follow-up were quantitatively analyzed for every lesion. Multivariate linear regression models using cluster analyses were constructed.RESULTS A total of 1,476 lesions were identified from 474 enrolled patients (mean age 61.2 +/- 9.3 years; 65.0% men). The mean PVAT density was-74.1 +/- 11.5 HU, and total PV was 48.1 +/- 83.5 mm3 (19.2 +/- 44.8 mm3 of calcified PV and 28.9 +/- 51.0 mm3 of noncalcified PV). On multivariate analysis (adjusted for clinical risk factors, medication use, change in lipid levels, total PV at baseline, luminal HU attenuation, location of lesions, and tube voltage), the increase in PVAT density was positively associated with the progression of total PV (estimate = 0.275 [95% CI: 0.004-0.545]; P = 0.047), driven by the association with fibrous PV (estimate = 0.245 [95% CI: 0.070-0.420]; P = 0.006). Calcified PV progression was not associated with the increase in PVAT density (P > 0.050). CONCLUSIONS Increase in vessel inflammation represented by PVAT density is independently associated with the progression of the lipid component of coronary atherosclerotic plaques. (Progression of AtheRosclerotic PlAque Deter-mIned by Computed TomoGraphic Angiography Imaging [PARADIGM]; NCT02803411) (J Am Coll Cardiol Img 2022;15:1760-1767) (c) 2022 by the American College of Cardiology Foundation.

Background and aims: Clinical atherosclerosis manifestations are different in women compared to men. Since endothelial shear stress (ESS) is known to play a critical role in coronary atherosclerosis development, we investigated differences in anatomical characteristics and endothelial shear stress (ESS)–related plaque growth in human coronary arteries in men compared to women. Methods: 1183 coronary arteries (male/female: 944/239) from the PREDICTION study were studied for differences in artery/plaque and ESS characteristics, and ESS-related plaque progression (6–10 months follow-up) among men and women and after stratification for age. All characteristics were derived from IVUS-based vascular profiling and reported per 3 mm-segments (13,030 3-mm-segments (male/female: 10,465/2,565)). Results: Coronary arteries and plaques were significantly smaller in females compared to males; but no important differences were observed in plaque burden, ESS and rate of plaque progression. Change in plaque burden was inversely related to ESS (p

Importance: Distinct plaque locations and vessel geometric features predispose to altered coronary flow hemodynamics. The association between these lesion-level characteristics assessed by coronary computed tomographic angiography (CCTA) and risk of future acute coronary syndrome (ACS) is unknown. Objective: To examine whether CCTA-derived adverse geometric characteristics (AGCs) of coronary lesions describing location and vessel geometry add to plaque morphology and burden for identifying culprit lesion precursors associated with future ACS. Design, Setting, and Participants: This substudy of ICONIC (Incident Coronary Syndromes Identified by Computed Tomography), a multicenter nested case-control cohort study, included patients with ACS and a culprit lesion precursor identified on baseline CCTA (n = 116) and propensity score-matched non-ACS controls (n = 116). Data were collected from July 20, 2012, to April 30, 2017, and analyzed from October 1, 2020, to October 31, 2021. Exposures: Coronary lesions were evaluated for the following 3 AGCs: (1) distance from the coronary ostium to lesion; (2) location at vessel bifurcations; and (3) vessel tortuosity, defined as the presence of 1 bend of greater than 90° or 3 curves of 45° to 90° using a 3-point angle within the lesion. Main Outcomes and Measures: Association between lesion-level AGCs and risk of future ACS-causing culprit lesions. Results: Of 548 lesions, 116 culprit lesion precursors were identified in 116 patients (80 [69.0%] men; mean [SD], age 62.7 [11.5] years). Compared with nonculprit lesions, culprit lesion precursors had a shorter distance from the ostium (median, 35.1 [IQR, 23.6-48.4] mm vs 44.5 [IQR, 28.2-70.8] mm), more frequently localized to bifurcations (85 [73.3%] vs 168 [38.9%]), and had more tortuous vessel segments (5 [4.3%] vs 6 [1.4%]; all P

ImportanceRecent clinical and imaging studies underscore that major adverse cardiac events (MACE) outcomes are associated not solely with severe coronary obstructions (ischemia hypothesis or stenosis hypothesis), but with the plaque burden along the entire coronary tree. New research clarifies the pathobiologic mechanisms responsible for plaque development/progression/destabilization leading to MACE (plaque hypothesis), but the translation of these insights to clinical management strategies has lagged. This narrative review elaborates the plaque hypothesis and explicates the current understanding of underlying pathobiologic mechanisms, the provocative destabilizing influences, the diagnostic and therapeutic implications, and their actionable clinical management approaches to optimize the management of patients with chronic coronary disease.ObservationsClinical trials of management strategies for patients with chronic coronary artery disease demonstrate that while MACE rate increases progressively with the anatomic extent of coronary disease, revascularization of the ischemia-producing obstruction does not forestall MACE. Most severely obstructive coronary lesions often remain quiescent and seldom destabilize to cause a MACE. Coronary lesions that later provoke acute myocardial infarction often do not narrow the lumen critically. Invasive and noninvasive imaging can identify the plaque anatomic characteristics (plaque burden, plaque topography, lipid content) and local hemodynamic/biomechanical characteristics (endothelial shear stress, plaque structural stress, axial plaque stress) that can indicate the propensity of individual plaques to provoke a MACE.Conclusions and RelevanceThe pathobiologic construct concerning the culprit region of a plaque most likely to cause a MACE (plaque hypothesis), which incorporates multiple convergent plaque features, informs the evolution of a new management strategy capable of identifying the high-risk portion of plaque wherever it is located along the course of the coronary artery. Ongoing investigations of high-risk plaque features, coupled with technical advances to enable prognostic characterization in real time and at the point of care, will soon enable evaluation of the entire length of the atheromatous coronary artery and broaden the target(s) of our therapeutic intervention to include all regions of the plaque (both flow limiting and nonflow limiting).

Introduction: Risk-stratification of individual coronary plaques is an important goal to detect high-risk plaques likely to progress/destabilize, which could inform preemptive intervention to prevent adverse cardiac events. IVUS imaging, the current gold standard to assess plaque risk, has shown that biomechanical variables, particularly local ESS, contributes critical synergistic prognostic insight when combined with anatomic high-risk plaque features. Non-invasive risk assessment of coronary plaques with CCTA would be invaluable to enable broad population risk screening, but it is unknown whether CCTA, which has less spatial resolution than IVUS, can adequately measure the critical local biomechanical and anatomic variables. Aim: To compare the accuracy of ESS computation of local ESS metrics by non-invasive CCTA vs invasive IVUS imaging. Methods: We analyzed 30 arteries (22 LAD, 4 LCx,4 RCA) from 30 patients selected from a registry of patients who underwent both IVUS and CCTA of the same artery for suspected CAD. CCTA images were acquired using a CCTA with either 64 or 256 detector rows. We segmented lumen, vessel, and plaque areas with both IVUS (manual segmentation) and CCTA (AI based software; Cleerly Inc, NY). Co-registration of IVUS and CCTA Images was performed using fiduciary anatomic landmarks. Images from IVUS and CCTA were used to generate a 3-D arterial reconstruction, and local ESS distribution was assessed by computational fluid dynamics and reported in consecutive 3-mm segments. Results: Table Conclusion: Compared to IVUS values, 256-slice is more accurate than 64-slice CCTA to measure lumen and vessel areas, but computation of detailed local ESS (average, low and high) is similar by both CCTA methods. Local ESS evaluation using non-invasive CCTA is feasible and comparable to invasive gold standard IVUS and is suitable to characterize the local flow patterns that play an important role in plaque development, progression, and destabilization

Introduction: The role of endothelial shear stress (ESS) in the development of coronary plaque erosion is unknown. High ESS gradient (ESSG) has been hypothesized to promote plaque erosion, but no studies have included matched control stable plaques with the same minimal and reference lumen area (MLA, RLA, respectively). No studies examined the location of plaque erosion (proximal vs distal to MLA of the culprit plaque) related to the max magnitude of upslope vs downslope of the lumen obstruction. Aims: (1) to compare ESSG between plaques with erosion and similar control plaques that remained stable; (2) among erosion plaques, to study the effect of max slope steepness (Δ lumen area/frame) up- and down-stream from the culprit plaque MLA on thrombus location. Methods: We studied 46 patients from TOTAL and COMPLETE trials who underwent angiography and OCT imaging: 46 arteries: 27 LAD, 6 LCX, 13 RCA. Plaques were divided into Plaque Erosion (n=24) with OCT features of erosion before PCI (17 definite, 7 probable erosion) and matched coronary plaques from separate control patients (n=22) without plaque disruption. Orthogonal angiographic views were used to generate a 3-D arterial reconstruction, and angio centerline was combined with OCT centerline. Local ESS distribution was assessed by computational fluid dynamics and reported in consecutive 3-mm segments. Among the plaque erosions, we calculated the up- and down-slope (Δ lumen area/frame) of lumen obstruction for each culprit plaque. Results: See Table Conclusion: In plaques with similarly severe obstruction, plaque erosion is associated with higher max ESS and max ESSG vs plaques that remain stable. Proximal plaque erosion/thrombus is associated with steeper plaque upslope vs downslope, and distal plaque erosion/thrombus is associated with steeper plaque downslope vs upslope. Absolute ESSG is higher in downslope vs upslope erosions. These features may help prognosticate individual plaques at risk for future erosion.

BACKGROUND AND AIMS:Different methodologies to report whole-heart atherosclerotic plaque on coronary computed tomography angiography (CCTA) have been utilized. We examined which of the three commonly used plaque burden definitions was least affected by differences in body surface area (BSA) and sex. METHODS:The PARADIGM study includes symptomatic patients with suspected coronary atherosclerosis who underwent serial CCTA >2 years apart. Coronary lumen, vessel, and plaque were quantified from the coronary tree on a 0.5mm cross-sectional basis by a core-lab, and summed to per-patient. Three quantitative methods of plaque burden were employed: (1) total plaque volume (PV) in mm3, (2) percent atheroma volume (PAV) in % [which equaled: PV/vessel volume * 100%], and (3) normalized total atheroma volume (TAVnorm) in mm3 [which equaled: PV/vessel length * mean population vessel length]. Only data from the baseline CCTA were used. PV, PAV, and TAVnorm were compared between patients in the top quartile of BSA vs the remaining, and between sexes. Associations between vessel volume, BSA, and the three plaque burden methodologies were assessed. RESULTS:The study population comprised 1479 patients (age 60.7±9.3 years, 58.4% male) who underwent CCTA. A total of 17,649 coronary artery segments were evaluated with a median of 12 (IQR 11-13) segments per-patient (from a 16-segment coronary tree). Patients with a large BSA (top quartile), compared with the remaining patients, had a larger PV and TAVnorm, but similar PAV. The relation between larger BSA and larger absolute plaque volume (PV and TAVnorm) was mediated by the coronary vessel volume. Independent from the atherosclerotic cardiovascular disease risk (ASCVD) score, vessel volume correlated with PV (P&nbsp

Introduction: Low ESS, a pro-inflammatory stimulus, is an important predictor of coronary plaque development/progression. Whether low ESS adds incremental predictive value for future major adverse cardiac events (MACE) in untreated coronary lesions in high-risk patients with an acute coronary syndrome (ACS) is unknown. Methods: In the PROSPECT study, 697 patients with ACS underwent 3-vessel intracoronary imaging. Independent predictors of non-culprit (nc) lesion MACE from untreated coronary lesions in 3 year followup (f/u) were large plaque burden (PB), small minimum lumen area (MLA), and thin cap fibroatheroma (TCFA) morphology. In the present analysis, all nc-lesions leading to a new MACE in f/u (nc-MACE lesions, n=50) and ~4-fold randomly selected control nc-lesions without f/u MACE (nc-non-MACE lesions) were analyzed. Baseline ESS for each lesion was calculated using computational fluid dynamics. A propensity score for low ESS was determined accounting for PB, MLA, TCFA, artery and location in the artery. Local ESS (lowest ESS in 90 o arc around the artery) was then examined for incremental association with MACE. Results: Imaging was sufficient for analysis in 32 nc-MACE lesions. Two nc-MACE lesions were excluded due to unreliable lesion morphology. Non-fibroatheromas were too few for analysis and excluded. Final dataset included 145 lesions: 13 nc-MACE TCFA, 10 nc-MACE thick cap fibroatheroma (ThCFA), and 122 non-nc-MACE lesions (63 TCFA, 59 ThCFA). Cumulative frequency distribution shows lesions responsible for future nc-MACE frequently exhibited low ESS (Figure). In a propensity-adjusted multivariable model, low ESS was strongly associated with nc-MACE in f/u (odds ratio 0.16 [95% CI 0.06-0.40], p Conclusions: After accounting for large PB, small MLA, TCFA, and lesion location, low local ESS adds significant and substantial incremental predictive value to identify high-risk untreated lesions likely to cause MACE during 3 year followup.

Background: The natural history and the role of the atherosclerotic plaque located behind the stent (PBS) are still poorly understood. We evaluated the serial changes in PBS following bare-metal (BMS) compared with first-generation drug-eluting stent (DES) implantation and the impact of these changes on in-stent neointimal hyperplasia (NIH). Methods: 3D coronary reconstruction by angiography and intravascular ultrasound were serially performed after intervention and at 6- to 10-month follow-up in 157 Japanese patients treated with BMS (n=90) and DES (n=98; 68 sirolimus-eluting and 30 paclitaxel-eluting stents) included in the PREDICTION Study. Each reconstructed stented coronary artery was divided into consecutive 1.5-mm segments. External elastic lamina, lumen, stent, and PBS area were measured for each segment at both baseline and follow-up. At follow-up NIH area was assessed. Due to the very low rate of events in our population we used significant NIH (defined as NIH area >50% of stent area) as a binary anatomic outcome. Results: Patient, lesion, and stent characteristics were comparable between BMS and DES. There was a significant decrease in PBS area after BMS (median relative change: -7.2%, IQR -19.3 to 5.2%, p Conclusions: The PBS significantly decreased 6 to 10 months after BMS implantation, whereas after DES it increased. The decrease in PBS area was significantly associated with the development of NIH at follow-up in both stent types. These findings raise the possibility of a communication between the lesion within the stent and the underlying native atherosclerotic plaque, and may have important implications regarding the pathobiology of in-stent restenosis.

This report focuses on the subset of 235 patients from the Asymptomatic Cardiac Ischemia Pilot (ACIP) study receiving randomly assigned medical therapy to treat angina and suppress ischemia detected on ambulatory electrocardiography: 121 patients received the sequence of atenolol and nifedipine, and 114 diltiazem and isosorbide dinitrate. After 12 weeks of therapy, the primary end point (absence of ambulatory electrocardiographic (ECG) ischemia and no clinical events) was reached in 47% of atenolol/nifedipine- versus 31% of diltiazem/isosorbide dinitrate-treated patients (adjusted p = 0.03). A trend to increased exercise time to ST depression was seen in the atenolol and nifedipine versus diltiazem and isosorbide dinitrate regimens (median treadmill duration 5.8 vs 4.8 minutes; p = 0.04). However, when adjusted for baseline imbalances in ambulatory ECG ischemia, the 2 medical combinations were similar in suppression of ambulatory ECG ischemia. In both medication regimens, an association between mean heart rate and ischemia on ambulatory electrocardiography after 12 weeks of treatment was observed so that patients on either regimen with a mean heart rate80 beats/min had ischemia detectable almost twice as often as those with a mean heart rate70 beats/min (p0.001).

Background: T-wave alternans is a marker of vulnerability to ventricular tachyarrhythmias and has been documented during myocardial ischemia associated with angioplasty, bypass graft occlusion, and episodes of Prinzmetal's variant angina. We examined whether this phenomenon was present during ambulatory ischemia in ten patients randomly selected from the placebo phase of the Angina and Silent Ischemia Study [ASIS]. Methods: The eligibility criteria for participation in the ASIS study were stable coronary disease, a positive exercise stress test, and verified ischemic episodes during ambulatory ECG (AECG) monitoring. For each patient, one ischemic episode was analyzed which met the criteria of > 2-mm ST segment depression for > 3 minutes with a relatively stable ST segment baseline of > 1 hour preceding the index episode. T-wave alternans was measured using the spectral analytical technique of complex demodulation. Results: In the stable coronary patients of the ASIS trial, we found that T-wave alternans magnitude nearly tripled from 0.27 ± 0.02 mV × ms before ischemia onset to 0.77 ± 0.08 mV × ms (P 2 mm and the ischemia-induced increase in T-wave alternans. Conclusions: We conclude that T-wave alternans often occurs in association with ambulatory ischemia. Thus, risk assessment in stable coronary patients may be enhanced by monitoring both ST segment deviation and T-wave alternans as they measure relevant but fundamentally different electrophysiological properties.

Background: T-wave alternans has been increasingly implicated as a potential marker of vulnerability to ventricular tachyarrhythmias in both experimental and clinical investigations. However, the suitability of ambulatory ECG (AECG) recorders for monitoring this parameter has not been systematically studied. Methods: We evaluated the frequency response characteristics and performance in monitoring a computer simulated alternans signal in three brands of amplitude-modulated (AM) and one frequency-modulated (FM) recorder and compared the results to those of the reference digital AECG unit. Results: A common feature of the AM recorders was distortion due to electronic head resonance, particularly at heart rates in the range of 60–100 beats/min. The maximum distortion of T-wave morphology by the AM units was —6% to +28%. Conclusions: We conclude that digital and FM recorders are preferable for AECG monitoring of T-wave alternans. AM recorders can be used if the distortion is not excessive.

Introduction: Low endothelial shear stress (ESS) activates pro-inflammatory pathways and is a powerful instigator of atherogenesis. Angiotensin receptor blockers and statins have been associated with anti-inflammatory actions in advanced plaques. However, their effect on the earliest pathobiologic manifestations of atherosclerosis has not been studied. We tested the hypothesis that valsartan (V) or V plus simvastatin (V/S) exerts an early vasculoprotective effect in coronary regions exposed to low ESS in a porcine model of human-like atherosclerosis. Methods: Twelve diabetic-hyperlipidemic swine (age: 3 mo) were grouped into controls (n=4), and those treated with V (320 mg; n=4) or V/S (320/40 mg; n=4). 3D reconstruction of coronary arteries by angiography and intravascular ultrasound was performed in vivo at 4 (baseline) and 8 (follow-up) wks post-induction. Baseline local ESS was calculated by computational fluid dynamics and 3 mm segments with low (≤1.2 Pa; n=46) or higher (>1.2 Pa; n=66) ESS were identified. Coronary arteries were harvested at follow-up. qRT-PCR was used for assessing the expression of intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), LDL receptor and lipoprotein-associated phospholipase-A 2 (LpPLA 2 ). Results: The upregulation of ICAM-1, MCP-1, LDL receptor (p2 (p Conclusion: V and V/S attenuate the proatherogenic effects of low ESS within only 8 wks. These results suggest a drug-induced mechanism of regional atheroprotection early in the natural history of coronary artery disease.

Introduction: Plaque inflammation is a critical step in the initiation and progression of atherosclerosis. Such inflammation is thought to originate from the luminal surface of plaque and infiltrate the intima-media in advanced lesions. Low endothelial shear stress (ESS) is known to induce intima-media inflammation and plaque growth. In this study we investigated in-vivo the hypothesis that low ESS induces also adventitial inflammation. Methods: We studied 11 swine at 23 (baseline) and 30 (followup) weeks after the induction of diabetes and hyperlipidemia. Using angiography and intravascular ultrasound data, we performed 3D coronary reconstruction of coronary arteries and calculated the ESS with computational fluid dynamics. In 56 segments, we assessed the adventitial inflammatory (CD45) and antigen-presenting (MHC-II) cell content at followup with immunohistochemistry. Segments were classified as low (≤ 1 Pa) or higher (>1 Pa) ESS. Results: MHC-II content in the adventitia (1.3±0.3%) was higher than in the media (0.3±0.1%, p Conclusion: Although total inflammation is not dependent on ESS, low ESS induces higher adventitial activated inflammatory cell content, as assessed by MHC-II immunostaining. This, in conjunction with the higher MHC-II content in the adventitia than in the media and the presence of an intact IEL suggests an additional source of inflammation in low-ESS plaque regions, originating from the vessel outer wall. The induction of neovascularization possibly accounts for this phenomenon.

The etiology of acquired aortic stenosis (AS) has changed dramatically as socioeconomic and hygienic conditions have improved and as the general population lives to an older age. Rheumatic disease was responsible for most cases of AS until a few decades ago, whereas now most are due to calcific degenerative or bicuspid etiologies. There is a long latency period from the initial discovery of a murmur and first onset of symptoms. In studies representing clinical experience prior to the 1960s, the mean age at symptomatic presentation was 48 years, while in series representing experience up the 1980s, it was 61 years. The changing etiology of AS has Important implications for following patients with AS, and monitoring those who are discovered to have significant AS in the absence of symptoms. AS has become more a disease of the elderly, and it is the elderly patient with AS, especially those with calcific degenerative AS, who develop the most rapid and significant progression of their disease, present with symptoms of left ventricular (LV) failure, and are most likely to have critical outflow tract obstruction at the time of their presentation. Once symptoms develop, the outcome of patients with AS is quite poor: in early studies approximately 50% of such patients were dead at 5 years and 90% were dead at 10 years. Symptoms that represent LV failure, e.g., dyspnea, are associated with a worse survival (average survival 2 years) compared to symptoms that represent LV hypertrophy, e.g., angina or outflow obstruction, syncope (average survival 3 years). There is uniform agreement that once symptoms develop, patients with Significant AS should undergo valve replacement. Management of the asymptomatic patient with moderate-to-severe AS has been more problematic. Early studies suggested that sudden death could occur in even asymptomatic patients with severe AS, and recommended that prophylactic valve replacement be considered in this group. More recent studies, however, confirm that in the absence of symptoms, overall survival of patients with AS is similar to that predicted for age- and gender-matched control subjects. Although cardiac death occurs in approximately 2% to 4% of these patients, symptoms of AS have developed approximately 1 to 3 months before death in each documented case. The mortality associated with prophylactic aortic valve replacement is higher than the mortality associated with medical management of asymptomatic AS. In conclusion, aortic valve replacement should be deferred in patients with asymptomatic AS until the onset of symptoms. Patients with calcific degenerative AS and elderly patients with AS may have particularly rapid progression of AS and should have close follow-up. Since the interval between the onset of AS symptoms and cardiac death may be quite brief, all asymptomatic patients with significant AS should be followed closely for the onset of symptoms. (J Card Surg 1994;9[Suppl]:139–144)

Background : ECG parameters such as low heart rate variability (HRV) identify patients at high risk post-ACS. We recently developed morphological variability (MV), a novel technique that quantifies differences in the morphology of entire beats using a dynamic time-warping algorithm. MV incorporates strictly more information than HRV, potentially offering a more complete evaluation of the ECG. We assessed the relationship among MV, HRV, and outcomes after NSTEACS. Methods: MV and HRV were calculated in 863 pts from the DISPERSE2 trial using the first 24 hrs of continuous ECG (CECG) after randomization for NSTEACS. Using each measure, pts were split into high and low variability groups (cutpoint for HRV (SDNN)= 75ms and for MV=0.7). Ischemia on CECG was defined as ≥1mm ST dep lasting ≥1min. Results: A total of 144 (16.7%) pts had high MV and 58 (6.7%) had low HRV. Pts with high MV experienced higher rates of death, death/MI/severe recurrent ischemia (SRI), and ischemia detected on CECG compared to low MV. (Table-Figure ) This relationship remained consistent in pts with no ischemia on CECG (hazard ratio for D/MI/SRI =2.5, p=0.016). There was no difference in mortality or ischemia on CECG in pts with low HRV v high HRV, but pts with low HRV did have higher rates of death/MI/SRI. (Table) Conclusions: MV correlates significantly with poor cardiovascular outcomes, including death, after NSTEACS, even after controlling for other high risk features and even among pts without electrocardiographic evidence of ischemia. MV may offer a new non-invasive measure for risk stratification after ACS.

Objectives: We investigated the role of V alone or in combination with S on the histomorphologic characteristics of thin cap fibroatheromas (TCFAs), and tested the hypothesis that V or VS attenuate the proinflammatory effect of low endothelial shear stress (ESS). We used vascular profiling of swine coronary arteries for in vivo assessment of ESS to prospectively identify these low ESS areas that are prone to develop TCFAs. Methods: 12 diabetic hyperlipidemic swine were allocated into 3 treatment groups: placebo (P, n=4), V (n=4) and VS (n=4). Blood pressure, serum cholesterol and glucose were similar between the treatment groups. IVUS-based geometrically correct 3D reconstruction of the coronary arteries was performed at baseline (wk 23) and follow up (wk 30). Baseline ESS was calculated using computational fluid dynamics and plaque-free subsegments of interest were identified (n=109). Coronary arteries (n=31) were harvested at follow up, cryosectioned at the subsegments of interest and stained histologically. Intima/media ratio and inflammation (CD45) were quantified. Lesions were classified into atheromas without evidence of fibrous cap (n=82) and TCFAs (n=60). Results: V alone or in combination with S reduced the amount of plaque inflammation, particularly in TCFAs (Fig A ). V and VS attenuated the proinflammatory effect of local low ESS compared to P (Fig B ). Conclusion: V alone or in combination with S exerts a stabilizing effect of reducing plaque inflammation, even in high-risk regions with low ESS. These results suggest a mechanism of regional atheroprotection associated with V or VS.

Improvements in solid-state digital technology have enhanced transtelephonic transmission of electrocardiography (ECG) data and increased the accuracy of software-based analysis systems. These advances, in addition to better signal quality and greater computer arrhythmia interpretation capabilities, have opened new potential uses for ambulatory electrocardiography (AECG). Traditional uses of AECG for arrhythmia detection have expanded as the result of increased use of multichannel and telemetered signals. The clinical application of arrhythmia monitoring to assess drug and device efficacy has been further defined by new studies. The analysis of transient ST-segment deviation remains controversial, but considerably more data are now available, especially about the prognostic value of detecting asymptomatic ischemia. Heart rate variability (HRV) analysis has shown promise for predicting mortality rates in cardiac patients at high risk. Despite these advances, a true automated analysis system has not been perfected and technician/physician participation is still essential. The widespread availability and low cost of personal computers and workstations has allowed for the development of extremely sophisticated and automated signal processing algorithms. Current AECG equipment provides for the detection and analysis of arrhythmias and ST-segment deviation as well as more sophisticated analyses of R-R intervals, QRS-T morphology including late potentials, Q-T dispersion, and T-wave alternans. There are 2 categories of AECG recorders: continuous recorders, typically used for 24 to 48 hours to investigate symptoms and ECG events that are likely to occur within that time frame, and intermittent recorders, which may be used for long periods of time (weeks to months) to provide briefer, intermittent recordings for investigating events that occur infrequently. ### A. Continuous Recorders Rapidly evolving technologies now allow for direct recording of the ECG signal in a digital format using solid-state recording devices. The direct digital recording avoids all of the biases introduced by the mechanical features of tape recording devices and the problems associated with …

The aim of this study was to characterize patients with and without prior coronary artery bypass grafting (CABG) among a prospectively identified cohort of patients presenting with unstable angina or non-Q-wave myocardial infarction. Patients in the Thrombolysis in Myocardial Infarction phase III Registry Prospective Study presented within 96 hours of an episode of unstable angina or non-Q-wave acute myocardial infarction. Of 2,048 patients, 336 (16.4%) had prior CABG. Compared with those without prior CABG, patients were the same age, but were more likely to be men, white, diabetic, have a history of angina or myocardial infarction, to have received anti-ischemic medications in the prior week, and to receive intravenous heparin or nitroglycerin, or both, during hospitalization. They were equally likely to undergo coronary angioplasty or CABG. Death or nonfatal myocardial infarction occurred by day 10 in 4.5% of patients with prior CABG and 2.8% of patients without prior CABG (p = 0.11); and by day 42 in 7.7% and 5.1%, respectively (p = 0.03). The composite of death, myocardial infarction, or recurrent ischemia at 1 year was more common among patients with prior CABG (39.3% vs 30.2%, p = 0.002). By multiple logistic regression, prior CABG was not independently associated with the occurrence of death or myocardial infarction, or the composite of death, myocardial infarction, or recurrent ischemia either at 6 weeks or at 1 year. The likelihood of recurrent ischemic events is greater among patients with than without prior CABG, but is not likely explained by differences in baseline or treatment characteristics which reflect the degree of underlying cardiac disease.

Advanced age has been recognized as adversely influencing the outcome of coronary revascularization procedures. To determine the validity of this relationship for patients (pts) with acute ischemic syndromes treated with contemporary medical therapy, the outcomes of 444 pts who had PTCA performed in TIMI IIIB were analyzed. Each pt received aspirin, heparin and antianginal therapy. Age g = 65 (N = 154) % (mean) Age l 65 (N = 290) % (mean) p-value Age (years) (69.7) (53.9) 0.000 Male Gender 51.9 73.8 0.000 Never Smoked 39.0 26.6 0.007 Prior MI 35.7 32.8 0.531 Hypertension 46.7 35.5 0.023 Non-Q-Wave MI 31.4 40.3 0.063 Abnormal ECG 92.9 94.1 0.597 LV EF (61.3) (58.7) 0.038 2 – 3 Vessel Disease 50.0 36.0 0.005 Angiographic Success 95.5 96.4 0.689 Events by 42 days Death 1.3 1.4 0.938 MI 6.5 5.5 0.671 Stroke 0.0 0.3 0.463 CABG 1.3 4.2 0.102 Death/MI/Stroke/CABG 8.4 9.0 0.864 In comparison to younger pts., elderly pts having PTCA in TIMI IIIB were more often female, had not smoked, had history of hypertension and had multivessel coronary disease. The results of PTCA were equally excellent in both groups. Thus, advanced age alone does not adversely affect the results of PTCA in selected pts with acute ischemic syndromes.

A submaximal treadmill exercise test performed before hospital discharge after an uncomplicated myocardial infarction is often utilized to estimate prognosis and guide management, but there is little experience with a maximalexercise test performed 6 months after infarction to identify prognosis later in the convalescent period. The performance characteristics during an exercise test 6 months after myocardial infarction were related to the development of death, recurrent nonfatal myocardial infarction and coronary artery bypass surgery in the subsequent 12 months (that is, 6 to 18 months after infarction) in 473 patients. Mortality was significantly greater in patients who exhibited any of the following: inability to perform the exercise test because of cardiac limitations, the development of ST segment elevation of 1 mm or greater during the exercise test, an inadequate blood pressure response during exercise, the development of any ventricular premature depolarizations during exercise or the recovery period and inability to exercise beyond stage I of the modified Bruce protocol. By utilizing a combination of four high risk prognostic features from the exercise test, it was possible to stratify patients in ternis of risk of mortality, from 1% if none of these features were present to 17% if three or four were present. Recurrent nonfatal myocardial infarction was predicted by an inability to perform the exercise test because of cardiac limitations, but not by any characteristics of exercise test performance. Coronary artery bypass surgery was associated with the development of ST segment depression of 1 mm or greater during the exercise test. Although clinical evidence of angina and heart failure 6 months after infarction was predictive of subsequent mortality among all survivors, among the low risk group without severely limiting cardiac disease, the exercise test provided unique prognostic information not available from clinical assessment alone. Therefore, a maximal exercise test performed 6 months after myocardial infarction is a valuable, noninvasive tool to evaluate prognosis. It provides information that is independent of and additive to clinical evaluation performed at the same time.

The exercise treadmill test (ETT) performance of 60 patients with angiographically documented left main coronary artery (LMCA) disease (LMD) was analyzed to determine the spectrum of ETT response in this distinct subset of patients with coronary disease (CAD). The location and extent of CAD was also determined to assess its effect on exercise response in patients having LMD. The ST segment response indicated ischemia in 46 patients (77%), and only one patient (2%) achieved a maximum predicted heart rate (HR) with a negative ST segment response. During ETT exertional hypotension developed in six patients (10%), frequent ventricular ectopic beats occurred in 19 patients (32%), and ST segment elevation occurred in five patients (8%). A "markedly positive" ETT response, defined as either ≥ 2.0 mm ischemic ST segment depression, a positive ST segment response in stage I of the Bruce protocol, termination of the exercise test in stage I or II, or the development of exertional hypotension was observed in 53 patients (88%). A "benign" treadmill test response, defined as either a negative test at the maximum predicted HR or the ability to exercise at least to stage IV, was observed in only four patients (7%). Patterns of coronary anatomy were divided into group I (nine patients), where only portions of the myocardium were in jeopardy of ischemia (patients with an obstruction in the LMCA but with a normal dominant right coronary artery [RCA]); and group II (51 patients), where the entire myocardium was in jeopardy (patients with LMD and either a dominant left coronary artery or a dominant RCA which was obstructed). There was a significantly higher prevalence in group II vs group I of exercise-induced frequent ventricular ectopic beats (19 patients vs 0 patient), termination of the treadmill test in stage I (28 patients vs 0 patients), and marked ischemic ST segment depression ≥ 2.0 mm (30 patients vs 2 patients), all p

Prior reports have demonstrated an unfavorable safety and efficacy profile of PTCA for women with coronary disease compared to men. To determine if such a gender difference exists for patients with acute coronary ischemic syndromes treated with contemporary medical therapy, the results of PTCA performed routinely or according to clinical course in 294 men and 150 Male % (mean) Male % (mean) p-value Age (yrs) (57.4) (63.2) 0.000 Never Smoked 24.1 44.0 0.000 Prior MI 35.7 30.0 0.229 Hypertension 32.1 53.7 0.000 Abnormal ECG 93.2 94.7 0.547 LVEF (58.7) (61.2) 0.040 Multivessel CAD 42.9 37.0 0.277 LAD Culprit Site 42.6 43.9 0.806 Stenosis Pre (83.4) (82.6) 0.533 Stenosis Post (25.3) (24.5) 072.6 TIMI Flow Grade Pre (2.4) (2.6) 0.007 TIMI Flow Grade Post (2.9) (3.0) 0.184 Angiographic Success 95.9 96.4 0.823 Complication at 42 Days Death 1.4 1.3 0.981 MI 5.4 6.7 0.606 Stroke 0.3 0.0 0.474 CABG 4.1 1.3 0.116 Death/Ml/Stroke/CABG 8.5 9.3 0.774 women with either unstable angina pectoris (n = 278) or non-Q-wave myocardial infarction (n = 165) enrolled in TIMI IIIB were analyzed. Women treated with PTCA in TIMI IIIB were older and more often had hypertension, were non-smokers and had better LV systolic function. PTCA in these women was associated with high success and low complication rates comparable to those of men. Thus, gender does not affect the outcome of PTCA for acute ischemic syndromes.