Akiko Maehara

A Prospective Natural-History Study of Coronary Atherosclerosis

BACKGROUNDnAtherosclerotic plaques that lead to acute coronary syndromes often occur at sites of angiographically mild coronary-artery stenosis. Lesion-related risk factors for such events are poorly understood.nnnMETHODSnIn a prospective study, 697 patients with acute coronary syndromes underwent three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention. Subsequent major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) were adjudicated to be related to either originally treated (culprit) lesions or untreated (nonculprit) lesions. The median follow-up period was 3.4 years.nnnRESULTSnThe 3-year cumulative rate of major adverse cardiovascular events was 20.4%. Events were adjudicated to be related to culprit lesions in 12.9% of patients and to nonculprit lesions in 11.6%. Most nonculprit lesions responsible for follow-up events were angiographically mild at baseline (mean [±SD] diameter stenosis, 32.3±20.6%). However, on multivariate analysis, nonculprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of 70% or greater (hazard ratio, 5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm(2) or less (hazard ratio, 3.21; 95% CI, 1.61 to 6.42; P=0.001) or to be classified on the basis of radiofrequency intravascular ultrasonography as thin-cap fibroatheromas (hazard ratio, 3.35; 95% CI, 1.77 to 6.36; P<0.001).nnnCONCLUSIONSnIn patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions. Although nonculprit lesions that were responsible for unanticipated events were frequently angiographically mild, most were thin-cap fibroatheromas or were characterized by a large plaque burden, a small luminal area, or some combination of these characteristics, as determined by gray-scale and radiofrequency intravascular ultrasonography. (Funded by Abbott Vascular and Volcano; ClinicalTrials.gov number, NCT00180466.).

Multicenter core laboratory comparison of the instantaneous wave-free ratio and resting Pd/Pa with fractional flow reserve: the RESOLVE study.

OBJECTIVESnThis study sought to examine the diagnostic accuracy of the instantaneous wave-free ratio (iFR) and resting distal coronary artery pressure/aortic pressure (Pd/Pa) with respect to hyperemic fractional flow reserve (FFR) in a core laboratory-based multicenter collaborative study.nnnBACKGROUNDnFFR is an index of the severity of coronary stenosis that has been clinically validated in 3 prospective randomized trials. iFR and Pd/Pa are nonhyperemic pressure-derived indices of the severity of stenosis with discordant reports regarding their accuracy with respect to FFR.nnnMETHODSniFR, resting Pd/Pa, and FFR were measured in 1,768 patients from 15 clinical sites. An independent physiology core laboratory performed blinded off-line analysis of all raw data. The primary objectives were to determine specific iFR and Pd/Pa thresholds with ≥90% accuracy in predicting ischemic versus nonischemic FFR (on the basis of an FFR cut point of 0.80) and the proportion of patients falling beyond those thresholds.nnnRESULTSnOf 1,974 submitted lesions, 381 (19.3%) were excluded because of suboptimal acquisition, leaving 1,593 for final analysis. On receiver-operating characteristic analysis, the optimal iFR cut point for FFR ≤0.80 was 0.90 (C statistic: 0.81 [95% confidence interval: 0.79 to 0.83]; overall accuracy: 80.4%) and for Pd/Pa was 0.92 (C statistic: 0.82 [95% confidence interval: 0.80 to 0.84]; overall accuracy: 81.5%), with no significant difference between these resting measures. iFR and Pd/Pa had ≥90% accuracy to predict a positive or negative FFR in 64.9% (62.6% to 67.3%) and 48.3% (45.6% to 50.5%) of lesions, respectively.nnnCONCLUSIONSnThis comprehensive core laboratory analysis comparing iFR and Pd/Pa with FFR demonstrated an overall accuracy of ~80% for both nonhyperemic indices, which can be improved to ≥90% in a subset of lesions. Clinical outcome studies are required to determine whether the use of iFR or Pd/Pa might obviate the need for hyperemia in selected patients.

Strut coverage and late malapposition with paclitaxel-eluting stents compared with bare metal stents in acute myocardial infarction: optical coherence tomography substudy of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial.

Background— The safety of drug-eluting stents in ST-segment elevation myocardial infarction (STEMI) continues to be debated. Pathological studies have demonstrated an association between uncovered struts and subsequent stent thrombosis. Optical coherence tomography can detect stent strut coverage in vivo on a micron-scale level. We therefore used optical coherence tomography to examine strut coverage in patients with STEMI treated with paclitaxel-eluting stents (PES) and bare metal stents (BMS). Methods and Results— In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, patients with STEMI were randomized 3:1 to PES or BMS implantation. In a formal substudy, optical coherence tomography at 13 months was performed in 118 consecutive randomized patients (89 PES, 29 BMS) in whom 188 stents were assessed (146 PES and 42 BMS). A total of 44 139 stent struts were analyzed by an independent core laboratory blinded to stent assignment. The primary prespecified end point, the percentage of uncovered stent struts per lesion at follow-up, was 1.1±2.5% in BMS lesions versus 5.7±7.0% in PES lesions (P<0.0001). Malapposed struts were observed in 0.1±0.2% of BMS lesions versus 0.9±2.1% of PES lesions (P=0.0003). Percentage net volume obstruction was 36.0±15.4% with BMS and 19.2±11.3% with PES (P<0.0001). Conclusions— In patients with STEMI undergoing primary percutaneous coronary intervention, implantation of PES as compared with BMS significantly reduces neointimal hyperplasia but results in higher rates of uncovered and malapposed stent struts as assessed by optical coherence tomography at 13-month follow-up. Further studies are required to determine the clinical significance of these findings. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00433966.

Intravascular Ultrasound Classification of Plaque Distribution in Left Main Coronary Artery Bifurcations Where Is the Plaque Really Located

Background—Angiographic classifications of the location and severity of disease in the main vessel and side branch of coronary artery bifurcations have been proposed and applied to distal left main coronary artery (LMCA) bifurcation. Methods and Results—We reviewed 140 angiograms of distal LMCA and ostial left anterior descending (LAD) and left circumflex (LCX) artery lesions with preintervention intravascular ultrasound (IVUS) of both the LAD and LCX arteries as well as the LMCA. Of 140 patients, 92.9% had at least 1 cross section with ≥40% IVUS plaque burden versus 57.2% of patients with an angiographic diameter stenosis ≥50%. Contrary to angiographic classifications, IVUS showed that bifurcation disease was rarely focal and that both sides of the flow divider were always disease-free. Continuous plaque from the LMCA into the proximal LAD artery was seen in 90%, from the LMCA into the LCX artery in 66.4%, and from the LMCA into both the LAD and LCX arteries in 62%. Plaque localized to either the LAD or LCX ostium and not involving the distal LMCA was seen in only 9.3% of LAD arteries and 17.1% of LCX arteries. Plaque distribution was not influenced by the LAD/LCX angiographic angle, lesion severity, LMCA length, or remodeling. We proposed an IVUS classification for bifurcation lesions illustrating longitudinal and circumferential spatial plaque distribution. Conclusions—Angiographic classification of LMCA bifurcation lesions is rarely accurate. IVUS shows that the carina is always spared and that the disease is diffuse rather than focal. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180466.

Age- and gender-related changes in plaque composition in patients with acute coronary syndrome: The PROSPECT study

AIMSnAtherosclerosis accelerates with increasing age; however, young women presenting with acute coronary syndromes (ACS) have adverse outcomes compared to men despite less obstructive coronary artery disease. We sought to evaluate the in vivo plaque characteristics and composition of untreated non-culprit lesions (NCL) at two ages (<65 years old and ≥65 years old) in patients with ACS and examine the effect of sex in both groups.nnnMETHODS AND RESULTSnUntreated NCLs from 697 patients with ACS were imaged with greyscale and radiofrequency intravascular ultrasound. NCL plaque morphology, burden, composition, and major adverse cardiac events (MACE) were analysed in both age groups, and a posterior sex-based sub-analysis was performed. Plaques from patients ≥65 (n=974) vs. <65 (n=2,275) years old were longer (median 12.62 mm vs. 10.75 mm, p=0.008) and had greater plaque burden (48.2% vs. 47.5%, p=0.001), necrotic core (12.5% vs. 11.0%, p=0.001) and dense calcium (5.7% vs. 4.0%, p<0.0001). Men <65 years old also had a greater number of fibroatheromas (3.0 vs. 2.0, p=0.007) and NCLs per patient (5.0 vs. 4.0, p=0.004) with larger plaque volumes (47.7% vs. 46.8%, p=0.04), and fewer fibrotic plaques (2.2% vs. 4.4%, p=0.03) than women in the same age group. These sex differences were not observed in patients ≥65 years old. The incidence of MACE during median 3.4 year follow-up did not significantly differ according to age in this study.nnnCONCLUSIONSnThe current study confirms in vivo that, with aging, plaque burden, necrotic core and calcium content increase significantly. Moreover, gender-specific differences in the extent and composition of coronary plaque are present in patients <65 years (but not ≥65 years) of age, which suggest differential sex-related effects on atherosclerosis development and progression.

Prevalence and Impact of High Platelet Reactivity in Chronic Kidney Disease Results From the Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents Registry

Background—Chronic kidney disease (CKD) is associated with increased rates of adverse events after percutaneous coronary intervention. We sought to determine the impact of CKD on platelet reactivity in clopidogrel-treated patients and whether high platelet reactivity (HPR) confers a similar or differential risk for adverse events among patients with CKD and non-CKD. Methods and Results—We performed a post hoc analysis of the Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) registry, which included 8582 patients undergoing percutaneous coronary intervention with drug-eluting stents and platelet function testing using the VerifyNow assay. We compared HPR and its impact on ischemic and bleeding events >2 years among patients with CKD and non-CKD. Patients with CKD (n=1367) were older, more often female, diabetic, and had lower ejection fraction compared with their non-CKD counterparts (n=7043). Although HPR prevalence increased with worsening renal function in unadjusted analyses, these associations were no longer present after adjustment. Major adverse cardiac event rates at 2 years among those without CKD or HPR, HPR alone, CKD alone, and both CKD and HPR were 9.0%, 11.2%, 13.3%, and 17.5%, respectively (P<0.001). Associations between HPR and adverse events were uniform across CKD strata without evidence of interaction. Conclusions—HPR is more common among those with versus without CKD, an association that is attributable to confounding risk factors that are more prevalent in CKD. The impact of HPR on ischemic and bleeding events is similar irrespective of CKD status. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794.

Characteristics and clinical significance of angiographically mild lesions in acute coronary syndromes.

OBJECTIVESnThe aim of this study was to assess whether residual nonculprit (NC) lesions, defined as visual diameter stenosis ≥ 30% after successful percutaneous coronary intervention, affect the rate of future events in patients with acute coronary syndromes.nnnBACKGROUNDnIn patients with acute coronary syndromes, approximately one-half of recurrent events after percutaneous coronary intervention arise from untreated lesions.nnnMETHODSnPatients enrolled in PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) were divided into 3 groups: those with no NC lesions, 1 NC lesion, or ≥ 2 NC lesions. Time to events for major adverse cardiac events was estimated up to 3 years.nnnRESULTSnAmong 697 patients, 13.3% had no NC lesions, 19.7% had 1 NC lesion, and 67.0% had ≥ 2 NC lesions. The median diameter stenoses of the NC lesions in the latter 2 groups were 36.7% (interquartile range: 31.0% to 43.4%) and 37.4% (interquartile range: 32.0% to 46.5%), respectively (p = 0.22). At least 1 thin-cap fibroatheroma was present in one-half the patients in each group. At 3 years, the incidence of major adverse cardiac events was 8.5%, 15.2%, and 24.3%, respectively (p = 0.0009). NC lesion-related events occurred in 0%, 5.0%, and 15.9% of patients, respectively (p < 0.0001). Of 105 NC lesion-related clinical events occurring during follow-up, 73 (69.5%) originated from angiographically evident baseline NC lesions (of which 36 had diameter stenosis >50%), while the other 32 arose from normal or near normal segments.nnnCONCLUSIONSnResidual NC lesions are common after percutaneous coronary intervention for acute coronary syndromes and portend a higher rate of recurrent ischemic events within 3 years, especially when angiographically more severe. Conversely, the absence of NC lesions by angiography is highly predictive of freedom from events not related to the originally treated culprit lesion(s).

Prognostic Determinants of Coronary Atherosclerosis in Stable Ischemic Heart Disease: Anatomy, Physiology, or Morphology?

Risk stratification in patients with stable ischemic heart disease is essential to guide treatment decisions. In this regard, whether coronary anatomy, physiology, or plaque morphology is the best determinant of prognosis (and driver an effective therapeutic risk reduction) remains one of the greatest ongoing debates in cardiology. In the present report, we review the evidence for each of these characteristics and explore potential algorithms that may enable a practical diagnostic and therapeutic strategy for the management of patients with stable ischemic heart disease.

THE AXIAL DISTRIBUTION OF LESION-SITE ATHEROSCLEROTIC PLAQUE COMPONENTS: AN IN VIVO VOLUMETRIC INTRAVASCULAR ULTRASOUND RADIO-FREQUENCY ANALYSIS OF LUMEN STENOSIS, NECROTIC CORE AND VESSEL REMODELING

Radio-frequency intravascular ultrasound (IVUS) analysis characterizes atherosclerotic plaques into necrotic core (NC), dense calcium (DC), fibrofatty (FF) and fibrotic (FI) tissue. We studied axial plaque component distribution with respect to stenosis and remodeling. Preintervention virtual histology (VH) IVUS was performed in 81 pts (90 de novo lesions: 43 left anterior descending artery [LAD] and 47 right coronary artery [RCA]). VH-IVUS at the reference, minimum lumen area (MLA) and maximum NC (MaxNC) sites were analyzed. Pullback length of 31.1 +/- 12.0 mm spanned a lesion length of 13.8 +/- 9.5 mm. The MaxNC site was located at the MLA in 3.3% of lesions, proximal to the MLA in 61% of lesions (by 4.11 mm) and distal to the MLA in 35.6% of lesions (by 3.56 mm). The %DC was greater at the MaxNC and %FI and %FF plaque were less than at the MLA site. Lesion fiberoatheromas (FAs) were more often detected at the MaxNC than the MLA (96% versus 51%) and were more often classified as thin-caped or multilayered than the MLA sites. The remodeling index was larger at the MaxNC than MLA sites and correlated with the NC area both at the MLA (r(2) 0.068, p = 0.013) and at the MaxNC (r(2) 0.074, p = 0.009). In conclusion, grey-scale and VH-IVUS analysis showed that the MLA is rarely at the site of greatest instability (largest NC and remodeling) and necrotic core on VH is correlated with remodeling index. These in vivo findings are consistent with previously reported histopathologic data and have important implications for the detection and treatment of coronary artery disease.

Benefits of optimising coronary flow before stenting in primary percutaneous coronary intervention for ST-elevation myocardial infarction: insights from INFUSE-AMI.

AIMSnTo determine the relation between thrombus aspiration (TA) and/or intra-lesion (IL) abciximab with pre-stent Thrombolysis In Myocardial Infarction (TIMI) flow grade and infarct size (IS) in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).nnnMETHODS AND RESULTSnThe INFUSE-AMI trial randomised 452 patients with anterior STEMI to IL abciximab vs. no abciximab, and to manual TA vs. no TA. The primary endpoint was cMRI-determined IS at 30 days. Patients were classified according to pre-stent TIMI flow. Complete data were available in 290 patients - 68 (25.2%) with pre-stent TIMI 0/1 flow, 47 (17.4%) with TIMI 2 flow and 175 (57.4%) with TIMI 3 flow. Patients with pre-stent TIMI 3 flow had significantly lower IS (15.5% [4.6, 21.8] vs. 22.6% [14.7, 28.0] for TIMI 2 vs. 19.5 [14.4, 27.8] for TIMI 0/1, p<0.0001) and fewer 30-day clinical events (p=0.03). Patients receiving TA with or without IL abciximab had the highest rate of pre-stent TIMI 3 flow (p<0.0001) and patients receiving both had the smallest IS (14.7% vs. 17.3% for the other three groups, p=0.03).nnnCONCLUSIONSnOptimisation of coronary flow prior to stent implantation may reduce infarct size and clinical events in STEMI patients undergoing primary PCI.