Optical Coherence Tomography of Coronary Plaque Progression and Destabilization: JACC Focus Seminar Part 3/3.

The development of optical coherence tomography (OCT) has revolutionized our understanding of coronary artery disease. In vivo OCT research has paralleled with advances in computational fluid dynamics, providing additional insights in the various hemodynamic factors influencing plaque growth and stability. Recent OCT studies introduced a new concept of plaque healing in relation to clinical presentation. In addition to known mechanisms of acute coronary syndromes such as plaque rupture and plaque erosion, a new classification of calcified plaque was recently reported. This review will focus on important new insights that OCT has provided in recent years into coronary plaque development, progression, and destabilization, with a focus on the role of local hemodynamics and endothelial shear stress, the layered plaque (signature of previous subclinical plaque destabilization and healing), and the calcified culprit plaque.

2-Year Outcomes for Transcatheter Repair in Patients With Mitral Regurgitation From the CLASP Study.

OBJECTIVES: This study reports 2-year outcomes from the multicenter, prospective, single-arm CLASP study with functional mitral regurgitation (FMR) and degenerative MR (DMR) analysis. BACKGROUND: Transcatheter repair is a favorable option to treat MR. Long-term prognostic impact of the PASCAL transcatheter valve repair system in patients with clinically significant MR remains to be established. METHODS: Patients had clinically significant MR ≥3+ as evaluated by the echocardiographic core laboratory and were deemed candidates for transcatheter repair by the heart team. Assessments were performed by clinical events committee to 1 year (site-reported thereafter) and core laboratory to 2 years. RESULTS: A total of 124 patients (69% FMR, 31% DMR) were enrolled with a mean age of 75 years, 56% were male, 60% were New York Heart Association functional class III to IVa, and 100% had MR ≥3+. At 2 years, Kaplan-Meier estimates showed 80% survival (72% FMR, 94% DMR) and 84% freedom from heart failure (HF) hospitalization (78% FMR, 97% DMR), with 85% reduction in annualized HF hospitalization rate (81% FMR, 98% DMR). MR ≤1+ was achieved in 78% of patients (84% FMR, 71% DMR) and MR ≤2+ was achieved in 97% (95% FMR, 100% DMR) (all p < 0.001). Left ventricular end-diastolic volume decreased by 33 ml (p < 0.001); 93% of patients were in New York Heart Association functional class I to II (p < 0.001). CONCLUSIONS: The PASCAL repair system demonstrated sustained favorable outcomes at 2 years in FMR and DMR patients. Results showed high survival and freedom from HF rehospitalization rates with a significantly reduced annualized HF hospitalization rate. Durable MR reduction was achieved with evidence of left ventricular reverse remodeling and significant improvement in functional status. The CLASP IID/IIF randomized pivotal trial is ongoing.

Comparison of activated clotting times obtained using Hemochron and Medtronic analysers in patients receiving anti-thrombin therapy during cardiac catheterisation.

Accurate monitoring of anti-thrombin therapy with activated clotting time (ACT) is important to prevent thrombotic and haemorrhagic complications during cardiac catheterisation. Significant variability in ACT tests exists when different analysers are used. Our objective was to compare ACT results obtained using Hemochron and Medtronic ACT PLUS devices and antiXa activity in patients undergoing cardiac catheterisation. Thirty-two patients who received unfractionated heparin or argatroban therapy during cardiac catheterisation were enrolled. Blood sampling was performed to determine ACT values using Hemochron and Medtronic (with high-range cartridges) devices in all patients (n = 130 pairs), and anti-Xa activity following heparin administration. In the heparin group, ACT tests (n = 95 pairs) showed very good correlation (r = 0.84, y = 1.31x-0.81; p<0.001). However, Hemochron values were consistently higher and the difference more pronounced with increasing ACT (for ACT>150 sec, mean difference 65 +/- 48 sec; p<0.001). Both Hemochron and Medtronic ACT tests correlated well with plasma anti-Xa levels (r = 0.85, r = 0.81, respectively; p<0.001); Hemochron ACT>300 sec corresponded to anti-Xa>1.48 IU/ml. With concomitant eptifibatide therapy, the divergence in ACT was greater compared to heparin alone. In the argatroban group, ACT tests (n = 35 pairs) demonstrated excellent correlation (r = 0.94, y = 0.61x+79.9; p<0.001). In contrast to the heparin group, ACT values were higher with Medtronic compared to Hemochron. Therefore, despite good correlation between Hemochron and Medtronic ACT results, and strong association with anti-Xa activity, Medtronic ACT values were consistently lower compared to Hemochron following heparin anticoagulation. Paradoxically, Medtronic ACT results were higher after argatroban therapy. Understanding this discrepancy is crucial when using ACT to guide invasive cardiac procedures.

Calcified plaque: measurement of area at thin-section flat-panel CT and 64-section multidetector CT and comparison with histopathologic findings.

The purpose of this study was to assess the blooming artifacts in ex vivo coronary arteries at multidetector computed tomography (CT) and flat-panel-volume CT by comparing measured areas of calcified plaque with respect to the reference standard of histopathologic findings. Three ex vivo hearts were scanned with multidetector CT and flat-panel-volume CT after institutional review board approval. The area of calcified plaque was measured at histopathologic examination, multidetector CT, and flat-panel-volume CT. The plaque area was overestimated at multidetector CT by 400% (4.61/1.15) on average, and the predicted difference between the measurements was significant (3.46 mm(2), P = .018). The average overestimation of plaque area at flat-panel-volume CT was twofold (214% [2.18/1.02]), and the predicted difference was smaller (1.16 mm(2), P = .08). The extent of the blooming artifact in visualizing calcified coronary plaque is reduced by using flat-panel-volume CT.

Relationship between a systemic inflammatory marker, plaque inflammation, and plaque characteristics determined by intravascular optical coherence tomography.

OBJECTIVE: The purpose of this study was to evaluate the relationships between the peripheral white blood cell (WBC) count, local plaque fibrous cap macrophage density, and the morphological features and presence of thin-cap fibroatheromas (TCFA) identified by optical coherence tomography (OCT). METHODS AND RESULTS: OCT was performed in patients undergoing catheterization. Images were analyzed using validated criteria for plaque characteristics. Baseline WBC count correlated with macrophage density (r=0.483, P<0.001). Both parameters were associated with lipid-rich plaque and correlated inversely with plaque fibrous cap thickness (r=-0.547 for macrophage density and -0.423 for WBC count, P<0.015). Plaques classified as TCFA had a higher median macrophage density than non-TCFA plaques (7.4 versus 4.99, P<0.001). Patients with TCFA had a higher WBC count compared with those without TCFA (11.0 versus 7.9, P=0.007). Receiver operator curves for WBC count, macrophage density, and these combined parameters for prediction of TCFA showed the area under the curves were 0.88, 0.91, and 0.97 (P<0.001), respectively. CONCLUSION: This study provides the first in vivo data linking the peripheral WBC count, plaque fibrous cap macrophage density, and the characteristics and presence of TCFA. Macrophage density correlated with the WBC count, and both parameters independently and particularly in combination predict the presence of TCFA.

Initial Q waves accompanying ST-segment elevation at presentation of acute myocardial infarction and 30-day mortality in patients given streptokinase therapy: an analysis from HERO-2.

BACKGROUND: The presence of pathological Q waves in the infarct leads on the surface electrocardiogram in an ST-elevation acute myocardial infarction indicates myocardial necrosis. Clinically it might be difficult to ascertain the onset of acute myocardial infarction. Our aim was to assess whether the presence or absence of Q waves at presentation could be used as an indicator of the duration of acute myocardial infarction and predict mortality. METHODS: 15,222 patients with ST-elevation acute myocardial infarction and normal intraventricular conduction were randomly assigned streptokinase and aspirin plus bivalirudin or unfractionated heparin in the HERO-2 trial; randomisation did not alter 30-day mortality. 10,244 patients (67%) had Q waves in the infarct territory at the time of randomisation, and 4978 (33%) did not. The primary endpoint was 30-day mortality. FINDINGS: There were more deaths at 30 days in patients with initial Q waves than in those without (1044 [10%] vs 344 [7%], p<0.0001). These findings were similar in patients with a first acute myocardial infarction and when stratified by time to randomisation (0-2, >2-4, >4 h) and by acute myocardial infarction location (anterior or inferior). Both the presence of initial Q waves and time to randomisation were positive univariate predictors, but only the presence of initial Q waves independently predicted 30-day mortality on multivariate analysis (adjusted OR 1.44, 95% CI 1.25-1.65 with clinical indices, and 1.31, 1.12-1.54 with clinical plus ST indices included as predictors). INTERPRETATION: The presence of Q waves in the infarct leads at presentation of ST-elevation acute myocardial infarction independently predicts higher 30-day mortality in patients treated with fibrinolytic therapy. Therefore, a more aggressive approach to reperfusion might be warranted in these patients.

Patients with prolonged ischemic chest pain and presumed-new left bundle branch block have heterogeneous outcomes depending on the presence of ST-segment changes.

OBJECTIVES: The purpose of this research was to examine the prognostic value of ST-segment changes (concordant ST-segment elevation and/or precordial V1 to V3 ST-segment depression) during presumed-new left bundle branch block (LBBB) in patients receiving fibrinolytic therapy. BACKGROUND: These patients are often considered high-risk, but their outcome is not well-defined. METHODS: The Hirulog and Early Reperfusion or Occlusion (HERO)-2 trial compared bivalirudin with heparin in patients receiving streptokinase for ST-segment elevation or presumed-new LBBB. Each patient with LBBB was matched with a control (with normal intraventricular conduction) for age, gender, pulse rate, systolic blood pressure, Killip class, and region. RESULTS: A total of 300 patients had LBBB (92 with and 208 without ST-segment changes) and 15,340 had normal conduction. Acute myocardial infarction (AMI) occurred in 80.7% of LBBB patients and 88.7% of controls (p = 0.006). ST-segment changes were specific (96.6%) but not sensitive (37.8%) for enzymatic diagnosis of AMI. Mortality at 30 days was similar in LBBB patients with ST-segment changes (21.7%) and controls (25.0%, p = 0.563), but lower in LBBB patients without ST-segment changes than in controls (13.5% vs. 21.6%, p = 0.022). In the whole HERO-2 cohort, the LBBB patients with ST-segment changes had higher mortality than patients with normal conduction (odds ratio [OR] 1.37, 95% confidence interval [CI] 0.78 to 2.42). The LBBB patients without ST-segment changes had lower mortality than patients with normal conduction (OR 0.52, 95% CI 0.33 to 0.80). CONCLUSIONS: ST-segment changes during LBBB are specific for the diagnosis of AMI and predict 30-day mortality; LBBB patients without ST-segment changes have lower adjusted 30-day mortality than those with normal conduction. Trials are required to determine the best treatment for high-risk and low-risk patients with LBBB.

Drug insight: Statin use in the elderly.

The elderly represent a notable proportion of patients who present with myocardial infarction or acute coronary syndromes. This subgroup of patients also experiences a higher incidence of adverse outcomes than younger age-groups, and, therefore, has more to gain from effective, evidence-based therapies. The efficacy of statins in secondary cardiovascular disease prevention is firmly established. The starting of therapy soon after an acute coronary event has been shown to provide added benefit. Uncertainties about the effectiveness of statins in the elderly, however, have resulted in their underuse in this population. In this review we evaluate the evidence for statin use in this important and increasingly large group of patients.

Cerebral Microcirculation during Experimental Normovolaemic Anemia.

Anemia is accepted among critically ill patients as an alternative to elective blood transfusion. This practice has been extrapolated to head injury patients with only one study comparing the effects of mild anemia on neurological outcome. There are no studies quantifying microcirculation during anemia. Experimental studies suggest that anemia leads to cerebral hypoxia and increased rates of infarction, but the lack of clinical equipoise, when testing the cerebral effects of transfusion among critically injured patients, supports the need of experimental studies. The aim of this study was to quantify cerebral microcirculation and the potential presence of axonal damage in an experimental model exposed to normovolaemic anemia, with the intention of describing possible limitations within management practices in critically ill patients. Under non-recovered anesthesia, six Merino sheep were instrumented using an intracardiac transeptal catheter to inject coded microspheres into the left atrium to ensure systemic and non-chaotic distribution. Cytometric analyses quantified cerebral microcirculation at specific regions of the brain. Amyloid precursor protein staining was used as an indicator of axonal damage. Animals were exposed to normovolaemic anemia by blood extractions from the indwelling arterial catheter with simultaneous fluid replacement through a venous central catheter. Simultaneous data recording from cerebral tissue oxygenation, intracranial pressure, and cardiac output was monitored. A regression model was used to examine the effects of anemia on microcirculation with a mixed model to control for repeated measures. Homogeneous and normal cerebral microcirculation with no evidence of axonal damage was present in all cerebral regions, with no temporal variability, concluding that acute normovolaemic anemia does not result in short-term effects on cerebral microcirculation in the ovine brain.

Drug eluting stents trapping intramural hematoma in spontaneous coronary artery dissection and healing pattern at six months: optical coherence tomography findings.

Spontaneous coronary artery dissections (SCAD) are often difficult to diagnose and manage. Intravascular imaging such as optical coherence tomography (OCT) improves diagnosis and may assist in management. Recent data suggest that percutaneous coronary interventions (PCI) in in SCAD are associated with poor outcomes. This report provides striking OCT images of potential complications associated with PCI in SCAD, as well as demonstrates medium term OCT data in residual hematoma healing and stent coverage in SCAD.

CT angiography with cardiac MRI: non-invasive functional and anatomical assessment for the etiology in newly diagnosed heart failure.

Exclusion of ischemia is important in patients with newly diagnosed systolic heart failure (HF). We prospectively compared standard-of-care invasive catheter angiography (iCA) and echocardiography to a novel non-invasive strategy of both Coronary Computed Tomographic Angiography (CCTA) and Cardiovascular MRI (CMR) to determine the etiology of myocardial dysfunction Prospective data were collected from consecutive patients referred for iCA to investigate echocardiographically-confirmed new onset HF. CMR (1.5T GE) and dual source CCTA were performed within 2-7 days of iCA. Results were blinded and separately analyzed by expert readers. 426 coronary segments from 28 prospectively enrolled patients were analyzed by CCTA and quantitative iCA. The per-patient sensitivity and specificity of CCTA was 100% and 90%, respectively, negative predictive value (NPV) 100%, positive predictive value (PPV) 78%. Mean ejection fraction by CMR was 24%. Presence of ischemic-type LGE on CMR conferred a 67% sensitivity, 100% specificity, 90% NPV and 100% PPV. Combining CCTA with CMR conferred 100% specificity, 100% sensitivity, 100% PPV and 100% NPV for detection or exclusion of coronary disease. In patients with negative CCTA all invasive angiograms could have been avoided. In addition, two patients with no ischemic LGE by CMR had severe coronary disease on both CCTA and iCA, indicating global hibernation. This is a noteworthy finding in contrast to previous reports which suggested that absence of LGE rules out significant CAD. CCTA with CMR in newly-diagnosed HF enables non-invasive assessment of coronary artery disease, the severity and etiology of myocardial dysfunction and defines suitability for revascularization. Absence of ischemic-type LGE at CMR does not exclude CAD as a cause of LV dysfunction. A first-line strategy of functional and anatomic imaging with CMR and CCTA appears appropriate in newly diagnosed HF.

Association of leukocyte and neutrophil counts with infarct size, left ventricular function and outcomes after percutaneous coronary intervention for ST-elevation myocardial infarction.

Elevated leukocyte count during ST-segment elevation myocardial infarction is associated with adverse clinical outcomes. Whether increased leukocyte count after primary percutaneous coronary intervention (PCI) directly reflects larger infarct size and left ventricular impairment is not known. The aim of this study was to assess the relation between leukocyte and neutrophil counts with infarct size and the left ventricular ejection fraction (LVEF) after primary PCI. Three hundred sixty-three patients from the Evaluation of MCC-135 for Left Ventricular Salvage in Acute Myocardial Infarction (EVOLVE) study, a randomized, double-blind, placebo-controlled trial assessing the efficacy of intracellular calcium modulator as an adjunct to primary PCI in patients with first ST-segment elevation myocardial infarctions, were evaluated. Total and differential leukocyte counts were measured before and serially after PCI. Infarct size and the LVEF were assessed using single-photon emission computed tomography after 5 and 30 days, and patients were followed up to 180 days. Total leukocyte and neutrophil counts obtained 24 hours after PCI were significantly correlated with infarct size (r = 0.34 and 0.37, respectively, p <0.001) and inversely correlated with the LVEF (r = -0.20 and -0.22, respectively, p <0.001). Patients with elevated leukocyte and neutrophil counts had larger infarct sizes (12.5% vs 5% and 13.5% vs 5%, respectively, p <0.001). The highest neutrophil quartile was associated with increased 180-day composite cardiac events (19% vs 20% vs 23% vs 45%, log-rank p <0.001). Elevated leukocyte and neutrophil counts independently predicted adverse cardiac events (hazard ratios 2.5 and 2.2, respectively, p = 0.001). In conclusion, elevated leukocyte and neutrophil counts after primary PCI in patients with ST-segment elevation myocardial infarctions are directly related to myocardial infarct size and the LVEF and are independent predictors of cardiovascular outcomes.

Elevated B-type natriuretic peptide despite normal left ventricular function on rest and exercise stress echocardiography in mitral regurgitation.

AIMS: To determine whether elevated B-type natriuretic peptide (BNP) predicts left ventricular (LV) contractile dysfunction on exercise stress echocardiography in patients with severe mitral regurgitation (MR). METHODS AND RESULTS: Thirty three patients with moderate-to-severe or severe MR, a LV ejection fraction > or =60% and New York Heart Association Class I or II symptoms, and 12 controls underwent resting and exercise stress echocardiography. In 20 MR patients, BNP was within the normal range (mean +/- SD, 7.7 +/- 2.7 pmol/L), and in 13 MR patients, BNP was >12 pmol/L (19.6 +/- 7.6 pmol/L). LV end-systolic volume index after exercise was lower in controls than patients with MR (P < 0.0001), but similar in MR patients with normal and elevated BNP, respectively (controls 8.5 +/- 3.9, MR 20 +/- 7 vs. 20 +/- 9 cm(2)/m(2), P > 0.05). However, pulmonary artery systolic pressure (PAP) after exercise was higher in MR with high BNP (70 +/- 20 vs. 48 +/- 11 mmHg, <0.0001) and controls (38+/-11 mmHg). A two-fold increase in plasma BNP was associated with an average increase in resting PAP of 7.6 (95% CI 2.9, 12.2) mmHg, an increase in post-exercise PAP of 14.4 (95% CI 9.0, 19.9) mmHg and increase in left atrial area index of 2.1 (95% CI 0.5, 3.8) cm(2)/m(2). However, there was no significant association between the plasma level of BNP and any rest or post-exercise measure of LV systolic function (r < 0.25, P > 0.05 for all). CONCLUSION: The plasma level of BNP may be within the normal range in patients with moderate-to-severe or severe MR despite significant increases in LV end-systolic volume. Increase in BNP is associated with pulmonary artery hypertension on exercise and left atrial enlargement even when LV systolic function on exercise stress echocardiography is normal.

Utility of cardiac biomarkers in predicting infarct size, left ventricular function, and clinical outcome after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.

OBJECTIVES: We sought to determine the best cardiac biomarker to predict infarct size, left ventricular ejection fraction (LVEF), and clinical outcome in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The cardiac biomarkers, creatine kinase (CK), CK-MB, and troponins T and I are routinely measured after myocardial infarction. However, their correlation with functional and clinical outcomes after PCI for STEMI is not well established. METHODS: In the EVOLVE (EValuation Of MCC-135 for Left VEntricular Salvage in Acute Myocardial Infarction) trial, patients were randomized to receive intracellular calcium modulator as adjunct to primary PCI for first large STEMI. Cardiac biomarker levels were determined in 378 patients before PCI and serially up to 72 h. Single-photon emission computed tomography was performed after 5 and 30 days, and patients were monitored up to 180 days. RESULTS: All single time-point, peak, and area under time-concentration curve of CK, CK-MB, and troponins T and I after PCI significantly correlated with infarct size and LVEF. In particular, 72-h troponin I (TnI72h) correlated strongly with 5-day and 30-day infarct size (r > 0.70; p < 0.001). A TnI72h threshold >55 ng/ml was 90% sensitive for large infarct size (> or =10%) and low LVEF (< or =40%) with specificities of 70% and 52%, respectively (c = 0.88, 0.81; p < 0.001). The highest TnI72h tertile was associated with increased 180-day composite clinical events (23% vs. 23% vs. 42%; p = 0.001) and independently predicted adverse events (hazard ratio = 2.3; p = 0.01). CONCLUSIONS: Assessing TnI72h after primary PCI is a simple, effective method to estimate infarct size, LVEF, and potentially useful for risk stratification.

Comparison of coronary plaque characteristics between diabetic and non-diabetic subjects: An in vivo optical coherence tomography study.

AIMS: Postmortem series have reported that subjects with diabetes mellitus have coronary plaques with larger necrotic cores and increased macrophage infiltration. Optical coherence tomography (OCT) is a high-resolution imaging modality that allows in vivo characterization of atherosclerotic plaques. Using OCT imaging, we compared in vivo plaque characteristics between diabetic and non-diabetic subjects. METHODS: Sixty-three patients undergoing cardiac catheterization were enrolled. OCT imaging was performed in culprit coronary arteries. Assessment of plaque lipid content, fibrous cap thickness and frequency of thin-cap fibroatheroma were made independently. Macrophage density was determined from the optical signal within fibrous cap. RESULTS: Eighty-two plaques in total were imaged (19 diabetic vs. 63 non-diabetic). There were no significant differences in frequency of lipid-rich plaques (68% vs. 71%; P=0.78), thin-cap fibroatheroma (29% vs. 36%; P=0.76) or minimum fibrous cap thickness (66.6microm vs. 62.9microm; P=0.87) between diabetic and non-diabetic patients. Fibrous cap macrophage density was higher in lipid-rich plaques (P=0.01) but showed no difference between diabetic and non-diabetic patients (5.94% vs. 5.94%; P=0.37). CONCLUSIONS: There were no significant differences in culprit vessel plaque characteristics between diabetic and non-diabetic patients presenting with coronary artery disease. This represents the first study to characterize coronary plaques in diabetic patients using OCT.

Coronary stent malapposition as a result of a post-stenotic aneurysm detected by optical coherence tomography.

Stent malapposition remains an important cause of complications following stent implantation. Stent underexpansion is a frequent cause of this. We describe a case of coronary stent malapposition as a result of a post-stenotic aneurysm. Both the malapposition and its etiology were clearly demonstrated by optical coherence tomography, a novel high-resolution imaging technology.