Impact of statins based on high-risk plaque features on coronary plaque progression in mild stenosis lesions: results from the PARADIGM study.

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.

Association between Aortic Valve Calcification Progression and Coronary Atherosclerotic Plaque Volume Progression in the PARADIGM Registry.

Background Aortic valve calcification (AVC) is a key feature of aortic stenosis, and patients with aortic stenosis often have coronary -artery disease. Therefore, proving the association between the progression of AVC and coronary atherosclerosis could improve follow-up and treatment strategies. Purpose To explore the association between the progression of AVC and the progression of total and plaque volume composition from a large multicenter registry of serial coronary CT angiographic examinations. Materials and Methods A prospective multinational registry (PARADIGM) of consecutive participants who underwent serial coronary CT angiography at intervals of every 2 years or more was performed (January 2003-December 2015). AVC and the total and plaque volume composition at baseline and follow-up angiography were quantitatively analyzed. Plaque volumes were normalized by using the mean total analyzed vessel length of the study population. Multivariable linear mixed-effects models were constructed. Results Overall, 594 participants (mean age ± standard deviation, 62 years ± 10; 330 men) were included (mean interval between baseline and follow-up angiography, 3.9 years ± 1.5). At baseline, the AVC score was 31 Agatston units ± 117, and the normalized total plaque volume at baseline was 122 mm3 ± 219. After adjustment for age, sex, clinical risk factors, and medication use, AVC was independently associated with total plaque volume (standardized ß = 0.24; 95% CI: 0.16, 0.32; P < .001) and both calcified (ß = 0.26; 95% CI: 0.18, 0.34; P < .001) and noncalcified (ß = 0.17; 95% CI: 0.08, 0.25; P < .001) plaque volumes at baseline. The progression of AVC was associated with the progression of total plaque volume (ß = 0.13; 95% CI: 0.03, 0.22; P = .01), driven solely by calcified plaque volume (ß = 0.24; 95% CI: 0.14, 0.34; P < .001) but not noncalcified plaque volumes (ß = -0.06; 95% CI: -0.14, 0.03; P = .17). Conclusion The overall burden of coronary atherosclerosis was associated with aortic valve calcification at baseline. However, the progression of aortic valve calcification was associated with only the progression of calcified plaque volume but not with the -progression of noncalcified plaque volume. Clinical trial registration no. NCT02803411 © RSNA, 2021 See also the editorial by Sinitsyn in this issue.

LncRNA VINAS regulates atherosclerosis by modulating NF-κB and MAPK signaling.

Long noncoding RNAs (lncRNAs) play important roles in regulating diverse cellular processes in the vessel wall, including atherosclerosis. RNA-Seq profiling of intimal lesions revealed a lncRNA, VINAS (Vascular INflammation and Atherosclerosis lncRNA Sequence), that is enriched in the aortic intima and regulates vascular inflammation. Aortic intimal expression of VINAS fell with atherosclerotic progression and rose with regression. VINAS knockdown reduced atherosclerotic lesion formation by 55% in LDL receptor-deficient (LDLR-/-) mice, independent of effects on circulating lipids, by decreasing inflammation in the vessel wall. Loss- and gain-of-function studies in vitro demonstrated that VINAS serves as a critical regulator of inflammation by modulating NF-κB and MAPK signaling pathways. VINAS knockdown decreased the expression of key inflammatory markers, such as MCP-1, TNF-α, IL-1ß, and COX-2, in endothelial cells (ECs), vascular smooth muscle cells, and bone marrow-derived macrophages. Moreover, VINAS silencing decreased expression of leukocyte adhesion molecules VCAM-1, E-selectin, and ICAM-1 and reduced monocyte adhesion to ECs. DEP domain containing 4 (DEPDC4), an evolutionary conserved human ortholog of VINAS with approximately 74% homology, showed similar regulation in human and pig atherosclerotic specimens. DEPDC4 knockdown replicated antiinflammatory effects of VINAS in human ECs. These findings reveal a potentially novel lncRNA that regulates vascular inflammation, with broad implications for vascular diseases.

Long noncoding RNA SNHG12 integrates a DNA-PK-mediated DNA damage response and vascular senescence.

Long noncoding RNAs (lncRNAs) are emerging regulators of biological processes in the vessel wall; however, their role in atherosclerosis remains poorly defined. We used RNA sequencing to profile lncRNAs derived specifically from the aortic intima of Ldlr -/- mice on a high-cholesterol diet during lesion progression and regression phases. We found that the evolutionarily conserved lncRNA small nucleolar host gene-12 (SNHG12) is highly expressed in the vascular endothelium and decreases during lesion progression. SNHG12 knockdown accelerated atherosclerotic lesion formation by 2.4-fold in Ldlr -/- mice by increased DNA damage and senescence in the vascular endothelium, independent of effects on lipid profile or vessel wall inflammation. Conversely, intravenous delivery of SNHG12 protected the tunica intima from DNA damage and atherosclerosis. LncRNA pulldown in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis showed that SNHG12 interacted with DNA-dependent protein kinase (DNA-PK), an important regulator of the DNA damage response. The absence of SNHG12 reduced the DNA-PK interaction with its binding partners Ku70 and Ku80, abrogating DNA damage repair. Moreover, the anti-DNA damage agent nicotinamide riboside (NR), a clinical-grade small-molecule activator of NAD+, fully rescued the increases in lesional DNA damage, senescence, and atherosclerosis mediated by SNHG12 knockdown. SNHG12 expression was also reduced in pig and human atherosclerotic specimens and correlated inversely with DNA damage and senescent markers. These findings reveal a role for this lncRNA in regulating DNA damage repair in the vessel wall and may have implications for chronic vascular disease states and aging.

Association of High-Density Calcified 1K Plaque With Risk of Acute Coronary Syndrome.

Importance: Plaque morphologic measures on coronary computed tomography angiography (CCTA) have been associated with future acute coronary syndrome (ACS). However, the evolution of calcified coronary plaques by noninvasive imaging is not known. Objective: To ascertain whether the increasing density in calcified coronary plaque is associated with risk for ACS. Design, Setting, and Participants: This multicenter case-control cohort study included individuals enrolled in ICONIC (Incident Coronary Syndromes Identified by Computed Tomography), a nested case-control study of patients drawn from the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) registry, which included 13 study sites in 8 countries. Patients who experienced core laboratory-verified ACS after baseline CCTA (n = 189) and control individuals who did not experience ACS after baseline CCTA (n = 189) were included. Patients and controls were matched 1:1 by propensity scores for age; male sex; presence of hypertension, hyperlipidemia, and diabetes; family history of premature coronary artery disease (CAD); current smoking status; and CAD severity. Data were analyzed from November 2018 to March 2019. Exposures: Whole-heart atherosclerotic plaque volume was quantitated from all coronary vessels and their branches. For patients who underwent invasive angiography at the time of ACS, culprit lesions were coregistered to baseline CCTA lesions by a blinded independent reader. Low-density plaque was defined as having less than 130 Hounsfield units (HU); calcified plaque, as having more than 350 HU and subcategorized on a voxel-level basis into 3 strata: 351 to 700 HU, 701 to 1000 HU, and more than 1000 HU (termed 1K plaque). Main Outcomes and Measures: Association between calcium density and future ACS risk. Results: A total of 189 patients and 189 matched controls (mean [SD] age of 59.9 [9.8] years; 247 [65.3%] were male) were included in the analysis and were monitored during a mean (SD) follow-up period of 3.9 (2.5) years. The overall mean (SD) calcified plaque volume (>350 HU) was similar between patients and controls (76.4 [101.6] mm3 vs 99.0 [156.1] mm3; P = .32), but patients who experienced ACS exhibited less 1K plaque (>1000 HU) compared with controls (3.9 [8.3] mm3 vs 9.4 [23.2] mm3; P = .02). Individuals within the highest quartile of 1K plaque exhibited less low-density plaque, as a percentage of total plaque, when compared with patients within the lower 3 quartiles (12.6% [10.4%] vs 24.9% [20.6%]; P < .001). For 93 culprit precursor lesions detected by CCTA, the volume of 1K plaque was lower compared with the maximally stenotic lesion in controls (2.6 [7.2] mm3 vs 7.6 [20.3] mm3; P = .01). The per-patient and per-lesion results were similar between the 2 groups when restricted to myocardial infarction cases. Conclusions and Relevance: Results of this study suggest that, on a per-patient and per-lesion basis, 1K plaque was associated with a lower risk for future ACS and that measurement of 1K plaque may improve risk stratification beyond plaque burden.

Clopidogrel response variability is associated with endothelial dysfunction in coronary artery disease patients receiving dual antiplatelet therapy.

OBJECTIVES: Dual antiplatelet therapy with aspirin and a platelet P2Y12 ADP receptor antagonist is the cornerstone of treatment following percutaneous coronary intervention (PCI). Several clinical and genetic factors can cause suboptimal clopidogrel response. We examined the impact of endothelial dysfunction on clopidogrel response variability in subjects with stable coronary artery disease (CAD) after PCI. METHODS: We consecutively enrolled 198 patients with stable CAD one month after successful PCI. All patients were receiving dual antiplatelet therapy (clopidogrel 75 mg and aspirin 100 mg/day). Platelet reactivity was measured by VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). VerifyNow reports its results in P2Y12 reaction units (PRU) and the diagnostic cut-off value is 230. Endothelial function was evaluated by flow mediated dilation (FMD). RESULTS: Patients with high on treatment platelet reactivity (32% of the study population), compared to subjects with low on treatment platelet reactivity, presented decreased FMD values (4.35 ± 2.22% vs. 5.74 ± 3.29%, p = 0.01). Moreover, an inverse association between endothelial function measurement and platelet reactivity (r = -0.24, p = 0.001) was found. Importantly, multivariate analysis after adjustment for age, gender and confounders revealed by the univariate analysis (left ventricle ejection fraction, body mass index, diabetes, dyslipidemia, coronary lesion number) showed that for every decrease in FMD by 1% there is an anticipated increased in the odds of patients to have HPR by 1.66 (95% CI 1.03-2.57, p = 0.037). CONCLUSIONS: Endothelial dysfunction is associated with clopidogrel response variability in patients after PCI receiving dual antiplatelet therapy. These findings shed some light on the mechanisms affecting individual platelet response to antiplatelet therapy and may explain the non-straight forward association between clopidogrel dose, platelet inhibition and cardiovascular outcome.

Association between symptoms of depression and anxiety with heart rate variability in patients with implantable cardioverter defibrillators.

OBJECTIVE: This study investigated whether depression and anxiety symptoms are associated with measures of autonomic nervous system dysfunction in patients with implantable cardioverter defibrillators who are at high risk of cardiac rhythm disturbances. Depression and anxiety are associated with autonomic nervous system dysfunction, which may promote the risk of malignant cardiac arrhythmias. METHODS: Patients with an implantable cardioverter defibrillator (ICD) underwent ambulatory electrocardiographic (ECG) monitoring (n = 44, mean age = 62.1 +/- 9.3 years). Depression was assessed using the Beck Depression Inventory and anxiety was evaluated using the Taylor Manifest Anxiety Scale. Heart rate variability was assessed using time (RMSSD, pNN50, and SDNN) and frequency domain measures derived from 24-hour R-R intervals. Multivariate models were adjusted for age, sex, hypertension, diabetes, and smoking status. RESULTS: Defibrillator patients with elevated depression symptoms (n = 12) had significantly lower RMSSD (15.25 +/- 1.66 ms versus 24.97 +/- 2.44 ms, p = .002) and pNN50 (1.83 +/- 0.77 versus 5.61 +/- 1.04, p = .006) than defibrillator patients with low depression symptoms (n = 32). These associations remained significant after multivariate adjustment for covariates. ICD patients with high anxiety levels (n = 10) displayed lower RMSSD (p = .013), which became marginally significant when adjusting for covariates (p = .069). CONCLUSIONS: Depression and anxiety in defibrillator patients are associated with autonomic nervous system dysfunction indices of reduced parasympathetic control. Autonomic nervous system dysfunction may partially explain the association between depression and anxiety with life-threatening cardiac outcomes in vulnerable patients.

Focused exposures to airborne traffic particles and heart rate variability in the elderly.

BACKGROUND: : Exposure to airborne particles may increase cardiac risk by altering autonomic balance. Because these risks may be particularly great for traffic-related particles, we examined associations between particles and heart rate variability as 44 subjects participated in 4 repeated trips aboard a diesel bus. METHODS: : Twenty-four hour electrocardiograms were correlated with continuous particle concentrations using generalized additive models controlling for subject, weekday, time, apparent temperature, trip type, activity, medications, and autoregressive terms. Associations were assessed for short- and medium-term moving averages of measured concentrations. RESULTS: : Heart rate variability was negatively associated with fine particulate matter. Positive associations were demonstrated with heart rate and the low-to-high frequency power ratio. Associations were strongest with 24-hour mean concentrations, although strong short-term associations also were found during bus periods, independent of daily exposures. Overall, associations were greatest for high-frequency power with the following effects per interquartile change in the 24-hour mean concentrations: -15% (95% confidence interval = -17% to -14%) for PM2.5 (4.6 mug/m); -19% (-21% to -17%) for black carbon (459 ng/m); and -14% (-15% to -12%) for fine particle counts (39 pt/cm). For each interquartile change in the 5-minute PM2.5 concentration (10 mug/m) aboard the bus, an 11% (95% confidence interval = -14% to -8%) decrease in high-frequency power was observed. CONCLUSIONS: : This investigation indicates that fine particles are negatively associated with heart rate variability, with an overall trend towards reduced parasympathetic tone. Although daily associations were evident for all particles, short-term associations were predominantly limited to traffic-related particles.

Current strategies for the prevention of angina in patients with stable coronary artery disease.

PURPOSE OF REVIEW: Angina pectoris affects at least 6.6 million people in the US and approximately 400,000 new cases of stable angina occur each year. Angina may be one of the first signs of ischemic heart disease, although it is likely not causally related to the likelihood of plaque rupture leading to an acute coronary syndrome. Modalities for treatment of angina should be used maximally to improve quality of life and decrease cardiovascular morbidity and mortality. The current recommended pharmacologic and invasive approaches, as well as novel therapies, are reviewed. RECENT FINDINGS: Antiischemic agents, including beta-blockers, nitrates and calcium channel blockers, remain the mainstay in the prevention of angina. Revascularization via percutaneous interventions or coronary bypass surgery are appropriate in specific cases or when medical treatment fails. Noninvasive treatment options for refractory angina, metabolic agents, and vasodilator therapies are adding to the armamentarium to prevent and treat angina. SUMMARY: A multifaceted approach is optimal to address the prevention of angina. Once angina is recognized, there are many modalities that lessen the incidence of daily life-induced and exercise-induced angina and ischemia. Angina management is best addressed by pharmacologic and lifestyle interventions.

A randomized trial to evaluate the relative protection against post-percutaneous coronary intervention microvascular dysfunction, ischemia, and inflammation among antiplatelet and antithrombotic agents: the PROTECT-TIMI-30 trial.

OBJECTIVES: The goal of this study was to evaluate glycoprotein IIb/IIIa inhibition with eptifibatide when administered with indirect thrombin inhibition as compared with monotherapy with direct thrombin inhibition with bivalirudin among patients with non-ST-segment elevation acute coronary syndromes (ACS). BACKGROUND: The optimal combination of antiplatelet and antithrombin regimens that maximizes efficacy and minimizes bleeding among patients with non-ST-segment elevation ACS undergoing percutaneous coronary intervention (PCI) is unclear. METHODS: A total of 857 patients with non-ST-segment elevation ACS were assigned randomly to eptifibatide + reduced dose unfractionated heparin (n = 298), eptifibatide + reduced-dose enoxaparin (n = 275), or bivalirudin monotherapy (n = 284). RESULTS: Among angiographically evaluable patients (n = 754), the primary end point of post-PCI coronary flow reserve was significantly greater with bivalirudin (1.43 vs. 1.33 for pooled eptifibatide arms, p = 0.036). Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade more often was normal with eptifibatide treatment compared with bivalirudin (57.9% vs. 50.9%, p = 0.048). The duration of ischemia on continuous Holter monitoring after PCI was significantly longer among patients treated with bivalirudin (169 vs. 36 min, p = 0.013). There was no excess of TIMI major bleeding among patients treated with eptifibatide compared with bivalirudin (0.7%, n = 4 vs. 0%, p = NS), but TIMI minor bleeding was increased (2.5% vs. 0.4%, p = 0.027) as was transfusion (4.4% to 0.4%, p < 0.001). CONCLUSIONS: Among moderate- to high-risk patients with ACS undergoing PCI, coronary flow reserve was greater with bivalirudin than eptifibatide. Eptifibatide improved myocardial perfusion and reduced the duration of post-PCI ischemia but was associated with higher minor bleeding and transfusion rates. Ischemic events and biomarkers for myonecrosis, inflammation, and thrombin generation did not differ between agents.

The Critical Care Safety Study: The incidence and nature of adverse events and serious medical errors in intensive care.

OBJECTIVE: Critically ill patients require high-intensity care and may be at especially high risk of iatrogenic injury because they are severely ill. We sought to study the incidence and nature of adverse events and serious errors in the critical care setting. DESIGN: We conducted a prospective 1-year observational study. Incidents were collected with use of a multifaceted approach including direct continuous observation. Two physicians independently assessed incident type, severity, and preventability as well as systems-related and individual performance failures. SETTING: Academic, tertiary-care urban hospital. PATIENTS: Medical intensive care unit and coronary care unit patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcomes of interest were the incidence and rates of adverse events and serious errors per 1000 patient-days. A total of 391 patients with 420 unit admissions were studied during 1490 patient-days. We found 120 adverse events in 79 patients (20.2%), including 66 (55%) nonpreventable and 54 (45%) preventable adverse events as well as 223 serious errors. The rates per 1000 patient-days for all adverse events, preventable adverse events, and serious errors were 80.5, 36.2, and 149.7, respectively. Among adverse events, 13% (16/120) were life-threatening or fatal; and among serious errors, 11% (24/223) were potentially life-threatening. Most serious medical errors occurred during the ordering or execution of treatments, especially medications (61%; 170/277). Performance level failures were most commonly slips and lapses (53%; 148/277), rather than rule-based or knowledge-based mistakes. CONCLUSIONS: Adverse events and serious errors involving critically ill patients were common and often potentially life-threatening. Although many types of errors were identified, failure to carry out intended treatment correctly was the leading category.

Effect of intensive lipid lowering, with or without antioxidant vitamins, compared with moderate lipid lowering on myocardial ischemia in patients with stable coronary artery disease: the Vascular Basis for the Treatment of Myocardial Ischemia Study.

BACKGROUND: Lipid lowering with statins prevents adverse cardiac events. Both lipid-lowering and antioxidant therapies may favorably affect vasomotor function and thereby improve ischemia. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled trial, 300 patients with stable coronary disease, a positive exercise treadmill test, 48-hour ambulatory ECG with > or =1 episode of ischemia, and fasting total cholesterol of 180 to 250 mg/dL were assigned to 1-year treatment with intensive atorvastatin to reduce LDL to <80 mg/dL (n=96), intensive atorvastatin to reduce LDL to <80 mg/dL plus antioxidant vitamins C (1000 mg/d) and E (800 mg/d) (n=101), or diet and low-dose lovastatin, if needed, to reduce LDL to <130 mg/dL (n=103; control group). Ischemia end points, including ambulatory ECG monitoring and exercise treadmill testing, and endothelial assessment using brachial artery flow-mediated dilation were obtained at baseline and at 6 and 12 months. Baseline characteristics were similar in all groups. LDL decreased from approximately 153 mg/dL at baseline in the 2 atorvastatin groups to approximately 83 mg/dL at 12 months (each P<0.0001) and from 147 to 120 mg/dL in the control group (P<0.0001). During ambulatory ECG monitoring, mean number of ischemic episodes per 48 hours decreased 31% to 61% in each group (each P<0.001; P=0.15 across groups), without a change in daily heart rate activity. Mean duration of ischemia for 48 hours decreased 26% to 62% in each group (each P<0.001; P=0.06 across groups). Mean exercise duration to 1-mm ST-segment depression significantly increased in each group, but total exercise duration and mean sum of maximum ST depression were unchanged. Angina frequency decreased in each group. There was no incremental effect of supplemental vitamins C and E on any ischemia outcome. Flow-mediated dilation studies indicated no meaningful changes. CONCLUSIONS: Intensive lipid lowering with atorvastatin to an LDL level of 80 mg/dL, with or without antioxidant vitamins, does not provide any further benefits in ambulatory ischemia, exercise time to onset of ischemia, and angina frequency than moderate lipid lowering with diet and low-dose lovastatin to an LDL level of <120 mg/dL.

Effect of reducing interns' work hours on serious medical errors in intensive care units.

BACKGROUND: Although sleep deprivation has been shown to impair neurobehavioral performance, few studies have measured its effects on medical errors. METHODS: We conducted a prospective, randomized study comparing the rates of serious medical errors made by interns while they were working according to a traditional schedule with extended (24 hours or more) work shifts every other shift (an "every third night" call schedule) and while they were working according to an intervention schedule that eliminated extended work shifts and reduced the number of hours worked per week. Incidents were identified by means of a multidisciplinary, four-pronged approach that included direct, continuous observation. Two physicians who were unaware of the interns' schedule assignments independently rated each incident. RESULTS: During a total of 2203 patient-days involving 634 admissions, interns made 35.9 percent more serious medical errors during the traditional schedule than during the intervention schedule (136.0 vs. 100.1 per 1000 patient-days, P<0.001), including 56.6 percent more nonintercepted serious errors (P<0.001). The total rate of serious errors on the critical care units was 22.0 percent higher during the traditional schedule than during the intervention schedule (193.2 vs. 158.4 per 1000 patient-days, P<0.001). Interns made 20.8 percent more serious medication errors during the traditional schedule than during the intervention schedule (99.7 vs. 82.5 per 1000 patient-days, P=0.03). Interns also made 5.6 times as many serious diagnostic errors during the traditional schedule as during the intervention schedule (18.6 vs. 3.3 per 1000 patient-days, P<0.001). CONCLUSIONS: Interns made substantially more serious medical errors when they worked frequent shifts of 24 hours or more than when they worked shorter shifts. Eliminating extended work shifts and reducing the number of hours interns work per week can reduce serious medical errors in the intensive care unit.

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

ST-Segment Elevation Myocardial Infarction.

ST-segment elevation myocardial infarction (MI) is an emergency medical condition. Expediting the steps leading to coronary reperfusion is of critical importance in improving survival after acute MI. After the diagnosis of acute MI is made, patients should be treated with oxygen, aspirin, nitroglycerin, beta-blockers, heparin, and analgesics, barring any contraindications. If an experienced cardiac catheterization laboratory is available within 60 to 90 minutes, then catheter-based reperfusion therapy is recommended; otherwise, thrombolysis should be considered as an alternate therapy. Therapy with a reduced-dose thrombolytic agent and a glycoprotein IIb/IIIa receptor inhibitor appears to be of an added benefit in establishing TIMI (Thrombolysis in Myocardial Infarction) 3 flow, but this approach awaits final approval prior to widespread use. The adjunctive use of glycoprotein IIb/IIIa receptor inhibitors with percutaneous transluminal coronary angioplasty, with or without stenting, appears to be beneficial and is being used more frequently in the acute setting. Coronary angiography should be performed in patients who fail to respond to thrombolytic therapy or who have evidence of recurrent ischemia. This procedure should not be routinely performed in patients who have responded to thrombolytic therapy. Four to 6 days after an acute MI event, assessment of left ventricular function is recommended. Submaximal exercise test (with or without nuclear or echocardiographic imaging) should be considered in patients prior to discharge from the hospital--an exception can be made in patients with one-vessel disease treated successfully with percutaneous transluminal coronary angioplasty. After discharge, a regular exercise test should be obtained 4 to 6 weeks after an uncomplicated acute MI event. Secondary prevention measures such as weight loss, cessation of smoking, aspirin, beta-blockers, lipid-lowering agents, and angiotensin-converting enzyme inhibitors should be considered in all patients, barring contraindications.