Spontaneous Myocardial Infarction Research Articles

Response to Letter Regarding Articles, “Long-Term Cardiovascular Mortality After Procedure-Related or Spontaneous Myocardial Infarction in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome: A Collaborative Analysis of Individual Patient Data From the FRISC II, ICTUS, and RITA-3 Trials (FIR)” and “American College of Cardiology/American Heart Association/European Society of Cardiology/World Heart Federation Universal Definition of Myocardial Infarction Classification System and the Risk

Response to Letter Regarding Articles, “Long-Term Cardiovascular Mortality After Procedure-Related or Spontaneous Myocardial Infarction in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome: A Collaborative Analysis of Individual Patient Data From the FRISC II, ICTUS, and RITA-3 Trials (FIR)” and “American College of Cardiology/American Heart Association/European Society of Cardiology/World Heart Federation Universal Definition of Myocardial Infarction Classification System and the Risk

Circulation Editors' Picks

<i>Circulation</i> Editors' Picks

3-year outcomes of self-expanding Corevalve prosthesis - The Italian Registry.

3-year outcomes of self-expanding Corevalve prosthesis - The Italian Registry.

Troponin elevation in patients with heart failure: on behalf of the third Universal Definition of Myocardial Infarction Global Task Force: Heart Failure Section

Cardiac troponin testing is commonly performed in patients with heart failure (HF). Despite being strongly linked to spontaneous (Type I) acute myocardial infarction (MI)--a common cause of acute HF syndromes--it is well recognized that concentrations of circulating troponins above the 99 th percentile of a normal population in the context of both acute and chronic HF are highly prevalent, and frequently unrelated to Type I MI. Other mechanism(s) leading to troponin elevation in HF syndromes remain elusive in many cases but prominently includes supply-demand inequity (Type II MI), which may be associated with coronary artery obstruction and endothelial dysfunction, or may occur in the absence of coronary obstruction due to increased oxygen demand related to increased wall tension, anaemia, or other factors provoking subendocardial injury. Non-coronary triggers, such as cellular necrosis, apoptosis, or autophagy in the context of wall stress may explain the troponin release in HF, as can toxic effects of circulating neurohormones, toxins, inflammation, and infiltrative processes, among others. Nonetheless, across a wide spectrum of HF syndromes, when troponin elevation occurs, independent of mechanism, it is strongly predictive of an adverse outcome. Clinicians should be aware of the high frequency of troponin elevation when measuring the marker in patients with HF, should keep in mind the possible causes of this phenomenon, and, independent of a diagnosis of 'acute MI', should recognize the considerable ramifications of troponin elevation in this setting.

Long-term Cardiovascular Mortality after Procedure-related or Spontaneous Myocardial Infarction in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome: A Collaborative Analysis of Individual Patient Data from the FRISC II, ICTUS, and RITA-3 Trials (FIR): Damman P, Wallentin L, Fox K, et al. Circulation 2012;125:568–76.

Long-term Cardiovascular Mortality after Procedure-related or Spontaneous Myocardial Infarction in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome: A Collaborative Analysis of Individual Patient Data from the FRISC II, ICTUS, and RITA-3 Trials (FIR): Damman P, Wallentin L, Fox K, et al. Circulation 2012;125:568–76.

Abstract 341: Akt1 Deletion Promotes Survival in a Model of Spontaneous Myocardial Infarction and Atherosclerosis

The role of Akt1 kinase in cardiac dysfunction and atherosclerosis is hotly contested. Many models use transient Akt1 activation or deletion to study its function in cardiac diseases. The effects of Akt1 knockout were tested in mouse models dependent on short-term Western diets to induce atherosclerotic lesions; however, in these models, the complete cascade ending in infarction does not occur. In contrast, the ApoE -/- /SR-BI -/- double knockout (DKO) mouse represents a model of spontaneous myocardial infarction resulting from severe dyslipidemia and atherosclerosis leading to death between 5-7 weeks of age. In DKO mice and humans, dyslipidemia and inflamed arterial occlusions lead to plaque rupture and myocardial infarction. Importantly, Akt1 activation is dramatically elevated in the myocardium and endothelium of DKO vs. WT mice. To assess the role of chronic Akt1 activation in atherosclerosis, we generated ApoE -/- /SR-BI -/- /Akt1 -/- triple knockout (TKO) mice. We found that TKO mice exhibited decreased cardiac dysfunction and hypertrophy resulting in longer lifespan vs. DKO. In addition, TKO mice have diminished endothelial VCAM expression, decreased atherosclerotic lesions in vivo , and reduced foam cell formation in vitro . ROS production, which is regulated by Akt1 signaling and contributes to atherosclerosis during dyslipidemia, was reduced in TKO hearts, plasma, endothelial cells, and macrophages. This led to reduced proatherogenic lipid oxidation product accumulation in TKO vs. DKO. Moreover, Akt1 deletion in TKO mice decreased levels of CD36, the main oxidized lipid receptor, in hearts, on endothelial cells, and on macrophages. Thus, during dyslipidemia, chronic Akt1 activation results in elevated oxidative stress, generation of proatherogenic lipid oxidation products, and expression of CD36 (a known atherothrombotic regulator) resulting in enhanced atherosclerosis and spontaneous myocardial infarction. Inhibition of Akt1 by genetic deletion results in partial rescue of mice leading to decreased atherosclerosis, improved cardiac function, and elongated lifespan. Continued study of chronic Akt1 activation and its effects on atherosclerosis will enable the development of additional targets for heart disease therapeutics.

Abstract 337: Extensive Coronary Artery Atherosclerosis and Myocardial Infarction in SR-BI/LDLR Double Knockout Mice Fed 4 Different Atherogenic Diets

Mice lacking the HDL receptor, SR-BI, are susceptible to spontaneous or diet-inducible occlusive coronary artery (CA) atherosclerosis and myocardial infarction (MI) in the context of an absence, or mutated form of apoE, respectively. We tested the effects of SR-BI deficiency on aortic sinus and CA atherosclerosis in LDL receptor deficient mice fed four different atherogenic diets; the HFCC and HFC diets are composed of 15% fat, 1.25% cholesterol and either contain or lack 0.5% sodium cholate, respectively, the HC diet is a normal chow diet supplemented with 2% cholesterol, and the western diet contains 21% butter fat and 0.15% cholesterol. SR-BI/LDLR double knockout (dKO) mice fed the HFCC and HFC diets exhibited reduced survival; average survival was 3.5 and 9.5 weeks, respectively. Reduced survival was not observed in LDLR single knockout (sKO) control mice. Plasma lipoprotein cholesterol levels and triglyercide secretion rates were lower in dKO mice compared to sKO mice. Conversely, dKO mice developed significantly larger atherosclerotic plaques in their aortic sinuses compared to sKO mice, and severe occlusive CA atherosclerosis which was not observed in sKO mice. DKO mice fed the HC diet or western diet did not exhibit reduced survival up to 12 weeks of feeding, however CA atherosclerosis was still observed. CA atherosclerosis was accompanied by platelet positive staining and myocardial fibrosis, indicating MI. CA plaques in dKO mice were characterized by the presence of collagen and both CD68 and smooth muscle actin positive staining, indicating complex fibrous plaques consisting of both macrophages and smooth muscle cells. Plaque free CAs and CAs containing small, non-occlusive plaques stained positive for markers of activated endothelium. Importantly, dKO mice fed the HC diet had largest burden of atherosclerosis in their aortic sinuses whereas the extent of atherosclerosis in their CAs was the mild in comparison to that observed dKO mice fed the HFCC and HFC diets. This observation suggests that the development of atherosclerosis in the CAs and the aortic sinus are influenced by different factors.

Impact of intravascular ultrasound guidance in routine percutaneous coronary intervention for conventional lesions: data from the EXCELLENT trial

BackgroundIntravascular ultrasound (IVUS) offers tomographic images of coronary artery, helping physicians refine percutaneous coronary intervention (PCI) procedures. However, it is still controversial whether routine use of IVUS in conventional lesions leads to improvement in clinical outcomes after PCI. MethodsFrom the EXCELLENT trial, patients were grouped into IVUS-guided versus IVUS-non-guided PCI (619 and 802 patients, respectively). The crude patients as well as the propensity score matched pairs were compared with regard to clinical outcomes. ResultsBaseline characteristics showed younger age and lower incidence of comorbidities in the IVUS group. IVUS-guided PCI was associated with more aggressive treatment such as longer stenting length, larger stent diameter, and greater number of stents implanted. In the total population, IVUS guidance was associated with a significantly higher risk of periprocedural MI with no significant differences in other outcomes. In the matched cohort (463 matched pairs, 926 patients), IVUS guidance was associated with significantly increased risk of target lesion failure (4.3% vs. 2.4%; p=0.047 by conditional logistic regression) and major adverse cardiovascular events at 1year almost exclusively due to increased risk of periprocedural myocardial infarction (MI) (1.6% vs. 0.2%; p=0.050), while the rates of cardiac death, spontaneous MI, and target lesion revascularization did not differ significantly between the two groups. ConclusionsThe adjunctive use of IVUS during PCI was associated with more stents implanted, longer stenting, and bigger stenting. There were no significant advantages of IVUS guidance, but rather a significant increase in periprocedural enzyme elevation, reflecting more aggressive procedures performed with IVUS guidance.

The Prequel

Troponins are recommended as the biomarkers of choice for the detection of myocardial infarction (MI) by the Universal Definition.1 This is well accepted for the diagnosis of type 1 or spontaneous MI, in which any elevation in the setting of ischemia is required but not for the diagnosis of type 4a or MI associated with percutaneous coronary intervention (PCI), in which an isolated 3× the upper reference limit elevation is required. Creatine kinase MB (CKMB) is widely favored because a number of studies support a relationship between CKMB elevation after PCI and long-term mortality with the cut-point appearing to be about 8 to 10× elevation of CKMB.2–5 Article see p 150 Troponins are much more sensitive than CKMB in detecting small areas of myocyte necrosis, but small amounts of myocyte necrosis may not be related to increased mortality6,7 In a meta-analysis of 4 studies with 2359 patients undergoing PCI, increases in troponin of >3 times upper reference limit were found in 14.5% and were associated at 18-month follow-up with increased events (death, MI, repeat target vessel PCI, and coronary artery bypass grafting) (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.26–4.00).8 However, none of the studies used a 99th percentile cutoff with a sensitive troponin assay to define a normal baseline. The situation is complex because PCI may reduce the risk of death in high-risk patients, and the risk of a small amount of myocardial injury related to PCI may be balanced by the success of the PCI. On the other hand, PCI in a low-risk patient, if associated with myocardial injury, may be associated with an adverse prognosis. Furthermore, increased biomarker release may be a trade-off for optimal stent implantation and related to the amount of underlying atherosclerosis. The prognostic …

Long-Term Cardiovascular Mortality After Procedure-Related or Spontaneous Myocardial Infarction in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome

Background— The present study was designed to investigate the long-term prognostic impact of procedure-related and spontaneous myocardial infarction (MI) on cardiovascular mortality in patients with non–ST-elevation acute coronary syndrome. Methods and Results— Five-year follow-up after procedure-related or spontaneous MI was investigated in the individual patient pooled data set of the FRISC-II (Fast Revascularization During Instability in Coronary Artery Disease), ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes), and RITA-3 (Randomized Intervention Trial of Unstable Angina 3) non–ST-elevation acute coronary syndrome trials. The principal outcome was cardiovascular death up to 5 years of follow-up. Cumulative event rates were estimated by the Kaplan-Meier method; hazard ratios were calculated with time-dependent Cox proportional hazards models. Adjustments were made for the variables associated with long-term outcomes. Among the 5467 patients, 212 experienced a procedure-related MI within 6 months after enrollment. A spontaneous MI occurred in 236 patients within 6 months. The cumulative cardiovascular death rate was 5.2% in patients who had a procedure-related MI, comparable to that for patients without a procedure-related MI (hazard ratio 0.66; 95% confidence interval, 0.36–1.20, P =0.17). In patients who had a spontaneous MI within 6 months, the cumulative cardiovascular death rate was 22.2%, higher than for patients without a spontaneous MI (hazard ratio 4.52; 95% confidence interval, 3.37–6.06, P &lt;0.001). These hazard ratios did not change materially after risk adjustments. Conclusions— Five-year follow-up of patients with non–ST-elevation acute coronary syndrome from the 3 trials showed no association between a procedure-related MI and long-term cardiovascular mortality. In contrast, there was a substantial increase in long-term mortality after a spontaneous MI. Clinical Trial Registration— URL: http://www.controlled-trials.com/ISRCTN82153174 (ICTUS); http://www.controlled-trials.com/ISRCTN07752711 (RITA-3).

Comparison of Outcomes in Patients Having Isolated Transcatheter Aortic Valve Implantation Versus Combined With Preprocedural Percutaneous Coronary Intervention

Coronary artery disease negatively affects the outcome of patients undergoing surgical aortic valve replacement and practice guidelines recommend revascularization at time of surgery. In patients undergoing transcatheter aortic valve implantation (TAVI), the impact of preprocedural percutaneous coronary intervention (PCI) on TAVI outcome has not been examined. We aimed in the present study to assess the feasibility and safety of performing PCI before TAVI and to evaluate procedural, 30-day, and 6-month clinical outcomes. We retrospectively analyzed 125 patients who underwent successful TAVI at a single institution and divided them into an isolated TAVI and a PCI + TAVI group. During the study period, a strategy of preprocedural PCI of all significant (>50%) lesions in major epicardial vessels was adopted. Study end points were adjudicated in accordance with the Valve Academic Research Consortium consensus on event definition. All patients were treated with the Medtronic CoreValve prosthesis (n = 55 with PCI + TAVI and n = 70 with isolated TAVI). Thirty-day mortality was 2% versus 6% for patients treated with PCI + TAVI versus isolated TAVI, respectively (p = 0.27). Neither periprocedural nor spontaneous myocardial infarction occurred in either group. Rates of 30-day stroke, major bleeding, major vascular complications, and the Valve Academic Research Consortium-defined combined safety end point (11% vs 13%, p = 0.74) did not differ between the 2 groups. Patients' symptoms significantly improved in the first month after TAVI, and extent of improvement did not differ between groups. Adverse events at 6 months were comparable. In conclusion, PCI before TAVI appears feasible and safe. Based on these early results revascularization should become an important consideration in patients with coronary artery disease undergoing TAVI.

Clinical Outcomes of High On-Treatment Platelet Reactivity in Koreans Receiving Elective Percutaneous Coronary Intervention (from Results of the CROSS VERIFY Study)

Platelet reactivity after clopidogrel therapy varies among patients. Whether clopidogrel response variability can predict clinical outcomes has not been verified in Asians. A prospective cohort was analyzed to evaluate clinical impact of clopidogrel response variability in patients who underwent elective percutaneous coronary intervention (PCI). A total of 809 consecutive patients receiving clopidogrel after elective PCI were followed for 1 year. On-treatment platelet reactivity (OPR) after clopidogrel therapy was measured with a point-of-care test, the VerifyNow P2Y12 assay. The primary end point was the composite of cardiac death and nonfatal myocardial infarction (MI) at 1 year. In this exclusively Korean cohort, the median OPR was 236 P2Y12 reactivity units. Using the definition of OPR ≥235 P2Y12 reactivity units as high OPR (HOPR), 50.3% of the cohort showed HOPR. The group with HOPR had significantly higher rates of cardiac death and spontaneous MI (2.5% vs 0.5%, p = 0.022) than the group without HOPR. Multivariate-adjusted analysis showed that HOPR was an independent predictor of the composite of cardiac death and nonfatal MI. The difference in major adverse cardiac events between the groups with and without HOPR was more profound in those without major cardiovascular disease, such as hypertension, diabetes mellitus, or dyslipidemia. In conclusion, HOPR to clopidogrel was significantly associated with cardiac death and spontaneous MI after elective PCI, suggesting that clopidogrel response variability may be a significant risk factor of hard end points in Koreans.

Relationship between clopidogrel-induced platelet P2Y12 inhibition and stent thrombosis or myocardial infarction after percutaneous coronary intervention—A case-control study

Insufficient platelet inhibition is a major determinant of stent thrombosis (STh), although the etiology is multifactorial. On-clopidogrel platelet reactivity was investigated in patients with previous angiographically confirmed STh, myocardial infarction (MI), and controls. Using the Swedish Coronary Angiography and Angioplasty Registry, we identified patients with angiographically confirmed STh (n = 48) or MI (n = 30) while on dual antiplatelet therapy within 6 months of percutaneous coronary intervention (PCI) and matched control patients (n = 78). On-clopidogrel platelet reactivity was measured with VerifyNow P2Y12 and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay. The mean P2Y12 reaction units (PRU) was higher (246.8 ± 75.9 vs 200.0 ± 82.7, P = .001) in STh patients compared with controls. The optimal cutoff for STh was 222 PRU or higher (area under the curve 0.69, P < .0001) in a receiver operating characteristics (ROC) analysis. The cutoff level resulted in 70.2% sensitivity and 67.3% specificity. There was no significant difference in mean PRU but a higher device-reported percent inhibition (45.1 ± 23.8 vs 32.1 ± 23.2, P = .04) in patients with MI compared with controls. Results with the VASP phosphorylation assay were not related to the occurrence of STh or MI. STh was associated with high on-clopidogrel platelet reactivity measured with VerifyNow (cutoff level of PRU ≥222) but spontaneous MI in stented patients on clopidogrel treatment was not. There was, however, a substantial overlap in on-clopidogrel platelet reactivity between patients with and without on-treatment STh questioning the clinical use of platelet function testing to identify patients at high risk for STh.

A pipeline that integrates the discovery and verification of plasma protein biomarkers reveals candidate markers for cardiovascular disease

We developed a pipeline to integrate the proteomic technologies used from the discovery to the verification stages of plasma biomarker identification and applied it to identify early biomarkers of cardiac injury from the blood of patients undergoing a therapeutic, planned myocardial infarction (PMI) for treatment of hypertrophic cardiomyopathy. Sampling of blood directly from patient hearts before, during and after controlled myocardial injury ensured enrichment for candidate biomarkers and allowed patients to serve as their own biological controls. LC-MS/MS analyses detected 121 highly differentially expressed proteins, including previously credentialed markers of cardiovascular disease and >100 novel candidate biomarkers for myocardial infarction (MI). Accurate inclusion mass screening (AIMS) qualified a subset of the candidates based on highly specific, targeted detection in peripheral plasma, including some markers unlikely to have been identified without this step. Analyses of peripheral plasma from controls and patients with PMI or spontaneous MI by quantitative multiple reaction monitoring mass spectrometry or immunoassays suggest that the candidate biomarkers may be specific to MI. This study demonstrates that modern proteomic technologies, when coherently integrated, can yield novel cardiovascular biomarkers meriting further evaluation in large, heterogeneous cohorts.

Spontaneous left side pneumothorax and myocardial infarction: rare but potentially lethal coexistence that can frustrate clinicians

Spontaneous pneumothorax is a common surgical disease that is a surgical emergency. It can be divided into primary (caused by microscopic blebs <1 cm in diameter) and secondary (asthmatic, catamenial, neonatal, caused by emphysematic bullae or chronic respiratory obstruction) varieties. This surgical entity has been closely associated to a variety of electrocardiographic (ECG) changes, which are pathophysiologically explained by spatial changes in the anatomical structure of the mediastinum caused by increased hemithoracic pressure. Several reports on ECG variations due to pneumothorax that masquerades as myocardial ischemia have been previously recorded. However, when the underlying disease involves two pathological entities, in this case pneumothorax and myocardial infarction, time limits can be pressing. Herein, we describe an interesting case of a patient who presented with left secondary spontaneous pneumothorax associated with acute myocardial infarction. It is an intriguing and rarely encountered case in which the patient's anamnesis can easily mislead the clinician and valuable time can be wasted.

Periprocedural Myocardial Infarction

Revascularization procedures (percutaneous coronary intervention [PCI] and coronary bypass graft surgery [CABG]) are performed in more than 1.7 million patients with ischemic heart disease in the United States; more than 2.2 million PCIs alone are performed worldwide on an annual basis.1 With technological advances in coronary intervention over the past 3 decades, procedural complications and long-term outcomes have significantly improved, yet periprocedural myocardial infarction (MI) remains common. We review the current state of knowledge of the incidence, risk factors, prognosis, and prevention of periprocedural MI after revascularization procedures, including PCI and CABG. The definition of MI after revascularization procedures has evolved with better understanding of the etiology and prognostic significance of these events. Historically, the World Health Organization definition of MI required 2 of 3 criteria, including clinical symptoms, ECG abnormality, and creatine kinase (CK) elevation (≥2× the upper limit of normal [ULN]). The World Health Organization biomarker threshold was then adopted to define periprocedural MI, irrespective of clinical syndrome or ECG findings.2 With increasingly sensitive serological biomarkers and imaging techniques, minute amounts of myocardial necrosis have become detectable. Although any level of periprocedural myonecrosis may be termed periprocedural MI, the prognostic implications are highly variable, depending on the biomarker thresholds applied and clinical circumstances.3 As such, it is essential to understand the relationship between periprocedural MI, causality, and prognosis. Varying diagnostic criteria including the type, extent, and timing of biomarker release, symptoms, ECG, and imaging criteria have been proposed in the Universal Definition of Myocardial Infarctions, which has been endorsed by most academic societies and regulatory bodies ( Table 1).4 PCI-related MI (type 4) is distinguished from spontaneous MI (type 1), secondary MI (type 2), and those associated with sudden death (type 3) or CABG (type 5) ( Table 1). After PCI among patients …

A new data mining approach for profiling and categorizing kinetic patterns of metabolic biomarkers after myocardial injury

The discovery of new and unexpected biomarkers in cardiovascular disease is a highly data-driven process that requires the complementary power of modern metabolite profiling technologies, bioinformatics and biostatistics. Clinical biomarkers of early myocardial injury are lacking. A prospective biomarker cohort study was carried out to identify, categorize and profile kinetic patterns of early metabolic biomarkers of planned myocardial infarction (PMI) and spontaneous (SMI) myocardial infarction. We applied a targeted mass spectrometry (MS)-based metabolite profiling platform to serial blood samples drawn from carefully phenotyped patients undergoing alcohol septal ablation for hypertrophic obstructive cardiomyopathy serving as a human model of PMI. Patients with SMI and patients undergoing catheterization without induction of myocardial infarction served as positive and negative controls to assess generalizability of markers identified in PMI. To identify metabolites of high predictive value in tandem mass spectrometry data, we introduced a new feature selection method for the categorization of metabolic signatures into three classes of weak, moderate and strong predictors, which can be easily applied to both paired and unpaired samples. Our paradigm outperformed standard null-hypothesis significance testing and other popular methods for feature selection in terms of the area under the receiver operating curve and the product of sensitivity and specificity. Our results emphasize that this new method was able to identify, classify and validate alterations of levels in multiple metabolites participating in pathways associated with myocardial injury as early as 10 min after PMI. The algorithm as well as supplementary material is available for download at: www.umit.at/page.cfm?vpath=departments/technik/iebe/tools/bi

NO Way to Relax

The roles of nitric oxide (NO) in the heart have been studied intensely ever since the first report nearly 2 decades ago showing that endogenous NO modulates cardiac myocyte function.1 All 3 NO synthase (NOS) isoforms have been found in mammalian heart tissues (see reviews in Massion et al2 and Belge et al3). A complex array of myocyte and nonmyocyte cells in the heart express NOS isoforms, and the local generation of NO2,3 and reactive oxygen species (ROS)4 may exert both autocrine and paracrine effects on cellular function. Not only is the endothelial isoform of NOS (eNOS, or NOS3) robustly expressed in the endothelial cells of the cardiac vasculature, but eNOS is also present within cardiac myocytes, where the enzyme associates with the scaffolding/regulatory protein caveolin-3 in T tubules in plasmalemmal caveolae.5 The neuronal NOS (nNOS, or NOS1) is also expressed in cardiac myocytes, where the enzyme appears to be localized in the sarcoplasmic reticulum and modulates phospholamban phosphorylation.6 Although both eNOS and nNOS appear to be physiologically expressed in cardiac tissues, the inflammation-related NOS isoform (iNOS, or NOS2) only appears in the heart after immunoactivation; iNOS may modulate the decline in myocardial function seen in sepsis.7 There have been innumerable studies of the cardiac effects of various NOS inhibitors, NO-donating drugs, and NO itself.2 The cardiac phenotypes of NOS “knockout” mouse models have been characterized extensively, and mice lacking 1, 2, or all 3 NOS isoforms have been generated and characterized.8 In addition, the roles of NOS substrates, cofactors, and allosteric modulators have been explored exhaustively in diverse cardiac model systems. Emerging from this broad range of experimental evidence is an increasingly clear view that NO and NOS are key determinants of cardiac function. Yet the molecular mechanisms and …

5-Year Clinical Outcomes in the ICTUS (Invasive versus Conservative Treatment in Unstable coronary Syndromes) Trial: A Randomized Comparison of an Early Invasive Versus Selective Invasive Management in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome

We present the 5-year clinical outcomes according to treatment strategy with additional risk stratification of the ICTUS (Invasive versus Conservative Treatment in Unstable coronary Syndromes) trial. Long-term outcomes may be relevant to decide treatment strategy for patients presenting with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and elevated troponin T. We randomly assigned 1,200 patients to an early invasive or selective invasive strategy. The outcomes were the composite of death or myocardial infarction (MI) and its individual components. Risk stratification was performed with the FRISC (Fast Revascularization in InStability in Coronary artery disease) risk score. At 5-year follow-up, revascularization rates were 81% in the early invasive and 60% in the selective invasive group. Cumulative death or MI rates were 22.3% and 18.1%, respectively (hazard ratio [HR]: 1.29, 95% confidence interval [CI]: 1.00 to 1.66, p = 0.053). No difference was observed in mortality (HR: 1.13, 95% CI: 0.80 to 1.60, p = 0.49) or MI (HR: 1.24, 95% CI: 0.90 to 1.70, p = 0.20). After risk stratification, no benefit of an early invasive strategy was observed in reducing death or spontaneous MI in any of the risk groups. In patients presenting with NSTE-ACS and elevated troponin T, we could not demonstrate a long-term benefit of an early invasive strategy in reducing death or MI. (Invasive versus Conservative Treatment in Unstable coronary Syndromes [ICTUS]; ISRCTN82153174).

Low lymphocyte count in acute phase of ST-segment elevation myocardial infarction predicts long-term recurrent myocardial infarction

We sought to determine the relationship between the lowest lymphocyte count (lymphocyte(min))obtained within the first 96 h of symptoms onset and the risk of postdischarge recurrent spontaneous myocardial infarction (re-MI) in patients admitted with ST-segment elevation MI (STEMI). We analyzed 549 consecutive patients admitted with STEMI from a single academic hospital. Lymphocyte counts were determined at admission and routinely during the first 96 h. Lymphocyte(min) was selected as the main exposure. Patients with inflammatory or infectious diseases, in-hospital death, or reinfarction were excluded from the analysis (final sample= 426 patients). Lymphocyte(min) was divided into quartiles (Q) and their association with re-MI was assessed by competing risk analysis. Postdischarge death and coronary revascularization were considered competing events. During a median follow-up of 36 months, 53 re-MI (12.4%) were registered. The re-MI crude rate was significantly higher in patients in the lowest lymphocyte(min) quartile (Q1r1045 cells/ml) compared with Q2-Q4: 22.4, 9.4, 8.4, 9.4%, respectively; P =0.005. In a multivariate setting, Q1 was also associated with a significant increased risk of re-MI compared with Q2-Q4 (hazard ratio: 2.04, 95% confidence interval: 1.11-3.76; P = 0.021). Low lymphocyte count obtained within the first 96 h of a STEMI predicts the risk of re-MI.