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Importance: Cardiac magnetic resonance (CMR) imaging can identify unrecognized myocardial infarction (UMI) in the general population. Unrecognized myocardial infarction by CMR portends poor prognosis in the short term but, to our knowledge, long-term outcomes are not known., Objective: To determine the long-term outcomes of UMI by CMR compared with clinically recognized myocardial infarction (RMI) and no myocardial infarction (MI)., Design, Setting, and Participants: Participants of the population-based, prospectively enrolled ICELAND MI cohort study (aged 67-93 years) were characterized with CMR at baseline (from January 2004-January 2007) and followed up for up to 13.3 years. Kaplan-Meier time-to-event analyses and a Cox regression were used to assess the association of UMI at baseline with death and future cardiovascular events., Main Outcomes and Measures: The primary outcome was all-cause mortality. Secondary outcomes were a composite of major adverse cardiac events (MACE: death, nonfatal MI, and heart failure)., Results: Of 935 participants, 452 (48.3%) were men; the mean (SD) age of participants with no MI, UMI, and RMI was 75.6 (5.3) years, 76.8 (5.2) years, and 76.8 (4.7) years, respectively. At 3 years, UMI and no MI mortality rates were similar (3%) and lower than RMI rates (9%). At 5 years, UMI mortality rates (13%) increased and were higher than no MI rates (8%) but still lower than RMI rates (19%). By 10 years, UMI and RMI mortality rates (49% and 51%, respectively) were not statistically different; both were significantly higher than no MI (30%) (P < .001). After adjusting for age, sex, and diabetes, UMI by CMR had an increased risk of death (hazard ratio [HR], 1.61; 95% CI, 1.27-2.04), MACE (HR, 1.56; 95% CI, 1.26-1.93), MI (HR, 2.09; 95% CI, 1.45-3.03), and heart failure (HR, 1.52; 95% CI, 1.09-2.14) compared with no MI and statistically nondifferent risk of death (HR, 0.99; 95% CI, 0.71-1.38) and MACE (HR, 1.23; 95% CI, 0.91-1.66) vs RMI., Conclusions and Relevance: In this study, all-cause mortality of UMI was higher than no MI, but within 10 years from baseline evaluation was equivalent with RMI. Unrecognized MI was also associated with an elevated risk of nonfatal MI and heart failure. Whether secondary prevention can alter the prognosis of UMI will require prospective testing.

Context: Unrecognized myocardial infarction (MI) is prognostically important. Electrocardiography (ECG) has limited sensitivity for detecting unrecognized MI (UMI)., Objective: Determine prevalence and mortality risk for UMI detected by cardiac magnetic resonance (CMR) imaging or ECG among older individuals., Design, Setting, and Participants: ICELAND MI is a cohort substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study (enrollment January 2004-January 2007) using ECG or CMR to detect UMI. From a community-dwelling cohort of older individuals in Iceland, data for 936 participants aged 67 to 93 years were analyzed, including 670 who were randomly selected and 266 with diabetes., Main Outcome Measures: Prevalence and mortality of MI through September 1, 2011. Results reported with 95% confidence limits and net reclassification improvement (NRI)., Results: Of 936 participants, 91 had recognized MI (RMI) (9.7%; 95% CI, 8% to 12%), and 157 had UMI detected by CMR (17%; 95% CI, 14% to 19%), which was more prevalent than the 46 UMI detected by ECG (5%; 95% CI, 4% to 6%; P < .001). Participants with diabetes (n = 337) had more UMI detected by CMR than by ECG (n = 72; 21%; 95% CI, 17% to 26%, vs n = 15; 4%; 95% CI, 2% to 7%; P < .001). Unrecognized MI by CMR was associated with atherosclerosis risk factors, coronary calcium, coronary revascularization, and peripheral vascular disease. Over a median of 6.4 years, 30 of 91 participants (33%; 95% CI, 23% to 43%) with RMI died, and 44 of 157 participants (28%; 95% CI, 21% to 35%) with UMI died, both higher rates than the 119 of 688 participants (17%; 95% CI, 15% to 20%) with no MI who died. Unrecognized MI by CMR improved risk stratification for mortality over RMI (NRI, 0.34; 95% CI, 0.16 to 0.53). Adjusting for age, sex, diabetes, and RMI, UMI by CMR remained associated with mortality (hazard ratio [HR], 1.45; 95% CI, 1.02 to 2.06, absolute risk increase [ARI], 8%) and significantly improved risk stratification for mortality (NRI, 0.16; 95% CI, 0.01 to 0.31), but UMI by ECG did not (HR, 0.88; 95% CI, 0.45 to 1.73; ARI, -2%; NRI, -0.05; 95% CI, -0.17 to 0.05). Compared with those with RMI, participants with UMI by CMR used cardiac medications such as statins less often (36%; 95% CI, 28% to 43%, or 56/157, vs 73%; 95% CI, 63% to 82%, or 66/91; P < .001)., Conclusions: In a community-based cohort of older individuals, the prevalence of UMI by CMR was higher than the prevalence of RMI and was associated with increased mortality risk. In contrast, UMI by ECG prevalence was lower than that of RMI and was not associated with increased mortality risk., Trial Registration: clinicaltrials.gov Identifier: NCT01322568.

Aortic stiffness increases with age and may contribute to adverse remodeling after myocardial infarction (MI). The authors examined whether vascular stiffness affects left ventricular (LV) size after MI using contrast-enhanced cardiac magnetic resonance imaging. Despite similar infarct sizes, patients aged 60 years or older (n=30) had a lower ejection fraction (42+/-15 vs 53+/-11%, P<.01) and greater end-systolic volume index (75+/-47 vs 44+/-18 mL/m(2), P<.01) than younger patients (n=19). As infarct size increased, LV end-systolic volumes (P<.0001) and ejection fraction (P<.0001) in the older participants were progressively greater. Participants with greater aortic stiffness had greater end-systolic volume indices (P<.0001) and lower ejection fraction (P<.0001) with increasing infarct size. Using multivariate analysis, MI size (P<.001) and aortic distensibility (P=.02) were significant predictors of end-systolic volume index. Older patients have increased LV size after MI compared with younger patients, possibly related to age-related decreases in aortic distensibility affecting LV remodeling.

Objectives: This study was designed to determine the diagnostic value of adenosine cardiac magnetic resonance (CMR) in troponin-negative patients with chest pain., Background: We hypothesized that adenosine CMR could determine which troponin-negative patients with chest pain in an emergency department have coronary artery disease (CAD) or future adverse cardiac events., Methods: Adenosine stress CMR was performed on 135 patients who presented to the emergency department with chest pain and had acute myocardial infarction (MI) excluded by troponin-I. The main study outcome was detecting any evidence of significant CAD. Patients were contacted at one year to determine the incidence of significant CAD defined as coronary artery stenosis >50% on angiography, abnormal correlative stress test, new MI, or death., Results: Adenosine perfusion abnormalities had 100% sensitivity and 93% specificity as the single most accurate component of the CMR examination. Both cardiac risk factors and CMR were significant in Kaplan-Meier analysis (log-rank test, p = 0.0006 and p < 0.0001, respectively). However, an abnormal CMR added significant prognostic value in predicting future diagnosis of CAD, MI, or death over clinical risk factors. In receiver operator curve analysis, adenosine CMR was a more accurate predictor than cardiac risk factors (p < 0.002)., Conclusions: In patients with chest pain who had MI excluded by troponin-I and non-diagnostic electrocardiograms, an adenosine CMR examination predicted with high sensitivity and specificity which patients had significant CAD during one-year follow-up. Furthermore, no patients with a normal adenosine CMR study had a subsequent diagnosis of CAD or an adverse outcome.

Background: Unfractionated heparin is widely used in patients with non-ST-elevation acute coronary syndromes but has important limitations. Anticoagulants with predictable kinetics and anticoagulant effects, better efficacy, and greater safety are needed., Objective: To investigate the efficacy and safety of a direct, selective factor Xa inhibitor, DX-9065a (Daiichi Pharmaceuticals LTD, Inc.) compared with heparin, in patients with non-ST-elevation acute coronary syndromes., Patients and Methods: Patients (n = 402) from the USA, Canada, and Japan were randomized to blinded, weight-adjusted heparin, low-dose DX-9065a, or high-dose DX-9065a., Results: The primary efficacy endpoint of death, myocardial infarction, urgent revascularization, or ischemia on continuous ST-segment monitoring occurred in 33.6%, 34.3%, and 31.3% of patients assigned to heparin, low-dose DX-9065a, and high-dose DX-9065a (P = 0.91 for heparin vs. combined DX-9065a). The composite of death, myocardial infarction, or urgent revascularization occurred in 19.5%, 19.3%, and 11.9% (P = 0.125 for heparin vs. high-dose DX-9065a) of patients; major or minor bleeding occurred in 7.7%, 4.2%, and 7.0% of patients; and major bleeding in 3.3%, 0.8%, and 0.9% of patients. Higher concentrations of DX-9065a were associated with a lower likelihood of ischemic events (P = 0.03) and a non-significant tendency toward a higher likelihood of major bleeding (P = 0.32)., Conclusions: In this small phase II trial, there was a non-significant tendency toward a reduction in ischemic events and bleeding with DX-9065a compared with heparin in patients with acute coronary syndromes. The absence of an effect on ST-monitor ischemia warrants further investigation. These data provide the rationale for adequately powered studies of DX-9065a in acute coronary syndromes or percutaneous intervention.

The development of anticoagulants for treating patients with atherothrombotic disorders of the arterial circulatory system has focused, either directly or indirectly, on thrombin - a pleuripotential effector enzyme with prothrombotic and proinflammatory properties. The pivotal role of factor (f) Xa in thrombin generation, coupled with its direct cellular effects and widely recognized limitations of currently available anticoagulants, has led to the development of pharmacologic inhibitors of this important protease. The following review focuses on DX-9065a - first in a class of direct, selective and reversible fXa antagonists - and its potential applications in the management of patients with cardiovascular disease.

Regions of the body with long T1, such as cerebrospinal fluid (CSF), may create ghost artifacts on gadolinium-hyperenhanced images of myocardial infarction when inversion recovery (IR) sequences are used with a segmented acquisition. Oscillations in the transient approach to steady state for regions with long T1 may cause ghosts, with the number of ghosts being equal to the number of segments. B1-weighted phased-array combining provides an inherent degree of ghost artifact suppression because the ghost artifact is weighted less than the desired signal intensity by the coil sensitivity profiles. Example images are shown that illustrate the suppression of CSF ghost artifacts by the use of B1-weighted phased-array combining of multiple receiver coils.

Background: Direct factor (F)Xa inhibition is an attractive method to limit thrombotic complications during percutaneous coronary intervention (PCI)., Objectives: To investigate drug levels achieved, effect on coagulation markers, and preliminary efficacy and safety of several doses of DX-9065a, an intravenous, small molecule, direct, reversible FXa inhibitor during PCI., Patients and Methods: Patients undergoing elective, native-vessel PCI (n = 175) were randomized 4 : 1 to open-label DX-9065a or heparin in one of four sequential stages. DX-9065a regimens in stages I-III were designed to achieve concentrations of > 100 ng mL-1, > 75 ng mL-1, and > 150 ng mL-1. Stage IV used the stage III regimen but included patients recently given heparin., Results: At 15 min median (minimum) DX-9065a plasma levels were 192 (176), 122 (117), 334 (221), and 429 (231) ng mL-1 in stages I-IV, respectively. Median whole-blood international normalized ratios (INRs) were 2.6 (interquartile range 2.5, 2.7), 1.9 (1.8, 2.0), 3.2 (3.0, 4.1), and 3.8 (3.4, 4.6), and anti-FXa levels were 0.36 (0.32, 0.38), 0.33 (0.26, 0.39), 0.45 (0.41, 0.51), and 0.62 (0.52, 0.65) U mL-1, respectively. Stage II enrollment was stopped (n = 7) after one serious thrombotic event. Ischemic and bleeding events were rare and, in this small population, showed no clear relation to DX-9065a dose., Conclusions: Elective PCI is feasible using a direct FXa inhibitor for anticoagulation. Predictable plasma drug levels can be rapidly obtained with double-bolus and infusion DX-9065a dosing. Monitoring of DX-9065a may be possible using whole-blood INR. Direct FXa inhibition is a novel and potentially promising approach to anticoagulation during PCI that deserves further study.

Background: Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa., Methods and Results: In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti-factor Xa activity (r=0.97), prothrombin time (r=0.77), and international normalized ratio (r=0.72) but less so with activated partial thromboplastin time (r=0.56; all P<0.001)., Conclusions: This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.

Background: Myocardial (re)infarction (MI), a common trial end point, can be difficult to identify because of inconclusive signs and symptoms. We examined disagreement between investigator and clinical events committee (CEC) reporting of MIs in an international, randomized trial., Methods: The primary end point of the PARAGON-B trial was a 30-day composite of death, MI (CEC adjudicated), or ischemia-driven intervention. If CEC and investigator determinations of MI differed, we sent investigators event summaries and rationales for CEC decisions and asked whether they now agreed with the CEC assessment. If they still disagreed, they were to provide a rationale and supporting data. Such cases were reviewed, and a final decision was made., Results: Overall, 1736 of 5225 (33%) patients had suspected MIs; the CEC adjudicated 483 of 1736 (28%) as MIs. In 404 patients (23%), investigator and CEC assessments of MI differed; 270 MIs were identified by the CEC but not investigators, and 134 were identified by investigators but not the CEC. Most disagreements concerned periprocedural MIs, but some reflected clinical ischemia and enzyme elevations. Letters for 382 disagreements were sent and returned by investigators, and investigators came to agree with CEC assessments in 307 cases (80%). For the other 75 cases (20%), after review the investigators' assessments were confirmed in 10 cases, and the original CEC decisions were supported in the other 65 cases., Conclusions: Investigators misreport MI end points, but most later agree with CEC assessments. These data support standard, independent adjudication of suspected MIs for accurate reporting, which may affect evaluations of therapies, sample-size calculations, and event-rate comparisons across trials.

Background: The A-to-Z Trial is an ongoing international, multicenter, randomized study designed to investigate 2 issues concerning contemporary care of patients with acute coronary syndromes (ACS). The first issue is whether the use of low-molecular-weight heparin versus unfractionated heparin affects outcomes and safety when used as a therapy adjunctive to baseline treatment with tirofiban and aspirin in patients with non-ST-elevation (nSTE) ACS. The second issue is whether early use of an aggressively dosed statin is superior to a current trial-based "accepted care" regimen of a lower-dose statin started 3 to 6 months after an acute event., Methods: The study is conceptually and functionally divided into 2 sequential parts-the "A" Aggrastat and "Z" Zocar phases. The primary A-phase end point is a composite of all-cause mortality, myocardial infarction (MI), and documented refractory ischemia at 7 days. Both nSTE-ACS patients from the A phase and patients with ST-elevation ACS who meet specific risk criteria are eligible to enter the subsequent "Z" (Zocor) chronic phase (Z phase). The primary end point of the Z phase is a composite of cardiovascular death, MI, readmission for ACS, and stroke. The trial will continue until 970 primary events have occurred in the Z-phase population., Conclusion: This trial is evaluating 2 temporally connected sequences of phamacotherapy for ACS. At completion, trial results will provide definitive evidence regarding efficacy and safety of early, intensive statin therapy and better define the role of low-molecular-weight heparin in patients with nSTE ACS.

To test the hypothesis that acetylcholine "spillover" from motor nerves contributes significantly to skeletal muscle vasodilation during exercise, we measured the forearm blood flow responses during attempted handgripping after local paralysis of the forearm with the neuromuscular-blocking drug pipecuronium. This compound blocks postsynaptic nicotinic receptors but has no impact on acetylcholine release from motor nerves. The drug was administered selectively to one forearm by using regional intravenous drug administration techniques in five subjects. Pipecuronium reduced maximum forearm grip strength from 40.0 +/- 3.2 kg before treatment to 0.0 kg after treatment. By contrast, drug administration had no effect on maximum voluntary contraction in the untreated forearm (41.3 +/- 3.3 vs. 41.4 +/- 2.7 kg). During 2 min of attempted maximal contraction of the paralyzed forearm, the forearm blood flow increased from only 3.4 +/- 0.8 to 4.8 +/- 1.2 ml.100 ml-1.min-1 (P < 0.05). Heart rate increased from 63 +/- 3 to 73 +/- 8 beats/min (P > 0.05) during attempted contraction, and only three of five subjects showed obvious increases in heart rate. Mean arterial pressure increased significantly (P < 0.05) from 102 +/- 6 to 109 +/- 9 mmHg during attempted contractions. When these increases in flow are considered in the context of the marked (10-fold or greater) increases in flow seen in contracting forearm skeletal muscle, it appears that acetylcholine spillover from motor nerves has, at most, a minimal impact on the hyperemic responses to contraction in humans.

The purpose of this study was to determine whether the reflex hemodynamic responses to static contraction of predominately glycolytic muscle are greater than the changes elicited by primarily oxidative muscle. Low-frequency electrical stimulation (continuous 21 days) of the tibial nerve of one hindlimb of adult rabbits converted the metabolic characteristics of the predominately glycolytic gastrocnemius to a muscle that was primarily oxidative. After 21 days of stimulation, the rabbits were decerebrated, and static contraction of the glycolytic muscle (unstimulated gastrocnemius) initially decreased heart rate (HR; -16 +/- 3 beats/min) and mean arterial pressure (MAP; -17 +/- 3 mmHg). Thereafter, MAP increased 13 +/- 3 mmHg above baseline. Static contraction of the oxidative muscle (stimulated gastrocnemius) produced similar decreases in HR and MAP (-12 +/- 4 beats/min and -12 +/- 3 mmHg, respectively). However, the subsequent increase in MAP (8 +/- 3 mmHg; above baseline) was less than that evoked by contraction of the glycolytic muscle. The responses evoked by stretch of each muscle and high-intensity electrical stimulation were the same, indicating that the afferents from the muscle were not destroyed by the chronic-stimulation technique. These results support the hypothesis that metabolic by-products play a role in the pressor response to static contraction of skeletal muscle. In addition, these data confirm that contraction of predominately oxidative muscle can evoke a reflex pressor response, albeit smaller than the change elicited from primarily glycolytic muscle.

1. We sought to determine whether the vasodilating molecule nitric oxide (NO) contributes to the forearm hyperaemia observed during prolonged rhythmic handgripping in humans. 2. Two bouts of exercise were performed during experimental protocols conducted on separate days. During each protocol the subject performed a 10 min and a 20 min bout of rhythmic (30 min-1) handgripping at 15% of maximum. Two exercise bouts were required to facilitate pharmacological interventions during the second protocol. Blood flow in the exercising forearm was measured every minute with plethysmography during brief pauses in the contractions. During both exercise bouts in the first protocol, forearm blood flow increased 2- to 3-fold above rest after 1 min of handgripping and remained constant at that level throughout the exercise. 3. During the 10 min bout of exercise in the second protocol, acetylcholine was given via a brachial artery catheter at 16 micrograms min-1 for 3 min to evoke NO release from the vascular endothelium. This caused forearm blood flow to increase above the values observed during exercise alone. 4. During the 20 min trial of handgripping in the second protocol, the NO synthase blocker NG-monomethyl-L-arginine (L-NMMA) was infused in the exercising forearm via the brachial catheter after 5 min of handgripping. The L-NMMA was infused at 4 mg min-1 for 10 min. 5. L-NMMA during exercise caused forearm blood flow to fall to values approximately 20-30% lower than those observed during exercise alone. When ACh was given during exercise after L-NMMA administration the rise in blood flow was also blunted, indicating blockade of NO synthase. These data suggest NO plays a role in exercise hyperaemia in humans.

The purpose of this study was to determine whether the biphasic arterial blood pressure responses elicited by static muscle contraction of decerebrate rabbits are mediated, at least in part, by an initial decrease and a subsequent increase in sympathetic outflow. Renal sympathetic nerve activity (RSNA) was used as an index of sympathetic outflow. Static contraction of the triceps surae muscle (n = 14) initially decreased mean arterial blood pressure (MAP) -20 +/- 3 mmHg and heart rate (HR) -15 +/- 5 beats/min (nadir values). After this initial decrease, MAP increased 12 +/- 2 mmHg (peak increase) above baseline and there was a tendency for HR to be elevated (6 +/- 3 beats/min). The changes in RSNA during muscle contraction (n = 6) mirrored the nadir and peak responses of MAP (-50 +/- 9 and 32 +/- 11%). Muscle stretch (n = 11) also evoked similar nadir and peak responses of MAP (-20 +/- 5 and 9 +/- 1 mmHg), HR (-17 +/- 7 and 3 +/- 3 beats/min), and RSNA (-43 +/- 9 and 46 +/- 15%). These data suggest that the initial depressor and subsequent pressor responses elicited by skeletal muscle contraction and stretch are mediated, at least in part, by biphasic changes in sympathetic outflow.