The effect of late thrombolysis in acute myocardial infarction (AMI)--ie, treatment beginning more than 6 h after the onset of symptoms--remains controversial. The Late Assessment of Thrombolytic Efficacy (LATE) study is a large randomised trial designed to resolve this question. 5711 patients with symptoms and electrocardiographic criteria consistent with AMI were randomised double-blind to intravenous alteplase (100 mg over 3 h) or matching placebo, between 6 and 24 h from symptom onset. Both groups received immediate oral aspirin and for later recruits intravenous heparin for 48 h was recommended. All patients were followed up for at least 6 months and 73% were followed up for 1 year. Intention-to-treat analysis of survival revealed a non-significant reduction in the alteplase group (397/2836 deaths) compared with placebo (444/2875). 35-day mortality was 8.86% and 10.31%, respectively, a relative reduction of 14.1% (95% CI 0-28.1%). Pre-specified survival analysis according to treatment within 12 h of symptom onset, however, showed a significant reduction in mortality in favour of alteplase: 35-day mortality was 8.90% versus 11.97% for placebo, a relative reduction of 25.6% (p = 0.0229, 95% CI 6.3-45.0%). Rates were 8.7% and 9.2%, respectively, for those treated at 12-24 h but subgroup analysis suggests that some patients may benefit even when treated after 12 h. Although treatment with alteplase resulted in an excess of haemorrhagic strokes, by 6 months the number of disabled survivors was the same in both treatment groups and other clinical events were observed with similar frequency in the two groups. We conclude that the time window for thrombolysis with alteplase should be extended to at least 12 h from symptom onset in patients with AMI.
We sought to evaluate the prognostic impact of right ventricular (RV) myocardial involvement in patients with inferior myocardial infarction (MI).
There is uncertainty regarding the risk of major complications in patients with inferior MI complicated by RV myocardial involvement. Whether these complications are related to RV myocardial involvement itself or simply to the extent of infarction involving the left ventricle (LV) is also unknown.
We examined the incidence of death and mechanical and electrical complications in patients with (n = 491) and without (n = 638) RV myocardial involvement and in patients with anterior MI (n = 971) in an analysis from the Collaborative Organization for RheothRx Evaluation (CORE) trial. Left ventricular infarct size was assessed by technetium-99m-sestamibi single-photon emission computed tomography and peak creatine kinase, and LV function was assessed by radionuclide angiography. We also performed a meta-analysis in which we pooled the results of our study with previous smaller studies addressing the same question.
Six-month mortality was 7.8% in inferior MI compared with 13.2% in anterior MI. Among patients with inferior MI, serious arrhythmias were significantly more common in patients with RV myocardial involvement who also had a trend toward higher mortality, pump failure and mechanical complications. However, this was not associated with a difference in LV infarct size or function. A meta-analysis of six studies (n = 1,198) confirmed that RV myocardial involvement was associated with an increased risk of death (odds ratio [OR] 3.2, 95% confidence interval [CI] 2.4 to 4.1), shock (OR 3.2, 95% CI 2.4 to 3.5), ventricular tachycardia or fibrillation (OR 2.7, 95% CI 2.1 to 3.5) and atrioventricular block (OR 3.4, 95% CI 2.7 to 4.2).
Patients with inferior MI who also have RV myocardial involvement are at increased risk of death, shock and arrhythmias. This increased risk is related to the presence of RV myocardial involvement itself rather than the extent of LV myocardial damage.
Dual antiplatelet therapy with aspirin and a thienopyridine has been shown to reduce cardiac events after coronary stenting. However, many patients and healthcare providers prematurely discontinue dual antiplatelet therapy, which greatly increases the risk of stent thrombosis, myocardial infarction, and death. This advisory stresses the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent and educating the patient and healthcare providers about hazards of premature discontinuation. It also recommends postponing elective surgery for 1 year, and if surgery cannot be deferred, considering the continuation of aspirin during the perioperative period in high-risk patients with drug-eluting stents.
Inflammatory responses after myocardial infarction profoundly impact tissue repair. Yet, efficient tools to serially and noninvasively assess cellular and molecular functions in postinfarct inflammation are lacking. Here we use multichannel fluorescent molecular tomography (FMT) for spatiotemporal resolution of phagocytic and proteolytic activities mediated by macrophages and neutrophils in murine infarcts. We performed FMT imaging to compare the course of efficient and impaired healing in wild-type and FXIII-/- mice, respectively. Mice subjected to coronary ligation received simultaneous injections with Prosense-680, an activatable fluorescence sensor reporting on cathepsin activity, and CLIO-VT750, a magneto-fluorescent nanoparticle for imaging of phagocyte recruitment. On FMT, Prosense-680 infarct signal was 19-fold higher than background (P<0.05). Protease activity was higher in the infarcted lateral wall than in the remote, uninjured septum on ex vivo fluorescence reflectance imaging (contrast to noise ratio 118+/-24). CLIO-VT750 FMT signal coregistered with contrast enhancement in the hypokinetic infarct on MRI. Microscopic fluorescence signal colocalized with immunoreactive staining for cathepsin, macrophages and neutrophils. Flow cytometry of digested infarcts revealed monocytes/macrophages and neutrophils as the source of the fluorescence signal. Phagocytic activity peaked on day 6, and proteolytic activity peaked on day 4 after myocardial infarction. FMT detected impaired recruitment of phagocytes and protease activity in FXIII-/- mice (P<0.05). FMT is a promising noninvasive molecular imaging approach to characterize infarct healing. Spectrally resolved imaging agents allow for simultaneous assesment of key processes of in vivo cellular functions. Specifically, we show that in vivo FMT detects impaired healing in FXIII-/- mice.
Excitation in the epicardial border zone of 3-5-day-old canine infarcts was mapped with an array of 192 bipolar electrodes during sustained ventricular tachycardia. Reentrant circuits were found in which activation occurred around long lines of apparent conduction block based on the criterion that excitation on opposite sides of the lines occurred with marked disparity in time. When the lines of apparent block were functional (i.e., occurred only during tachycardia and not during sinus rhythm or ventricular pacing) they were oriented parallel to the long axis of epicardial muscle fiber bundles. Isochrones distal to the lines were oriented parallel to them because widely separate sites within these isochrones were activated nearly simultaneously. This suggested that excitation not only occurred around the lines of block but also slowly across them. This slow activation occurred transverse to the long axis of the myocardial fibers and therefore might result because of the anisotropic tissue properties. To test this hypothesis, the epicardial border zone was stimulated during sinus rhythm through electrodes around its margin and at the center of the recording array. Activation transverse to the myocardial fibers in regions where lines of block occurred during tachycardia was slow, whereas it was rapid parallel to fibers' orientation. During tachycardia electrograms along the lines of apparent block had long durations and were fractionated, a characteristic that can also result from activation transverse to the myocardial fiber long axis. Therefore, we propose that the parallel orientation of the muscle bundles in the epicardial border zone is an important cause of ventricular tachycardia because activation transverse to myocardial fibers is sufficiently slow to permit the occurrence of reentry.
It has been suggested that the survival benefit associated with primary percutaneous coronary intervention (PPCI) in ST-segment elevation myocardial infarction may be attenuated if door-to-balloon (DB) time is delayed by >1 hour beyond door-to-needle (DN) times for fibrinolytic therapy. Whereas DB times are rapid in randomized trials, they are often prolonged in routine practice. We hypothesized that in clinical practice, longer DB-DN times would be associated with higher mortality rates and reduced PPCI survival advantage. We also hypothesized that in addition to PPCI delays, patient risk factors would significantly modulate the relative survival advantage of PPCI over fibrinolysis.
DB-DN times were calculated by subtracting median DN time from median DB time at a hospital using data from 192,509 patients at 645 National Registry of Myocardial Infarction hospitals. Hierarchical models that adjusted simultaneously for both patient-level risk factors and hospital-level covariates were used to evaluate the relationship between PCI-related delay, patient risk factors, and in-hospital mortality. Longer DB-DN times were associated with increased mortality (P<0.0001). The DB-DN time at which mortality rates with PPCI were no better than that of fibrinolysis varied considerably depending on patient age, symptom duration, and infarct location.
As DB-DN times increase, the mortality advantage of PPCI over fibrinolysis declines, and this advantage varies considerably depending on patient characteristics. As indicated in the American College of Cardiology/American Heart Association guidelines, both the hospital-based PPCI-related delay (DB-DN time) and patient characteristics should be considered when a reperfusion strategy is selected.
Excessive activation of the β-adrenergic, angiotensin II (Ang II) and aldosterone signaling pathways promotes mortality after myocardial infarction, and antagonists targeting these pathways are core therapies for treating this condition. Catecholamines and Ang II activate the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), the inhibition of which prevents isoproterenol-mediated and Ang II-mediated cardiomyopathy. Here we show that aldosterone exerts direct toxic actions on myocardium by oxidative activation of CaMKII, causing cardiac rupture and increased mortality in mice after myocardial infarction. Aldosterone induces CaMKII oxidation by recruiting NADPH oxidase, and this oxidized and activated CaMKII promotes matrix metalloproteinase 9 (MMP9) expression in cardiomyocytes. Myocardial CaMKII inhibition, overexpression of methionine sulfoxide reductase A (an enzyme that reduces oxidized CaMKII) or NADPH oxidase deficiency prevented aldosterone-enhanced cardiac rupture after myocardial infarction. These findings show that oxidized myocardial CaMKII mediates the cardiotoxic effects of aldosterone on the cardiac matrix and establish CaMKII as a nodal signal for the neurohumoral pathways associated with poor outcomes after myocardial infarction.
To complement the current process measures for treating patients with heart attacks and with heart failure, which target gaps in quality but do not capture patient outcomes, the Centers for Medicare and Medicaid Services (CMS) has proposed the public reporting of hospital-level thirty-day mortality for these conditions in 2007. We present the case for including measurements of outcomes in the assessment of hospital performance, focusing on the care of patients with heart attacks and with heart failure. Recent developments in the methodology and standards for outcomes measurement have laid the groundwork for incorporating outcomes into performance monitoring efforts for these conditions.
The chest pain history, physical examination, determination of coronary artery disease (CAD) risk factors, and the initial electrocardiogram compose the information immediately available to clinicians to help determine the probability of acute myocardial infarction (AMI) or acute coronary syndrome (ACS) in patients with chest pain. However, conflicting data exist about the usefulness of the chest pain history and which components are most useful.
To identify the elements of the chest pain history that may be most helpful to the clinician in identifying ACS in patients presenting with chest pain.
MEDLINE and Ovid were searched from 1970 to September 2005 by using specific key words and Medical Subject Heading terms. Reference lists of these articles and current cardiology textbooks were also consulted.
Certain chest pain characteristics decrease the likelihood of ACS or AMI, namely, pain that is stabbing, pleuritic, positional, or reproducible by palpation (likelihood ratios [LRs] 0.2-0.3). Conversely, chest pain that radiates to one shoulder or both shoulders or arms or is precipitated by exertion is associated with LRs (2.3-4.7) that increase the likelihood of ACS. The chest pain history itself has not proven to be a powerful enough predictive tool to obviate the need for at least some diagnostic testing. Combinations of elements of the chest pain history with other initially available information, such as a history of CAD, have identified certain groups that may be safe for discharge without further evaluation, but further study is needed before such a recommendation can be considered reasonable.
Although certain elements of the chest pain history are associated with increased or decreased likelihoods of a diagnosis of ACS or AMI, none of them alone or in combination identify a group of patients that can be safely discharged without further diagnostic testing.
Most studies are unable to follow nonrespondents prospectively to determine whether their disease rates are comparable with those of the respondents. The authors followed respondents and nonrespondents to a mailed questionnaire, sent to a random sample of Iowa women aged 55-69 years in 1986 (total sample, 98,029; 43% response), to characterize 5-year mortality rates for myocardial infarction and all causes, and attack rates for breast, endometrial, colon, lung, and all-site cancers. Compared with respondents, nonrespondents had higher myocardial infarction (1.47 vs. 0.93 per 1,000 person-years) and all-cause (12.32 vs. 7.89 per 1,000 person-years) mortality. They also had substantially higher attack rates for lung cancer (1.45 vs. 1.10 per 1,000 person-years), and slightly higher attack rates for all-site cancer (11.86 vs. 10.89 per 1,000 person-years). The associations of reported body mass index (weight/height2) with the study endpoints were generally similar among respondents and the total eligible sample, except for a more pronounced U-shaped total mortality association for the nonrespondents. Thus, although the occurrence of several diseases, especially those related to smoking, differed among respondents and nonrespondents, the association of body mass index with cancer occurrence was not appreciably affected by nonresponse bias.