Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Effect of Early Metoprolol on Infarct Size in ST-Segment–Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention: The Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) Trial
- Levels and Changes of HDL Cholesterol and Apolipoprotein A-I in Relation to Risk of Cardiovascular Events Among Statin-Treated Patients: A Meta-Analysis
- Yield of Molecular and Clinical Testing for Arrhythmia Syndromes: Report of 15 Years’ Experience
- Dispatcher-Assisted Cardiopulmonary Resuscitation: Time to Identify Cardiac Arrest and Deliver Chest Compression Instructions
- Contribution and Risks of Left Ventricular Endomyocardial Biopsy in Patients With Cardiomyopathies: A Retrospective Study Over a 28-Year Period
- Innate Immune Interleukin-1 Receptor–Associated Kinase 4 Exacerbates Viral Myocarditis by Reducing CCR5+CD11b+ Monocyte Migration and Impairing Interferon Production
- Depressing Mitochondria-Reticulum Interactions Protects Cardiomyocytes From Lethal Hypoxia-Reoxygenation Injury
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Effect of Early Metoprolol on Infarct Size in ST-Segment–Elevation Myocardial Infarction Patients Undergoing Primary Percutaneous Coronary Intervention: The Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) Trial
The capacity of β-blockers to reduce infarct size was evaluated extensively in the prereperfusion era with controversial results. In the context of reperfusion as the treatment of choice for ST-segment–elevation myocardial infarction (STEMI), this has been poorly investigated. Experimental data suggest that the β-blocker metoprolol is able to reduce infarct size only when administered intravenously before reperfusion. Here, we present the results of the Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction (METOCARD-CNIC) trial, the first randomized, clinical trial prospectively evaluating the effect of early intravenous β-blockade on infarct size in conjunction with primary angioplasty. A total of 270 patients with anterior STEMI (Killip class II or less) revascularized within 6 hours after symptom onset were randomized to receive intravenous metoprolol or not before reperfusion. All patients received oral metoprolol according to clinical guidelines (first dose, 12–24 hours after infarction). Infarct size, evaluated by magnetic resonance imaging and creatine kinase release, was significantly reduced in the intravenous metoprolol group with no excess side effects. Left ventricular ejection fraction was higher in the intravenous metoprolol group. This cardioprotective effect appeared to be restricted to patients with a preangioplasty Thrombolysis in Myocardial Infarction grade 0 to 1 flow. Here, we show that an inexpensive medication already approved in the context of STEMI can significantly reduce infarct size just by administering it intravenously before reperfusion in patients with no contraindications. Given the important role of final infarct size as a main determinant of long-term mortality in STEMI survivors, the possibility of applying inexpensive strategies available to a wide proportion of STEMI patients is of clinical value. See p 1495.
Levels and Changes of HDL Cholesterol and Apolipoprotein A-I in Relation to Risk of Cardiovascular Events Among Statin-Treated Patients: A Meta-Analysis
Although levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) are strongly and negatively associated with risk of cardiovascular events, it is unclear whether these associations persist among patients who achieve very low levels of low-density lipoprotein cholesterol on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a stronger reduction in cardiovascular risk. The authors performed a meta-analysis of 8 large statin trials, where lipid and apolipoprotein levels were measured both at baseline and at follow-up in the entire study population. The authors show that both HDL-C levels and apoA-I levels remain associated with cardiovascular risk even among patients achieving very low low-density lipoprotein cholesterol levels on statin therapy. In addition, the authors show that a rise in HDL-C level after initiation of statin therapy was not associated with a stronger reduction in cardiovascular risk. However, a rise in apoA-I level was associated with lower cardiovascular risk. These findings suggest that the value of HDL-C and apoA-I as cardiovascular risk factors does not become irrelevant among people achieving very low low-density lipoprotein cholesterol levels. These findings also suggest that therapies aimed at raising HDL-C levels may be less promising than therapies that increase apoA-I levels. See p 1504.
Yield of Molecular and Clinical Testing for Arrhythmia Syndromes: Report of 15 Years’ Experience
This study reports on 15 years of experience in genetic counseling, DNA testing, and cascade screening in cardiogenetics. In 1996, we started a cardiogenetics clinic in Amsterdam aimed at diagnosing inherited arrhythmia syndromes (primary electric diseases and cardiomyopathies), and providing timely (often presymptomatic) treatment to individuals from families who have such syndromes or have experienced a sudden cardiac death. We studied the yield of targeted genetic testing in almost 2300 probands. We found that the overall yield of DNA testing was as high as 47% (in long-QT syndrome and hypertrophic cardiomyopathy). This yield decreased over time, which was explained, at least in part, by the referral of probands with a less severe phenotype in more recent years. Moreover, the yield was significantly higher in familial cases than in isolated cases. These findings demonstrate that a clear phenotype is associated with a higher yield of DNA testing. Although these findings may be intuitive, this study is the first large study to provide solid evidence to verify this intuition. Moreover, with the rapid emergence of next-generation sequencing and exome-sequencing techniques, this study may be used as a reference to compare the yield of this targeted manner of DNA testing to newer high-throughput methods. See p 1513.
Dispatcher-Assisted Cardiopulmonary Resuscitation: Time to Identify Cardiac Arrest and Deliver Chest Compression Instructions
For out-of-hospital cardiac arrest, the time interval from collapse to the start of chest compressions is a strong predictor of survival. When cardiopulmonary resuscitation (CPR) is started by bystanders, the odds for survival increases 200% to 300% compared with survival when CPR is started by emergency medical services personnel. Efforts to train the general public in CPR go some way toward ensuring rapid delivery of CPR, but a more powerful strategy is for emergency dispatchers to deliver instant chest compression instructions to callers reporting a cardiac arrest. This study identifies the barriers to rapid identification of the need for CPR by emergency dispatchers and the reasons for delay in delivering chest compression instructions. In the population studied, cardiac arrest was correctly identified by the dispatcher in 80% of cases in a median time of 75 seconds. Chest compressions following dispatcher instructions occurred in 62% of cases in a median time of 176 seconds. We suggest performance standards for the recognition of CPR and time to deliver the first compression that seek to improve on these findings. If these performance standards are adopted on a national level and measured by local emergency medical services agencies, rates of bystander CPR might increase, potentially leading to greater survival from out-of-hospital cardiac arrest. See p 1522.
Contribution and Risks of Left Ventricular Endomyocardial Biopsy in Patients With Cardiomyopathies: A Retrospective Study Over a 28-Year Period
Endomyocardial biopsy (EMB) has a recognized and increasing role in the diagnosis, prognosis, and treatment of myocarditis and other nonischemic cardiomyopathies. However, the risk of complications still limits its use, particularly when a left ventricular (LV) approach is considered. In the present single-center study, over a 28-year period, 3549 patients received an LVEMB either selectively (n=1153) or associated with a right ventricular (RV) EMB (n=2396), and 672 patients received an isolated RV biopsy. We retrospectively analyzed the incidence of complications and the diagnostic advantages of LVEMB versus RVEMB. Biopsies were performed via the femoral approach by 2 experienced operators. The patients were treated with high-dose aspirin before the procedure to prevent thromboembolic risk. The EMB samples were processed with state-of-the-art histological, immunohistochemical, molecular biology, and electron microscopy techniques. The major complication rate was 0.33% for LVEMB and 0.45% for RVEMB with a significant decrease with time, denoting a steep learning curve for the operators. No patient died. EMB showed abnormal specific and nonspecific changes in 97% of patients, and biventricular EMB showed a major diagnostic yield compared with isolated LVEMB. When the structural and functional abnormalities affected the LV exclusively, the diagnostic yield of LVEMB significantly increased compared with RVEMB, whereas it was comparable when the RV was also involved. Thus, LVEMB appears to be as safe as RVEMB and diagnostically more contributive when a cardiomyopathy is associated with a normal RV. Experienced operators can guarantee a safe procedure even with an LV approach. See p 1531.
Innate Immune Interleukin-1 Receptor–Associated Kinase 4 Exacerbates Viral Myocarditis by Reducing CCR5+CD11b+ Monocyte Migration and Impairing Interferon Production
The ability of the host to limit viral proliferation while minimizing tissue injury attributable to inflammatory responses is a prerequisite of favorable outcome. The major issue in myocarditis, which currently has few standard treatment strategies, is to determine the cause of inflammation and then use the most appropriate approaches to reestablish proper heart function. If viral genome or other signatures have been found, in addition to traditional hemodynamic and cardiovascular support, it may be useful to modulate the innate immune system to attenuate the cardiotropic virus. Thus far, immunosuppressive therapies have been only partially successful, whereas interferon-based antiviral approaches showed promising outcomes. In the present study, we clarified the role of interleukin-1 receptor–associated kinase 4 (IRAK4), downstream of the Toll-like receptor, in a mouse model of coxsackievirus-induced myocarditis. IRAK4 induces excessive inflammatory tissue damage leading to heart dysfunction. We found that inhibition of IRAK4 in monocytes simultaneously prevented inflammation on one side while enhancing interferon-dependent antiviral protection on the other. This double beneficial effect was also emphasized by rapid recruitment of protective CCR5-expressing monocytes from the bone marrow to the infected heart. Because recently developed compounds specifically targeting IRAK4 kinase activity have been produced to treat various inflammatory and autoimmune diseases, we believe that IRAK4 kinase inhibitors may also be effective to treat viral myocarditis. Future therapeutic strategies targeting IRAK4 may at the same time reduce excessive inflammatory stimuli and enhance antiviral protection in affected hearts. See p 1542.
Depressing Mitochondria-Reticulum Interactions Protects Cardiomyocytes From Lethal Hypoxia-Reoxygenation Injury
Our clinical group recently demonstrated via proof-of-concept clinical trials that both ischemic and pharmacological postconditioning (with the use of cyclosporine, an inhibitor of the opening of the mitochondrial permeability transition pore) reduced infarct size and improved long-term functional recovery in patients undergoing myocardial infarction. However, there is still an obvious need for new therapeutics to prevent myocardial damage in acute ischemic syndromes. Accumulating evidence suggests that mitochondria–sarcoplasmic reticulum interactions are relevant to the adult heart despite the complex and distinctive arrangement of mitochondria and reticulum in this organ. Indeed, the interactions of these 2 organelles are involved in local Ca2+ exchange and therefore in the control of the fate of cardiomyocytes and excitation-contraction coupling in the heart. In the present study, we demonstrated a new role for cyclophilin D, a well-known regulator of the mitochondrial permeability transition pore opening, in the modulation of Ca2+ exchange between mitochondria and sarcoplasmic reticulum via the IP3 receptors during hypoxia-reoxygenation. Furthermore, we showed that decreasing these functional contact points between mitochondria and sarcoplasmic reticulum at the level of the IP3 receptor Ca2+ channeling complex protected cardiomyocytes by preventing mitochondrial Ca2+ overload and cell death. These results suggest that the mitochondria-reticulum interface may be a new target to reduce infarct size after myocardial ischemia. These results are promising for the development of new therapeutics to attenuate lethal reperfusion injury after myocardial infarction. See p 1555.
- © 2013 American Heart Association, Inc.
- Yield of Molecular and Clinical Testing for Arrhythmia Syndromes: Report of 15 Years’ Experience
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