Circulation. 2008;117:1499
doi: 10.1161/CIRCULATIONAHA.107.189183
doi: 10.1161/CIRCULATIONAHA.107.189183
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(Circulation. 2008;117:1499.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Epicardium-Derived Cells in Development of Annulus Fibrosis and Persistence of Accessory Pathways |
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Epicardium-Derived Cells in...
Vernakalant Hydrochloride for...Atrioventricular reentrant tachycardia is a common arrhythmia in both children and adults; however, the causal mechanisms underlying the appearance of accessory pathways remain a subject of debate. During cardiogenesis, initial slow conduction over the circumferential myocardial AV continuity, which results in sequential activation of the preseptated heart, is replaced by apex-to-base conduction through the specialized AV node/His-Purkinje system in the septated heart. Concurrently, incorporation of the AV junctional myocardium in the lower atrial rim by fusion of the endocardial AV cushions and epicardial AV sulcus results in formation of the isolating annulus fibrosis. Migration of multipotent epicardium-derived cells (EPDCs) through the continuous AV junctional myocardium, ultimately reaching the endocardium-derived AV cushions, spatiotemporally correlates with annulus fibrosis formation. The AV junction has been postulated to be subject to physiological perinatal remodeling, which temporarily leaves functional small accessory pathways as anatomic substrates for spontaneously resolving neonatal AV reentrant tachycardias. Dyssynchrony in the delicate interplay between EPDCs and AV junctional cells, as shown in the EPDC-inhibited quail model in the present study, may result in marked defects in the isolating annulus fibrosis, with the persistence of large accessory pathways functionally resulting in ventricular preexcitation. We speculate that absence of EPDCs or a delay in EPDC migration results in the persistence of pathological substrates for postnatally persistent accessory pathways and AV reentrant tachycardias into childhood or adult life. See p 1508.
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Vernakalant Hydrochloride for Rapid Conversion of Atrial Fibrillation: A Phase 3, Randomized, Placebo-Controlled Trial |
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Pharmacological cardioversion often is used to restore sinus rhythm in patients with hemodynamically stable and recent-onset atrial fibrillation. However, currently available antiarrhythmic agents have modest efficacy, and the risk of proarrhythmia is of concern. Vernakalant is a new and relatively atrium-selective antiarrhythmic agent undergoing investigation for the conversion of atrial fibrillation to sinus rhythm. The results of this placebo-controlled trial demonstrate the efficacy of intravenous vernakalant in terminating recent-onset atrial fibrillation. Moreover, conversion was rapid and not associated with ventricular proarrhythmia. The clinical implication is that intravenous vernakalant may represent a valuable new antiarrhythmic drug for the acute conversion of atrial fibrillation to sinus rhythm, and it may be particularly useful in patients with recent-onset atrial fibrillation in the emergency room setting. See p 1518.
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Prevalence of Angina in Women Versus Men: A Systematic Review and Meta-Analysis of International Variations Across 31 Countries |
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Is male sex a risk factor for stable angina pectoris in the same way that it is for acute coronary syndromes? In this meta-analysis based on almost 25 000 angina cases in women and men from 31 countries, we found that women had a slightly higher prevalence of stable angina pectoris than men. This study adds to current understanding by demonstrating for the first time that the female excess of angina is remarkably consistent across countries with widely differing myocardial infarction mortality rates, spanning 4 decades of study period and 4 decades of participant age. Such generalizability may suggest an inherent biological basis rather than artifactual explanations. The sex ratio of angina contrasts with the ubiquitous male excess of myocardial infarction, is unexplained, and warrants further study. The observation of a female excess of angina, independent of diagnostic and treatment practices, has clinical implications for understanding the quality of care in women. See p 1526.
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Variation in the 3-Hydroxyl-3-Methylglutaryl Coenzyme A Reductase Gene Is Associated With Racial Differences in Low-Density Lipoprotein Cholesterol Response to Simvastatin Treatment |
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Statins reduce low-density lipoprotein (LDL) cholesterol by inhibiting hydroxymethyl glutaryl coenzyme A reductase (HMGCR), a rate-limiting enzyme of cholesterol synthesis. Although statins are highly efficacious for most patients, there is a wide range of response among individuals, and there is evidence that genetic factors can contribute to this variation in response. In the present study, we identified common single nucleotide polymorphisms in the gene encoding HMGCR and tested the associations of 11 of these single nucleotide polymorphisms (all noncoding) with the magnitude of change of LDL cholesterol and other lipids and lipoproteins in response to simvastatin (40 mg/d for 6 weeks) in 596 whites and 326 blacks with a wide range of LDL cholesterol levels. We found that carriers of 2 interrelated HMGCR single nucleotide polymorphism clusters (haplotypes) manifested both lower plasma levels of LDL cholesterol (3.27±0.05 versus 3.48±0.03 mmol/L) and a smaller magnitude of LDL cholesterol change in response to statin (–1.28±0.03 versus –1.45±0.02 mmol/L) than did noncarriers. Notably, these effects were observed only in blacks, in whom the prevalence of one of the haplotypes was substantially greater than in whites. Although the absolute magnitudes of these genetic effects are not large enough to warrant their analysis in clinical practice, the findings point to the possibility that other genetic markers may be discovered that may collectively improve prediction of statin efficacy and toxicity and hence may be useful in guiding optimal therapy. Furthermore, these findings point to the need for considering racial and ethnic differences in studies aimed at identifying genetic factors affecting drug treatment response. See p 1537.
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Hemodynamic Effects of Volume Expansion in Patients With Cardiac Tamponade |
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Cardiac tamponade may be a life-threatening syndrome that requires urgent therapy. The optimal treatment is pericardial drainage, either by needle pericardiocentesis or by a surgical procedure; however, these procedures may not be readily available, and alternative methods can be considered as interim therapy. Intravascular fluid expansion has been proposed as a potentially useful procedure for this purpose, but the scientific evidence for its clinical effectiveness is very poor. The present report is based on 49 patients with large pericardial effusion and medical tamponade who underwent combined pericardiocentesis and cardiac catheterization and were submitted to fluid overload with administration of 500 mL of intravenous normal saline over a 10-minute period. At baseline, all patients met hemodynamic criteria of tamponade (equalization of intrapericardial and intracavitary pressures). Volume expansion caused a significant increase in mean arterial pressure and cardiac index, but only half of the patients had an increase in cardiac index >10%. The only predictor of this favorable response was low systolic blood pressure (<100 mm Hg). Volume expansion caused a significant increase in intrapericardial, right atrial, and left ventricular end-diastolic pressures. Remarkably, cardiac index decreased in 30% of patients, although no patient developed clinical complications. In conclusion, volume expansion should not be considered for all patients with cardiac tamponade on a systematic basis, but it can help to stabilize hypotensive patients while they are being prepared for pericardiocentesis. This beneficial effect should be put against a consistent increase in left ventricular end-diastolic pressure. See p 1545.
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Restrictive Left Ventricular Filling Pattern Does Not Result From Increased Left Atrial Pressure Alone |
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Diastolic function has been evaluated noninvasively from the dynamics of left ventricular filling, reflected in the pattern of mitral valve flow velocity measured by Doppler echocardiography and by tissue Doppler assessment of mitral annular velocity. A restrictive filling pattern with a high peak early diastolic peak filling velocity (E), short E deceleration time, and reduced and delayed peak early diastolic mitral annular velocity (E') has been thought to indicate severe diastolic dysfunction. However, because the restrictive filling pattern occurs in patients with elevated left atrial pressure, it may be merely a manifestation of an overfilled ventricle, not diastolic dysfunction. We tested this hypothesis by evaluating left ventricular filling in chronically instrumented animals in 2 situations with similar elevations of left atrial pressure: normal animals after acute volume loading and animals with severe heart failure with restrictive filling. We found that the restrictive filling pattern is differentiated from overfilling of a normal ventricle by a decreased and delayed E' reflecting slow relaxation and a short E deceleration time resulting from increased left ventricular operating stiffness. Thus, restrictive filling indicates the presence of diastolic dysfunction and is not due to elevated left atrial pressure alone. See p 1550.
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Magnetic Resonance Imaging Overestimates Ferumoxide-Labeled Stem Cell Survival After Transplantation in the Heart |
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Iron labeling of stem cells has been touted as a reliable method to assess engraftment and migration after cell transplantation by magnetic resonance imaging (MRI). Cardiac-derived stem cells or mesenchymal stem cells labeled with iron oxide were injected intramyocardially into rats to investigate the relationship between iron-dependent MRI signals and cell survival. Comparing in vivo images with histological results in the same hearts, we found that intense MRI signals, generated by iron in tissue macrophages, persisted for 3 to 5 weeks after rapid loss of viable transplanted cells, as in the case of xenogenic transplantation. The iron-derived MRI signals were similar whether they arose from macrophages or viable or dead stem cells. Importantly, the results were not cell (cardiac-derived or mesenchymal stem cells) or substrate (normal versus infarcted myocardium) specific. Iron oxide labeling and MRI may be appropriate for localization of cell injection sites, but these methods are not reliable for in vivo tracking of viable cells in the heart. See p 1555.
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Human Apolipoprotein A-I Gene Transfer Reduces the Development of Experimental Diabetic Cardiomyopathy |
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The present study reports that an increase in high-density lipoprotein (HDL) via human apolipoprotein A-I gene transfer reduces the development of experimental diabetic cardiomyopathy. Besides the demonstration of cardiac antiinflammatory, antioxidative, and antiapoptotic features of HDL, the present study describes new cardioprotective effects of HDL. It shows for the first time that fibrosis and glycogen accumulation are reduced after human apolipoprotein A-I transfer in an experimental model of diabetic cardiomyopathy. This study, performed in an animal model characterized by severe hyperglycemia, oxidative stress, and a ratio of HDL cholesterol to low-density lipoprotein cholesterol of 1, strongly suggests that HDL has direct cardioprotective effects, which is strengthened by the finding that HDL directly improves impaired cardiomyocyte contractility ex vivo. Our findings underscore the cardioprotective effects of HDL; however, the relevance of the use of HDL-raising therapies for the cotreatment of diabetic cardiomyopathy should be examined in future studies investigating the effect of increasing HDL on established diabetic cardiomyopathy. Moreover, it has to taken into account that the current HDL-elevating drugs only moderately increase HDL compared with apolipoprotein A-I gene transfer. Furthermore, the way that these drugs interfere with HDL metabolism differs, which might contribute to important differences in success and tolerability. See p 1563.
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Ablation of Matrix Metalloproteinase-9 Increases Severity of Viral Myocarditis in Mice |
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Matrix metalloproteinase (MMP)-9 is expressed in the myocardium during cardiac injury. It has been postulated that the presence of this MMP is detrimental to cardiac repair after infectious and ischemic heart injury. Potential treatments have even been devised that suppress the expression of MMPs during infectious myocarditis. We show that the absence of MMP-9 in a knockout (KO) mouse model enhances susceptibility to cardiac infection by coxsackievirus. There was a lower viral load in the pancreas in wild-type (WT) mice than in KO mice, and importantly, there was limited infection of the WT myocardium. The MMP-9 KO mice had significantly more pancreatic and myocardial infection (cross-sectional myocardial foci count of 102 versus 19 in WT mice) and significantly decreased cardiac output. Immune infiltration was increased in MMP-9 KO mice compared with WT mice (15.2% versus. 2.0%, respectively). Our study is consistent with other evidence of the suppression of bacterial infection by MMP-9, but a similar effect has never been shown in a viral model of infection. This study suggests that MMP-9 plays a role in suppressing viremia to the point of protecting the heart from infection, while mediating an appropriate immune response. Therefore, treatments meant to prevent the onset of infectious myocarditis by coxsackievirus would be best to preserve MMP-9 function. See p 1574.
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Survivin Determines Cardiac Function by Controlling Total Cardiomyocyte Number |
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Cardiomyocyte death leading to loss of contractile units has been implicated in the pathogenesis of all forms of heart failure. Although the exact stimuli, mechanisms, and rate of apoptosis in the adult human heart are unknown, a dynamic balance exists between cardiomyocyte loss and replacement during life and disease. We found that the small antiapoptotic molecule survivin controls both cell death and cell division during cardiac development; its deletion in a cardiomyocyte-specific fashion in mice led to progressive heart failure resulting from a profound reduction in total cardiomyocyte numbers per heart. By systematically counting total cardiomyocytes, we were able to determine the minimal cardiomyocyte number sufficient for normal lifelong cardiac function. Survivin overexpression in cultured cardiomyocytes inhibited apoptosis, induced DNA synthesis, and promoted cell cycle progression. In the failing human heart, survivin was potently induced and decreased again after hemodynamic relief through a mechanical left ventricular assist device. We observed that the long-known existence of polyploidy of cardiomyocytes in the failing human heart was remarkably decreased after hemodynamic support and correlated with the level of survivin expression at any time. Thus, survivin may be a marker of DNA synthesis, polyploidy, or possibly even cell cycle traverse in the failing human heart, making it a bona fide target for myocardial regeneration therapies. We suggest that the individual number of "cardiomyocyte working units" that are under the control of survivin may be an independent factor in the susceptibility to cardiac diseases independently of their cause. See p 1583.
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