Circulation. 2008;117:331-332
doi: 10.1161/CIRCULATIONAHA.107.188517
doi: 10.1161/CIRCULATIONAHA.107.188517
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(Circulation. 2008;117:331-332.)
© 2008 American Heart Association, Inc.
Clinical Summaries
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Angiotensin II Activates Signal Transducer and Activators of Transcription 3 via Rac1 in Atrial Myocytes and Fibroblasts: Implication for the Therapeutic Effect of Statin in Atrial Structural Remodeling |
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Angiotensin II Activates Signal...
Mayo Clinic Risk Score...The renin-angiotensin-aldosterone system plays a pivotal role in various cardiovascular diseases. Clinical use of angiontensin-converting enzyme inhibitors or angiotensin blockers is helpful in preventing the progression of many cardiovascular diseases. Basic investigations of the angiotensin II receptor pathways in the heart have focused primarily on ventricular cells. In the present study, we investigated the downstream pathways of the angiotensin II receptor in atrial cells in an attempt to understand the pathogenesis of atrial structural remodeling. An important angiotensin II signaling pathway, the Janus kinase/signal transducers and activators of transcription (STAT) pathway, which has rarely been characterized in the atrium, was found to mediate angiotensin II–induced atrial structural remodeling. Angiotensin II activates signal transducer and activator of transcription 3 through a Rac1-dependent mechanism, which is inhibited by losartan (an angiotensin II type 1 receptor blocker) and a cholesterol-lowering agent, simvastatin, which inhibits Rac1 translocation. Our investigation not only reappraised the beneficial effects of blockade of the renin-angiotensin-aldosterone system in atrial fibrillation but also further elucidated the downstream pathways of the angiotensin II receptor involved in atrial structural remodeling. We also provide a rationale for the use of statins to prevent angiotensin II–related atrial structural remodeling. The clinical effects of statins in the treatment of atrial fibrillation merit further investigation. See p 344.
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Mayo Clinic Risk Score for Percutaneous Coronary Intervention Predicts In-Hospital Mortality in Patients Undergoing Coronary Artery Bypass Graft Surgery |
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This study established that the new Mayo Clinic Risk Score, originally derived to predict outcomes after percutaneous coronary intervention with preprocedure variables, can also predict in-hospital mortality after coronary artery bypass graft surgery. This is the first risk score to demonstrate good discriminatory ability in both patients undergoing percutaneous coronary intervention and those undergoing coronary artery bypass grafting. Favoring its widespread deployment is that it is simple, easy to use, and derived from preprocedural variables without reliance on subjective variables. Using the Society of Thoracic Surgeons database, we found overall acceptable discriminatory ability of the Mayo Clinic Risk Score, with an increase in the observed in-hospital mortality rate with higher Mayo Clinic Risk Scores. Moreover, the model was robust across most low- and high-risk subgroups. See p 356.
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Implantable Cardioverter-Defibrillators in Tetralogy of Fallot |
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Tetralogy of Fallot represents the most common form of congenital heart disease in implantable cardioverter-defibrillator (ICD) recipients; however, little is known about the utility of ICDs in this patient population. We conducted a multicenter cohort study in high-risk patients with tetralogy of Fallot to assess this therapy. In particular, we sought to quantify rates of appropriate and inappropriate ICD shocks, identify risk factors, and characterize ICD-related complications. Overall, 121 patients from 11 sites were included and followed up for a median of 3.7 years. ICD placement was indicated for primary (56%) or secondary (44%) prevention; major indications for primary prevention included palpitations, syncope, or ventricular tachycardia. A high rate of appropriate shocks was present in both primary (7.7%/year) and secondary (9.8%/year) prevention groups, and ICDs were highly effective in interrupting ventricular tachyarrhythmias. In patients with primary prevention indications, the risk of appropriate shocks was modulated by a combination of surgical, hemodynamic, ECG, and electrophysiological factors. Overall, these results suggest that ICDs are effective in primary and secondary prevention against sudden death in this patient population; however, major drawbacks include a high rate of inappropriate shocks (5.8% per year) and late lead-related complications (21%). See p 363.
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Electronic Alerts Versus On-Demand Decision Support to Improve Dyslipidemia Treatment: A Cluster Randomized Controlled Trial |
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Clinical decision support systems have been demonstrated to improve the implementation of evidence-based guidelines by influencing physicians’ behavior. Some systems require the physician to ask for support (that is, the system only provides support when the physician demands that support). Other systems generate alerts to the physician independent of a request by the physician for those alerts. Indirect evidence suggests that alerting users is more effective in changing physician behavior than on-demand systems. However, randomized trials comparing these methods in a clinical setting were lacking. We constructed a clinical decision support system for screening and treatment decisions in the area of dyslipidemia in primary care. The system was integrated into the electronic health record of general practitioners and could function in either an alerting mode or on demand. The system was based on the 1999 guidelines of the Dutch College of General Practitioners. In a clustered randomized trial design, we studied the effect of both alerting and on-demand decision support with respect to screening and treatment of dyslipidemia. In the 38 Dutch practices, with 87 886 eligible patients, we demonstrated that a clinical decision support system alerting users to dyslipidemia-based screening and treatment actions changed physician behavior more than on-demand decision support. In efforts to improve care by using evidence-based guidelines, decision support systems that alert physicians should be considered as an implementation strategy. See p 371.
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Nanoparticle PET-CT Imaging of Macrophages in Inflammatory Atherosclerosis |
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Phagocytic cells in inflammatory atherosclerotic lesions are a key histological component. They actively secrete enzymes involved in plaque progression and rupture and thus have been used as biomarkers for lesion severity. Here, we show that dextran-coated nanoparticles labeled with 64Cu can be used for positron emission tomography imaging of these phagocytes. Combined with computed tomography imaging for anatomic coregistration, the developed approach was highly accurate for detection of inflamed plaques in murine arteries and at tracer concentration. Compared with conventional 18F-fluoro-2-deoxyglucose positron emission tomography imaging, 64Cu-TNP yielded higher target-to-background ratio, presumably as a result of specific targeting to the phagocytic compartment. The approach may have important clinical applications in surveying lesion severity among different vascular beds and as a surrogate for therapeutic efficacy. See p 379.
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Noninvasive In Vivo Imaging of Monocyte Trafficking to Atherosclerotic Lesions |
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Inflammation drives many aspects of atherogenesis and lesion progression and complication. Monocytes, the most numerous inflammatory cells in plaques, function as major effectors of this inflammatory response. Traditional imaging techniques generally visualize the structure of atherosclerotic lesions but do not report the cellular events that critically control the clinical consequences of the disease. The present study describes a technique that enables noninvasive in vivo imaging of monocyte trafficking to atheromata, with the use of Food and Drug Administration–approved components. Its application could provide novel biological insights, aid the evaluation of antiatherogenic drugs, and sharpen the risk stratification of selected patients. See p 388.
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Nix-Mediated Apoptosis Links Myocardial Fibrosis, Cardiac Remodeling, and Hypertrophy Decompensation |
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Left ventricular hypertrophy after hemodynamic overload tends inexorably to functionally decompensate through the process of ventricular remodeling. Ventricular dilation and diminished ejection performance in remodeled ventricles have been associated with histological changes reflecting "dropout" of cardiac myocytes and their replacement with fibrous tissue. An unanswered question is whether genetically programmed cardiomyocyte death in the form of apoptosis, which is observed in pressure overloaded hearts, contributes mechanistically to progressive remodeling and functional decompensation in cardiac hypertrophy. We previously observed stimulated expression of specific apoptosis genes in hearts undergoing physiological stress and recently found that ablation of the ischemia-regulated proapoptotic gene Bnip3 prevented postinfarction left ventricular remodeling in gene-targeted mice (J Clin Invest. 2007;117:2825–2833). Here, we show that a related proapoptotic factor, Nix, which is strikingly induced in pathological cardiac hypertrophy, contributes to adverse remodeling of pressure overload and genetic cardiac hypertrophies. Using mouse models in which the Nix gene was ablated in either the whole animal or specifically in cardiac myocytes, we show that absence of Nix in the heart prevents
50% of apoptotic cardiomyocyte cell death in response to pressure overload or genetically stimulated hypertrophy, restrains left ventricular dilation, and preserves contractile function, thereby preventing development of heart failure. These studies demonstrate feasibility for a general therapeutic strategy of "myocardial regeneration in reverse" by targeting specific stress-induced proapoptotic factors. In the case of pressure overload hypertrophy, functional decompensation can be prevented by minimizing apoptotic myocardial loss and the adverse remodeling that it causes by targeting hypertrophy-inducible Nix. See p 396. |
Perinatal Risk Factors for Ischemic Heart Disease: Disentangling the Roles of Birth Weight and Preterm Birth |
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Several studies have reported an increased risk for ischemic heart disease in adult life among people with a low birth weight. At present, however, it remains unclear whether the association between low birth weight and ischemic heart disease is mediated through poor fetal growth and/or short gestational duration. To study the associations between poor fetal growth and short gestational duration and risk of ischemic heart disease with greater precision than previous studies, we examined all birth records at 4 major delivery units in Sweden for the period of 1925 through 1949 and assembled a cohort of
3000 born preterm and/or with a low birth weight. For comparison, an equal number of subjects with no history of low birth weight or short gestational duration were identified within the same source population. We obtained information on ischemic heart disease through the nationwide Hospital Discharge and Cause of Death Registries for the period of 1987 through 2002. The cohort included >600 cases of ischemic heart disease, and we found that compared with subjects with a normal fetal growth, those born small for gestational age (birth weight 
–2 SD below the mean) had a statistically significant increase in risk of ischemic heart disease of 64%. The negative association between fetal growth and risk of ischemic heart disease was independent of gestational duration. Our study suggests that the association between low birth weight and adult risk of ischemic heart disease is mediated entirely by poor fetal growth. See p 405. |
Osteoprotegerin Inhibits Vascular Calcification Without Affecting Atherosclerosis in ldlr(–/–) Mice |
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Several observational studies show that serum osteoprotegerin levels correlate positively with the severity and progression of coronary artery disease, atherosclerosis, and vascular calcification in patients. However, animal studies suggest that osteoprotegerin may protect against vascular calcification (eg, mice deficient in osteoprotegerin develop aortic calcification). To address this paradox, atherosclerotic ldlr(–/–) mice were fed an atherogenic diet and treated with osteoprotegerin or vehicle. Although serum osteoprotegerin levels increased with initiation of the atherogenic diet (before treatment), exogenous recombinant osteoprotegerin treatment significantly reduced the calcified lesion area and level of the osteogenic marker osteocalcin in the aorta without a significant change in atherosclerosis or cholesterol level. These data support a role for osteoprotegerin in the vasculature as an inhibitor of calcification and a marker, rather than a mediator, of atherosclerosis. See p 411.
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Dietary  -Lipoic Acid Supplementation Inhibits Atherosclerotic Lesion Development in Apolipoprotein E–Deficient and Apolipoprotein E/Low-Density Lipoprotein Receptor–Deficient Mice
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The recognition that inflammation is a key mechanism in the pathogenesis of atherosclerosis and its clinical manifestations (eg, angina pectoris, myocardial infarction, and stroke) has significant implications for cardiovascular disease prevention, treatment, and research at the basic, clinical, and population levels. It is now clear that chronic inflammatory processes and immune mechanisms contribute to the development of atherosclerosis at all stages of the disease. Obesity and hyperlipidemia, as risk factors for atherosclerosis, also are strongly linked to increased vascular inflammation. The present study provides several important new findings: Dietary
-lipoic acid supplementation inhibits atherosclerotic lesion formation in apolipoprotein E– and apolipoprotein E/low-density lipoprotein receptor–deficient mice, 2 widely accepted animal models of human atherosclerosis; and the inhibition of atherosclerosis by -lipoic acid was associated with reduced weight gain, decreased plasma triglycerides, and decreased vascular inflammation. Although our results obtained in animal models cannot be directly extrapolated to humans, they strongly suggest that -lipoic acid supplementation may be useful as an inexpensive but effective intervention strategy that targets inflammation, obesity, and hypertriglyceridemia, thereby reducing known risk factors for the development of atherosclerosis and other inflammatory vascular diseases in humans. See p 421.
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