Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Percutaneous Coronary Intervention Versus Optimal Medical Therapy for Prevention of Spontaneous Myocardial Infarction in Subjects With Stable Ischemic Heart Disease
- Targeting GGTase-I Activates RHOA, Increases Macrophage Reverse Cholesterol Transport, and Reduces Atherosclerosis in Mice
- A Meta-Analysis of Aortic Root Size in Elite Athletes
- Resequencing and Clinical Associations of the 9p21.3 Region: A Comprehensive Investigation in the Framingham Heart Study
- Disparities in Revascularization Rates After Acute Myocardial Infarction Between Aboriginal and Non-Aboriginal People in Australia
- Cost-Effectiveness of Percutaneous Coronary Intervention With Drug Eluting Stents Versus Bypass Surgery for Patients With Diabetes Mellitus and Multivessel Coronary Artery Disease: Results From the FREEDOM Trial
- Quantitative Analysis of Mitral Valve Morphology in Mitral Valve Prolapse With Real-Time 3-Dimensional Echocardiography: Importance of Annular Saddle Shape in the Pathogenesis of Mitral Regurgitation
- Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis
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Percutaneous Coronary Intervention Versus Optimal Medical Therapy for Prevention of Spontaneous Myocardial Infarction in Subjects With Stable Ischemic Heart Disease
Contemporary studies have shown that spontaneous myocardial infarction (MI) but not procedural MI is related to subsequent mortality. In trials in which procedural MI preferentially occurs with higher frequency in one arm, such as percutaneous coronary intervention versus optimal medical therapy trials, the definition and prognostic significance of these biomarker elevations assume significance because the trial interpretation will change on the basis of the frequency of these events. Procedural MI, which occurs at a frequency as high as 50% on the basis of the biomarker tested and the definition used, has the potential to completely change the results of clinical trials. In the present study of patients with stable ischemic heart disease, percutaneous coronary intervention compared with optimal medical therapy alone was associated with significant reduction in the risk of spontaneous non–procedure-related MI at the risk of procedural MI with no difference in all MI, thus suggesting that the interpretation of these trials varies depending on the MI definition used. The present report shows that the point estimate for mortality parallels the prevention of spontaneous MI but not procedural MI, suggesting that spontaneous non–procedure-related MI is prognostically more important, consistent with recently published reports. Further trials are needed to determine whether these associations are causal. If the results of the percutaneous coronary intervention versus optimal medical therapy trials are true (with no difference in MI) and are to be seen in routine clinical practice, postprocedure marker measurement (rarely drawn routinely in the United States) needs to be implemented universally. This only applies if procedural MI is determined to be prognostically important in future studies. See p 769.
Targeting GGTase-I Activates RHOA, Increases Macrophage Reverse Cholesterol Transport, and Reduces Atherosclerosis in Mice
The RHO family proteins undergo posttranslational lipidation by protein geranylgeranyltransferase (GGTase-I). It is widely believed that geranylgeranylation is essential for membrane targeting and activity of the RHO proteins; this notion is supported by numerous studies using statins to reduce prenylation in cells. However, we recently demonstrated that knockout of GGTase-I in macrophages hyperactivates RHOA, RAC1, and CDC42; increases cytokine production; and induces rheumatoid arthritis in mice. In this study, we tested whether the increased inflammatory signaling of GGTase-I–deficient macrophages and the systemic inflammation and rheumatoid arthritis would accelerate atherosclerosis development in low-density lipoprotein receptor–deficient mice. As expected, aortic lesions in mice lacking GGTase-I in macrophages contained significantly more T lymphocytes compared with control. But surprisingly, aortic lesions were markedly reduced. Analyses of GGTase-I–deficient macrophages revealed reduced foam cell formation and a striking increase in basal and high-density lipoprotein–stimulated cholesterol efflux, which resulted in increased levels of macrophage-stimulated reverse cholesterol transport in vivo. The increased cholesterol efflux of GGTase-I–deficient macrophages was caused by RHOA-mediated upregulation of cyclooxygenase 2–peroxisome proliferator-activated receptor-γ signaling, which resulted in increased expression of the scavenger receptors SR-B1 and CD36. The results are clinically relevant in that they demonstrate a potent antiatherogenic effect of blocking prenylation in the face of inflammation and rheumatoid arthritis, diseases that normally carry increased risks of atherosclerosis. Moreover, reduced prenylation of RHO proteins is frequently cited as a mechanism for the antiatherogenic properties of statins. See p 782.
A Meta-Analysis of Aortic Root Size in Elite Athletes
The aorta is exposed to hemodynamic stress during exercise, but whether or not the aorta is larger in athletes is not clear. We performed a systematic literature review and meta-analysis to examine whether athletes demonstrate increased aortic root dimensions compared with nonathlete controls. We identified 23 studies reporting aortic root dimensions at the aortic valve annulus or sinus of Valsalva in 5580 unique elite athletes. Athletes were compared directly with controls (n=727) in 13 studies. On meta-regression, the weighted mean aortic root diameter measured at the sinuses of Valsalva was 3.2 mm (P=0.02) larger in athletes than in the nonathletic controls, whereas aortic root size at the aortic valve annulus was 1.6 mm (P=0.04) greater in athletes than in controls. Our analysis shows that elite athletes have a small but significantly larger aortic root diameter at the sinuses of Valsalva and aortic valve annulus, but this difference is minor and clinically insignificant. Clinicians evaluating athletes should know that marked aortic root dilatation likely represents a pathological process and not a physiological adaptation to exercise. See p 791.
Resequencing and Clinical Associations of the 9p21.3 Region: A Comprehensive Investigation in the Framingham Heart Study
The chromosome region 9p21.3 of the human genome is among the strongest and most consistently nonmendelian gene regions associated with subclinical coronary artery disease, coronary artery disease, and myocardial infarction, but questions remain about the impacted genes and mechanisms. We tested the hypothesis that rare variants, deletions, or duplications in the region may underlie the associations in the region and directly alter expression of both protein-coding and noncoding genes. The present study sequenced the 9p21.3 region of the genome in myocardial infarction case subjects (n=94), individuals with no myocardial infarction but a high burden of subclinical disease (n=94), and control individuals (n=93). Identified genetic markers were tested in thousands of participants in the Framingham Heart Study in association with disease risk factors, subclinical vascular disease, clinical myocardial infarction, and RNA levels of genes in the region. Additional sequencing data from myocardial infarction case and control subjects in other studies were used to examine associations of rare variants with disease. We observed that modest effects of frequent population variants (single-nucleotide polymorphisms) that alter RNA levels produced from the CDKN2B gene and/or the non–protein-coding gene ANRIL are the most likely explanation for subclinical and clinical disease associations at 9p21.3. These findings suggest pathways for therapies to prevent or treat subclinical and clinical coronary artery disease and suggest that further mechanistic studies may require detailed tissue- and context-dependent molecular studies. A lack of association of 9p21.3 markers with traditional cardiovascular risk factors argues strongly against mechanisms that involve these known risk factors. See p 799.
Disparities in Revascularization Rates After Acute Myocardial Infarction Between Aboriginal and Non-Aboriginal People in Australia
Ischaemic heart disease is a leading contributor to the health gap experienced by Aboriginal Australians. Despite Australia’s universal health care system, Aboriginal people have lower rates of revascularization after acute myocardial infarction (AMI). However, because a greater proportion of Aboriginal people live in rural areas, they are more likely than other Australians to be admitted to smaller, regional hospitals without the facilities to perform revascularization. This study modelled Aboriginal and non-Aboriginal revascularization rates after AMI from July 2001 to December 2008, using administrative hospital data. To better understand the reasons for the population-level disparity in revascularization rates, we sequentially adjusted for demographic characteristics, hospital of admission, and individual risk factors. We found that among patients of the same age, sex, year of admission and AMI type, Aboriginal patients had an overall 37% lower rate of revascularization after AMI compared with non-Aboriginal patients, but an 18% lower rate of revascularization compared with non-Aboriginal patients admitted to the same hospital. The disparity was further reduced after adjusting for the presence of comorbidities such as diabetes mellitus, chronic obstructive pulmonary disease and renal failure, as well as smoking, drug and alcohol use and private health insurance, leaving a nonsignificant 4% disparity. In summary, we found the overall disparity in revascularization rates for Aboriginal compared with non-Aboriginal Australians was associated with lower revascularization rates for all patients admitted to smaller regional and rural hospitals and, among Aboriginal patients, higher levels of chronic conditions and risk behaviors, and lower levels of private health insurance. See p 811.
Cost-Effectiveness of Percutaneous Coronary Intervention With Drug Eluting Stents Versus Bypass Surgery for Patients With Diabetes Mellitus and Multivessel Coronary Artery Disease: Results From the FREEDOM Trial
Clinical results from the Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) Trial showed that for patients with diabetes and multivessel coronary artery disease, coronary artery bypass graft (CABG) versus percutaneous coronary intervention (PCI) with drug-eluting stents was associated with lower rates of death, myocardial infarction, or stroke, with the benefit driven by significant reductions in both death and myocardial infarction. This prospective economic evaluation was performed to provide additional insight into the relative value of CABG versus PCI in the drug-eluting stents era from the perspective of the US healthcare system. FREEDOM enrolled patients with complex coronary artery disease and approximately one-third of PCI patients required more than one index PCI procedure, with a mean of 4.1 drug-eluting stents implanted per patient. Total procedure costs were roughly $3000 higher with PCI ($13 000 versus $9700), whereas postprocedure costs were twice as high with CABG, yielding total hospitalization costs that were ≈$8600 higher with CABG ($35 000 versus $26 000). Over the 5-year follow-up period, higher initial costs with CABG were offset by lower costs associated with the need for repeat revascularization, yielding incremental costs with CABG of $3600 at 5 years. Cost-effectiveness analysis based on lifetime projections of quality-adjusted life-years and costs demonstrated that CABG was a highly cost-effective treatment with an incremental cost-effectiveness ratio of roughly $8000/quality-adjusted life-year gained, and showed similarly favorable results across a broad range of sensitivity and subgroup analyses. These findings therefore provide additional support for existing guidelines that recommend CABG for diabetic patients with multivessel coronary artery disease. See p 820.
Quantitative Analysis of Mitral Valve Morphology in Mitral Valve Prolapse With Real-Time 3-Dimensional Echocardiography: Importance of Annular Saddle Shape in the Pathogenesis of Mitral Regurgitation
Mitral valve prolapse is a common disorder with a prognosis determined by the development of mitral regurgitation (MR). Decades of echocardiography and cardiac surgery have shown that degenerative MR is a consequence of pathologically altered valve morphology. However, attempts to use 2-dimensional slices to comprehend a complex 3-dimensional structure of the mitral valve have provided an incomplete picture. We undertook a quantitative 3-dimensional echocardiographic study in patients with mitral valve prolapse with a wide spectrum of MR severity to characterize the link between mitral morphology and MR severity. For the first time in humans, we demonstrated that annular flattening, represented by a reduced ratio of annular height to commissural width, is strongly associated with progressive leaflet billowing, higher frequencies of chordal rupture, and greater regurgitant orifices. The lower limit of the ratio of annular height to commissural width in healthy population appears to be 15%, and a ratio <15% is strongly associated with moderate or severe MR among patients with mitral valve prolapse. Importantly, annular height and ratio of annular height to commissural width are reduced even in patients with mitral valve prolapse and no or mild MR, suggesting the possibility of primary annular abnormality. Such annular flattening was not observed in patients with organic MR due to nonprolapse leaflet pathologies. We proposed annular flattening as a novel geometric mechanism in the pathogenesis of degenerative MR, adding to our understanding of how MR begets MR: A decrease in annular nonplanarity will exert increased tension on the leaflets and chordae, promoting rupture of mechanically weakened chords and the progressive disease seen clinically. See p 832.
Vascular Endothelial Adrenomedullin-RAMP2 System Is Essential for Vascular Integrity and Organ Homeostasis
Adrenomedullin (AM), originally identified as a vasodilating peptide, is now recognized to be a pleiotropic vasoactive molecule involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis. Because of its wide range of bioactivity, AM has been attracting attention for its potential clinical applications. On the other hand, the clinical applicability of AM, like that of other bioactive endogenous peptides, has limitations: AM has a very short half-life in the blood, which makes the use of AM impractical for the treatment of chronic diseases. It is noteworthy that we were able to modulate the vascular function of AM by modulating receptor activity-modifying protein 2 (RAMP2). RAMP2 in particular could be a therapeutic target by which to manipulate the vascular functions of AM. Because RAMPs are low-molecular-weight proteins, structural analysis and the synthesis of specific agonists or antagonists are much more realistic compared with the AM receptor calcitonin-receptor-like receptor, which belongs to 7-transmembrane domain G protein–coupled receptors. The vascular AM-RAMP2 system plays critical roles in the regulation of vascular integrity, including the maintenance of vascular structure, regulation of angiogenesis, and vasoprotection against vascular injury. In that context, studies of AM and RAMP2 should bring about novel approaches for the treatment of diseases derived from vascular failure. Conditional gene targeting models in this study, which enable the spatial and temporal modulation of the gene expression, could elucidate the detailed pathophysiological roles of the AM-RAMP2 system. See p 842.
- © 2013 American Heart Association, Inc.
- A Meta-Analysis of Aortic Root Size in Elite Athletes
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