- Peripheral Arterial Disease Is Associated With Higher Rates of Hip Bone Loss and Increased Fracture Risk in Older Men
- A Functional Single-Nucleotide Polymorphism in the TRPC6 Gene Promoter Associated With Idiopathic Pulmonary Arterial Hypertension
- Genetic Deficit of SK3 and IK1 Channels Disrupts the Endothelium-Derived Hyperpolarizing Factor Vasodilator Pathway and Causes Hypertension
- Evaluation of the Novel Myocardial Perfusion Positron-Emission Tomography Tracer 18F-BMS-747158-02: Comparison to 13N-Ammonia and Validation With Microspheres in a Pig Model
- One-Year Clinical Outcomes, Midterm Survival, and Predictors of Mortality After Carotid Stenting in Elderly Patients
- Unprotected Left Main Stenting in the Real World: Two-Year Outcomes of the French Left Main Taxus Registry
- MicroRNA-320 Is Involved in the Regulation of Cardiac Ischemia/Reperfusion Injury by Targeting Heat-Shock Protein 20
- Conventional Dendritic Cells at the Crossroads Between Immunity and Cholesterol Homeostasis in Atherosclerosis
- Aortic Arch Plaques and Risk of Recurrent Stroke and Death
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Peripheral Arterial Disease Is Associated With Higher Rates of Hip Bone Loss and Increased Fracture Risk in Older Men
Fractures related to osteoporosis and peripheral arterial disease are major causes of morbidity and mortality in older people. Previous large observational studies have provided evidence of an association between bone loss and either incident cardiovascular disease or subclinical atherosclerosis. Evidence also exists to support an association between atherosclerosis of peripheral vessels and osteoporosis. Using the ankle-brachial index and initial and repeat hip bone mineral density in a cohort of community-dwelling men 65 years of age and older in the Osteoporotic Fractures in Older Men (MrOS) study, we found that men with peripheral arterial disease have higher rates of hip bone loss and an increased risk of nonspine fractures. These findings suggest that peripheral arterial disease should be added to the list of secondary medical conditions that are associated with a greater likelihood of higher rates of bone loss and fracture among older people. Future research should examine potential biological mechanisms underlying this association. See p 2305.
A Functional Single-Nucleotide Polymorphism in the TRPC6 Gene Promoter Associated With Idiopathic Pulmonary Arterial Hypertension
Genetic modifications of key genes have been associated with increased pulmonary vascular remodeling and incidence of disease in idiopathic pulmonary arterial hypertension (IPAH). We previously reported that upregulation of canonical transient receptor potential 6 (TRPC6) may be responsible for the abnormal pulmonary artery smooth muscle cell proliferation and pulmonary vascular medial hypertrophy in IPAH patients. This study identifies a gain-in-function single-nucleotide polymorphism (SNP) in the TRPC6 promoter −254(C→G) with a significantly higher allele frequency in IPAH patients from the USA and Germany. This −254(C→G) variation generates a functional binding site for nuclear factor-κB, which results in regulation of TRPC6 expression and function in modulating cytosolic Ca2+ levels in pulmonary artery smooth muscle cells. Examination of isolated pulmonary artery smooth muscle cells from IPAH patients further confirms that the presence of the −254(C→G) single-nucleotide polymorphism is linked to TRPC6 expression and function. These findings provide a strong putative link between the inflammatory response (or activated nuclear factor-κB), which has been suggested in part to underlie IPAH, and altered TRPC6 channel function, providing an alternative therapeutic strategy to treat IPAH patients and to prevent the occurrence of IPAH. See p 2313.
Genetic Deficit of SK3 and IK1 Channels Disrupts the Endothelium-Derived Hyperpolarizing Factor Vasodilator Pathway and Causes Hypertension
The arterial endothelium modulates vascular tone and blood pressure by releasing nitric oxide and prostacyclin, as well as by a third factor or signalling pathway termed “endothelium-derived hyperpolarizing factor” (EDHF). Herein, we show that EDHF-type signalling and dilations strongly depend on the presence of endothelial KCa-channels (SK3/IK1) and that their lack has a significant impact on vascular dilation and blood pressure control in vivo. Thus, SK3/IK1-deficient mice may help to shed light on the role of EDHFs in cardiovascular pathologies such as atherosclerosis, hypertension, and stroke. Strikingly, the EDHF-potentiating effects of the IK1-opener SKA-31 and the partial rescue of EDHF deficiency by overexpression of SK3 returned blood pressure to almost normotensive levels, suggesting that selective pharmacological activators of endothelial SK3 and IK1 may be of therapeutic value in the treatment of hypertension. In support of this hypothesis, we recently demonstrated that SKA-31 significantly lowers blood pressure in angiotensin II hypertensive mice. Pharmacological activation of endothelial KCa channel activity might be particularly desirable in situations where the EDHF response is impaired because of a decreased activity of endothelial KCa channels, as has been reported after cardiopulmonary bypass, balloon catheter angioplasty, and chronic renal failure. See p 2323.
Evaluation of the Novel Myocardial Perfusion Positron-Emission Tomography Tracer 18F-BMS-747158-02: Comparison to 13N-Ammonia and Validation With Microspheres in a Pig Model
Because of its unique ability to quantify regional myocardial perfusion in absolute terms, positron-emission tomography (PET) provides high sensitivity for detection of coronary artery disease and allows evaluation of early abnormalities in coronary vasoreactivity in patients at risk. However, the short half-life, on the order of minutes, of typical myocardial blood flow PET tracers limits its clinical use, unless an on-site cyclotron is available. 18F-BMS-747158-02 is a novel 18F-labeled PET perfusion tracer that targets the mitochondrial complex. Its longer half-life allows distribution from a central cyclotron facility. In the present study, we evaluated its imaging properties in a large animal model using a clinical PET scanner and validated its use for quantification of myocardial blood flow using kinetic modeling. 18F-BMS-747158-02 PET provided excellent image quality that allowed accurate delineation of perfusion defects caused by transient constriction of a coronary artery. Ratios of 18F-BMS-747158-02 uptake between the heart and surrounding tissues, including liver, lung, and blood, were significantly higher than those of the current standard tracer, ammonia. Compared with the “gold standard,” microspheres, 18F-BMS-747158-02 PET proved to be highly accurate in measuring blood flow over a wide range of flow values under rest and pharmacological stress. Thus, 18F-BMS-747158-02 is a very attractive new PET perfusion tracer that provides excellent image quality and quantitative measures of regional myocardial perfusion. These, combined with its long tracer half-life, indicate that this tracer has potential in the clinical workup of patients with suspected or proven coronary artery disease. See p 2333.
One-Year Clinical Outcomes, Midterm Survival, and Predictors of Mortality After Carotid Stenting in Elderly Patients
Carotid stenting (CS) is increasingly performed as a method of carotid revascularization. CS has been shown to be noninferior compared with carotid endarterectomy in high–surgical-risk patients. The Carotid Revascularization Endarterectomy Versus Stent Trial (CREST) lead-in phase showed that octogenarians had a markedly elevated 30-day periprocedural stroke or death rate compared with nonoctogenarians that was independent of other factors. Several registries and single-center studies have also reported increased adverse events in this elderly group. Recent reports suggest, however, that CS can be performed in octogenarians with low complication rates. Our previous study showed that CS performed by experienced operators in carefully selected patients resulted in event rates that were within the American Heart Association guidelines for both symptomatic and asymptomatic patients. However, it remains uncertain whether elderly patients, particularly the asymptomatic subgroup, will benefit because, in addition to periprocedural risks, longevity after revascularization is an important consideration. Symptomatic patients derive benefit from carotid revascularization within 2 years, whereas asymptomatic patients require 5 years. No data on survival or predictors of mortality after CS in elderly patients are available. This study demonstrates that a high proportion (85%) of appropriately selected elderly patients survive 2 years and >75% survive at least 3 years after CS. Thus, CS can be considered a revascularization option in most elderly patients. Better patient selection using the predictors of mortality identified may help to optimize the likelihood of survival and to reduce unwarranted procedures. Larger studies are warranted to determine long-term survival, to further identify predictors of mortality, and to validate the role of stenting in the elderly. See p 2343.
Unprotected Left Main Stenting in the Real World: Two-Year Outcomes of the French Left Main Taxus Registry
This was the largest prospective, multicenter, real-world registry of patients with unprotected left main disease who were treated with a paclitaxel-eluting stent with a uniform technical strategy of provisional side-branch T-stenting for distal left main coronary artery disease. The advanced age and the high proportion of bifurcation disease account for the unselected nature of the population. The results obtained at the 2-year follow-up, complete for 99% of patients, illustrate the safety and efficacy of this technique, with a device-oriented major adverse cardiac event rate of 15.8% (including cardiac death in 5.4% and target-lesion revascularization in 8.7% of patients). Particular attention was paid to left main stent thrombosis, with a low rate of definite or probable stent thrombosis according to Academic Research Consortium definitions at 2-year follow-up (0.7%). This study also provides valuable information about clinical outcomes after distal left main stenting, which in the past has been associated with a higher risk of adverse outcomes. Furthermore, this study addresses the important issue of outcomes in patients with left main restenosis, showing that the vast majority of these patients had stable presentations and focal restenosis, treated in the majority of cases by repeat percutaneous coronary intervention with very acceptable outcomes. See p 2349.
MicroRNA-320 Is Involved in the Regulation of Cardiac Ischemia/Reperfusion Injury by Targeting Heat-Shock Protein 20
MicroRNAs (miRNAs) are a class of small noncoding RNAs with important posttranscriptional regulatory functions. Recent data suggest that miRNAs are aberrantly expressed in many human diseases including cardiovascular disease, which leads to an increasing interest in miRNA regulation as a therapeutic and diagnostic approach. Of note, multiple genes/proteins have been shown to be aberrantly expressed in infarcted hearts, which are responsible for cardiac remodeling after ischemia/reperfusion (I/R). In the present study, we used microarrays to profile the expression of 640 probed miRNAs in murine hearts on I/R in vivo and ex vivo. Several miRNAs were differentially expressed between shams and I/R hearts, with miR-320 showing downregulation consistently in I/R hearts ex vivo and in vivo relative to the shams. Gain-of-function and loss-of-function approaches were employed in cultured adult rat cardiomyocytes and in mouse hearts to investigate the functional roles of miR-320. Our data indicate that the increased levels of miR-320 may be responsible for cardiac I/R injury, whereas downregulation of miR-320 may be protective. Administration of antagomir-320, which specifically knocked down endogenous miR-320, significantly decreased cardiac infarction size. Thus, systemically or locally applied mimic or inhibitory miRNA molecules (ie, antagomir) that influence specific cardiac miRNAs may finally open novel miRNA-based therapies for heart disease. See p 2357.
Conventional Dendritic Cells at the Crossroads Between Immunity and Cholesterol Homeostasis in Atherosclerosis
In healthy and pathological tissues, dendritic cells (DCs) are the most effective cells to present antigens and to initiate immune responses. DCs have an elevated capacity to stimulate T lymphocytes, natural killer lymphocytes, and B lymphocytes. Thus, they represent a potential tool for vaccination or immunotherapy in infectious disease, cancers, transplant rejection, autoimmune diseases, and immunoinflammatory diseases. During atherogenesis, immunoinflammatory mechanisms contribute to the progression of atherosclerotic lesions; however, the precise role of DCs in the progression of atherosclerosis and related cardiovascular disease is indeterminate. To address this question, we created transgenic mice in which the lifespan of DCs was increased in response to elevated resistance to apoptosis (CD11c-hBcl2) on the one hand, and on the other, we used mice in which targeted depletion of DCs (CD11c-DTR [diphtheria toxin receptor]) could be achieved. The present data provide the first in vivo evidence that DCs profoundly and broadly impact immune responses in atherosclerosis and, unexpectedly, circulating cholesterol levels, a major cardiovascular risk factor. The impact of DCs on cholesterolemia level is relevant to data published in preclinical and clinical studies using granulocyte-macrophage colony stimulating factor, a well-known DC growth factor. Indeed, granulocyte-macrophage colony stimulating factor induced a reduction in circulating cholesterol levels in treated patients. Considered together, the potential role of DCs as a central regulator of both immunity and cholesterol homeostasis opens new therapeutic horizons in the treatment of atherosclerosis. See p 2367.
Aortic Arch Plaques and Risk of Recurrent Stroke and Death
Large aortic arch plaques are associated with increased risk of ischemic stroke. The efficacy of antithrombotic therapies in reducing this risk has not been established. This study examined the risk of recurrent stroke and death associated with the presence of aortic plaques in 516 patients with acute ischemic stroke randomized to warfarin or aspirin treatment. The prevalence of large plaques (ie, ≥4 mm thick) in this study group was 19.6%; that of large complex plaques (ie, large plaques with ulcerations or mobile components) was 8.5%. After 2 years of follow-up, the presence of large aortic plaques was associated with a 2-fold increase in risk of stroke and death after adjustment for other risk factors; the risk was especially high (2.5-fold increase) when complex plaque morphology was present. Patients whose index stroke had no clear explanation (ie, cryptogenic stroke) had a much greater risk of recurrent events when large arch plaques were present, especially when complex plaque features existed. Therefore, in patients with cryptogenic stroke, the aortic arch should be examined for the presence of plaque, and plaque thickness and morphology should be recorded for risk stratification. In this study, the risk of recurrent stroke and death associated with large aortic plaques remained significant despite prophylactic treatment with warfarin or aspirin, suggesting that different treatment strategies or better selection of patients for antithrombotic strategies may be necessary. See p 2376.
- Aortic Arch Plaques and Risk of Recurrent Stroke and Death
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