Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Clinical Events as a Function of Proton Pump Inhibitor Use, Clopidogrel Use, and Cytochrome P450 2C19 Genotype in a Large Nationwide Cohort of Acute Myocardial Infarction: Results From the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) Registry
- Nationwide Cohort Study of Risk of Ischemic Heart Disease in Patients With Celiac Disease
- Efficacy of Quantified Home-Based Exercise and Supervised Exercise in Patients With Intermittent Claudication: A Randomized Controlled Trial
- Appropriate Use Criteria For Stress Single-Photon Emission Computed Tomography Sestamibi Studies: A Quality Improvement Project
- Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality After Myocardial Infarction
- Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide–Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia
- Dexamethasone Arterializes Venous Endothelial Cells by Inducing Mitogen-Activated Protein Kinase Phosphatase-1: A Novel Antiinflammatory Treatment for Vein Grafts?
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Clinical Events as a Function of Proton Pump Inhibitor Use, Clopidogrel Use, and Cytochrome P450 2C19 Genotype in a Large Nationwide Cohort of Acute Myocardial Infarction: Results From the French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) Registry
Over the past months, there has been an intense scientific debate on the potential clinical impact of proton pump inhibitor use in patients treated with clopidogrel. There is a potential for drug-drug interactions because many proton pump inhibitors are metabolized by or are inhibitors of the cytochrome P450 2C19 (CYP2C19) enzyme. The stakes are considerable, given the huge number of patients treated with these medications. Specifically, the impact of CYP2C19 genetic polymorphisms on clinical outcomes in patients receiving a proton pump inhibitor and clopidogrel has not been evaluated. Overall, proton pump inhibitor use was not associated with an increased risk for any of the main outcomes (in-hospital and 1-year survival, 1-year myocardial infarction– and stroke-free survival, 1-year major ischemic events in hospital survival, in-hospital bleeding and transfusion) in either the overall population or any of the subgroups tested. One of the key new findings of the present analysis is that there was no clinically relevant association in adverse cardiovascular events or mortality among patients with no or 1 CYP2C19 loss-of-function allele. Thus, in this population, the results do not support the avoidance of proton pump inhibitor use for those patients receiving clopidogrel who are at increased risk of gastrointestinal bleeding. However, because of the low number of patients and resultant large confidence interval ranges, the possibility that a higher early risk may exist in patients with 2 CYP2C19 variant alleles cannot be dismissed and needs further clinical studies. We believe that these results are important for physicians in charge of these patients. See p 474.
Nationwide Cohort Study of Risk of Ischemic Heart Disease in Patients With Celiac Disease
Celiac disease (CD) is an immune-mediated disease that occurs in some 1% of the Western population. Triggered by exposure to gluten, CD is characterized by small intestinal villous atrophy and inflammation. Ischemic heart disease (IHD) is one of the main causes of death. The underlying pathology in IHD is atherosclerosis, and it seems that chronic inflammation plays an important role in the development of atherosclerosis. The present study found a 19% increased risk of IHD in individuals with CD. This study also found a 28% increased risk of IHD in individuals with small intestinal inflammation but no villous atrophy and a 14% increase in individuals with normal mucosa but positive CD serology (latent CD). This corresponded to excess risks of 60 per 100 000 person-years in CD (179 in inflammation and 31 in latent CD). Some 16% of all IHD in patients with CD could be attributed to the underlying CD. Because cardiovascular disease is the most common cause of death in this group of patients, our findings may have important implications in patients with CD. Increased awareness of IHD risk factors in this patient group is warranted, and if our findings are corroborated by others, clinical guidelines of treatment of CD may have to include a more detailed cardiovascular risk assessment than what is current practice. See p 483.
Efficacy of Quantified Home-Based Exercise and Supervised Exercise in Patients With Intermittent Claudication: A Randomized Controlled Trial
A primary therapeutic goal for patients with peripheral artery disease and intermittent claudication is to regain lost ambulatory function through exercise rehabilitation. Medically supervised exercise programs are efficacious for improving claudication onset time and peak walking time, but more patients could benefit from an exercise program transported to the community setting (ie, home-based walking). However, home exercise has been poorly studied. This prospective, randomized, controlled clinical trial compared changes in claudication onset time, peak walking time, and daily ambulatory activity in peripheral artery disease patients with intermittent claudication after home-based exercise, supervised exercise, and usual-care control. Both exercise programs consisted of intermittent walking to near-maximal claudication pain for 12 weeks. We used a step activity monitor to address the primary flaw of previous home exercise programs by objectively measuring ambulatory cadence during home exercise sessions. Patients in home-based exercise completed 83% of their exercise sessions, averaging 42 minutes per session at a cadence of 37 strides per minute, and they increased claudication onset time, peak walking time, and daily ambulatory cadences apart from the exercise sessions. The changes in claudication onset time and peak walking time after home-based exercise were similar to those after supervised exercise, whereas the change in daily ambulatory cadences was greater. The clinical implication is that a home-based exercise program consisting of ambulatory monitoring, biweekly 15-minute meetings with staff, and feedback motivated patients to adhere to the program and may serve as a new model for improving claudication measures in more patients with less effort and fewer resources than a traditional supervised exercise program. See p 491.
Appropriate Use Criteria For Stress Single-Photon Emission Computed Tomography Sestamibi Studies: A Quality Improvement Project
In a previous study, we reported the application of the published American College of Cardiology Foundation appropriate use criteria for stress single-photon emission computed tomography (SPECT) imaging to patients at Mayo Clinic (Rochester, MN) in 2005 and 2006. This study reports the results of a subsequent internal quality improvement project focused on physician education, including a presentation at Medical Grand Rounds, a publication in the staff newsletter, meetings with physician administrators, and focused presentations to pertinent department/divisions of ordering physicians. Remeasurement of the appropriateness of SPECT studies was then performed using previously published methods. Unfortunately, the rate of inappropriate SPECT studies did not decrease as hoped but in fact showed a borderline increase (P=0.06). Thus, this quality improvement project did not achieve the desired reduction in the rate of inappropriate stress SPECT studies in a single academic medical center. More extensive intervention may be necessary to achieve quality improvement with appropriateness criteria. See p 499.
Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality After Myocardial Infarction
Paracrine mechanisms are thought to contribute to the beneficial effects of bone marrow cells on perfusion and function of the infarcted heart that have been demonstrated in experimental studies and some clinical trials. We have previously identified fibroblast growth factor 9 (FGF9) as 1 of >100 paracrine factors that are secreted from bone marrow cells after myocardial infarction. In the embryonic heart, FGF9 is expressed by the epicardium and endocardium and provides an epithelial-to-mesenchymal signal to stimulate coronary artery formation and cardiomyoblast expansion in the developing myocardium. FGF9, however, is expressed only at very low levels in the adult heart. Using a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter, we show here that conditional expression of FGF9 in the adult mouse myocardium supports functional adaptation and survival after myocardial infarction. Transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion, reduced interstitial fibrosis, attenuated fetal gene expression, preserved diastolic but improved systolic function, and markedly reduced heart failure mortality. A single injection of an adenoviral vector encoding FGF9 promoted similar improvements in left ventricular systolic function and survival after myocardial infarction. Mechanistically, FGF9 acted primarily on endothelial cells to promote angiogenesis and paracrine release of prohypertrophic factors, including bone morphogenetic protein 6. These observations support the idea that secretome analyses in bone marrow cells can lead to the identification of secreted factors with therapeutic activity after myocardial infarction. Specifically, the data suggest a previously unrecognized therapeutic potential for FGF9 after myocardial infarction. See p 504.
Inhibition of p38 Mitogen-Activated Protein Kinase Improves Nitric Oxide–Mediated Vasodilatation and Reduces Inflammation in Hypercholesterolemia
Hypercholesterolemia is associated with impaired vasomotor endothelial function, which is a recognized surrogate marker of outcome. We tested the hypothesis that a novel p38 MAP kinase inhibitor, losmapimod, could improve nitric oxide–mediated responses in such a cohort. We demonstrated for the first time that moderate blockade of this pathway improved endothelial-dependent and -independent nitric oxide–mediated vasodilatation in addition to reducing systemic inflammation, as evidenced by an almost 60% reduction in high-sensitivity C-reactive protein, without alteration in cholesterol levels. Inhibition of p38 may be an attractive target in patients with underlying vascular inflammation. See p 515.
Dexamethasone Arterializes Venous Endothelial Cells by Inducing Mitogen-Activated Protein Kinase Phosphatase-1: A Novel Antiinflammatory Treatment for Vein Grafts?
Vein or artery grafts are used as conduits in cardiac and vascular surgery. Vein grafts are susceptible to inflammation, intimal hyperplasia, and accelerated atherosclerosis, which cause late failure rates of up to 40% of grafts within 10 years of surgery, whereas artery grafts are relatively resistant. Blood flow influences the physiology of vascular endothelial cells by exerting a frictional force, shear stress, on the vascular wall. To elucidate the molecular mechanisms that control differential responses of arteries and veins to grafting, we compared the effects of arterial flow on proinflammatory activation of venous and arterial endothelial cells. We demonstrate that arterial but not venous endothelial cells are protected from proinflammatory activation in response to arterial flow through the induction of mitogen-activated protein (MAP) kinase phosphatase-1, which negatively regulated inflammatory p38 MAP kinase signaling. Because inflammation of vein grafts leads to intimal hyperplasia and failure, strategies to suppress early inflammatory responses to arterial hemodynamics may prolong graft survival. A key observation from our study is that pharmacological induction of MAP kinase phosphatase-1, via a brief treatment with dexamethasone, can arterialize endothelial cells in porcine or human veins, thus protecting them from inflammatory activation in response to arterial flow. We suggest that brief perioperative treatment of veins using dexamethasone may therefore provide an attractive novel therapeutic strategy to reduce graft inflammation while avoiding the undesirable side effects associated with systemic glucocorticoid treatment. See p 524.
- © 2011 American Heart Association, Inc.
- Nationwide Cohort Study of Risk of Ischemic Heart Disease in Patients With Celiac Disease
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