- Randomized Comparison of Strategies for Type B Aortic Dissection: The INvestigation of STEnt Grafts in Aortic Dissection (INSTEAD) Trial
- The Bypass Angioplasty Revascularization Investigation 2 Diabetes Randomized Trial of Different Treatment Strategies in Type 2 Diabetes Mellitus With Stable Ischemic Heart Disease: Impact of Treatment Strategy on Cardiac Mortality and Myocardial Infarction
- Comparison of Clinical Presentations and Outcomes Between Patients With TGFBR2 and FBN1 Mutations in Marfan Syndrome and Related Disorders
- Economic Outcomes of Treatment Strategies for Type 2 Diabetes Mellitus and Coronary Artery Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial
- Patient Characteristics and Cell Source Determine the Number of Isolated Human Cardiac Progenitor Cells
- Endothelial Estrogen Receptor-α Plays a Crucial Role in the Atheroprotective Action of 17β-Estradiol in Low-Density Lipoprotein Receptor–Deficient Mice
- Randomized Double-Blind Assessment of the ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients With Stable Coronary Artery Disease: The ONSET/OFFSET Study
- Association of Cyclooxygenase-1–Dependent and –Independent Platelet Function Assays With Adverse Clinical Outcomes in Aspirin-Treated Patients Presenting for Cardiac Catheterization
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Randomized Comparison of Strategies for Type B Aortic Dissection: The INvestigation of STEnt Grafts in Aortic Dissection (INSTEAD) Trial
INSTEAD, the first randomized comparison between elective endovascular stent grafting and best medical treatment, justifies medical management for uncomplicated type B aortic dissection and corroborates excellent survival rate with tight blood pressure control and close surveillance. For patients with complications such as progressive expansion or late malperfusion who fail to respond to medical management, deferred endovascular therapy is feasible and safe. The results of INSTEAD do not challenge the endovascular treatment alternative to open surgery and confirm the potential of endovascular therapy to successfully deal with late expansion and distal malperfusion. Nevertheless, primary endovascular therapy in stable type B dissection failed to improve the 2-year survival rate and was associated with spinal injury in 2.9% of cases. Although low death and complication rates in both groups suggest a need for a reappraisal of standardized medical management with monitored blood pressure control, TEVAR is an appropriate crossover strategy in cases of emerging complications. Interestingly, all crossover patients survived elective TEVAR with uneventful follow-up and remodeling despite rather late intervention. INSTEAD supports the notion of a complication-specific approach instead of TEVAR for all type B dissections; patients who survive type B dissection and are given best medical management with surveillance show an excellent 2-year survival rate, with progression to crossover/conversion in only 21%. Surveillance can be used to identify patients with evidence of progression who qualify for safe crossover or conversion. Finally, INSTEAD confirmed that stent-graft scaffolding enhances false-lumen thrombosis and aortic remodeling in type B dissection not only in the early phase of dissections but also in the chronic phase after false-lumen expansion, a notion that may translate to prognostic benefits that could potentially be seen at longer (5-year) follow-up. See p 2519.
The Bypass Angioplasty Revascularization Investigation 2 Diabetes Randomized Trial of Different Treatment Strategies in Type 2 Diabetes Mellitus With Stable Ischemic Heart Disease: Impact of Treatment Strategy on Cardiac Mortality and Myocardial Infarction
In this report from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, we comment on the secondary end points of cardiac death and myocardial infarction. Cardiac death accounted for 43% of all-cause mortality during an average 5.3-year follow-up, emphasizing the critical importance of intensive medical therapy to reduce death rates from cardiovascular disease in patients with type 2 diabetes mellitus and obstructive coronary artery disease. The low cardiac mortality rate is even more impressive when one considers that the Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trials reported that 50% to 53% of deaths were cardiovascular and only 32% to 35% of the population entered had a prior history of known coronary artery disease. The BARI 2D trial enrolled 2368 patients with stable ischemic heart disease assigned before randomization to percutaneous coronary intervention or coronary artery bypass grafting strata, and we found similar 5-year all-cause and cardiac mortality rates with insulin sensitization versus insulin provision therapy and with a strategy of prompt initial coronary revascularization plus intensive medical therapy or intensive medical therapy alone with revascularization reserved for clinical indication(s). We did not find any difference in the percutaneous coronary intervention stratum compared with intensive medical therapy in all-cause death, cardiac death, or myocardial infarction. Thus, for many patients with type 2 diabetes mellitus and stable but less severe and extensive coronary artery disease, intensive medical therapy is an excellent first-line strategy and does not require immediate prophylactic percutaneous coronary intervention to prevent cardiac death or myocardial infarction. In contrast, prompt coronary artery bypass grafting with an intensive medical therapy and insulin sensitization strategy is superior to a strategy of “watchful waiting” and intensive medical therapy alone in patients with more severe and extensive coronary artery disease to prevent nonprocedural myocardial infarctions that are associated with an increased cardiac mortality risk. See p 2529.
Comparison of Clinical Presentations and Outcomes Between Patients With TGFBR2 and FBN1 Mutations in Marfan Syndrome and Related Disorders
Marfan syndrome has been related to mutations in the FBN1 gene coding for fibrillin. More recently, mutations in the TGFBR2 gene coding for transforming growth factor-β receptors have been associated with overlapping phenotypes, familial thoracic aortic aneurysms, and the newly described Loeys-Dietz syndrome characterized by arterial aneurysms, arterial tortuosity, Marfanoid habitus, and craniofacial features. We report here the findings of a study of a large group of patients with TGFBR2 mutations, including probands and affected relatives, and compare them with nonaffected relatives and patients with classic Marfan syndrome related to FBN1 mutation. We show the following: Aortic dilatation is variable among patients even within the same family; skeletal features are also variable, usually that of a mild Marfan phenotype without excessive height; ophthalmological features are mild if present; and early diagnosis is crucial because medical care (regular follow-up and individualized care) is associated with an improved survival rate, similar to that of patients with classic Marfan syndrome related to a mutation in the FBN1 gene. In contrast, in the absence of diagnosis, the spontaneous prognosis is poor. Systematic screening of the family and routine assessment of the mutation in patients with clinical features suggestive of Marfan syndrome are therefore mandatory. See p 2541.
Economic Outcomes of Treatment Strategies for Type 2 Diabetes Mellitus and Coronary Artery Disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes Trial
The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) clinical trial randomized patients with diabetes mellitus and coronary disease to prompt coronary revascularization versus medical therapy, as well as to strategies of glycemia control based on use of either insulin sensitizers or drugs that increase insulin provision. Mortality over 5 years was not significantly different, but major cardiovascular events were reduced by revascularization in the coronary artery bypass grafting stratum. The present study shows that revascularization increases 4-year cost significantly, by roughly $5700 (percutaneous coronary intervention) to $20 300 (coronary artery bypass grafting), whereas insulin sensitization increases costs by $1100. Medical therapy was highly cost-effective compared with prompt revascularization in the percutaneous coronary intervention stratum ($600/life-year added), suggesting that revascularization can be delayed until clinically indicated in patients with less extensive coronary disease. Revascularization may be cost-effective in patients with more extensive disease amenable to coronary artery bypass grafting, but this result was less certain with the limited follow-up available. See p 2550.
Patient Characteristics and Cell Source Determine the Number of Isolated Human Cardiac Progenitor Cells
The isolation and expansion of autologous human cardiac progenitor cells may offer new therapies for myocardial regeneration and repair. The present study shows that human cardiac progenitor cells can be obtained from small, clinically relevant myocardial specimens that could be collected during any cardiac surgery or percutaneous myocardial biopsy. Furthermore, these cells can be isolated from a wide range of patients, including young and old patients, those with various comorbidities such as hypertension and diabetes mellitus, and those with diverse types and severity of heart disease. Our study suggests that the best source for cardiac progenitor cells is the right atrium and that these cells are more abundant in women. Our findings could enhance the development of novel approaches in regenerative cardiovascular medicine. These isolated cells could be expanded in vitro, thereby providing a large number of cells for therapeutic applications. Alternatively, if these progenitor cells could be stimulated and activated in situ, with certain growth factors or small molecules, they could provide a tool for myocardial regeneration and the treatment of patients with heart disease. See p 2559.
Endothelial Estrogen Receptor-α Plays a Crucial Role in the Atheroprotective Action of 17β-Estradiol in Low-Density Lipoprotein Receptor–Deficient Mice
Epidemiological studies have shown that women are protected from coronary heart diseases before menopause, which suggests a beneficial action of endogenous estrogens. Consistently, the prevention of early atheroma by estrogens has been demonstrated clearly in several animal models, including mice and monkeys. Although the main randomized controlled trial (the Women’s Health Initiative) did not confirm the preventive action of estrogens against coronary heart disease, women who initiated hormone therapy closer to menopause tended to have reduced coronary heart disease risk, compared with the increase in coronary heart disease risk evident among women more distant from menopause. Interestingly, animal models mimic this discrepancy well, because both mouse and primate studies have revealed that the efficacy of estrogens on the prevention of plaque progression was inversely related to the duration of the estrogen-deprivation period after ovariectomy. The goal of the present study was to further define the cellular target(s) of the beneficial action of estradiol in early atheroma. Inactivation of estrogen receptor-α in endothelial cells of hypercholesterolemic mice completely abolished the atheroprotective action of estradiol, whereas hematopoietic estrogen receptor-α was dispensable. Thus, endothelial estrogen receptor-α represents a key target of the atheroprotective effect of estradiol, and selective estrogen receptor modulators that mimic the endothelial action of estradiol should now be considered in atheroprotection. The mechanisms responsible for the lack of beneficial action of estrogens in advanced atheroma remain to be elucidated. See p 2567.
Randomized Double-Blind Assessment of the ONSET and OFFSET of the Antiplatelet Effects of Ticagrelor Versus Clopidogrel in Patients With Stable Coronary Artery Disease: The ONSET/OFFSET Study
In the present study, ticagrelor compared with high-loading-dose clopidogrel achieved more rapid and greater platelet inhibition in patients with stable coronary artery disease. Greater inhibition was also sustained during the maintenance phase, and the offset of action was faster with ticagrelor therapy than with clopidogrel. These pharmacodynamic effects may explain why ticagrelor treatment was associated with a lower occurrence of the primary end point (myocardial infarction, stroke, or cardiovascular death), similar coronary artery bypass graft–related bleeding, and no overall difference in major bleeding compared with clopidogrel therapy in the PLATO (PLATelet inhibition and patient Outcomes) trial. See p 2577.
Association of Cyclooxygenase-1–Dependent and –Independent Platelet Function Assays With Adverse Clinical Outcomes in Aspirin-Treated Patients Presenting for Cardiac Catheterization
The term aspirin resistance has been used to describe either the clinical observation of a thrombotic event despite aspirin therapy or the laboratory observation of less-than-expected inhibition in aspirin-sensitive laboratory tests of platelet function. Whether major adverse cardiovascular events that occur in aspirin-treated patients are the result of inadequate inhibition of platelet cyclooxygenase-1 (COX-1), and therefore may be amenable to alterations of aspirin therapy, or are independent (or partly independent) of platelet COX-1 activity is unclear because clinical outcomes have not been determined in the same patients in whom platelet COX-1 function has been specifically measured. In the present prospective study, we measured serum thromboxane B2, a product directly dependent on platelet COX-1 activity, as well as other COX-1–dependent and –independent platelet function assays. In 700 aspirin-treated patients presenting for angiographic evaluation of coronary artery disease, residual platelet COX-1 function measured by serum thromboxane B2 and COX-1–independent platelet function measured by the platelet function analyzer-100 collagen/ADP closure time, but not indirect COX-1–dependent assays (arachidonic acid–stimulated platelet markers [platelet surface activated glycoprotein IIb/IIIa and P-selectin, leukocyte–platelet aggregates], platelet function analyzer-100 collagen/epinephrine closure time), correlated with subsequent major adverse cardiovascular events. This study suggests that multiple mechanisms, including but not confined to inadequate inhibition of COX-1, are responsible for poor clinical outcomes in aspirin-treated patients. Therefore, the term aspirin resistance is inappropriate, and increasing aspirin dosage would not be expected to be very effective in altering clinical outcomes in these patients. See p 2586.
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