- Novel Associations of Multiple Genetic Loci With Plasma Levels of Factor VII, Factor VIII, and von Willebrand Factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium
- Mode of Death in Patients With Heart Failure and a Preserved Ejection Fraction: Results From the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) Trial
- Lack of Association Between Migraine Headache and Patent Foramen Ovale: Results of a Case-Control Study
- Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts
- Mitral Annular Dynamics in Myxomatous Valve Disease: New Insights With Real-Time 3-Dimensional Echocardiography
- B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage Renal Disease: Results of a Randomized Controlled Trial
- Erectile Dysfunction Predicts Cardiovascular Events in High-Risk Patients Receiving Telmisartan, Ramipril, or Both: The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials
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Novel Associations of Multiple Genetic Loci With Plasma Levels of Factor VII, Factor VIII, and von Willebrand Factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium
Elevated circulating levels of coagulation factor VIII (FVIII) and von Willebrand factor (vWF) are risk factors for venous thrombosis, but the data supporting an association of coagulation factor VII (FVII) levels with arterial thrombosis are less consistent. Hemorrhagic complications are associated with deficiency in FVII and vWF (von Willebrand disease), as well as X-linked deficiency in FVIII (hemophilia A). To date, our understanding of genetic variation influencing plasma levels has been focused primarily on variation in the genes encoding each protein product (F7, F8, and VWF, respectively). Using data from 23 608 adults drawn from community populations, we investigated genome-wide associations between common genetic variation and plasma levels of FVII, FVIII, and vWF. For FVII, we identified 5 loci on 5 chromosomes that exceeded genome-wide significance. All loci were within or near genes, including 4 new candidate genes and F7. For vWF, we identified 8 loci on 6 chromosomes. All loci were within genes, including 6 new candidate genes, as well as ABO and VWF. For FVIII, 5 loci were identified and overlapped vWF findings. We replicated 9 of the 10 new findings in independent samples. In summary, new genetic associations were discovered in biological pathways not previously associated with circulating levels of these factors, including proteins implicated in uptake and intracellular transport of the factors. These findings may point to novel prevention and treatment targets of hemostasis disorders. See p 1382.
Mode of Death in Patients With Heart Failure and a Preserved Ejection Fraction: Results From the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) Trial
Defining the mode of death in patients with heart failure and a preserved ejection fraction (HFPEF) may help to improve our understanding of the underlying pathophysiology in these patients with heart failure and provide insights into appropriate targets for the development of new therapies. Despite advanced age and the presence of comorbid states in patients with HFPEF, the mode of death was cardiovascular in 60% of the patients. In addition, the most common modes of cardiovascular death in patients with HFPEF were heart failure death and sudden death. These facts have implications both for the development of novel management strategies and for the design of future studies to test these strategies in patients with HFPEF. Management strategies that reduce causes of sudden death (such as reduction of arrhythmias) and prevent progression of heart failure (such as improvement in diastolic function and reduction of diastolic pressures) may be able to decrease cardiovascular death rates in patients with HFPEF. Therefore, new management strategies for patients with HFPEF should focus on treatments that can reduce arrhythmias and improve diastolic function. However, management strategies that target cardiovascular causes of mortality are not likely to affect the 30% of mortalities caused by noncardiovascular modes of death. Therefore, treatment of patients with HFPEF should also target the noncardiovascular comorbid states that are commonly present in these patients. See p 1393.
Lack of Association Between Migraine Headache and Patent Foramen Ovale: Results of a Case-Control Study
There has been considerable debate on the possible association between migraine and patent foramen ovale (PFO). Some small observational studies in patients with stroke have suggested a pathophysiological relationship between these 2 common conditions. Recent randomized studies of PFO closure have not definitively answered the question of whether an association exists. No prior observational studies have been designed prospectively to assess whether a pathophysiological association between migraine and PFO in the absence of stroke truly exists, and any single randomized trial of a specific device may be limited in its ability to test this general association. We therefore designed and executed a large, prospective, case-control study using quantitative measures of migraine severity and core laboratory assessment of PFO with transthoracic echocardiogram and transcranial Doppler to test this association and found no association between migraine headaches and the presence of PFO. In addition, we found no association between the severity of a right-to-left shunt and migraine or the severity of migraine and the presence of PFO. This study provides strong evidence against a pathophysiological association between PFO and migraine and would indicate that investigation of migraine pathophysiology should focus more on other mechanisms to prevent migraine. See p 1406.
Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts
Despite very good short-term results, the long-term survival of cardiac allograft recipients has not improved. Although the currently used immunosuppressive drugs efficiently inhibit the proliferation of alloreactive T cells, they have severe side effects such as infections, malignancies, and metabolic problems and do not prevent the development of cardiac allograft arteriosclerosis, a manifestation of chronic rejection. Here, we used rat and mouse heart transplantation models to investigate whether lymphatic vessel–targeted therapies modulate the exit of antigen-presenting cells from the allograft to secondary lymphoid organs and the development of acute and chronic rejection. Chronic inflammation increased the expression of allograft lymphatic vessel growth factor (VEGF-C) and induced lymphangiogenesis in rat cardiac allografts. Lymphatic vessels were active and functional in that they contained antigen-presenting cells and expressed dendritic cell chemokine CCL21 and VEGF-C receptor VEGFR-3. Inhibition of VEGFR-3 with gene therapy or monoclonal antibodies decreased allograft CCL21 production, dendritic cell traffic to the secondary lymphoid organs, and the development of acute and chronic cardiac allograft rejection. These results suggest VEGFR-3 inhibition as a novel lymphatic vessel–targeted immunomodulatory therapy for cardiac allograft rejection and indicate an active role for lymphatic vessels in inflammation-driven arteriosclerosis. See p 1413.
Mitral Annular Dynamics in Myxomatous Valve Disease: New Insights With Real-Time 3-Dimensional Echocardiography
The mitral valve is formed by leaflets (1 anterior and 1 posterior) attached to the ventricular wall (by chordae and papillary muscles) and by the annulus, a fibrous ring-shaped structure that attaches leaflets to the base of the heart. The mitral annulus has been little studied because of the difficulty in imaging this wide structure completely and quickly enough. Real-time 3-dimensional echocardiography is a new technology that allows imaging of a pyramid of the heart structure at high speed. We used this new technology to image the mitral annulus, to define its characteristics and dynamics in patients with myxomatous valve disease in contrast to normal control subject, and to assess ischemic mitral regurgitation. First, we validated annular measurements by real-time 3-dimensional echocardiography versus direct intraoperative dimension. Second, we found that the normal mitral annulus is dynamic with complex changes throughout the cardiac cycle. Early during systole, normal annulus shows contraction with shape changes similar to a mouth with lips pursed, bringing leaflets closer and allowing the valve to remain competent while it is not yet “locked.” Later during systole, the annulus returns to its baseline size without excess enlargement. The myxomatous valve disease annulus is dynamic but different, losing regurgitation-preventive mechanisms, with ventricular-annular contraction decoupling and later excess enlargement contributing to leaflet separation. The wide and dynamic myxomatous valve disease annulus also contrasts with the narrow and mostly adynamic ischemic mitral regurgitation annulus. These new insights by real-time 3-dimensional echocardiography provide a new understanding of the mitral pathophysiology and should lead to improved repairs and annuloplasty, percutaneous or surgical, to improve long-term outcomes. See p 1423.
B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage Renal Disease: Results of a Randomized Controlled Trial
We studied the effect of homocysteine-lowering treatment with B vitamins in patients with end-stage renal disease in a randomized controlled trial. After each dialysis session, patients received either a high-dose vitamin supplement (active treatment: 5 mg folic acid, 50 μg vitamin B12, and 20 mg vitamin B6) or a low-dose vitamin supplement to avoid vitamin deficiencies (control: 0.2 mg folic acid, 4 μg vitamin B12, and 1 mg vitamin B6). Homocysteine concentrations were significantly lowered in the group receiving high amounts of vitamins. Patients were followed up for a median period of 25 months. The vitamin treatment did not affect total mortality (hazard ratio, 1.13; 95% confidence interval, 0.85 to 1.50; P=0.51) or cardiovascular morbidity (hazard ratio, 0.80; 95% confidence interval, 0.60 to 1.07; P=0.13). Adjustment for other risk factors did not change these results substantially. In this randomized clinical trial, a significant clinical benefit of additional amounts of B vitamins for lowering of homocysteine concentrations was not shown. The results are in accordance with other trials that used B vitamins in patients with renal disease. See p 1432.
Erectile Dysfunction Predicts Cardiovascular Events in High-Risk Patients Receiving Telmisartan, Ramipril, or Both: The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials
The prevalence of erectile dysfunction is 20% to 30% in the general population but increases to more than 50% in the cardiovascular high-risk population of the ONTARGET/TRANSCEND trials, who are commonly encountered in clinical practice. Moreover, erectile dysfunction is associated with cardiovascular risk factors owing to the physiology of penile erection, which is crucially dependent on endothelial function and nitric oxide synthesis. The prospective erectile dysfunction substudy of the ONTARGET/TRANSCEND trials shows for the first time that erectile function is a predictor of cardiovascular morbidity and mortality. These results remained after adjustment for possible confounders. Thus, erectile dysfunction represents an early symptom of endothelial dysfunction and atherosclerosis, and patients with erectile dysfunction are at a particularly high cardiovascular risk. The identification of these patients with erectile dysfunction offers the opportunity for early risk-adjusted treatment with the goal of further reducing cardiovascular events. See p 1439.
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