Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Integrating Genetic, Transcriptional, and Functional Analyses to Identify 5 Novel Genes for Atrial Fibrillation
- Age-Specific Incidence, Outcome, Cost, and Projected Future Burden of Atrial Fibrillation–Related Embolic Vascular Events: A Population-Based Study
- Circulating Omega-6 Polyunsaturated Fatty Acids and Total and Cause-Specific Mortality: The Cardiovascular Health Study
- Rethinking Composite End Points in Clinical Trials: Insights From Patients and Trialists
- Cardiac CaM Kinase II Genes δ and γ Contribute to Adverse Remodeling but Redundantly Inhibit Calcineurin-Induced Myocardial Hypertrophy
- Alternatively Spliced Tissue Factor Promotes Plaque Angiogenesis Through the Activation of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Signaling
- Info & Metrics
Integrating Genetic, Transcriptional, and Functional Analyses to Identify 5 Novel Genes for Atrial Fibrillation
Atrial fibrillation (AF) is a multifactorial disease with many risk factors, including family history. To date, genome-wide association studies have identified 9 susceptibility loci that do not fully explain the heritability of the arrhythmia. In the present work, 5 novel genetic loci for AF were identified in large populations of European and Japanese descent in or near the genes NEURL, TBX5, CAND2, GJA1, and CUX2. Profiling the expression of candidate genes at these loci, we found that the AF risk variants significantly modified the expressions of CAND2 in skeletal muscle and of GJA1 and TBX5 in left atrial tissue. For NEURL and CAND2, gene knockdown in a zebrafish model demonstrated a significant prolongation of the atrial action potential duration. Finally, we found that variants at GJA1, TBX5, and CUX2 were significantly associated with ischemic stroke. In summary, the present results expand on the pathophysiological mechanisms underlying the development and maintenance of AF. Ultimately, therapeutic approaches that target these pathways may help to reduce the burden of AF and the sequela of heart failure and stroke. See p 1225.
Age-Specific Incidence, Outcome, Cost, and Projected Future Burden of Atrial Fibrillation–Related Embolic Vascular Events: A Population-Based Study
The prevalence of atrial fibrillation (AF) at age ≥80 years is ≈10%, but the rate of AF-related ischemic events and the projected impact of the aging population are unknown. In our prospective population-based study of 92 728 individuals in Oxfordshire, United Kingdom (2002–2012), we identified 454 incident AF-related ischemic strokes and systemic emboli, 60% of which occurred at age ≥80 years. In comparison with a previous study in our population in 1981 to 1986, numbers of AF-related ischemic strokes at age ≥80 years have trebled, despite convincing trial evidence of the effectiveness of anticoagulation and the use of AF registers in primary care as part of a remuneration scheme in the United Kingdom. Unless prevention is improved, numbers will treble again by 2050 because of demographic change alone. We also documented high levels of residual disability and healthcare costs of potentially preventable AF-related ischemic events. Our data are specific to the United Kingdom, but the demographic changes and rates of underanticoagulation are applicable to most developed countries, including the United States. Ongoing monitoring and improved primary prevention of AF-related ischemic events should be a public health priority. See p 1236.
Circulating Omega-6 Polyunsaturated Fatty Acids and Total and Cause-Specific Mortality: The Cardiovascular Health Study
Current U.S. dietary guidelines recommend higher intake of omega-6 polyunsaturated fatty acids (n-6 PUFA) to reduce the risk of coronary heart disease. However, the influence and potential dose–response relationship of n-6 PUFA on health remain contentious, including concerns over their theorized proinflammatory effects. We investigated associations of circulating n-6 PUFA, including linoleic acid (LA, the major dietary PUFA), γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DGLA), and arachidonic acid (AA), with total and cause-specific mortality among 2792 older adults (aged ≥65 years) in the Cardiovascular Health Study, a community-based U.S. cohort. During 18 years of follow-up, 1994 deaths occurred (678 cardiovascular deaths). After adjustment for other risk factors, participants in the top quintile of LA had 13% lower risk of total mortality compared with the lowest quintile (P-trend=0.005). Lower death was largely attributable to cardiovascular disease causes, especially nonarrhythmic coronary heart disease mortality, with a 49% lower risk among participants in the highest versus lowest quintile (P trend=0.001). Circulating GLA, DGLA, and AA were not significantly associated with total or cause-specific mortality (eg, for AA and coronary heart disease death, the extreme-quintile difference in risk was 3%; P trend=0.87). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both circulating n-6 and n-3 PUFA, lowest risk was evident with highest levels of both. Although it is not possible to infer causality based on this observational study, our findings suggest increased intake of LA may lower risk of total and cardiovascular disease mortality in generally healthy older adults, without evidence for increased risk. See p 1245.
Rethinking Composite End Points in Clinical Trials: Insights From Patients and Trialists
Although clinical trials provide the fundamental backbone for contemporary medical care, many studies use composite end points to improve trial efficiency and to decrease study costs. Of note, these composite end points are analyzed with the use of statistical methods that weigh each individual component equally, even though the individual end points often have different degrees of importance. We examined how patients and trialists assessed the severity of each individual component of a composite end point by conducting a survey of 785 cardiovascular patients and 164 authors of cardiovascular clinical trials. Each respondent assigned 25 “spending weights” across 5 common end points in cardiovascular clinical trials: death, stroke, myocardial infarction, repeat revascularization, and hospitalization for angina. We found that both patients and clinical trial authors considered “hard” cardiovascular events (death, myocardial infarction, stroke) significantly more important than repeat revascularization or hospitalization for angina. Moreover, the relative value of these end points varied substantially between patients and trialists, with clinical trialists placing greater emphasis on avoiding death than avoiding myocardial infarction or stroke, whereas patients viewed avoiding death, stroke, and myocardial infarction as equally important. Furthermore, there was heterogeneity in how patients weighed clinical end points according to age, race, and household income. Collectively, our findings provide important insights into how clinical trialists and patients prioritize the goals of medical treatment and, we hope, should stimulate further study into how best to develop and assign relative weights for composite end points so that clinical trials may accurately reflect the relative importance of each end point component. See p 1254.
Cardiac CaM Kinase II Genes δ and γ Contribute to Adverse Remodeling but Redundantly Inhibit Calcineurin-Induced Myocardial Hypertrophy
Cardiac remodeling during heart failure is usually described by a combined appearance of myocardial hypertrophy, activation of a so-called fetal gene program, cell death, and interstitial fibrosis. Ca2+-dependent signaling pathways including CaMKII and calcineurin were both proposed to play pivotal roles in adverse cardiac remodeling. By generating mice lacking the 2 cardiac CaMKII isoforms δ and γ in cardiomyocytes, we introduce a new specific and complete CaMKII loss-of-function model, and demonstrate that CaMKII—under unstressed conditions—is dispensable in cardiomyocytes with regard to integrity, growth, cardiomyocyte contractility, and Ca2+ handling. Furthermore, we show that—on pathological stress conditions—CaMKII plays a dual role in the regulation of cardiac remodeling. On the one hand, CaMKII mediates cell death, cardiac fibrosis, and left ventricular dysfunction. On the other hand, CaMKII inhibits cardiac hypertrophy and expression of certain fetal genes such as ANP and BNP. The latter is mediated through a previously underestimated cross talk to calcineurin. Importantly, in the absence of CaMKII, calcineurin does not contribute to adverse cardiac remodeling. Taken together, these data indicate that inhibition of CaMKII but not calcineurin is a promising therapeutic strategy to combat heart failure. See p 1262.
Alternatively Spliced Tissue Factor Promotes Plaque Angiogenesis Through the Activation of Hypoxia-Inducible Factor-1α and Vascular Endothelial Growth Factor Signaling
Phenotypic switching of atherosclerotic plaques from a stable to a vulnerable phenotype plays a key role in the onset of cardiovascular events (ie, acute myocardial infarct and ischemic stroke). Despite the proven efficacy of existing lipid-lowering treatment, statins reduce cardiovascular events by only 30% to 40%. Increased neovascularization has been implicated in plaque hemorrhage and rupture and sudden onset of clinical events. In the present study, we examined the role of the angiogenic factor alternatively spliced tissue factor (asTF) on atherosclerosis. In human carotid and coronary plaques, we showed that asTF is highly expressed within lesions complicated by hemorrhage or disruption versus uncomplicated lesions. Cellular distribution analysis showed that asTF was highly expressed by monocytes/macrophages and endothelial cells within complicated human atherosclerotic plaques. Of note, asTF expression was higher in coronary lesions from patients with acute coronary syndrome versus stable angina. The angiogenic activity of asTF is mediated via the increased expression of hypoxia-inducible factor-1α though integrins and activation of the mitogen-activated protein kinase and phosphatidylinositol-3-kinase/Akt pathways. As a consequence of hypoxia-inducible factor-1 activation, vascular endothelial growth factor signaling appears involved in the angiogenic effect of asTF. Importantly, local gene transfer of asTF in a murine model of carotid injury in ApoE−/− mice on Western diet resulted in increased neointima formation and neovascularization. The identification of asTF as a potent angiogenic factor driving neointima neovascularization improves our understanding of the angiogenic factors and mechanisms involved in plaque angiogenesis and may contribute to the development of tailored therapies for atherosclerotic plaque stabilization. See p 1274.
- © 2014 American Heart Association, Inc.
- Rethinking Composite End Points in Clinical Trials: Insights From Patients and Trialists
- Info & Metrics