Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- n-3 Polyunsaturated Fatty Acids in the Prevention of Atrial Fibrillation Recurrences After Electrical Cardioversion: A Prospective, Randomized Study
- Atrial Sources of Reactive Oxygen Species Vary With the Duration and Substrate of Atrial Fibrillation: Implications for the Antiarrhythmic Effect of Statins
- Low Prevalence of Abdominal Aortic Aneurysm Among 65-Year-Old Swedish Men Indicates a Change in the Epidemiology of the Disease
- Role of RBM25/LUC7L3 in Abnormal Cardiac Sodium Channel Splicing Regulation in Human Heart Failure
- Platelet Reactivity and Cardiovascular Outcomes After Percutaneous Coronary Intervention: A Time-Dependent Analysis of the Gauging Responsiveness With a VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) Trial
- Donor Simvastatin Treatment Abolishes Rat Cardiac Allograft Ischemia/Reperfusion Injury and Chronic Rejection Through Microvascular Protection
- Diabetes Mellitus Worsens Diastolic Left Ventricular Dysfunction in Aortic Stenosis Through Altered Myocardial Structure and Cardiomyocyte Stiffness
- Role of Perivascular Adipose Tissue–Derived Methyl Palmitate in Vascular Tone Regulation and Pathogenesis of Hypertension
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n-3 Polyunsaturated Fatty Acids in the Prevention of Atrial Fibrillation Recurrences After Electrical Cardioversion: A Prospective, Randomized Study
Atrial fibrillation (AF) is the most common sustained arrhythmia and represents a growing burden on the healthcare system. The prevalence of AF increases with age and has been estimated at 3.8% in persons >60 years of age and at 9.0% in those ≥80 years of age. Atrial fibrillation is associated with considerable morbidity and mortality, related mainly to increased risk of thromboembolic events and of new-onset or worsening heart failure. Treatment of AF remains controversial. Although rhythm control and rate control strategies seem to provide comparable results, restoration and maintenance of sinus rhythm would be the preferable pathophysiological approach. However, current pharmacological antiarrhythmic therapies have limited efficacy and poor safety profiles, and invasive or surgical treatments are indicated only in a minority of patients and are not free of failure and procedural risks. In this study, we tested the efficacy of n-3 polyunsaturated fatty acids in the prevention of AF recurrences in 199 patients with persistent AF on amiodarone and a renin-angiotensin inhibitor. Participants were randomized to n-3 polyunsaturated fatty acids 2 g/d or placebo followed, after at least 4 weeks, by direct current cardioversion. At 1 year, the probability of maintenance of sinus rhythm was significantly higher in the n-3 polyunsaturated fatty acids group than in the placebo group. Our results indicate that the addition of n-3 polyunsaturated fatty acids 2 g/d in patients with persistent AF and structural heart disease and on amiodarone and a renin-angiotensin inhibitor may exert beneficial effects in the prevention of AF recurrence. See p 1100.
Atrial Sources of Reactive Oxygen Species Vary With the Duration and Substrate of Atrial Fibrillation: Implications for the Antiarrhythmic Effect of Statins
Atrial fibrillation (AF) is a very common arrhythmia, and its therapy remains a challenge. There is considerable interest in developing treatment strategies that target mechanisms upstream of ion channel modifications; however, whereas ion channel modifications are the common denominator of virtually all types of AF, the myocardial signaling upstream of atrial electric and structural remodeling differs with the stage and substrate of AF, demanding a more refined ad hoc approach to the prevention and management of this arrhythmia. Here, we show that the mechanisms responsible for the nitric oxide–redox imbalance in the fibrillating atrial myocardium change with the duration of AF and the development of atrial structural remodeling. Upregulation of atrial NOX2 activity and expression is an early but transient event in the natural history of AF and may be causally linked to both new-onset AF and early AF-induced atrial remodeling. Once AF becomes established and atrial structural remodeling ensues, the oxidase systems underlying the increase in reactive oxygen species shift from NOX2 to mitochondrial oxidases and uncoupled nitric oxide synthases. Ex vivo atorvastatin induces a mevalonate-reversible inhibition of atrial Rac1 and NOX2 activity in patients who developed AF after cardiac surgery, but it does not affect atrial reactive oxygen species production and nitric oxide synthase activity in patients with permanent AF. These findings imply that NOX2 inhibition by drugs such as statins may be effective only in preventing new-onset AF or early AF-induced electric remodeling of the atrial myocardium. See p 1107.
Low Prevalence of Abdominal Aortic Aneurysm Among 65-Year-Old Swedish Men Indicates a Change in the Epidemiology of the Disease
On the basis of results from 4 randomized controlled trials, screening elderly men with ultrasound for abdominal aortic aneurysm (AAA) has emerged as an evidence-based way of reducing mortality from ruptured AAA. Although no trial has assessed the optimum age for AAA screening, current recommendations generally consist of a 1-time ultrasound examination at 65 years of age. In this contemporary population-based AAA screening study of a large cohort of 65-year-old Swedish men, a lower-than-expected AAA prevalence was found. This was attributed mainly to a changed exposure to known risk factors over the past decades, particularly a significant decline in smoking. At the same time, the life expectancy of the target population has increased significantly while the surgical caseload of AAA has remained unchanged. These observed changes in the epidemiology of AAA disease highlight the need to reevaluate different screening strategies on the basis of modern epidemiological data, which may influence the design of future screening programs. See p 1118.
Role of RBM25/LUC7L3 in Abnormal Cardiac Sodium Channel Splicing Regulation in Human Heart Failure
We have previously shown that human heart failure is associated with abnormal mRNA splicing of the cardiac sodium channel. This abnormal mRNA splicing results in truncated sodium channels that are nonfunctional and a reduction in sodium channel current to levels known to cause sudden death. Here, we explored the mechanisms by which this abnormal splicing occurs. Using microarray comparisons of diseased and normal human hearts, we identified 2 splicing factors, RBM25 and LUC7L3, that were necessary and sufficient to cause the abnormal sodium channel splicing. These factors were upregulated by hypoxia and elevated angiotensin II, conditions known to be present in heart failure. Moreover, we showed that the responses of white cells and heart to these 2 inciting stimuli were equivalent. The potential clinical implications of these findings include a possible mechanism whereby hypoxia is arrhythmogenic and blockade of the renin-angiotensin system is antiarrhythmic. Moreover, if white cell sodium channel splicing in vivo correlates with that in the myocardium, it may be possible to develop a blood test to assess sodium channel availability and arrhythmic proclivity. Finally, this work defines potential therapeutic targets to address arrhythmic risk in human heart failure. See p 1124.
Platelet Reactivity and Cardiovascular Outcomes After Percutaneous Coronary Intervention: A Time-Dependent Analysis of the Gauging Responsiveness With a VerifyNow P2Y12 Assay: Impact on Thrombosis and Safety (GRAVITAS) Trial
A variable pharmacodynamic response to clopidogrel has been well documented, and an association between high on-treatment reactivity while patients are receiving clopidogrel and adverse clinical outcomes after percutaneous coronary intervention has been shown in prospective, observational studies. In the Gauging Responsiveness With a VerifyNow P2Y12 Assay: Thrombosis and Safety (GRAVITAS) trial, high-dose clopidogrel was not superior to standard-dose clopidogrel in preventing cardiovascular events after percutaneous coronary intervention in patients with high on-treatment reactivity, defined as on-treatment reactivity ≥230 P2Y12 reaction units according to the VerifyNow P2Y12 platelet function test. The aim of this analysis was to examine the relationship between outcomes and on-treatment reactivity over the course of the trial. In the 2796 patients with evaluable platelet function data, on-treatment reactivity <208 P2Y12 reaction units at randomization or during follow-up was associated with a lower risk of cardiovascular death, myocardial infarction, and stent thrombosis, even after adjustment for other predictors of outcome. The treatment strategy of high-dose clopidogrel achieved this level of reactivity in <50% of patients. These findings support the prognostic utility of serial platelet function testing after percutaneous coronary intervention, including in patients with stable coronary artery disease, and suggest that in patients who display high on-treatment reactivity while receiving standard-dose therapy, double-dose clopidogrel is largely ineffective in achieving a level of on-treatment reactivity associated with improved outcome. Therefore, the safety and efficacy of alternative approaches using more potent P2Y12 inhibitors in patients with high on-treatment reactivity merit further investigation. See p 1132.
Donor Simvastatin Treatment Abolishes Rat Cardiac Allograft Ischemia/Reperfusion Injury and Chronic Rejection Through Microvascular Protection
Ischemia/reperfusion injury after heart transplantation may result in primary graft dysfunction or initiation of fibroproliferative cascades, leading to the development of cardiac fibrosis, allograft arteriosclerosis, and compromised long-term survival. Vascular dysfunction, including permeability and perfusion disturbances, plays a central role in ischemia/reperfusion injury. Statins are widely used to lower cholesterol levels, but they also have cholesterol-independent pleiotropic effects through Rho GTPase inhibition. We used heterotopic rat heart transplantation models to investigate whether a single dose of simvastatin administered to cardiac allograft donors perorally 2 hours before graft removal protects the cardiac allograft through direct vasculoprotective effects. Donor simvastatin treatment abolished cardiac allograft ischemia/reperfusion injury by preventing the no-reflow phenomenon and reducing vascular permeability, inflammation and cardiomyocyte injury. These early vasculoprotective and cardioprotective effects were mirrored with sustained antiinflammatory, antifibrotic, and antiarteriosclerotic effects in a chronic rejection heart transplantation model. Mechanistic studies indicated that donor simvastatin treatment decreased cardiac allograft microvascular endothelial cell and pericyte RhoA activation, modified the expression of vasculoprotective genes, and improved endothelial barrier function. In contrast to donor simvastatin treatment, recipient simvastatin treatment did not protect against ischemia/reperfusion injury. In vitro studies also showed that simvastatin decreased endothelial-mesenchymal transition, a recently characterized mechanism participating in cardiac fibrosis. Collectively, our results highlight the rapid vasculoprotective effects of simvastatin during ischemia/reperfusion injury and suggest donor simvastatin as a novel, clinically feasible strategy to protect cardiac allografts. See p 1138.
Diabetes Mellitus Worsens Diastolic Left Ventricular Dysfunction in Aortic Stenosis Through Altered Myocardial Structure and Cardiomyocyte Stiffness
In aging populations, diabetes mellitus (DM) and aortic stenosis (AS) are becoming frequent comorbidities. Studies looking at the interaction between DM and AS investigated mainly the progression of sclerocalcific valvular dysfunction. In heart failure (HF), DM raises diastolic left ventricular (LV) stiffness, which adversely affects morbidity and mortality. The DM-related rise in diastolic LV stiffness was observed both in HF with reduced ejection fraction and in HF with normal ejection fraction. In HF with reduced ejection fraction, DM affected myocardial stiffness through excessive fibrosis and arteriolar or capillary deposition of advanced glycation end products, whereas in HF with normal ejection fraction, DM increased myocardial stiffness through elevation of cardiomyocyte resting tension (Fpassive). The present clinical study extended these observations on DM-related worsening of diastolic LV stiffness to symptomatic AS and confirmed a similar increase in diastolic LV stiffness in patients suffering from both AS and DM. This increase was evident from higher LV end-diastolic pressure at comparable LV end-diastolic volume index. Furthermore, the increase in diastolic LV stiffness was shown to result from all 3 aforementioned mechanisms, namely excessive fibrosis, intramyocardial vascular advanced glycation end product deposition, and elevated cardiomyocyte Fpassive. The latter could be attributed to hypophosphorylation of the stiff isoform of the cytoskeletal protein titin, which is largely responsible for cardiomyocyte Fpassive. The observed increase in diastolic LV stiffness in patients suffering from both AS and DM could predispose them to earlier development of heart failure symptoms and an earlier need for aortic valve replacement. See p 1151.
Role of Perivascular Adipose Tissue–Derived Methyl Palmitate in Vascular Tone Regulation and Pathogenesis of Hypertension
Methyl palmitate or palmitic acid methyl ester is released spontaneously from the perivascular adipose tissue, causing vasorelaxation by opening voltage-dependent K+ channels on vascular smooth muscle cells of normotensive rats. In established hypertensive rats, diminished palmitic acid methyl ester release and its vasorelaxing activity are accompanied by an increased release of angiotensin II from the aortic perivascular adipose tissue. The diminished palmitic acid methyl ester–induced relaxation of aortic arteries from hypertensive rats is significantly reversed by losartan. These findings suggest a noble role of the perivascular adipose tissue in the pathogenesis of hypertension and provide a new mechanism for losartan in that its antihypertensive effect is partly attributed to its reversing the diminished palmitic acid methyl ester–induced vasorelaxation caused by angiotensin II. See p 1160.
- © 2011 American Heart Association, Inc.
- Role of RBM25/LUC7L3 in Abnormal Cardiac Sodium Channel Splicing Regulation in Human Heart Failure
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