Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death
- Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo
- Circulating Biomarkers and Abdominal Aortic Aneurysm Incidence: The Atherosclerosis Risk in Communities (ARIC) Study
- Polyunsaturated Fat Intake Estimated by Circulating Biomarkers and Risk of Cardiovascular Disease and All-Cause Mortality in a Population-Based Cohort of 60-Year-Old Men and Women
- Segmental Aortic Stiffness in Children and Young Adults With Connective Tissue Disorders: Relationships With Age, Aortic Size, Rate of Dilation, and Surgical Root Replacement
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Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death
We performed a comprehensive parallel study on patients with mitral valve prolapse (MVP) who died suddenly and living patients with MVP who had complex ventricular arrhythmias in the absence of valve incompetence and left ventricular remodeling. Clear-cut evidence of a substrate of electric instability in MVP is provided here for the first time and consists of myocardial scarring targeting the papillary muscles and the inferobasal left ventricular free wall, well in keeping with the site of origin of ventricular arrhythmias with either an inferior or a superior axis. The myocardial fibrosis observed at histology in sudden cardiac death victims was then confirmed in the clinical arm of the study, with evidence of late gadolinium enhancement on contrast-enhanced cardiac magnetic resonance in arrhythmic patients with MVP. The arrhythmogenic role of the myocardial scarring is supported by the morphology of arrhythmias and by electrophysiological studies in MVP indicating that the most common site of arrhythmias origin is the inferobasal left ventricular wall. Considering that performing contrast-enhanced cardiac magnetic resonance in all patients with MVP would be an expensive proposition, some clinical markers that could target a high-risk subgroup destined for screening by contrast-enhanced cardiac magnetic resonance are needed, including ECG depolarization abnormalities on inferior or inferolateral leads, complex ventricular arrhythmias with right bundle-branch block morphology on 12-lead ECG Holter monitoring, and a history of presyncope or syncope. Prospective and multicenter studies are warranted to support the role of contrast-enhanced cardiac magnetic resonance and electrovoltage mapping for risk stratification and to assess the efficacy of traditional antiarrhythmic therapy and targeted catheter ablation in selected cases. See p 556.
Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo
Normal activity of voltage-gated Na+ channels (Nav) is critical for proper heart function. Although Nav current normally activates and inactivates rapidly to generate the myocyte action potential upstroke, a small late component persists even under normal conditions. Increases in late current have been directly linked with arrhythmias in both congenital and acquired disease states. Previous studies have identified an important role for Nav phosphorylation by Ca2+/calmodulin-dependent protein kinase II in the regulation of Nav activity. Although in vitro studies and phosphoproteomic screens have identified Ser571 in the Nav1.5 DI-DII linker as a potential Ca2+/calmodulin-dependent protein kinase II phosphorylation site, the relationship between Ser571 phosphorylation, late current, arrhythmias, and heart function in vivo remain unknown. Here, we use 2 novel Scn5a knock-in mouse models (S571A and S571E) to generate mechanistic insight into the link between phosphorylation at Ser571 and control of Nav activity in vivo. Surprisingly, we find that Ser571 phosphorylation is highly specific for control of late current over other Nav properties (eg, steady-state inactivation). Furthermore, we report that Ser571 phosphorylation alters action potential repolarization and intracellular Ca2+ homeostasis. Finally, we show that phosphorylation of Ser571 controls susceptibility to arrhythmias at baseline and maladaptive remodeling in response to pressure overload (transaortic constriction). Based on these findings and in light of recent preclinical studies and clinical trials demonstrating potential antiarrhythmia efficacy of drugs that block late current (eg, ranolazine), we propose Ser571 as an important locus for specific control of late current with therapeutic implications. See p 567.
Circulating Biomarkers and Abdominal Aortic Aneurysm Incidence: The Atherosclerosis Risk in Communities (ARIC) Study
Epidemiological studies have identified several risk factors for abdominal aortic aneurysms (AAAs). The most important AAA risk factors are advanced age, male sex, white race, smoking, and family history, with hypertension and hypercholesterolemia playing less important roles. In the Atherosclerosis Risk in Communities Study cohort, we measured multiple blood biomarkers of inflammation, hemostasis, thrombin generation, cardiac dysfunction, and vascular stiffness and identified incident AAAs during follow-up using hospital discharge codes. Six biomarkers (white blood cell count, fibrinogen, D-dimer, troponin T, N-terminal pro-brain natriuretic peptide, and high-sensitivity C-reactive protein) were strongly positively associated with AAA incidence. Compared with having none of these 6 biomarkers in the highest quartile, the hazard ratios of AAA for those with 1, 2, 3, or 4 to 6 biomarkers in the highest quartile were 2.2, 3.3, 4.0, and 9.9, respectively (P for trend <0.0001), after adjustment for other risk factors. Our results show that multiple positive biomarkers can identify a subgroup of patients at high risk of AAAs. Further research is needed to document the utility of these biomarkers in clinical monitoring and management of patients at high risk of AAA. See p 578.
Polyunsaturated Fat Intake Estimated by Circulating Biomarkers and Risk of Cardiovascular Disease and All-Cause Mortality in a Population-Based Cohort of 60-Year-Old Men and Women
The present prospective cohort study has used circulating biomarkers of fatty acid intake to examine the link between dietary polyunsaturated fatty acids (PUFAs) and incident cardiovascular disease (CVD) and all-cause mortality. Considering the potential shortcomings with self-reported dietary intakes, biomarkers are valuable objective tools to add knowledge about the role of dietary PUFAs in preventing CVD and mortality. In general, the results of the present study support current international and American dietary recommendations to include sufficient amounts of PUFAs in the diet at the expense of trans fats and saturated fats. On the basis of our results, an increased intake of n-3 PUFA derived from fatty fish, together with an increased intake of n-6 PUFAs from nuts, seeds, and nontropical vegetable oils (eg, canola oil, soybean oil, and sunflower oil), may be linked to reduced risk of CVD and death resulting from all causes. Although both dietary n-3 and n-6 PUFAs have well-known favorable effects on CVD risk factors (ie, blood lipids), the present study indicates that PUFAs are also associated with reduced risk of non-CVD mortality in the population. However, the results indicate sex-specific associations between PUFAs and risk of CVD and mortality; for example, fish-derived n-3 PUFA was linked to reduced CVD incidence only in women, whereas vegetable oil–derived n-6 PUFA was linked to reduced all-cause mortality in men but not in women. As implied by these results, sex-specific recommendations on PUFA intake may be considered when future dietary guidelines are formed. See p 586.
Segmental Aortic Stiffness in Children and Young Adults With Connective Tissue Disorders: Relationships With Age, Aortic Size, Rate of Dilation, and Surgical Root Replacement
Historically, surgical management of patients with Marfan syndrome and related connective tissue disorders is based on the assessment of aortic size. However, aortic size is an imperfect predictor of aortic complications, and additional markers of the vascular phenotype severity have been sought. Structural changes within the aortic wall have been previously shown to result in increased aortic stiffness, but the relationship of aortic stiffness with aortic complications has not been determined. In this study, we examined the relationship between the cardiac MRI parameters of segmental aortic stiffness and the rates of surgical aortic root replacement and aortic growth rate. We found that aortic stiffness was elevated independent of connective tissue disorder type, and higher aortic stiffness was associated with a higher rate of aortic root replacement and with a higher aortic root growth rate. Future studies to assess whether aortic stiffness measures independently predict aortic dissection and death may help further refine imaging and treatment guidelines. See p 595.
- © 2015 American Heart Association, Inc.
- Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death
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