Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Transient Receptor Potential Canonical-3 Channel–Dependent Fibroblast Regulation in Atrial Fibrillation
- Use of a Novel Endoscopic Catheter for Direct Visualization and Ablation in an Ovine Model of Chronic Myocardial Infarction
- Phosphoinositide 3-Kinase γ Protects Against Catecholamine-Induced Ventricular Arrhythmia Through Protein Kinase A–Mediated Regulation of Distinct Phosphodiesterases
- Ca2+/Calmodulin-Dependent Protein Kinase II–Based Regulation of Voltage-Gated Na+ Channel in Cardiac Disease
- Targeted Sarcoplasmic Reticulum Ca2+ ATPase 2a Gene Delivery to Restore Electrical Stability in the Failing Heart
- Trends in Antihypertensive Medication Use and Blood Pressure Control Among United States Adults With Hypertension: The National Health and Nutrition Examination Survey, 2001 to 2010
- Clinical and Angiographic Risk Stratification and Differential Impact on Treatment Outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial
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Transient Receptor Potential Canonical-3 Channel–Dependent Fibroblast Regulation in Atrial Fibrillation
Atrial fibrillation (AF) is the most common clinical arrhythmia, and its therapy is problematic. There is a need for novel treatment interventions, and mechanistic insights may be helpful in developing such new therapies. Here, we examined the role of a new type of ion channel, the nonselective cation channel TRPC3 (transient receptor potential canonical-3), in AF. TRPC3 can carry a number of ions but may be particularly important as an entry pathway for calcium into nonexcitable cells such as fibroblasts. Tissue fibrosis is produced by an overproduction of extracellular matrix proteins by fibroblasts and is believed to be important in AF. In addition, fibroblasts may contribute to AF via electric interactions with excitable heart cells (cardiomyocytes). We first found that cardiac fibroblasts expressed functional TRPC3 channels, and TRPC3-mediated calcium entry into fibroblasts activated a signaling molecule (extracellular signal-regulated kinase) that induced fibroblast proliferation and differentiation into activated myofibroblasts. We also noted that TRPC3 expression was upregulated in AF patients and 2 experimental AF models. We then studied the role of TRPC3 in atrial remodeling of dogs kept in AF for 7 days by atrial tachypacing. We found that AF increased TRPC3 protein expression and current, although it activated fibroblasts, and that blocking TRPC3 suppressed fibroblast activation and the AF-promoting remodeling caused by AF. We also identified the molecular pathway that leads to TRPC3 upregulation in AF: Downregulation of a TRPC3-suppressing microRNA, miR-26, caused by AF-induced nuclear translocation/regulation by nuclear factor of activated T-lymphocytes (NFAT) in fibroblasts. This work provides novel insights into molecular mechanisms underlying AF, as well as potential new anti-AF targets. See p 2051.
Use of a Novel Endoscopic Catheter for Direct Visualization and Ablation in an Ovine Model of Chronic Myocardial Infarction
Substrate mapping of ventricular tachycardia typically uses indirect measures of identifying myocardial scar, including electroanatomic voltage mapping and intracardiac echocardiography. We describe a novel catheter capable of direct endocardial visualization during mapping and irrigated radiofrequency ablation. The catheter contains a small fiberscope capable of directly visualizing the endocardial surface through a clear hood on the catheter tip with a 6.8-mm field of view. Saline is constantly flushed through the catheter to clear blood from the hood and allow visualization of the endocardial surface. Electrograms can be recorded from 4 orthogonal electrodes on the catheter tip; irrigated radiofrequency ablation can be performed via an electrode proximal to the catheter tip that heats the saline irrigant. We tested whether this catheter could visually differentiate among dense scar, border zone, and normal myocardium in an ovine model of chronic myocardial infarction. With the use of image processing techniques, the visual whiteness in the field of view was quantified and correlated well with electrogram measures of scar. Irrigated ablation lesions were delivered and could be observed in both healthy myocardium and myocardial scar. This approach offers a new paradigm in catheter ablation. Advantages include confirmation of catheter contact with the endocardium, direct visualization of anatomic structures such as the papillary muscles and myocardial scar, improved efficacy and safety of catheter ablation through visualization of lesion formation, and the ability to visually confirm contiguity of lesions delivered in a linear fashion during catheter ablation. See p 2065.
Phosphoinositide 3-Kinase γ Protects Against Catecholamine-Induced Ventricular Arrhythmia Through Protein Kinase A–Mediated Regulation of Distinct Phosphodiesterases
Ventricular arrhythmia is a leading cause of sudden death. Malignant ventricular arrhythmias such as ventricular tachycardia can develop in otherwise healthy individuals carrying proarrhythmic mutations and in patients affected by cardiomyopathies such as ischemic heart disease and heart failure. Although the administration of classic antiarrhythmic drugs (ie, β-blockers and amiodarone) and the implantation of cardiac defibrillators constitute a cornerstone of current patient management, only a better understanding of the molecular circuitries underlying ventricular arrhythmogenesis will pave our way toward new frontiers in sudden cardiac death prevention. For this purpose, experimental dissection of the molecular pathways that fine-tune both second messenger signaling and excitation-contraction coupling in cardiomyocytes is paramount. In the present work, using genetically modified mice, we have uncovered that the enzyme phosphoinositide 3-kinase γ (PI3Kγ) is required to maintain a physiological function of important myocardial phosphodiesterases such as phosphodiesterase 3A, 4A, and 4B. Biochemical and functional data indicate that PI3Kγ constitutes a necessary scaffold for these phosphodiesterases because the loss of PI3Kγ leads to abnormal cAMP accumulation, to inappropriate activation of cAMP targets such as L-type calcium channel, and to spontaneous calcium release events in cardiomyocytes. Although in normal hearts the loss of PI3Kγ leads to benign premature ventricular beats on β-adrenergic stimulation, cardiac pressure overload precipitates the development of ventricular tachycardia and rapidly results in substantial mortality. These findings indicate that the β-adrenergic/PI3Kγ/phosphodiesterase signaling hub may constitute a promising molecular target for the development of novel antiarrhythmic therapeutic interventions. See p 2073.
Ca2+/Calmodulin-Dependent Protein Kinase II–Based Regulation of Voltage-Gated Na+ Channel in Cardiac Disease
Defects in ion channel activity have been linked to increased susceptibility to cardiac arrhythmia in congenital and acquired forms of heart disease. Over the past 20 years, gene variants in ion channels have been discovered that increase arrhythmia susceptibility by altering ion channel biophysics. Although these studies have generated insight into molecular mechanisms underlying human disease and have advanced our understanding of ion channel function, the mechanistic link between specific molecular defects and arrhythmias remains elusive in many cases. Membrane protein posttranslational modifications are an essential mechanism for regulating cell function in heart. Importantly, alterations in posttranslational modification of ion channel proteins have now been identified in heart disease. Our findings demonstrate that human variants that modify a validated phosphorylation motif for Ca2+/calmodulin-dependent kinase in the cardiac sodium channel confer a proarrhythmic cellular phenotype by mimicking the Ca2+/calmodulin-dependent protein kinase II–phosphorylated channel. Moreover, we provide data that a similar defect in posttranslational modification of Nav1.5 is present in a large-animal model of ischemic heart disease and human heart failure. We propose that the A572D and Q573E human arrhythmia variants belong to an emerging class of atypical ion channel mutations that confer arrhythmia susceptibility by affecting posttranslational modification. These studies add to mounting evidence that defects in local signaling and protein posttranslational modification help define disease phenotypes associated with a broad range of cardiac arrhythmia syndromes. See p 2084.
Targeted Sarcoplasmic Reticulum Ca2+ ATPase 2a Gene Delivery to Restore Electrical Stability in the Failing Heart
Sudden arrhythmic death is a major risk in heart failure, yet the mechanisms are incompletely understood. T-wave alternans arises from beat-to-beat alternans of cellular repolarization, is a consistent precursor to ventricular fibrillation in experimental animals, and is a marker of electrical instability in patients. Previously, we reported that sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a), the pump responsible for reuptake of cytosolic calcium during diastole, plays a central role in the molecular mechanism of cardiac alternans. In the present study, SERCA2a gene transfer in the failing heart not only improved contractile function but also restored electric stability through the amelioration cardiac alternans and sarcoplasmic reticulum Ca2+ leak. This finding provides evidence that dysfunctional sarcoplasmic reticulum Ca2+ cycling links contractile and electrophysiological dysfunction in the failing heart and that therapy targeting key sarcoplasmic reticulum Ca2+ cycling proteins (ie, SERCA2a) can restore both contractile function and electric stability. Thus, therapies targeting SERCA2a warrant further evaluation in heart failure. See p 2095.
Trends in Antihypertensive Medication Use and Blood Pressure Control Among United States Adults With Hypertension: The National Health and Nutrition Examination Survey, 2001 to 2010
Trends in antihypertensive medication use and blood pressure control for US adults were examined at a population level during the decade 2001 to 2010 with the use of National Health and Nutrition Examination Survey data. The decade showed significant increases in the percentage of people with hypertension who are treated with medication (from 64% to 77%). Blood pressure control rates have improved from 29% to 47%, and treated control rates have improved from 45% to 60%. Consistent with the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines, significantly more patients with hypertension are on combination therapy now than a decade ago. In addition, the current data indicate that those receiving antihypertensive polytherapy were significantly more likely to meet their blood pressure goals than those who were on monotherapy regimens. Increased usage of multiple antihypertensive drugs has made substantial contributions to the overall control of blood pressure in the general population. This underscores the important role of antihypertensive polytherapy for achieving blood pressure control previously demonstrated in clinical drug trials. Patients whose hypertension is not controlled with monotherapy could benefit from more effective polytherapy regimens. The data also identify key population subgroups that apparently continue to lag behind. Younger adults and Mexican-American people appeared to be undertreated, as did those without health insurance. Older adults and non-Hispanic black people were more likely to be treated, but their hypertension was less likely to be controlled once they were on treatment. The same was true for those with chronic kidney disease and diabetes mellitus. Continued efforts are needed to close these gaps in treatment and to control rates and maximize the public health and clinical benefits of hypertensive therapy. See p 2105.
Clinical and Angiographic Risk Stratification and Differential Impact on Treatment Outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial
In this report, we examine angiographic and clinical risk scores in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial to test the hypothesis that differences in the end points of death and myocardial infarction and the composite end points of death/myocardial infarction/stroke and cardiac death/myocardial infarction observed between coronary revascularization and intensive medical therapy might be related to coronary disease extent and clinical characteristics. In the group of patients in whom percutaneous coronary intervention was chosen as the preferred revascularization option, there were no treatment differences between an initial strategy of percutaneous coronary intervention or intensive medical therapy regardless of angiographic or clinical risk score. This was not the case in the patients in whom coronary artery bypass graft surgery was selected as the preferred revascularization option because there was an increasing benefit of coronary artery bypass graft surgery in terms of reduction of cardiac end points in the highest-angiographic-risk patients, particularly in those with high clinical risk scores. Our findings indicate that among patients with diabetes mellitus and stable ischemic heart disease, a strategy of prompt coronary artery bypass graft surgery is preferred to an initial strategy of intensive medical therapy for those with extensive coronary artery disease or impaired left ventricular function to reduce the rates of myocardial infarction and death/myocardial infarction/stroke. See p 2115.
- © 2012 American Heart Association, Inc.
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