- Downloadable Algorithm to Reduce Inappropriate Shocks Caused by Fractures of Implantable Cardioverter-Defibrillator Leads
- A Randomized Trial of On-Pump Beating Heart and Conventional Cardioplegic Arrest in Coronary Artery Bypass Surgery Patients With Impaired Left Ventricular Function Using Cardiac Magnetic Resonance Imaging and Biochemical Markers
- Antiplatelet Therapy Use After Discharge Among Acute Myocardial Infarction Patients With In-Hospital Bleeding
- Collectrin Is Involved in the Development of Salt-Sensitive Hypertension by Facilitating the Membrane Trafficking of Apical Membrane Proteins via Interaction With Soluble N-Ethylmaleiamide–Sensitive Factor Attachment Protein Receptor Complex
- Transcriptional Regulation of Bim by FOXO3a and Akt Mediates Scleroderma Serum–Induced Apoptosis in Endothelial Progenitor Cells
- Increased Vascular Senescence and Impaired Endothelial Progenitor Cell Function Mediated by Mutation of Circadian Gene Per2
- Inhibition of Protein Kinase Cβ Prevents Foam Cell Formation by Reducing Scavenger Receptor A Expression in Human Macrophages
- Exercise-Induced Pulmonary Arterial Hypertension
- Info & Metrics
Downloadable Algorithm to Reduce Inappropriate Shocks Caused by Fractures of Implantable Cardioverter-Defibrillator Leads
Fractures of pace-sense electrodes in implantable cardioverter-defibrillator patients are a common cause of inappropriate shocks. These fractures result in high pacing impedance and oversensing of rapid, nonphysiological potentials. Despite automated, daily measurements of impedance to provide advance warning, their most common presentation is inappropriate shocks. We developed and tested an algorithm to enhance early identification of lead fractures and to reduce inappropriate shocks. This lead-integrity algorithm, which can be downloaded into presently implanted implantable cardioverter-defibrillators, alerts the patient and/or physician when triggered by either oversensing or abnormal impedance. Because oversensing associated with lead fracture typically is transient, we hypothesized that increasing the number of intervals to detect ventricular fibrillation reduces inappropriate shocks. Thus, the lead-integrity algorithm also increases the number of intervals to detect ventricular fibrillation when triggered. In a simulated retrospective analysis, the lead-integrity algorithm improved advance warning of lead fractures compared with present impedance monitoring. Its clinical value depends on rapid response to alerts by the patient and physician. This lead-integrity algorithm is the first downloadable RAMware developed to enhance the performance of nominally functioning implantable cardioverter-defibrillators and is the first implantable cardioverter-defibrillator monitoring feature that triggers real-time changes in ventricular fibrillation detection parameters to reduce inappropriate shocks. See p 2122.
A Randomized Trial of On-Pump Beating Heart and Conventional Cardioplegic Arrest in Coronary Artery Bypass Surgery Patients With Impaired Left Ventricular Function Using Cardiac Magnetic Resonance Imaging and Biochemical Markers
Although the financial burden of heart failure is growing in the United States, surgical research in this area is limited by difficult patient demographics. Coronary artery bypass grafting (CABG) affects both mortality and morbidity in heart failure patients; however, the benefits are balanced heavily by high operative risks. Beating heart CABG has benefits in terms of postoperative morbidity; however, the application of this technique in patients with impaired ventricular function remains untested. In a small randomized trial of patients with severe coronary artery disease and impaired ventricular function, a novel hybrid approach of on-pump beating heart surgery (ONBEAT) was compared with conventional cardioplegic arrest (ONSTOP). Left ventricular function and injury were assessed with cardiac magnetic resonance imaging before and 7 days after surgery with additional serial assessment of cardiac biochemical markers over the first 120 hours. Counterintuitively, the study clearly demonstrates a higher incidence of myocardial injury associated with the novel ONBEAT approach. We conclude that physiological coronary perfusion in patients with severe proximal coronary disease may not be sufficient to perfuse distal coronary beds, and in the absence of formal myocardial protection with cardioplegia, it renders these territories ischemic. Although this study is small, it has important implications for the application of beating heart techniques in patients with inadequate cardiac output and severe coronary artery disease. See p 2130.
Antiplatelet Therapy Use After Discharge Among Acute Myocardial Infarction Patients With In-Hospital Bleeding
Although bleeding in the setting of an acute myocardial infarction is known to be associated with worse long-term outcomes, the mechanism is unclear. Our study suggests an explanation: Proven secondary prevention therapies, such as antiplatelet agents, are withheld long beyond the resolution of the bleeding event. Postdischarge cardiology follow-up was associated with greater antiplatelet therapy use than either primary care or no clinical follow-up. Thus, early reassessment of antiplatelet eligibility may represent an opportunity to reduce the long-term risks associated with bleeding, and future larger studies examining the impact of early antiplatelet medication resumption on ischemic and bleeding outcomes are warranted. See p 2139.
Collectrin Is Involved in the Development of Salt-Sensitive Hypertension by Facilitating the Membrane Trafficking of Apical Membrane Proteins via Interaction With Soluble N-Ethylmaleiamide–Sensitive Factor Attachment Protein Receptor Complex
Salt-sensitive hypertension is a common clinical problem, particularly in certain subsets of hypertensive patients, including blacks, the elderly, and patients with chronic kidney disease. Recent long-term follow-up data suggest that even a short period of dietary salt restriction significantly improves cardiovascular risk. Accordingly, identifying mechanisms of salt sensitivity is clinically important. The renin-angiotensin-aldosterone system plays a central role in salt handling in the kidney, and aldosterone upregulates Sgk1 and recruits α-epithelial Na+ channel on the apical membrane, which results in sodium retention. However, aldosterone levels are significantly reduced under a high-salt diet, and the mechanism of salt-sensitive hypertension is not well understood. The present studies link collectrin, a transmembrane protein localized to the apical membrane of collecting duct cells, to sodium retention in rats exposed chronically to high dietary salt. Collectrin binds to the soluble N-ethylmaleiamide–sensitive factor attachment protein receptor (SNARE) complex, and upregulation of collectrin by a high-salt diet independent of aldosterone functionally links to the facilitation of vesicle fusion and trafficking of apical membrane proteins such as α-epithelial Na+ channel. In clinical settings, blockade of the renin-angiotensin-aldosterone system by a renin inhibitor, angiotensin-converting enzyme inhibitor, angiotensin receptor antagonist, and selective aldosterone blockers is a major therapeutic option to prevent cardiovascular events and the progression of chronic kidney disease. Upregulation of collectrin in collecting duct cells by a high-salt diet may blunt the efficacy of renin-angiotensin system inhibitors in salt-sensitive hypertension. Salt restriction is further warranted in the clinic, and collectrin may be the new therapeutic target in hypertension. See p 2146.
Transcriptional Regulation of Bim by FOXO3a and Akt Mediates Scleroderma Serum–Induced Apoptosis in Endothelial Progenitor Cells
The origin of systemic sclerosis is still not completely understood but appears to be autoimmune. Immune activation targets mature endothelial cells, resulting in vascular integrity breakdown and ensuing fibrosis. Endothelial progenitor cells (EPCs) are bone marrow–derived nonleukocyte cells that participate in vascular repair and homeostasis. It has been shown that injury of endothelial cells not only induces a cascade of proinflammatory events, contributing to vascular lesion formation, but also stimulates the mobilization of EPCs from the bone marrow, mediating vascular repair. Hence, the availability of circulating EPCs plays a critical role in maintaining the integrity and functional activity of the endothelial monolayer and in vasculogenesis. Several lines of evidence indicate that increased demand for vascular repair in the context of repeated injury could exhaust the supply of EPCs in the bone marrow, interrupting the balance between vascular repair and injury. In this report, we provide evidence showing, for the first time, that the factors in the peripheral blood of systemic sclerosis patients that cause endothelial cell injury also may damage EPCs. Moreover, probably owing to the lack of protective mechanisms in these immature cells, EPCs are more sensitive to the toxic factors than endothelial cells, implicating excessive EPC destruction in the pathogenesis of systemic sclerosis. Importantly, we have identified an Akt-FOXO3a-Bim pathway to mediate EPC apoptosis. Although much work needs to be done to determine the exact factors in the systemic sclerosis serum causing EPC apoptosis, targeting the Akt-FOXO3a-Bim pathway may be considered a venue for future therapies. See p 2156.
Increased Vascular Senescence and Impaired Endothelial Progenitor Cell Function Mediated by Mutation of Circadian Gene Per2
Alteration of the circadian rhythm is associated with increased incidence of pathological diseases such as sleep disorders, cardiovascular diseases, metabolic syndromes, and cancers. However, the mechanism by which alteration of the circadian rhythm leads to impaired vascular function is not known. In this study, we showed that mutation of the circadian gene, Per2, in mice leads to increased vascular senescence or aging through excessive activation of protein kinase Akt. This was associated with decreased endothelial cell proliferation and impaired vascular network formation. Indeed, compared with normal or wild-type mice, Per2 mutant (Per2m/m) mice exhibit defective angiogenic response to distal limb ischemia as a result of endothelial dysfunction and impaired mobilization of endothelial progenitor cells. When Per2m/m mice were injected with bone marrow–derived endothelial progenitor cells or mated with haploinsufficient Akt1+/− mutant mice to reduce excessive Akt activation, the impaired angiogenic response, endothelial cell proliferation, and vascular network formation were completely rescued or restored. These findings suggest that polymorphisms or alteration of circadian genes may be linked to cardiovascular disease through increased vascular senescence, endothelial dysfunction, and impaired bone marrow stem cell function. Thus, restoration of circadian gene function and prevention of excessive Akt activation may lead to mitigation of age-related vascular diseases. See p 2166.
Inhibition of Protein Kinase Cβ Prevents Foam Cell Formation by Reducing Scavenger Receptor A Expression in Human Macrophages
Low-density lipoprotein (LDL) uptake by monocyte-derived macrophages is a hallmark and key event of early atherogenesis. On exposure to modified lipoproteins such as oxidized LDL and acetylated LDL, these macrophages become foam cells. Increasing evidence supports that activation of PKCβ is involved in many mechanisms promoting atherosclerosis. In this study, we demonstrate that inhibition of protein kinase Cβ (PKCβ) prevents uptake of modified LDL by reducing human monocyte-derived macrophage scavenger receptor A expression. Several studies have strongly implicated activation of PKCβ in the pathogenesis of the vascular complications of diabetes. The synthesis of isoform-specific inhibitors for PKCβ has provided not only important insights into diabetic cardiovascular disease but also effective drugs against its microvascular complications. Interestingly enough, our data unmask an antiatherosclerotic effect of PKCβ inhibitors even in the nondiabetic condition of hypercholesterolemia. Specific siRNA-mediated knockdown of PKCβ further supports our conclusion. Indeed, on silencing of PKCβ, LDL uptake was blunted, scavenger receptor A expression was reduced, and hence foam cell formation was prevented. Of particular interest is the fact that in our study the PKCβ inhibitor LY379196, as a drug targeting macrophages, prevents only foam cell formation without affecting macrophage host defense activity. Although PKCβ inhibitors are currently being tested in clinical trials with microvascular end points, the present findings suggest a role for PKCβ in atherogenesis even in the nondiabetic condition and anticipate the application of PKCβ inhibitors as putative antiatherosclerotic drugs. See p 2174.
Exercise-Induced Pulmonary Arterial Hypertension
We provide the first large invasive characterization of symptomatic patients with exercise-induced pulmonary arterial hypertension (PAH). In contrast to previous studies that utilized stress echocardiography, our use of in-dwelling pulmonary arterial catheters during maximum incremental cardiopulmonary exercise testing allows the appropriate exclusion of patients whose exertional pulmonary hypertension is due to either elevated left-sided filling pressures or increased cardiac output (and normal pulmonary vascular resistance). We further demonstrate that the patient with exercise-induced PAH has physiological characteristics that are intermediate between those with normal values and those with resting PAH. We conclude that exercise-induced pulmonary arterial hypertension is a mild but clinically relevant form of PAH. Given the progressive nature of PAH, our findings may have important implications in its early recognition and treatment. See p 2183.
- Exercise-Induced Pulmonary Arterial Hypertension
- Info & Metrics