- Deficient Zebrafish Ether-à-Go-Go–Related Gene Channel Gating Causes Short-QT Syndrome in Zebrafish Reggae Mutants
- Clinical Characteristics and In-Hospital Outcomes of Patients With Cardiogenic Shock Undergoing Coronary Artery Bypass Surgery: Insights From the Society of Thoracic Surgeons National Cardiac Database
- Intracoronary KAI-9803 as an Adjunct to Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction
- Measurement of Walking Distance and Speed in Patients With Peripheral Arterial Disease: A Novel Method Using a Global Positioning System
- Trends and Cardiovascular Mortality Effects of State-Level Blood Pressure and Uncontrolled Hypertension in the United States
- Monitoring of the Biological Response to Murine Hindlimb Ischemia With 64Cu-Labeled Vascular Endothelial Growth Factor-121 Positron Emission Tomography
- Two-Year Clinical Outcomes With Drug-Eluting Stents for Diabetic Patients With De Novo Coronary Lesions: Results From a Real-World Multicenter Registry
- Matrix Metalloproteinase-14 Deficiency in Bone Marrow–Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic Plaques
- Signal Transducer and Activator of Transcription-1 Is Critical for Apoptosis in Macrophages Subjected to Endoplasmic Reticulum Stress In Vitro and in Advanced Atherosclerotic Lesions In Vivo
- Phosphorylation of LKB1 at Serine 428 by Protein Kinase C-ζ Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells
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Deficient Zebrafish Ether-à-Go-Go–Related Gene Channel Gating Causes Short-QT Syndrome in Zebrafish Reggae Mutants
Various genetic defects, primarily in cardiac ion channels, are known to cause human cardiac repolarization disorders such as long- and short-QT syndrome; however, suitable genetic animal models to study disease mechanisms and evaluate new treatment strategies are largely lacking. In search of suitable arrhythmia models, we isolated the zebrafish mutation reggae (reg), which displays clinical features of the malignant human short-QT syndrome such as accelerated cardiac repolarization accompanied by cardiac fibrillation. By positional cloning, we identified the reg mutation that resides within the voltage sensor of the zebrafish ether-à-go-go–related gene (zERG) potassium channel. The mutation causes premature zERG channel activation and defective inactivation, which results in shortened action potential duration and accelerated cardiac repolarization. Consequently, QT intervals in ECGs from heterozygous and homozygous reg mutant adult zebrafish are considerably shorter than in wild-type zebrafish. Hence, with its molecular and pathophysiological concordance to the human arrhythmia syndrome, zebrafish reg represents the first animal model for human short-QT syndrome and may help to further dissect disease mechanisms and to identify new pharmacological treatment options in high-throughput screens. See p 866.
Clinical Characteristics and In-Hospital Outcomes of Patients With Cardiogenic Shock Undergoing Coronary Artery Bypass Surgery: Insights From the Society of Thoracic Surgeons National Cardiac Database
Because few patients with cardiogenic shock (CS) undergo coronary artery bypass grafting (CABG), the contemporary clinical features and outcomes or risk factors for operative mortality in these patients are not well known. Our study of 708 593 patients with and without CS undergoing CABG enrolled in the Society of Thoracic Surgeons National Cardiac Database (2002–2005) found that patients with preoperative CS constituted 14 956 (2.1%) of patients undergoing CABG yet accounted for 16% of all CABG deaths. Operative mortality in CS patients was high and surgery specific, rising from 20% for isolated CABG to 33% for CABG plus valve surgery and 58% for CABG plus ventricular septal repair. Although overall CABG mortality improved during the 4-year study period, that for CS patients undergoing CABG did not. Finally, we identified factors associated with higher death risk for CS patients undergoing CABG using multivariable analysis and summarized these into a simple bedside risk score (c statistic=0.74) that accurately stratified those with low (<10%) to very high (>60%) mortality risk. We believe that estimation of patient-specific risk of mortality is feasible with the simplified additive risk tool developed in our study with the use of routinely available preprocedural data and that physicians will find this tool applicable and useful in routine clinical practice. See p 876.
Intracoronary KAI-9803 as an Adjunct to Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction
KAI-9803, a δ-protein kinase C inhibitor, reduced infarct size, enhanced early recovery of regional left ventricular contractility, and improved microvascular function in animal models of acute myocardial infarction. The safety, tolerability, and activity of escalating intracoronary doses of KAI-9803 were evaluated among patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention in the “first-in-human” Direct Inhibition of δ-Protein Kinase C Enzyme to Limit Total Infarct Size in Acute Myocardial Infarction (DELTA MI) trial. A total of 154 patients who had an occluded left anterior descending infarct artery on angiography were randomized in a 2:1 fashion and received 1 of 4 doses of KAI-9803 (cohort 1, 0.05 mg; cohort 2, 0.5 mg; cohort 3, 1.25 mg; cohort 4, 5.0 mg) versus blinded concurrent placebo delivered in 2 divided doses via intracoronary injection before and after reestablishment of antegrade epicardial flow with percutaneous coronary intervention. The incidence of serious adverse events and other safety end points was similar between patients treated with KAI-9803 versus placebo. Although the study was not powered to demonstrate efficacy with the biomarker end points assessed, signs of drug activity with KAI-9803 were suggested by trends for consistent, nonsignificant reductions in cardiac marker elevations, ST-segment recovery, and 99mtechnetium sestamibi infarct size values across dosing cohorts with KAI-9803. Thus, KAI-9803 had an acceptable safety and tolerability profile when delivered via intracoronary injection during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction, and signs of potential drug activity were demonstrated with biomarker end points in this small, exploratory study. See p 886.
Measurement of Walking Distance and Speed in Patients With Peripheral Arterial Disease: A Novel Method Using a Global Positioning System
Treadmill testing is the “gold standard” in the evaluation of maximal walking capacity in patients with Fontaine stage 2 claudication, although treadmills are not readily accessible to all physicians. Furthermore, walking on a treadmill imperfectly reflects unconstrained outdoor walking. In 24 patients with peripheral arterial disease, we compared the maximal walking distance measured on a treadmill with the maximal walking distance observed during a 1-hour community-based outdoor walk while the patient’s position was monitored with a global positioning system (GPS). Our data support the evidence that global positioning system–determined maximal walking distance is correlated with the maximal walking distance observed on a treadmill. To the best of our knowledge, this is the first report on the use of a global positioning system in vascular patients. Ultimately, we believe that the use of a global positioning system might lead to new insights in the evaluation of walking capacity in arterial claudication and specifically to approaches for measurement of new dimensions in the evaluation of these patients, such as walking speed, fatigue, and walking gait. See p 897.
Trends and Cardiovascular Mortality Effects of State-Level Blood Pressure and Uncontrolled Hypertension in the United States
High blood pressure is one the most important risk factors for cardiovascular disease. Information on blood pressure and uncontrolled hypertension is needed for priority setting and for interventions. In the United States, national data on blood pressure are obtained by measurement, but at the state level, the data are limited to self-reported hypertension diagnosis. Such self-reported data may be biased for several reasons, including undiagnosed hypertension among people who may not have had health system contact and reduced risk among those with diagnosis who have effectively controlled their hypertension status. This analysis uses self-reported hypertension diagnosis and a number of other indicators such as insurance status, history of contact with a doctor, body mass index, age, and other sociodemographic factors to estimate true blood pressure and hypertension status. The results show that uncontrolled hypertension was highest in the District of Columbia, Mississippi, Louisiana, Alabama, Texas, Georgia, and South Carolina (18% to 21% of men and 24% to 26% of women in these states had uncontrolled hypertension after accounting for differences in age in these states). Uncontrolled hypertension was lowest in Vermont, Minnesota, Connecticut, New Hampshire, Iowa, and Colorado, ranging from 15% to 16% for men and ≈21% for women. In the 1990s, uncontrolled hypertension increased among women, especially those ≥60 years of age, in every state. As a result, early in the 2000s, women had a higher prevalence of uncontrolled hypertension than men in every state by 4 to 7 percentage points. Lifestyle and pharmacological interventions for lowering blood pressure are particularly needed in the South and Appalachia, with emphasis on control among women. See p 905.
Monitoring of the Biological Response to Murine Hindlimb Ischemia With 64Cu-Labeled Vascular Endothelial Growth Factor-121 Positron Emission Tomography
Angiogenesis, the recruitment of new vessels, is part of the adaptive processes in ischemia and involves the interaction of various angiogenic factors. One of the major regulators of angiogenesis is vascular endothelial growth factor (VEGF) receptor type 2 (VEGFR2). VEGFR2 is an endothelium-specific receptor tyrosine kinase that is overexpressed in ischemic tissues and that triggers multiple signaling networks that result in endothelial cell survival, mitogenesis, migration, differentiation, and vascular permeability. By radiolabeling the natural ligand of VEGFR2, the isoform VEGF121, using copper-64 (64Cu), we found that temporal and spatial expression levels of VEGFR2 can be tracked by positron emission tomography (PET) in a chronic hindlimb ischemia model in mice. In mice that underwent treadmill exercise training over several weeks, VEGFR2 expression levels were increased compared with nonexercised mice and could be monitored noninvasively by 64Cu-labeled VEGF121 PET imaging in vivo. With PET imaging being increasingly used for cardiovascular applications in clinics, our proof-of-concept study suggests that molecular imaging with PET-based approaches may be valuable for noninvasive monitoring of angiogenesis in patients with peripheral arterial disease. In particular, in patients with peripheral arterial disease and refractory symptoms who are undergoing novel therapeutic approaches such as gene- and cell-based therapies, quantitative PET imaging may be helpful in patient stratification and decision making in future clinical studies. See p 915.
Two-Year Clinical Outcomes With Drug-Eluting Stents for Diabetic Patients With De Novo Coronary Lesions: Results From a Real-World Multicenter Registry
In most centers, treatment with drug-eluting stents (DES) provides the current standard of care for diabetic patients undergoing percutaneous coronary interventions. The rationale for this choice is derived more from knowledge that diabetic patients are at high risk of restenosis after bare metal stent implantation than robust clinical evidence; indeed, diabetes mellitus is currently an “off-label” indication for DES. This article reports the 2-year results of a prospective multicenter registry subanalysis of 1648 diabetic patients treated by bare metal stent (n=1089) or DES (n=559) implantation. Selection of patients for treatment with DES was left to the physician’s discretion. After adjustment for known confounders, use of DES was associated with a moderate reduction (11.6% versus 15%; P=0.04) in the need for new revascularizations (no benefit was detected in insulin-dependent diabetics). No difference was detected in adjusted 2-year rates of mortality, mortality or reinfarction, or major adverse events. Although no statistically significant difference could be observed in 2-year rates of angiographic stent thrombosis (1.5% for DES versus 0.7% for bare metal stents; P=0.17), it is noteworthy that very late stent thrombosis episodes occurred only in the DES group. In this large real-world diabetic population, use of DES was associated with a modest reduction in the 2-year risk of target vessel revascularization, a benefit that was limited to non–insulin-dependent diabetic patients. Larger long-term studies are needed to clarify the long-term effectiveness and safety of DES in diabetic patients. See p 923.
Matrix Metalloproteinase-14 Deficiency in Bone Marrow–Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic Plaques
Many data support the concept that the collagen content of the fibrous cap of an atherosclerotic plaque governs its propensity to rupture and causes thrombotic complications. The mechanisms that regulate the plaque collagen content thus have considerable clinical interest. Members of the matrix metalloproteinase (MMP) family possess interstitial collagenase activity capable of breaking down this critical component of the plaque structure. Previous work has highlighted a role for MMP-13, a secreted interstitial collagenase, in collagen breakdown in mouse atherosclerotic plaques. The present study tested the role of a membrane-bound MMP (MMP-14) present in plaques in regulating the interstitial collagen content of atheromatous lesions. Animals that lack MMP-14 do not survive to adulthood, so these experiments used animals with bone marrow cells lacking MMP-14 to test the hypothesis that this enzyme contributes to collagen catabolism in mouse atheromata. After 16 weeks of an atherogenic diet, low-density lipoprotein receptor–deficient mice engrafted with MMP-14–deficient bone marrow contain significantly more interstitial collagen compared with those receiving wild-type bone marrow. The effect of MMP-14 on collagen metabolism may be indirect through activation of the latent zymogen form of MMP-13 as shown by biochemical experiments. Thus, MMP-14 from bone marrow–derived cells can influence the collagen content of atheromata, a critical component of plaque stability. See p 931.
Signal Transducer and Activator of Transcription-1 Is Critical for Apoptosis in Macrophages Subjected to Endoplasmic Reticulum Stress In Vitro and in Advanced Atherosclerotic Lesions In Vivo
In industrialized societies, virtually all young adults have atherosclerosis. Most of these lesions are asymptomatic and will remain so for the rest of the person’s life. However, a small percentage will progress to a dangerous stage involving plaque breakdown, acute luminal thrombosis, and acute vascular events like myocardial infarction and sudden cardiac death. Thus, a major goal is to elucidate the cellular-molecular events involved in benign-to-vulnerable plaque progression. A key feature of vulnerable plaques is necrotic cores, which likely promote plaque breakdown and acute thrombosis. Necrotic cores are “graveyards of dead macrophages,” a prominent cell type in atherosclerosis. This study used a cell-culture model of macrophage death to explore death-promoting molecules that may be relevant to advanced atherosclerosis. These experiments revealed an important role for a calcium-signaling pathway involving 2 molecules, calcium/calmodulin-dependent protein kinase II and signal transducer and activator of transcription-1 (STAT-1). Both mouse and human advanced atheromata have activated STAT-1. Most important, when macrophages were made deficient in STAT-1 in a mouse model of advanced atherosclerosis, macrophage death and plaque necrosis were diminished. Two important caveats of this study need to be mentioned. First, the processes of macrophage death and plaque necrosis are complex, so the calcium/calmodulin-dependent protein kinase II–STAT1 pathway represents only 1 piece of the puzzle. Second, the mouse is a poor model of plaque disruption and acute thrombosis. Thus, additional studies are needed to explore other pathways involved in advanced lesional macrophage death, and improved mouse models are required to prove the hypothesis that macrophage death and plaque necrosis promote plaque disruption and acute thrombosis. Nonetheless, this study provides important new molecular-cellular information related to the progression of advanced atherosclerotic lesions—information that someday may be translated into therapy designed to block benign-to-vulnerable plaque transformation. See p 940.
Phosphorylation of LKB1 at Serine 428 by Protein Kinase C-ζ Is Required for Metformin-Enhanced Activation of the AMP-Activated Protein Kinase in Endothelial Cells
Metformin is one of most commonly used drugs for the treatment of type II diabetes mellitus. Unlike traditionally used glucose-lowering reagents, such as sulfonylureas or insulin, metformin improves cardiovascular functions and reduces cardiovascular risks in diabetes. Earlier studies from us and others found that clinically relevant concentrations of metformin activated the AMP-activated protein kinase (AMPK); these studies ascribed the beneficial effects of metformin on vascular function to AMPK activation. The present study was designed to elucidate the mechanism by which metformin activates AMPK. Exposure of cultured endothelial cells to metformin significantly increased the phosphorylation of both AMPK at Thr172 and LKB1 at Ser428, an AMPK kinase, which was paralleled by increased activation of protein kinase C (PKC)-ζ, as evidenced by increased activity, phosphorylation, and nuclear translocation of PKC-ζ. Consistently, either pharmacological or genetic inhibition of PKC-ζ ablated metformin-enhanced phosphorylation of both AMPK at Thr172 and LKB1 at Ser428. Our data suggest that the Ser428 phosphorylation of LKB1 by PKC-ζ is required for metformin-triggered AMPK activation. See p 952.
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