Circulation: Clinical Summaries

Abstract

HomeCirculationVol. 126, No. 25Circulation: Clinical Summaries Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBCirculation: Clinical SummariesOriginal Research Put Into Perspective for the Practicing Clinician Originally published18 Dec 2012https://doi.org/10.1161/CIR.0b013e3182801524Circulation. 2012;126:2911–2914Sprint Fidelis Lead Fractures in Patients With Cardiac Resynchronization Therapy Devices: Insight From the Resynchronization/Defibrillation for Ambulatory Heart Failure (RAFT) StudyIn this multicenter, randomized trial, Sprint Fidelis fractures were found to occur more frequently in the group that received both an implantable cardioverter-defibrillator and cardiac resynchronization therapy than in the group that received only an implantable cardioverter-defibrillator. This is the first study to have adjudicated lead fracture in a blinded fashion, with systematic follow-up in a clinical trial. Our main findings were an overall rate of lead fracture of 1.65%, with a hazard ratio of 2.42 for patients with both an implantable cardioverter-defibrillator and cardiac resynchronization therapy. The only predictor of lead fracture in this population was having undergone both implantation of an implantable cardioverter-defibrillator and cardiac resynchronization therapy. The Fidelis lead issue has provided invaluable information on lead behavior and risks for fracture. The Resynchronization/Defibrillation for Ambulatory Heart Failure (RAFT) study has been able to contribute further information on how cardiac resynchronization therapy influences the risk of fracture related to this lead. The increased risk of fracture in cardiac resynchronization therapy patients should be taken into account when such patients appear for generator change, where the risk for fracture is higher than in a standard implantable cardioverter-defibrillator. Prophylactic revision of the lead in such cases needs to be considered carefully in terms of risks and benefits of this intervention. See p 2928.Bilateral Internal Mammary Artery Grafting Enhances Survival in Diabetic Patients: A 30-Year Follow-Up of Propensity Score–Matched CohortsThe prevalence of diabetes mellitus is increasing at an unprecedented rate, affecting nearly 8% of the population. Previous studies have demonstrated a potential benefit for surgical over interventional revascularization in this group of patients, perhaps because of the diffuse nature of coronary atherosclerosis in this population. Similarly, multiple studies have shown the superiority of bilateral internal mammary artery (BIMA) grafting over single internal mammary artery grafting in select populations. However, concerns about sternal wound infection have discouraged the use of BIMA grafting in diabetics. Therefore, we studied the long-term results of BIMA versus single internal mammary artery grafting in a large population of diabetic patients in whom BIMA grafting was broadly applied. Because of the uncontrolled surgical selection process for single internal mammary artery versus BIMA grafting, we applied propensity score matching to create matched sets of single internal mammary artery and BIMA patients among 1107 consecutive coronary artery bypass graft patients. Although there was no difference in operative mortality, morbidity, or sternal wound infection between groups, there was a clear long-term survival benefit, even among matched patients, for BIMA over single internal mammary artery grafting. Given the increasing prevalence of diabetes mellitus, the high incidence of extensive coronary artery disease in diabetics, and the proven benefit of coronary artery bypass graft surgery as a strategy for revascularization, these findings address an issue of high clinical impact. Because the findings are compelling and radically alter current clinical practice, this research is novel and warrants serious attention from both future researchers and clinical decision makers. See p 2935.Arginase Inhibition Improves Endothelial Function in Patients With Coronary Artery Disease and Type 2 Diabetes MellitusVascular complications associated with type 2 diabetes mellitus are a widespread clinical problem. The mechanism behind these complications is far from understood, and specific treatment is lacking. Endothelial dysfunction with reduced bioavailability of nitric oxide has been suggested to be of importance for development of atherosclerosis and diabetic vascular complications. Emerging evidence suggests that increased activity and the expression of arginase via the metabolism of l-arginine, which is a substrate for both arginase and nitric oxide synthase, may result in reduced levels of arginine available for nitric oxide production and hence endothelial dysfunction. In the current study, we demonstrate that patients with coronary artery disease with and without diabetes mellitus have impaired endothelial function in comparison with age-matched control subjects. Furthermore, we show that inhibition of arginase activity in the forearm of patients with diabetes mellitus and coronary artery disease markedly improves endothelial function. The improvement in endothelial function is more pronounced in patients with coronary artery disease and diabetes mellitus than in those with coronary artery disease alone. The beneficial effect of arginase inhibition is completely dependent on the increased bioavailability of nitric oxide. These novel observations suggest that arginase activity is a key factor for endothelial dysfunction in patients with coronary artery disease, in particular, among those with diabetes mellitus, by regulating the bioavailability of nitric oxide. Our findings suggest that arginase inhibition could be an effective pharmacological intervention to improve the vascular function in these patients. See p 2943.Associations of Total and High-Molecular-Weight Adiponectin With All-Cause and Cardiovascular Mortality in Older Persons: The Cardiovascular Health StudyAdiponectin is the most abundant protein secreted by adipocytes. This adipokine, which is suppressed in obesity, exhibits insulin-sensitizing and atheroprotective signaling properties. Clinical studies in healthy middle-aged adults document an inverse relationship between adiponectin and adverse outcomes, but in cohorts with prevalent coronary disease, heart failure, or advanced age, a direct association has been reported. We investigated these findings further by assessing the relationship of total and high-molecular-weight adiponectin with fatal events in a large cohort of older adults stratified by baseline cardiovascular disease and heart failure/atrial fibrillation. There was evidence of effect modification by baseline cardiovascular status for both adiponectin measures, such that after adjustment for potential confounders, the relationship was U-shaped among participants without prevalent cardiovascular disease, heart failure, or atrial fibrillation, null in those with prevalent cardiovascular disease only, and direct in subjects with prevalent heart failure/atrial fibrillation. Additional adjustment for putative metabolic/inflammatory intermediates abolished the inverse association with mortality at the lower range of concentrations in the first group, suggested a direct association in the second, and strengthened the association in the third. Together, these findings advance understanding of the adiponectin paradox, showing that among older adults, the associations with mortality become progressively more adverse across subgroups with increasing cardiovascular risk. Disappearance of the protective association at lower adiponectin concentrations after accounting for metabolic factors suggests that the beneficial actions of the adipokine are counterbalanced by as yet undetermined deleterious influences. Further investigation to elucidate the underlying mechanisms could lead to the identification of novel therapeutic targets in aging and related disorders. See p 2951.Loss of AngiomiR-126 and 130a in Angiogenic Early Outgrowth Cells From Patients With Chronic Heart Failure: Role for Impaired In Vivo Neovascularization and Cardiac Repair CapacityCell-based cardiac repair mechanisms such as that stimulated by angiogenic early outgrowth cells (EOCs) or CD34+ cells are currently being intensely examined as a potential therapeutic target in patients with chronic heart failure (CHF) caused by ischemic cardiomyopathy. Clinical studies have suggested that administration of angiogenic EOCs may improve cardiac function, but the effects have been more modest compared with experimental studies, particularly in patients with ischemic cardiomyopathy. These observations raised the question of what underlying molecular mechanisms limit the cardiac repair capacity of angiogenic EOCs or CD34+ cells derived from patients with CHF caused by ischemic cardiomyopathy. Recent experimental studies have indicated that the angiogenic effects of these cells are important to promote cardiac repair and to improve cardiac function. In the present study, we have observed that cardiac neovascularization and repair capacity of angiogenic EOCs derived from patients with CHF caused by ischemic cardiomyopathy were substantially impaired compared with angiogenic EOCs from healthy subjects. MicroRNAs, small noncoding RNAs, have been identified as key regulators of angiogenic processes. Here, we have shown a marked downregulation of the proangiogenic microRNA-126 in angiogenic EOCs and CD34+ cells from patients with CHF. Moreover, miR-126 mimic transfection of angiogenic EOCs from patients with CHF increased their capacity to enhance cardiac neovascularization and to improve cardiac function. These studies identify a novel mechanism limiting the cardiac repair capacity of angiogenic EOCs and CD34+ cells in patients with CHF that can be therapeutically targeted by miR-126 mimic treatment. See p 2962.Renal Sympathetic Denervation for Treatment of Drug-Resistant Hypertension: One-Year Results From the Symplicity HTN-2 Randomized, Controlled TrialPatients with uncontrolled hypertension are at significant risk for cardiovascular events, and a subset of these patients who do not respond to aggressive pharmacological treatment (≥3 antihypertensive drugs including a diuretic) are considered to have treatment-resistant hypertension. It has been shown that activation of the sympathetic nervous system is involved in the pathogenesis and maintenance of hypertension. Renal denervation with the Symplicity catheter is a minimally invasive procedure based on the premise that interruption of renal afferent and efferent nerves with resultant decreased sympathetic outflow to the kidneys will reduce renin release and sodium retention, increase renal blood flow, and lower blood pressure. The Symplicity HTN-2 trial demonstrates that radiofrequency ablation of renal nerves can significantly lower blood pressure in patients with systolic blood pressures >160 mm Hg with no loss of treatment effect through 1 year and thus may provide a safe and effective adjunctive therapy for treatment-resistant hypertensive patients. See p 2976.Body Mass Index and Risk of Incident Hypertension Over the Life Course: The Johns Hopkins Precursors StudyIn this long-term prospective cohort study, we studied the association of body mass index with risk of developing hypertension from young adulthood into middle age and through late life. Repeated assessments of body mass index, blood pressure, and risk factors for developing hypertension over the life course enabled us to examine the influence of lifestyle and behavior in young adult life through middle age on health later in life. Obesity in young adulthood conferred a 3-fold risk of hypertension after 46 years of follow-up, even after we accounted for change in lifestyle factors over the life course. Men who were of normal weight in early adulthood but who became overweight or obese in midlife were twice as likely to develop hypertension as men who maintained a normal weight. Loss of weight between young adulthood and middle age conferred no additional risk. Rate of change of body mass index over the life course was an independent predictor of risk of hypertension, independent of the level of body mass index, cigarette smoking, alcohol intake, physical activity, and coffee drinking. Although the data were observational, the temporal relationship established by the long follow-up and repeated assessment of both body weight and blood pressure provided strong evidence for the association between body mass index and hypertension. This study showed that increase of weight at any time in the life course increased the risk of developing hypertension after adjustment for other risk factors. See p 2983.Cytochrome P450 Subfamily 2J Polypeptide 2 Expression and Circulating Epoxyeicosatrienoic Metabolites in PreeclampsiaPreeclampsia remains the greatest cause of perinatal maternal and fetal morbidity with long-term cardiovascular ramifications for mother and child. New mechanistic insights are desperately needed for improved preventative and therapeutic strategies. We used microarray expression to screen placenta (fetal tissue) and decidua (maternal tissue) from preeclamptic women and controls. We identified upregulation of the cytochrome P450 (CYP) epoxygenase, CYP2J2, and located the protein in trophoblasts, placental cells that invade into the decidua. We next screened maternal plasma for CYP2J2 metabolites and observed an elevation of 5,6-epoxyeicosatrienoic acid (EET) and 14,15-EET, as well as the corresponding dihydroxyeicosatrienoic acids (DHETs) in preeclamptic women compared with controls in the latter two thirds of pregnancy. In a trophoblast-derived cell line, the preeclampsia-associated cytokine, tumor necrosis factor-α, enhanced CYP2J2 gene and protein expression. Furthermore, we observed increased CYP2J2 metabolites in 2 different rat models of preeclampsia, in which pharmacological CYP epoxygenase inhibition ameliorated the preeclamptic condition. Finally, we observed that 5,6-EET is metabolized to a thromboxane analog that stimulated calcium-activated potassium channel (KCa1.1) activity. Our results suggest a novel link between CYP eicosanoids and preeclampsia. The findings support the common hypothesis that the preeclampsia begins in the placenta and is translated to a maternal syndrome by circulating factors. Because 5,6 EET can be metabolized to thromboxane, our data also provide a molecular mechanism linking thromboxane metabolism with preeclampsia. We believe that this complex series of findings may permit various treatment avenues that could conceivably be extended to patients. See p 2990.Computed Tomography Coronary Angiography in Patients With Acute Myocardial Infarction Without Significant Coronary StenosisAlmost 10% of patients with acute myocardial infarction have normal or nonsignificant coronary stenosis at coronary angiography. The absence of critical stenosis may challenge the diagnosis, however atherosclerosis may be present also in angiographically normal coronary arteries attributable to outward remodeling and acute myocardial infarction may result from disruption of nonobstructive atherosclerotic plaques. In this study, we enrolled 50 consecutive patients with acute myocardial infarction confirmed by late gadolinium–enhanced cardiac magnetic resonance without obstructive coronary stenosis at coronary angiography. In this population, coronary computed tomography angiography showed a significant number of angiographically invisible atherosclerotic plaques. Moreover, coronary plaques located on infarct-related arteries were more frequently mixed or noncalcified with higher mean plaque area and remodeling index, compatible with vulnerable plaques. These findings may support the use of optimal secondary prevention therapy to reduce the risk of recurrent events. See p 3000.Impact of a High Loading Dose of Atorvastatin on Contrast-Induced Acute Kidney InjuryPatients with chronic kidney disease were randomly assigned to (1) the atorvastatin group (atorvastatin loading dose [80 mg] within 24 hours before contrast media exposure; n=202) or (2) the control group (n=208). All patients received a high dose of N-acetylcysteine and sodium bicarbonate solution. Contrast-induced acute kidney injury (defined as an increase >10% of serum cystatin C) occurred in 9 of 202 patients in the atorvastatin group (4.5%) and in 37 of 208 patients in the control group (17.8%) (P=0.005; odds ratio=0.22; 95% confidence interval, 0.07–0.69). In the in vitro model, pretreatment with atorvastatin (1) prevented contrast media–induced renal cell apoptosis by reducing activation of stress kinases and (2) restored survival signals (mediated by Akt and ERK pathways). The present study demonstrates that a single high loading dose of atorvastatin administered within 24 hours before contrast media exposure (on top of conventional strategies) is effective in reducing the rate of contrast-induced acute kidney injury by preventing contrast media–induced epithelial tubular renal cell apoptosis and increasing survival signaling pathways. See p 3008.Hypoxia Induces Myocardial Regeneration in ZebrafishCardiac ischemia leads to a reduction in oxygen supply and subsequent induction of hypoxia. At present, the consensus is that the hypoxia associated with cardiac ischemia initially induces a cardioprotective response; however, prolonged exposure ultimately leads to necrosis and loss of myocardial tissue. Treatment of patients who have suffered an ischemic episode aims to reduce hypoxia. Our data now indicate that hypoxia could also play a beneficial role. We have found that hypoxia positively regulates myocardial regeneration in zebrafish. We have also found that some of the processes that are regulated by hypoxia during zebrafish heart regeneration have also been reported in mammals/humans after cardiac ischemia. In particular, we have observed that hypoxia induces zebrafish cardiomyocytes to dedifferentiate, a process that is also associated with cardiomyocytes in ischemic patients. Unfortunately, although they are capable of this initial dedifferentiation, human cardiomyocytes fail to proliferate and subsequently regenerate the heart. Future strategies attempting to regenerate a damaged human heart should take into account that hypoxia can play a beneficial role in inducing a regenerative response. See p 3017.CKIP-1 Inhibits Cardiac Hypertrophy by Regulating Class II Histone Deacetylase Phosphorylation Through Recruiting PP2AAmong the intracellular signaling pathways involved in the regulation of cardiac hypertrophy, class II histone deacetylases (HDACs) have been identified as important signal-responsive repressors for cardiac hypertrophy. Little is known about the regulation of HDAC4 in response to extracellular stimuli leading to cardiac hypertrophy. Here we identified casein kinase-2 interacting protein-1 (CKIP-1) as a novel regulator of pathological cardiac hypertrophy and class II HDACs/myocyte enhancer factor-2 signaling in cardiac myocytes. In this research, our data showed that CKIP-1 is induced early after pressure overload, but sharply reduced in the late phases of cardiac hypertrophy in mouse and human hearts. CKIP-1 systemically deficient mice exhibit spontaneous pathological cardiac hypertrophy by 8 months and display exaggerated responses to pressure overload. Conversely, cardiac specific overexpression of CKIP-1 attenuates pathological remodeling during chronic pressure overload. HDAC4 was identified to be a CKIP-1 interaction partner through unbiased interaction screening. HDAC4 is involved in the regulation of myocyte enhancer factor-2 transcription activity via decreasing the phosphorylation of HDAC4. CKIP-1 could increase the association of HDAC4 with protein phosphatase 2A and promote the dephosphorylation of HDAC4. These results demonstrated that CKIP-1 was required to inhibit the occurrence of cardiac hypertrophy and represented a promising candidate target for preventing hypertrophic cardiomyopathy. See p 3028.Timing, Predictive Factors, and Prognostic Value of Cerebrovascular Events in a Large Cohort of Patients Undergoing Transcatheter Aortic Valve ImplantationTranscatheter aortic valve implantation has been associated with a higher rate of cerebrovascular events (CVEs) compared with medical treatment or surgical aortic valve replacement. This multicenter study evaluated the timing, predictors, and clinical impact of CVEs after transcatheter aortic valve implantation in a large cohort of consecutive patients (n=1061). The incidence of 30-day CVEs was 5.1% (stroke, 4.2%), with about half of these events occurring immediately or within the first few hours after the procedure. The predictors of acute (≤24 hours) CVEs were mechanical factors such as further stretching of the valve prosthesis with balloon postdilation (odds ratio, 2.46; P=0.034) and valve dislodgment/embolization (odds ratio, 4.36; P=0.024), whereas subacute (1–30 days) CVEs were determined mainly by the occurrence of atrial arrhythmias (new-onset atrial fibrillation; odds ratio, 2.76; P=0.028). There were no differences in 30-day CVE rate between different types of valves (balloon expandable, self-expandable) or access routes (transfemoral, transapical). The rate of late (<30 days) CVEs was 3.3% (stroke, 2.1%) at a median follow-up of 12 months (3–23 months). The predictors of late CVEs were chronic atrial fibrillation (hazard ratio, 2.84; P=0.002), peripheral vascular disease (hazard ratio, 2.02; P=0.043), and prior cerebrovascular disease (hazard ratio, 2.04; P=0.047). The impact of CVEs on mortality was determined mainly by the severity of the event, and only the occurrence of major stroke was independently associated with an increased 30-day (hazard ratio, 7.43; P=0.001) and late cumulative (hazard ratio, 1.75; P=0.043) mortality. These results providing important insight into the pathophysiology and prognosis value of CVEs after transcatheter aortic valve implantation procedures should help to determine the most appropriate therapeutic measures to reduce the high incidence of CVEs associated with transcatheter aortic valve implantation. See p 3041.Stroke After Carotid Stenting and Endarterectomy in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST)Stroke is a feared complication of carotid endarterectomy (CEA) and carotid stenting (CAS). The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) and European trials have shown that CAS is associated with a greater risk of stroke than CEA. CREST also showed that CEA was associated with a greater risk of myocardial infarction (MI) than CAS. The greater risk of MI numerically balanced the greater risk of stroke, so that the composite primary outcome (periprocedural stroke, MI, or death and ipsilateral stroke at up to 4 years) was similar for CEA and CAS. This result has invited criticism because of the differing directions of stroke and MI within the composite outcome. To understand further, we examined the strokes that occurred as a complication of the procedure. Stroke was still more common after CAS, but overall the risk of severe stroke was <1% and was similar for CEA and CAS. The delayed timing of some major strokes, particularly intracerebral hemorrhage that occurred a few days postoperatively, makes it plausible that these postoperative strokes are preventable, perhaps with careful attention to blood pressure control. Minor stroke occurred most commonly on the same day as CAS, which suggests that the technical aspects of the procedure could be improved to minimize stroke as a complication. Previously, we reported that MI, including biomarker-only MI, was associated with an increased risk in long-term mortality. Here we report that stroke, including minor stroke, was also associated with an increased risk in long-term mortality. Carotid intervention with CEA or CAS is safe. Periprocedural stroke incurred significant morbidity and mortality. See p 3054.Association Between 2 Angiographic Subtypes of Renal Artery Fibromuscular Dysplasia and Clinical CharacteristicsFibromuscular dysplasia is a heterogeneous group of idiopathic, noninflammatory, and nonatherosclerotic stenosing vascular diseases mostly involving renal and cervical arteries. It is the second most frequent cause of renovascular hypertension. Its historical classification based on histology is no longer relevant now that percutaneous revascularization has replaced surgery in most cases. In this study, we describe an angiographic classification of renal artery fibromuscular dysplasia lesions into a unifocal and a multifocal subtype. Fewer patients have unifocal lesions (18% of all patients with renal artery fibromuscular dysplasia), and their characteristics contrast with those of patients with multifocal lesions: They are younger at diagnosis (30 versus 49 years); the proportion of women is lower (69% versus 83%); they are more often current smokers (50% versus 26%) with higher blood pressure levels (157/97 versus 146/88 mm Hg); the disease is more often unilateral (79% versus 38%); they are more amenable to revascularization (90% versus 35%); and have a higher cure rate when revascularization is performed (54% versus 26%). See p 3062.Neutrophil-Derived Matrix Metalloproteinase 9 Triggers Acute Aortic DissectionAcute aortic dissection (AAD) is a potentially fatal vascular disease, and prompt diagnosis and treatment by timely surgery are required for survival of the patients. No efficient biomarkers are available for diagnosis of AAD prior to determination of the disease by computed tomography. Medial degeneration is known as an important risk factor for the development of AAD; however, the emergent nature of the disease and the paucity of animal models prevent us from studying the molecular mechanisms for triggering the disease. We found that matrix metalloproteinase 9 (MMP9) and angiotensin II were increased significantly in blood samples from AAD patients compared with those from normal subjects and the patients with nonruptured aortic aneurysm. This was accompanied by enhanced infiltrations of MMP9-producing neutrophils in the dissected aortas. Based on the data, we established a mouse model of AAD, which was induced by infusion of angiotensin II to mice pretreated with β-aminopropionitrile monofumarate (a lysyl oxidase inhibitor). All mice exhibited AAD within 24 hours after angiotensin II infusion. Aortic tissue from the AAD mice showed enhanced expression and activity of MMP9, and MMP9-immunoreactive neutrophils were infiltrated in both dissected media and intima of nondissected lesions. Genetic depletion or pharmaceutical inhibition of MMP9 and neutrophil ablation attenuated the AAD incidence. These data demonstrate that neutrophil-derived MMP9 is responsible for triggering AAD in this model. Taken together, MMP9 could serve as a potential biomarker for diagnostic screening of AAD, and administration of angiotensin II receptor blockers or MMP9 inhibitors could be effective therapeutic approaches to AAD. See p 3070. Previous Back to top Next FiguresReferencesRelatedDetails December 18, 2012Vol 126, Issue 25 Advertisement Article InformationMetrics © 2012 American Heart Association, Inc.https://doi.org/10.1161/CIR.0b013e3182801524 Originally publishedDecember 18, 2012 PDF download Advertisement