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1.  Running Forward: New Frontiers in Endurance Exercise Biology 
Circulation  2014;129(7):798-810.
PMCID: PMC3981549  PMID: 24550551
exercise; skeletal muscle exercise; metabolism; aging; heart; myokine; endurance
2.  The Association between Insomnia Symptoms and Mortality: A Prospective Study of US Men 
Circulation  2013;129(7):737-746.
Insomnia complaints are common in older adults and may be associated with mortality risk. However, evidence regarding this association is mixed. We thus prospectively examined whether men with insomnia symptoms had an increased risk of mortality during 6 years of follow-up.
Methods and Results
A prospective cohort study of 23,447 US men participating in the Health Professionals Follow-up Study and free of cancer, reported on insomnia symptoms in 2004 were followed through 2010. Deaths were identified from state vital statistic records, the National Death Index, family reports, and the postal system. We documented 2025 deaths during 6 years of follow-up (2004-2010). The multivariable-adjusted hazard ratios (HRs) of total mortality were 1.25 (95% confidence interval (CI):1.04-1.50) for difficulty initiating sleep, 1.09 (95%CI:0.97-1.24) for difficulty maintaining sleep, 1.04 (95%CI:0.88-1.22) for early-morning awakenings, and 1.24 (95%CI:1.05-1.46) for non-restorative sleep, comparing men with those symptoms most of the time to men without those symptoms, after adjusting for age, lifestyle factors and presence of common chronic conditions. Men with difficulty initiating sleep and non-restorative sleep most of the time had a 55% (HR:1.55; 95% CI:1.19-2.04; P-trend= 0.01) and 32% (HR:1.32; 95% CI:1.02-1.72; P-trend=0.002) increased risk of CVD mortality, respectively, relative to men without those symptoms.
Some insomnia symptoms, especially difficulty initiating asleep and non-restorative sleep, are associated with a modestly higher risk of mortality.
PMCID: PMC3987964  PMID: 24226807
Mortality; Sleep Disorders; Cardiovascular Outcomes; Insomnia
3.  Epicardial Interventions in Electrophysiology 
Circulation  2012;126(14):1752-1769.
PMCID: PMC4326668  PMID: 23027811
catheter ablation; epicardial; arrhythmias
4.  Long-Term Coffee Consumption and Risk of Cardiovascular Disease: A Systematic Review and a Dose-Response Meta-Analysis of Prospective Cohort Studies 
Circulation  2013;129(6):643-659.
Considerable controversy exists regarding the association between coffee consumption and cardiovascular disease (CVD) risk. A meta-analysis was performed to assess the dose-response relationship of long-term coffee consumption with CVD risk.
Methods and Results
Pubmed and EMBASE were searched for prospective cohort studies of the relationship between coffee consumption and CVD risk, which included coronary heart disease, stroke, heart failure, and CVD mortality. Thirty-six studies were included with 1,279,804 participants and 36,352 CVD cases. A non-linear relationship of coffee consumption with CVD risk was identified (P for heterogeneity = 0.09, P for trend < 0.001, P for non-linearity < 0.001). Compared with the lowest category of coffee consumption (median: 0 cups/d), the relative risk of CVD was 0.95 (95% CI, 0.87 to 1.03) for the highest (median: 5 cups/d) category, 0.85 (0.80 to 0.90) for the second highest (median: 3.5 cups/d), and 0.89 (0.84 to 0.94) for the third highest category (median: 1.5 cups/d). Looking at separate outcomes, coffee consumption was non-linearly associated with both CHD (P for heterogeneity = 0.001, P for trend < 0.001, P for non-linearity < 0.001) and stroke risks (P for heterogeneity = 0.07, P for trend < 0.001, P for non-linearity< 0.001) (P for trend differences > 0.05).
A non-linear association between coffee consumption with CVD risk was observed in this meta-analysis. Moderate coffee consumption was inversely significantly associated with CVD risk, with the lowest CVD risk at 3 to 5 cups/d, and heavy coffee consumption was not associated with elevated CVD risk.
PMCID: PMC3945962  PMID: 24201300
coffee; cardiovascular disease; meta-analysis
5.  Survivin-Induced Abnormal Ploidy Contributes to Cystic Kidney and Aneurysm Formation 
Circulation  2013;129(6):660-672.
Cystic kidneys and vascular aneurysms are clinical manifestations seen in patients with polycystic kidney disease (PKD), a cilia-associated pathology (ciliopathy). Survivin overexpression is associated with cancer, but the clinical pathology associated with survivin down-regulation or knockout has never been studied before. The present studies aim to examine if and how cilia function (Pkd1 or Pkd2) and structure (Tg737) play a role in cystic kidney and aneurysm through survivin down-regulation.
Methods and Results
Cysts and aneurysms from PKD patients, Pkd mouse and zebrafish models are characterized by chromosome instability and low survivin expression. This triggers cytokinesis defects and formation of nuclear polyploidy or aneuploidy. In vivo conditional mouse and zebrafish models confirm that survivin gene deletion in the kidneys results in a cystic phenotype. As in hypertensive Pkd1, Pkd2 and Tg737 deletion, aneurysm formation can also be induced in vascular-specific normotensive survivin mice. Survivin knockout also contributes to abnormal oriented cell division in both kidney and vasculature. Furthermore, survivin expression and ciliary localization are regulated by flow-induced cilia activation through PKC, Akt and NF-κB. Circumventing ciliary function by re-expressing survivin can rescue PKD phenotypes.
For the first time, our studies offer a unifying mechanism that explains both renal and vascular phenotypes in PKD. Although primary cilia dysfunction accounts for aneurysm formation and hypertension, hypertension itself does not cause aneurysm. Furthermore, aneurysm and cyst formation share a common cellular and molecular pathway involving cilia function or structure, survivin expression, cytokinesis, cell ploidy, symmetrical cell division and tissue architecture orientation.
PMCID: PMC3946000  PMID: 24235270
aurora; cardiovascular; fluid-shear stress; renal epithelia; vascular endothelia
6.  Lipoprotein(a) Concentrations, Rosuvastatin Therapy, and Residual Vascular Risk: An Analysis from the JUPITER Trial 
Circulation  2013;129(6):635-642.
Lipoprotein(a) [Lp(a)] is an LDL-like particle largely independent of known risk factors and predictive of cardiovascular disease (CVD). Statins may offset the risk associated with elevated Lp(a), but it is unknown if Lp(a) is a determinant of residual risk in the setting of low LDL-cholesterol after potent statin therapy.
Methods and Results
Baseline and on-treatment Lp(a) concentrations were assessed in 9,612 multiethnic JUPITER trial participants before and after random allocation to rosuvastatin 20 mg/day or placebo, with outcomes reported for whites (N=7,746). Lp(a) concentrations (nmol/L) were highest in blacks (median [25th–75th percentile] 60 [34–100]), then Asians (38 [18–60]), hispanics (24 [11–46]), and whites (23 [10–50]); p<0.001. While the median change in Lp(a) with rosuvastatin and placebo was zero, rosuvastatin nonetheless resulted in a small but statistically significant positive shift in the overall Lp(a) distribution (p<0.0001). Baseline Lp(a) concentrations were associated with incident CVD: adjusted hazard ratio (HR) per 1-SD increment in Ln[Lp(a)] 1.18 (95%CI 1.03 – 1.34; p=0.02). Similarly, on-statin Lp(a) concentrations were associated with residual risk of CVD: adjusted HR 1.27 (95%CI 1.01 – 1.59; p=0.04), which was independent of LDL-cholesterol and other factors. Rosuvastatin significantly reduced incident CVD among participants with baseline Lp(a)≥median (HR 0.62, 0.43–0.90) and Lp(a)
Among white JUPITER participants treated with potent statin therapy, Lp(a) was a significant determinant of residual risk. The magnitude of relative risk reduction with rosuvastatin was similar among participants with high or low Lp(a).
PMCID: PMC3946056  PMID: 24243886
Lipoproteins; Statins; Risk Factors
Circulation  2013;129(6):673-682.
Aortic 3D blood flow was analyzed to investigate altered ascending aorta (AAo) hemodynamics in bicuspid aortic valve (BAV) patients and its association with differences in cusp fusion patterns (right-left, RL versus right-noncoronary, RN) and expression of aortopathy.
Methods and Results:
4D flow MRI measured in vivo 3D blood flow in the aorta of 75 subjects: BAV patients with aortic dilatation stratified by leaflet fusion pattern (n=15 RL-BAV, mid AAo diameter=39.9±4.4mm; n=15 RN-BAV, 39.6±7.2mm); aorta size controls with tricuspid aortic valves (n=30, 41.1±4.4mm); healthy volunteers (n=15, 24.9±3.0mm). Aortopathy type (0-3), systolic flow angle, flow displacement, and regional wall shear stress (WSS) were determined for all subjects. Eccentric outflow jet patterns in BAV patients resulted in elevated regional WSS (p<0.0125) at the right-anterior walls for RL-BAV and right-posterior walls for RN-BAV compared to aorta size controls. Dilatation of the aortic root only (type 1) or involving the entire AAo and arch (type 3) was found in the majority of RN-BAV patients (87%) but was mostly absent for RL-BAV (87% type 2). Differences in aortopathy type between RL-BAV and RN-BAV were associated with altered flow displacement in the proximal and mid AAo for type 1 (42-81% decrease versus type 2) and distal AAo for type 3 (33-39% increase versus type 2).
The presence and type of BAV fusion was associated with changes in regional WSS distribution, systolic flow eccentricity, and expression of BAV aortopathy. Hemodynamic markers suggest a physiologic mechanism by which valve morphology phenotype can influence phenotypes of BAV aortopathy.
PMCID: PMC3946057  PMID: 24345403
MRI; Bicuspid Aortic Valve; Wall Shear Stress; Hemodynamics; Aortic Disease; 4D flow MRI
Circulation  2014;130(1):4-6.
PMCID: PMC4322865  PMID: 24795391
Editorials; atherosclerosis; clinical trial; farnesyltransferase; genetics; humans; progeria
Circulation  2007;115(7):909-917.
Obesity and diabetes mellitus are complex metabolic problems of pandemic proportion, contributing to significant cardiovascular mortality. Recent studies have shown altered mitochondrial function in the hearts of diabetic animals. We hypothesized that regulatory events involved in the control of mitochondrial function are activated in the prediabetic, insulin-resistant stage.
Methods and Results
Morphometric analyses demonstrated that cardiac myocyte mitochondrial volume density was increased in insulin-resistant uncoupling protein-diptheria toxin A (UCP-DTA) transgenic mice, a murine model of metabolic syndrome, compared with littermate controls. Mitochondrial DNA content and expression of genes involved in multiple mitochondrial pathways were also increased in insulin-resistant UCP-DTA hearts. The nuclear receptor, peroxisome proliferator-activated receptor-α (PPARα), is known to activate metabolic genes in the diabetic heart. Therefore, we evaluated the role of PPARα in the observed mitochondrial biogenesis response in the insulin-resistant heart. Insulin-resistant UCP-DTA mice crossed into a PPARα-null background did not exhibit evidence of mitochondrial biogenesis or induction of mitochondrial gene expression. Conversely, transgenic mice with cardiac-specific overexpression of PPARα exhibited signatures of cardiac mitochondrial biogenesis. A screen for candidate mediators of the PPARα-driven mitochondrial biogenic response revealed that expression of PPARγ coactivator-1α (PGC-1α), a known regulator of mitochondrial biogenesis, was activated in wild-type UCP-DTA mice but not in PPARα-deficient UCP-DTA mice.
These results demonstrate that mitochondrial biogenesis occurs early in the development of diabetic cardiac dysfunction through a transcriptional regulatory circuit that involves activation of PGC-1α gene expression by the fatty acid–activated nuclear receptor PPARα.
PMCID: PMC4322937  PMID: 17261654
diabetes mellitus; cardiomyopathy; mitochondria; metabolism
Circulation  2014;130(6):496-507.
Pulmonary hypertension (PH) is a life-threatening disorder characterized by increased pulmonary artery pressure, remodeling of the pulmonary vasculature, and right ventricular failure. Loss of endothelium-derived nitric oxide (NO) and prostacyclin (PGI2) contributes to PH pathogenesis and current therapies are targeted to restore these pathways. Phosphodiesterases (PDEs) are a family of enzymes that break down cGMP and cAMP which underpin the bioactivity of NO and PGI2. The PDE5 inhibitor (PDE5i) sildenafil is licensed for PH, but a role for PDE2 in lung physiology and disease has yet to be established. Herein, we investigated whether PDE2 inhibition modulates pulmonary cyclic nucleotide signaling and ameliorates experimental PH.
Methods and Results
The selective PDE2 inhibitor BAY 60-7550 augmented atrial natriuretic peptide (ANP) and treprostinil -evoked pulmonary vascular relaxation in isolated arteries from chronically hypoxic rats. BAY 60-7550 prevented the onset of both hypoxia- and bleomycin-induced PH, and produced a significantly greater reduction in disease severity when given in combination with a neutral endopeptidase inhibitor (enhances endogenous natriuretic peptides), the PGI2 analogue treprostinil, inorganic nitrate (NO donor), or a PDE5i. Proliferation of pulmonary artery smooth muscle cells from PAH patients was reduced by BAY 60-7550, an effect further enhanced in the presence of ANP, NO and treprostinil.
PDE2 inhibition elicits pulmonary dilation, prevents pulmonary vascular remodeling, and reduces the RVH characteristic of PH. This favorable pharmacodynamic profile is dependent on natriuretic peptide bioactivity, and is additive with PGI2 analogues, PDE5i, and NO. PDE2 inhibition represents a viable, orally-active therapy for PH.
PMCID: PMC4124037  PMID: 24899690
Pulmonary hypertension; phosphodiesterase; natriuretic peptide; nitric oxide; prostacyclin; cGMP; cAMP; vasodilatation; endothelium; hypoxia
Circulation  2013;129(5):580-586.
The ICD Registry™ was established in 2006 in part to measure quality of care in patients undergoing ICD implantation; however, whether outcomes have improved since initiation of the registry is unknown. Our objective was to examine changes over time in three quality metrics available from the registry.
Methods and Results
We performed an observational study of 367,153 patients receiving new ICD implants from 4/2006-3/2010. Three quality metrics were selected: adverse events (inhospital complications or mortality), optimal medical therapy (OMT), and cardiac resynchronization therapy (CRT). OMT was defined as prescription of beta blocker and either ACE inhibitor or ARB in eligible patients. CRT eligibility was determined by QRS ≥120ms, LVEF ≤35%, and NYHA class III/IV. Observation periods were divided into four 12-month intervals. We analyzed changes over time, and used hierarchical logistic regression to adjust for potential confounders. Adverse events decreased over time (3.7% to 2.8%, P<0.001). Among eligible patients, rates of OMT and CRT increased over time (OMT: 69.0% to 74.3%, P <0.001; CRT: 80.5% to 84.2%, P<0.001). After adjustment for potential confounders, patients were significantly less likely to experience adverse events in Year 4 compared with Year 1 (OR 0.75, 95% CI 0.71-0.79), and significantly more likely to receive OMT (OR 1.29, 95% CI 1.26-1.32) and CRT (OR 1.42, 95% CI 1.35-1.49).
Since initiation of the ICD Registry, adverse events are decreasing, and rates of OMT and CRT among eligible patients are increasing, although there is still significant room for improvement.
PMCID: PMC3946506  PMID: 24192798
electrophysiology; registries; cardioverter-defibrillators; quality
Circulation  2013;129(5):598-606.
Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Extracellular RNA (eRNA) has recently been implicated to become enriched at sites of tissue damage, and to act as a pro-inflammatory mediator. We here addressed the role of eRNA in high-fat-diet (HFD)-induced atherosclerosis and neointima formation after injury in atherosclerosis-prone mice.
Methods and Results
The presence of eRNA was revealed in atherosclerotic lesions from HFD-fed low density lipoprotein receptor-deficient (Ldlr−/−) mice in a time-progressive fashion. RNase activity in plasma increased within the first 2 weeks (44 ± 9 vs. 70 ± 7 mU/mg protein; p=0.0012), followed by a decrease to levels below baseline after 4 weeks of HFD (44 ± 9 vs. 12 ± 2 mU/mg protein; p<0.0001). Exposure of bone marrow-derived macrophages to eRNA resulted in a concentration-dependent upregulation of the pro-inflammatory mediators tumor necrosis factor-α, arginase-2, Interleukin (IL)-1β, IL-6 and Interferon-γ. In a model of accelerated atherosclerosis after arterial injury in apolipoprotein E-deficient (apoE−/−) mice, treatment with RNase1 diminished the increased plasma level of eRNA, evidenced after injury. Likewise, RNase1 administration reduced neointima formation compared to vehicle-treated apoE−/− controls (25.0 ± 6.2 vs. 46.9 ± 6.9 × 103 µm2, p=0.0339), and was associated with a significant decrease in plaque macrophage content. Functionally, RNase1 treatment impaired monocyte arrest on activated smooth muscle cells under flow conditions in vitro, and inhibited leukocyte recruitment to injured carotid arteries in vivo.
As eRNA is associated with atherosclerotic lesions and contributes to inflammation-dependent plaque progression in atherosclerosis-prone mice, its targeting with RNase1 may serve as a new treatment option against atherosclerosis.
PMCID: PMC3946546  PMID: 24201302
vascular biology; atherosclerosis; inflammation; nucleic acid
Circulation  2013;129(5):539-541.
PMCID: PMC4286869  PMID: 24345401
Editorials; coronary disease; lipids; lipoproteins; low-density lipoprotein cholesterol
Circulation  2014;130(15):1262-1273.
Ca2+-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear.
Methods and Results
We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca2+ handling nor functional and structural changes. On pathological pressure overload and β-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling.
We established a mouse model in which CaMKII’s activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.
PMCID: PMC4316667  PMID: 25124496
calcineurin; CaMKII; cardiac hypertrophy; heart failure; signal transduction
Circulation  2013;129(4):471-478.
Inflammation and insulin resistance (IR) are associated processes that potentiate risk for cardiovascular disease in obesity. The temporal relation between IR and inflammation is not completely characterized. We hypothesized that endothelial cell adhesion molecule (ECAM) expression in large arteries is an early event that coincides with diet-induced obesity and IR in primates.
Methods and Results
Ten adult male rhesus macaques were studied at baseline and every 4-6 months on high-fat diet (HFD) for 2 years. Truncal fat, carotid intima-media thickness (IMT), plasma inflammatory biomarkers, and carotid P-selectin and VCAM-1 expression by contrast-enhanced ultrasound molecular imaging were assessed. Intravenous glucose tolerance test (IVGTT) was performed at baseline, 4 and 18 months. HFD produced a rapid increase (p<0.01) in weight, truncal fat, and degree of IR indicated by the insulin area-under-the-curve and glucose disappearance rate on IVGTT; all of which worsened minimally thereafter. Molecular imaging detected a progressive increase in ECAM expression over time (5-7-fold greater than control agent signal at 2 yrs, p<0.01). Changes in IMT were not detected until 2 years and, while there was a trend toward an increase in plasma markers of inflammation (MCP-1, CRP), the pattern of increase varied considerably over time.
In primates with diet-induced obesity, endothelial inflammatory activation is an early event that occurs coincident with the development of IR and long before any measurable change carotid IMT. Endothelial activation is more related to the duration rather than severity of IR and is not mirrored by changes in plasma biomarkers.
PMCID: PMC3909516  PMID: 24163066
Endothelium; inflammation; molecular imaging; insulin resistance; obesity
Circulation  1998;97(13):1246-1256.
The frequency of, course of, and factors associated with cardiovascular abnormalities in pediatric HIV are incompletely understood.
Methods and Results
A baseline echocardiogram (median age, 2.1 years) and 2 years of follow-up every 4 months were obtained as part of a prospective study on 196 vertically HIV-infected children. Age- or body surface area–adjusted z scores were calculated by use of data from normal control subjects. Although 88% had symptomatic HIV infection, only 2 had CHF at enrollment, with a 2-year cumulative incidence of 4.7% (95% CI, 1.5% to 7.9%). All mean cardiac measurements were abnormal at baseline (decreased left ventricular fractional shortening [LV FS] and contractility and increased heart rate and LV dimension, mass, and wall stresses). Most of the abnormal baseline cardiac measurements correlated with depressed CD4 cell count z scores and the presence of HIV encephalopathy. Heart rate and LV mass showed significantly progressive abnormalities, whereas FS and contractility tended to decline. No association was seen between longitudinal changes in FS and CD4 cell count z score. Children who developed encephalopathy during follow-up had depressed initial FS, and FS continued to decline during follow-up.
Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. Dilated cardiomyopathy (depressed contractility and dilatation) and inappropriate LV hypertrophy (elevated LV mass in the setting of decreased height and weight) were noted. Depressed LV function correlated with immune dysfunction at baseline but not longitudinally, suggesting that the CD4 cell count may not be a useful surrogate marker of HIV-associated LV dysfunction. However, the development of encephalopathy may signal a decline in FS.
PMCID: PMC4307393  PMID: 9570194
HIV; AIDS; pediatrics; heart failure; cardiomyopathy
Circulation  2001;104(3):310-316.
To assess the reliability of pediatric echocardiographic measurements, we compared local measurements with those made at a central facility.
Methods and Results
The comparison was based on the first echocardiographic recording obtained on 735 children of HIV-infected mothers at 10 clinical sites focusing on measurements of left ventricular (LV) dimension, wall thicknesses, and fractional shortening. The recordings were measured locally and then remeasured at a central facility. The highest agreement expressed as an intraclass correlation coefficient (ICC=0.97) was noted for LV dimension, with much lower agreement for posterior wall thickness (ICC=0.65), fractional shortening (ICC=0.64), and septal wall thickness (ICC=0.50). The mean dimension was 0.03 cm smaller in central measurements (95% prediction interval [PI], −0.32 to 0.25 cm) for which 95% PI reflects the magnitude of differences between local and central measurements. Mean posterior wall thickness was 0.02 cm larger in central measurements (95% PI, −0.18 to 0.22 cm). Mean fractional shortening was 1% smaller in central measurements. However, the 95% PI was −10% to 8%, indicating that a fractional shortening of 32% measured centrally could be anywhere between 22% and 40% when measured locally. Central measurements of mean septal thickness were ≈0.1 cm thicker than local ones (95% PI, −0.18 to 0.34 cm). Centrally measured wall thickness was more closely related to mortality and possibly was more valid than local measurements.
Although LV dimension was reliably measured, local measurements of LV wall thickness and fractional shortening differed from central measurements.
PMCID: PMC4307394  PMID: 11457750
echocardiography; pediatrics; AIDS
Circulation  2000;102(13):1542-1548.
Left ventricular (LV) dysfunction is common in children infected with the human immunodeficiency virus (HIV), but its clinical importance is unclear. Our objective was to determine whether abnormalities of LV structure and function independently predict all-cause mortality in HIV-infected children.
Methods and Results
Baseline echocardiograms were obtained on 193 children with vertically transmitted HIV infection (median age, 2.1 years). Children were followed up for a median of 5 years. Cox regression was used to identify measures of LV structure and function predictive of mortality after adjustment for other important demographic and baseline clinical risk factors. The time course of cardiac variables before mortality was also examined. The 5-year cumulative survival was 64%. Mortality was higher in children who, at baseline, had depressed LV fractional shortening (FS) or contractility; increased LV dimension, thickness, mass, or wall stress; or increased heart rate or blood pressure (P≤0.02 for each). Decreased LV FS (P<0.001) and increased wall thickness (P=0.004) were also predictive of increased mortality after adjustment for CD4 count (P<0.001), clinical center (P<0.001), and encephalopathy (P<0.001). FS showed abnormalities for up to 3 years before death, whereas wall thickness identified a population at risk only 18 to 24 months before death.
Depressed LV FS and increased wall thickness are risk factors for mortality in HIV-infected children independent of depressed CD4 cell count and neurological disease. FS may be useful as a long-term predictor and wall thickness as a short-term predictor of mortality.
PMCID: PMC4307402  PMID: 11182983
viruses; mortality; pediatrics; AIDS
Circulation  2013;129(3):321-329.
The duration and exclusivity of breastfeeding in infancy have been inversely associated with future cardiometabolic risk. We investigated the effects of an experimental intervention to promote increased duration of exclusive breastfeeding on cardiometabolic risk factors in childhood.
Methods and results
We followed-up children in the Promotion of Breastfeeding Intervention Trial, a cluster-randomized trial of a breastfeeding promotion intervention based on the World Health Organization/United Nations Children’s Fund Baby-Friendly Hospital Initiative. 17,046 breastfeeding mother-infant pairs were enrolled in 1996/7 from 31 Belarussian maternity hospitals and affiliated polyclinics (16 intervention vs 15 control sites); 13,879 (81.4%) children were followed-up at 11.5 years, with 13,616 (79.9%) fasted and without diabetes. The outcomes were blood pressure; fasting insulin, adiponectin, glucose and apolipoprotein A1; and presence of metabolic syndrome. Analysis was by intention to treat, accounting for clustering within hospitals/clinics. The intervention substantially increased breastfeeding duration and exclusivity compared with the control arm (43% vs. 6% and 7.9% vs. 0.6% exclusively breastfed at 3 and 6 months, respectively). Cluster-adjusted mean differences at 11.5 years between experimental vs control groups were: 1.0mmHg (95% CI: −1.1, 3.1) for systolic and 0.8mmHg (−0.6, 2.3) for diastolic blood pressure; −0.1mmol/l (−0.2, 0.1) for glucose; 8% (−3%, 34%) for insulin; −0.33μ/ml (−1.5, 0.9) for adiponectin; and 0.0g/l (−0.1, 0.1) for ApoA1. The cluster-adjusted odds ratio for metabolic syndrome, comparing experimental vs control groups, was 1.21 (0.85, 1.72).
An intervention to improve breastfeeding duration and exclusivity among healthy term infants did not influence cardiometabolic risk factors in childhood.
Clinical Trial Registration Information
Current Controlled Trials: ISRCTN37687716 (; Identifier: NCT01561612.
PMCID: PMC3946966  PMID: 24300437
Breastfeeding; lactation; blood pressure; fasting insulin; glucose; adiponectin; lipids; randomized controlled trial; childhood
Circulation  2013;129(3):359-372.
The generation of vascular progenitors (VP) from human induced pluripotent stem cells (hiPSC) has great potential for treating vascular disorders such as ischemic retinopathies. However, long-term in vivo engraftment of hiPSC-derived VP into retina has not yet been reported. This goal may be limited by the low differentiation yield, greater senescence, and poor proliferation of hiPSC-derived vascular cells. To evaluate the potential of hiPSC for treating ischemic retinopathies, we generated VP from a repertoire of viral-integrated and non-integrated fibroblast and cord blood (CB)-derived hiPSC lines, and tested their capacity for homing and engrafting into murine retina in an ischemia-reperfusion (I/R) model.
Methods and Results
VP from human embryonic stem cells (hESC) and hiPSC were generated with an optimized hemato-vascular differentiation system. FACS-purification of human embryoid body (hEB) cells differentially expressing endothelial/pericytic markers identified a CD31+ CD146+ VP population with high vascular potency. Episomal CB-iPSC generated these VP with higher efficiencies than fibroblast-iPSC. Moreover, in contrast to fibroblast-iPSC-VP, CB-iPSC-VP maintained expression signatures more comparable to hESC-VP, expressed higher levels of immature vascular markers, demonstrated less culture senescence and sensitivity to DNA damage, and possessed fewer transmitted reprogramming errors. Luciferase transgene-marked VP from hESC, CB-iPSC, and fibroblast-iPSC were injected systemically or directly into the vitreous of retinal I/R-injured adult NOD-SCID mice. Only hESC- and CB-iPSC-derived VP reliably homed and engrafted into injured retinal capillaries, with incorporation into damaged vessels for up to 45 days.
VP generated from CB-iPSC possessed augmented capacity to home, integrate into, and repair damaged retinal vasculature.
PMCID: PMC4090244  PMID: 24163065
Human induced pluripotent cells; embryonic stem cells; progenitor; endothelial differentiation; vasculature; retinopathy; ischemia-reperfusion; transplantation
Circulation  2009;119(9):1241-1252.
RNA interference (RNAi) has the potential to be a novel therapeutic strategy in diverse areas of medicine. We report on targeted RNAi for the treatment of heart failure (HF), an important disorder in humans resulting from multiple etiologies. Successful treatment of HF is demonstrated in a rat model of transaortic banding by RNAi targeting of phospholamban (PLB), a key regulator of cardiac Ca2+ homeostasis. Whereas gene therapy rests on recombinant protein expression as its basic principle, RNAi therapy employs regulatory RNAs to achieve its effect.
Methods and Results
We describe structural requirements to obtain high RNAi activity from adenoviral (AdV) and adeno-associated virus (AAV9) vectors and show that an AdV short hairpin RNA vector (AdV-shRNA) silenced PLB in cardiomyocytes (NRCMs) and improved hemodynamics in HF rats 1 month after aortic root injection. For simplified long-term therapy we developed a dimeric cardiotropic AAV vector (rAAV9-shPLB) delivering RNAi activity to the heart via intravenous injection. Cardiac PLB protein was reduced to 25% and SERCA2a suppression in the HF groups was rescued. In contrast to traditional vectors rAAV9 shows high affinity for myocardium, but low affinity for liver and other organs. rAAV9-shPLB therapy restored diastolic (LVEDP, dp/dtmin, Tau) and systolic (fractional shortening) functional parameters to normal range. The massive cardiac dilation was normalized and the cardiac hypertrophy, cardiomyocyte diameter and cardiac fibrosis significantly reduced. Importantly, there was no evidence of microRNA deregulation or hepatotoxicity during these RNAi therapies.
Our data show, for the first time, high efficacy of an RNAi therapeutic strategy in a cardiac disease.
PMCID: PMC4298485  PMID: 19237664
Heart Failure; RNA Interference; Gene Therapy; Adeno-Associated Virus; Phospholamban
Circulation  2013;129(2):211-223.
Clinical trials have demonstrated that second-generation cobalt-chromium everolimus-eluting stent (CoCr-EES) is superior to first-generation paclitaxel-eluting stent (PES) and is non-inferior or superior to sirolimus-eluting stent (SES) in terms of safety and efficacy. It remains unclear whether vascular responses to CoCr-EES are different from SES and PES, since the pathology of CoCr-EES has not been described in humans.
Methods and Results
A total of 204 lesions (SES=73, PES=85, CoCr-EES=46) from 149 autopsy cases with duration of implant >30 days and ≤3 years were pathologically analyzed, where comparison of vascular responses was corrected for duration of implant. The observed frequency of late and very late stent thrombosis (LST/VLST) was less in CoCr-EES (4%) versus SES (21%, p=0.029) and PES (26%, p=0.008). Neointimal thickness was comparable among the groups, while the percent uncovered struts was strikingly lower in CoCr-EES (median=2.6%) versus SES (18.0%, p≤0.0005) and PES (18.7%, p<0.0005). CoCr-EES showed less inflammation score (with no hypersensitivity) and less fibrin deposition versus SES and PES. The observed frequency of neoatherosclerosis, however, did not differ significantly among the groups (CoCr-EES=29%, SES=35%, PES=19%). CoCr-EES had the least frequency of stent fracture (CoCr-EES=13%, SES=40%, PES=19%; p=0.007 for CoCr-EES versus SES), whereas fracture-related restenosis or thrombosis was comparable among the groups (CoCr-EES=6.5%, SES=5.5%, PES=1.2%).
CoCr-EES demonstrated greater strut coverage with less inflammation, less fibrin deposition, and less LST/VLST as compared to SES and PES in human autopsy analysis. Nevertheless, the observed frequencies of neoatherosclerosis and fracture-related adverse pathologic events were comparable in these devices, indicating that careful long-term follow-up remains important even after CoCr-EES placement.
PMCID: PMC3915802  PMID: 24163064
coronary disease; pathology; restenosis; stents; thrombosis
Circulation  2013;129(2):139-141.
PMCID: PMC3926753  PMID: 24190956
Editorial; mental disorder; coronary heart disease risk; sleep; psychology and behavior
Circulation  2014;129(2):254-257.
PMCID: PMC3979345  PMID: 24421360
Thrombosis; Venous thromboembolism; Hyperhomocysteinemia; Inherited type 1 antithrombin deficiency
Circulation  2014;129(2):258-265.
PMCID: PMC4004630  PMID: 24421361
left main stenosis; cardiogenic shock; ethics

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