arrhythmia (mechanisms); calcium; Editorials; sodium; Na channel; cardiac myocites
arrhythmia (mechanisms); calcium; ion channels or ion channel; structural heart disease; CaMKII
Beat-to-beat alternation of the cardiac action potential (Vm-Alt) attributable to fluctuations in cellular calcium cycling (Ca-Alt) is a recognized mechanism of ventricular fibrillation (VF). Recently, we reported that SERCA2a, the pump responsible for re-uptake of cytosolic calcium during diastole, plays a central role in the molecular mechanism of cardiac alternans. Heart failure (HF) is associated with impaired myocardial calcium handling, deficient SERCA2a, and increased susceptibility to cardiac alternans. Therefore, we hypothesized that restoring deficient SERCA2a by gene transfer will significantly reduce arrhythmogenic cardiac alternans in the failing heart.
Methods and Results
Adult guinea pigs that were divided into 3 groups: 1) Control, 2) HF by thoracic aorta banding, and 3) HF + SERCA2a gene transfer using a cardiotropic vector (AAV9.SERCA2a) delivered by intra-coronary methods 6±2 months after aortic banding but 6 weeks prior to all measurements. Electrophysiological studies were performed in isolated myocytes and Langendorff-perfused hearts using standard patch clamp and optical mapping techniques, respectively. HF resulted in a decrease in LV fractional shortening (25±2%) compared to controls (50±2%, p<0.001). As expected, isolated HF myocytes demonstrated slower SR calcium uptake (361±30 ms vs 243±21 ms, p=0.05), decreased Ca2+ release (182±20 nM vs 368±73 nM, p< 0.05) and increase diastolic Ca2+ (333±37 nM vs 229±26 nM, p<0.05) compared to controls. Moreover, SERCA2a, RyR2 and NCX protein expression were decreased in HF when compared to control (p<0.05). As predicted, HF increased susceptibility to cardiac alternans as evidenced by decreased heart rate thresholds for both Vm-ALT (290±12 bpm vs. 388±8 bpm, p<0.01) and Ca-ALT (230±15 bpm vs 370±13 bpm, p<0.01) compared to controls. In vivo gene transfer of AAV9.SERCA2a increased LV fractional shortening and SERCA2a protein expression compared to HF alone (p<0.01). Importantly, targeted restoration of SERCA2a overexpression in HF reduced cardiac alternans (APD-ALT threshold – HF + SERCA2a: 430 bpm, vs HF: 290 bpm, and Control: 393 bpm; p<0.01) and susceptibility to inducible ventricular arrhythmias (50% vs 100% and 100%, respectively; p=0.05) compared to both HF alone and control.
These data provide new evidence that in HF reduced expression of a single calcium handling protein, SERCA2a modulates susceptibility to arrhythmogenic cardiac alternans. Moreover, therapies targeting SERCA2a can improve contractile dysfunction and restore electrical stability in HF.
alternans; action potentials; intracellular calcium; adenoviral gene transfer, repolarization, arrhythmia
In non-hypertensive individuals, a high sodium diet has little acute effect on blood pressure but, for unclear reasons, is associated with hypertension if consumed chronically. We hypothesized that a chronically high sodium intake would be associated with increases in biomarkers of endothelial dysfunction, specifically serum uric acid (SUA) and urine albumin excretion (UAE), and that high sodium intake would be associated with incident hypertension among those with higher SUA and UAE.
Methods and Results
We prospectively analyzed the associations between sodium intake and the change in SUA (N=4062) and UAE (N=4146) among participants of the PREVEND study who were not taking antihypertensive medications. We also examined the association of sodium intake with the incidence of hypertension (N=5556) among non-hypertensive participants. After adjusting for confounders, each 1 gram higher sodium intake was associated with a 1.2µmol/L increase in SUA (p=0.01) and a 4.6mg/d increase in UAE (p<0.001). The relation between sodium intake and incident hypertension varied according to SUA and UAE. For each 1 gram higher sodium intake, the adjusted hazard ratio for developing hypertension was 0.98 (0.89–1.08) among those in the lowest tertile of SUA, and 1.09 (1.02–1.16) among those in the highest. Corresponding hazard ratios were 0.99 (0.93–1.06) among participants whose UAE was <10mg/d, and 1.18 (1.07–1.29) among those whose UAE was >15mg/d.
Over time, higher sodium intake is associated with increases in SUA and UAE. Among individuals with higher SUA and urine UAE, a higher sodium intake is an independent risk factor for developing hypertension.
diet; epidemiology; hypertension; risk factors; sodium
Epigenetic programming, dynamically regulated by histone acetylation, is a key mechanism regulating cell proliferation and survival. Little is known about the contribution of histone deacetylase (HDAC) activity to the development of pulmonary arterial hypertension (PAH), a condition characterised by profound structural remodelling of pulmonary arteries and arterioles.
Methods and results
HDAC1 and HDAC5 protein levels were elevated in lungs from human idiopathic PAH and in lungs and right ventricles from rats exposed to hypoxia. Immunohistochemistry localised increased expression to remodelled vessels in the lung. Both valproic acid (VPA), a class I HDAC inhibitor, and suberoylanilide hydroxamic acid (SAHA), an inhibitor of class I, II and IV HDACs, mitigated the development and reduced established hypoxia-induced pulmonary hypertension in the rat. Both VPA and SAHA inhibited the “imprinted” highly proliferative phenotype of fibroblasts and R-cells from pulmonary hypertensive bovine vessels and PDGF-stimulated growth of human vascular smooth muscle cells in culture. Exposure to VPA and SAHA was associated with increased levels of p21and FOXO3 and reduced expression of survivin. The significantly higher level of expression of cKIT, MCP-1, IL-6, SDF-1, PDGFb and S100A4 in the R-cells were down regulated by VPA and SAHA treatment.
Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors VPA and SAHA, in models of PAH, support a therapeutic strategy based on HDAC inhibition in PAH.
Recent findings suggest that chronic kidney disease (CKD) may be associated with increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted.
Methods and Results
We pooled individual participant data from five community-based cohorts from Europe (HUNT2, PREVEND and Tromsø study) and United States (ARIC and CHS study) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria and CKD with objectively verified VTE. To estimate adjusted hazard ratios (HRs) for VTE, categorical and continuous spline models were fit using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1,178 VTE events occurred over 599,453 person-years follow-up. Relative to eGFR 100 mL/min/1.73m2, HRs for VTE were 1.29 (95%CI, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for 60, 1.82 (1.27-2.60) for 45 and 1.95 (1.26-3.01) for 30 mL/min/1.73m2. Compared with albumin-creatinine ratio (ACR) of 5.0 mg/g, the HRs for VTE were 1.34 (1.04-1.72) for 30 mg/g, 1.60 (1.08-2.36) for 300 mg/g and 1.92 (1.19-3.09) for 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted HR for CKD defined as eGFR <60 mL/min/1.73m2 or albuminuria ≥30 mg/g (vs. no CKD) was 1.54 (95%CI, 1.15-2.06). Associations were consistent in subgroups according to age, gender, and comorbidities as well as for unprovoked versus provoked VTE.
Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.
chronic kidney disease; deep vein thrombosis; epidemiology; pulmonary embolism; thromboembolism
Clinical trial and epidemiological data support that the cardiovascular effects of estrogen are complex, including a mixture of both potentially beneficial and harmful effects. In animal models, estrogen protects females from vascular injury and inhibits atherosclerosis. These effects are mediated by estrogen receptors (ERs), which when bound to estrogen can bind to DNA to directly regulate transcription. ERs can also activate several cellular kinases by inducing a “rapid” non-nuclear signaling cascade. However, the biologic significance of this rapid signaling pathway has been unclear.
Methods and Results
Here, we develop a novel transgenic mouse in which rapid signaling is blocked by over-expression of a peptide that prevents ERs from interacting with the scaffold protein, striatin (the Disrupting Peptide Mouse, DPM). Microarray analysis of ex vivo-treated mouse aortas demonstrates that rapid ER signaling plays an important role in estrogen-mediated gene regulatory responses. Disruption of ER-striatin interactions also eliminates the ability of estrogen to stimulate cultured endothelial cell migration and to inhibit cultured vascular smooth muscle cell growth. The importance of these findings is underscored by in vivo experiments demonstrating loss of estrogen-mediated protection against vascular injury in the DPM mouse following carotid artery wire injury.
Taken together, these results support that rapid, non-nuclear ER signaling contributes to the transcriptional regulatory functions of ER, and is essential for many of the vasoprotective effects of estrogen. These findings also identify the rapid ER signaling pathway as a potential target for the development of novel therapeutic agents.
cardiovascular diseases; hormones; molecular biology; signal transduction
Two opposite views of cardiac growth are currently held: one views the heart as a static organ, characterized by a large number of cardiomyocytes, which are present at birth and live as long as the organism; and the other views the heart a highly plastic organ in which the myocyte compartment is restored several times during the course of life.
Methods and Results
The average age of cardiomyocytes, vascular endothelial cells (ECs), and fibroblasts and their turnover rates were measured by retrospective 14C birth dating of cells in 19 normal hearts, 2 to 78 years of age, and in 17 explanted failing hearts, 22 to 70 years of age. We report that the human heart is characterized by a significant turnover of ventricular myocytes, ECs, and fibroblasts, physiologically and pathologically. Myocyte, EC, and fibroblast renewal is very high shortly after birth, decreases during postnatal maturation, remains relatively constant in the adult organ, and increases dramatically with age. From 20 to 78 years of age, the adult human heart replaces entirely its myocyte, EC, and fibroblast compartment ~8, ~6, and ~8 times, respectively. Myocyte, EC, and fibroblast regeneration is further enhanced with chronic heart failure (CHF).
The human heart is a highly dynamic organ that retains a remarkable degree of plasticity throughout life and in the presence of CHF. However, the ability to regenerate cardiomyocytes, vascular ECs, and fibroblasts cannot prevent the manifestations of myocardial aging or oppose the negative effects of ischemic and idiopathic dilated cardiomyopathy.
14C birth dating; cardiac cell turnover; myocyte cytokinesis
Hypertension is common and treatable but detection and control remain a major health challenge. This study sought to determine population trends in blood pressure and in the control of hypertension in the Minneapolis/St. Paul area (2010 population: 2.85 million) from 1980–2009.
Methods and Results
Surveys of risk factors were carried out every five years among randomly selected adults aged 25–74.
Data on hypertension knowledge and use of medications were collected by interview. Blood pressure was measured using standardized methods with hypertension defined as blood pressure ≥140 and/or 90 mmHg or controlled (<140 and/or 90mmHg) on medications.
Six surveys included 11,192 men and 12,795 women. Mean systolic blood pressure (SBP) fell from 124.9 mmHg in 1980–82 to 121.1 mmHg in 2007–09 for men (p<.0001) and for women from 120.1 mmHg to 114.7 mmHg (p<.0001). Similar trends for diastolic blood pressure wereobserved. Adults with uncontrolled blood pressure (≥140 and/or 90 mmHg) with or without medication fell from 20.3% to 5.8% (p<.001) for men and 13.1% to 2.7% (p<.0001) for women. Anti-hypertensive medication use rose to over 50% among all adults aged 55–74. Men (66%) and women (72%) with hypertension were treated and controlled by 2007–09. A majority of the decline in mean population blood pressure was the result of control with aggressive use of anti-hypertensive drugs. Stroke mortality in this population fell in parallel.
Hypertension detection and control in this community is among the highest observed in a US population and already exceeds Health People 2020 goals.
Hypertension; Blood Pressure; Stroke; Epidemiology
Diabetes increases the risk of adverse cardiac outcomes and is considered a coronary artery disease (CAD) equivalent. We examined whether coronary vascular dysfunction, an early manifestation of CAD, accounts for increased risk among patients with diabetes compared to non-diabetics.
Methods and Results
2783 consecutive patients (1172 diabetics and 1611 non-diabetics) underwent quantification of coronary flow reserve (CFR=stress divided by rest myocardial blood flow) by PET and were followed for a median of 1.4 years (Q1–Q3: 0.7–3.2). The primary endpoint was cardiac death. Impaired CFR (below the median) was associated with an adjusted 3.2 and 4.9-fold increase in the rate of cardiac death for diabetics and non-diabetics, respectively (p=0.0004). Addition of CFR to clinical and imaging risk models improved risk discrimination both diabetics and non-diabetics (c-index: 0.77 to 0.79, p=0.04, and 0.82 to 0.85, p=0.03, respectively). Diabetic patients without known CAD with impaired CFR experienced a rate of cardiac death comparable to that for non-diabetic patients with known CAD (2.8 vs 2.0%/year, P=0.33). Conversely, diabetics without known CAD and preserved CFR had very low annualized cardiac mortality, which was similar to patients without known CAD or diabetes and normal stress perfusion and systolic function (0.3 vs. 0.5%/year, P=0.65).
Coronary vasodilator dysfunction is a powerful, independent correlate of cardiac mortality among both diabetics and non-diabetics and provides meaningful incremental risk stratification. Among diabetic patients without CAD, those with impaired CFR have event rates comparable to patients with prior CAD while those with preserved CFR have event rates comparable to non-diabetics.
coronary disease; diabetes mellitus; imaging; myocardial perfusion imaging
The human 9p21.3 chromosome locus has been shown to be an independent risk factor for atherosclerosis in multiple large scale genome-wide association studies, but the underlying mechanism remains unknown. We set out to investigate the potential role of the 9p21.3 locus neighboring genes, including Mtap, the two isoforms of Cdkn2a, p16Ink4a and p19Arf, and Cdkn2b in atherosclerosis using knockout mice models.
Methods and Results
Gene targeted mice for neighboring genes, including Mtap, Cdkn2a, p19Arf, and Cdkn2b, were each bred to mice carrying the human APO*E3 Leiden transgene which sensitizes the mice for atherosclerotic lesions through elevated plasma cholesterol. We found that the mice heterozygous for Mtap developed larger lesion compared to wild-type mice (49623±21650 vs. 18899±9604 μm2/section (Mean±SD); p=0.01), with similar morphology as wild type mice. The Mtap heterozygous mice demonstrated changes in metabolic and methylation profiles and CD4+ cell counts. The Cdkn2a knockout mice had smaller lesions compared to wild-type and heterozygous mice and there were no significant differences in lesion size in p19Arf and Cdkn2b mutants as compared to wild type. We observed extensive, tissue-specific compensatory regulation of the Cdkn2a and Cdkn2b genes among the various knockout mice, making the effects on atherosclerosis difficult to interpret.
Mtap plays a protective role against atherosclerosis, whereas Cdkn2a appears to be modestly proatherogenic. However, no relation was found between the 9p21 genotype and the transcription of 9p21 neighboring genes in primary human aortic vascular cells in vitro. There is extensive compensatory regulation in the highly conserved 9p21 orthologous region in mice.
Atherosclerosis; 9p21 risk locus; Gene targeted mice; Methylthioadenosine Phosphorylase
Previous studies on gene-lifestyle interaction and obesity have mostly focused on the FTO gene and physical activity, while little attention has been paid to sedentary behavior as indicated by television (TV) watching.
Methods and Results
We analyzed interactions between TV watching, leisure-time physical activity and genetic predisposition in relation to body mass index (BMI) in 7740 women and 4564 men from 2 prospective cohorts: the Nurses’ Health Study and Health Professionals Follow-up Study. Data on physical activity and TV watching were collected 2 years prior to assessment of BMI. A weighted genetic risk score (GRS) was calculated on the basis of 32 established BMI-associated variants. In both women and men, the genetic associations with BMI strengthened with increased hours of TV watching. An increment of 10 points in the weighted GRS was associated with 0.8 [SE 0.4], 0.8 [0.2], 1.4 [0.2], 1.5 [0.2] and 3.4 [1.0] kg/m2 higher BMI across the 5 categories of TV watching (0-1, 2-5, 6-20, 21-40, and >40h/wk) (P for interaction=0.001). In contrast, the genetic association with BMI weakened with increased levels of physical activity. An increment of 10 points in the weighted GRS was associated with 1.5 [0.2], 1.3 [0.2], 1.2 [0.2], 1.2 [0.2] and 0.8 [0.2] kg/m2 higher BMI across the quintiles of physical activity. The interactions of TV watching and physical activity with genetic predisposition in relation to BMI were independent of each other.
Sedentary lifestyle indicated by prolonged TV watching may accentuate predisposition to elevated adiposity, whereas greater leisure-time physical activity may attenuate the genetic association.
Body mass index; Genetics; Gene-lifestyle interaction; Television watching; Physical activity
Human cardiac troponin I is known to be phosphorylated at multiple amino acid residues by several kinases. Advances in mass spectrometry allow sensitive detection of known and novel phosphorylation sites and measurement of the level of phosphorylation simultaneously at each site in myocardial samples.
Methods and Results
On the basis of in silico prediction and liquid chromatography/mass spectrometry data, 14 phosphorylation sites on cardiac troponin I, including 6 novel residues (S4, S5, Y25, T50, T180, S198), were assessed in explanted hearts from end-stage heart failure transplantation patients with ischemic heart disease or idiopathic dilated cardiomyopathy and compared with samples obtained from nonfailing donor hearts (n=10 per group). Thirty mass spectrometry–based multiple reaction monitoring quantitative tryptic peptide assays were developed for each phosphorylatable and corresponding nonphosphorylated site. The results show that in heart failure there is a decrease in the extent of phosphorylation of the known protein kinase A sites (S22, S23) and other newly discovered phosphorylation sites located in the N-terminal extension of cardiac troponin I (S4, S5, Y25), an increase in phosphorylation of the protein kinase C sites (S41, S43, T142), and an increase in phosphorylation of the IT-arm domain residues (S76, T77) and C-terminal domain novel phosphorylation sites of cardiac troponin I (S165, T180, S198). In a canine dyssynchronous heart failure model, enhanced phosphorylation at 3 novel sites was found to decline toward control after resynchronization therapy.
Selective, functionally significant phosphorylation alterations occurred on individual residues of cardiac troponin I in heart failure, likely reflecting an imbalance in kinase/phosphatase activity. Such changes can be reversed by cardiac resynchronization.
heart failure; mass spectrometry; phosphorylation; troponin
Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction (MI) in transgenic mice with cardiomyocyte-specific over-expression of PDE5 (PDE5-TG).
Methods and Results
Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening and calcium handling in isolated cardiomyocytes, and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates (WT). Ten days after MI, LV cGMP levels increased to a greater extent in WT than PDE5-TG (P<0.05). Ten weeks after MI, LV end-systolic and -diastolic volumes were larger in PDE5-TG than in WT (57±5 vs 39±4 and 65±6 vs 48±4 µL, respectively, P<0.01 for both). LV systolic and diastolic dysfunction was more marked in PDE5-TG than WT associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium.
Increased PDE5 expression predisposes mice to adverse LV remodeling after MI. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.
phosphodiesterase-5; cyclic guanosine monophosphate (cGMP); myocardial infarction; heart failure
Previous cross-sectional studies suggested a positive association between restless legs syndrome (RLS) and coronary heart disease (CHD). This observation was not confirmed by subsequent prospective studies. However, these prospective studies did not take into account the duration of RLS symptoms. We thus prospectively examined whether RLS was associated with an increased risk of CHD in women who participated in the Nurses’ Health Study taking into account the duration of RLS symptoms.
Methods and Results
A total of 70, 694 women (mean age 67 years) who were free of CHD and stroke at baseline (2002) were followed until 2008. Physician-diagnosed RLS was collected via questionnaire. CHD was defined as nonfatal myocardial infarction or fatal CHD. Women with RLS at baseline had a marginally higher risk of developing CHD (multivariable-adjusted hazard ratio (HR), 1.46; 95% confidence interval (CI), 0.97–2.18) as compared with women without RLS. The risk was dependent on duration of symptoms-0.98 (95% CI, 0.44–2.19) for women with RLS less than three years and 1.72 (95% CI, 1.09–2.73) for women with RLS for three years or longer (P trend=0.03). The multivariable-adjusted HRs of women with RLS for three years or longer were 1.80 (95%CI, 1.07–3.01) for nonfatal myocardial infarction and 1.49 (95%CI, 0.55–4.04) for fatal CHD, relative to women without RLS.
We observed that women with RLS for at least three years had an elevated risk of CHD. These results suggest that RLS or RLS associated conditions may contribute to the etiology of cardiovascular disease.
Restless legs syndrome (Willis Ekbom Disease); coronary heart disease; sleep; prospective cohort study
Changes in right ventricular (RV) morphology are associated with morbidity and mortality in heart and lung disease. We examined the association of abnormal RV structure and function with the risk of heart failure (HF) or cardiovascular death in a population-based multiethnic sample free of clinical cardiovascular disease at baseline.
Methods and Results
The Multi-Ethnic Study of Atherosclerosis (MESA) performed cardiac magnetic resonance imaging (MRI) on 5098 participants between 2000–2002 with follow-up for incident heart failure and cardiovascular death (“death”) until January 2008. RV volumes and mass were available for 4204 participants. The study sample (N = 4,144) was 61.4 ± 10.1 years old and 47.6 % male. The presence of RV hypertrophy (increased RV mass) was associated with a more than twice the risk of heart failure or death after adjustment for demographics, body mass index, education, C-reactive protein level, hypertension, and smoking status (HR = 2.52, 95%CI 1.55–4.10, p < 0.001) and a doubling of risk (or more) with left ventricular mass at the mean value or lower (p for interaction = 0.05).
RV hypertrophy was associated with the risk of heart failure or death in a multi-ethnic population free of clinical cardiovascular disease at baseline.
right ventricle; pulmonary heart disease; magnetic resonance imaging; pulmonary hypertension; survival
Supravalvular aortic stenosis (SVAS) is caused by mutations in the elastin (ELN) gene and is characterized by abnormal proliferation of vascular smooth muscle cells (SMCs) that can lead to narrowing or blockage of the ascending aorta and other arterial vessels. Availability of patient-specific SMCs may facilitate studying disease mechanisms and developing novel therapeutic interventions.
Methods and Results
Here, we report the development of a human induced pluripotent stem cell (iPSC) line from a patient with SVAS caused by the premature termination in exon 10 of the ELN gene due to an exon 9 4-nucleotide insertion. We showed that SVAS iPSC-derived SMCs (iPSC-SMCs) had significantly fewer organized networks of smooth muscle alpha actin (SM α-actin) filament bundles, a hallmark of mature contractile SMCs, compared to control iPSC-SMCs. Addition of elastin recombinant protein or enhancement of small GTPase RhoA signaling was able to rescue the formation of SM α-actin filament bundles in SVAS iPSC-SMCs. Cell counts and BrdU analysis revealed a significantly higher proliferation rate in SVAS iPSC-SMCs than control iPSC-SMCs. Furthermore, SVAS iPSC-SMCs migrated at a markedly higher rate to the chemotactic agent platelet-derived growth factor (PDGF) in comparison with the control iPSC-SMCs. We also provided evidence that elevated activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is required for hyper-proliferation of SVAS iPSC-SMCs. The phenotype was confirmed in iPSC-SMCs generated from a patient with deletion of elastin due to Williams-Beuren syndrome (WBS).
Thus, SVAS iPSC-SMCs recapitulate key pathological features of patients with SVAS and may provide a promising strategy to study disease mechanisms and to develop novel therapies.
elastin; induced pluripotent stem cells; smooth muscle alpha actin filament bundle; smooth muscle cells; supravalvular aortic stenosis
Childhood obesity has important consequences for health and wellbeing both during childhood and also in later adult life. The rising prevalence of childhood obesity poses a major public health challenge in both developed and developing countries by increasing the burden of chronic non-communicable diseases. Despite the urgent need for effective preventative strategies, there remains disagreement over its definition due to a lack of evidence on the optimal cut-offs linking childhood BMI to disease risks, and limited evidence on the most effective components of interventions to prevent childhood obesity. This article reviews the trends in childhood obesity, its genetic, nutritional and other risk factors, and preventative and treatment strategies. Particular emphasis is given to early-onset obesity in pre-school children, which, as a precursor to later childhood and adult obesity, provides insights into the developmental and genetic origins of obesity and also offers the potential for early preventative approaches with long-lasting benefits.
Exposure to ambient air pollutants increases risk for cardiovascular health outcomes in adults. The contribution of childhood air pollutant exposure to cardiovascular health has not been thoroughly evaluated.
Methods and results
The Testing Responses on Youth study consists of 861 college students recruited from the University of Southern California in 2007–2009. Participants attended one study visit during which blood pressure, heart rate and carotid artery intima-media thickness (CIMT) were assessed. Self-administered questionnaires collected information about health and socio-demographic characteristics and a 12-hr fasting blood sample was drawn for lipid and biomarker analyses. Residential addresses were geocoded and used to assign cumulative air pollutant exposure estimates based on data derived from the U.S. Environmental Protection Agency’s Air Quality System (AQS) database. The associations between CIMT and air pollutants were assessed using linear regression analysis. Mean CIMT was 603 μm (± 54 SD). A 2 standard deviation (SD) increase in childhood (aged 0–5 years) or elementary school (aged 6–12) O3 exposure was associated with a 7.8 μm (95% CI −0.3, 15.9) or 10.1 μm (95% CI 1.8, 18.5) higher CIMT, respectively. Lifetime exposure to O3 showed similar but non-significant associations. No associations were observed for PM2.5, PM10 or NO2 although adjustment for these pollutants strengthened the childhood O3 associations.
Childhood exposure to O3 may be a novel risk factor for CIMT in a healthy population of college students. Regulation of air pollutants and efforts that focus on limiting childhood exposures continue to be important public health goals.
atherosclerosis; cardiovascular diseases; carotid arteries; epidemiology; pediatrics
Menopausal hormone therapy (MHT) increases risk of coronary heart disease (CHD) in older women with elevated low-density lipoprotein (LDLC) levels. The endogenous estrogen receptor antagonist 27-hydroxycholesterol (27OHC) is correlated with LDLC levels and may block beneficial effects of estrogen on the cardiovascular system.
Methods and Results
We conducted a nested case-control study in the Women’s Health Initiative trials of 350 CHD cases and 813 matched controls to explore potential mediation by 27OHC of the dependence of the CHD risk elevation with MHT on LDLC. Baseline levels of 27OHC were not associated with CHD risk when LDLC was included in the multivariable models. The odds ratio for CHD associated with increased LDLC was 1.15 (95% confidence interval 1.08, 1.23) and was unchanged at 1.14 (1.07, 1.22) when 27OHC was added to the model. Baseline 27OHC did not interact with MHT on CHD risk (p = 0.81). In contrast, LDLC levels modified the effect of MHT on CHD risk (p for interaction = 0.02), and adding 27OHC did not affect this result. Using log scales the MHT effect on CHD increased linearly with increasing level of baseline LDLC, with a transition from no risk to increased risk at approximately 3.36 mmol/L (130 mg/dl).
27OHC does not independently increase risk of CHD, does not modify the increased risk of CHD due to MHT, and does not mediate the interaction of LDLC with MHT. Measuring blood lipids may aid in counseling individual women about initiating MHT and cardiovascular risk mitigation.
acute coronary syndrome; atherosclerosis; estrogen; low-density lipoprotein (LDL)-cholesterol; pathophysiology
Biomarkers for predicting cardiovascular events in community-based populations have not consistently added information to standard risk factors. A limitation of many previously studied biomarkers is their lack of cardiovascular specificity.
Methods and Results
To determine the prognostic value of 3 novel biomarkers induced by cardiovascular stress, we measured soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I in 3,428 participants (mean age 59, 53% women) in the Framingham Heart Study. We performed multivariable-adjusted proportional hazards models to assess the individual and combined ability of the biomarkers to predict adverse outcomes. We also constructed a “multimarker” score composed of the 3 biomarkers, in addition to B-type natriuretic peptide and high-sensitivity C-reactive protein. During a mean follow-up of 11.3 years, there were 488 deaths, 336 major cardiovascular events, 162 heart failure events, and 142 coronary events. In multivariable-adjusted models, the 3 new biomarkers were associated with each endpoint (p<0.001) except for coronary events. Individuals with multimarker scores in the highest quartile had a 3-fold risk of death (adjusted hazard ratio, 3.2, 95% CI, 2.2–4.7; p<0.001), 6-fold risk of heart failure (6.2, 95% CI, 2.6–14.8; p<0.001), and 2-fold risk of cardiovascular events (1.9, 95% CI, 1.3–2.7; p=0.001). Addition of the multimarker score to clinical variables led to significant increases in the c-statistic (p=0.007 or lower) and net reclassification improvement (p=0.001 or lower).
Multiple biomarkers of cardiovascular stress are detectable in ambulatory individuals, and add prognostic value to standard risk factors for predicting death, overall cardiovascular events, and heart failure.
biomarkers; risk assessment; risk prediction
The purpose of this study was to evaluate trends in awareness of cardiovascular disease (CVD) risk among women between 1997 and 2012 by racial/ethnic and age groups, as well as knowledge of CVD symptoms and preventive behaviors/barriers.
Methods and Results
A study of awareness of CVD was conducted by the American Heart Association in 2012 among US women >25 years of age identified through random-digit dialing (n=1205) and Harris Poll Online (n=1227), similar to prior American Heart Association national surveys. Standardized questions on awareness were given to all women; additional questions about preventive behaviors/barriers were given online. Data were weighted, and results were compared with triennial surveys since 1997. Between 1997 and 2012, the rate of awareness of CVD as the leading cause of death nearly doubled (56% versus 30%; P<0.001). The rate of awareness among black and Hispanic women in 2012 (36% and 34%, respectively) was similar to that of white women in 1997 (33%). In 1997, women were more likely to cite cancer than CVD as the leading killer (35% versus 30%), but in 2012, the trend reversed (24% versus 56%). Awareness of atypical symptoms of CVD has improved since 1997 but remains low. The most common reasons why women took preventive action were to improve health and to feel better, not to live longer.
Awareness of CVD among women has improved in the past 15 years, but a significant racial/ethnic minority gap persists. Continued effort is needed to reach at-risk populations. These data should inform public health campaigns to focus on evidenced-based strategies to prevent CVD and to help target messages that resonate and motivate women to take action.
AHA Scientific Statements; awareness; cardiovascular diseases; prevention and control; risk factors
The involvement of complement system in brain injury has been scarcely investigated. Here we document the pivotal role of mannose binding lectin (MBL), one of the recognition molecules of the lectin complement pathway, in brain ischemic injury.
Methods and Results
Focal cerebral ischemia was induced in mice (by permanent or transient middle cerebral artery occlusion) and rats (by 3-vessels occlusion). We first observed that MBL is deposited on ischemic vessels up to 48h after injury and that functional MBL/MASP2 complexes are increased. Next we demonstrated that: 1) MBL−/− mice are protected from both transient and permanent ischemic injury; 2) Polyman2, the newly synthesized mannosylated molecule selected for its binding to MBL, improves neurological deficits and infarct volume when given up to 24h after ischemia in mice; 3) anti-MBL-A antibody improves neurological deficits and infarct volume when given up to 18h after ischemia, as assessed following 28d in rats.
Our data show an important role for MBL in the pathogenesis of brain ischemic injury and provide a strong support to the concept that MBL inhibition may be a relevant therapeutic target in humans, one with a wide therapeutic window of application.
cerebral ischemia; endothelium; inflammation; stroke; complement system
Whether mitral valve repair (MVRep) during coronary artery bypass grafting (CABG) improves survival in patients with ischemic mitral regurgitation (MR) remains unknown.
Methods and Results
Patients with ejection fraction ≤ 35% and coronary artery disease amenable to CABG were randomized at 99 sites worldwide to medical therapy (MED) with or without CABG. The decision to treat the mitral valve during CABG was left to the surgeon. The primary endpoint was mortality. Of 1212 randomized patients, 435 (36%) had none/trace, 554 (46%) mild, 181 (15%) moderate, and 39 (3%) severe MR. In the medical arm, 70 deaths (32%) occurred in patients with none/trace, 114 (44%) with mild and 58 (50%) in moderate-severe MR. In patients with moderate-severe MR, there were 29 deaths (53%) among 55 patients randomized to CABG who did not receive mitral surgery (HR vs. MED 1.20, 95% CI 0.77–1.87) and 21 deaths (43%) among 49 patients who received mitral surgery (HR vs. MED 0.62, 95% CI 0.35–1.08). After adjustment for baseline prognostic variables, the HR for CABG with mitral surgery vs. CABG alone was 0.41 (95%CI 0.22–0.77; p=0.006).
While these observational data suggest that adding MVRep to CABG in patients with LV dysfunction and moderate-severe MR may improve survival compared with CABG alone or MED alone, a prospective randomized trial would be necessary to confirm the validity of these observations.
cardiomyopathy; coronary disease; mitral valve; surgery; trials
The metabolic syndrome (MetS) is a constellation of clinical features that include central obesity, hypertension, atherogenic dyslipidemia, and insulin resistance (IR). However, the concept remains controversial; it has been debated whether MetS represents nothing more than simultaneous co-occurrence of individual risk factors, or whether there are common, shared pathophysiologic mechanisms that link the individual components.
Methods and Results
To investigate the emergence of metabolic and cardiovascular components during the development of MetS, we identified MetS-predisposed animals (n=35) in a large population of rhesus macaques (Macaca mulatta, 12.7 ± 2.9 years old, n=408), acclimated them to standardized conditions, and monitored the progression of individual component features over 18 months. In total 18 MetS animals with recently developed fasting hyperinsulinemia, central obesity, hypertension, and atherogenic dyslipidemia, we found that individual metabolic and cardiovascular components track together during the transition from pre-MetS to onset of MetS; MetS was associated with a 60% impairment of flow mediated dilation (FMD), establishing the mechanistic link with vascular dysfunction. Pioglitazone treatment (3 mg/kg body weight/day for 6 weeks), a PPARγ agonist, reversibly improved atherogenic dyslipidemia and IR, and fully restored FMD with persistent benefits.
Co-emergence of metabolic and cardiovascular components during MetS progression and complete normalization of vascular dysfunction with PPARγ agonists suggest shared underlying mechanisms rather than separate processes, arguing for the benefit of early intervention of MetS components. Predictive NHP models of MetS should be highly valuable in mechanistic and translational studies on the pathogenesis of MetS in relation to cardiovascular disease and diabetes.
Metabolic Syndrome (MetS); Nonhuman Primates; Cardiovascular Disease; Pathogenesis; PPARγ agonists