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2.  Admission hypoxia-inducible factor 1α levels and in-hospital mortality in patients with acute decompensated heart failure 
Background
Hypoxia-inducible factor 1 (HIF-1) is a critical regulator for cellular oxygen balance. Myocardial hypoxia can induce the increased expression of HIF-1α. Our goals were to evaluate the value of HIF-1α in predicting death of patients with acute decompensated heart failure (ADHF) and describe the in vivo relationship between serum HIF-1α and N-terminal–pro-brain natriuretic peptide (NT-proBNP) levels.
Method
We included 296 patients who were consecutively admitted to the emergency department for ADHF. The primary end point was in-hospital death. The patients were categorized as HFrEF (patients with reduced systolic function) and HFpEF (patients with preserved systolic function) groups.
Results
In our patients, the median admission HIF-1α level was 2.95 ± 0.85 ng/ml. The HIF-1α level was elevated significantly in HFrEF patients and deceased patients compared with HFpEF patients and patients who survived. The HIF-1α level was positively correlated with NT-proBNP and cardiac troponin T levels, and negatively correlated with left ventricular ejection fraction and systolic blood pressure. Kaplan–Meier curves revealed a significant increase in in-hospital mortality in ADHF patients with higher HIF-1α levels. Multivariable Cox regression analysis showed that HIF-1α levels were not correlated with the short-term prognosis of ADHF patients.
Conclusions
This is the first study to evaluate the circulating levels of HIF-1α in ADHF patients. Serum HIF-1α levels may reflect a serious state in patients with ADHF. Due to the limitations of the study, serum HIF-1α levels were not correlated with the in-hospital mortality based on regression analysis. Further studies are needed to demonstrate the diagnostic and/or prognostic role of HIF-1α as a risk biomarker in patients with ADHF.
doi:10.1186/s12872-015-0073-6
PMCID: PMC4518524
Hypoxia-inducible factor 1α; Acute decompensated heart failure; N-terminal–pro-brain natriuretic peptide; In-hospital mortality
3.  FGF21 protects against ox-LDL induced apoptosis through suppressing CHOP expression in THP1 macrophage derived foam cells 
Background
FGF21,as a member of the fibroblast growth factor superfamily, is an important endogenous regulator to systemic glucose and lipid metabolism. Elevated serum FGF21 levels have been reported in subjects with coronary heart disease and carotid artery plaques. The formation and apoptosis of foam cell, induced by ox-LDL and oxysterols, are key steps in the development of atherosclerosis.
Methods
In this study, THP1 derived macrophages were induced into foam cells by ox-LDL or sterols. The formation and apoptosis of foam cells treated with or without FGF21 were analyzed.
Results
We demonstrated that the accumulation of cholesterol was decreased after FGF21 treatment in THP1 macrophage derived foam cells. Consistently, the apoptosis of macrophage was alleviated dramatically with FGF21 treatment. ERK1/2 knockdown didn’t abrogate the effect of FGF21 on THP1 macrophage derived foam cells. However, FGF21 suppressed the induced expression of CHOP and DR5 in THP1 macrophage derived foam cells.
Conclusion
FGF21 protects against the formation and apoptosis of THP1 macrophages derived foam cells through suppressing the expression of CHOP.
doi:10.1186/s12872-015-0077-2
PMCID: PMC4518604
Macrophage; ER stress; FGF21; Foam cell; CHOP
4.  Role of SIRT3 in Angiotensin II-induced human umbilical vein endothelial cells dysfunction 
Background
SIRT3, a member of the sirtuin family of NAD+-dependent deacetylases, resides primarily in the mitochondria and has been shown to deacetylate several metabolic and respiratory enzymes that regulate important mitochondrial functions. Previous researches show an important role of SIRT3 in regulating the production of reactive oxygen species (ROS), and highlight the ability of SIRT3 to protect cells from oxidative damage. A key substance of renin-angiotensin-aldosterone system (RAAS), Angiotensin II (AngII) can induce cells dysfunction by increasing the production of ROS. In this paper, we focus on the role of SIRT3 in AngII-induced human umbilical vein endothelial cells (HUVECs) dysfunction.
Methods
To study the influence of AngII on SIRT3 expression, HUVECs were treated with AngII of 10−7, 10−6, 10−5 mol/L for 24 h. SIRT3 expression was detected by wester-blotting analysis and RT-PCR. In addition, to research the role of SIRT3 in AngII-induced HUVECs,we used SIRT3 siRNA to knock down SIRT3 expression in HUVECs. Cells pretreated with negative control siRNA or SIRT3 siRNA were exposed to AngII for 24 h, and endothelial nitric oxide synthase (eNOS) expression, eNOS activity, total level of nitric oxide (NO) and ROS generation of each group were detected.
Results
Here we show that AngII treatment could increase generation of ROS, and decrease eNOS activity and total level of NO, while upregulated eNOS expression as a compensatory mechanism. The stimulation of AngII upregulated the expression of SIRT3 in HUVECs. SIRT3 siRNA worsen the AngII-induced effects above, besides, downregulated eNOS protein expression.
Conclusion
These data suggest that SIRT3 plays a role of protection in AngII-induced HUVECs dysfunction via regulation of ROS generation.
doi:10.1186/s12872-015-0075-4
PMCID: PMC4520206
SIRT3; Endothelial dysfunction; AngII; Reactive oxygen species; HUVECs
5.  Preconditioning offers cardioprotection in hyperlipidemic rat hearts: possible role of Dopamine (D2) signaling 
Background
Ischemic preconditioning (IPC) induced cardioprotection has been reported to be blunted in hyperlipidemic subjects. Dopamine, via its D2 receptor signaling, appears to mimic the signaling cascade involved in myocardial preconditioning and is also involved in the inhibition of hyperlipidemia induced mediators. The present study was designed to investigate the possible involvement of D2 receptors in IPC and to see whether dopamine preconditioning can offer cardioprotection in hyperlipidemic rat hearts.
Methods
Wistar albino rats were divided into 8 groups and fed on normal or high fat diet for 4 weeks. Hyperlipidemia was confirmed after 4 weeks by serum lipid estimations. Isolated perfused hearts were subjected to ischemic preconditioning or dopamine induced pharmacological preconditioning followed by 30-min ischemic insult and 60-min reperfusion. Clozapine was administered as D2 antagonist. Coronary perfusate (basal and post-ischemic) was collected for the estimations of LDH (Lactate dehydrogenase) and CKMB (Creatine kinase MB). Hearts were then removed and frozen for infarct size measurement.
Results
A significant increase body weight, serum lipids except HDL was noted in high fat diet fed rats, as compared to normal rats. The level of LDH, CKMB in coronary effluent and infarct size were found to be decreased in preconditioned normal hearts, as compared to hearts treated with ischemia reperfusion. This effect was found to be blunted in hyperlipidemic animals. Dopamine (10 μM) alone and in combination with ischemic preconditioning significantly reduced the levels of LDH, CKMB and infarct size in hyperlipidemic hearts, as compared to preconditioned and non-preconditioned hyperlipidemic hearts. This effect was abolished significantly by Clozapine (D2 antagonist).
Conclusion
The present study reveals possible involvement of D2 receptors in ischemic preconditioning and suggests that dopamine preconditioning may offer significant cardioprotection in hyperlipidemic rat hearts.
doi:10.1186/s12872-015-0071-8
PMCID: PMC4515884  PMID: 26216101
Dopamine; Preconditioning; Hyperlipidemia; Infarct
6.  Feasibility of a new method using two-dimensional transesophageal echocardiography for aortic annular sizing in patients undergoing transcatheter aortic valve implantation; a case–control study 
Background
Accurate preoperative assessment of the aortic annulus dimension is crucial for successful transcatheter aortic valve implantation (TAVI). In this study we validated a new method using two-dimensional transesophageal echocardiography (2D-TEE) for measurement of the aortic annulus prior to TAVI.
Methods
We analysed 124 patients who underwent successful TAVI using a self-expandable prosthesis, divided equally into two groups; in the study group we used the cross sectional short axis 2D-TEE for measurement of the aortic annulus and in the control group we used the long axis 2D-TEE.
Results
Both groups were comparable regarding the clinical parameters. On the other hand, patients in the study group had less left ventricular ejection fraction (38.9 % versus 45.6 %, p = 0.01). The aortic valve annulus was, although not statistically significant, smaller in the study group (21.58 versus 23.28 mm, p = 0.25).
Post procedural quantification of the aortic regurgitation revealed that only one patient in both groups had severe aortic regurgitation (AR), in this patient the valve was implanted deep. The incidence of significant AR was higher in the control group (29.0 % versus 12.9 %, p = 0.027).
Conclusions
Sizing of the aortic valve annulus using cross-sectional 2D-TEE offers a safe and plausible method for patients undergoing TAVI using the self-expandable prosthesis and is significantly superior to using long axis 2D-TEE.
doi:10.1186/s12872-015-0072-7
PMCID: PMC4517415  PMID: 26216218
TAVI; Sizing; Echocardiography
7.  Risk factors and in-hospital outcome of acute ST segment elevation myocardial infarction in young Bangladeshi adults 
Background
South Asians have a higher overall incidence rate and younger age of onset for acute myocardial infarction (AMI) compared to Western populations. However, limited information is available on the association of preventable risk factors and outcomes of AMI among young individuals in Bangladesh. The aim of this study was to determine the risk factors and in-hospital outcome of AMI among young (age ≤40 years) adults in Bangladesh.
Methods
We conducted a prospective observational study among consecutive 50 patients aged ≤40 years and 50 patients aged >40 years with acute ST Segment Elevation Myocardial Infarction (STEMI) and followed-up in-hospital at the National Institute of Cardiovascular Diseases (NICVD). Clinical characteristics, biochemical findings, diet, echocardiography and in-hospital outcomes were compared between the two groups. Multivariate logistic regression was performed to assess the association between risk factors and in-hospital outcome in young patients adjusting for other confounding variables.
Results
The mean age of the young and older patient groups was 36.5 ± 4.6 years and 57.0 ± 9.1 years respectively. Male sex (OR 3.4, 95 % CI 1.2 − 9.75), smoking (OR 2.4, 95 % CI 1.04 − 5,62), family history of MI (OR 2.4, 95 % CI 1.11 − 5,54), homocysteine (OR 1.2, 95 % CI 1.08 − 1.36), eating rice ≥2 times daily (OR 3.5, 95 % CI 1.15 − 10.6) and eating beef (OR 4.5, 95 % CI 1.83 − 11.3) were significantly associated with the risk of AMI in the young group compared to older group. In multivariate analysis, older patients had significantly greater chance of developing heart failure (OR 7.5, 95 % CI 1.51 to 37.31), re-infarction (OR 7.0, 95 % CI 1.08 − 45.72), arrhythmia (OR 15.3, 95 % CI 2.69 − 87.77) and cardiogenic shock (OR 69.0, 95 % CI 5.81 − 85.52) than the younger group.
Conclusion
Younger AMI patients have a different risk profile and better in-hospital outcomes compared to the older patients. Control of preventable risk factors such as smoking, unhealthy diet, obesity and dyslipidemia should be reinforced at an early age in Bangladesh.
doi:10.1186/s12872-015-0069-2
PMCID: PMC4509563  PMID: 26197888
8.  Prevalence of hypertension among federal ministry civil servants in Addis Ababa, Ethiopia: a call for a workplace-screening program 
Background
The prevalence of hypertension (HTN) is increasing rapidly in Ethiopia, but data are limited on hypertension prevalence in specific workplaces. Therefore, the aim of this study was to assess the prevalence and associated factors of hypertension among federal ministry civil servants.
Methods
Institutional based cross sectional study was conducted from February to April 2014. Simple random sampling technique was used to select 655study participants. A standardized questionnaire adapted from The World Health Organization’s (WHO) STEP tool was used to collect the data. In this study, HTN was defined as mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) of 140/90 mmHg and above, and patients on regular drug therapy for H. Data were entered into EPI-Info 3.5.2 and analyzed by SPSS version 20. Binary logistic regression model was used to identify associated factors. Odds ratio with 95 % CI was computed to assess the strength of the association and significant level.
Result
The prevalence of hypertension was found to be 27.3 % (95 % CI 23.3 – 31 %). Civil servants of age 48 years and above [AOR = 5.88, 95 % CI: 2.36-14.67], age 38-47 years [AOR = 2.80, 95 % CI: 1.18-6.60] and age 28-37 years [AOR = 2.35, 95 % CI: 1.00-5.56]) were more likely to be hypertensive. Similarly, ever cigarette smoking [AOR =2.34(1.31-4.17), family history of hypertension [AOR = 3.26, 95 % CI 1.96-5.40], self-reported Diabetes Mellitus (DM) [AOR = 13.56, 95 % CI: 6.91-26.6], and body mass index (BMI > 25 kg/m2) [AOR = 7.36, 95 % CI: 2.36-14.67] were found to be significantly associated with hypertension.
Conclusion
The prevalence of hypertension among federal ministry civil servants was found to be high; which is an indication for institution based hypertension-screening programs especially focusing on those aged 28 years and above, obese, DM patients and cigarette smokers.
doi:10.1186/s12872-015-0062-9
PMCID: PMC4511244  PMID: 26197712
Hypertension; Ministries civil servants; Ethiopia
9.  Functional capacity and heart rate response: associations with nocturnal hypertension 
Background
Absences of normative, 10–20 % declines in blood pressure (BP) at night, termed nocturnal non-dipping, are linked to increased cardiovascular mortality risks. Current literature has linked these absences to psychological states, hormonal imbalance, and disorders involving hyper-arousal. This study focuses on evaluating associations between nocturnal non-dipping and indices of functional cardiac capacity and fitness.
Methods
The current study was a cross-sectional evaluation of the associations between physical capacity variables e.g. Metabolic Equivalent (MET) and Maximum Heart Rate (MHR), Heart rate reserve (HRR), and degree of reduction in nocturnal systolic blood pressure (SBP) or diastolic blood pressure (DBP), also known as ‘dipping’. The study sample included 96 cardiac patient participants assessed for physical capacity and ambulatory blood pressure monitoring. In addition to evaluating differences between groups on nocturnal BP ‘dipping’, physical capacity, diagnoses, and medications, linear regression analyses were used to evaluate potential associations between nocturnal SBP and DBP ‘dipping’, and physical capacity indices.
Results
45 males and 14 females or 61.5 % of 96 consented participants met criteria as non-dippers (<10 % drop in nocturnal BP). Although non-dippers were older (p = .01) and had a lower maximum heart rate during the Bruce stress test (p = .05), dipping was only significantly associated with Type 2 Diabetes co-morbidity and was not associated with type of medication. Within separate linear regression models controlling for participant sex, MHR (β = 0.26, p = .01, R2 = .06), HRR (β = 0. 19, p = .05, R2 = .05), and METs (β = 0.21, p = .04, R2 = .04) emerged as significant but small predictors of degree of nighttime SBP dipping. Similar relationships were not observed for DBP.
Conclusions
Since the variables reflecting basic heart function and fitness (MHR and METs), did not account for appreciable variances in nighttime BP, nocturnal hypertension appears to be a complex, multi-faceted phenomena.
doi:10.1186/s12872-015-0064-7
PMCID: PMC4511245  PMID: 26197812
Ambulatory blood pressure monitoring; Abnormal nocturnal blood pressure; Nocturnal non-dipping
10.  Specific inhibition of bile acid transport alters plasma lipids and GLP-1 
Background
Elobixibat is a minimally absorbed ileal bile acid (BA) transporter (IBAT) inhibitor in development against chronic constipation (CC) and constipation-predominant Irritable Bowel Syndrome (IBS-C). CC is associated with an increased risk for cardiovascular disease and type2 diabetes mellitus. The objectives of this study were to evaluate metabolic effects of elobixibat. Effects on plasma lipids and BA synthesis were evaluated utilizing a 4-week, placebo-controlled study in patients with dyslipidemia while changes of glucagon-like peptide-1 (GLP-1) by elobixibat was assayed in samples from a 14 day high-dose elobixibat study in patients with CC.
Methods
Thirty-six dyslipidemic patients, 21 females, mean age 63 years, were randomized to 2.5 mg or 5 mg elobixibat or placebo once daily for four weeks. The primary endpoint was the change in low density lipoprotein (LDL) cholesterol. Secondary endpoints included other lipid parameters and serum 7α-hydroxy-4-cholesten-3-one (C4), a marker of BA (bile acid) synthesis. Another study, in 36 patients with CC treated with high dose elobixibat; 15 mg or 20 mg/day or placebo for 14 days, was evaluated for changes in GLP-1.
Results
In the dyslipidemia study LDL cholesterol was reduced by 7.4 % (p = 0.044), and the LDL/HDL ratio was decreased by 18 % (p = 0.004). Serum C4 increased, indicating that BA synthesis was induced. No serious adverse events were recorded. In the CC study, GLP-1 increased significantly in both the 15 mg (20.7 ± 2.4 pmol/L; p = 0.03) and the 20 mg group (25.6 ± 4.9 pmol/L; p = 0.02).
Conclusions
Elobixibat reduces LDL cholesterol and LDL/HDL ratio and increase circulating peak GLP-1 levels, the latter in line with increased intestinal BA mediated responses in humans.
Trial registrations
ClinicalTrial.gov: NCT01069783 and NCT01038687.
doi:10.1186/s12872-015-0070-9
PMCID: PMC4511433  PMID: 26197999
Dyslipidemia; Elobixibat; Glucagon-like peptide-1 (GLP-1); Ileal bile acid (BA) transporter (IBAT) inhibitor
11.  Troponin in diabetic patients with and without chronic coronary artery disease 
Background
Cardiac-specific troponin detected with the new high-sensitivity assays can be chronically elevated in response to cardiovascular comorbidities and confer important prognostic information, in the absence of unstable coronary syndromes. Both diabetes mellitus and coronary artery disease are known predictors of troponin elevation. It is not known whether diabetic patients with coronary artery disease have different levels of troponin compared with diabetic patients with normal coronary arteries. To investigate this question, we determined the concentrations of a level 1 troponin assay in two groups of diabetic patients: those with multivessel coronary artery disease and those with angiographically normal coronary arteries.
Methods
We studied 95 diabetic patients and compared troponin in serum samples from 50 patients with coronary artery disease (mean age = 63.7, 58 % male) with 45 controls with angiographically normal coronary arteries. Brain natriuretic peptide and the oxidative stress biomarkers myeloperoxidase, nitrotyrosine and oxidized LDL were also determined.
Results
Diabetic patients with coronary artery disease had higher levels of troponin than did controls (median values, 12.0 pg/mL (95 % CI:10–16) vs 7.0 pg/mL (95 % CI: 5.9-8.5), respectively; p = 0.0001). The area under the ROC curve for the diagnosis of CAD was 0.712 with a sensitivity of 70 % and a specificity of 66 %. Plasma BNP levels and oxidative stress variables (myeloperoxidase, nitrotyrosine, and oxidized LDL) were not different between the two groups. In a multivariate analysis, gender (p = 0.04), serum glucose (0.03) and Troponin I (p = 0.01) had independent statistical significance.
Conclusion
Troponin elevation is related to the presence of chronic coronary artery disease in diabetic patients with multiple associated cardiovascular risk factors. Troponin may serve as a biomarker in this high-risk population.
Trial registration
http://www.controlled-trials.com Registration number:ISRCTN26970041
doi:10.1186/s12872-015-0051-z
PMCID: PMC4508806  PMID: 26195004
Biological markers; Troponin; Diabetes mellitus; Coronary artery disease
12.  The impact of social deprivation on mortality following acute myocardial infarction, stroke or subarachnoid haemorrhage: A record linkage study 
Background
The impact of social deprivation on mortality following acute myocardial infarction (AMI), stroke and subarachnoid haemorrhage (SAH) is unclear. Our objectives were, firstly, to determine, for each condition, whether there was higher mortality following admission according to social deprivation and secondly, to determine how any higher mortality for deprived groups may be correlated with factors including patient demographics, timing of admission and hospital size.
Methods
Routinely collected, linked hospital inpatient, mortality and primary care data were analysed for patients admitted as an emergency to hospitals in Wales between 2004 and 2011 with AMI (n = 30,663), stroke (37,888) and SAH (1753). Logistic regression with Bonferroni correction was used to examine, firstly, any significant increases in mortality with social deprivation quintile and, secondly, the influence of patient demographics, timing of admission and hospital characteristics on any higher mortality among the most socially deprived groups.
Results
Mortality was 14.3 % at 30 days for AMI, 21.4 % for stroke and 35.6 % for SAH. Social deprivation was significantly associated with higher mortality for AMI (25 %; 95 % CI = 12 %, 40 %) higher for quintile V compared with I), stroke (24 %; 14 %, 34 %), and non-significantly for SAH (32 %; −7 %, 87 %).
The higher mortality at 30 days with increased social deprivation varied significantly according to patient age for AMI patients and time period for SAH. It was also highest for both AMI and stroke patients, although not significantly for female patients, for admissions on weekdays and during autumn months.
Conclusions
We have demonstrated a positive association between social deprivation and higher mortality following emergency admissions for both AMI and stroke. The study findings also suggest that the influence of patient demographics, timing of admission and hospital size on social inequalities in mortality are quite similar for AMI and stroke.
Electronic supplementary material
The online version of this article (doi:10.1186/s12872-015-0045-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12872-015-0045-x
PMCID: PMC4506594  PMID: 26187051
Mortality; Social deprivation; Risk factors; Acute myocardial infarction; Stroke; Subarachnoid haemorrhage
13.  Serum S-100β and NSE levels after off-pump versus on-pump coronary artery bypass graft surgery 
Background
We aimed to evaluate serum levels of S-100 beta (S-100β) and neuron specific enolase (NSE) in patients with coronary heart disease (CHD) after off-pump versus on-pump coronary artery bypass graft (CABG) surgery.
Methods
The PubMed (~2013) and the Chinese Biomedical Database (CBM) (1982 ~ 2013) were searched without language restrictions. After extraction of relevant data from selected studies, meta-analyses were conducted using STATA software (Version 12.0, Stata Corporation, College Station, Texas USA). Possible sources of heterogeneity were examined through univariate and multivariate meta-regression analyses and verified by Monte Carlo Simulation.
Results
Eleven studies with a total of 411 CHD patients met the inclusion criteria. Our meta-analysis showed no significant difference in serum S-100β and NSE levels between the on-pump group and the off-pump group before surgery. In the on-pump group, there was a significant difference in serum S-100β levels of CHD patients between before and after surgery, especially within the first 24 h after surgery. Furthermore, in the on-pump group, there was a significant difference in serum NSE levels of CHD patients between before and after surgery, particularly at 0 h after surgery. In the off-pump group, there was an obvious difference in serum S-100β levels between before and after surgery, especially within 24 h after surgery. Our results also demonstrated that serum S-100β and NSE levels of CHD patients in the on-pump group were significantly higher than those of patients in the off-pump group, especially within 24 h after surgery.
Conclusions
Our findings provide empirical evidence that off-pump and on-pump CABG surgeries may increase serum S-100β and NSE levels in CHD patients, which was most prominent within 24 h after on-pump CABG surgery.
doi:10.1186/s12872-015-0050-0
PMCID: PMC4504080  PMID: 26179379
S-100β; NSE; Coronary heart disease; Coronary artery bypass grafting; Meta-analysis
14.  Cathether-based interventional strategies for cor triatriatum in the adult – feasibility study through a hybrid approach 
Background
Cor triatriatum is a rare congenital cardiac abnormality, consisting of an obstructing membrane between the pulmonary veins and the mitral valve in varying patterns. The entitiy can mimick the pathophysiology of mitral stenosis, necessitating surgical resection. Occasionally, percutaneous balloon dilatation of the membrane has been successfully performed.
Case presentation
We report two cases with cor triatriatum where intraoperative balloon dilatation of the membrane was attempted followed by surgical resection, to explore the feasibility of cathether-based interventional strategies for cor triatriatum.
Conclusions
Various anatomical variations exist of cor triatriatum, depending on the drainage of the pulmonary veins and the drainage of the proximal chamber in the right or left atrium. Only isolated forms of cor triatriatum where all pulmonary veins ultimately drain into the left atrium can be recommended for percutaneous strategies. In addition, several anatomical characteristics should be considered to predict technical success of cathether-based interventional strategies, such as the location of the membrane, the degree of pulmonary vein stenosis, the extent of calcification, and the presence of other (congenital) cardiovascular abnormalities. Furthermore, long-term efficacy of these strategies remains to be confirmed. As such, surgical treatment of cor triatriatum remains the mainstay of treatment in adult patients, especially when other cardiovascular anomalies are present which require surgical correction.
doi:10.1186/s12872-015-0067-4
PMCID: PMC4499942  PMID: 26169911
Congenital heart disease; Cardiovascular intervention; Cardiac surgery
15.  Performance of Sokolow-Lyon index in detection of echocardiographically diagnosed left ventricular hypertrophy in a normal Eastern German population - results of the CARLA study 
Background
Arterial hypertension is a common disease with high prevalence in the general population. Left ventricular hypertrophy (LVH) is an independent risk factor in arterial hypertension. Electrocardiographic indices like the Sokolow-Lyon index (SLI) are recommended as diagnostic screening methods for LVH.
We assessed the diagnostic performance of the SLI in a cohort of a large general population.
Methods
We used electrocardiographic and echocardiographic data from the prospective, population-based cohort study CARdio-vascular Disease, Living and Ageing in Halle (CARLA). Linear and logistic regression models were used to assess the association of SLI with LVH. To assess the impact of the body-mass-index (BMI), we performed interaction analyses.
Results
AUC of SLI to predict LVH was 55.3 %, sensitivity of the SLI was 5 %, specificity 97 %. We found a significant association of SLI after covariate-adjustment with echocardiographically detected LVH (increase of left-ventricular mass index, LVMI 7.0 g/m2 per 1 mV increase of SLI, p < 0.0001). However, this association was mainly caused by an association of SLI with the left-ventricular internal diameter (LVIDd, increase of 0.06 cm/m2 per 1 mV increase of SLI, p < 0.0001). In obese (BMI > 30 kg/m2) we found the strongest association with an increase of 9.2 g/m2 per 1 mV.
Conclusions
Although statistically significant, relations of SLI and echocardiographic parameters of LVH were weak and mainly driven by the increase in LVIDd, implicating a more eccentric type of LVH in the collective. The relations were strongest when obese subjects were taken into account. Our data do not favour the SLI as a diagnostic screening test to identify patients at risk for LVH, especially in non-obese subjects without eccentric LVH.
doi:10.1186/s12872-015-0066-5
PMCID: PMC4501293  PMID: 26169782
Left ventricular hypertrophy; Hypertrophy; ECG; Sokolow-Lyon index; Sokolow; Obesity
16.  Lack of “obesity paradox” in patients presenting with ST-segment elevation myocardial infarction including cardiogenic shock: a multicenter German network registry analysis 
Background
Studies have associated obesity with better outcomes in comparison to non-obese patients after elective and emergency coronary revascularization. However, these findings might have been influenced by patient selection. Therefore we thought to look into the obesity paradox in a consecutive network STEMI population.
Methods
The database of two German myocardial infarction network registries were combined and data from a total of 890 consecutive patients admitted and treated for acute STEMI including cardiogenic shock and cardiopulmonary resuscitation according to standardized protocols were analyzed. Patients were categorized in normal weight (≤24.9 kg/m2), overweight (25-30 kg/m2) and obese (>30 kg/m2) according to BMI.
Results
Baseline clinical parameters revealed a higher comorbidity index for overweight and obese patients; 1-year follow-up comparison between varying groups revealed similar rates of all-cause death (9.1 % vs. 8.3 % vs. 6.2 %; p = 0.50), major adverse cardiac and cerebrovascular [MACCE (15.1 % vs. 13.4 % vs. 10.2 %; p = 0.53)] and target vessel revascularization in survivors [TVR (7.0 % vs. 5.0 % vs. 4.0 %; p = 0.47)] with normal weight when compared to overweight or obese patients. These results persisted after risk-adjustment for heterogeneous baseline characteristics of groups. An analysis of patients suffering from cardiogenic shock showed no impact of BMI on clinical endpoints.
Conclusion
Our data from two network systems in Germany revealed no evidence of an “obesity paradox”in an all-comer STEMI population including patients with cardiogenic shock.
doi:10.1186/s12872-015-0065-6
PMCID: PMC4498506  PMID: 26162888
Coronary stent; Obesity paradox; Mortality; Cardiogenic shock
17.  Influence of glycemic control on gain in VO2 peak, in patients with type 2 diabetes enrolled in cardiac rehabilitation after an acute coronary syndrome. The prospective DARE study 
Background
Gain in VO2 peak after cardiac rehabilitation (CR) following an acute coronary syndrome (ACS), is associated with reduced mortality and morbidity. We have previously shown in CR, that gain in VO2 peak is reduced in Type 2 diabetic patients and that response to CR is impaired by hyperglycemia.
Methods
We set up a prospective multicenter study (DARE) whose primary objective was to determine whether good glycemic control during CR may improve the gain in VO2 peak. Sixty four type 2 diabetic patients, referred to CR after a recent ACS, were randomized to insulin intensive therapy or a control group with continuation of the pre-CR antidiabetic treatment. The primary objective was to study the effect of glycemic control during CR on the improvement of peak VO2 by comparing first the 2 treatment groups (insulin intensive vs. control) and second, 2 pre-specified glycemic control groups according to the final fructosamine level (below and above the median).
Results
At the end of the CR program, the gain in VO2 peak and the final fructosamine level (assessing glycemic level during CR) were not different between the 2 treatment groups. However, patients who had final fructosamine level below the median value, assessing good glycemic control during CR, showed significantly higher gain in VO2 peak (3.5 ± 2.4 vs. 1.7 ± 2.4 ml/kg/min,p = 0.014) and ventilatory threshold (2.7 ± 2.5 vs. 1.2 ± 1.9 ml/kg/min,p = 0.04) and a higher proportion of good CR-responders (relative gain in VO2 peak ≥ 16 %): 66 % vs. 36 %, p = 0.011. In multivariate analysis, gain in VO2 peak was associated with final fructosamine level (p = 0.010) but not with age, gender, duration of diabetes, type of ACS, insulin treatment or basal fructosamine.
Conclusions
The DARE study shows that, in type 2 diabetes, good glycemic control during CR is an independent factor associated with gain in VO2 peak. This emphasizes the need for good glycemic control in CR for type 2 diabetic patients.
Trial registration
Trial registered as NCT00354237 (19 July 2006).
doi:10.1186/s12872-015-0055-8
PMCID: PMC4495681  PMID: 26152221
Diabetes; Cardiac rehabilitation; Myocardial infarction; Hyperglycemia
18.  Neither endothelial function nor carotid artery intima-media thickness predicts coronary computed tomography angiography plaque burden in clinically healthy subjects: a cross-sectional study 
Background
Cardiovascular risk assessment is usually based on traditional risk factors and risk assessment algorithms. However, a number of risk markers that might provide additional predictive power have been identified. Endothelial function determined by digital reactive hyperemia peripheral arterial tonometry (RH-PAT) and carotid artery intima-media thickness (IMT) have both been proposed as surrogate markers for coronary artery disease (CAD). We aimed to examine the ability of RH-PAT and IMT to predict coronary computed tomography angiography (CTA) plaque burden in clinically healthy subjects.
Methods
Fifty-eight clinically healthy volunteers (50–73 years old) underwent testing for RH-PAT and IMT as well as coronary CTA, including coronary artery calcium (CAC) scoring. Coronary CTA was analyzed with respect to any atheromatous plaques, stenotic as well as non-stenotic. The Mann–Whitney U-test was used to compare the groups with and without CAD and the Spearman test was used to test for correlation between variables.
Results
Twenty-five (43 %) subjects had normal coronary arteries, without any signs of atherosclerosis. The median (range) number of diseased segments was 1 (0–10), RH-PAT index 2.2 (1.4-4.9), IMT 0.70 (0.49-0.99) mm and CAC 4 (0–1882). There was no association between presence or extent of CAD and RH-PAT index (Spearman correlation coefficient rs = 0.13) or IMT (rs = 0.098). As expected, CAC was strongly correlated to presence and extent of CAD by coronary CTA (rs =0.86; p < 0.0001).
Conclusions
Neither evaluation of endothelial function by RH-PAT nor assessment of carotid artery IMT can reliably be used to predict coronary CTA plaque burden in clinically healthy subjects.
doi:10.1186/s12872-015-0061-x
PMCID: PMC4494716  PMID: 26148508
CAD; Coronary artery disease; RH-PAT; PAT; Endothelial function; IMT; CIMT; Intima-media thickness; Coronary CTA; Coronary computed tomography angiography
19.  Microarray profiling of long non-coding RNA (lncRNA) associated with hypertrophic cardiomyopathy 
Background
Hypertrophic cardiomyopathy (HCM) is an inherited disorder with around 1400 known mutations; however the molecular pathways leading from genotype to phenotype are not fully understood. LncRNAs, which account for approximately 98 % of human genome, are becoming increasingly interesting with regard to various diseases. However, changes in the expression of regulatory lncRNAs in HCM have not yet been reported.
To identify myocardial lncRNAs involved in HCM and characterize their roles in HCM pathogenesis.
Methods
Myocardial tissues were obtained from 7 HCM patients and 5 healthy individuals, and lncRNA and mRNA expression profiles were analyzed using the Arraystar human lncRNA microarray. Real-time PCR was conducted to validate the expression pattern of lncRNA and mRNA. Gene ontology (GO) enrichment and KEGG analysis of mRNAs was conducted to identify the related biological modules and pathologic pathways.
Results
Approximately 1426 lncRNAs (965 up-regulated and 461 down-regulated) and 1715 mRNAs (896 up-regulated and 819 down-regulated) were aberrantly expressed in HCM patients with fold change > 2.0. GO analysis indicated that these lncRNAs–coexpressed mRNAs were targeted to translational process. Pathway analysis indicated that lncRNAs–coexpressed mRNAs were mostly enriched in ribosome and oxidative phosphorylation.
Conclusion
LncRNAs are involved in the pathogenesis of HCM through the modulation of multiple pathogenetic pathways.
Electronic supplementary material
The online version of this article (doi:10.1186/s12872-015-0056-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12872-015-0056-7
PMCID: PMC4490660  PMID: 26141701
Hypertrophic cardiomyopathy; LncRNA; Gene ontology; KEGG pathway
20.  Additional value of associating aortic valve calcification to coronary calcium as a gatekeeper for coronary tomography angiography 
Background
Aortic valve calcification shares risk factors with coronary artery disease. Coronary calcium has been used has a gatekeeper to performing coronary tomography angiography. The aim of this study was to evaluate aortic valve calcification as a predictor of obstructive coronary artery disease by computed tomography, and its possible usefulness, alongside with coronary calcium, to improve the decision of whether or not to proceed with computed tomography angiography.
Methods
Transversal case–control study including 154 consecutive patients (62 ± 12 years, 57.6 % female, without known coronary or valve disease) undergoing calcium scoring and angiography through computed tomography (Phillips Brilliance, 16-slice). Predictors of aortic valve calcification and obstructive coronary artery disease were identified. Usefulness of aortic valve calcification when added to calcium score for prediction of obstructive coronary artery disease was assessed by binary logistic regression and net reclassification index.
Results
Aortic valve calcification was associated with higher coronary calcium, extent and prevalence of obstructive coronary disease, which was identified in 22.1 % of patients and was discriminated by aortic valve calcium with an area under curve 0.749 (p < 0.001, Youden index: 61). A higher discriminative power was achieved with a model based on coronary and aortic valve calcification (AUC 0.900, p < 0.001). Compared with calcium score >400 as a gatekeeper to angiography, the association of aortic calcium >61 allowed a net reclassification index of +7.7 % of patients.
Conclusions
Aortic valve calcification is associated with the prevalence and extent of obstructive coronary artery disease by computed tomography angiography and is an easy, fast and useful method to improve the selection of patients for angiography.
doi:10.1186/s12872-015-0058-5
PMCID: PMC4486129  PMID: 26130116
Aortic valve calcification; Cardiac computed tomography; Coronary artery calcification; Coronary artery disease; Coronary CT angiography
21.  Correlation of single nucleotide polymorphisms in the pregnancy-associated plasma protein-A gene with carotid plaques 
Background
Pregnancy-associated plasma protein A (PAPP-A) is abundantly expressed in carotid plaques. This study investigated the association between single nucleotide polymorphisms (SNPs) of PAPP-A and the presence of carotid plaques.
Methods
A total of 408 patients with carotid plaques and 493 controls were included in the study. All subjects were Southern Chinese Han. Carotid plaques were analyzed by computer tomography angiography. PAPP-A SNPs were identified by ligase detection reaction-polymerase chain reaction analysis. The PAPP-A genotypes rs3747823, rs7020782, and rs13290387 were analyzed.
Results
The rs7020782 C allele genotype correlated with an increased risk of developing carotid plaques under the dominant, recessive, and additive models (adjusted odds ratios: 2.60, 2.36, and 3.48, respectively; P ≤ 0.001). Only C allele-carrying genotypes correlated with a significantly increased risk of carotid plaque based on studies stratified by age and sex under the dominant model. rs7020782 remained significantly associated with the risk of carotid plaque calcification after adjusting for age and potential confounders (adjusted odds ratio, 1.89; 95 % confidence interval, 1.17–3.08; P = 0.010).
Conclusions
This study found, for the first time, that the A˃C variation of rs7020782 might be an independent risk factor for carotid plaque development and calcification. The determination of such genotypes could provide a new tool for identifying individuals at high risk for carotid atherosclerosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12872-015-0041-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12872-015-0041-1
PMCID: PMC4485363  PMID: 26122709
Calcified plaque; Carotid plaque; Pregnancy-associated plasma protein A; Single nucleotide polymorphisms
22.  Diastolic dysfunction in spontaneous type 2 diabetes rhesus monkeys: a study using echocardiography and magnetic resonance imaging 
Background
Diastolic heart failure is a common and deadly complication of diabetes mellitus, with the development of diabetic cardiomyopathy as one of the key determinants of the disease’s complex pathology. The cause of the association is unknown and has no approved therapy strategies as of yet. However significant advances in this area may come from studies on suitable animal models.
Methods
A total of 25 male rhesus monkeys (12-16 years, 9-13 kg) were enrolled. Fifteen of them were diagnosed as spontaneous type 2 diabetes mellitus (T2DM, FPG ≥ 104 mg/dl, HbA1c: 4.7-5.5 %, diabetes duration: 1-4 years). The other 10 monkeys were non-diabetic (ND, FPG < 90 mg/dl). Echocardiography and cardiac magnetic resonance were used for evaluating the cardiac structure and function. One T2DM monkey with impaired diastolic function and another ND monkey were both sacrificed to gain the necessary pathology and protein expression studies displayed here.
Results
Six out of 15 T2DM rhesus monkeys were diagnosed with diastolic dysfunction (DD) by echocardiography. Additionally, no abnormalities were found in the group which we determined as the ND monkeys. The six DD monkeys all showed low e’ velocity and decreased e’/a’ ratio, among which three of them showing decreased E/A ratio and the other 3 having elevated E/A ratio, this appears to be similar to the impaired relaxation pattern and pseudonormal pattern found in human patients respectively. The EF and FS of monkeys with pseudonormal pattern decreased significantly compared with ND subjects. A CMR study showed that LVID at end systole of 5 DD monkeys is significantly longer than that of 3 ND monkeys. Of great interest, myocardium lesions and mitochondria impairments and increased expression of AGEs and caspase-3 were found in a sacrificed DD subject.
Conclusion
The changes in the imaging and physiological markers of spontaneous T2DM rhesus monkeys are similar to those key markers found in human type 2 diabetes and diastolic dysfunction. This monkey model could help the medical community and us to understand the pathology of this debilitating disease and serve as a beginning to explore important measures to prevent and treat diabetic cardiomyopathy.
doi:10.1186/s12872-015-0046-9
PMCID: PMC4480511  PMID: 26113016
23.  Rs7193343 polymorphism in zinc finger homeobox 3 (ZFHX3) gene and atrial fibrillation: an updated meta-analysis of 10 case-control comparisons 
Background
The previous genome-wide studies have shown that rs7193343 single-nucleotide polymorphism (SNP) in zinc finger homeobox 3 (ZFHX3) gene correlate with risk of atrial fibrillation (AF). However, the distribution of this SNP differs significantly among various populations. The present study was to investigate whether combined evidence shows the association between ZFHX3 rs7193343 SNP and the risk of AF in various populations.
Methods
A systematic search of all studies published through Dec 2014 was conducted using the Medline, Embase, WanFang, ScienceDirect, CNKI, and OVID databases. The case-control studies that evaluated an association between rs7193343 SNP and risk of AF were identified. The association between the ZFHX3 rs7193343 SNP and AF susceptibility was assessed using genetic models.
Results
We collected 10 comparisons from six studies for rs7193343 SNP, including 1037 cases and 4310 controls in Asian, 5583 cases and 38215 controls in Caucasian, and then performed an updated meta-analysis and subgroup analysis based on ethnicity. In overall population, the occurrence of AF was found to be associated with T-allelic of rs7193343 SNP in ZFHX3 (OR =1.17, 95% CI 1.10-1.26). In subgroup analysis, we observed there was significant association between T-allele of rs7193343 and risk of AF in Caucasian subgroups (OR =1.20, 95% CI 1.12-1.30), but no statistically significance (OR = 1.07, 95% CI 0.92-1.24) in Asian population.
Conclusion
In Caucasian population, genetic variant rs7193343 SNP is associated with risk of AF in Caucasian population. However, no association is found in Asian population based on the current evidence. Further studies with larger sample size involving case-control populations with multiple ethnics are still required in the future.
doi:10.1186/s12872-015-0044-y
PMCID: PMC4480884  PMID: 26112950
Atrial fibrillation; Meta-analysis; Zinc finger homeobox 3 gene; Polymorphism; Rs7193343
24.  Characterization of exercise limitations by evaluating individual cardiac output patterns: a prospective cohort study in patients with chronic heart failure 
Background
Patients with chronic heart failure (CHF) suffer from exercise intolerance due to impaired central hemodynamics and subsequent alterations in peripheral skeletal muscle function and structure. The relative contribution of central versus peripheral factors in the reduced exercise capacity is still subject of debate. The main purpose was to investigate heterogeneity in the nature of exercise intolerance by evaluating individual cardiac output (Q) patterns. The secondary purpose was to evaluate whether patient and disease characteristics were associated with a central hemodynamic exercise limitation.
Methods
Sixty-four stable CHF patients performed a symptom limited incremental exercise test with respiratory gas analysis and simultaneous assessment of Q, using a radial artery pulse contour analysis method. A central hemodynamic exercise limitation was defined as a plateau or decline in Q from 90 to 100 % of exercise duration.
Results
Data from 61 patients were analyzed. A central hemodynamic exercise limitation was observed in 21 patients (34 %). In these patients, a higher occurrence of a plateau/decrease in oxygen uptake (VO2) (52 % vs 23 %, p = 0.02), stroke volume (SV) (100 % vs. 75 %, p = 0.01) and chronotropic incompetence (31 % vs. 2.5 %, p = 0.01) was observed, while presence of a left bundle branch block (LBBB) occurred significantly less (19 % vs 48 %, p = 0.03) There was no difference in disease characteristics such as etiology, duration, NYHA class, mitral regurgitation or ischemia.
Conclusions
The study revealed considerable heterogeneity in the nature of exercise limitations between moderately impaired CHF patients. In one third of the study population a plateau or decrease in Q towards peak exercise was demonstrated, which is indicative of a central hemodynamic exercise limitation. A central hemodynamic exercise limitation was associated with an impairment to augment stroke volume and heart rate.
doi:10.1186/s12872-015-0057-6
PMCID: PMC4476170  PMID: 26100151
Cardiac output; Oxygen uptake; Patterns; Chronic heart failure; Exercise intolerance
25.  Expression of circulating miR-486 and miR-150 in patients with acute myocardial infarction 
Background
With its high morbidity and mortality, acute myocardial infarction (AMI) places a major burden on society and on individual patients. Correct, early correct diagnosis is crucial to the management of AMI.
Methods
In this study, the expression of circulating miR-486 and miR-150 was investigated in AMI patients and the two miRNAs were evaluated as potential biomarkers for AMI. Plasma samples from 110 patients with AMI (65 patients with ST-segment elevation myocardial infarction (STEMI) and 45 patients with non-ST-segment elevation myocardial infarction (NSTEMI)) and 110 healthy adults were collected. Circulating levels of miR-486 and miR-150 were detected using quantitative real-time PCR in plasma samples.
Results
Results showed that the levels of miR-486 and miR-150 were significantly higher in AMI patients than in healthy controls. Receiver operating characteristic (ROC) curve analyses indicated that the two plasma miRNAs were of significant diagnostic value for AMI, especially NSTEMI. The combined ROC analysis revealed an AUC value of 0.771 in discriminating AMI patients from healthy controls and an AUC value of 0.845 in discriminating NSTEMI patients from healthy controls.
Conclusion
Results indicated that the levels of circulating miR-486 and miR-150 are associated with AMI. They may be novel and powerful biomarkers for AMI, especially for NSTEMI.
doi:10.1186/s12872-015-0042-0
PMCID: PMC4466864  PMID: 26077801
Acute myocardial infarction; MicroRNAs; Biomarker

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