Clinical Efficacy and Safety of Combination Therapy with Amlodipine and Olmesartan or an Olmesartan/Hydrochlorothiazide Compound for Hypertension: A Prospective, Open-Label, and Multicenter Clinical Trial in China.

BACKGROUND: Amlodipine (AML) is the initial therapy most commonly prescribed for patients with hypertension in China. However, AML monotherapy is often less effective in achieving blood pressure (BP) control than other agents. OBJECTIVE: We performed a clinical study to evaluate efficacy and safety of a combination therapy with AML, olmesartan (OLM), or an OLM/hydrochlorothiazide (HCTZ) compound for Chinese patients with mild-to-moderate hypertension. METHODS: In the clinical trial, patients were initially treated with OLM 20 mg/d combined with AML 5 mg/d. Then OLM was uptitrated to 40 mg/d or changed to an OLM/HCTZ (20/12.5 mg/d) compound if the patients did not reach the target of seated diastolic BP <90 mm Hg (<80 mm Hg in patients with diabetes) after 8 weeks. RESULTS: The overall response rate of the combination therapy was 59.2% (95% CI, 54.23%-63.97%) at Week 2 and gradually increased to 97.1% (95% CI, 94.93%-98.47%) at the end of the study (Week 16). CONCLUSIONS: The combination therapy with OLM or OLM/HCTZ was well tolerated. The total incidence of adverse events was 42.9% (n = 176). Most of the adverse events were mild in severity (39.5%; n = 162) and not associated with the drugs (33.2%). In conclusion, combination therapy with AML, OLM, or OLM/HCTZ can significantly lower BP safely and achieve a high BP control rate in patients with mild-to-moderate hypertension in China. ClinicalTrial.org identifier: ChiCTR-ONC-12001963.

WITHDRAWN: Toll-like receptor-4 Signaling Improved the Migration of Sca-1+stem/progenitor Cells.

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Effects of GRK5 and ADRB1 polymorphisms influence on systolic heart failure.

BACKGROUND: G-protein receptor kinase 5 (GRK5) Gln41 > Leu and ß1-adrenergic receptor (ADRB1) Arg389 > Gly polymorphisms presented the different distribution of genotype frequencies between Caucasian American and African American, and produced the difference in ß-blocker treatment effect among them with systolic heart failure (SHF). OBJECTIVE: This study sought to identify the distributed characteristics of these variant genotypes in Chinese population, and influence of GRK5 and ADRB1 polymorphisms on SHF morbidity and ß-blocker treatment effect in patients with SHF. METHODS: This study was based on cross-sectional survey data. 1794 and 1718 subjects' ADRB1 and GRK5 gene sequencing (sanger method) data were achieved respectively. Blood samples collection, clinical laboratory detection, electrocardiogram and echocardiography examinations were performed. Medication usage was confirmed at in-hospital visits or the questionnaire by personal interview. RESULTS: GRK5 Leu41Leu genotype was not found in our Chinese population. In non-SHF population, allele frequencies of GRK5 Gln41 and Leu41 were 2782 (0.992) and 22 (0.008) (Hardy-Weinberg equilibrium test χ(2) = 0.088, P = 0.767), and allele frequencies of ADRB1 Arg389 and Gly389 were 2127 (0.715) and 849 (0.285) (χ(2) = 0.272, P = 0.602). In SHF patients, allele frequencies of Gln41 and Leu41 were 446 (0.991) and 4 (0.009) (χ(2) = 0.018, P = 0.893), and allele frequencies of Arg389 and Gly389 were 331 (0.726) and 125 (0.274) (χ(2) = 1.892, P = 0.169). Further in logistic regression model, these ADRB1 and GRK5 variants were not significantly independently associated with the risk of SHF morbidity. Those carrying genotype ADRB1 Gly389Gly did not reduce significantly the risk of SHF morbidity after ß-blocker therapy. CONCLUSIONS: GRK5 Leu41Leu genotype was not found in our Chinese population, neither ADRB1 nor GRK5 variants presented independently associated with the risk of SHF morbidity, most ADRB1 and GRK5 polymorphisms did decrease significantly the risk of SHF morbidity after ß-blocker therapy except for those carrying genotype ADRB1 Gly389Gly.

Pressure overload-induced cardiac hypertrophy response requires janus kinase 2-histone deacetylase 2 signaling.

Pressure overload induces cardiac hypertrophy through activation of Janus kinase 2 (Jak2), however, the underlying mechanisms remain largely unknown. In the current study, we tested whether histone deacetylase 2 (HDAC2) was involved in the process. We found that angiotensin II (Ang-II)-induced re-expression of fetal genes (Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)) in cultured cardiomyocytes was prevented by the Jak2 inhibitor AG-490 and HDAC2 inhibitor Trichostatin-A (TSA), or by Jak2/HDAC2 siRNA knockdown. On the other hand, myocardial cells with Jak2 or HDAC2 over-expression were hyper-sensitive to Ang-II. In vivo, pressure overload by transverse aorta binding (AB) induced a significant cardiac hypertrophic response as well as re-expression of ANP and BNP in mice heart, which were markedly reduced by AG-490 and TSA. Significantly, AG-490, the Jak2 inhibitor, largely suppressed pressure overload-/Ang-II-induced HDAC2 nuclear exportation in vivo and in vitro. Meanwhile, TSA or HDAC2 siRNA knockdown reduced Ang-II-induced ANP/BNP expression in Jak2 over-expressed H9c2 cardiomyocytes. Together, these results suggest that HDAC2 might be a downstream effector of Jak2 to mediate cardiac hypertrophic response by pressure overload or Ang-II.

Relationship of arterial stiffness and early mild diastolic heart failure in general middle and aged population.

AIMS: The brachial-ankle pulse wave velocity (baPWV) has been recognized as a marker that reflects arterial stiffness. We conducted an investigation to evaluate whether baPWV is independently associated with early mild diastolic heart failure (DHF) in a general middle and aged population. METHODS AND RESULTS: From 1 July 2009 until 31 August 2009, we investigated 2095 subjects for the relevant factors of heart failure in the Lujiazui Community, Shanghai. The baPWV, echocardiography, and blood sampling were performed in the morning after a 12 h overnight fast. A total of 1929 subjects had the complete data, including questionnaire, age, gender, baPWV, brain natriuretic peptide, and E/A ratio. Early mild DHF was defined as a left ventricular ejection fraction >50%, E/A ratio <0.8, and E/E' ≤ 8; finally, 482 subjects with early mild DHF and 1282 subjects with non-DHF entered into analysis. Among 1764 subjects, 31.6% of the subjects were male (average age was 58.0 ± 12.3), 35.8% of the subjects had hypertension, the average body mass index (BMI) was 24.2 ± 3.3 kg/m(2), baPWV was 1513.0 (1329.1, 1763.5) cm/s, and the baPWV was significantly correlated with the E/A ratio (r = -0.39, P < 0.01). There was a difference of the baPWV [1456.0 (1295.3, 1698.3) vs. 1670.5 (1465.6, 1910.8) cm/s] between the non-DHF group and the early mild DHF group (P < 0.01). Multiple logistic-regression analyses demonstrated that age, male gender, BMI, baPWV, posterior left ventricular wall thickness (PVWT), interventricular septal thickness (IVST), E/E' ratio, left ventricular mass index (LVMI), systolic blood pressure (≥140 mmHg), and diastolic blood pressure (≥90 mmHg) were independently correlated with early mild DHF. CONCLUSIONS: The increased arterial stiffness is associated with early mild DHF in a general middle and aged population independently of age, male gender, BMI, PVWT, IVST, E/E' ratio, LVMI, and high blood pressure. The non-invasive techniques described may allow serial measurements to be made over time to monitor baPWV changes in arteries provided the introduction of anti-arteriosclerosis therapy.

The effects of G-CSF on proliferation of mouse myocardial microvascular endothelial cells.

This paper explores the effect of granulocyte colony-stimulating factor (G-CSF) on mouse myocardial microvascular endothelial cell (CMECs) proliferation. CMECs were harvested from C57/BL6 mice. CMECs were cultured in medium containing G-CSF (0 ng/mL, 20 ng/mL, 40 ng/mL, 60 ng/mL) for five days. Proliferative activity of CMECs was examined by CCK-8 method. Hypoxia inducible factor-1 (HIF-1) and p53 expression levels was determined from the mRNA obtained by reverse transcription polymerase chain reaction (RT-PCR). Results showed that the purity quotient of the CMECs, which were cultured by the method of modified myocardial tissue explant culture, was higher than 95%. Compared with control untreated cells, the proliferative activity of CMECs and the expression level of HIF-1 mRNA in these cells were enhanced by G-CSF treatment, whereas the expression level of p53 mRNA was markedly reduced. It may be concluded that G-CSF could promote the proliferative activity of CMECs, which might be mediated by upregulation of HIF-1 and downregulation of p53.

Relationship between plasma ghrelin levels and insulin resistance and blood pressure in octogenarians.

The association between fasting plasma ghrelin levels and insulin resistance and blood pressure (BP) in octogenarians was investigated in this study. A total of 487 unrelated octogenarians (including 203 men and 284 women) were enrolled in this cross-sectional study at the Healthy Care Center of Shanghai East Hospital, Tongji University, China, from October 2008 to April 2009. Plasma ghrelin was determined by using the enzyme linked immunosorbent assay (ELISA). Insulin sensitivity was assessed using the homeostasis model of assessment-insulin resistance (HOMA-IR). The age of the participants ranged from 80 to 89 years (mean=83.9+/-4.8 years) with a body mass index (BMI) of 25.3+/-4.9 kg/m2. Plasma ghrelin levels were 20.94+/-5.34 microg/L, being 20.89+/-5.53 microg/L in men and 21.38+/-3.73 microg/L in women respectively. Plasma ghrelin was not associated with systolic (P=0.981) or diastolic (P=0.724) BP, waist circumference (P=0.278), fasting insulin (P=0.246), fasting blood glucose (FBG) (P=0.693) and HOMA-IR (P=0.232). In the control cohort, no significant differences in plasma ghrelin were found between genders (P=0.489), and among subjects with hypertension (BP>140/90 mmHg) (P=0.284) and type 2 diabetes (P=0.776). In conclusion, fasting plasma ghrelin levels are not directly correlated with insulin resistance and BP among octogenarians.

Safety and efficacy of zotarolimus-eluting stents in the treatment of diabetic coronary lesions in Chinese patients: The RESOLUTE-DIABETES CHINA Study.

BACKGROUND: The RESOLUTE-DIABETES CHINA study was specifically designed to investigate the safety and efficacy of Resolute zotarolimus-eluting stents (ZES; Medtronic, Santa Rosa, CA, USA) in the treatment of diabetic coronary lesions in the Chinese population. METHODS: In all, 945 patients with de novo native coronary lesions and type 2 diabetes mellitus were recruited at 32 cardiac centers across the Chinese mainland and were implanted with Resolute ZES. The primary endpoint was target vessel failure (TVF); secondary endpoints were clinical outcomes, namely all-cause death, stroke, bleeding, target lesion revascularization (TLR), target vessel revascularization (TVR), non-TVR, and stent thrombosis (ST). The follow-up period for all endpoints was 12 months after the procedure. RESULTS: In all, 933 patients (98.73%) had clinical follow-up at 12 months. The rate of TVF was 11.60%, whereas the rate of occurrence of secondary endpoints was 5.47%, with four patients (0.43%) having subacute or late ST. There were no significant differences in TVF rates comparing patients with different HbA1c levels or receiving different glucose control treatments (all P > 0.05). Patients with multivessel lesions had higher TVF rates (95% confidence intervals) than those with single-vessel lesions (16.76% [12.10%-22.97%) vs 9.72% [7.79%-12.11%], respectively; P = 0.006). There were no significant differences in TVF rates in patients with or without small vessels, bifurcated lesions, or chronic total occlusions (all P > 0.05). [Correction added on 17 January 2019, after first online publication: in the second sentence of Results section, "TLF" was changed to "TVF".]. CONCLUSIONS: Resolute ZES may perform well in the Chinese diabetic population, especially in those with poor glucose control, complex lesions, and certain unfavorable clinical features. Further studies are needed to determine why ZES perform well in this population.

Protosappanin A protects against atherosclerosis via anti- hyperlipidemia, anti-inflammation and NF-κB signaling pathway in hyperlipidemic rabbits.

OBJECTIVES: Protosappanin A (PrA) is an effective and major ingredient of Caesalpinia sappan L. The current study was aimed to explore the effect of PrA on atherosclerosis (AS). MATERIALS AND METHODS: Firstly, the experimental model of AS was established in rabbits by two-month feeding of high fat diet. Then, the rabbits were randomly divided into five groups and treated with continuous high lipid diet (model control), high lipid diet containing rosuvastatin (positive control), 5 mg/kg PrA (low dose) or 25 mg/kg PrA (high dose). RESULTS: Our results showed that PrA markedly alleviated AS as indicated by hematoxylin/eosin (HE) staining. PrA also reduced hyperlipidemia (as demonstrated by the serum levels of total blood cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL) and high-density lipoprotein (HDL)) in a time and dose-dependent manner, and decreased inflammation (as indicated by the serum levels of matrix metalloproteinase-9 [MMP-9], interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]). Moreover, PrA significantly inactivated nuclear factor kappa B (NF-κB) signaling as indicated by nuclear NF-κB p65 protein expression, as well as the mRNA expression and serum levels of downstream genes, interferon-γ (IFN-γ) and interferon-gamma-inducible protein 10 (IP10). CONCLUSION: This study proved that PrA might protect against atherosclerosis via anti-hyperlipidemia, anti-inflammation and NF-κB signaling pathways in hyperlipidemic rabbits.

Clinical Study on efficacy of allopurinol in patients with acute coronary syndrome and its functional mechanism.

OBJECTIVE: To investigate the therapeutic effect of allopurinol treatment on acute coronary syndrome and to elucidate its possible mechanism. METHODS: Patients with acute coronary syndrome (n = 100) were recruited as research subjects in our hospital. The patients were randomly divided into two groups, an allopurinol group (n = 50) and a control group (n = 50). These two groups were treated with conventional antiplatelet, anticoagulation and anti-ischemic therapy; allopurinol therapy was added to the allopurinol group based on conventional treatment indications. Biochemical markers such as serum creatinine, uric acid, BNP, blood glucose and blood lipid were compared between the two groups. Indicators of oxidative stress and inflammatory response (MDA, OX-LDL, NO, hs-CRP and TNF-α), as well as cardiovascular events during 2-years follow-up, were recorded. RESULTS: On admission, there was no difference in serum creatinine, uric acid, BNP, blood glucose or lipid levels between the two groups (P > 0.05). However, after 1 month of treatment, these levels were improved in patients in the allopurinol group compared to the control group (P < 0.05). MDA, OX-LDL, hs-CRP and TNF-α decreased after treatment periods of 14 days and 1 month. They were also decreased at 3 month, 6 month, 1 year, and 2 year follow-up visits. However, data from the allopurinol group demonstrated significantly lower levels than in the control group (P < 0.05). Additionally, compared with the control group, allopurinol treatment significantly elevated the level of NO (P < 0.05). The total effective rates of the allopurinol group are much higher than in the control group for both angina pectoris (93.2% and 76%, respectively) and ECG (96% and 82%, respectively). Most patients in the allopurinol group (n = 40) and the control group (n = 41) received stent implantation with no significant difference shown between them. The incidence of cardiovascular events during 2 years of follow-up in the allopurinol group was 10%; it was 30% in the control group. CONCLUSION: Allopurinol has a remarkable effect in the treatment of ACS and can improve the oxidative stress and inflammatory reaction indicators of patients. The protective mechanism of allopurinol might be achieved by suppressing the secretion and release of inflammatory mediators such as TNF-α, hs-CRP, OX-LDL and MDA while increasing levels of NO.

Experimental study of the anti-atherosclerotic effect of demethylzeylasteral.

This study aimed to confirm that atherosclerosis (AS) is a systemic immune-mediated chronic inflammatory disease and to investigate the anti-atherosclerotic effect of demethylzeylasteral by testing the immunocompetent cells and inflammatory mediators in the blood and atherosclerotic plaques of the rabbit model of AS. For this purpose, 60 male New Zealand white rabbits were given 150 g high-fat diet (1% cholesterol, 5% lard, and 15% egg yolk powder) daily for a total of 90 days. On day 61, the rabbits were randomly divided into the saline group (n=15), the rosuvastatin group (n=15), the low-dose demethylzeylasteral group (n=15), and the high-dose demethylzeylasteral group (n=15). The CD3+ T lymphocytes and the subsets CD4+, CD8+, and CD4+/CD8+, as well as the soluble interleukin-2 receptor (sIL-2R) were measured before and after the treatment. The contents of immunoglobulins IgG, IgA and IgM and the levels of complements C3 and C4 were also monitored. In addition, the level of anti-oxidized low-density lipoprotein (ox-LDL) antibody, the inflammatory cytokines tumor necrosis factor-α (TNF-α), IL-6 and metalloproteinase-9 (MMP-9), the blood lipids triglyceride (TG), total cholesterol (TC), LDL cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured, and the severity of plaque lesions was also evaluated. Our results showed that the saline group, the rosuvastatin group and the low-dose demethylzeylasteral group had significantly lower activated T lymphocyte parameters CD3+, CD4+, CD8+ and CD4+/CD8+ (P<0.05), and significantly higher levels of sIL-2R, immunoglobulins IgG, IgA and IgM, complements C3 and C4, anti-ox-LDL antibody, TNF-α, IL-6 and MMP-9 (P<0.01) when compared with the high-dose demethylzeylasteral group. Moreover, TG, TC, LDL-C contents were found significantly lower and their HDL-C contents were significantly higher in high-dose demethylzeylasteral group (P<0.01) as compared to the other three groups. Furthermore, Sudan staining and haematoxylin and eosin staining of the thoracic aorta showed that, after 30-day treatment, the high-dose demethylzeylasteral group had the smoothest intima and the lightest plaque lesions among the four groups. Based on these results, we concluded that AS is a systemic immune-mediated chronic inflammatory disease and the relatively high dose of demethylzeylasteral used in the treatment of atherosclerotic rabbits could significantly alleviate AS. This implies that demethylzeylasteral may be considered as a suitable drug for anti-immunization therapy.

Expression of microRNAs differed in the omental adipose tissue of obese rats.

OBJECTIVE: To establish obese rat models by high-fat diet, screen microRNAs by microarray in the omental adipose tissue, and find out differential expression of microRNAs in obese rats, for further understanding the role of microRNAs as regulating molecules in obesity-induced lipid metabolism disorders. METHODS: 40 male SD rats were randomly divided into normal diet group and high-fat diet group, respectively. After fed for 8 weeks, rats were weighted, measured length and other characteristics were observed. Eye blood was taken to test blood glucose level, blood lipids level, insulin level and other indicators. The omental adipose tissue was measured by electronic analytical scales and saved at -80°C liquid nitrogen. Fat cells were stained by oil red to observe their morphology under microscopy. The expression of microRNAs was screened by microarray, and verified by Real-Time PCR. RESULTS: After high-fat diet for 4 and 8 weeks, some fatty indicators changed, including increased body weight, omental fat weight, triglycerides, total cholesterol, low-density lipoprotein, blood glucose level and insulin level, and decreased high-density lipoprotein, and differential phenotype of fat cells. Besides, by microarray techniques and Real-Time PCR, 13 differential expression microRNAs were identified, including 7 up-regulated microRNAs (microRNA30a, microRNA7e, microRNA30c, microRNA335, microRNA103, microRNA107, microRNA139-5p), and 6 down-regulated microRNAs (microRNA494, microRNA140, microRNA342-5p, microRNA382, microRNA17-1-3p, microRNA92a). CONCLUSION: Changes in the expression of microRNAs contribute to the pathogenesis of many diseases, including obesity disorders. These alterations can be due to various mechanisms, such as cell proliferation, apoptosis, migration, and differentiation, providing new therapies for diseases.

Angiogenesis and anti-angiogenesis activity of Chinese medicinal herbal extracts.

The aqueous extracts of 24 herbs traditionally used as curing ischemic heart disease in clinic in China were screened for their in vitro angiogenic activity, another twenty-four traditionally used as anti-tumor or anti-inflammatory remedies in China were screened for their in vitro anti-angiogenic activity. The activity of angiogenesis was determined by quantitation of vessels on chick embryo chorioallantoic membrane (CAM) model and cell proliferation of cultured bovine aortic endothelial cells (BAECs). Among the herbal extracts examined, the aqueous extracts of Epimedium sagittatum, Trichosanthes kirilowii and Dalbergia odorifera showed the strong angiogenetic activity both in CAM and BAECs models; and the aqueous extracts of Berberis paraspecta, Catharanthus roseus, Coptis chinensis, Taxus chinensis, Scutellaria baicalensis, Polygonum cuspidatum and Scrophularia ningpoensis elicited significant inhibition at a concentration of 1g dry herb /ml.

MicroRNA-34a regulates cardiac fibrosis after myocardial infarction by targeting Smad4.

BACKGROUND: Although few microRNAs (miRNAs) have been involved in the regulation of post-ischemic cardiac fibrosis, the exact effect and underlying mechanism of miRNAs in cardiac fibrosis remains unclear. Here, we sought to investigate whether microRNA-34 (miR-34) plays a role in the pathogenic development of myocardial fibrosis. METHODS: The myocardial infarction (MI) mice model was induced and cardiac fibroblasts were cultured. Histological analyses, quantitative real-time polymerase chain reaction and Western blotting analysis were used. RESULTS: We found that the miR-34 cluster, especially miR-34a, was upregulated in the MI heart. In vivo, inhibition of miR-34a reduces the severity of experimental cardiac fibrosis in mice. TGF-ß1 increased miR-34a expression in cardiac fibroblasts. Overexpressing miR-34a levels increased the profibrogenic activity of TGF-ß1 in cardiac fibroblast, whereas inhibition miR-34a levels weakened the activity. Finally, we showed that miR-34a's underlying mechanism during cardiac fibrosis occurs through the targeting of Smad4 expression. CONCLUSIONS: Our findings provide evidence that miR-34a plays a critical role in the progression of cardiac tissue fibrosis by directly targeting Smad4, which suggests that miR-34a may be new marker for cardiac fibrosis progression and that inhibition of miR-34a may be a promising strategy in the treatment of cardiac fibrosis.

A novel PITX2c loss-of-function mutation associated with familial atrial fibrillation.

Atrial fibrillation (AF) represents the most prevalent form of sustained cardiac arrhythmia and contributes substantially to cardiovascular morbidity and mortality. Aggregating evidence demonstrates that genetic risk factors play an important role in the pathogenesis of AF. However, AF is a genetically heterogeneous disease and the genetic defects responsible for AF in an overwhelming majority of patients remain unclear. In the present study, the whole coding region and splice junction sites of the PITX2c gene, which encodes a paired-like homeobox transcription factor essential for normal cardiovascular development, were sequenced in 160 unrelated patients with lone AF, and a novel heterozygous mutation, c.349C > T equivalent to p.P117S, was identified in a patient with positive family history of AF. The missense mutation, which co-segregated with AF in the family with complete penetrance and was absent in 700 unrelated ethnically matched healthy individuals, altered the amino acid completely conserved evolutionarily across species and was predicted to be pathogenic by MutationTaster and PolyPhen-2. Biological assays revealed that the mutant PITX2c protein was associated with significantly decreased transcriptional activity when compared with its wild-type counterpart. The findings implicate PITX2c loss-of-function mutation in familial AF for the first time, providing novel insight into the molecular pathology of AF.

NKX2-6 mutation predisposes to familial atrial fibrillation.

Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia and is associated with substantially increased morbidity and mortality rates. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of AF and a number of AF-associated genes have been identified. Nevertheless, AF is a genetically heterogeneous disorder and the genetic components underpinning AF in an overwhelming majority of patients remain unclear. In this study, the entire coding exons and splice junction sites of the NK2 homeobox 6 (NKX2-6) gene, which encodes a homeodomain transcription factor important for cardiovascular development, were sequenced in 150 unrelated patients with lone AF, and a novel heterozygous NKX2-6 mutation, p.Q175H, was identified in an index patient. Genetic analysis of the available family members of the mutation carrier revealed that the mutation co-segregated with AF transmitted in an autosomal dominant pattern. The missense mutation was absent in the 200 unrelated ethnically matched healthy individuals used as controls and the altered amino acid was completely conserved evolutionarily among species. Due to unknown transcriptional targets of NKX2-6, the functional characteristics of the mutation as regards transcriptional activity were analyzed using NKX2-5 as a surrogate. Alignment between human NKX2-6 and NKX2-5 proteins displayed that the Q175H-mutant NKX2-6 was equivalent to the Q181H-mutant NKX2-5, and the introduction of Q181H into NKX2-5 significantly decreased its transcriptional activity at the atrial natriuretic factor promoter. The present study firstly associates genetically defective NKX2-6 with enhanced susceptibility to AF, providing novel insight into the molecular mechanisms underlying AF and suggesting potential strategies for the antenatal prophylaxis and personalized treatment of AF.

Percutaneous closure of postinfarct muscular ventricular septal defects: a multicenter study in China.

BACKGROUND: Surgical repair is an effective method to treat ventricular septal defect (VSD) complicating acute myocardial infarction (AMI). However, the mortality rate remains high. This study was designed to assess the immediate and mid-term results of transcatheter closure of postinfarct muscular VSDs. METHODS: Data were retrospectively collected from 42 AMI patients who underwent attempted transcatheter VSD closure between 2008 and 2012 in seven heart centers of China. RESULTS: Nine patients underwent emergent VSD closure in the acute phase (within two weeks from VSD) while the others underwent elective closure. The time between VSD occurrence and closure in emergency group and elective group was 7.7 ± 2.3 days and 35 ± 14.5 days, respectively (p<0.01). The percentage of procedure success in the emergency group and elective group was 77.8% (7/9) and 97% (32/33), respectively (p=0.048). The hospital mortality was higher for emergent closure in comparison to elective closure (66.7% vs. 6.1%, p<0.01). During a median follow-up of 25 months (0-58 months), two patients died at 8 and 29 months, respectively, and no serious complications occurred in other patients. CONCLUSION: Interventional postinfarct VSD closure is a safe and effective approach that can be performed with a high procedural success rate, with favorable outcomes if it can be undertaken >14 days postinfarct.

Modified clopidogrel loading dose according to platelet reactivity monitoring in patients carrying ABCB1 variant alleles in patients with clopidogrel resistance.

OBJECTIVES: The aim of the present study was to investigate the impact of a adjusted clopidogrel loading dose (LD) according to platelet reactivity index in carriers of ABCB1 mutant allele undergoing percutaneous coronary intervention (PCI). METHODS: All patients met the inclusion criteria were recruited in the present study. Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) index. High treatment platelet reactivity (HTPR) was determined by a cut-off value of >50%. The genetic polymorphism of ABCB1 was determined by allele-specific polymerase chain reaction (PCR). In patients carrying ABCB1 and HTPR after a first 300-mg LD of clopidogrel, dose adjustment was performed by using up to 3 additional 300-mg LDs to obtain a VASP index<50%. The rate of major adverse cardiovascular events (MACE) and major or minor bleeding in one month were recorded. RESULTS: 536 patients were included in the present study. One hundred seventy-two patients (32%) carried ABCB1 mutant allele (11 homozygotes [2%] and 161 heterozygotes [30%]). The VASP index in these patients was significantly higher than in homozygotic patients for the wild allele (65.5±13.8% vs. 47.6±21.8%; p<0.001). Of the 172 ABCB1 mutant allele carriers, 130 were considered to have HTPR. After a second clopidogrel LD, the VASP index was significantly decreased in these patients (66.9±12.8% vs.50.2±18.3%; <0.001). Finally, dose adjustment according to platelet reactivity monitoring enabled 88% of ABCB1 mutant allele carriers and 91% of wild allele carriers exhibiting HTPR to reach a VASP index<50%. The rate of MACE and major or minor bleeding in one-month follow-up between the wild allele carriers and the mutant allele carriers didn't differentiate significantly. CONCLUSIONS: Increased and adjusted clopidogrel loading dose according to platelet reactivity monitoring attenuated clopidogrel resistance in carriers of ABCB1 mutant allele.

Association between risk factors and left ventricular remodeling in middle-aged and aged population: a community-based study.

BACKGROUND: Left ventricular remodeling plays a vital role in the progression of heart failure and contributes to the clinical and symptomatic deterioration. METHOD: We conducted a community-based, cross-sectional study in the middle-aged and geriatric population to assess various potential risk factors for predicting left ventricular enlargement (LVE) and hypertrophy (LVH). LVE was defined by indexing left ventricular internal diameter at end-diastole to height and LVH was defined in the light of calculation of left ventricular mass index. A more specific classification of left ventricular remodeling was further identified. Multiple correspondence analysis and multiple logistic regression analysis were applied. RESULTS: Of 1914 participants, 32.3% were men and average age was 59.5 ±â€Š8.9 years. Statistical analysis indicated that BMI [odds ratio (OR) 1.255, 95% confidence interval (CI) 1.191-1.322], central blood pressure (CBP; OR 1.016, 95% CI 1.008-1.024), radial augmentation index (radial AI; OR 1.014, 95% CI 1.0001-1028), and B-type natriuretic peptide (BNP; OR 1.001, 95% CI 1.0003-1.002) were independently related to LVE, whereas BMI (OR 1.301, 95% CI 1.232-1.374), CBP (OR 1.020, 95% CI 1.012-1.029), and BNP (OR 1.002, 95% CI 1.001-1.003) showed a strong association with LVH. However, radial AI failed to be predictive for any specific patterns of remodeling. BMI, CBP, and BNP were demonstrated to be associated with all other patterns except concentric remodeling, although BNP had no significant correlation with eccentric remodeling. Serum high-sensitivity C-reactive protein and homocysteine were not predictive for remodeling. CONCLUSION: Our findings limited the utility of augmentation index as an early predictor for left ventricular remodeling, whereas BMI, CBP, and BNP probably were independently robust predictors.