OBJECTIVE: To assess the association of polymorphisms of receptor of advanced glycation end products (RAGE) gene, monocyte to high-density lipoprotein cholesterol ratio (MHR) and variability of heart rate among patients with coronary heart disease (CHD). METHODS: 120 patients with CHD and 120 healthy individuals were respectively selected as the observation group and the control group. Allelic and genotypic differences of -429T>C, 1704G>T, 82G>S, MHR ratio and heart rate variability between the two groups and patients with different severity were analyzed. The correlation between their genotypes and MHR ratio and heart rate variability was analyzed. RESULTS: The 82G>S polymorphism of the RAGE gene and the allelic difference between the two groups and patients with different severity were statistically significant (P< 0.05). Compared with the control group and patients with mild to moderate phenotype, monocyte, total cholesterol, triglyceride, low density lipoprotein, MHR, low frequency in the observation group and patients with severe symptoms were significantly higher, while their high density lipoprotein, standard deviation of NN intervals (SDNN), standard deviation average of NN intervals (SDANN), root mean square successive differences, percentage of differences exceeding 50ms between adjacent normal number of intervals (PMN50), high frequency (HF) were significantly lower. The gene frequencies of G-Gly-T, T-Gly-T, G-Ser-T and G-Gly-C were correlated with SDNN, SDANN, rMSSD, PMN50, HF and MHR, but negatively correlated with low frequency. CONCLUSION Polymorphisms of the RAGE gene in patients with coronary heart disease are associated with the MHR ratio and heart rate variability, which can be used as markers for the diagnosis and efficacy evaluation.
Antigens, Neoplasm ; Coronary Disease/genetics* ; Gene Frequency ; Glycation End Products, Advanced ; Heart Rate ; Humans ; Mitogen-Activated Protein Kinases ; Polymorphism, Genetic

BACKGROUND/AIMS: We evaluated the association between coding region variants of adrenergic receptor genes and therapeutic effect in patients with congestive heart failure (CHF). METHODS: One hundred patients with stable CHF (left ventricular ejection fraction [LVEF] < 45%) were enrolled. Enrolled patients started 1.25 mg bisoprolol treatment once daily, then up-titrated to the maximally tolerable dose, at which they were treated for 1 year. RESULTS: Genotypic analysis was carried out, but the results were blinded to the investigators throughout the study period. At position 389 of the beta-1 adrenergic receptor gene (ADRB1), the observed minor Gly allele frequency (Gly389Arg + Gly389Gly) was 0.21, and no deviation from Hardy-Weinberg equilibrium was observed in the genotypic distribution of Arg389Gly (p = 0.75). Heart rate was reduced from 80.8 +/- 14.3 to 70.0 +/- 15.0 beats per minute (p < 0.0001). There was no significant difference in final heart rate across genotypes. However, the Arg389Arg genotype group required significantly more bisoprolol compared to the Gly389X (Gly389Arg + Gly389Gly) group (5.26 +/- 2.62 mg vs. 3.96 +/- 2.05 mg, p = 0.022). There were no significant differences in LVEF changes or remodeling between two groups. Also, changes in exercise capacity and brain natriuretic peptide level were not significant. However, interestingly, there was a two-fold higher rate of readmission (21.2% vs. 10.0%, p = 0.162) and one CHF-related death in the Arg389Arg group. CONCLUSIONS: The ADRB1 Gly389X genotype showed greater response to bisoprolol than the Arg389Arg genotype, suggesting the potential of individually tailoring beta-blocker therapy according to genotype.
Adrenergic beta-1 Receptor Antagonists/adverse effects/*therapeutic use ; Adult ; Aged ; Bisoprolol/adverse effects/*therapeutic use ; Female ; Gene Frequency ; Genotype ; Heart Failure/diagnosis/*drug therapy/*genetics/physiopathology ; Heart Rate/drug effects ; Humans ; Male ; Maximum Tolerated Dose ; Middle Aged ; Pharmacogenomic Testing ; Phenotype ; *Polymorphism, Genetic ; Precision Medicine ; Receptors, Adrenergic, beta-1/*drug effects/*genetics ; Republic of Korea ; Stroke Volume/drug effects ; Time Factors ; Treatment Outcome ; Ventricular Function, Left/drug effects ; Ventricular Remodeling/drug effects

The traditional Chinese medicine Shensong Yangxin (SSYX) can improve the clinical symptoms of arrhythmia in an integrated manner. This study aimed to investigate the electrophysiological effect of SSYX on the hearts of myocardial-infarcted rabbits and further explore the mechanism by which SSYX alleviates myocardial fibrosis. Myocardial infarction (MI) was established in rabbits by ligation of the left circumflex coronary. The rabbits were treated with SSYX (0.5 g/kg/d) or saline for 8 weeks by oral administration. Microelectrode array (MEA) technology was used in vivo for extracellular electrophysiological recordings of the infarct border zone. Masson's trichrome staining was used to observe myocardial fibrosis. Western blotting was performed to evaluate the protein expression levels of collagen I (COL I) and collagen III (COL III). Quantitative real-time polymerase chain reaction (real-time PCR) was performed to evaluate the TGF-β1 and MMP-2 mRNA expression levels. The results showed that the total activation time (TAT) and the dispersion of TAT were significantly increased and the excitation propagation markedly disordered after MI. SSYX could significantly decrease TAT and the dispersion of TAT, and significantly ameliorate the chaotic spread pattern of excitation. Furthermore, SSYX treatment could significantly decrease COL I and COL III protein levels and down-regulate TGF-β1 and MMP-2 mRNA expression levels in MI rabbits. It was concluded that SSYX may ameliorate cardiac electrophysiological abnormalities in infarcted hearts by decreasing the protein levels of COL I and COL III, down-regulating the mRNA expression levels of TGF-β1 and MMP2, and thereby reducing adverse cardiac remodeling.
Animals ; Collagen Type I ; genetics ; metabolism ; Collagen Type III ; genetics ; metabolism ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; therapeutic use ; Female ; Heart Rate ; drug effects ; Hyperplasia ; Male ; Matrix Metalloproteinase 2 ; genetics ; metabolism ; Myocardial Infarction ; drug therapy ; pathology ; Myocardium ; metabolism ; pathology ; Rabbits ; Transforming Growth Factor beta ; genetics ; metabolism

OBJECTIVETo explore the effects of principal-subordinate acupoints combination on improving myocardial ischemia, and the gene regulatory pathways for the protection of myocardial ischemia.

METHODSAccording to the random number table method, 70 SPF Wistar male rats were divided into a normal group, a model group, a LY294002 group, an insulin-like growth factors-1(IGF-1) group, a Neiguan group, an acupoint combination group and an acupoint combination + LY294002 group, 10 rats in each one. Rats in the normal group were injected with 0.9% NaCl solution, while rats in the remaining groups were treated with abdominal subcutaneous injection of isoroterenol hydrochloride to establish the rat model of myocardial ischemia. Rats in the LY294002 group and IGF-1 group were treated with injection of LY294002 solution and IGF-1 solution for 14 days. Rats in the Neiguan group were treated with electroacupuncture (EA) at "Neiguan" (PC 6) by using Han-200 EA apparatus for 10 min per treatment. Rats in the acupoint combination group were treated with EA at "Neiguan" (PC 6), "Zusanli" (ST 36) and "Guanyuan" (CV 4) by using Han-200 EA apparatus for 10 min per treatment. Rats in the acupoint combination + LY294002 group were treated with LY294002 solution for 14 days, and EA at "Neiguan" (PC 6), "Zusanli" (ST 36) and "Guanyuan" (CV 4) was given before model establishment, once a day for 21 days. EA pretreatment was given before model establishment in all acupuncture groups. The heart rate (HR) and ST segment voltage were detected before and after treatment; the myocardial pathological morphology was observed by HE staining; the expressions of P13K mRNA and Akt mRNA were tested.

RESULTSAfter modeling, HR and ST segment voltage in all intervention groups were higher than those in the normal group (all P < 0.01); after the intervention, the HR and the ST segment voltage in the acupoint combination group, IGF-1 group and IGF-1 group were improved (P < 0.01, P < 0.05), which was more significant in the acupoint combination group and Neiguan group (all P < 0.01). As for the myocardial pathological morphology, obvious myocardial ischemia was observed in the model group, and that in the LY294002 group was the most serious, and that in the acupoint combination+ LY294002 group was moderate. After intervention, the myocardial pathological damage in the IGF-1 group, Neiguan group and acupoint combination group was significant improved, which was more significant in the IGF-1 group and acupoint combination group. As for the expression of PI3K mRNA and Akt mRNA, compared with normal group, the expression of PI3K mRNA was increased in the remaining groups after modeling (P < 0.01, P < 0.05), which was more significant in the IGF-1 group and acupoint combination group (all P < 0. 01). The expression of Akt mRNA in the LY294002 group and acupoint combination + LY294002 group was reduced (P < 0. 01, P < 0.05), while that in the remaining groups was increased (P < 0.01, P < 0.05), which was more significant in the IGF-1 group and acupoint combination group (all P < 0.01).

CONCLUSIONThe principal-subordinate acupoints combination could improve heart rate and ST segment voltage in rats with chronic myocardial ischemia, reduce myocardial pathological damage, which is superior to single selection of "Neiguan" (PC 6). The PI3K/Akt signaling pathway may be involved in the regulation mechanism of principal-subordinate acupoints combination for the protection of chronic myocardial ischemia.

Acupuncture Points ; Acupuncture Therapy ; Animals ; Chronic Disease ; therapy ; Electroacupuncture ; Electrocardiography ; Heart Rate ; Humans ; Insulin-Like Growth Factor I ; metabolism ; Male ; Myocardial Ischemia ; enzymology ; pathology ; physiopathology ; therapy ; Myocardium ; pathology ; Phosphatidylinositol 3-Kinases ; genetics ; metabolism ; Proto-Oncogene Proteins c-akt ; genetics ; metabolism ; Rats ; Rats, Wistar

PURPOSE: Recently, mitochondrial DNA 4977bp deletion (mtDNA4977-mut), a somatic mutation related to oxidative stress, has been shown to be associated with atrial fibrillation (AF). We hypothesized that patient age, as well as electroanatomical characteristics of fibrillating left atrial (LA), vary depending on the presence of mtDNA4977-mut in peripheral blood among patients with non-valvular AF. MATERIALS AND METHODS: Analyzing clinical and electroanatomical characteristics, we investigated the presence of the mtDNA4977-mut in peripheral blood of 212 patients (51.1+/-13.2 years old, 83.5% male) undergoing catheter ablation for non-valvular AF, as well as 212 age-matched control subjects. RESULTS: The overall frequency of peripheral blood mtDNA4977-mut in patients with AF and controls was not significantly different (24.5% vs. 19.3%, p=0.197). When the AF patient group was stratified according to age, mtDNA4977-mut was more common (47.4% vs. 20.0%, p=0.019) in AF patients older than 65 years than their age-matched controls. Among AF patients, those with mtDNA4977-mut were older (58.1+/-11.9 years old vs. 48.8+/-11.9 years old, p<0.001). AF patients positive for the mtDNA mutation had greater LA dimension (p=0.014), higher mitral inflow peak velocity (E)/diastolic mitral annular velocity (Em) ratio (p<0.001), as well as lower endocardial voltage (p=0.035), and slower conduction velocity (p=0.048) in the posterior LA than those without the mutation. In multivariate analysis, E/Em ratio was found to be significantly associated with the presence of mtDNA4977-mut in peripheral blood. CONCLUSION: mtDNA4977-mut, an age-related somatic mutation detected in the peripheral blood, is associated with advanced age and electro-anatomical remodeling of the atrium in non-valvular AF.
Adult ; Aged ; Atrial Fibrillation/blood/*genetics/*physiopathology ; Atrial Remodeling/*genetics ; Base Pairing/*genetics ; Case-Control Studies ; DNA, Mitochondrial/*blood/*genetics ; Female ; Heart Atria/pathology/physiopathology ; Humans ; Kaplan-Meier Estimate ; Logistic Models ; Male ; Middle Aged ; Mutation Rate ; Phenotype ; Sequence Deletion/*genetics

OBJECTIVETo analyze the association between T393C single nucleotide polymorphism (SNP) of GNAS1 gene and non-valvular atrial fibrillation (AF) in Chinese Han patients.

METHODSNinety patients with non-valvular AF and 90 healthy subjects were examined for T393C SNP of GNAS1 gene using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The allele genotypes and the distribution of allele frequencies were analyzed and compared between the two groups. The relationship between allele frequency distribution characteristics and the heart rate variability (HRV) were also studied for analysis of the association between T393C SNP of GNAS1 gene and the autonomic nervous activation in non-valvular AF.

RESULTSThe two groups showed a significant difference in the frequencies of genotypes of T393C SNP of GNAS1 gene and allele frequencies (P<0.01). CC genotype and T393C allele frequency were significantly increased in the case group. pNN50, LF, or LF/HF showed no significant difference between different genotypes (P<0.05).

CONCLUTIONSThe T393C SNP of GNAS1 gene is closely associated with non-valvular AF in Chinese Han patients.

Adult ; Aged ; Aged, 80 and over ; Alleles ; Asian Continental Ancestry Group ; genetics ; Atrial Fibrillation ; genetics ; metabolism ; physiopathology ; Chromogranins ; Female ; GTP-Binding Protein alpha Subunits, Gs ; genetics ; Gene Frequency ; Genotype ; Heart Rate ; Humans ; Male ; Middle Aged ; Polymerase Chain Reaction ; Polymorphism, Restriction Fragment Length ; Polymorphism, Single Nucleotide ; Risk Factors

The purpose of this study was to investigate the therapeutic effects of small hairpin RNA (shRNA) targeting endothelin-converting enzyme (ECE)-1 in monocrotaline (MCT)-induced pulmonary hypertensive rats. Ninty-four Sprague-Dawley rats were divided into three groups: control (n = 24), MCT (n = 35) and shRNA (n = 35). Four-week survival rate in the shRNA group was significantly increased compared to that in the MCT group. The shRNA group showed a significant improvement of right ventricular (RV) pressure compared with the MCT group. The MCT and shRNA groups also showed an increase in RV/(left ventricle + septum) ratio and lung/body weight. Plasma endothelin (ET)-1 concentrations in the shRNA group were lower than those in the MCT group. Medial wall thickness of pulmonary arterioles were increased after MCT injection and was significantly decreased in the shRNA group. The number of intra-acinar muscular pulmonary arteries was decreased in the shRNA group. The mRNA expressions of ET-1 and ET receptor A (ETA) were significantly decreased in the shRNA group in week 4. The protein levels of ETA were decreased in the shRNA group in week 2. The protein levels of tumor necrosis factor-alpha and vascular endothelial growth factor were decreased in the shRNA group in week 4. In conclusion, the gene silencing with lentiviral vector targeting ECE-1 could be effective against hemodynamic, histopathological and gene expression changes in pulmonary hypertension.
Animals ; Aspartic Acid Endopeptidases/*antagonists & inhibitors/blood/genetics ; Body Weight ; Heart Ventricles/physiopathology ; Hypertension, Pulmonary/chemically induced/*enzymology/mortality ; Lentivirus/genetics ; Lung/anatomy & histology/metabolism/pathology ; Male ; Metalloendopeptidases/*antagonists & inhibitors/blood/genetics ; Monocrotaline/toxicity ; Pulmonary Artery/drug effects/physiopathology ; RNA, Small Interfering/*metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Endothelin A/genetics/metabolism ; Survival Rate ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Endothelial Growth Factor A/metabolism

Oxidative stress may reduce cardiovascular function. Glutathione Stransferases(GSTs) play an important role in cell defending against oxidative stress. Glutathione S-transferase P1 (GSTP1) gene is one of the most intensively investigated glutathione S-transferase genes in epidemiologic studies. The GSTP1 gene displays a polymorphism at codon 105 (Ile105 Val), which results in an enzyme with altered substrate affinity. To date, there have been few studies evaluating whether Ilel05Val polymorphism of GSTP1 gene has an effect on cardiovascular function in the broad masses of people. In this study, we investigated the relationship between Ile105 Val polymorphism of GSTP1 gene and heart rate and blood pressure in 197 unrelated adult males of Han nationality. It was found that there were two types of the GSTP1 genotypes, Ile105/Ile105 and Ile105/Val105, but genotype Val105/Val105 was not found, and the frequencies of IleIes/Ileos and Ile105/Val105 genotypes were 78% and 22% respectively. Comparison with individuals with lie105/Val105 genotype showed that those with Ile105/Ile105 genotype had higher rest heart rate and maximal heart rate mean values. However, whether for rest heart rate and maximal heart rate or for heart rate reserve, no significant differences were found between the two genotype groups (P>0.05). Compared with individuals with Ile105/Val105 genotype, those with Iler105/Ile105 genotype had higher systolic blood pressure and pulse pressure mean values and lower diastolic blood pressure mean value. However, for systolic blood pressure, diastolic blood pressure and pulse pressure, no significant differences were found between the two genotype groups (P>0.05). The results suggested that Ile105 Val polymorphism of GSTP1 gene may not be associated with heart rate and blood pressure in the broad masses of people.
Adult ; Blood Pressure ; physiology ; Genotype ; Glutathione S-Transferase pi ; genetics ; Heart Rate ; physiology ; Humans ; Male ; Polymorphism, Genetic

BACKGROUNDGenetic factors can influence antihypertensive response to metoprolol, and many studies focused on the relationship between the genotype in beta1-adrenergic receptor and blood pressure (BP), little was known about the association of angiotensin-converting enzyme (ACE) genotype with the therapeutic result of metoprolol. The present study aimed to investigate whether the ACE gene insertion (I)/deletion (D) polymorphism is related to the response to metoprolol in Chinese Han hypertensive patients.

METHODSNinety-six patients with essential hypertension received metoprolol (100 mg once daily) as monotherapy for 8 weeks. Twenty-four hours ambulatory blood pressure monitoring and dynamic electrocardiogram were performed before and after treatment. Genotyping analysis was performed using PCR. The association of the ACE gene I/D polymorphism with variations in BP and heart rate (HR) was observed after the 8-week treatment.

RESULTSThe patients with ACE gene II polymorphism showed greater reduction in 24-hour average HR than those with ID or DD polymorphisms (P = 0.045), no effect of this genotype on the reduction in seating HR or in BP was observed. After adjusting for age, gender, body mass index, BP and HR at baseline, the ACE gene I/D polymorphism was still an independent predictor for variations in 24-hour average HR.

CONCLUSIONSThe II polymorphism in ACE gene could be a candidate predictor for greater reduction in 24-hour average HR in Chinese Han hypertensive patients treated by metoprolol. Greater benefits would be obtained by patients with II polymorphism from the treatment with metoprolol. Larger studies are warranted to validate this finding.

Adult ; Aged ; Antihypertensive Agents ; therapeutic use ; Female ; Genotype ; Heart Rate ; drug effects ; genetics ; Humans ; Hypertension ; drug therapy ; genetics ; Male ; Metoprolol ; therapeutic use ; Middle Aged ; Peptidyl-Dipeptidase A ; genetics ; Polymorphism, Genetic ; genetics

OBJECTIVETo assess the effects of penehyclidine hydrochloride on patients with acute lung injury (ALI), to observe the expression of Toll-like receptor 4 (TLR4) on the peripheral monocytes of ALI patients and changes of inflammatory and anti-inflammatory cytokines and to investigate the mechanism of TLR4 in ALI.

METHODSForty-five patients with ALI were randomly divided into penehyclidine hydrochloride treatment group (P group, n equal to 21) and conventional treatment group (control group, C group, n equal to 24). Patients in both groups received conventional treatment, including active treatment of the primary disease, respiratory support, nutritional support and fluid management therapy, while those in P group were given penehyclidine hydrochloride (1 mg, im, q. 12 h) in addition. The TLR4 expression of 20 healthy volunteers were detected. The clinical effect, average length of stay in ICU and hospital, values of PaO2 and PaO2/FiO2, expression of TLR4 on the surface of peripheral blood mononuclear cells and some serum cytokines were evaluated for 48 h.

RESULTSThe general conditions of the two groups were improved gradually and PaO2 increased progressively. Compared with 0 h, PaO2 and PaO2/FiO2 at 6, 12, 24 and 48 h after treatment were significantly increased (P less than 0.05). The improvement in P group was obviously greater than that in C group (P less than 0.05). The average length of hospitalization showed no difference between the two groups, but penehyclidine hydrochloride significantly decreased the average length of stay in ICU (t equal to 3.485, P less than 0.01). The expression of TLR4 in two groups were both obviously higher than that of healthy volunteers (P less than 0.01). It decreased significantly at 24 h (t equal to 2.032, P less than 0.05) and 48 h (t equal to 3.620, P less than 0.01) and was lower in P group than in C group. The patients who showed a higher level of TLR4 expression in early stage had a worse prognosis and most of them developed acute respiratory distress syndrome (ARDS). The incidence of ARDS was 23.8% in P group and 29.17% in C group at 24 h. Untill 48 h, there were other two patients developing ARDS in control group. Serum IL-1, IL-8 and TNF-alpha expressions reduced after 24 h in both groups. The reduction in P group was more obvious than that in C group (P less than 0.05). IL-13 increased gradually from 0 h to 24 h, and decreased slightly at 48 h, which showed no difference between two groups (t equal to 1.028, P larger than 0.05).

CONCLUSIONSPenehyclidine hydrochloride improves the arterial oxygen pressure, down-regulates the expression of TLR4 and restrains the inflammatory cytokines in the downstream of TLR4 signaling pathway. It prevents the development of ALI and can be considered as an important drug in ALI treatment.

Acute Lung Injury ; drug therapy ; etiology ; physiopathology ; Cytokines ; blood ; Heart Rate ; drug effects ; Humans ; Oxygen ; blood ; Prognosis ; Quinuclidines ; therapeutic use ; Toll-Like Receptor 4 ; genetics ; physiology