Global Longitudinal Strain at Rest for Detection of Coronary Artery Disease in Patients without Diabetes Mellitus.

Global longitudinal strain (GLS) at rest on two-dimensional speckle tracking echocardiography (2D STE) was demonstrated to help detect coronary artery disease (CAD). However, the optimal cut-off point of GLS and its diagnostic power for detecting critical CAD in non-diabetes mellitus (DM) patients are unknown. In the present study, 211 patients with suspected CAD were prospectively included, with DM patients excluded. All patients underwent echocardiography and subsequently coronary angiography within 3 days. Left ventricular (LV) GLSs were quantified by 2D STE. Territorial peak systolic longitudinal strains (TLSs) were calculated based on the perfusion territories of the 3-epicardial coronary arteries in a 17-segment LV model. Critical CAD was defined as an area stenosis ≥70% in ≥1 epicardial coronary artery (≥50% in left main coronary artery). Totally 145 patients were diagnosed as having critical CAD by coronary angiography. Significant differences were observed in all strain parameters between patients with and without critical CAD. The area under the receiver operating charcteristic (ROC) curve (AUC) for GLS in the detection of left main (LM) or threevessel CAD was 0.875 at a cut-off value of -19.05% with sensitivity of 78.1% and specificity of 72.7%, which increased to 0.926 after exclusion of apical segments (cut-off value -18.66%; sensitivity 84.4% and specificity 81.8%). The values of TLSs were significantly lower in regions supplied by stenotic arteries than in those by non-stenotic arteries. The AUC for the TLSs to identify critical stenosis of left circumflex (LCX) artery, left anterior descending (LAD) artery and right coronary artery (RCA), in order of diagnostic accuracy, was 0.818 for LCX, 0.764 for LAD and 0.723 for RCA, respectively. In conclusion, in non-DM patients with suspected CAD, GLS assessed by 2D STE is an excellent predictor for LM or three-vessel CAD with high diagnostic accuracy, and a higher cut-off point than reported before should be used. Excluding apical segments in the calculation of GLS can further improve the predictive accuracy of GLS. It is unsatisfactory for TLSs to be used to identify stenotic coronary arteries.

ß1-Adrenoceptor blocker aggravated ventricular arrhythmia.

OBJECTIVES: To assess the impact of ß1 -adrenoceptor blockers (ß1 -blocker) and isoprenaline on the incidence of idiopathic repetitive ventricular arrhythmia that apparently decreases with preprocedural anxiety. METHODS: From January 2010 to July 2012, six patients were identified who had idiopathic ventricular arrhythmias that apparently decreased (by greater than 90%) with preprocedural anxiety. The number of ectopic ventricular beats per hour (VPH) was calculated from Holter or telemetry monitoring to assess the ectopic burden. The mean VPH of 24 hours from Holter before admission (VPH-m) was used as baseline (100%) for normalization. ß1 -Blockers, isoprenaline, and/or aminophylline were administrated successively on the ward and catheter lab to evaluate their effects on the ventricular arrhythmias. RESULTS: Among 97 consecutive patients with idiopathic ventricular arrhythmias, six had reduction in normalized VPHs in the hour before the scheduled procedure time from (104.6 ± 4.6%) to (2.8 ± 1.6%) possibly due to preprocedural anxiety (P < 0.05), then increased to (97.9 ± 9.7%) during ß1 -blocker administration (P < 0.05), then quickly reduced to (1.6 ± 1.0%) during subsequent isoprenaline infusion. Repeated ß1 -blocker quickly counteracted the inhibitory effect of isoprenaline, and VPHs increased to (120.9 ± 2.4%) from (1.6 ± 1.0%; P < 0.05). Isoprenaline and ß1 -blocker showed similar effects on the arrhythmias in catheter lab. CONCLUSIONS: In some patients with structurally normal heart and ventricular arrhythmias there is a marked reduction of arrhythmias associated with preprocedural anxiety. These patients exhibit a reproducible sequence of ß1 -blocker aggravation and catecholamine inhibition of ventricular arrhythmias, including both repetitive ventricular premature beats and monomorphic ventricular tachycardia.

Polymorphisms of genes in nitric oxide-forming pathway associated with ischemic stroke in Chinese Han population.

AIM: To investigate the association of polymorphisms in four critical genes implicated in the NO-forming pathway with ischemic stroke (IS) in a Chinese Han population. METHODS: DNA samples of 558 IS patients and 557 healthy controls from Chinese Han population were genotyped using the Taqman(TM) 7900HT Sequence Detection System. Six SNPs (rs841, rs1049255, rs2297518, rs1799983, rs2020744, rs4673) of the 4 related genes (eNOS, iNOS, GCH1, and CYBA) in the NO forming pathway were analyzed using the SPSS 13.0 software package for Windows. RESULTS: One SNP located in the intron of GCH1 (rs841) was associated with IS independent of the traditional cardiovascular risk factors in co-dominant and dominant models (P=0.003, q=0.027; P=0.00006, q=0.0108; respectively). Moreover, the combination of rs1049255 CC+CT and rs841 GA+AA genotypes was associated with significantly higher risk for IS after adjustments (OR=1.73, 95% CI: 1.27-2.35, P<0.0001, q<0.0001). CONCLUSION: The data suggest that genetic variants within the NO-forming pathway alter susceptibility to IS in Chinese Han population. Replication of the present results in other independent cohorts is warranted.

[Impact of growth-factor hormone control on the outcome of acromegalic cardiomyopathy].

OBJECTIVE: To observe the impact of growth-factor hormone control on the outcome of acromegalic cardiomyopathy by reviewing cases from our own center and from literatures. METHODS: Two cases of acromegalic cardiomyopathy from Tongji hospital and 29 acromegalic cardiomyopathy cases with fully accessible data retrieved from PubMed and CNKI websites were included in present study for analysis. They were divided into "Controlled (< 5 microg/L)" or "Uncontrolled" group according to the serum level of growth factor hormone after treatments. Outcome of patients was evaluated by symptom, NYHA class, LV size and function status. RESULTS: Incidence of patients with improved symptoms and cardiac performance was significantly higher in "Controlled" group (18/19) compared to those in "Uncontrolled" group (0/12; P < 0.01, chi(2) = 27.1). Post-treatment growth-factor hormone level < 5 microg/L is significantly associated with a satisfactory outcome of acromegalic cardiomyopathy (r = 0.935, P < 0.01). CONCLUSIONS: Control of serum growth-factor concentration to a value < 5 microg/L is critical and associated with a favorable outcome for patients with acromegalic cardiomyopathy.

[Throat infection, neck spinal disease, chest pain and cardiac response: a new clinical syndrome?].

OBJECTIVE: To analyze the characteristics of a new clinical syndrome, including throat infection, neck spinal disease, chest pain and cardiac response. METHODS: A total of 165 patients with above mentioned symptoms admitted to Tongji hospital from 2003 to 2005 were included in this study and underwent further medical history inquiry, physical examination and laboratory tests. Eighty-five healthy subjects served as controls. Serum myocardial auto-antibodies against beta(1)-adrenoceptor, alpha-myosin heavy chain, M(2)-muscarinic receptor and adenine-nucleotide translocator were detected, inflammatory cytokines, high sensitivity C-reaction protein, serum antibodies against Coxsackie virus-B, cytomegalovirus, Mycoplasma pneumoniae and Chlamydia pneumoniae were determined and lymphocyte subclasses were assayed by flow cytometry. RESULTS: All patients had a complex of four symptoms or tetralogy: (1) persistent throat or upper respiratory tract infection; (2) neck pain; (3) chest pain; (4) chest depression or dyspnea, some of them with anxiety. Anti-myocardial auto-antibodies (AMCA) were present in all patients vs. 8% in controls. TNF-alpha, IL-1 and IL-6 were significantly higher in patients than controls (P < 0.01). CD3(+) and CD4(-)CD8(+) lymphocytes were significantly higher and CD56(+) lymphocytes lower in patients than those in controls (P < 0.01). The ratios of serum pathogen antibodies positive against Coxsackie virus-B, cytomegalovirus, Mycoplasma pneumoniae and Chlamydia pneumoniae were all significantly higher in patients than in controls. CONCLUSIONS: These data led to identification of a persistent respiratory infection-related clinical syndrome, including persistent throat infection, neck spinal lesion, rib cartilage inflammation, symptoms of cardiac depression and dyspnea with or without anxiety.

Recombinant adeno-associated virus-mediated human kallikrein gene therapy protects against hypertensive target organ injuries through inhibiting cell apoptosis.

AIM: Overexpression of human tissue kallikrein (HK), mediated by recombinant adeno-associated virus (rAAV), decreased blood pressure in spontaneous hypertensive rats (SHRs) and reduced injury to the heart, aorta and kidney. In this study, we used both an in vivo animal model and in vitro cell culture system to investigate whether rAAV-mediated HK gene therapy protects against organ damage by inhibiting cell apoptosis. METHODS: rAAV encoding HK (rAAV-HK) or LacZ (rAAV-lacZ) were delivered as a control to spontaneously hypertensive rats (SHRs) and cultured human embryonic kidney (HEK) 293 cells. RESULTS: Treatment with rAAV-HK decreased cell apoptosis in the target organs of SHRs and also inhibited lipopolysaccharide (LPS)-induced HEK 293 apoptosis. The rAAV-HK delivery system also increased the levels of apoptosis-inhibiting proteins bcl-2 and bcl-x(L), and decreased the level of Bax and the activity of caspase 3, two promoters of apoptosis. In addition to its role in the inhibition of apoptosis, rAAV-HK also activated the cell survival and proliferation signaling pathways ERK1/2 and PI3K/AKT. CONCLUSION: rAAV-mediated HK gene delivery has multiple therapeutic possibilities for treating hypertension, not only by decreasing blood pressure, but also by directly inhibiting end-organ damage.

C-reactive protein polymorphisms and genetic susceptibility to ischemic stroke and hemorrhagic stroke in the Chinese Han population.

AIM: The inflammatory marker C-reactive protein (CRP) has been strongly correlated with the risk of cardiovascular disease. Some single-nucleotide polymorphisms (SNPs) have been reported to be associated with serum CRP levels. In this study, we assessed the genetic association between SNPs within the CRP gene and ischemic and hemorrhagic stroke in the Han Chinese population. METHODS: This study comprises 564 ischemic stroke patients, 220 hemorrhagic stroke patients and 564 controls from the ethnic Han Chinese population in Wuhan. Four CRP SNPs, -757A>G (rs3093059), -717A>G (rs2794521), -286C>T>A (rs3091244) and +2147C>T (rs1205), were genotyped from patients using TaqMan assays. RESULTS: The A allele frequency for the -717A>G polymorphism was significant higher in controls than in ischemic stroke patients (P=0.037), after adjustment for traditional risk factors (odds ratio 0.28; 95% CI 0.12-0.65; P=0.003), suggesting a protective effect for this allele against ischemic stroke. Haplotype analysis showed that the H3 (G-C-C) haplotype conferred a significantly increased risk of ischemic stroke (odds ratio 1.052, 95% CI 1.001-1.106: P=0.047). Neither CRP genotypes nor haplotypes showed an association with hemorrhagic stroke. However, the frequency for haplotype H5 (A-T-C) was significantly higher in ischemic stroke than hemorrhagic stroke patients (P=0.0003). CONCLUSION: These data suggest that the CRP gene -717A allele confers a protective effect against ischemic stroke. Furthermore, the H3 haplotype (G-C-C) is an independent risk marker for ischemic stroke, whereas the H5 haplotype (A-T-C) can be used as a prognostic marker of hemorrhagic stroke.

Recombinant adeno-associated virus-mediated human kallikrein gene therapy prevents high-salt diet-induced hypertension without effect on basal blood pressure.

AIM: To investigate the effects of the expression of human kallikrein (HK) on basal level blood pressure and high-salt diet-induced hypertension. METHODS: We delivered the recombinant adeno-associated viral (rAAV)-mediated HK (rAAV- HK) gene and rAAV-LacZ (as the control) to normal, adult Sprague-Dawley rats. The animals were administered a normal diet in the first 4 weeks, followed by a high-salt diet. The expression of HK in the rats was assessed by ELISA and RT- PCR. Blood pressure and Na+ and K+ urinary excretion were monitored. RESULTS: Under the normal diet, no obvious changes in blood pressure and Na+ and K+ urinary excretion were observed. When the high-salt diet was administered, systolic blood pressure in the control animals receiving rAAV-LacZ increased from 122.3+/-1.13 mmHg to a stable 142.4+/-1.77 mmHg 8 weeks after the high-salt diet. In contrast, there was no significant increase in the blood pressure in the rAAV-HKtreated group, in which the blood pressure remained at 121.9+/-1.73 mmHg. In the rAAV-HK-treated group, Na+ and K+ urinary excretion were higher compared to those of the control group. The morphological analysis showed that HK delivery remarkably protected against renal damage induced by a high-salt intake. CONCLUSION: Our study indicates that rAAV-mediated human tissue kallikrein gene delivery is a potentially safe method for the long-term treatment of hypertension. More importantly, it could be applied in the salt-sensitive population to prevent the occurrence of hypertension.

Cystatin C, associated with hemorrhagic and ischemic stroke, is a strong predictor of the risk of cardiovascular events and death in Chinese.

BACKGROUND AND PURPOSE: Cystatin C, a serum measure of renal function, has been reported as a strong predictor of risk of death and cardiovascular events in elderly people. We investigated the association between cystatin C and first-ever stroke and evaluated the predictive value of cystatin C in cardiovascular events and death from all causes based on the outcomes of a 5-year follow-up. METHODS: We recruited 293 stroke patients (199 cases of cerebral infarction, 94 cases of cerebral hemorrhage) and 894 controls. For each measure, the study population was divided into quintiles. RESULTS: Total plasma cystatin C levels were significantly higher in patients than controls. Higher cystatin C levels were directly associated with a higher risk of stroke. As compared with the first (lowest) quintile, the hazard ratios (and 95% CIs) for stroke were as follows: second quintile, 1.97 (1.07 to 3.64); third quintile, 2.71 (1.50 to 4.90); fourth quintile, 3.79 (2.12 to 6.75); fifth quintile, 6.38 (3.60 to 11.32). Follow-up of the patients and controls also showed that high cystatin C levels were associated with high prevalence of cardiovascular events or death from all causes. CONCLUSIONS: Elevated cystatin C levels were independently associated with both ischemic and hemorrhagic stroke, and cystatin C was a strong predictor for the risk of cardiovascular events and death.

Recombinant adeno-associated virus-mediated delivery of antisense angiotensin II receptor 1 gene attenuates hypertension development.

AIM: The renin-angiotensin system plays a crucial role in the development and establishment of hypertension, and the pharmacological blockade of the system results in a reduction in blood pressure. In the present study, we investigated whether the effects of a novel, double-stranded, recombinant adeno-associated virus vector (rAAV)-mediated antisense angiotensin II receptor 1 (AT1R) gene efficiently prevents the development of hypertension induced by a high-salt diet in adult, male Sprague-Dawley (SD) rats. METHODS: A rAAV was prepared with a cassette containing a cytomegalovirus promoter and partial cDNA (660 base pairs) for the AT1R inserted in the antisense direction (rAAV-AT1-AS). A single tail vein injection of the rAAV-AT1-AS or rAAV-GFP (green fluorescent protein, a reporter gene) was performed in adult, male SD rats. Two weeks after injection, the animals were fed a diet containing 8% NaCl, and the systolic blood pressure was measured weekly using the tail-cuff method for 12 weeks. RESULTS: The high-salt diet induced a significant rise in systolic blood pressure in the rAAV-GFP-treated animals; however, the rAAV-AT1-AS treatment attenuated the rise in blood pressure (142.7+/-4.5 mmHg vs 117+/-3.8 mmHg, P<0.01), and the hypotensive effect was maintained until the experiments ended at 12 weeks. In the rAAV-GFP-treated animals AT1 was overexpressed in various tissues, especially in the aorta and kidney at mRNA levels; in contrast, rAAV-AT1-AS treatment markedly attenuated AT1 expression. Furthermore, rAAV-AT1-AS treatment prevented target organ damages from hypertension, including cardiac dysfunction and renal injury compared to the rAAV-GFP group. CONCLUSION: These results suggest that rAAVmediated anti-AT1 delivery attenuates the development of hypertension and protects against renal injury and cardiac remodeling.

Effects of bezafibrate on the expression of endothelial nitric oxide synthase gene and its mechanisms in cultured bovine endothelial cells.

OBJECTIVE: Peroxisome proliferator-activated receptors alpha (PPARalpha) is a target gene for atherosclerosis and cardiovascular diseases. However, effects of PPARalpha on endothelial nitric oxide synthase (eNOS) remain unknown. We investigated the eNOS regulation by bezafibrate, a ligand of PPARalpha, and involved signaling pathways. METHODS AND RESULTS: Firstly, in cultured bovine aorta endothelial cells (BAEC), bezafibrate significantly upregulated eNOS at protein, mRNA levels and NO production, respectively, in a concentration-dependent fashion (50-200muM). Next, the effects of bezafibrate on signal pathways and eNOS mRNA stability in BAEC were investigated. Results showed that bezafibrate induced phosphorylation of MAPK. Inhibitors of PPARalpha, PI3 kinase and MAPK, respectively, markedly attenuate bezafibrate-induced upregulation of eNOS. Bezafibrate incubation increased eNOS mRNA half-life, activated eNOS promoter, enhanced phosphorylation of eNOS ser-1179 site, and decreased phosphorylation of eNOS thr-497 site via activating ERK and Akt. CONCLUSIONS: Bezafibrate can upregulate eNOS expression, enhance phosphorylation of eNOS ser-1179, increase NO production and transcription level and stability of eNOS mRNA through pathway dependent of PPARalpha and nongenomic effects mediated by MAPK and PI3K pathways. Hence, PPARalpha ligands exert direct benefits on vessel endothelial functions through an increase in eNOS expression level and phosphorylation of eNOS ser-1179. This mechanism provides additional anti-atherosclerotic and anti-hypertension benefits of bezafibrate in addition of lipid-lowering effects.

[Aldosterone/plasma renin activity ratio is a sensitive parameter for screening patients with primary aldosteronism].

OBJECTIVE: To screen primary aldosteronism cases with ARR (aldosterone/plasma renin activity, ARR) from patients with hypertension, and to evaluate the diagnosis value of ARR in primary aldosteronism cases and analysis the clinical characters of primary aldosteronism cases. METHODS: Nine hundred and two patients with hypertension were collected, the plasma aldosterone concentration to plasma renin activity ratio were detected by radio-immunity method, after that, ARR were calculated. Retrospective analysis was made of clinical data in 126 primary aldosteronism cases, which ARR were over 25. RESULTS: One hundred and twenty-six cases (14%) were diagnosed as primary aldosteronism, and of them, 49 cases had hypokalemia. 25 patients received surgical operation and the rate of efficiency and cure of surgery treatment were 100% and 48%, respectively. The rate of efficiency and cure of drug treatment was 89% and 24% respectively. CONCLUSIONS: Primary aldosteronism affects over 10% of patients with hypertension in China. Patients with hypertension and most patients with treatment-resistant hypertension should undergo screening for primary aldosteronism with ARR. A high ARR is a positive screening test result, a finding that warrants confirmatory testing.

Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase.

Arachidonic acid cytochrome P-450 (CYP) hydroxylase 4A isoforms, including 4A1, 4A2, 4A3 and 4A8 in the rat kidney, catalyze arachidonic acid to produce 19/20-Hydroxyeicosatetraenoic acids (20-HETE), a biologically active metabolite, which plays an important role in the regulation of blood pressure. However, controversial results have been reported regarding the exact role of 20-HETE on blood pressure. In the present study, we used recombinant adeno-associated viral vector (rAAV) to deliver CYP 4A1 cDNA and antisense 4A1 cDNA into Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR), respectively, to investigate the effects of long-term modifications of blood pressure and the potential for gene therapy of hypertension. The mean systolic pressure increased by 14.2+/-2.5 mm Hg in rAAV.4A1-treated SD rats and decreased by 13.7+/-2.2 mm Hg in rAAV.anti4A1-treated SHR rats 5 weeks after the injection compared with controls and these changes in blood pressure were maintained until the experiments ended at 24 weeks. In 4A1 treated animals CYP4A was overexpressed in various tissues, but preferentially in the kidney at both mRNA and protein levels. In anti-4A1-treated SHR, CYP4A mRNA in various tissues was probed, especially in kidneys, but 4A1 protein expression was almost completely inhibited. These results suggest that arachidonic acid CYP hydroxylases contribute not only to the maintenance of normal blood pressure but also to the development of hypertension. rAAV-mediated anti4A administration strategy has the potential to be used as targeted gene therapy in human hypertension by blocking expression of CYP 4A in kidneys.

[The relationship between microalbuminuria and plasma high sensitivity C reactive protein].

OBJECTIVE: To investigate the relationship between microalbuminuria (MA) and plasma high sensitivity C reactive protein (hsCRP). METHOD: The plasma hsCRP level and urine albumin level of 746 Chinese people were detected with ELISA and analyzed, respectively. RESULT: The hsCRP level of MA group increased significantly compared with the control group (2.23 +/- 3.35 mg/L vs 1.68 +/- 2.58 mg/L, P < 0.05), the incidence of MA increased significantly when the plasma hsCRP level was beyond 0.77 mg/L (P < 0.05); logistic analysis showed that the occurrence of MA was associated with the plasma hsCRP level (OR = 1.153, P < 0.05). CONCLUSION: Increased plasma hsCRP was probably involved in the occurrence of MA, suggesting that inflammation may deteriorate endothelial dysfunction.

[Study on the distribution of serum homocysteine and on multi-stepwise regression analysis of the associated factors in the population of community areas in Wuhan].

OBJECTIVE: To study the serum homocysteine (Hcy) distribution and characteristics in different sex and age groups in the community residents in Wuhan, and to analyse its associated factors with multi-stepwise regression analysis. METHODS: The population under study was from three community areas in Wuhan. Demographic distribution and the correlation with other risk factors of serum Hcy were analyzed statistically. RESULTS: (1) Geometric mean of serum Hcy was 14.43 micromol/L in males and 10.89 micromol/L in females with P <0.001. (2) Hcy of per age level in males was also higher (P <0.001). (3) The prevalence rate of hyperhomocysteinemia was 23.94% in the general population in Wuhan. The prevalence rate of hyperhomocysteinemia in males was 2.62 times higher than in females. (4) Multi-stepwise regression analysis showed that Hcy had different affecting factors in males and females. The affecting factors of Hcy in males were daily cigarettes smoking, urine micro-albumin (UMALB) and times of exercise per week. The affecting factors of Hcy in females were duration of exercise each time, weight, triglyceride (TG), high-density lipoprotein (HDL), urine micro-albumin (UMALB) and age. CONCLUSIONS: (1) Hcy at the population level was significantly different by sex and age. (2) Population living in the community in Wuhan had a higher serum level and prevalence rate of Hcy comparing to some other cities in China and even in developed countries. (3) The important affecting factors of Hcy in population also showed sex difference, unlike the reports from other countries or other areas in China. Serum Hcy seemed to be affected by environmental and other factors.

[A case-control study on the relationship between stroke and plasma homocysteine level and the mutation of MTHFR gene].

OBJECTIVE: To study the relationship of stroke and plasma homocysteine (Hcy) level and the mutation of methylenetetrahydrofolate reductase (MTHFR) gene. METHODS: Three hundred patients with stroke were included as the case group in this study while 300 subjects without stroke matched with the case group for sex and age were collected as the control group. Plasma Hcy level was measured using HPLC and MTHFR 667C-->T mutant was determined by polymerase chain reaction and restriction fragment analysis. The relationship of stroke and plasma Hcy level and the mutation of MTHFR gene was then analysed. RESULTS: The plasma Hcy level of the case group was significantly higher than that of the control group (16.92 +/- 3.43 micromol/L vs. 14.57 +/- 2.59 micromol/L, P <0.05). There was no significant difference in mutation rate of MTHFR C677T between stroke group and control group (P >0.05), as well as between ischemic stroke group and homorrhagic stroke group (P >0.05). The mutation of MTHFR C677T had no significant influence on the Hcy level (15.28 +/- 2.17 micromol/L vs. 15.11 +/- 3.81 micromol/L, P >0.05). CONCLUSION: Increased plasma Hcy level played an important role in the occurrence of stroke in Chinese people, and the mutation of MTHFR C677T was not associated with Hcy level or stroke which led to the speculation that plasma Hcy level was important in the prevention of cardio-cerebro-vascular diseases among Chinese people.