Xiaohan Fan

Disorders of Orthostatic Blood Pressure Response Are Associated With Cardiovascular Disease and Target Organ Damage in Hypertensive Patients

BACKGROUND The prevalence and clinical significance of orthostatic hypertension (OHT) remain largely undetermined in hypertensive patients. This study investigated the association of OHT and orthostatic hypotension (OH) with cardiovascular disease (CVD) and target organ damage (TOD) in hypertensive patients. METHODS A cross-sectional study was conducted in 4,711 hypertensives and 826 normotensives, aged 40-75 years. OHT was defined as an increase in systolic blood pressure (SBP) of > or =20 mm Hg, and OH was defined as either a reduction in SBP of at least 20 mm Hg or a reduction in diastolic BP (DBP) of at least 10 mm Hg during the first 3 min after standing. RESULTS Hypertension was only independently associated with a risk of OHT. After controlling for age, sex, and other confounders, OH was associated with peripheral artery disease (PAD) (odds ratio (OR) 1.49, 95% confidence interval (CI) 1.15-1.89, P < 0.01), left ventricular hypertrophy (LVH) (OR 1.48, 95% CI 1.12-1.93, P < 0.001), coronary artery disease (CAD) (OR 1.71, 95% CI 1.12-2.61, P < 0.01), and stroke (OR 1.72, 95% CI 1.19-2.34, P < 0.01), but OHT was only associated with PAD (OR 1.36, 95% CI 1.05-1.81, P < 0.05) and stroke (OR 1.76, 95% CI 1.27-2.26, P < 0.01). The adjusted OR for PAD, predicted by the quintiles of the orthostatic SBP changes, showed a J-shaped relationship in untreated hypertensive patients, as was also the case for LVH in hypertensive women. CONCLUSIONS OH is associated with CV risk; the associations of OHT with TOD and stroke in hypertensive patients still need to be confirmed in prospective studies.

Polymorphisms of ACE2 Gene are Associated With Essential Hypertension and Antihypertensive Effects of Captopril in Women

ACE2 appears to counterbalance the vasopressor effect of angiotensin I converting enzyme (ACE) in the renin‐angiotensin system. We hypothesized that ACE2 polymorphisms could confer a high risk of hypertension and have an impact on the antihypertensive response to ACE inhibitors. The hypothesis was tested in two case‐control studies and a clinical trial of 3,408 untreated hypertensive patients randomized to Atenolol, Hydrochlorothiazide, Captopril, or Nifedipine treatments for 4 weeks. ACE2 rs2106809 T allele was found to confer a 1.6‐fold risk for hypertension in women (95% confidence interval (CI), 1.13–2.06), whereas when combined with the effect of the ACE DD genotype, the risk was 2.34‐fold (95% CI, 1.75–4.85) in two independent samples. The adjusted diastolic blood pressure response to Captopril was 3.3 mm Hg lower in ACE2 T allele carriers than in CC genotype carriers (P=0.019) in women. We conclude that the ACE2 T allele confers a high risk for hypertension and reduced antihypertensive response to ACE inhibitors.

Correlation of ventricular arrhythmias with genotype in arrhythmogenic right ventricular cardiomyopathy.

Background—Although mutations of several genes are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), the exact correlation between genotype and ventricular arrhythmia features remains unclear. This study was aimed to examine the possible association of the 9 known genes of ARVC with clinical and electrophysiological characteristics. Methods and Results—Ninety subjects diagnosed with ARVC who underwent electrophysiological study were recruited for screening the 9 known ARVC-causing genes. A total of 53 mutations were identified in 57 (63%) subjects. Mutation carriers had more frequent clinical ventricular tachycardia (VT; 89% versus 55%; P<0.001) and negative T waves in V1 to V3 (61% versus 33%; P=0.016). Subjects with plakophilin-2 (PKP2) mutations also had more frequent VT than those without mutations in PKP2. Comparison between subjects with multiple and single mutations showed that syncope occurred more often in the former group (58% versus 24%; P=0.018). VT was significantly more often induced in mutation carriers compared with noncarriers (75% versus 39%; P=0.001), as well as in PKP2 mutation carriers compared with subjects without PKP2 mutations (80% versus 48%; P=0.002). Induced VT with a rate ≥200 bpm was more often documented in mutation carriers (88% versus 54%; P=0.013), as well as in PKP2 mutation carriers (91% versus 67%; P=0.041). Conclusions—Pathogenic gene mutations were found in nearly two thirds of subjects diagnosed with ARVC. Mutation carriers, especially PKP2, had a higher proportion of a history of VT and more inducible fast VT.

Association of Intergenic Polymorphism of Organic Anion Transporter 1 and 3 Genes With Hypertension and Blood Pressure Response to Hydrochlorothiazide

BACKGROUND Organic anion transporter (OAT) 1 and OAT3, encoded by a tightly linked gene pair, play a key role in renal secretion of diuretics. However, no study has yet examined the influence of OAT1 and OAT3 polymorphisms on high blood pressure (BP) and the response to thiazide diuretics. We hypothesized that intergenic polymorphisms between OAT1 and OAT3 might be associated with adult hypertension and the antihypertensive effects of hydrochlorothiazide (HCTZ). METHODS The association of an intergenic polymorphism (rs10792367) with hypertension risk was investigated in two independent case-control studies (n = 1,592 and 602), and then a combined analysis was performed for improving power (1,106 cases and 1,088 controls) with adjustment for geographic location. Two clinical trials (n = 542 and 274) were conducted in untreated hypertensive patients for the association of rs10792367 with antihypertensive responses to 4 and 8 weeks of HCTZ treatment. RESULTS No significant association was found between rs10792367 and hypertension after adjustment for conventional risk factors in either the two populations, respectively, or the combined two population. After adjustment for pretreatment BP and other confounders, HCTZ-induced reduction in systolic BP was 4.8 mm Hg (P = 0.006, first trial) and 6.1 mm Hg (P = 0.003, in second trial) lower, respectively, in C allele carriers than in GG carriers in the two clinical trials. CONCLUSIONS Intergenic polymorphism rs10792367 between OAT1 and OAT3 is not associated with hypertension, but appears to be involved in between-individual variations in antihypertensive responses to HCTZ.

Patients with metabolic syndrome have prolonged corrected QT interval (QTc).

Prolongation of corrected QT interval (QTc) increases morbidity and mortality and QTc has been found to be longer in patients with diabetes mellitus than in healthy controls. It is still inconclusive whether the metabolic syndrome results in QTc prolongation.

KCTD10 interacts with proliferating cell nuclear antigen and its down-regulation could inhibit cell proliferation†

A novel gene (GenBank accession No. AF113208) named KCTD10 (potassium channel tetramerisation domain‐containing 10) was cloned from our 5300 EST database of human aorta cDNA library. Computational analysis showed that KCTD10 cDNA is 2,638 bp long, encoding 313 amino acids with a proliferating cell nuclear antigen binding motif, mapped to chromosome 12q24.11 with 7 exons, ubiquitously expressed in all 12 tested normal tissues and 7 of 8 tested tumor cell lines from MTN membranes by Northern blot. Nuclear localization of KCTD10 was observed in A549 cells. Yeast two‐hybrid analysis and immunoprecipitation assay showed that KCTD10 can interact with PCNA. In A549 cells, KCTD10 down‐regulation could inhibit cell proliferation, but its over‐expression could not influence cell proliferation. The results suggest that KCTD10 may be associated with DNA synthesis and cell proliferation. J. Cell. Biochem. 106: 409–413, 2009.

Polymorphisms of angiotensin-converting enzyme (ACE) and ACE2 are not associated with orthostatic blood pressure dysregulation in hypertensive patients

AbstractAim:The genetic background of orthostatic blood pressure dysregulation remains poorly understood. Since the renin-angiotensin system plays an important role in blood pressure regulation and response to position change, we hypothesized that angiotensin-converting enzyme (ACE) and ACE2 genetic polymorphisms might contribute, at least partially, to orthostatic blood pressure dysregulation in hypertensive patients.Methods:Two tag single nucleotide polymorphisms (SNPs) of ACE2 and ACE I/D were genotyped in 3630 untreated hypertensive patients and 826 normotensive subjects. Orthostatic hypertension was defined as an increase in systolic blood pressure of 20 mmHg or more and orthostatic hypotension as a drop in blood pressure of 20/10 mmHg or more within three minutes of assumption of upright posture.Results:Female and male patients had similar rates of orthostatic hypertension (16.5% vs 15.3%) and hypotension (22.5% vs 23.8%). No significant differences were detected in the minor allele frequency of ACE2 rs2106809, rs2285666, or ACE I/D in either female or male patients with orthostatic hypertension (15.1%, 22.7%, 19.6%, respectively), hypotension (13.8%, 25%, 16.5%), or normal orthostatic blood pressure response (14.4%, 21.9%, 15.8%) in additive, dominant or recessive models after adjustment for confounders (all P>0.05). The orthostatic changes in systolic and diastolic blood pressure were also comparable among patients carrying different genotypes. Similar results were observed in normotensive subjects.Conclusion:These data provide no support for the involvement of ACE or ACE2 in the genetic predisposition to orthostatic hypotension or hypertension.

Plasma D-dimer and in-hospital mortality in patients with Stanford type A acute aortic dissection.

Plasma D-dimer has been used as a complementary initial diagnostic marker for acute aortic dissection (AAD). However, its prognostic role in patients with Stanford type A AAD has not been clarified. We prospectively enrolled a consecutive series of patients with suspect AAD presented to our emergency department and measured the plasma D-dimer level (Stago-evolution, France) immediately following the admission. The diagnosis of type A AAD was confirmed by aorta angiography with multidetector computed tomography for each patient. Patients were divided into two groups: the deceased group, who died during hospitalization, and the survival group. The predictive value of D-dimer for in-hospital mortality was determined by using univariate and multivariate Cox proportional hazards analyses. A total of 133 patients with Stanford type A AAD were included. During hospitalization, death occurred in 19 (14.3%) patients. The average hospitalization period was 12.2 days. The plasma D-dimer level of the deceased group was significantly higher than that of the survival group (14.7 ± 8.1 vs. 9.0 ± 7.2 &mgr;g/ml, P = 0.003). The in-hospital mortality was significantly higher in patients with plasma D-dimer level of at least 20 &mgr;g/ml than in those with plasma D-dimer level less than 20 &mgr;g/ml (32.3 vs. 7.5%, log rank P < 0.001). In patients not receiving surgical treatment, the in-hospital mortality was significantly higher in patients with plasma D-dimer of at least 20 &mgr;g/ml than that in those with plasma D-dimer less than 20 &mgr;g/ml (52.4 vs. 16.7%, P = 0.007). After adjustment for age, systolic blood pressure, platelet counts, and intervals from symptom onset to hospital, a high admission D-dimer level (≥20 &mgr;g/ml) was still a powerful independent predictor of in-hospital mortality (hazard ratio 3.195, 95% confidence interval 1.110–9.196, P = 0.031). However, the predictive value of high admission D-dimer level disappeared when surgery was added to the Cox multivariate model. Our results suggest a high admission D-dimer level (≥20 &mgr;g/ml) might be a powerful predictor for increased in-hospital mortality in patients with Stanford type A AAD, and these patients may benefit more from surgical intervention.

Orthostatic Blood Pressure Dysregulation and Polymorphisms of β-Adrenergic Receptor Genes in Hypertensive Patients

The genetic susceptibility to orthostatic blood pressure dysregulation remains poorly understood. The association between polymorphisms of beta‐adrenergic receptor (β‐AR) genes and orthostatic blood pressure dysregulation in hypertensive patients was investigated. Two polymorphisms of β1‐AR (Arg389/Gly) and β2‐AR (Arg16/Gly) were genotyped in untreated hypertensive patients and normotensive patients. In patients with untreated hypertension, the frequency of β1‐AR Gly389 homozygote was significantly higher in patients with orthostatic hypotension (OH) (P<.0001) and lower in patients with orthostatic hypertension (OHT) (P=.002) as compared with patients with orthostatic normotension (ONT) even after Bonferroni correction. After analysis by sex and adjustment for conventional risk factors, the β1‐AR Gly389 homozygote conferred about a 3‐fold risk of OH and independently predicted a 6.5 mm Hg greater orthostatic SBP decrease (GG −8.9±13 mm Hg vs CC+CG −2.4±12 mm Hg, P<.001) only in female hypertensive patients. The association of β2‐AR Arg16/Gly with OH was not significant after adjustment for conventional risk factors. In normotensive patients, no association was identified between these two polymorphisms and OHT or OH. These results indicated that the β1‐AR Arg389/Gly polymorphism may be associated with increased risk of OH in female hypertensive patients.

Incidence and predictors of sudden cardiac death in patients with reduced left ventricular ejection fraction after myocardial infarction in an era of revascularisation

Objective To determine the incidence and predictors of sudden cardiac death (SCD) in the current era of revascularisation of myocardial infarction (MI) survivors with reduced LVEF. Methods A prospective observational study was conducted in FuWai Hospital from 2004 to 2009. A total of 1018 consecutive patients who had an LVEF ≤35% and New York Heart Association Class II/III heart failure at least 40 days after MI were enrolled if they were not available for implantation of an implantable cardioverter defibrillator. The degree of coronary artery disease and revascularisation were analysed. The primary outcome was SCD and secondary outcome was all-cause death. Results During a mean follow-up of 2.8 years, the SCD rate was 5% and all-cause mortality was 7.4%. The annual incidence of SCD was 1.8%. Kaplan–Meier analysis showed that the cumulative rate of SCD was significantly increased in patients with triple-vessel disease (6.7% vs 0.6%), left main coronary disease (10.3% vs 4.1%), EF ≤25% (8.3% vs 3.9%) and non-revascularisation therapy (9.6% vs 2.7%) (all log-rank, p<0.05). After multivariable Cox regression analysis, the risk of SCD was predicted by age (HR 1.05, 95% CI 1.02 to 1.09), EF ≤25% (HR 1.82, 95% CI 1.04 to 3.21) and non-revascularisation (HR 3.97, 95% CI 2.15 to 7.31). Conclusions Revascularisation may reduce the risk of SCD in post-MI patients with an LVEF ≤35% on the basis of medical therapy, and the increased risk for SCD may be predicted by age, LVEF ≤25% and non-revascularisation.