The Beneficial Effect of the SGLT2 Inhibitor Dapagliflozin in Alleviating Acute Myocardial Infarction-Induced Cardiomyocyte Injury by Increasing the Sirtuin Family SIRT1/SIRT3 and Cascade Signaling.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have a variety of cardiovascular and renoprotective effects and have been developed as novel agents for the treatment of heart failure. However, the beneficial mechanisms of SGLT2i on cardiac tissue need to be investigated further. In this study, we established a mouse model of acute myocardial infarction (AMI) using coronary artery constriction surgery and investigated the role of dapagliflozin (DAPA) in protecting cardiomyocytes from hypoxic injury induced by AMI. In vitro experiments were done using hypoxic cultured H9c2 ventricular cells to verify this potential mechanism. Expression of the SIRT family and related genes and proteins was verified by qPCR, Western blotting and immunofluorescence staining, and the intrinsic potential mechanism of cardiomyocyte death due to AMI and hypoxia was comprehensively investigated by RNA sequencing. The RNA sequencing results of cardiomyocytes from AMI mice showed that the SIRT family may be mainly involved in the mechanisms of hypoxia-induced cardiomyocyte death. In vitro hypoxia-induced ventricular cells showed the role of dapagliflozin in conferring resistance to hypoxic injury in cardiomyocytes. It showed that SIRT1/3/6 were downregulated in H9c2 cells in a hypoxic environment, and the addition of dapagliflozin significantly increased the gene and protein expression of SIRT1, 3 and 6. We then verified the underlying mechanisms induced by dapagliflozin in hypoxic cardiomyocytes using RNA-seq, and found that dapagliflozin upregulated the hypoxia-induced gene downregulation, which includes ESRRA, EPAS1, AGTRAP, etc., that associated with SIRTs-related and apoptosis-related signaling to prevent H9c2 cell death. This study provides laboratory data for SGLT2i dapagliflozin treatment of AMI and confirms that dapagliflozin can be used to treat hypoxia-induced cellular necrosis in cardiomyocytes, in which SIRT1 and SIRT3 may play an important role. This opens up further opportunities for SGLT2i in the treatment of heart disease.

Prescription Pattern in Angiotensin Receptor Neprilysin Inhibitor is Associated with Heart Failure Events.

Background: Angiotensin receptor neprilysin inhibition (ARNI) is superior to enalapril in reducing the risk of cardiovascular death and heart failure hospitalization (HFH). However, whether prescription pattern is associated with heart failure outcome is unknown. Methods: This is a retrospective study of 153 patients who received ARNI in a tertiary medical center in Taiwan. We analyzed the impact of dose up-titration and prescription timing including during initial admission, within 3 months after initial HFH discharge, and at outpatient clinics without prior HFH. The primary endpoint was the composite of cardiovascular death and HFH. Results: After a mean follow-up period of 287 ± 197 days, the primary endpoint occurred in 43 (28.1%) subjects. Patients without and with a primary endpoint significantly differed in terms of history of valvular heart disease (VHD, p = 0.006), ventricular tachyarrhythmia (VT, p = 0.043), percutaneous coronary intervention (p = 0.007), coronary artery bypass grafting (p = 0.002), chronic kidney disease (p = 0.002), age (p = 0.002), diastolic blood pressure (p = 0.025), and prescription timing (p = 0.002). Kaplan-Meier analysis showed ARNI up-titration and prescription timing had a significant association with primary endpoint-free survival (Breslow test; p = 0.032, and log-rank test; p = 0.001, respectively). Cox regression analysis showed that independent predictors for the primary endpoint were ARNI up-titration [hazard ratio (HR): 0.41, p = 0.024], non-hospital ARNI versus hospital ARNI (HR: 0.41, p = 0.009), VHD (HR: 2.71, p = 0.013), VT (HR: 3.09, p = 0.02), and age (HR: 1.03, p = 0.033). Conclusions: The prescription pattern of ARNI could be associated with heart failure events.

Using CHADS2, R2CHADS2, CHA2DS2-VASc score for mortality prediction in patients with abnormal low and high ankle-brachial index.

Abnormal low and high ankle brachial index (ABI) is regarded as peripheral artery disease (PAD) which has extremely high morbidity and mortality. How to identify high-risk PAD patients with increased mortality is very important to improve the outcome. CHADS2, R2CHADS2, and CHA2DS2-VASc score are clinically useful scores to evaluate the annual risk of stroke in patients with atrial fibrillation. However, there was no literature discussing the usefulness of these scores for cardiovascular (CV) and all-cause mortality prediction in the patients with abnormal ABI. This longitudinal study enrolled 195 patients with abnormal low (< 0.9) and high ABI (> 1.3). CHADS2, R2CHADS2, and CHA2DS2-VASc score were calculated for each patient. CV and all-cause mortality data were collected for outcome prediction. The median follow-up to mortality was 90 months. After multivariate analysis, CHADS2, R2CHADS2, and CHA2DS2-VASc score were significant predictors of CV and all-cause mortality (all P < 0.001). CHA2DS2-VASc score had a better additive predictive value than CHADS2 and R2CHADS2 score for CV mortality prediction. R2CHADS2 and CHA2DS2-VASc score had better additive predictive values than CHADS2 score for all-cause mortality prediction. In conclusion, our study is the first study to investigate the usefulness of CHADS2, R2CHADS2, and CHA2DS2-VASc score for mortality prediction in patients with abnormal ABI. Our study showed all three scores are significant predictors for CV and all-cause mortality although there are some differences between the scores. Therefore, using the three scoring systems may help physicians to identify the high-risk PAD patients with increased mortality.

CHA2DS2-VASc Score and Risk of New-Onset Peripheral Arterial Occlusive Disease in Patients without Atrial Fibrillation.

BACKGROUND: CHA2DS2-VASc score is a useful score to evaluate the risk of stroke in patients with atrial fibrillation (AF), and it has been shown to outperform CHADS2 score. Our recent cross-sectional study showed that CHA2DS2-VASc score was associated with an ankle-brachial index < 0.9. The aim of the current study was to evaluate whether CHA2DS2-VASc score is a useful predictor of new-onset peripheral artery occlusive disease (PAOD) and whether it can outperform CHADS2 and R2CHADS2 scores. METHODS: We used the National Health Insurance Research Database to survey 723750 patients from January 1, 2000 to December 31, 2001. CHADS2, R2CHADS2, and CHA2DS2-VASc scores were calculated for every patient. Finally, 280176 (score 0), 307209 (score 1), 61093 (score 2), 35594 (score 3), 18956 (score 4), 11032 (score 5), 6006 (score 6), 2696 (score 7), 843 (score 8), and 145 (score 9) patients were studied and followed to evaluate new-onset PAOD. We further divided the study patients into six groups: group 1 (score 0), group 2 (score 1-2), group 3 (score 3-4), group 4 (score 5-6), group 5 (score 7-8), and group 6 (score 9). RESULTS: Overall, 24775 (3.4%) patients experienced new-onset PAOD during 9.8 years of follow-up. The occurrence rate of PAOD increased from 1.3% (group 1) to 23.4% (group 6). Subgroup analysis by gender also showed an association between CHA2DS2-VASc score and the occurrence rate of PAOD. After multivariate analysis, groups 2-6 were significantly associated with new-onset PAOD. CHA2DS2-VASc score also outperformed CHADS2 and R2CHADS2 scores for predicting new-onset PAOD. CONCLUSIONS: CHA2DS2-VASc score was a more powerful predictor of new-onset PAOD than CHADS2 and R2CHADS2 scores in patients without AF.

Usefulness of four-limb blood pressure measurement in prediction of overall and cardiovascular mortality in acute myocardial infarction.

Four-limb blood pressure measurement could improve mortality prediction in the elderly. However, there was no study to evaluate whether such measurement was still useful in predicting overall and cardiovascular (CV) mortality in acute myocardial infarction (AMI). Two hundred AMI patients admitted to cardiac care unit were enrolled. The 4-limb blood pressures, inter-limb blood pressure differences, and ankle brachial index (ABI) were measured using an ABI-form device. The median follow-up to mortality was 64 months (25th-75th percentile: 5-174 months). There were 40 and 138 patients documented as CV and overall mortality, respectively. After multivariable adjustment, the ankle diastolic blood pressure (DBP) on the lower side, ABI value, ABI < 0.9, interarm DBP difference, interankle systolic blood pressure (SBP) and DBP differences, interankle SBP difference ≥ 15 mmHg, and interankle DBP difference ≥ 10 mmHg could predict overall mortality (P ≤ 0.025). The ankle DBP on the lower side, interankle DBP difference, and interankle DBP difference ≥ 10 mmHg could predict CV mortality (P ≤ 0.031). In addition, in the Nested Cox model, the model including the ankle DBP on the lower side and the model including interankle DBP difference had the best value for overall and CV mortality prediction, respectively (P ≤ 0.031). In AMI patients, 4-limb blood pressure measurement could generate several useful parameters in predicting overall and CV mortality. Furthermore, ankle DBP on the lower side and interankle DBP difference were the most powerful parameters in prediction of overall and CV mortality, respectively.

Association of renal systolic time intervals with brachial-ankle pulse wave velocity.

Aims: The renal systolic time intervals (STIs), including renal pre-ejection period (PEP), renal ejection time (ET), and renal PEP/renal ET measured by renal Doppler ultrasound, were associated with poor cardiac function and adverse cardiac outcomes. However, the relationship between renal hemodynamic parameters and arterial stiffness in terms of brachial-ankle pulse wave velocity (baPWV) has never been evaluated. The aim of this study was to assess the relationship between renal STIs and baPWV. Methods: This cross-sectional study enrolled 230 patients. The renal hemodynamics was measured from Doppler ultrasonography and baPWV was measured from ABI-form device by an oscillometric method. Results: Patients with baPWV ≧ 1672 cm/s had a higher value of renal resistive index (RI) and lower values of renal PEP and renal PEP/ET (all P< 0.001). In univariable analysis, baPWV was significantly associated with renal RI, renal PEP, and renal PEP/renal ET (all P< 0.001). In multivariable analysis, renal PEP (unstandardized coefficient ß = -3.185; 95% confidence interval = -5.169 to -1.201; P = 0.002) and renal PEP/renal ET (unstandardized coefficient ß = -5.605; 95% CI = -10.217 to -0.992; P = 0.018), but not renal RI, were still the independent determinants of baPWV. Conclusion: Our results found that renal PEP and renal PEP/renal ET were independently associated with baPWV. Hence, renal STIs measured from renal echo may have a significant correlation with arterial stiffness.

Pro-arrhythmogenic Effects of the V141M KCNQ1 Mutation in Short QT Syndrome and Its Potential Therapeutic Targets: Insights from Modeling.

Gain-of-function mutations in the pore-forming subunit of IKs channels, KCNQ1, lead to short QT syndrome (SQTS) and lethal arrhythmias. However, how mutant IKs channels cause SQTS and the possibility of IKs-specific pharmacological treatment remain unclear. V141M KCNQ1 is a SQTS associated mutation. We studied its effect on IKs gating properties and changes in the action potentials (AP) of human ventricular myocytes. Xenopus oocytes were used to study the gating mechanisms of expressed V141M KCNQ1/KCNE1 channels. Computational models were used to simulate human APs in endocardial, mid-myocardial, and epicardial ventricular myocytes with and without ß-adrenergic stimulation. V141M KCNQ1 caused a gain-of-function in IKs characterized by increased current density, faster activation, and slower deactivation leading to IKs accumulation. V141M KCNQ1 also caused a leftward shift of the conductance-voltage curve compared to wild type (WT) IKs (V1/2 = 33.6 ± 4.0 mV for WT, and 24.0 ± 1.3 mV for heterozygous V141M). A Markov model of heterozygous V141M mutant IKs was developed and incorporated into the O'Hara-Rudy model. Compared to the WT, AP simulations demonstrated marked rate-dependent shortening of AP duration (APD) for V141M, predicting a SQTS phenotype. Transmural electrical heterogeneity was enhanced in heterozygous V141M AP simulations, especially under ß-adrenergic stimulation. Computational simulations identified specific IK1 blockade as a beneficial pharmacologic target for reducing the transmural APD heterogeneity associated with V141M KCNQ1 mutation. V141M KCNQ1 mutation shortens ventricular APs and enhances transmural APD heterogeneity under ß-adrenergic stimulation. Computational simulations identified IK1 blockers as a potential antiarrhythmic drug of choice for SQTS.

VLDL from Metabolic Syndrome Individuals Enhanced Lipid Accumulation in Atria with Association of Susceptibility to Atrial Fibrillation.

Metabolic syndrome (MetS) represents a cluster of metabolic derangements. Dyslipidemia is an important factor in MetS and is related to atrial fibrillation (AF). We hypothesized that very low density lipoproteins (VLDL) in MetS (MetS-VLDL) may induce atrial dilatation and vulnerability to AF. VLDL was therefore separated from normal (normal-VLDL) and MetS individuals. Wild type C57BL/6 male mice were divided into control, normal-VLDL (nVLDL), and MetS-VLDL (msVLDL) groups. VLDL (15 µg/g) and equivalent volumes of saline were injected via tail vein three times a week for six consecutive weeks. Cardiac chamber size and function were measured by echocardiography. MetS-VLDL significantly caused left atrial dilation (control, n = 10, 1.64 ± 0.23 mm; nVLDL, n = 7, 1.84 ± 0.13 mm; msVLDL, n = 10, 2.18 ± 0.24 mm; p < 0.0001) at week 6, associated with decreased ejection fraction (control, n = 10, 62.5% ± 7.7%, vs. msVLDL, n = 10, 52.9% ± 9.6%; p < 0.05). Isoproterenol-challenge experiment resulted in AF in young msVLDL mice. Unprovoked AF occurred only in elderly msVLDL mice. Immunohistochemistry showed excess lipid accumulation and apoptosis in msVLDL mice atria. These findings suggest a pivotal role of VLDL in AF pathogenesis for MetS individuals.

Statin Dose and the Risk of Intracerebral Hemorrhage: A Population-Based Longitudinal Study in Taiwan.

BACKGROUND: In the last 15 years, there has been considerable interest in statin use as a means to reduce the likelihood of vascular events. Several clinical trials have shown that high-dose statin (HDS) treatment could reduce vascular events. In high-risk populations, lipid treatment guidelines have generally suggested prescribing statin up to the highest recommended dosage. However, there remains concern about the risk of intracerebral hemorrhage (ICH) with HDS treatment. METHODS: This was a national population-based cohort study from the National Health Insurance Research Database of Taiwan extending from July 2001 to December 2008. Patients with cerebrovascular or cardiovascular disease were enrolled. The HDS group was defined as those patients receiving more than 420 mg per year of atorvastatin or an equivalent potency statin. Moderate dose statin group (MDS) was defined as those patients receiving atorvastatin in amounts between 196-420 mg per year or an equivalent potency statin. Low dose statin (LDS) group was defined as those receiving less than 196 mg per year of atorvastatin or an equivalent statin. The primary endpoint is ICH. The secondary endpoints are myocardial infarction (MI), ischemic stroke (IS) and new-onset DM (NDM). RESULTS: A total of 5459 patients were enrolled in our study, with study participant ages ranging from 62.91 ± 11.85 years and a mean follow-up time of 2039 ± 6 days. After adjusting for age, gender, diabetes and hypertension, Cox regression analysis found ICH risk was lower in HDS and MDS groups compared with LDS (HR 0.49, 95% CI 0.26-0.91, p = 0.0246 and HR 0.45, 95% CI 0.24-0.86, p = 0.0157). The risk of IS is lower in patients with HDS treatment (HR 0.68, 95% CI 0.55-0.83, p < 0.01). However, the risk of MI and NDM incidence are not statistically significant between the different dose groups. CONCLUSIONS: In the real-world data provided by Taiwan's National Health Insurance research database, it was shown that patients who received a higher dose of statin had a reduced and not elevated risk of intracerebral hemorrhage. KEY WORDS: High-dose statin; Hyperlipidemia; Intracerebral hemorrhage; Ischemic stroke; New-onset DM.

Four Statin Benefit Groups Defined by The 2013 ACC/AHA New Cholesterol Guideline are Characterized by Increased Plasma Level of Electronegative Low-Density Lipoprotein.

BACKGROUND: Significantly higher cytotoxic and thrombogenic human electronegative low-density lipoprotein (LDL), or L5, has been found in patients with stable coronary artery disease and acute coronary syndrome. We hypothesized that the statin-benefit groups (SBGs) defined by the new cholesterol guideline were of higher electronegative L5. METHODS: In total, 62 hyperlipidemia patients (mean age 59.4 ± 10.5, M/F 40/22) were retrospectively divided into SBGs (n = 44) and N-SBGs (n = 18). The levels of complete basic lipid panel, biochemical profile and electronegative L5 of each individual were obtained before and after rosuvastatin 10 mg/day for 3 months. RESULTS: After 3 months' statin therapy, significant reduction of total cholesterol, LDL-C and triglyceride were demonstrated (all p-values < 0.05), with 38.4% LDL-C reduction. The percentage of L5 was significantly reduced by 40.9% (from 4.4% to 2.6%) after statin therapy (p = 0.001). Regarding absolute L5 concentration, derived from L5% multiplied by LDL-C, there was approximate 63.8% reduction (from 6.3 mg/dL to 2.3 mg/dL) of absolute L5 (p < 0.001) after statin treatment. Notably, while plasma LDL-C levels were similar between SBGs and N-SBGs (152.8 ± 48.6 vs. 146.9 ± 35.0 mg/dL), the SBGs had significantly elevated L5% (5.2 ± 7.4% vs. 2.6 ± 1.9%, p = 0.031) and higher absolute L5 concentration (7.4 ± 10.4 vs. 3.7 ± 3.1 mg/dL, p = 0.036). Linear regression showed the significantly positive correlation between the plasma L5 concentration and the 10-year cardiovascular risk by pooled cohort equation (r = 0.297, p < 0.05). CONCLUSIONS: The four SBGs defined by the 2013 ACC/AHA new cholesterol guideline tend to have increased atherogenic electronegative L5. Statin therapy can effectively reduce the electronegative L5 of these four major SBGs.

Longitudinal Stent Deformation Caused by Retraction of the Looped Main Branch Guidewire.

A 66-year-old male was treated percutaneously for a bifurcation lesion of the left anterior descending coronary artery by provisional stenting using the jailed wire technique. After successfully stenting the main branch, retraction of the looped main branch guidewire was impossible. After using an intravascular ultrasound we discovered the guidewire was entangled with a stent strut. Thereafter, the proximal stent elongated after retraction. With the support of an over-the-wire microcatheter, we finally pulled out the entrapped guidewire. This rare complication should remind physicians that it is important to prevent the distal guidewire from being looped while retracting it through a stent, regardless of whether it is in the side branch or main vessel. If the guidewire becomes entangled with a stent, a microcatheter or low-profile balloon can be advanced to rescue it before the stent is damaged. Furthermore, the microcather should be maintained after successful retraction of the entangled guidewire to facilitate further wiring and subsequent rescue angioplasty as necessary.

The Current Status of Performing Left Ventriculography in Taiwan.

BACKGROUND: Left ventriculography (LVG) is a gold standard examination of left ventricular function, although it also involves a small but significant risk of complications. However, it was recently reported to be overused in the USA in comparison to an alternative imaging modality. In this study, our aim was to analyze the real-world use of LVG in Taiwan. METHODS: This cohort study analyzed the data in the Taiwan National Health Insurance Bureau database for patients undergoing coronary angiography from 1996-2008. The most recent imaging modalities were used to evaluate left ventricular function including echocardiography and single-photon emission computed tomography (SPECT) within 30-day. The primary outcome was the concomitant use of LVG during coronary angiography. RESULTS: Of 8653 patients who underwent coronary angiography, LVG was performed on 4634 (53.6%) of those study participants. The frequency of LVG use was lower in the groups indicating left ventricular function evaluation, including acute myocardial infarction, heart failure and shock (49.5 vs. 57.1%, p < 0.001). In the population that had undergone a recent left ventricular assessment, the use of LVG was lower (52.2% vs. 54.7%, p = 0.03). Multivariate analysis found that 30-day imaging tests are not a predictor for use of LVG. CONCLUSIONS: In Taiwan, about one half of those patients whose data we reviewed actually received coronary angiography and LVG at the same time. Ultimately, we found that there was no overuse of LVG in those patients with recent alternative imaging modality performed. KEY WORDS: Angiography; Coronary; Ventriculography.

Lipid paradox in acute myocardial infarction-the association with 30-day in-hospital mortality.

OBJECTIVES: Elevated low-density lipoprotein cholesterol and triglycerides are major risk factors for coronary artery disease. However, fatty acids from triglycerides are a major energy source, low-density lipoprotein cholesterol is critical for cell membrane synthesis, and both are critical for cell survival. This study was designed to clarify the relationship between lipid profile, morbidity as assessed by Killip classification, and 30-day mortality in patients with acute myocardial infarction. DESIGN: A noninterventional observational study. SETTING: Coronary care unit in a university hospital. PATIENTS: Seven hundred twenty-four patients with acute myocardial infarction in the coronary care program of the Bureau of Health Promotion were analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Low-density lipoprotein cholesterol and triglyceride levels were significantly lower in high-Killip (III+IV) patients compared with low-Killip (I+II) patients and in those who died compared with those who survived beyond 30 days (both p<0.001). After adjustment for risk factors, low-density lipoprotein cholesterol less than 62.5 mg/dL and triglycerides less than 110 mg/dL were identified as optimal threshold values for predicting 30-day mortality and were associated with hazard ratios of 1.65 (95% CI, 1.18-2.30) and 5.05 (95% CI, 1.75-14.54), and the actual mortality rates were 23% in low low-density lipoprotein, 6% in high low-density lipoprotein, 14% in low triglycerides, and 3% in high triglycerides groups, respectively. To test the synergistic effect, high-Killip patients with triglycerides less than 62.5 mg/dL and low-density lipoprotein cholesterol less than 110 mg/dL had a 10.9-fold higher adjusted risk of mortality than low-Killip patients with triglycerides greater than or equal to 62.5 mg/dL and low-density lipoprotein cholesterol greater than or equal to 110 mg/dL (p<0.001). The lipid paradox also improved acute myocardial infarction short-term outcomes prediction on original Killip and thrombolytic in myocardial infarction scores. CONCLUSIONS: Low low-density lipoprotein cholesterol, low triglycerides, and high Killip severity were associated with significantly higher 30-day in-hospital mortality in patients presenting with acute myocardial infarction. The initial lipid profile of patients with acute myocardial infarction may therefore hold prognostic value.

Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation.

Platelet activation and aggregation underlie acute thrombosis that leads to ST-elevation myocardial infarction (STEMI). L5-highly electronegative low-density lipoprotein (LDL)-is significantly elevated in patients with STEMI. Thus, we examined the role of L5 in thrombogenesis. Plasma LDL from patients with STEMI (n = 30) was chromatographically resolved into 5 subfractions (L1-L5) with increasing electronegativity. In vitro, L5 enhanced adenosine diphosphate-stimulated platelet aggregation twofold more than did L1 and induced platelet-endothelial cell (EC) adhesion. L5 also increased P-selectin expression and glycoprotein (GP)IIb/IIIa activation and decreased cyclic adenosine monophosphate levels (n = 6, P < .01) in platelets. In vivo, injection of L5 (5 mg/kg) into C57BL/6 mice twice weekly for 6 weeks shortened tail bleeding time by 43% (n = 3; P < .01 vs L1-injected mice) and increased P-selectin expression and GPIIb/IIIa activation in platelets. Pharmacologic blockade experiments revealed that L5 signals through platelet-activating factor receptor and lectin-like oxidized LDL receptor-1 to attenuate Akt activation and trigger granule release and GPIIb/IIIa activation via protein kinase C-α. L5 but not L1 induced tissue factor and P-selectin expression in human aortic ECs (P < .01), thereby triggering platelet activation and aggregation with activated ECs. These findings indicate that elevated plasma levels of L5 may promote thrombosis that leads to STEMI.

Anemia as an Independent Predictor of Adverse Cardiac Outcomes in Patients with Atrial Fibrillation.

BACKGROUND: Anemia and echocardiographic systolic and diastolic parameters are useful predictors of cardiovascular outcomes in patients with atrial fibrillation (AF). However, no studies have evaluated the use of anemia for predicting cardiovascular outcome in AF patients when the important echocardiographic parameters are known. Therefore, this study was designed to evaluate whether low hemoglobin is a useful parameter for predicting poor cardiac outcome after adjustment for important echocardiographic parameters in AF patients. METHODS: Index beat method was used to measure echocardiographic parameters in 166 patients with persistent AF. Cardiac events were defined as death and hospitalization for heart failure. The association of hemoglobin with adverse cardiac events was assessed by Cox proportional hazards model. RESULTS: The 49 cardiac events identified in this population included 21 deaths and 28 hospitalizations for heart failure during an average follow-up of 20 months (25th-75th percentile: 14-32 months). Multivariable analysis showed that increased left ventricular mass index (LVMI) and decreased body mass index, estimated glomerular filtration rate, and hemoglobin (hazard ratio 0.827; P = 0.015) were independently associated with increased cardiac events. Additionally, tests of a Cox model that included important clinic variables, LVMI, left ventricular ejection fraction, and the ratio of transmitral E-wave velocity to early diastolic mitral annulus velocity showed that including hemoglobin significantly increased value in predicting adverse cardiac events (P = 0.010). CONCLUSIONS: Hemoglobin is a useful parameter for predicting adverse cardiac events, and including hemoglobin may improve the prognostic prediction of conventional clinical and echocardiographic parameters in patients with AF.

Plasma High-Sensitivity C-Reactive Protein Level is Associated with Impaired Estimated Glomerular Filtration Rate in Hypertensives.

BACKGROUND: Both inflammation and chronic kidney disease (CKD) are related to cardiovascular disease. Whether inflammatory biomarkers are associated with impaired glomerular filtration rate (GFR) is unclear in hypertensives. METHODS: We recruited hypertension patients from the cardiovascular clinic of a tertiary medical center in Taiwan. GFR was calculated using the 7-item Modification of Diet in Renal Disease (MDRD) study equation and impaired GFR (IGFR) was defined as GFR less than 60 ml/min/1.73 m(2). High-sensitivity C-reactive protein (hsCRP) kits were used for the measurement of the CRP levels. RESULTS: In our study, 572 consecutive hypertensive patients were enrolled. The range of patient age was 26-91 years (mean 60.5 ± 11.7), and hsCRP and GFR ranged from 0.01 to 9.99 mg/L and 16.6 to 239.6 ml/min//1.73 m(2), respectively. HsCRP levels were correlated with GFR (p = 0.01) and the presence of IGFR (p = 0.009). Multivariate regression analysis showed hsCRP (p = 0.03), age (p < 0.001) and urinary albumin-to-creatinine ratio (UACR) (p = 0.002) are independent factors associated with GFR. Furthermore, hsCRP levels [odds ratio (OR) = 1.16, 95% CI = 1.03-1.31, p = 0.02], age (OR = 1.09, 95% CI = 1.07-1.12, p < 0.001), and UACR (OR = 1.02, 95% CI = 1.01-1.04, p < 0.001) independently predicted the presence of IGFR using binary logistic regression analysis. CONCLUSIONS: Information obtained from our study showed that hsCRP is associated with IGFR in hypertensives. KEY WORDS: Chronic kidney disease; C-reactive protein; Glomerular filtration rate; Hypertension; Inflammation.

Significant Correlation between Brachial Pulse Pressure Index and Renal Resistive Index.

BACKGROUND: The renal resistive index (RI) is calculated as (peak systolic velocity - minimum diastolic velocity)/peak systolic velocity, and has been significantly associated with renal function. Pulse pressure index (PPI) is derived from a formula similar to renal RI, i.e. (systolic blood pressure - diastolic blood pressure)/systolic blood pressure. The purpose of this study was to investigate whether brachial PPI had a significant correlation with renal RI and could be used in identifying patients with impaired renal function. METHODS: We consecutively enrolled 255 patients referred for echocardiographic examination. The renal RI was measured from Doppler ultrasonography and blood pressure was measured from an ABI-form device. RESULTS: Patients with brachial PPI ≥ 0.428 (mean value of brachial PPI) had a lower estimated glomerular filtration rate (eGFR) than those with brachial PPI < 0.428 (p < 0.001). After the multivariate analysis was completed, brachial PPI had a significant correlation with renal RI (unstandardized coefficient ß = 0.53, p < 0.001). The areas under the curve for brachial PPI and renal RI in prediction of eGFR < 45 mL/min/1.73 m(2) were 0.682 and 0.893 (both p < 0.001), respectively. CONCLUSIONS: Brachial PPI was significantly correlated with renal RI. Patients with higher brachial PPI had a more reduced renal function. Hence, brachial PPI may be able to quickly reflect the intrarenal vascular hemodynamics, and may serve as an important tool for screening and follow-up for patients with abnormal renovascular resistance. KEY WORDS: Chronic kidney disease; Pulse pressure index; Resistive index.

Common quantitative trait locus downstream of RETN gene identified by genome-wide association study is associated with risk of type 2 diabetes mellitus in Han Chinese: a Mendelian randomization effect.

OBJECTIVE: Plasma resistin level is a potential molecular link between obesity and diabetes. Causal role of resistin, type 2 diabetes mellitus (T2DM) and genetic variants have not been thoroughly investigated. Therefore, we conducted a genome-wide association study (GWAS) to identify quantitative trait loci associated with resistin levels and investigated whether these variants were prospectively associated with the development of metabolic syndrome (MetS) and T2DM in an independent community-based cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS). RESEARCH DESIGN AND METHODS: We genotyped 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 chips and searched for quantitative trait loci (QTLs) of resistin in the 1(st) stage GWAS and confirmed the finding in another 559 YOH subjects. Logistic regression was used to examine the Mendelian randomization effects between genotypes of confirmed QTLs and metabolic outcomes in 3400 subjects of CVDFACTS. RESULTS: Two single nucleotide polymorphisms (SNP) (rs3745367 and rs1423096) were significantly associated with resistin levels (p = 5.52 × 10(-15) and p = 2.54 × 10(-20) ) and replicated in another 559 YOH subjects (p = 1.29 × 10(-3) and p = 1.13 × 10(-7) ), respectively. The SNP rs1423096 was further associated with the levels of HDL-C (p = 0.006), the risk of MetS (OR = 2.21, p = 0.0034) and T2DM (OR = 1.62, p = 0.0063) in the CVDFACTS. People with the haplotypes A-G and G-G determined by rs3745367 and rs1423096 showed a significantly increased T2DM risk (p = 0.0068 and p = 0.0035, respectively) compared with those with A-A haplotype. CONCLUSION: We have found that rs3745367 and rs1423096 on the RETN gene were significantly associated with resistin levels. However, rs1423096, downstream of RETN, seems to be associated with MetS and T2DM risk more so than rs3745367. The established genotype-disease association points to a causal association of resistin and T2DM.

The hOGG1 Ser326Cys gene polymorphism and the risk of coronary ectasia in the Chinese population.

Oxidative stress (OS) is related to vascular inflammation possibly, contributing to the development of coronary ectasia (CE). Base excision repair (BER) and nucleotide excision repair are the main DNA repair pathways that can help to remove 8-hydroxydeoxyguanine (8-OHdG), a marker of OS. Human 8-oxoguanine DNA glycosylase 1 (hOGG1) is a key enzyme of the BER pathway and catalyzes the removal of 8-OHdG. The aim of our study was to investigate the association between hOGG1 Ser326Cys gene polymorphism and CE in a Chinese population. Five-hundred forty-seven patients who underwent diagnostic coronary angiography in a tertiary medical center were recruited. The angiographic definition of CE is the diameter of the ectatic segment being more than 1.5 times larger compared with an adjacent healthy reference segment. The gene polymorphisms were analyzed by polymerase chain reaction. The urine 8OHdG concentration was measured using a commercial ELISA kit. The distribution of hOGG1 Ser326Cys genotypes was significantly different between CE and non-CE groups (p = 0.033). The odds ratio of CE development for the Ser to the Cys variant was 1.55 (95% confidence interval (CI), 1.04-2.31, p = 0.033). Both univariate and logistic regression analysis showed a significant association of hOGG1 Ser326Cys polymorphism in the dominant model with CE development (p = 0.009 and 0.011, respectively). Urine 8-OHdG levels were significantly higher in subjects carrying the hOGG1 Ser variant than in those with the Cys/Cys genotype (p < 0.03). In conclusion, our study suggests that the hOGG1 Ser326Cys gene variant might play a role in susceptibility to the development of CE.