Wei-Kung Tseng

LDLR and ApoB are Major Genetic Causes of Autosomal Dominant Hypercholesterolemia in a Taiwanese Population

BACKGROUND/PURPOSEnAutosomal dominant hypercholesterolemia (ADH) is an autosomal dominant inherited disease characterized by an increase in low-density lipoprotein cholesterol levels and premature coronary heart disease, which can be caused by mutations in genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9). There is scant information with regard to the role played by each gene in the Taiwanese ADH population, especially the newly discovered PCSK9 gene.nnnMETHODSnWe used coupling heteroduplex analysis based on a denaturing high performance liquid chromatography system and DNA sequencing to screen for the LDLR gene, APOB gene and PCSK9 gene in 87 ADH cases recruited from 30 unrelated Taiwanese families.nnnRESULTSnWe did not find any mutation-causing variant of the PCSK9 gene in our cases and thus excluded PCSK9 as the major culprit mutation in these families. On the other hand, we identified six previously reported LDLR gene mutations (C107Y, D69N, R385W, W462X, G170X, V408M), two novel LDLR gene mutations (FsG631 and splice junction mutation of intron 10), and one known mutation (R3500W) and one novel missense mutation (T3540M) in the APOB gene that were present in 55 members from 18 ADH families (60%). R3500W, rather than R3500Q, could be the principle mutation responsible for familial defective apolipoprotein B in Taiwanese.nnnCONCLUSIONnThe results of our study reveal a characteristic mutation pattern of ADH in Taiwan, mainly in the LDLR and APOB genes. However, PCSK9 gene mutation may not be a major cause of ADH in our study population.

Determinants for Achieving the LDL-C Target of Lipid Control for Secondary Prevention of Cardiovascular Events in Taiwan

Background Epidemiological and clinical studies have clearly established the link between low-density lipoprotein cholesterol (LDL-C) and atherosclerosis-related cardiovascular consequences. Although it has been a common practice for physicians to prescribe lipid-lowering therapy for patients with dyslipidemia, the achievement rate is still not satisfied in Taiwan. Therefore, the determinants for achieving the LDL-C target needed to be clarified for better healthcare of the patients with dyslipidemia. Method This registry-type prospective observational study enrolled the patients with cardiovascular diseases (coronary artery disease (CAD) and cerebrovascular disease (CVD)) from 18 medical centers across Taiwan, and clinically followed them for five years. At every clinical visit, vital signs, clinical endpoints, adverse events, concurrent medications and laboratory specimens were obtained as thoroughly as possible. The lipid profile (total cholesterol, high-density lipoprotein cholesterol, LDL-C, triglyceride), liver enzymes, and creatinine phosphokinase were evaluated at baseline, and every year thereafter. The cross sectional observational data was analyzed for this report. Result Among the 3,486 registered patients, 54% had their LDL-C < 100 mg/dL. By univariate analysis, the patients achieving the LDL-C target were associated with older age, more male sex, taller height, lower blood pressure, more under lipid-lowering therapy, more smoking cessation, more history of CAD, DM, physical activity, but less history of CVD. The multivariate analysis showed statin therapy was the most significant independent determinant for achieving the treatment target, followed by age, history of CAD, diabetes, blood pressure, and sex. However, most patients were on regimens of very-low to low equipotent doses of statins. Conclusion Although the lipid treatment guideline adherence is improving in recent years, only 54% of the patients with cardiovascular diseases have achieved their LDL-C target in Taiwan, and the most significant determinant for this was statin therapy.

Dobutamine stress Echocardiography Compared With Exercise thallium-201 Single-Photon Emission Computed Tomography in Detecting Coronary Artery Disease - Effect of Exercise Level on Accuracy

Dobutamine stress echocardiography (DSE) and exercise thallium-201 single-photon emission computed tomography (SPECT) were compared for the accuracy in detecting coronary artery disease (CAD) in 51 consecutive patients. Twenty-six (group 1) of the 51 patients achieved adequate exercise end points, and 25 (group 2) did not. There were 38 patients with angiographically documented CAD. The overall sensitivity of DSE and thallium-201 SPECT in detecting CAD was 92 and 76% (p = NS), and the specificity was 77 and 77% (p = NS), respectively. The sensitivity of DSE is the same as that of SPECT in group 1 (90 vs. 90%; p = NS) and higher than that of SPECT in group 2 (94 vs. 61%; p < 0.05). In patients with CAD without a history of acute myocardial infarction or pathological Q wave on resting electrocardiogram, the sensitivity of DSE is the same as that of SPECT in group 1 (82 vs. 82%; p = NS) and also higher than that of SPECT in group 2 (90 vs. 40%; p = 0.03). The sensitivity in detecting individual coronary artery lesions with DSE and thallium-201 SPECT was not affected by the exercise level. The agreement between DSE and thallium SPECT in detecting patients with CAD was 88% in group 1 (kappa = 0.69; p < 0.001) and 76% in group 2 (kappa = 0.45; p = 0.01). The agreement in detecting vascular territories with ischemia was 68% in group 1 (kappa = 0.30; p < 0.01) and 75% in group 2 (kappa = 0.33; p < 0.001). The agreement in detecting vascular territories with a scar was 87% in group 1 (kappa = 0.55; p < 0.001) and 85% in group 2 (kappa = 0.44; p < 0.001). In conclusion, the sensitivity and specificity of DSE in detecting CAD are similar to that of thallium-201 SPECT with an exercise level > or =85% of the maximal predicted heart rate. However, in patients who cannot exercise adequately, DSE is more accurate than thallium SPECT. The agreement between DSE and thallium SPECT in detecting patients with CAD and identifying ischemia of individual vascular territories is also affected by the exercise level.

TSOC-HFrEF Registry: A Registry of Hospitalized Patients with Decompensated Systolic Heart Failure: Description of Population and Management

INTRODUCTIONnHeart failure (HF) is a medical condition with a rapidly increasing incidence both in Taiwan and worldwide. The objective of the TSOC-HFrEF registry was to assess epidemiology, etiology, clinical management, and outcomes in a large sample of hospitalized patients presenting with acute decompensated systolic HF.nnnMETHODSnThe TSOC-HFrEF registry was a prospective, multicenter, observational survey of patients presenting to 21 medical centers or teaching hospitals in Taiwan. Hospitalized patients with either acute new-onset HF or acute decompensation of chronic HFrEF were enrolled. Data including demographic characteristics, medical history, primary etiology of HF, precipitating factors for HF hospitalization, presenting symptoms and signs, diagnostic and treatment procedures, in-hospital mortality, length of stay, and discharge medications, were collected and analyzed.nnnRESULTSnA total of 1509 patients were enrolled into the registry by the end of October 2014, with a mean age of 64 years (72% were male). Ischemic cardiomyopathy and dilated cardiomyopathy were diagnosed in 44% and 33% of patients, respectively. Coronary artery disease, hypertension, diabetes, and chronic renal insufficiency were the common comorbid conditions. Acute coronary syndrome, non-compliant to treatment, and concurrent infection were the major precipitating factors for acute decompensation. The median length of hospital stay was 8 days, and the in-hospital mortality rate was 2.4%. At discharge, 62% of patients were prescribed either angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers, 60% were prescribed beta-blockers, and 49% were prescribed mineralocorticoid receptor antagonists.nnnCONCLUSIONSnThe TSOC-HFrEF registry provided important insights into the current clinical characteristics and management of hospitalized decompensated systolic HF patients in Taiwan. One important observation was that adherence to guideline-directed medical therapy was suboptimal.

Localizing Individual Coronary Artery Obstructions with the Dobutamine Stress Echocardiography

The diagnostic accuracy of detecting individual coronary artery lesions using dobutamine stress echocardiography was evaluated in 206 patients with clinical manifestations of agnina pectoris. The sensitivity, specificity, and accuracy in detecting individual coronary artery lesions was described. The sensitivity was higher in the single-vessel group than in the double- or triple-vessel group. Furthermore, the sensitivity of dobutamine stress echocardiography in localizing vascular territories was greater for proximal segment lesions than for distal segment lesions. The increment of total score and score index at peak dose did not reach statistical significance between the left main lesion and the double-vessel lesions of left anterior descending artery and left circumflex artery (4.88 +/- 1.44 vs. 3.79 +/- 0.39, nonsignificant; 0.83 +/- 0.25 vs. 0.54 +/- 0.06, nonsignificant). In conclusion, although dobutamine stress echocardiography is sensitive for diagnosing coronary artery disease, localizing individual coronary artery lesions is less sensitive for triple-vessel disease and distal lesions.

Association of low serum albumin concentration and adverse cardiovascular events in stable coronary heart disease

OBJECTIVEnCoronary heart disease (CHD) is a leading cause of death in developed countries. Exploration of indicators to identify high risk individuals who develop adverse outcomes despite stable baseline condition is important. This study is to evaluate the association between serum albumin concentration and cardiovascular (CV) outcomes in individuals of stable CHD.nnnMETHODSnSeven-hundred-thirty-four participants from Biosignature study, a nationwide prospective cohort study aimed to identity risk factors among patients with stable CHD, were enrolled for analysis. They were divided into low serum albumin group (baseline albumin concentration <3.5g/dL, n=98) and normal albumin group (baseline albumin concentration ≥3.5g/dL, n=636). The relations between baseline albumin and adverse CV outcomes within 18months of follow-up were analyzed.nnnRESULTSnCompared baseline characteristics with normal albumin group, subjects in low albumin group are older, having more diabetic patients, lower hemoglobin level, lower estimated glomerular filtration rate, lower total cholesterol level, lower left ventricular ejection fraction, and higher blood glucose. While there is no significant difference of total CV events between two groups, low serum albumin concentration is associated with an increased risk of all-cause mortality (10.2% vs. 0.5%, p<0.001) and hard CV events (7.1% vs. 1.4%, p<0.001). The association remains significant after adjustments for confounders (all-cause mortality, HR: 6.81, 95% CI: 1.01-45.62; hard CV events, HR: 3.68, 95% CI: 1.03-13.19).nnnCONCLUSIONSnLow serum albumin concentration (<3.5g/dL) worsens prognosis of patients with stable CHD.

The Obesity-Mortality Paradox in Patients With Heart Failure in Taiwan and a Collaborative Meta-Analysis for East Asian Patients

A global heart failure (HF) registry suggested that the inverse association between body mass index (BMI) and all-cause mortality differed by race, particularly stronger in Japanese patients at 1-year follow-up. Whether this finding was consistent across all East Asian populations was unknown. In a multicenter prospective study in Taiwan, we enrolled 1,301 patients hospitalized for systolic HF from 2013 to 2014 and followed up the mortality after their discharge for a median of 1-year period. Cox proportional hazard regression analyses were used to assess the association of BMI with all-cause mortality. The results showed that BMI was inversely associated with all-cause mortality (hazard ratio and 95% CI per 5-kg/m(2) increase: 0.75 [0.62 to 0.91]) after adjusting for demographics, traditional risk factors, HF severity, and medications at discharge. Subsequently, we sought previous studies regarding the BMI association with mortality for East Asian patients with HF from Medline, and a random-effect meta-analysis was performed by the inverse variance method. The meta-analysis including 7 previous eligible studies (3 for the Chinese and 4 for the Japanese cohorts) and the present one showed similar results that BMI was inversely associated with all-cause mortality (hazard ratio 0.65 [0.58 to 0.73], I(2)xa0= 37%). In conclusion, our study in Taiwan and a collaborative meta-analysis confirmed a strong inverse BMI-mortality association consistently among East Asian patients with HF.

The impact of chronic kidney disease on lipid management and goal attainment in patients with atherosclerosis diseases in Taiwan.

Background: Patients with chronic kidney disease (CKD) is a very high risk cardiovascular disease population and should be treated aggressively. We investigated lipid management in CKD patients with atherosclerosis in Taiwan. Methods: 3057 patients were enrolled in a multi-center study (T-SPARCLE). Lipid goal are defined as total cholesterol (TC) < 160mg/dl, low-density lipoprotein (LDL) <100 mg/dl, high-density lipoprotein (HDL) > 40 mg/dl in men, HDL > 50 mg/dl in women, non-HDL cholesterol < 130mg/dl, and triglyceride < 150 mg/dl. Results: Compared with those without CKD (n=2239), patients with CKD (n=818) had more co-morbidities (hypertension, glucose intolerance, stroke and heart failure) and lower HDL but higher triglyceride levels. Overall 2168 (70.5%) patients received lipid-lowering agents. There was similar equivalent statin potency between CKD and non-CKD groups. The goal attainment is lower in HDL and TG in the CKD group as compared with non-CKD subjects (47.1 vs. 51.9% and 63.2 vs. 68.9% respectively, both p < 0.02). Analysis of sex and CKD interaction on goals attainment showed female CKD subjects had lower non-HDL and TG goals attainment compared with non-CKD males (both p < 0.019). Conclusion: Although presenting with more comorbidities, the CKD population had suboptimal lipid goal attainment rate as compared with the non-CKD population. Further efforts may be required for better lipid control especially on the female CKD subjects.

Residual Risk Factors to Predict Major Adverse Cardiovascular Events in Atherosclerotic Cardiovascular Disease Patients with and without Diabetes Mellitus

A prospective observational study was conducted to investigate the residual risk factors to predict recurrence of major adverse cardiovascular events (MACE) in atherosclerotic cardiovascular disease (ASCVD) patients with a high prevalence under lipid-lowering therapy, particularly in the subpopulations of diabetic and nondiabetic individuals. A total of 5,483 adults (with a mean age of 66.4 and 73.3% male) with established coronary heart disease, cerebrovascular disease, or peripheral artery disease were identified from the T-SPARCLE multi-center registry. Of them, 38.6% had diabetes. The residual risk factors for MACE are divergent in these atherosclerotic patients with and without diabetes. In diabetic subpopulation, the risk of MACE was significantly increased with heart failure (HF), chronic kidney disease (CKD) stage 4–5 (vs. stage 1–2), without beta blocker use, and higher non-HDL-C, after controlling for covariates including statin use and the intensity of therapy. Increased LDL-C and TG levels were also associated with increased risk, but to a much less extent. Among nondiabetic individuals, HF, CKD stage 4–5, and history of myocardial infarction were the significant independent predictors of MACE. It is suggested that ASCVD patients with concomitant diabetes need stricter control of lipid, particularly non-HDL-C levels, to reduce cardiovascular risk when on statin therapy.

Identification of new biosignatures for clinical outcomes in stable coronary artery disease - The study protocol and initial observations of a prospective follow-up study in Taiwan

BackgroundEither classic or novel biomarkers have not been well investigated for clinical outcomes of coronary artery disease (CAD) in Asian people especially ethnic Chinese. We reported here a prospective national-based follow-up study that aims to elucidate the clinical profiles and to identify the new biosignatures (especially the non-lipid profile and inflammatory biomakers) for future clinical outcomes in a sizable cohort of stable CAD patients in Taiwan.MethodsA total of 2500 CAD patients under stable condition after successful percutaneous coronary intervention will be enrolled for clinical data collection and blood/urine sampling in northern, southern, western, or eastern part of Taiwan between 2012 and 2017. They will be regularly followed up at least annually for 5xa0years to assess all cause deaths, hard clinical events (including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke), and total cardiovascular events (including hard events, unplanned revascularization procedures, unplanned hospitalization for refractory or unstable angina, and for other causes such as stroke, transient ischemic attack, heart failure, or peripheral arterial occlusive disease). The classic and newly defined biosignatures will be compared in patients with and without clinical events during follow-up. The novel biomarkers will be identified via metabolomics analyses. Additionally, psychological personality and lifestyle data will be incorporated to explore the new dimensional views of the complex mechanisms of the disease. Till December 2014, the initial 1663 patients have been successfully enrolled. Among them, 85.93% are male; 36.22% have type 2 diabetes; 64.82% have hypertension; 56.04% are smokers and 20.44% have a family history of CAD. Their lipid profiles are under contemporary medical control with a mean plasma total cholesterol level of 163.51u2009±u200936.99xa0mg/dL and a mean low-density lipoprotein cholesterol level of 95.21u2009±u200929.98xa0mg/dL.DiscussionThis nationwide study has successfully started to update the contemporary information and to investigate the potential predictors for clinical outcomes of stable CAD patients in Taiwan. The identification of new biomarkers, lifestyle and psychological personality may help to elucidate the complex mechanisms and provide the novel rational to the individual treatment strategies in Asian especially ethnic Chinese patients with CAD.