High Triglyceride Variability Increases the Risk of First Attack of Acute Pancreatitis.

INTRODUCTION: Hypertriglyceridemia is the third most common etiology of acute pancreatitis. Whether triglyceride variability, independent of absolute triglyceride levels, is a predictor of acute pancreatitis is unknown. METHODS: We identified 98,819 patients who were diagnosed with hyperlipidemia between January 1, 2007, and December 31, 2013, and had at least 1 triglyceride measurement annually for 4 consecutive years from the Chang Gung Research Database in Taiwan. Triglyceride variability, defined as variability independent of the mean, was calculated in the 4-year run-in period. The patients were stratified according to the quartiles of triglyceride variability and were followed until December 31, 2019, for first attack of acute pancreatitis. RESULTS: During a mean follow-up of 5.9 years, 825 (0.83%) patients were newly diagnosed with acute pancreatitis (14.1 events per 10,000 person-years; 95% confidence interval 13.2-15.1). Triglyceride variability was significantly associated with an increased risk of acute pancreatitis, independent of baseline triglyceride and mean triglyceride levels (hazard ratio, 1.28 [95% confidence interval 1.05-1.57] for the highest vs the lowest quartiles of triglyceride variability; P for trend = 0.006 over the quartiles of triglyceride variability). Subgroup analysis showed that this association was more pronounced among the patients with a higher neutrophil-to-lymphocyte ratio ( P for trend = 0.022). DISCUSSION: In this multi-institutional cohort study, high triglyceride variability was associated with an increased risk of first attack of acute pancreatitis, independent of baseline and mean triglyceride levels. The association between triglyceride variability and acute pancreatitis may be partly mediated by subclinical inflammation.

Outcomes of Pulmonary Endarterectomy for Chronic Thromboembolic Pulmonary Hypertension at a Single Center in Taiwan.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is classified as group IV pulmonary hypertension. This study aimed to report our institutional experience in managing CTEPH. METHODS: We prospectively collected the data of 23 patients diagnosed with CTEPH between August 2001 and August 2017 in Linkou Chang Gung Memorial Hospital. Baseline characteristics including functional class (FC), 6-minute walk distance (6MWD), comorbidities, hematological and biochemical data, echocardiography, cardiac catheterization, and selective pulmonary angiography were recorded at diagnosis. All patients were referred to a cardiac surgeon for pulmonary endarterectomy (PEA) assessment. RESULTS: The mean age at diagnosis was 48.4 ± 16.1 years. Nineteen patients (83%) underwent PEA with mean postoperative follow-up of 37.7 ± 42.8 months. The in-hospital mortality rate of PEA was 11%. The 1-, 2-, 3- and 5-year overall survival rates were 89%, 89%, 81%, and 50%, respectively. After 3 months of PEA, all patients had improvements in FC, 6MWD (from 326 ± 62 to 420 ± 63 m), B-type natriuretic peptide level (from 602 ± 599 to 268 ± 565 pg/mL), and systolic pulmonary artery pressure (from 79 ± 19 to 48 ± 19 mmHg). The patients with proximal disease (Jamieson type 1 or 2) had better survival than those with distal disease (Jamieson type 3 or 4), but there was no significant difference in mortality between FC III and IV. All of the four patients who did not undergo PEA survived for more than 3 years. CONCLUSIONS: Significant improvements in symptoms, functional capacity, and hemodynamics were achieved in the CTEPH patients after PEA. However, the overall survival was still unsatisfactory.

Roles of impaired intracellular calcium cycling in arrhythmogenicity of diabetic mouse model.

BACKGROUND: Diabetes mellitus is associated an increased risk of ventricular arrhythmias (VAs), but the underlying electrophysiological mechanisms are not fully explored. This study was aimed to test whether dynamic factors and Cai handling play roles in arrhythmogenesis of a diabetic animal model. METHODS: We used 26 db/db type 2 diabetes mice and 28 control mice in this study. VA inducibility was evaluated in vivo under isoflurane general anesthesia. The intracellular Ca2+ (Cai ) and membrane voltage (Vm ) signals of the Langendorff-perfused mouse hearts were simultaneously recorded using the optical mapping technique. Action potential duration (APD), Cai dynamics conduction velocity (CV), and arrhythmogenic alternans were analyzed. Western blot was conducted to examine expressions of calcium handling and associated ion channels proteins. RESULTS: The diabetic db/db mice showed significantly increased VA inducibility and severity. Longer APD and Cai transient duration and slower Cai decay and CV in the db/db mice than these in the control ones were observed. Dynamic pacing showed increased incidence of spatially discordant alternans leading to more VA inducibility in the db/db mice. Western blot analyses revealed increased phosphorylated-Ca2+ /calmodulin-dependent protein kinase II protein expression and decreased ryanodine receptor protein expression, which probably underlay the molecular mechanisms of enhanced arrhythmogenicity in db/db mice. CONCLUSIONS: The type 2 diabetic mouse hearts show impaired repolarization, Cai handling homeostasis, and cardiac conduction reserve, leading to vulnerability of spatially discordant alternans development and induction of VA. Altered Cai -handling protein expressions probably underlie the molecular mechanisms of arrhythmogenicity in the type 2 diabetes animal model.

Revascularization in Patients With Non-ST Elevation Myocardial Infarction and Advanced Chronic Kidney Disease.

OBJECTIVE: To investigate the impact of revascularization on long-term survival and renal outcome in non-ST-elevation myocardial infarction (NSTEMI) patients with severe chronic kidney disease (CKD). PATIENTS AND METHODS: This study includes NSTEMI patients with an estimated glomerular filtration rate <30 mL/min per 1.73 m2, including those on chronic hemodialysis who were identified from the multicenter Chang Gung Research Database from January 1, 2007, to December 31, 2017. Inverse probability of treatment weighting was used to generate comparable groups. The survival and the risk of progression to chronic hemodialysis between those receiving revascularization, either percutaneous coronary intervention or coronary artery bypass graft, and those receiving medical therapy during index hospitalization were compared. RESULTS: A total of 2821 NSTEMI patients with severe CKD, including 1141 patients on chronic hemodialysis, were identified. Of these, 1149 patients received revascularization and 1672 received medical therapies. The differences in demographics, comorbidities, and presentations between groups were balanced after inverse probability of treatment weighting. After a mean follow-up of 1.82 years, revascularization was associated with a lower risk of all-cause mortality (adjusted HR, 0.61; 95% CI, 0.54-0.70). For non-dialysis-dependent patients who had survival to discharge, revascularization had a higher risk of progression to chronic hemodialysis (adjusted HR, 1.83; 95% CI, 1.49-2.26) after a mean follow-up of 2.3 years. CONCLUSION: Revascularization was associated with a lower risk of all-cause mortality in NSTEMI patients with severe CKD. For non-dialysis-dependent patients who survived to discharge, revascularization was associated with a higher risk of progression to chronic hemodialysis.

Outcomes of Percutaneous Coronary Interventions for Long Diffuse Coronary Artery Disease with Extremely Small Diameter.

BACKGROUND: The optimal percutaneous coronary intervention (PCI) strategy and clinical outcomes of long lesions with an extremely small residual lumen remain unclear. This study aimed to assess the efficacy of a modified stenting strategy for diffuse coronary artery disease (CAD) with an extremely small distal residual lumen. METHODS: 736 Patients who received PCI using second-generation drug-eluting stents (DES) ≥38 mm long were retrospectively included and categorized into an extremely small distal vessel (ESDV) group (≤2.0 mm) and a non-ESDV group (>2.0 mm) according to the maximal luminal diameter of the distal vessel (dsDMax). A modified stenting technique was applied by landing an oversized DES in the distal segment with the largest luminal diameter and maintaining the distal stent edge partially expanded. RESULTS: The mean dsDMax and stent lengths were 1.7 ± 0.3 mm and 62.6 ± 18.1 mm in the ESDV group and 2.7 ± 0.5 mm and 59.1 ± 16.0 mm in non-ESDV groups, respectively. The acute procedural success rate was high in both the ESDV and non-ESDV groups (95.8% and 96.5%, p = 0.70) with rare distal dissection (0.3% and 0.5%, p = 1.00). The target vessel failure (TVF) rate was 16.3% in the ESDV group and 12.1% in the non-ESDV group at a median follow-up of 65 months without significant differences after propensity score matching. CONCLUSIONS: PCI using contemporary DES with this modified stenting technique is effective and safe for diffuse CAD with extremely small distal vessels.

Comparative effectiveness of generic nifedipine versus Adalat long-acting nifedipine for hypertension treatment: A multi-institutional cohort study.

This retrospective multi-institutional database analysis aimed to evaluate the blood-pressure-lowering efficacy and clinical outcomes of a generic versus brand-name nifedipine for hypertension management. A total of 12 693 patients who were prescribed a generic or brand-name nifedipine between January 1, 2011, and December 31, 2018, were identified from the Chang Gung Research Database of Chang Gung Memorial Hospitals, Taiwan. Among them, 2112 (21.4%) were prescribed generic nifedipine. After propensity score matching, both the generic and brand-name groups consisted of 2102 patients. At a mean follow-up of 3 years, the changes in office systolic (p for interaction = .791) and diastolic blood pressure (p for interaction = .689) did not differ significantly between the patients who received the generic and the brand-name nifedipine. There was no significant difference between the two study groups regarding the composite of all-cause mortality, acute myocardial infarction, stroke, coronary revascularization, or hospitalization for heart failure (hazard ratio 0.98, 95% confidence interval 0.85-1.13; p = .774). In conclusion, the generic nifedipine was comparable to its brand-name counterpart regarding office blood pressure reduction and the composite cardiovascular outcome for the treatment of patients with hypertension.

The preferential accumulation of cadmium ions among various tissues in mice.

Cadmium (Cd) is hazardous to human health because of its toxicity and long half-life of clearance. Many studies have explored the relationship between chronic Cd exposure and different human diseases. However, most of the studies limited the study targets of Cd toxicity to two or three organ systems. The goal of this study was to establish a mouse model of Cd accumulation in most organ systems and to particularly investigate the potential toxic effects of Cd to the cardiovascular system. Mice were divided into three groups: the control group, Cd-100 group, and Cd-200 group. In the control group, Cd was detected in the kidney, lung, liver, heart and urine but was undetectable in the aorta, intestine, thigh bone, spinal bone and serum. Upon chronic exposure in the Cd-100 and Cd-200 groups, Cd accumulated in all tissues, with a dramatic increase in concentration. We confirmed that Cd could accumulate significantly in the heart and aorta upon chronic exposure. This finding might help to explain the potential toxic effects of Cd on these organs. In addition, the calcium concentration in the bones and kidney declined when the exposure to Cd increased. This finding aligned with the negative effects of Cd on bony mineralization and the potential direct toxic effects of Cd on bones. The impacts of Cd on the cardiovascular system were explored. Histologically, chronic Cd exposure led to myocytes hypertrophy and myocardial architecture disarray in the Cd-100 group compared to those in the control group. Our research confirms that Cd can accumulate in all of the organs studied upon chronic exposure, and suggests that the toxicity of Cd accumulation may play important roles in mediating the pathophysiologic effects in these target organs, especially the bone and heart.

Association between body mass index and survival in Taiwanese heart failure patients with and without diabetes mellitus.

ABSTRACT: Body mass index (BMI) is positively associated with survival in heart failure (HF) patients with reduced ejection fraction (HFrEF). However, emerging evidence shows that this benefit may not exist in diabetic patients with HFrEF. As this relationship has not been investigated in Asian patients, the aim of this study was to examine the association between obesity and outcomes in HrEFF patients with and without diabetes mellitus (DM), and discuss the potential underlying mechanisms.The analysis included 900 patients with acute decompensated HF from the Taiwan Society of Cardiology-Heart Failure with Reduced Ejection Fraction Registry, of whom 408 had DM (45%). The association between BMI and all-cause mortality was examined using multivariate Cox proportional hazards regression after adjusting for covariates and Kaplan-Meier survival analysis. Echocardiography parameters were also analyzed in patients with different BMI and DM status.After adjusting for confounding factors, BMI was a significant independent predictive factor for all-cause mortality in the non-diabetic patients (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.81-0.95) and in Kaplan-Meier survival analysis (log-rank test, P = .034). For diabetic patients, BMI was not a significant predictive factor for all-cause mortality (HR, 0.96; 95% CI, 0.90-1.02) and in Kaplan-Meier survival analysis (log-rank test P = .169). Both DM (47.8 vs 45.4 mm, P = .014) and higher BMI (48.6 vs 44.9 mm, P < .001) are independently associated with higher left atrial size. Patients with a higher BMI had a lower proportion of severe mitral regurgitation (10.0% vs 14.1%, P < .001).In non-diabetic patients with HFrEF, BMI was a significant predictor of survival. However, in diabetic patients with HF, BMI was not a significant predictor of survival. Diastolic dysfunction in patients with DM and obesity may have played a role in this finding.

Expression and role of lumican in acute aortic dissection: A human and mouse study.

INTRODUCTION: Aortic dissection (AD) is a life-threatening emergency, and lumican (LUM) is a potential Biomarker for AD diagnosis. We investigated LUM expression patterns in patients with AD and explored the molecular functions of Lum in AD mice model. METHODS: LUM expression patterns were analyzed using aortic tissues of AD patients, and serum soluble LUM (s-LUM) levels were compared between patients with acute AD (AAD) and chronic AD (CAD). Lum-knockout (Lum-/-) mice were challenged with ß-aminopropionitrile (BAPN) and angiotensin II (Ang II) to induce AD. The survival rate, AD incidence, and aortic aneurysm (AA) in these mice were compared with those in BAPN-Ang II-challenged wildtype (WT) mice. Tgf-ß/Smad2, Mmps, Lum, and Nox expression patterns were examined. RESULTS: LUM expression was detected in the intima and media of the ascending aorta in patients with AAD. Serum s-LUM levels were significantly higher in patients with AAD than CAD. Furthermore, AD-associated mortality and thoracic aortic rupture incidence were significantly higher in the Lum-/- AD mice than in the WT AD mice. However, no significant pathologic changes in AA were observed in the Lum-/- AD mice compared with the WT AD mice. The BAPN-Ang II-challenged WT and Lum-/- AD mice had higher Tgf-ß, p-Smad2, Mmp2, Mmp9, and Nox4 levels than those of non-AD mice. We also found that Lum expression was significantly higher in the BAPN-Ang II-challenged WT in comparison to the unchallenged WT mice. CONCLUSION: LUM expression was altered in patients with AD display increased s-LUM in blood, and Lum-/- mice exhibited augmented AD pathogenesis. These findings support the notion that LUM is a biomarker signifying the pathogenesis of injured aorta seen in AAD. The presence of LUM is essential for maintenance of connective tissue integrity. Future studies should elucidate the mechanisms underlying LUM association in aortic changes.

Aging effects on glycemic control and inflammation for politicians in Taiwan.

UNLABELLED: Insulin sensitivity is deteriorating with age leading to many metabolic complications, yet fasting glucose is the common metabolic predictor in preventive medicine. In this study we compared the differences in fasting glucose, glucose tolerance, and inflammatory markers between two generations in politically active families. Their physical activity levels and dietary intake amounts were also evaluated. Eight elected councilors and their first order descendents participated in this study. Oral glucose tolerance test (OGTT), insulin, triglyceride, cholesterol, and inflammatory markers including C-reactive protein (CRP) and interleukin-6 (IL-6) were determined. Fasting glucose concentration in politicians was smaller than 100 mg/dL (considered clinically normal), and only approximately 14% concentration difference was observed between two generations. However, all politicians were substantially insulin resistant, compared with their young descendents, evidenced by exaggerated glucose and insulin responses (>100% greater area under curves above baseline) under oral glucose challenged condition. Their waist circumference, diastolic blood pressure, and cholesterol levels were significantly greater than controls. Furthermore, CRP of the politicians was approximately 2.3 folds of the control value suggesting a low grade inflammation. The levels of physical activity and dietary intake were not different between groups. However, the weekly walking energy expenditure for the politician group was approximately 3 times greater than that of the control. CONCLUSION: To reflect the age-dependent metabolic deterioration for the purpose of prevention, OGTT and CRP are far more sensitive measures than fasting glucose value. Greater walking activity in politicians was not sufficient to counterbalance the age-dependent changes.

Clinical outcomes in hypertensive patients treated with a single-pill fixed-dose combination of renin-angiotensin system inhibitor and thiazide diuretic.

Two or more antihypertensive agents are required to achieve blood pressure control for the most hypertensive patients. However, comparison of clinical outcomes between fixed-dose combinations (FDC) and free-equivalent combinations of renin-angiotensin system (RAS) inhibitor and thiazide diuretic is lacking nowadays. Patients who were newly diagnosed with hypertension between July 1st, 2008 and December 31st, 2011 and prescribed with FDC (n = 13 176) or free combinations of RAS inhibitors and thiazide diuretic (n = 4392) were identified from the National Health Insurance Research Database of Taiwan and matched in 3:1 ratio using the propensity score method. The primary end point was major adverse cardiovascular events (MACE). The secondary end points were hospitalization of heart failure, new diagnosis of chronic kidney disease, and the initiation of dialysis. Compared with he FDC group was associated with better medication adherence compared with the free combination group. FDC of RAS inhibitor and thiazide diuretic reduced MACE (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.74-0.97; P = 0.017), hospitalization for heart failure and initiation of dialysis compared with the free combination regimens. The outcome benefits of FDC was mainly driven by reduced cardiovascular and renal events in the patients with proportion of days covered <80%. In this retrospective claims database analysis, compared with the free combination regimens, the use of FDC of RAS inhibitor and thiazide diuretic was associated with improved medication compliance and clinical outcomes in the management of hypertension, particularly in the patients with poor medication adherence.

Improving glucose tolerance by muscle-damaging exercise.

Tissue damage is regarded as an unwanted medical condition to be avoided. However, introducing tolerable tissue damages has been used as a therapeutic intervention in traditional and complementary medicine to cure discomfort and illness. Eccentric exercise is known to cause significant necrosis and insulin resistance of skeletal muscle. The purpose of this study was to determine the magnitude of muscle damage and blood glucose responses during an oral glucose tolerance test (OGTT) after eccentric training in 21 young participants. They were challenged by 5 times of 100-meter downhill sprinting and 20 times of squats training at 30 pounds weight load for 3 days, which resulted in a wide spectrum of muscle creatine kinase (CK) surges in plasma, 48 h after the last bout of exercise. Participants were then divided into two groups according the magnitude of CK increases (low CK: +48% ± 0.3; high CK: +137% ± 0.5, P < 0.05). Both groups show comparable decreases in blood glucose levels in OGTT, suggesting that this muscle-damaging exercise does not appear to decrease but rather improve glycemic control in men. CONCLUSION: The result of the study rejects the hypothesis that eccentric exercise decreases glucose tolerance. Improved glucose tolerance with CK increase implicates a beneficial effect of replacing metabolically weaker muscle fibers by eccentric exercise in Darwinian natural selection fashion.