Statin therapy in individuals with intermediate cardiovascular risk.

BACKGROUND: As intermediate cardiovascular risk group accounts for a large part of the total population, determining appropriate cholesterol target in this population is critical. Herein, we investigated the optimal low-density lipoprotein cholesterol (LDL-C) level in individuals with intermediate cardiovascular risk after statin therapy. METHODS: This was a nationwide observational and validation cohort study (median duration of follow-up: 7.5 and 8.7 years, respectively), using data from the Korean National Health Insurance Service and a tertiary hospital database. Among individuals who underwent regular health examinations, those with ≥2 cardiovascular risk factors except diabetes mellitus, LDL-C 100-189 mg/dL, and newly used statins were enrolled. Of the 358,694 screened people, 57,594 met the inclusion criteria, of whom 27,793 were finally analyzed. The study population was stratified according to post-treatment LDL-C levels as follows: <100, 100-119, 120-139, and ≥ 140 mg/dL. The primary outcome variable was composite cardiovascular events (myocardial infarction, coronary revascularization, and ischemic stroke). From the patients screened of Severance Hospital cohort, 1859 meeting inclusion criteria were used for validation. RESULTS: The rates of composite events ranged from 7.74 to 9.10 (mean 8.38)/1000 person-years in the three lower LDL-C groups. Adjusted hazard ratios (aHRs) ranged from 0.78 to 0.95 in the three groups with lower LDL-C, and a lower event risk was more evident in the groups that achieved LDL-C levels <120 mg/dL (p = 0.001-0.009). The total mortality risk did not differ between groups. In the validation cohort, the mean rate of composite events was 10.83/1000 person-years. aHRs ranged from 0.52 to 0.78 in the groups with lower LDL-C, and a lower risk was more obvious in patients who achieved LDL-C levels <100 mg/dL (p = 0.006-0.03). CONCLUSIONS: Individuals with intermediate cardiovascular risk who achieved LDL-C levels <120 mg/dL after statin therapy had lower event risk. This result provides clinically useful evidence on target LDL-C levels in this population.

Delayed blood pressure recovery after exercise stress test is associated with autonomic dysfunction and pulse pressure in a middle-aged healthy group.

BACKGROUND: Delayed heart rate (HR) and blood pressure recovery after exercise test is known as the reliable indexes of autonomic dysfunction. Here we tried to evaluate the serial changes in various indicators during exercise test and correlations with recovery of HR and blood pressure in a normotensive healthy middle-aged group. METHODS: A total of 122 patients without hypertension or diabetes was enrolled (mean age, 55.6 ± 11.0; male, 56.6%; mean blood pressure, 124.8 ± 16.6 / 81.5 ± 9.6 mmHg). Treadmill test was performed for evaluation of chest pain. Patients with coronary artery disease, positive treadmill test result, left ventricular dysfunction or renal failure were excluded. Heart rate recovery was calculated by subtracting the HR in the first or second minute of recovery period from the HR of peak exercise (HRR1 or HRR2). Systolic blood pressure in the 4th minute of recovery stage (SBPR4) was used to show delayed blood pressure recovery. RESULTS: Metabolic equivalents (METs) and HR in stage 2 to 4 were significantly correlated with both HRR1 and HRR2. Multiple regression analysis of HRR revealed significant correlation of METs and SBPR4. SBPR4 was significantly correlated with both HRR1 and HRR2 (HRR1, r = -0.376, p<0.001; HRR2, r = -0.244, p = 0.008) as well as SBP in the baseline to stage 3 and pulse pressure (r = 0.406, p<0.001). CONCLUSIONS: Delayed BP recovery after peak exercise test revealed significant association with autonomic dysfunction and increased pulse pressure in normotensive middle-aged healthy group. It can be a simple and useful marker of autonomic dysfunction and arterial stiffness.

The characteristic large-scale annual analysis by gender and age in heart failure patients: cohort for 10 years in Korea.

AIMS: The prevalence and incidence rate of heart failure (HF) continues to increase along with the aging of the population and the increase of ischaemic heart disease. The morbidity and mortality of HF are also on the rise in the industrialized countries; it can be a great public health problem. A detailed and accurate analysis of the demographical incidence and prevalence of HF is an important first step in predicting the occurrence of the disease in the future and proper preparing for prevention. Here, we aimed to analyse the annual prevalence and incidence of HF by gender and age using long-term national health insurance service data in the Republic of Korea. METHODS AND RESULTS: A total of 47 243 patients newly diagnosed with HF between 2006 and 2015 among nationally representative random subjects of 1 000 000 were included. The data of age and gender were analysed by year, and the total population information of the Ministry of Land, Infrastructure, and Transport of Korea was referred to compare the data of HF patients with the total population (2008-15). Over the decade from 2006 to 2015, the prevalence of HF patients showed tendency of increase (P < 0.001). The overall incidence rate was also gradually increasing (P < 0.001), but in women, it tended to decrease gradually. Women significantly accounted higher than the male group in incidence of HF over the period (54.6% vs. 45.4%, P < 0.001). The mean age at the time of diagnosis gradually increased (P = 0.002 for total, P = 0.001 for each gender). Total incidence was highest in 70s (27.22%), but males were the most in their 60s and females were in their 70s. Analysis of annual trend by age and gender distribution of HF incidence in men presented highest in the 50s-70s with a similar pattern annually, and the incidence is increasing more recently. Different from that of men, in the case of women, the incidence gradually increased with age in a similar annual pattern, peaking in their 70s and gradually decreasing in recent years. CONCLUSIONS: The prevalence and incidence of HF are gradually increasing. It increased rapidly in their 50s and older. It showed an increased incidence of HF especially in men between their 50s and 70s, and more observation and caution for the management of the risk factors may be needed to prevent HF in the male group.

A case series: patients with complicated popliteal artery entrapment syndrome successfully treated with a hybrid surgical and interventional treatment.

Background: Popliteal artery entrapment syndrome (PAES) is an underreported and underdiagnosed condition that affects the lower extremities. Previous case reports mainly presented young and uncomplicated PAES. Here, we report the cases of complicated PAES in middle-aged patients. Furthermore, we discuss the importance of a multidisciplinary team approach from diagnosis to treatment to obtain favourable clinical outcomes against this rare disease. Case summary: Two middle-aged patients presented with recent claudication and were diagnosed with popliteal artery obstruction due to a complicated PAES. At the multidisciplinary meeting, the decided treatment plan was to prioritize the gastrocnemius tendon accessory transfer and surgical thromboendarterectomy. In case the popliteal artery patency was unsatisfactory, an additional on-site percutaneous intervention was planned. Follow-up lower extremity computed tomographic angiography showed a patent popliteal artery without any claudication in both two cases. Discussion: Popliteal artery entrapment syndrome is a rare vascular disorder. Clinical suspicion and advanced imaging modalities can lead to an accurate diagnosis. A multidisciplinary team approach helps in obtaining favourable clinical results using minimally invasive hybrid surgical and interventional treatments.

Perioperative Antiplatelet Strategy in Patients Undergoing Noncardiac Surgery Within One Year After Percutaneous Coronary Intervention.

BACKGROUND: The optimal antiplatelet therapy (APT) for patients undergoing non-cardiac surgery within 1 year after percutaneous coronary intervention (PCI) is not yet established. METHODS: Patients who underwent non-cardiac surgery within 1 year after second-generation drug-eluting stent implantation were included from a multicenter prospective registry in Korea. The primary endpoint was 30-day net adverse clinical event (NACE), including all-cause death, major adverse cardiovascular event (MACE), and major bleeding events. Covariate adjustment using propensity score was performed. RESULTS: Among 1130 eligible patients, 708 (62.7%) continued APT during non-cardiac surgery. After propensity score adjustment, APT continuation was associated with a lower incidence of NACE (3.7% vs 5.5%; adjusted odds ratio [OR], 0.48; 95% confidence interval [CI], 0.26-0.89; P = .019) and MACE (1.1% vs 1.9%; adjusted OR, 0.35; 95% CI, 0.12-0.99; P = .046), whereas the incidence of major bleeding events was not different between the 2 APT strategies (1.7% vs 2.6%; adjusted OR, 0.61; 95% CI, 0.25-1.50; P = .273). CONCLUSIONS: The APT continuation strategy was chosen in a substantial proportion of patients and was associated with the benefit of potentially reducing 30-day NACE and MACE with similar incidence of major bleeding events, compared with APT discontinuation. This study suggests a possible benefit of APT continuation in non-cardiac surgery within 1 year of second-generation drug-eluting stent implantation.

Consensus Decision-Making for the Management of Antiplatelet Therapy before Non-Cardiac Surgery in Patients Who Underwent Percutaneous Coronary Intervention With Second-Generation Drug-Eluting Stents: A Cohort Study.

Background Although antiplatelet therapy (APT) has been recommended to balance ischemic-bleeding risks, it has been left to an individualized decision-making based on physicians' perspectives before non-cardiac surgery. The study aimed to assess the advantages of a consensus among physicians, surgeons, and anesthesiologists on continuation and regimen of preoperative APT in patients with coronary drug-eluting stents. Methods and Results A total of 3582 adult patients undergoing non-cardiac surgery after percutaneous coronary intervention with second-generation stents was retrospectively included from a multicenter cohort. Physicians determined whether APT should be continued or discontinued for a recommended period before non-cardiac surgery. There were 3103 patients who complied with a consensus decision. Arbitrary APT, not based on a consensus decision, was associated with urgent surgery, high bleeding risk of surgery, female sex, and dual APT at the time of preoperative evaluation. Arbitrary APT independently increased the net clinical adverse event (adjusted odds ratio [ORadj], 1.98; 95% CI, 1.98-3.11), major adverse cardiac event (ORadj, 3.11; 95% CI, 1.31-7.34), and major bleeding (ORadj, 2.34; 95% CI, 1.45-3.76) risks. The association was consistently noted, irrespective of the surgical risks, recommendations, and practice on discontinuation of APT. Conclusions Most patients were treated in agreement with a consensus decision about preoperative APT based on a referral system among physicians, surgeons, and anesthesiologists. The risk of perioperative adverse events increased if complying with a consensus decision was failed. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03908463.

Clinical Outcomes of Transcatheter Aortic Valve Implantation for Native Aortic Valves in Patients with Low Coronary Heights.

PURPOSE: Acute coronary occlusion is a rare but fatal complication that may occur during trans-catheter aortic valve implantation (TAVI) and appears more frequently in patients with low coronary heights. We evaluated the feasibility of self-expanding valves in patients with low coronary heights undergoing TAVI. MATERIALS AND METHODS: TAVI for native aortic valve stenosis was conducted in 276 consecutive patients between 2015 and 2019 at our institute. Using multi-detector computed tomography (MDCT), information on the aortic valve, coronary arteries, and vascular anatomy in 269 patients was analyzed. Patients with low coronary heights were defined as those with coronary heights of 10 mm or less during MDCT analysis. RESULTS: Among the 269 patients, 29 (10.8%) patients had coronary arteries with low heights. The mean coronary height was 8.9±1.2 mm in the left coronary artery. These patients with low coronary heights were treated with self-expandable (n=28) or balloon-expandable (n=1) valves. Prophylactic coronary protection with a guidewire, balloon, or stent prepositioned down at-risk coronary arteries was not pursued in all patients. No acute coronary occlusion occurred in any of these patients during TAVI. Five patients (17.9%) died during follow-up (average of 553.8 days), including four from non-cardiogenic causes and one from a cardiogenic (aggravation of heart failure) cause. CONCLUSION: A considerable number of patients with low coronary heights were observed among TAVI candidates in this study. Use of a self-expandable valve may be feasible for successful TAVI without acute coronary occlusion in patients with low coronary heights.

Analysis of gait pattern between genders in Korean old people and the effect of dimensionless numbers.

The purpose of this study was to comparatively analyze normal gait on the plains by gender for old people reference data for the normal gait pattern for the old people. Participants were selected according to the Korean standard body type provided by the Ministry of Health and Welfare and used a three-dimensional motion analysis system. Cortex, Orthotrak, and Excel were used as the software for analyzing the extracted data, and IBM SPSS Statistics ver. 24.0 was used for statistical analysis. When data standardization was performed using the dimensionless numbers conversion, the step length and stride length of the lower extremities, which had differences between genders before dimensionless numbers conversion, showed no difference after dimensionless numbers conversion. Cadence, step time, and single support time of the left lower extremity, which had no difference between genders before dimensionless numbers conversion, were found to have significant differences after dimensionless numbers conversion. In addition, as a result of analyzing the coefficient of variation value to find out the degree of change in data due to dimensionless numbers conversion, there were increase and decrease in the coefficient of variation value ranging from -8.11% to 6.67% before and after dimensionless numbers conversion, which means dimensionless numbers conversion can affect the statistical test.

Serum phosphorus levels are associated with carotid intima-media thickness in asymptomatic postmenopausal women.

OBJECTIVE: Serum phosphorous is a significant risk factor for increased carotid intima-media thickness. Increased thickness of the carotid intima is a known cause of cardiovascular disease. Coronary heart disease is a significant cause of mortality and morbidity in postmenopausal women. This study aimed to compare the relationship between serum phosphorous concentration and carotid intima-media thickness in healthy asymptomatic postmenopausal women. METHODS: A retrospective review of the medical records from a health checkup center in Gangnam Severance hospital between March 2007 and September 2017 was conducted. We examined asymptomatic postmenopausal female patients with age range between 56 and 66 (N = 361) who underwent measurement of carotid intima-media thickness by B-mode ultrasonography. The physiological variables analyzed included mean blood pressure, body mass index, renal function (serum creatinine and estimated glomerular filtration rate), cholesterol levels (total cholesterol, triglyceride, and high- and low-density lipoprotein), serum phosphorous, calcium, electrolytes, diabetic status, hypertension, and albumin. RESULTS: Pearson correlation test showed that carotid intima-media thickness was significantly associated with age (r = 0.192, P < 0.001), mean blood pressure (r = 0.116, P = 0.029), diastolic blood pressure (r = 0.146, P = 0.029), serum phosphorous (r = 0.134, P = 0.012), and lactate dehydrogenase (r = 0.106, P = 0.047). On the basis of age-adjusted multivariate linear regression analysis, carotid intima-media thickness was significantly correlated with serum phosphorous levels (ß = 0.273, P = 0.022) in asymptomatic menopausal women. Increased carotid intima-media thickness (cut-off 1.5 mm) was detected, although serum phosphorous was within the normal range (2.8-4.5 mg/dL). CONCLUSIONS: Serum phosphorus concentration is significantly associated with carotid intima-media thickness in asymptomatic menopausal women.

Patterns of Antiplatelet Therapy During Noncardiac Surgery in Patients With Second-Generation Drug-Eluting Stents.

Background Continuing antiplatelet therapy (APT) has been generally recommended during noncardiac surgery, but it is uncertain if preoperative discontinuation of APT has been avoided or harmful in patients with second-generation drug-eluting coronary stents. Methods and Results Patients undergoing noncardiac surgery after second-generation drug-eluting coronary stent implantation were assessed in a multicenter cohort in Korea. Net adverse clinical events within 30 days postoperatively, defined as all-cause death, major adverse cardiac events, and major bleeding, were evaluated. Of 3582 eligible patients, 49% patients discontinued APT during noncardiac surgery. The incidence of net adverse clinical events was comparable between patients with continuation versus discontinuation (4.1% versus 3.4%; P=0.257) of APT during noncardiac surgery. Perioperative discontinuation of APT did not impact on net adverse clinical events (adjusted hazard ratio [HR], 1.00; 95% CI, 0.69-1.44; P=0.995). In subgroup analysis, patients undergoing intra-abdominal surgery were exposed to less risk of major bleeding by discontinuing APT (adjusted HR, 0.26; 95% CI, 0.08-0.91; P=0.035). Prolonged discontinuation of APT for ≥9 days was associated with higher risk of a major adverse cardiac event compared with continuing APT (adjusted HR, 3.38; 95% CI, 1.36-8.38; P=0.009). Conclusions APT was discontinued preoperatively in almost half of patients with second-generation drug-eluting coronary stents. Our explorative analysis showed that there was no significant impact of discontinuing APT on the risk of perioperative adverse events except that discontinuing APT may be associated with decreased hemorrhagic risk in patients undergoing intra-abdominal surgery. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NCT03908463.

A prospective survey of the persistence of warfarin or NOAC in nonvalvular atrial fibrillation: a COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation (CODE-AF).

BACKGROUND/AIMS: Efforts to reduce stroke in patients with atrial fibrillation (AF) have focused on increasing physician adherence to oral anticoagulant (OAC) guidelines; however, the high early discontinuation rate of vitamin K antagonists (VKAs) is a limitation. Although non-VKA OACs (NOACs) are more convenient to administer than warfarin, their lack of monitoring may predispose patients to nonpersistence. We compared the persistence of NOAC and VKA treatment for AF in real-world practice. METHODS: In a prospective observational registry (COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation [CODE-AF] registry), 7,013 patients with nonvalvular AF (mean age 67.2 ± 10.9 years, women 36.4%) were consecutively enrolled between June 2016 and June 2017 from 10 tertiary hospitals in Korea. This study included 3,381 patients who started OAC 30 days before enrollment (maintenance group) and 572 patients who newly started OAC (new-starter group). The persistence rate of OAC was evaluated. RESULTS: In the maintenance group, persistence to OAC declined during 6 months, to 88.3% for VKA and 95.5% for NOAC (p < 0.0001). However, the persistence rate was not different among NOACs. In the new-starter group, persistence to OAC declined during 6 months, to 78.9% for VKA and 92.1% for NOAC (p < 0.0001). The persistence rate was lower for rivaroxaban (83.7%) than apixaban (94.6%) and edoxaban (94.1%, p < 0.001). In the new-starter group, diabetes, valve disease, and cancer were related to nonpersistence of OAC. CONCLUSION: Nonpersistence was significantly lower with NOAC than VKA in both the maintenance and new-starter groups. In only the new-starter group, apixaban or edoxaban showed higher persistence rates than rivaroxaban.

Activities of ankle muscles during gait analyzed by simulation using the human musculoskeletal model.

The purpose of this study was to analyze the activity of ankle muscles during normal gait by simulation method using the human musculoskeletal model. The equipment used in this study was three-dimensional motion capture system and force platform, and OpenSim was used for simulation. Collected data was scaled to Gait2392 that is the human musculoskeletal simulation model using in the OpenSim. Tibialis anterior (TA) worked as a major muscle during gait, producing a higher force than other muscles. Main muscles contributing to propulsion were gastrocnemius medial head (GMH) and soleus (SOL) with their maximum forces appear to be more than 1.5 times the body weight. GMH and SOL showed cooperation for maintaining propulsion around left foot initial contact in the gait cycle. This study has shown a difference between activation and force pattern. The peak-activation of the TA and extensor digitorum longus (EDL) was similarly shown to be around 0.8 in the initial double stance, but the peak-force produced by these muscles in the same period showed a difference with 0.4 Newton/body weight higher in TA than in EDL. We suggest that when assessing muscle contribution to gait, it would be reasonable to consider the force generated because the human movement was generated by the mechanical net force of muscles.

Cost-Effectiveness of Rivaroxaban Compared to Warfarin for Stroke Prevention in Atrial Fibrillation.

BACKGROUND AND OBJECTIVES: Rivaroxaban is noninferior to warfarin for preventing stroke or systemic embolism in patients with high-risk atrial fibrillation (AF) and is associated with a lower rate of intracranial hemorrhage (ICH). We assessed the cost-effectiveness of rivaroxaban compared to adjusted-dose warfarin for the prevention of stroke in patients with nonvalvular AF. METHODS: We built a Markov model using the Korean Health Insurance Review & Assessment Service database. The base-case analysis assumed a cohort of patients with prevalent AF who were aged 18 years or older without contraindications to anticoagulation. RESULTS: Number of patients with CHA2DS2-VASc scores 0, 1 and ≥2 were 56 (0.2%), 1,944 (6.3%) and 28,650 (93.5%), respectively. In patients with CHA2DS2-VASc scores ≥2, the incidence rate of ischemic stroke was 3.11% and 3.76% in warfarin and rivaroxaban groups, respectively. The incidence rates of ICH were 0.42% and 0.15%, and those of gastrointestinal bleeding were 0.32% and 0.15% in warfarin and rivaroxaban, respectively. Patients with AF treated with rivaroxaban lived an average of 11.8 quality-adjusted life years (QALYs) at a lifetime treatment cost of $20,886. Those receiving warfarin lived an average of 11.4 QALYs and incurred costs of $17,151. Patients with rivaroxaban gained an additional 0.4 QALYs over a lifetime with an additional cost of $3,735, resulting in an incremental cost-effectiveness ratio of $9,707 per QALY. CONCLUSIONS: Patients who had been treated with rivaroxaban may be a cost-effective alternative to warfarin for stroke prevention in Korean patients with AF.

A Prospective Survey of Atrial Fibrillation Management for Real-world Guideline Adherence: COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation (CODE-AF) Registry.

BACKGROUND AND OBJECTIVES: The aging population is rapidly increasing, and atrial fibrillation (AF) is becoming a significant public health burden in Asia, including Korea. This study evaluated current treatment patterns and guideline adherence of AF treatment. METHODS: In a prospective observational registry (COmparison study of Drugs for symptom control and complication prEvention of Atrial Fibrillation [CODE-AF] registry), 6,275 patients with nonvalvular AF were consecutively enrolled between June 2016 and April 2017 from 10 tertiary hospitals in Korea. RESULTS: The AF type was paroxysmal, persistent, and permanent in 65.3%, 30.0%, and 2.9% of patients, respectively. Underlying structural heart disease was present in 11.9%. Mean CHA2DS2-VASc was 2.7±1.7. Oral anticoagulation (OAC), rate control, and rhythm control were used in 70.1%, 53.9%, and 54.4% of patients, respectively. OAC was performed in 82.7% of patients with a high stroke risk. However, antithrombotic therapy was inadequately used in 53.4% of patients with a low stroke risk. For rate control in 192 patients with low ejection fraction (<40%), ß-blocker (65.6%), digoxin (5.2%), or both (19.3%) were adequately used in 90.1% of patients; however, a calcium channel blocker was inadequately used in 9.9%. A rhythm control strategy was chosen in 54.4% of patients. The prescribing rate of class Ic antiarrythmics, dronedarone, and sotalol was 16.9% of patients with low ejection fraction. CONCLUSION: This study shows how successfully guidelines can be applied in the real world. The nonadherence rate was 17.2%, 9.9%, and 22.4% for stroke prevention, rate control, and rhythm control, respectively.

Effect of betaine on the hepatic damage from orotic acid-induced fatty liver development in rats.

Betaine prevents hepatic damage caused by ethanol and carbone tetrachloride (CCl4) in rats. Present study was to investigate the effect of betaine on the hepatic microsomal triglyceride transfer protein (MTP) mRNA expression in orotic acid (OA)-induced fatty liver in rats. OA feeding was attributed to the significant increase in the hepatic levels of triglyceride and the serum levels of ALT and AST and resulted in typical histology of fatty liver contained numerous largely fat droplets. While concomitant supplementation of betaine to OA diet was slightly reduced the hepatic triglyceride concentrations and was significantly decreased ALT activity. Hepatic MTP mRNA expression by OA treatment increased by 14% despite triglyceride accumulation in the liver in OA treatment rats relative to rats fed a normal diet without OA supplemented, but MTP expression by simultaneous supplementation of OA and betaine was slightly decreased by 7.9% as compared to the OA-feeding rats. A significant elevation of TBARS contents in the liver homogenate, microsome, and mitochondrial fractions of the OA-feeding rats compared with the normal rats, however, these increases were significantly or slightly decreased by simultaneous addition of OA and betaine. The increases of hepatic OA and betaine levels in OA feeding rats was also found when compared to the normal rats, but these increases were significantly lowered in the concomitant supplementation OA and betaine. The content of Fe was significantly increased in the OA feeding rats, but this elevation showed significantly recovered as low as the normal level by concomitant with OA and betaine. Zinc content was also significantly decreased in the OA feeding rats compared with the normal rats, but this reduction was more significantly elevated by concomitant with OA and betaine. Hepatic glutathione content in the OA feeding rats was similar to that of the normal rats, but this content was slightly reduced without statistically significant differences. But, a significant elevation in the hepatic glutathione content was found in the simultaneously administration OA and betaine. The hepatocytes contained numerous largely fat droplets induced by OA administration and was slightly reduced by simultaneous supplementation of OA and betaine. Present study demonstrated that betaine has a weak preventive action on the OA-induced triglyceride accumulation.

The opposite correlation between calcium ion and cyclic-AMP regarding the activation of microsomal triglyceride transfer protein in rat liver.

In this study, the effects of Ca(2+) and cyclic adenosine monophosphate (cAMP) on microsomal triglyceride (TG) transfer protein (MTP) activity were investigated in rat liver. MTP activity was high when liver contained low levels of cAMP, which was induced by administration of glucose, or high levels of total Ca(2+) and TG. However, MTP activity increased by high levels of Ca(2+) and TG was reduced in a dose-dependent manner by treatment with dibutyryl-cAMP (db-cAMP), a cAMP analogue. Conversely, when homogenates of liver from normal rats, with low levels of total Ca(2+) and high levels of cAMP, were incubated with thapsigargin, a Ca(2+)-inducer, MTP activity was increased in a dose-dependent manner compared to control. Therefore, our results suggest that high levels of Ca(2+) cause hypertriglyceridemia through the elevation of MTP activity, as opposed to high levels of cAMP, which suppress MTP activity and inhibit hypertriglyceridemia.

Inhibitory effects of oligopeptides from hen egg white on both human platelet aggregation and blood coagulation.

Egg white proteins have many biological functions and substantial nutritional benefits when used as a food source; however, they also contain allergens such as ovalbumin, ovomucoid, and ovotransferrin. We prepared oligopeptides without allergens from hen egg whites via the use of several proteases, and assessed their effects on platelet aggregation and blood coagulation, known to both of which are known to be major risk factors in thrombogenesis. Egg white oligopeptides (EWOP) inhibited collagen-induced human platelet aggregation in a dose-dependent manner. Additionally, we attempted to determine whether cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), aggregation-inhibiting intracellular molecules, regulate EWOP-inhibited platelet aggregation. EWOP caused an increase in cAMP levels, but did not affect cGMP levels, which suggests that the anti-platelet activity of EWOP operates in a cAMP-dependent manner, rather than via a cGMP-dependent process, in collagen-induced platelet aggregation. In addition, EWOP induced a significantly prolonged prothrombin time (PT) as compared with the controls. These data show that EWOP inhibits the conversion of fibrinogen to fibrin in a plasmatic atmosphere on an extrinsic pathway. Accordingly, these findings suggest that EWOP may be an excellent candidate as a crucial inhibitor of platelet activation, and its anti-platelet effects appear to involve the inhibition of both platelet aggregation and blood coagulation within the cardiovascular system.

Inhibitory effects of cordycepin (3'-deoxyadenosine), a component of Cordyceps militaris, on human platelet aggregation induced by thapsigargin.

Cordycepin (3'-deoxyadenosine) is an adenosine analog, isolated from Cordyceps militaris, and it has been used as an anticancer and anti-inflammation ingredient in traditional Chinese medicine. We investigated the effects of cordycepin (3'-deoxyadenosine) on human platelet aggregation, which was induced by thapsigargin, a tumor promoter, and determined the cytosolic free Ca2+ levels ([Ca2+]i) (an aggregation-stimulating molecule) and cyclic-guanosine monophosphate (cGMP) (an aggregation-inhibiting molecule). Cordycepin inhibited thapsigargin-induced platelet aggregation in a dose-dependent manner, and it clearly reduced the levels of [Ca+]i, which was increased by thapsigargin (1 microM) or U46619 (3 microM). Cordycepin also increased the thapsigargin-reduced cGMP levels. Accordingly, our data demonstrated that cordycepin may have a beneficial effect on platelet aggregation-mediated thrombotic diseases through the [Ca2+]i-regulating system such as cGMP.

Augmentation of Ca2+-induced microsomal triglyceride transfer protein activity by glucose supply enhances hypertriglyceridemia in vivo.

We have investigated possible roles of intra-glucose supply on microsomal triglyceride (TG) transfer protein (MTP) in the secretion of TG-rich very low-density lipoprotein (VLDL) from the liver. Due to the activation of MTP, TG and apolipoprotein B (apoB) in the liver are assembled into VLDL and then the VLDL is transferred into the blood stream. High MTP activity can increase the release of VLDL into the blood stream, and this would lead high levels of TG and apoB in the blood. High MTP activity was found when the liver (or hepatocytes) contained a high level of total Ca2+ as a response of glucose administration. However, the MTP activity was reduced in response to the calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7, Ki=25 microM), the intracellular Ca2+ chelator BAPTA-AM, and the extracellular Ca2+ chelator EDTA. These suggested that there might be a very close relationship between high MTP activity and high Ca2+ level in the liver by glucose administration. Glucose-derived hyperglycemic condition resulted from those elevations of TG and total cholesterol in the liver. This hyperglycemic phenomenon may be associated with the increase of TG and apoB levels in blood. The possibility for the regulation of VLDL formation in the liver and, further, those related circulatory diseases due to the excess of VLDL in the blood stream by controlling MTP activity in association with Ca2+ was investigated.