Cardioprotective Effects of a Phlorotannin Extract Against Doxorubicin-Induced Cardiotoxicity in a Rat Model.

Long-term therapy with doxorubicin (DOX) is associated with high incidence of cumulative and irreversible dilated cardiomyopathy. The goal of this study was to evaluate the cardioprotective effects and safety of a phlorotannin extract from a brown algae Ecklonia cava (Seapolynol™, SPN) against DOX-induced cardiotoxicity in a rat model. A total of 42 rats were divided into six groups: control, low-dose SPN (LDS), high-dose SPN (HDS), DOX, DOX with low-dose SPN (DOX+LDS), and DOX with high-dose SPN (DOX+HDS). Echocardiography was performed at baseline and after 6 weeks. In left ventricular (LV) ejection fraction, DOX and DOX+LDS groups showed significant decreases (P < .001), while LDS, HDS, and DOX+HDS groups showed no significant change compared with control group. In LV mass index, DOX and DOX+LDS groups showed significant increases (P < .001 and P = .013), while LDS, HDS, and DOX+HDS groups showed no significant change compared with control group. In electron microscopy of the LV wall tissue, DOX+HDS group showed markedly less impaired myofibrils and mitochondria compared with both DOX and DOX+LDS groups. On the findings in echocardiography and electron microscopy, 6-week oral administration of SPN was safe and cardioprotective in a DOX-induced rat cardiotoxicity model in a dose-dependent manner.

Efficacy and Tolerability of Combination Therapy Versus Monotherapy with Candesartan and/or Amlodipine for Dose Finding in Essential Hypertension: A Phase II Multicenter, Randomized, Double-blind Clinical Trial.

PURPOSE: Intensive blood pressure (BP) lowering is important for the treatment of hypertension; however, it has been a challenge to achieve target BP in many patients. The purpose of this study was to explore the optimal dosage of a fixed-dose combination of candesartan cilexetil (CAN) and amlodipine besylate (AML), by examining the tolerability and efficacy of CAN/AML combination therapy compared with those of monotherapy with either drug in patients with essential hypertension. METHODS: This Phase II multicenter, randomized, double-blind clinical trial enrolled patients aged 19 years or older with essential hypertension, defined as a mean sitting diastolic BP (msDBP) between 95 and 115 mm Hg, and a mean sitting systolic BP (msSBP) of <200 mm Hg after a 2-week placebo run-in period. A total of 635 patients were screened, of whom 439 were randomized to receive treatment; 425 patients were included in the full analysis set (combination therapy, 212; monotherapy, 213). Participants were randomly assigned to receive 1 of 8 treatments: CAN (8 or 16 mg), AML (5 or 10 mg), CAN/AML (8 mg/5 mg, 8 mg/10 mg, 16 mg/5 mg, or 16 mg/10 mg), once daily for 8 weeks. FINDINGS: After 8 weeks of treatment, changes in msDBP were significantly greater in the groups receiving CAN/AML combination therapies compared with monotherapies at matched doses, with the exception of CAN 8 mg/AML 10 mg versus AML 10 mg. The response to treatment and the achievement of target BP (both msSBP and msDBP) at week 8 were significantly greater overall in the groups that received combination therapy versus monotherapy. All medications were relatively well tolerated in each group. IMPLICATIONS: Eight-week administration of CAN/AML (8 mg/5 mg, 16 mg/5 mg, and 16 mg/10 mg) resulted in a significantly greater BP reduction than that with CAN or AML monotherapy, and was determined to be well tolerated. ClinicalTrials.gov identifier: NCT02944734.

Three-year patient-related and stent-related outcomes of second-generation everolimus-eluting Xience V stents versus zotarolimus-eluting resolute stents in real-world practice (from the Multicenter Prospective EXCELLENT and RESOLUTE-Korea Registries).

Long-term outcomes are imperative to confirm safety of drug-eluting stents. There have been 2 randomized controlled trials comparing everolimus-eluting stents (EESs) and Resolute zotarolimus-eluting stents (ZES-Rs). To date, long-term clinical outcomes of these stents were limited to only 1 report, which has recently reported 4-year comparisons of these stents. Therefore, more evidence is needed regarding long-term clinical outcomes of the second-generation stents. This study compared the long-term clinical outcomes of EES with ZES-R in "all-comer" cohorts up to 3-year follow-up. The EXCELLENT and RESOLUTE-Korea registries prospectively enrolled 3,056 patients treated with EES and 1,998 with ZES-R, respectively, without exclusions. Stent-related composite outcomes (target lesion failure) and patient-related composite events up to 3-year follow-up were compared in crude and propensity score-matched analyses. Of 5,054 patients, 3,830 patients (75.8%) had off-label indication (2,217 treated with EES and 1,613 treated with ZES-R). The stent-related outcome (189 [6.2%] vs 127 [6.4%], p = 0.812) and the patient-related outcome (420 [13.7%] vs 250 [12.5%], p = 0.581) did not differ between EES and ZES-R, respectively, at 3 years, which was corroborated by similar results from the propensity score-matched cohort (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.70 to 1.20, p = 0.523 and 0.85, 95% CI 0.70 to 1.02, p = 0.081, for stent- and patient-related outcomes, respectively). The rate of definite or probable stent thrombosis up to 3 years (22 [0.7%] vs 10 [0.5%], p = 0.370) was also similar. The rate of very late definite or probable stent thrombosis was very low and comparable between the 2 stents (3 [0.1%] vs 1 [0.1%], p = 0.657). In multivariate analysis, chronic renal failure (adjusted HR 3.615, 95% CI 2.440 to 5.354, p <0.001) and off-label indication (adjusted HR 1.782, 95% CI 1.169 to 2.718, p = 0.007) were the strongest predictors of target lesion failure at 3 years. In conclusion, both stents showed comparable safety and efficacy at 3-year follow-up in this robust real-world registry with unrestricted use of EES and ZES-R. Overall incidences of target lesion failure and definite stent thrombosis, including very late stent thrombosis, were low, even in the patients with off-label indications, suggesting excellent long-term safety and sustained efficacy of both types of second-generation drug-eluting stents.

Correlations between the level of high-sensitivity C-reactive protein and cardiovascular risk factors in Korean adults with cardiovascular disease or diabetes mellitus: the CALLISTO study.

AIM: We assessed the relationship between the level of high-sensitivity C-reactive protein (hsCRP) and cardiovascular risk factors in Korean adults. METHODS: We reviewed 1,561 patients with cardiovascular disease or diabetes mellitus with hsCRP levels measured within the past year. Four cardiovascular risk groups were determined: low (<10%, 0-1 risk), moderate (<10%, >2 risk), high (10-20%) and very high (>20%) risk, according to the number of risk factors and the Framingham/NCEP ATP III risk score. The correlations between the hsCRP level and cardiovascular risk factors (age, smoking, hypertension, lipid profiles and familial history of premature coronary heart disease) were investigated. RESULTS: The mean and median hsCRP (mg/L) levels were 1.32 ± 9.69 and 0.29 (range: 0.01-7.48), respectively. Men had a higher median level of hsCRP than women (p<0.001). The levels of hs CRP significantly increased from the low to the very high risk group (0.15, 0.23, 0.27 and 0.47, respectively) and were significantly correlated with age, the level of glycosylated hemoglobin, body mass index (BMI), the level of high-density lipoprotein cholesterol (HDL-C), the low-density lipoprotein cholesterol (LDL-C)/HDL-C ratio, the LDL-C/total cholesterol (TC) ratio, the HDL-C/TC ratio, the HDL-C/triglyceride (TG) ratio and the TC/TG ratio. Neither smoking, the LDL-C level nor the TG level affected the hsCRP level. In a multivariate regression analysis, age, the HDL-C level, the LDL-C/TC ratio and BMI were found to be independently correlated with the hsCRP level. CONCLUSIONS: There is a significant relationship between the degree of cardiovascular risk and the hsCRP level in Korean adults with cardiovascular disease or diabetes mellitus. Assessing the hsCRP levels may thus provide additive value in predicting cardiovascular risks.

Randomized trial comparing the efficacy between different types of paclitaxel-eluting stents: the comparison of efficacy between COroflex PLEASe ANd Taxus stent (ECO-PLEASANT) randomized controlled trial.

AIMS: Paclitaxel-eluting stents (PESs) have been shown to inhibit neointimal hyperplasia after percutaneous coronary intervention. Coroflex Please (B Braun, Melsungen, Germany) is a newly developed PES. We compared the clinical and angiographic efficacy of Coroflex Please with Taxus Liberte (Boston Scientific, Natick, MA) in a real-world practice. METHODS AND RESULTS: We performed a prospective, open-label, randomized, controlled study that enrolled 945 patients undergoing percutaneous coronary interventions in 18 centers in Korea. The primary end point was clinically driven target vessel revascularization at 9 months. The baseline characteristics were mostly similar and comparable between 2 groups. At 9 months, the incidence of clinically driven target vessel revascularization was 14.6% for Coroflex and 6.4% for Taxus, which was significantly different (hazard ratio 2.43, 95% CI 1.50-3.94, noninferiority P value = 1.000). This is well corroborated by the difference of in-stent late loss between 2 stents (0.71 ± 0.64 mm vs 0.52 ± 0.50 mm, P < .001) by 9-month follow-up angiography (n = 415 vs 215). Among secondary clinical end points, stent thrombosis (definite and probable) for 1 year was 2.2% in Coroflex and 1.3% in Taxus (P = .317). Also, myocardial infarction for 9 months was higher in Coroflex group than that in Taxus (4.9% vs 1.6%, P = .012), which was partly contributed by the higher incidence of periprocedural myocardial infarction in Coroflex arm (2.2% vs 0.3%, P = .028). CONCLUSIONS: Coroflex Please was inferior to Taxus Liberte with regard to clinical and angiographic efficacy.

Left atrial eccentricity in chronic mitral regurgitation: relation to left atrial function.

AIMS: The aim of this study was to assess the changes in the left atrial (LA) shape and to identify the determinants of these changes in chronic mitral regurgitation (MR). METHODS AND RESULTS: We enrolled 125 consecutive patients (56 ± 16 years, 51% men) with chronic MR caused by myxomatous mitral valve disease in sinus rhythm and 45 control patients (54 ± 15 years, 55% men) undergoing transthoracic Doppler echocardiography. The LA eccentricity index (LAEi) and the LA volume index (LAVi) were used to estimate the LA shape and size, respectively. There were significant decreases in LAEi (r= -0.723, P< 0.001) and increases in LAVi (r= 0.642, P< 0.001) with increasing severity of MR. In multivariate stepwise linear regression analysis, regurgitant fraction (RF) was an independent determinant of the LAE, whereas RF, left ventricular (LV) mass index and LV diastolic dysfunction grade were independent determinants of the LA volume. The LAEi was positively related to the velocity of A' in the entire population (r = 0.238, P = 0.002). On the receiver operating characteristic (ROC) curve analysis, LAEi ≤1.30 was the best cut-off value to reflect the LA systolic dysfunction (A' velocity <7 cm/s; area under the curve was 0.78, P < 0.001). CONCLUSION: LA becomes more spherical with increasing severity of MR, suggesting a decrease in LAE, which is mainly determined by the volume overload. LAE might be closely related to the LA systolic function in chronic MR.

Effects of Ecklonia cava polyphenol in individuals with hypercholesterolemia: a pilot study.

We evaluated the efficacy and safety of Ecklonia cava polyphenol (Seapolynol™, a polyphenol antioxidant and anti-inflammatory agent purified from E. cava) during a 12-week treatment period (400 mg orally once daily) in individuals with hypercholesterolemia and performed subgroup analysis for metabolic syndrome (MetS). As a noncomparative study, forty-six individuals (M:F=22:24, mean age=54±11 years) with fasting total cholesterol concentration >240 mg/dL or low-density lipoprotein cholesterol (LDL-C) concentration >130 mg/dL were enrolled. Hip circumference (100±7 cm vs. 98±7 cm, P<.01), total cholesterol (244±25 mg/dL vs. 225±37 mg/dL, P<.01), LDL-C (161±24 mg/dL vs. 146±34 mg/dL, P<.01), and C-reactive protein (2.51±3.55 mg/L vs. 1.37±1.32 mg/L, P<.05) were significantly decreased without significant adverse effect. A differential assessment according to the presence [MetS(+) group, n=18] and absence [MetS(-) group, n=28] of MetS showed that Hb(A1c) decreased significantly following 12-week Seapolynol treatment in the MetS(+) compared with the MetS(-) group (-0.3%±0.5% vs. 0.1%±0.3%, P<.01). In conclusion, although our results showed that Seapolynol treatment is effective and safe without significant adverse events or abnormal laboratory findings during a 12-week period in individuals with hypercholesterolemia, more research in a larger population with a longer-term follow-up period in a randomized placebo-controlled study is needed to confirm the results.

Coronary flow reserve is a comprehensive indicator of cardiovascular risk factors in subjects with chest pain and normal coronary angiogram.

BACKGROUND: The aim of the present study was to analyze the parameters related to baseline coronary flow velocity (CFV) and coronary flow reserve (CFR) using Doppler transthoracic echocardiography (TTE), and to assess their associations with components of the Framingham risk score (FRS), which estimates 10-year risk of coronary heart disease, in subjects with chest pain and a normal coronary angiogram. METHODS AND RESULTS: A total of 354 individuals (mean age: 55+/-11 years, M:F ratio =186:168) with angina or angina-like chest pain and a normal coronary arteriogram were enrolled. CFR, using TTE and adenosine or dipyridamole, was measured within 2 weeks after coronary angiogram. The clinical, electrocardiographic, echocardiographic and laboratory parameters related to baseline CVF and CFR were analyzed, and CFR was compared with FRS. There was an inverse correlation between baseline CFV and CFR (r=-0.374, P<0.001). On multivariate analysis the fulfilling of left ventricular hypertrophy criteria on electrocardiography was an independent predictor of baseline CFV for the upper 75% quartile (23.2> or =cm/s; odds ratio (OR) = 2.840, 95% confidence interval (CI) =1.155-6.983, P=0.023). On multivariate analysis hemoglobin A(1c) level was independently related to a CFR <2.0 (OR = 2.195, 95%CI = 0.920-1.005, P=0.013). CFR had an inverse correlation with FRS (r=-0.222, P<0.001). On multiple regression analysis among the components of the FRS system (FRSS), independent factors related to a CFR <2.0 included age (OR =1.033, 95%CI =1.000-1.067, P=0.041), high-density lipoprotein-cholesterol level (OR = 0.961, 95%CI = 0.933-0.991, P=0.012) and smoking status (OR = 2.461, 95%CI =1.078-5.618, P=0.033), respectively. CONCLUSIONS: CFR can be a comprehensive indicator of cardiovascular risk factors, including parameters of the FRSS, in subjects with chest pain and a normal coronary angiogram.

Prevalence and risk factors for aspirin and clopidogrel resistance in patients with coronary artery disease or ischemic cerebrovascular disease.

The objective of this study was to identify possible risk factors associated with a lack of response to aspirin and clopidogrel treatments in patients with coronary or cerebral ischemic artery disease. A point-of-care analyzer, VerifyNow (Accumetrics, San Diego, CA), was used to measure adenosine-5-diphosphate and platelet P2YI2 receptor blockage to investigate the responses of a group of 197 patients to aspirin and/ or clopidogrel therapies (aspirin therapy, 178; clopidogrel therapy, 139; both drugs, 144). Of these 197 patients, 135 (68.5%) had coronary artery disease and 72 (31.5%) had ischemic cerebrovascular disease. Aspirin resistance was defined as an ARU (aspirin reaction units) > or =550, and clopidogrel resistance was defined as platelet inhibition <20%. Twenty-five of 178 aspirin users (14.0%) were resistant to aspirin, and 54 of 139 (38.8%) clopidogrel users were resistant to clopidogrel. The data indicate that low hemoglobin (Hb) level in aspirin users and high systolic and diastolic blood pressures in clopidogrel users are significantly related to treatment resistance (p < 0.05). The latter finding is possibly due to the greater adhesiveness and increased aggregability of platelets in hypertensive patients.

Comparison of efficacy and tolerability of amlodipine orotate versus amlodipine besylate in adult patients with mild to moderate hypertension: a multicenter, randomized, double-blind, placebo-controlled, parallel-group, 8-week follow-up, noninferiority trial.

OBJECTIVE: The purpose of this study was to compare the efficacy and tolerability of amlodipine orotate with those of amlodipine besylate in Korean patients with mild to moderate hypertension. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was designed as a noninferiority study. To be included in the study, previously untreated patients had to have a sitting diastolic blood pressure (SiDBP) of 90 to 109 mm Hg. Previously treated patients had to discontinue their current annhypertensive medications and have a baseline SiDBP between 90 and 109 mm Hg after a 2-week washout period. Patients who met the inclusion criteria were randomly assigned to receive 5 mg amlodipine orotate or 5 mg amlodipine besylate for 8 weeks. The medication dose was doubled (10 mg QD for either amlodipine orotate or amlodipine besylate) 4 weeks after enrollment if SiDBP was >or=90 mm Hg. The primary efficacy analysis was noninferiority of the difference in mean trough SiDBP changes from baseline for amlodipin eorotate as compared with amlodipine besylate after 8 weeks of treatment. For the secondary efficacy analysis, 2 other measures were analyzed after 8 weeks of treatment. The SiDBP response rate was defined as an SiDBP measurement<90 mm Hg at the last clinical follow-up visit or an absolute reduction of >or=10 mm Hg in SiDBP from baseline until the last clinical follow-up visit. In addition, noninferiority of the difference in mean trough sitting systolic blood pressure (SiSBP) changes from baseline was analyzed for amlodipine orotate as compared with amlodipine besylate. The drug compliance rate was estimated by pillcount. RESULTS: Eligible patients (n=109; 43 women and 66 men) were randomly assigned to receive amlodipine orotate (n=53) or amlodipine besylate (n=56). No significant differences were found in sex, age, weight, or current smoking between the groups (all, P=NS). The proportion of patients with previous antihypertensive medications was not different between the groups (47.2% [25/53] in the amlodipine orotate group and 50.0% [28/56] in the amlodipine besylate group; P=NS). No significant differences were found in baseline SiDBP (mean [SD], 100 [6] mm Hg [range, 90-109 mm Hg] in the amlodipine orotate group and 100 [6] mm Hg [range, 90-108 mm Hg] in the amlodipine besylate group; P=NS) or in baseline SiSBP (mean [SD], 149 [14] mm Hg [range, 125-179 mm Hg] in the amlodipine orotate group and 146 [10] mm Hg [range, 123-167 mm Hg] in the amlodipine besylate group; p=NS). The mean (SD) changes in SiDBP were -15.6 (6.3) mm Hg for the amlodipine orotate group and -14.5 (5.5) mm Hg for the amlodipine besylate groups was 1.1 (5.9) mm Hg (95% CI, -0.87 to infinity), and because the lower boundary of the 95% CI was greater than -5 mm Hg, amlodipine orotate was considered noninferior to amlodipine besylate. The response rate was 48 of 51 (94.1%) in the amlodipine orotate group compared with 50 (92.6%) of 54 in the amlodipine besylate group after 8 weeks of treatment (P=NS). The mean (SD) compliance rates were 97.6% (3.6%) in the amlodipine orotate group and 96.5% (4.3%) in the amlodipine besylate group (P=NS). The incidence of drug-related adverse events (AEs) was similar between the groups (1/53 [1.9%]) in the amlodipine orotate group vs 4/55 [7.3%] in the amlodipine besylate group; P=NS). The most common drug-related AE overall was peripheral edema (2/55 [3.6%]), and the most common of all the AEs was upper respiratory tract infection (4/55 [7.3%]) in the amlodipine besylate group. The most common drug-related AE was headache (1/53 [1.9%]) in the amlodipine orotate group and peripheral edema (2/55 [3.6%]) in the amlodipine besylate group. No severe AEs were found in either group. CONCLUSION: The reduction in SiDBP after 8 weeks of amlodipine orotate treatment was noninferior to that of amlodipine besylate in these Korean patients with mild to moderate hypertension. The SiDBP response rate and the reduction in SISBP after 8 weeks of amlodipine orotate treatment were not significantly different from those of amlodipine besylate treatment. Both agents were wel tolerated.

Relation between flow reserve capacity of penetrating intramyocardial coronary arteries and myocardial fibrosis in hypertension: study using transthoracic Doppler echocardiography.

OBJECTIVE: The purpose of this study was to compare coronary flow reserve (CFR) capacity of penetrating intramyocardial coronary artery (PICA) using transthoracic Doppler echocardiography and biochemical marker of myocardial fibrosis in hypertension (HTN). METHODS: In 58 patients (male:female ratio = 31:27; mean age 47 +/- 9 years) with chest pain and normal coronary angiogram findings, the width of color Doppler signal and peak diastolic velocity of PICA flow were measured in the myocardium just beneath the apical impulse window using transthoracic Doppler echocardiography. PICA-CFR and PICA-width ratio were calculated as the ratio of hyperemic to baseline peak diastolic velocity and as the ratio of hyperemic to baseline width after the adenosine infusion (140 mug/kg/min), respectively. Serum carboxy-terminal propeptide of procollagen type I, as a biochemical marker, was measured and patients were divided into 3 groups: 19 with HTN and PICA-CFR less than 2.0 (group A); 23 with HTN and PICA-CFR of 2.0 or more (group B); and 16 who were normotensive with PICA-CFR of 2.0 or more (group C). RESULTS: Baseline peak diastolic velocity for group A was higher than the other two groups (P < .005 vs groups B and C). PICA-width ratio was higher than the other two groups (P < .005 vs groups B and C). Serum propeptide of type I was 137.1 +/- 16.6 ng/mL in group A, 96.2 +/- 13.7 ng/mL in group B, and 78.8 +/- 11.2 ng/mL in group C (P < .0001 vs group B and group C). PICA-CFR was closely related to serum propeptide of type I (P < .001, r = -0.723). CONCLUSION: The impaired PICA-CFR is related to myocardial fibrosis in patients with HTN, chest pain, and normal coronary angiogram results.

The impaired flow reserve capacity of penetrating intramyocardial coronary arteries in apical hypertrophic cardiomyopathy.

BACKGROUND: Coronary flow reserve (CFR) capacity of penetrating intramyocardial coronary artery (PICA) in apical hypertrophic (AH) cardiomyopathy has not been studied yet. METHODS: We studied 65 patients with normal coronary angiogram results (mean age 56 +/- 10 years; 33 men, 32 women). Of these, 30 were normotensive without any left ventricular hypertrophy (control group), 24 had hypertension (HTN) without any left ventricular hypertrophy (HTN group), and 11 had AH cardiomyopathy (AH group). PICA-CFR and PICA-width ratio were calculated after the intravenous infusion of adenosine (140 microg/kg/min) just beneath the apical impulse window at a depth of 3 to 5 cm by using high-frequency transthoracic Doppler echocardiography. RESULTS: PICA-CFR was successfully measured in 59 (90.8%) of 65 patients. PICA-CFR was 1.65 +/- 0.49 in AH group, 2.50 +/- 0.77 in HTN group, and 2.42 +/- 0.73 in control group ( P < .005 vs HTN and control). PICA-width ratio was 1.45 +/- 0.42 in AH group, 2.14 +/- 0.72 in HTN group, and 1.81 +/- 0.55 in control group ( P = .025 vs HTN and control). PICA-CFR was closely related to width-ratio of PICA ( r = 0.448, P = .002). Conclusion PICA in AH has higher resting diastolic velocity, wider diameter, and impaired CFR compared with nonhypertrophied myocardium.