Clinical features differentiating Takotsubo cardiomyopathy in the peripartum period from peripartum cardiomyopathy.

There are some similarities in clinical features between Takotsubo cardiomyopathy during the peripartum period (PTCM) and peripartum cardiomyopathy (PPCM). Both conditions present as acute heart failure and decreased left ventricular (LV) ejection fraction in the peripartum period in previously heart-healthy women. The present study aimed to evaluate the differences in clinical features and outcomes between PTCM and PPCM. Between January 2004 and December 2016, 37 consecutive patients who demonstrated LV dysfunction during the peripartum period without previous heart disease were recruited retrospectively. The clinical, laboratory, and echocardiographic data of these patients were comprehensively reviewed. Twenty-one (57%) and 16 (43%) patients were classified into PPCM and PTCM groups, respectively, based on echocardiographic findings. The initial LV ejection fraction did not differ significantly between the 2 groups. However, all patients with PTCM showed complete recovery of LV ejection fraction at the 1-month follow-up. However, among 20 patients with PPCM who underwent 1-month echocardiography, only 6 (30%) showed complete recovery of LV ejection fraction at the 1-month follow-up. At the 12-month follow-up, only 10 patients showed complete recovery of LV ejection fraction. The incidence of PTCM was much higher than expected. Although LV dysfunction was similar at the initial diagnosis, the prognosis of LV recovery was more favorable in PTCM than in PPCM. Therefore, physicians should differentiate these two diseases entities, although they have several similarities in acute LV dysfunction.

Cell-Penetrating Function of the Poly(ADP-Ribose) (PAR)-Binding Motif Derived from the PAR-Dependent E3 Ubiquitin Ligase Iduna.

Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates cellular responses such as proteasomal degradation and DNA repair upon interaction with its substrate. We identified a highly cationic region within the PAR-binding motif of Iduna; the region was similar among various species and showed amino acid sequence similarity with that of known cell-penetrating peptides (CPPs). We hypothesized that this Iduna-derived cationic sequence-rich peptide (Iduna) could penetrate the cell membrane and deliver macromolecules into cells. To test this hypothesis, we generated recombinant Iduna-conjugated enhanced green fluorescent protein (Iduna-EGFP) and its tandem-repeat form (d-Iduna-EGFP). Both Iduna-EGFP and d-Iduna-EGFP efficiently penetrated Jurkat cells, with the fluorescence signals increasing dose- and time-dependently. Tandem-repeats of Iduna and other CPPs enhanced intracellular protein delivery efficiency. The delivery mechanism involves lipid-raft-mediated endocytosis following heparan sulfate interaction; d-Iduna-EGFP was localized in the nucleus as well as the cytoplasm, and its residence time was much longer than that of other controls such as TAT and Hph-1. Moreover, following intravenous administration to C57/BL6 mice, d-Iduna-EGFP was efficiently taken up by various tissues, including the liver, spleen, and intestine suggesting that the cell-penetrating function of the human Iduna-derived peptide can be utilized for experimental and therapeutic delivery of macromolecules.

Association of insulin resistance and coronary artery remodeling: an intravascular ultrasound study.

BACKGROUND: There are few studies that investigated the correlation between insulin resistance (IR) and the coronary artery remodeling. The aim of the study is to investigate the association of IR measured by homeostasis model assessment of insulin resistance (HOMA-IR) and coronary artery remodeling evaluated by intravascular ultrasound (IVUS). METHODS: A total of 298 consecutive patients who received percutaneous coronary interventions under IVUS guidance were retrospectively enrolled. The value of HOMA-IR more than 2.5 was considered as IR positive. Metabolic syndrome was classified according to NCEP ATP III guidelines. The remodeling index was defined as the ratio of the external elastic membrane (EEM) area at the lesion site to the EEM area at the proximal reference site. RESULTS: A total of 369 lesions were analyzed (161 lesions in HOMA-IR positive and 208 lesions in HOMA-IR negative). Remodeling index was significantly higher in the HOMA-IR positive group compared with the negative group (HOMA-IR positive vs. negative: 1.074 ± 0.109 vs. 1.042 ± 0.131, p = 0.013). There was a significant positive correlation between remodeling index and HOMA-IR (p = 0.010). Analysis of HOMA-IR according to remodeling groups showed increasing tendency of HOMA-IR, and it was statistically significant (p = 0.045). Multivariate analysis revealed that only HOMA-IR was an independent predictor of remodeling index (r = 0.166, p = 0.018). CONCLUSION: Increased IR estimated by HOMA-IR was significantly associated with a higher remodeling index and positive coronary artery remodeling.

Sex differences in the impact of body mass index on outcomes of coronary artery disease in Koreans.

BACKGROUND: Obesity is often considered a risk factor for cardiovascular disease, but recent studies have shown conflicting results regarding the effect of BMI on the prognosis of coronary artery disease (CAD). This study aimed to evaluate the relationship between BMI and clinical outcomes of CAD according to sex in a Korean population. METHODS: A total of 3476 patients with a significant CAD who underwent percutaneous coronary intervention (PCI) were enrolled. Patients were classified as follows according to BMI using the Asia-Pacific cutoff points: underweight (<18.5 kg/m 2 ), normal weight (18.5-22.9 kg/m 2 ), overweight (23.0-24.9 kg/m 2 ) and obese (≥25 kg/m 2 ) patients. Underweight and normal weight patients were further categorized into the lower BMI group, whereas overweight and obese patients were categorized into the higher BMI group. The primary endpoint was all-cause mortality. RESULTS: Among women, the higher BMI group showed poor clinical features in the prevalence of hypertension and chest pain presentation, and among men, the higher BMI group had a significantly lower rate of chronic renal failure. At the end of the follow-up period (median 53.5 months), the all-cause mortality rate was lower in the higher BMI group in men, and cardiovascular death and stroke rates were significantly lower in the higher BMI group in women. CONCLUSION: In Korean CAD patients treated with PCI, inverse correlations were observed between the clinical outcomes and BMI, but there were differences between men and women.

Prevalence and prognostic significance of malnutrition in patients with acute coronary syndrome treated with percutaneous coronary intervention.

The incidence and impact of malnutrition on acute coronary syndrome (ACS) remain unclear. This study aimed to evaluate the prevalence, clinical relevance, and prognostic outcomes of malnutrition in patients with ACS treated with percutaneous coronary intervention. This retrospective study included 1930 consecutive patients with ACS undergoing percutaneous coronary intervention and assessed their nutritional status using 3 scoring systems: Controlling Nutritional Status score, nutritional risk index (NRI), and prognostic nutritional index (PNI). The primary endpoint was all-cause mortality. The Controlling Nutritional Status, NRI, and PNI scores showed that 5.2%, 17.5%, and 3.9% of patients were moderately or severely malnourished, respectively. During a median follow-up of 67.2 months (interquartile range: 46.8-88.5 months), 74 (3.8%) patients died. Malnutrition was associated with a significantly increased risk for all-cause mortality compared with good nutrition (adjusted hazard ratios for moderate and severe malnutrition, respectively: 5.65 [95% confidence interval: 3.27-9.78] and 15.26 [7.50-31.05] for the NRI score, 5.53 [2.10-14.49] and 11.08 [5.69-21.59] for the PNI; P < .001). The current findings demonstrated that malnutrition is prevalent among patients with ACS and is closely associated with increased mortality. Further study is needed to evaluate the effects of nutritional interventions on the outcomes of patients with ACS.

A Multicenter, Randomized, Double-blind, Active-controlled, Factorial Design, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Combination Therapy of Pitavastatin and Ezetimibe Versus Monotherapy of Pitavastatin in Patients With Primary Hypercholesterolemia.

PURPOSE: Pitavastatin is a unique lipophilic statin with moderate efficacy in lowering LDL-C levels by 30% to 50% with a tolerable safety profile. However, the efficacy of adding ezetimibe to pitavastatin in patients with dyslipidemia has not been well investigated. Therefore, the objective of this double-blind, multicenter, randomized, Phase III study was to compare the efficacy and safety of pitavastatin and ezetimibe combination therapy with those of pitavastatin monotherapy in Korean patients with primary hypercholesterolemia. METHODS: Korean men and women aged >19 and <80 years with primary hypercholesterolemia requiring medical treatment were included in this study. During the 8-week screening period, all patients were instructed to make therapeutic lifestyle changes. The screening period consisted of a 4-week washout period and a placebo run-in period (4-8 weeks). During treatment period I, patients were randomly assigned to receive 1 of 4 treatments: pitavastatin 2 mg plus ezetimibe 10 mg, pitavastatin 2 mg, pitavastatin 4 mg plus ezetimibe 10 mg, or pitavastatin 4 mg. The 8-week double-blind treatment period then commenced. Adverse events (AEs), clinical laboratory data, and vital signs were assessed in all patients. FINDINGS: The percentages in LDL-C from baseline after 8 weeks of double-blind treatment decreased significantly in the pooled pitavastatin/ezetimibe (-52.8% [11.2%]) and pooled pitavastatin (-37.1% [14.1%]) groups. Treatment with pitavastatin/ezetimibe resulted in a significantly greater LDL-C-lowering effect than that with pitavastatin (difference, -15.8 mg/dL; 95% CI, -18.7 to -12.9; P < 0.001). The precentages of achieving LDL-C goal in pooled pitavastatin/ezetimibe and pooled pitavastatin groups were 94.2% and 69.1%, respectively (P < 0.001). There were no significant differences in the incidence of overall AEs and adverse drug reactions. Serious AEs were comparable between the groups. IMPLICATIONS: Pitavastatin and ezetimibe combinations effectively and safely decreased LDL-C levels by >50% in patients with dyslipidemia. The safety and tolerability of pitavastatin and ezetimibe combination therapy were comparable with those of pitavastatin monotherapy. CLINICALTRIALS: gov identifier: NCT04584736.

LRR domain of NLRX1 protein delivery by dNP2 inhibits T cell functions and alleviates autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system (CNS), which is a chronic progressive disease and is caused by uncontrolled activation of myelin antigen specific T cells. It has high unmet medical needs due to the difficulty of efficient drug delivery into the CNS to control tissue inflammation. In this study, we demonstrate that a fusion protein of NOD-like receptor family member X1 (NLRX1) and blood brain barrier (BBB)-permeable peptide, dNP2 ameliorates experimental autoimmune encephalomyelitis (EAE). Methods: We purified recombinant LRR or NBD regions of NLRX1 protein conjugated with dNP2. To examine intracellular delivery efficiency of the recombinant protein, we incubated the proteins with Jurkat T cells or murine splenic T cells and their delivery efficiency was analyzed by flow cytometry. To investigate the therapeutic efficacy in an EAE model, we injected the recombinant protein into mice with 3 different treatment schemes e.g., prevention, semi-therapeutic, and therapeutic. To analyze their functional roles in T cells, we treated MACS-sorted naïve CD4 T cells with the proteins during their activation and differentiation into Th1, Th17, and Treg cells. Results: dNP2-LRR protein treatment showed significantly higher delivery efficiency than TAT-LRR or LRR alone in Jurkat T cells and mouse splenic T cells. In all three treatment schemes of EAE experiments, dNP2-LRR administration showed ameliorated tissue inflammation and disease severity with reduced number of infiltrating T cells producing inflammatory cytokines such as IFNγ. In addition, dNP2-LRR inhibited T cell activation, cytokine production, and Th1 differentiation. Conclusion: These results suggest that dNP2-LRR is a novel agent, which regulates effector T cell functions and could be a promising molecule for the treatment of CNS autoimmune diseases such as multiple sclerosis.

Efficacy and Tolerability of Telmisartan/Amlodipine and Rosuvastatin Coadministration in Hypertensive Patients with Hyperlipidemia: A Phase III, Multicenter, Randomized, Double-blind Study.

PURPOSE: Dyslipidemia and hypertension increase the risk for cardiovascular disease. Combination therapy improves patient compliance. This study was conducted to compare the efficacy and tolerability of the combination therapies telmisartan/amlodipine + rosuvastatin, telmisartan/amlodipine, and telmisartan + rosuvastatin in patients with hypercholesterolemia and hypertension. METHODS: In this Phase III, multicenter, 8-week randomized, double-blind study, participants with hypertension and dyslipidemia (defined as a sitting systolic blood pressure [sitSBP] of ≥140 mm Hg, a low-density lipoprotein-cholesterol [LDL-C] level of ≤250 mg/dL, and a triglyceride level of ≤400 mg/dL) were screened. After a 4-week washout/run-in period involving therapeutic lifestyle changes and telmisartan 80 mg once a day, eligible patients had a sitSBP of ≥140 mm Hg and met the LDL-C level criteria according to the National Cholesterol Education Program Adult Treatment Panel III cardiovascular disease risk category. Patients were randomly assigned to 1 of 3 groups: (1) telmisartan/amlodipine 80/10 mg + rosuvastatin 20 mg (TAR group); (2) telmisartan/amlodipine 80/10 mg (TA group); or (3) telmisartan 80 mg + rosuvastatin 20 mg (TR group). The primary efficacy end points were the percentage changes from baseline in LDL-C in the TAR and TA groups and the mean changes in sitSBP in the TAR and TR groups at week 8 compared to baseline. Continuous variables were compared using the unpaired t test or the Wilcoxon rank sum model, and categorical variables were compared using the χ2 or Fisher exact test. Tolerability was assessed based on adverse events found on physical examination including vital sign measurements, laboratory evaluations, and 12-lead ECG. FINDINGS: A total of 134 patients were enrolled. The least squares mean percentage changes in LDL-C at 8 weeks after administration of the drug compared to baseline were -51.9% (3.0%) in the TAR group and -3.2% (2.9%) in the TA group (P < 0.001). At 8 weeks after baseline, the least squares mean (SE) changes sitSBP were -28.3 (2.4) mm Hg in the TAR group and -10.7 (2.1) mm Hg in the TR group (P < 0.001). The prevalence rates of treatment-emergent adverse events were 15.0%, 25.0%, and 12.2% in the TAR, TA, and TR groups, respectively; those of adverse drug reactions were 15.0%, 22.7%, and 10.2%. None of the differences in rates were significant among 3 groups. IMPLICATIONS: Triple therapy with TAR can be an effective treatment in patients with dyslipidemia and hypertension. The TAR combination has value for hypertensive patients with hyperlipidemia in terms of convenience, tolerability, and efficacy. ClinicalTrials.gov identifier: NCT03566316.

A Phase III, Multicenter, Randomized, Double-blind, Active Comparator Clinical Trial to Compare the Efficacy and Safety of Combination Therapy With Ezetimibe and Rosuvastatin Versus Rosuvastatin Monotherapy in Patients With Hypercholesterolemia: I-ROSETTE (Ildong Rosuvastatin & Ezetimibe for Hypercholesterolemia) Randomized Controlled Trial.

PURPOSE: Combination therapy with ezetimibe and statins is recommended in cases of statin intolerance or insufficiency. The objective of this study was to compare the efficacy and safety of combination therapy with ezetimibe and rosuvastatin versus those of rosuvastatin monotherapy in patients with hypercholesterolemia. METHODS: I-ROSETTE (Ildong ROSuvastatin & ezETimibe for hypercholesTElolemia) was an 8-week, double-blind, multicenter, Phase III randomized controlled trial conducted at 20 hospitals in the Republic of Korea. Patients with hypercholesterolemia who required medical treatment according to National Cholesterol Education Program Adult Treatment Panel III guidelines were eligible for participation in the study. Patients were randomly assigned to receive ezetimibe 10 mg/rosuvastatin 20 mg, ezetimibe 10 mg/rosuvastatin 10 mg, ezetimibe 10 mg/rosuvastatin 5 mg, rosuvastatin 20 mg, rosuvastatin 10 mg, or rosuvastatin 5 mg in a 1:1:1:1:1:1 ratio. The primary end point was the difference in the mean percent change from baseline in LDL-C level after 8 weeks of treatment between the ezetimibe/rosuvastatin and rosuvastatin treatment groups. All patients were assessed for adverse events (AEs), clinical laboratory data, and vital signs. FINDINGS: Of 396 patients, 389 with efficacy data were analyzed. Baseline characteristics among 6 groups were similar. After 8 weeks of double-blind treatment, the percent changes in adjusted mean LDL-C levels at week 8 compared with baseline values were -57.0% (2.1%) and -44.4% (2.1%) in the total ezetimibe/rosuvastatin and total rosuvastatin groups, respectively (P < 0.001). The LDL-C-lowering efficacy of each of the ezetimibe/rosuvastatin combinations was superior to that of each of the respective doses of rosuvastatin. The mean percent change in LDL-C level in all ezetimibe/rosuvastatin combination groups was >50%. The number of patients who achieved target LDL-C levels at week 8 was significantly greater in the ezetimibe/rosuvastatin group (180 [92.3%] of 195 patients) than in the rosuvastatin monotherapy group (155 [79.9%] of 194 patients) (P < 0.001). There were no significant differences in the incidence of overall AEs, adverse drug reactions, and serious AEs; laboratory findings, including liver function test results and creatinine kinase levels, were comparable between groups. IMPLICATIONS: Fixed-dose combinations of ezetimibe/rosuvastatin significantly improved lipid profiles in patients with hypercholesterolemia compared with rosuvastatin monotherapy. All groups treated with rosuvastatin and ezetimibe reported a decrease in mean LDL-C level >50%. The safety and tolerability of ezetimibe/rosuvastatin therapy were comparable with those of rosuvastatin monotherapy. ClinicalTrials.gov identifier: NCT02749994.

Efficacy and Tolerability of Telmisartan/Amlodipine + Hydrochlorothiazide Versus Telmisartan/Amlodipine Combination Therapy for Essential Hypertension Uncontrolled With Telmisartan/Amlodipine: The Phase III, Multicenter, Randomized, Double-blind TAHYTI Study.

PURPOSE: This 8-week study in Korea aimed to evaluate the efficacy and tolerability of a telmisartan/amlodipine + hydrochlorothiazide (TAH) combination versus telmisartan/amlodipine (TA) combination in patients with essential hypertension that did not respond appropriately to 4-week treatment with TA. METHODS: All patients who met the inclusion criteria received TA (40/5 mg) during a 4-week run-in period (period 1). Patients who met the criteria for essential hypertension (mean sitting systolic blood pressure [MSSBP], ≥140 and <200 mm Hg, or ≥130 and<200 mm Hg in those with diabetes mellitus or chronic kidney disease) after period 1 were randomly assigned to receive TA 40/5 mg + hydrochlorothiazide 12.5 mg (test group) or TA only (control group). The test and control drugs were administered in each group for 2 weeks (period 2). Patients who completed period 2 underwent 6-week treatment (period 3) with a TAH and TA dose twice that in period 2. The primary end point was the change in MSSBP at week 8 of treatment. Secondary end points were the change in MSSBP at week 2 and MS diastolic BP, BP control rate, and BP response rate at weeks 2 and 8. Treatment tolerability was assessed based on adverse events (AEs), laboratory evaluations (chemistry, hematology, and urinalysis), 12-lead ECG, and physical examination including vital sign measurements. FINDINGS: We randomized 310 patients to the treatment groups. The mean (SD) ages of the TAH and TA groups were 62.0 (10.8) and 63.4 (10.4) years, respectively. The least squares mean change in MSSBP was significantly greater in the TAH group than in the TA group after 8 weeks (-18.7 vs -12.2 mm Hg; P < 0.001). Similar results were obtained on changes in MSSBP after 2 weeks and changes in sitting diastolic BP, BP control rate, and BP response rate at weeks 2 and 8 compared with the respective baseline values. The prevalences of treatment-emergent AEs (29.0% vs 16.3%; P = 0.008) and adverse drug reactions (20.0% vs 10.5%; P = 0.020) were significantly greater in the TAH group than in the TA group. Most treatment-emergent AEs were mild or moderate; none were severe. The most frequently reported AEs were dizziness and headache. IMPLICATION: TAH triple therapy was more effective than was TA double therapy in reducing BP in these patients in Korea with essential hypertension that did not adequately respond to TA. ClinicalTrials.gov identifier: NCT02738632.

Serial measurements of neutrophil gelatinase-associated lipocalin: prognostic value in patients with ST-segment elevation myocardial infarction treated with a primary percutaneous coronary intervention.

BACKGROUND: There are no previous data on serial changes in neutrophil gelatinase-associated lipocalin (NGAL) levels in ST-segment elevation myocardial infarction (STEMI) patients before and after a primary percutaneous coronary intervention (pPCI). The aim of the present study was to evaluate the prognostic value of serial NGAL measurements in patients with STEMI treated by pPCI. MATERIALS AND METHODS: We identified 169 STEMI patients who underwent pPCI within 12 h of symptom onset and had plasma NGAL measurements before (pre-NGAL) and 6 h after (post-NGAL) pPCI. The primary endpoint was 30-day all-cause mortality, including cardiac death, whereas the secondary endpoint was the change in NGAL levels from before to after pPCI. RESULTS: The mean pre-NGAL and post-NGAL levels were 109.2±76.1 and 93.3±83.8 ng/ml, respectively. Thirty-day mortality occurred in 12 (7.1%) patients. In terms of changes in serial NGAL levels, post-NGAL levels were decreased in 132 (79%) patients. Patients with elevated post-NGAL levels showed increased mortality compared with patients with decreased post-NGAL levels (P=0.005). Multivariate analyses indicated that old age and high post-NGAL levels were independent risk factors for 30-day mortality. CONCLUSION: In a large percentage of STEMI patients, plasma post-pPCI NGAL levels were decreased compared with pre-pPCI NGAL levels, even with the administration of potentially nephrotoxic contrast medium. Post-NGAL levels seemed to be superior to pre-NGAL levels for the prediction of 30-day mortality outcome.

A case of a resected benign myxoma-like hemorrhagic cyst, which later recurred as undifferentiated pleomorphic sarcoma in the left atrium.

RATIONALE: An intracardiac cystic mass is a rare type of mass found in the left atrium. The differential diagnosis of an intracardiac cystic mass includes hydatid cysts, bronchogenic cysts, intracardiac varices, and hemorrhages in some tumor types, including myxoma. PATIENT CONCERNS: We present the case of a 68-year-old woman who presented with episodic dyspnea. DIAGNOSES-INTERVENTIONS-OUTCOMES: Transthoracic echocardiography (TTE) revealed the presence of a left atrial mass mimicking myxoma. However, in postoperative findings, it was determined that the mass was actually a hemorrhagic cyst. Eighteen months later, the patient presented with recurrent exertional dyspnea and TTE revealed the recurrence of a left atrial mass. Computed tomography showed that the mass extended into the right atrium, inferior vena cava, and coronary sinus. After re-operation, the final histological diagnosis was determined to be an undifferentiated pleomorphic sarcoma in the left atrium. LESSONS: An intracardiac hemorrhagic cyst was suspected during the operation of a benign-looking LA mass. As such, we recommend that other rare etiologies be considered and more biopsies be performed when possible.

A Randomized, Multicenter, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and the Tolerability of a Triple Combination of Amlodipine/Losartan/Rosuvastatin in Patients With Comorbid Essential Hypertension and Hyperlipidemia.

PURPOSE: The objective of this study was to evaluate the efficacy and tolerability of a triple combination of amlodipine/losartan/rosuvastatin in patients with hypertension and hypercholesterolemia. METHODS: A randomized, multicenter, double-blind, placebo-controlled study was conducted. Eligible patients with hypertension and a sitting diastolic blood pressure (SiDBP) of >90 mm Hg and LDL-C levels <250mg/dL were screened. After a 4-week run-in period with therapeutic lifestyle changes and losartan potassium 100mg once daily, patients who met both blood pressure criteria (80 mm Hg ≤ SiDBP < 110 mm Hg) and the LDL-C level criteria (defined in the National Cholesterol Education Program Adult Treatment Panel III cardiovascular risk categories) were randomized to 1 of 3 groups and treated once daily for 8 weeks: losartan potassium 100mg + rosuvastatin 20mg treatment (L/R 100/20) group, amlodipine camsylate 5mg + losartan potassium 100mg treatment (A/L 5/100) group, and amlodipine 5mg+ losartan potassium 100mg + rosuvastatin 20mg (A/L/R 5/100/20) group. The primary efficacy variables were the percent change in LDL-C in the A/L/R 5/100/20 and A/L 5/100 groups and the mean change of SiDBP in the A/L/R 5/100/20 and L/R 100/20 groups after 8 weeks of treatment, relative to baseline values. FINDINGS: A total of 146 patients were enrolled and the demographic characteristics were similar among the 3 treatment groups. After 8 weeks of treatment, the mean (SD) percent change in LDL-C was significantly greater in the A/L/R group than in the A/L group (-48.40% [2.77%] vs -6.70% [3.00%]; P < 0.0001). Moreover, the mean change in SiDBP was significantly greater in the A/L/R group than in the L/R group (-9.75 [0.92] mm Hg vs -1.73 [1.03] mm Hg; P < 0.0001). SiDBP and LDL-C reductions in the A/L/R group were comparable to reductions in the A/L and L/R groups, respectively. Ten adverse events were reported in 7 patients (4.83%), and 1 patient from the A/L group (0.69%) experienced 2 adverse drug reactions (tachycardia and face edema), which were mild and resolved without specific treatment. There were no clinically significant tolerability issues during the treatment period. IMPLICATIONS: Triple combination therapy with amlodipine/losartan/rosuvastatin can be an effective therapeutic strategy in patients with hypertension combined with dyslipidemia. These findings will form the foundation of the future development of a single-pill triple combination. ClinicalTrials.gov identifier: NCT02899455.

Prognostic value of preoperative N-terminal pro-brain natriuretic peptide in non-cardiac surgery of elderly patients with normal left ventricular systolic function.

AIM: We investigated the prognostic value of preoperative N-terminal pro-brain natriuretic peptide (NT-proBNP) in non-cardiac surgery in elderly patients who showed normal left ventricular function on preoperative echocardiography. METHODS: We analyzed 1459 patients aged older than 70 years who had consulted a cardiologist for the evaluation of cardiovascular risk for non-cardiac surgery. Of the 721 patients who simultaneously underwent echocardiography and NT-proBNP assessments, 506 who showed normal left ventricular systolic function were included. The predictive power of NT-proBNP for the risk of major adverse cardiac and cerebrovascular events (MACCE) was evaluated. RESULTS: MACCE occurred in 40 (7.9%) of the 506 patients, and the median value of NT-proBNP was higher in patients with complications than in those without (MACCE group: 1700.5 pg/mL vs non MACCE group: 206.35 pg/mL; P < 0.001). The area under the receiver operating characteristic curve was 0.804 (P < 0.001), with an optimal cut-off of 425.3 pg/mL. Multivariate analysis showed that increased NT-proBNP (>425.3 pg/mL; odds ratio 6.381; P < 0.001) was the only independent risk factor for the prediction of MACCE. CONCLUSIONS: In elderly patients who showed normal left ventricular systolic function on echocardiography, measurement of preoperative NT-proBNP concentration might be a useful test for predicting the occurrence of MACCE after non-cardiac surgery. Geriatr Gerontol Int 2016; 16: 1109-1116.

miRNA polymorphisms (miR­146a, miR­149, miR­196a2 and miR­499) are associated with the risk of coronary artery disease.

Small non­coding microRNAs (miRNAs) are not only important for heart and vascular development but are also important in cardiovascular pathophysiology and diseases, such as ischemia and atherosclerosis­related diseases. However, the effect of miR­146a, miR­149, miR­196a2 and miR­499 polymorphisms on coronary artery disease (CAD) susceptibility remain unknown. The aim of the present study was to examine the genotype frequencies of miR­146a, miR­149, miR­196a2 and miR­499 polymorphisms in patients with CAD, and assess their clinical applications for diagnosing and monitoring CAD. Using polymerase chain reaction­amplified DNA, microRNA polymorphisms were analyzed in 522 patients with CAD and 535 control subjects. The miR­149 rs2292832 C>T and miR­196a2 rs11614913 T>C polymorphisms were shown to be significantly associated with CAD prevalence. In subgroup analyses according to disease severity, the miR­146a rs2910164GG genotype was significantly associated with CAD risk in the stent ≥2 group. In addition, miR­146aG/­149T/­196a2C/­499 G allele combination was significantly associated with CAD prevalence (G­T­C­G and G­C­C­G of miR­146a/­149/­196a2/­499). The combination genotypes of miR­146aGG/149TC+CC and miR­149CC/196a2TC were significantly associated with CAD incidence. In subgroup analyses, miR­146a rs2910164 C>G increased the risk of developing CAD in non­smoking, hypertensive and nondiabetic subgroups. Furthermore, miR­149 rs2292832 C>T and miR­196a2 rs11614913 T>C was shown to increase CAD risk in females and patients aged >63 years old. The miR­149T allele, miR­196a2C allele and miR­146aG/­149T/­196a2C/­499 G allele combination were associated with CAD pathogenesis. The combined effects of environmental factor and genotype combination of miRNA polymorphisms may contribute to CAD prevalence.

The impact of lesion length and reference vessel diameter on angiographic restenosis and target vessel revascularization in treating in-stent restenosis with radiation.

OBJECTIVES: The study assessed the influence of lesion length and reference vessel diameter (RVD) on recurrent restenosis after gamma intracoronary radiation therapy (ICRT) for in-stent restenosis (IRS). BACKGROUND: Intracoronary radiation therapy reduces angiographic and clinical restenosis in patients with ISR. The impact of ICRT on challenging subgroups, such as long lesions and small vessels, has not been established. METHODS: Six-month quantitative coronary angiography and clinical follow-up were conducted to evaluate the influence of lesion length and RVD in patients with ISR treated with ICRT who were enrolled in gamma radiation trials. Angiographic binary restenosis (>50% diameter stenosis) and clinical events were assessed in 311 patients treated with gamma ICRT and 105 patients who received placebo. RESULTS: Baseline demographic, angiographic and procedural details were similar in the two treatment groups. The ICRT group had reduced binary restenosis in vessels of all sizes (30% vs. 66%, p < 0.001), with the most benefit seen in small vessels. A trend toward reduced restenosis with ICRT was found across all lesion lengths. At six months, major adverse cardiac events (MACE) were reduced in the ICRT group compared to placebo (34% vs. 71%, p < 0.0001), driven by reduced target vessel revascularization (27% vs. 71%, p < 0.0001). The independent predictors of angiographic restenosis include ICRT (OR [odds ratio] 0.16; CI [confidence interval] 0.10 to 0.28, p < 0.001), lesion length (OR 1.03; CI 1.01 to 1.05, p = 0.004) and RVD (OR 0.40; CI 0.23 to 0.67, p < 0.001). CONCLUSIONS: Intracoronary radiation therapy, compared to placebo, results in a significant reduction of angiographic restenosis across all vessel sizes, with a trend toward reduction of angiographic restenosis across all lesion lengths; this effect is seen predominantly in small vessels and diffuse lesions.

The outcome of percutaneous coronary intervention in patients with in-stent restenosis who failed intracoronary radiation therapy.

OBJECTIVES: This study reports the outcome of patients who failed intracoronary radiation therapy (IRT) for the treatment of in-stent restenosis (ISR). BACKGROUND: Intracoronary radiation therapy has demonstrated a reduction in the recurrence rate of restenosis for patients with ISR. However, 10% to 30% of these patients require repeat intervention to the irradiated site. METHODS: Of 961 patients who were assigned to gamma or beta radiation for the treatment of diffuse ISR, we evaluated the outcome of 282 (29%) consecutive patients who failed IRT and compared them with the 679 (71%) patients who had successful IRT. For patients who failed radiation, the mean time to the first target vessel revascularization (TVR) was 173 +/- 127 days after the index procedure and the total duration of follow-up was 494 +/- 304 days. RESULTS: Patients who failed IRT were younger (60 +/- 10 vs. 63 +/- 11 years, p = 0.002) and had a higher incidence of restenting (51% vs. 41%, p = 0.003). The majority (55%) of the restenotic lesions after IRT failure were focal (< or =10 mm), with a mean lesion length of 11.9 +/- 1.9 mm. Of the 257 patients who had subsequent TVR after failed IRT, 68 (26%) underwent coronary artery bypass grafting and 189 (74%) underwent percutaneous coronary intervention using balloon in 61%, restenting in 26%, atheroablation in 11%, and the cutting balloon in 2% of cases. At six months, 6% of patients died, 1% had Q-wave MI, 17% had repeat TVR, and the overall rate of major adverse cardiac events was 21%. CONCLUSIONS: The predominant angiographic pattern of lesions in patients who failed IRT is focal restenosis, with these lesions responding well to conventional revascularization methods.

Evaluation of the Efficacy and Safety of the Lercanidipine/Valsartan Combination in Korean Patients With Essential Hypertension Not Adequately Controlled With Lercanidipine Monotherapy: A Randomized, Multicenter, Parallel Design, Phase III Clinical Trial.

PURPOSE: The objective of this study was to evaluate the efficacy and safety of the lercanidipine/valsartan combination compared with lercanidipine monotherapy in patients with hypertension. METHODS: Part 1 of this study was the randomized, multicenter, double-blind, parallel group, Phase III, 8-week clinical trial to compare superiority of lercanidipine 10 mg/valsartan 80 mg (L10/V80) and lercanidipine 10 mg/valsartan 160 mg (L10/V160) combinations with lercanidipine 10 mg (L10) monotherapy. At screening, hypertensive patients, whose diastolic blood pressure (DBP) was >90 mm Hg after 4 weeks with L10, were randomized to 3 groups of L10, L10/V80, and L10/V160. The primary end point was the change in the mean sitting DBP from baseline (week 0) after 8 weeks of therapy. Patients who were randomly assigned to L10/V160 and whose mean DBP was still ≥ 90 mm Hg in part 1 were enrolled to the up-titration extension study with lercanidipine 20 mg/valsartan 160 mg (L20/V160) (part 2). FINDINGS: Of 772 patients screened, 497 were randomized to 3 groups (166 in the L10 group, 168 in the L10/V80 group, and 163 in the L10/V160 group). Mean (SD) age was 55 (9.9) years, and male patients comprised 69%. The mean (SD) baseline systolic blood pressure (SBP)/DBP were 148.4 (15.1)/94.3 (9.5) mm Hg. No significant differences were found between groups in baseline characteristics except the percentages of previous history of antihypertensive medication. The primary end points, the changes of mean (SD) DBP at week 8 from the baseline were -2.0 (8.8) mm Hg in the L10 group, -6.7 (8.5) mm Hg in L10/V80 group, and -8.1 (8.4) mm Hg in L10/V160 group. The adjusted mean difference between the combination groups and the L10 monotherapy group was -4.6 mm Hg (95% CI, -6.5 to -2.6; P < 0.001) in the L10/V80 group and -5.9 mm Hg (95% CI, -7.9 to -4.0, P < 0.001) in the L10/V160 group, which had significantly greater efficacy in BP lowering. A total of 74 patients were enrolled in the part 2 extension study. Changes of mean (SD) DBP and SBP from week 8 to week 12 and week 16 were -5.6 (7.9)/-8.0 (12.0) mm Hg and -5.5 (7.0)/-8.5 (11.3) mm Hg, respectively. For evaluation of the safety profile, the frequencies of adverse events between groups were also not significantly different. The most frequently reported adverse events were headache (6 cases, 20.7%) in the L10 group, dizziness (8 cases, 16.3%) in L10/V80 group, and nasopharyngitis (3 cases, 9.4%) in L10/V160 group, and the incidences of adverse events were not different between groups. IMPLICATIONS: Treatment of L10/V80 or L10/V160 combination therapy resulted in significantly greater BP lowering compared with L10 monotherapy. Moreover, the L20/V160 high dose combination had additional BP lowering effect compared with nonresponders with the L10/V160 combination. ClinicalTrials.gov: NCT01928628.

Comparison of intracoronary gamma radiation for in-stent restenosis in saphenous vein grafts versus native coronary arteries.

Intracoronary gamma radiation is effective in reducing recurrent in-stent restenosis (ISR) involving native coronary arteries. This study compares the effectiveness and safety of intracoronary gamma radiation for the treatment of ISR in saphenous vein grafts (SVGs) versus native coronary arteries. In the Washington Radiation for In-Stent restenosis Trial (WRIST) series of gamma radiation trials, 1,142 patients with ISR (230 in SVG and 912 in native coronary arteries) completed 6-month clinical follow-up. All patients underwent balloon angioplasty, atherectomy, and/or restenting. Different ribbon lengths containing 6 to 23 seeds of iridium-192 were used to cover lesion lengths <80 mm. The prescribed radiation doses were 14 or 15 Gy at 2-mm radial distance from the center of the source. Baseline demographics showed that patients with SVGs were older (65 +/- 13 vs 61 +/- 11 years, p <0.001), more likely male (79% vs 64%, p <0.001), had more multivessel coronary disease (81% vs 50%, p <0.001), and less diffuse lesions (17 +/- 10 vs 24 +/- 12 mm, p <0.001). At 6 months, event-free survival was similar for patients with SVG ISR and native coronary ISR (82% vs 84%, p = 0.35). The SVG ISR population had a low rate of late total occlusion (4.6%) and late thrombosis (3.5%). Thus, treatment of ISR with gamma radiation in SVGs had similar outcome to native coronary arteries. The use of gamma radiation for the treatment of ISR should expand to SVGs.

Usefulness of periprocedural creatinine phosphokinase-MB release to predict adverse outcomes after intracoronary radiation therapy for in-stent restenosis.

We aimed to analyze periprocedural creatinine phosphokinase (CPK)-MB elevation in patients treated with intracoronary radiation therapy (IRT) for in-stent restenosis (ISR) to risk stratify these patients. The clinical significance of periprocedural CPK-MB elevation after IRT for ISR is unknown. An elevated CPK-MB has been associated with increased mortality after conventional angioplasty. We evaluated 1,326 patients who were enrolled in radiation trials for ISR at the Washington Hospital Center using gamma- and beta-emitters. Patients were analyzed according to degree of CPK-MB increase within 24 hours of the index IRT procedure (normal CPK-MB, CPK-MB 1 to 3 times the upper limit of normal, or CPK-MB >3 times the upper limit of normal). Patients with CPK-MB >3 times the upper limit of normal were older (64 +/- 12 years, p = 0.04), more likely to be smokers (64%, p = 0.04), hypertensive (85%, p <0.01), and diabetic (49%, p = 0.04). The cohort with the highest CPK-MB release (CPK-MB >3 times the upper limit of normal) had significantly higher rates of adverse clinical events at 12 months (major adverse cardiac events 40%, p <0.01), including death (9.3%, p <0.01) and late thrombosis (6.3%, p <0.01). Periprocedural CPK-MB elevation is of prognostic importance in patients treated with IRT for ISR, and its analysis appears to be mandatory to risk stratify these patients. The impact of glycoprotein IIb/IIIa antagonists in reducing periprocedural CPK-MB release awaits evaluation.