Predictors of Optical Coherence Tomography-Defined Calcified Nodules in Patients With Acute Coronary Syndrome　- A Substudy From the TACTICS Registry.

BACKGROUND: Recent studies suggest that the presence of calcified nodules (CN) is associated with worse prognosis in patients with acute coronary syndrome (ACS). We investigated clinical predictors of optical coherence tomography (OCT)-defined CN in ACS patients in a prospective multicenter registry.Methods and Results: We investigated 695 patients enrolled in the TACTICS registry who underwent OCT assessment of the culprit lesion during primary percutaneous coronary intervention. OCT-CN was defined as calcific nodules erupting into the lumen with disruption of the fibrous cap and an underlying calcified plate. Compared with patients without OCT-CN, patients with OCT-CN (n=28) were older (mean [±SD] age 75.0±11.3 vs. 65.7±12.7 years; P<0.001), had a higher prevalence of diabetes (50.0% vs. 29.4%; P=0.034), hemodialysis (21.4% vs. 1.6%; P<0.001), and Killip Class III/IV heart failure (21.4% vs. 5.7%; P=0.003), and a higher preprocedural SYNTAX score (median [interquartile range] score 15 [11-25] vs. 11 [7-19]; P=0.003). On multivariable analysis, age (odds ratio [OR] 1.072; P<0.001), hemodialysis (OR 16.571; P<0.001), and Killip Class III/IV (OR 4.466; P=0.004) were significantly associated with the presence of OCT-CN. In non-dialysis patients (n=678), age (OR 1.081; P<0.001), diabetes (OR 3.046; P=0.014), and Killip Class III/IV (OR 4.414; P=0.009) were significantly associated with the presence of OCT-CN. CONCLUSIONS: The TACTICS registry shows that OCT-CN is associated with lesion severity and poor clinical background, which may worsen prognosis.

Prognostic value of right atrial strain in systemic sclerosis based on tissue tracking analysis using cine cardiac magnetic resonance imaging: a retrospective observational study.

Interstitial lung disease and cardiac involvement are common manifestations and prognostic factors of systemic sclerosis. However, it is unclear whether impaired right atrial function associated with interstitial lung disease in systemic sclerosis can be used as a prognostic factor in this patient population. Therefore, this study aimed to investigate the relationship between right atrial function, interstitial lung disease, and prognosis in patients with systemic sclerosis using tissue tracking analysis with cine cardiac magnetic resonance imaging. In this retrospective observational study, a total of 40 patients with systemic sclerosis were enrolled. Tissue tracking analysis was used to obtain time curves of right atrial strain. Reservoir (total strain), conduit (passive strain), and booster (active strain) pump function were calculated, and right atrial strain, interstitial lung disease, and clinical outcomes were examined. An adverse clinical event was defined as all-cause death. Overall, 23 patients had interstitial lung disease (58%). Six patients died during the follow-up (median, 44 months). The total skin score and right ventricular systolic pressure on echocardiography were higher in patients with an event than in those without an event (28 ± 16% vs. 13 ± 13%, P = 0.02; 46.3 ± 10.7 mmHg vs. 36.0 ± 8.5 mmHg, P = 0.01, respectively). Further, right atrial total strain and active strain were significantly lower in patients with an event than in those without an event (14.3 ± 11.3% vs. 25.8 ± 11.4%, P = 0.03; 3.48 ± 2.37 vs. 11.7 ± 6.78, P = 0.007, respectively). Multivariate analysis revealed that active strain was an independent predictor of all-cause death (hazard ratio 0.76, P = 0.029). Kaplan-Meier analysis revealed that the survival rate was significantly higher in patients with right atrial active strain levels above the cutoff 7.4 (P < 0.05). In systemic sclerosis, right atrial booster function was predictive of mortality. Hence, right atrial functional assessment may have incremental prognostic value for patients with systemic sclerosis, leading to better risk stratification.

Relationship between the HeartMate Risk Score category on admission and outcome in patients with acute heart failure referred to a cardiac intensive care unit.

The HeartMate Risk Score (HMRS), a simple clinical prediction rule based on the patients' age, albumin, creatinine, and the international normalized ratio of the prothrombin time (PT-INR), is correlated with mortality in the cohort of left ventricular assist device (LVAD) recipients. However, in an aging society, an LAVD is indicated for only a small proportion of patients with acute heart failure (AHF), and whether the HMRS has prognostic implications for unselected patients with AHF is unknown. This study aimed to assess the prognostic value of HMRS categories on admission in patients with AHF. We analyzed 339 hospitalized patients with AHF who had albumin, creatinine, and the PT-INR recorded on admission. The patients were categorized as follows: the High group (HMRS > 2.48, n = 131), Mid group (HMRS of 1.58-2.48, n = 97) group, and Low group (HMRS < 1.58, n = 111). The endpoints of this study were all-cause death and readmission for heart failure (HF). During a median follow-up of 247 days, 24 (18.3%) patients died in the High group, 7 (7.2%) died in the Mid group, and 8 (7.2%) died in the Low group. In a multivariable analysis adjusted for highly imbalanced baseline variables, a high HMRS was independently associated with survival, with a hazard ratio of 2.90 (95% confidence interval 1.42-5.96, P = 0.004). With regard to the composite endpoint of all-cause death and readmission for HF, the Mid group had a worse prognosis than the Low group, and the High group had the worst prognosis. A high HMRS on admission is associated with all-cause mortality and readmission for HF, and a mid-HMRS is associated with readmission for HF after AHF hospitalization. The HMRS may be a valid clinical tool to stratify the risk of adverse outcomes after hospitalization in unselected patients with AHF.

Preclinical Metabolism and Disposition of TP0473292, a Novel Oral Prodrug of the Potent Metabotropic Glutamate 2/3 Receptor Antagonist TP0178894 for the Treatment of Depression.

TP0473292 is an adamantane carboxylic acid (ACA) ester prodrug for enhancing the oral bioavailability of the hydrophilic glutamate analog TP0178894, a novel metabotropic glutamate 2 and 3 receptor antagonist, and being developed as an antidepressant. TP0473292 showed high membrane permeability and rapid hydrolysis to TP0178894 in rat, monkey, and human liver S9 fractions, with a conversion rate of such that complete conversion by first-pass metabolism was expected. TP0473292 was also hydrolyzed in the intestinal, renal, and lung S9 fractions, coinciding with the result that TP0473292 was activated by carboxylesterase (CES) 1 and more efficiently by CES2. Despite the rapid hydrolysis of TP0473292 in the intestinal S9 fraction, TP0473292 achieved good oral bioavailability of poorly permeable TP0178894 (approximately 60%) in rats and monkeys, with no TP0473292 detected in the plasma, revealing that rapid hydrolysis in the intestine is not necessarily a disadvantage. We also confirmed the penetration of TP0178894 into the cerebrospinal fluid and its unmetabolized excretion in urine. The ester promoiety, ACA, was metabolized to chemically stable acyl glucuronide and excreted in urine in rats and monkeys, suggesting a low risk of idiosyncratic drug toxicity. TP0473292 and its metabolites did not show a drug-drug interaction potential via cytochrome P450 in humans. These results suggested that TP0473292 functions as an ideal oral prodrug in humans; this was later confirmed to be true in phase 1 clinical trials. Furthermore, ACA was firstly confirmed to be a useful promoiety for hydrophilic drugs to enhance their oral bioavailability. SIGNIFICANCE STATEMENT: Hydrolysis in the intestine reportedly has negative effects on the oral bioavailability of hydrophilic active metabolites of ester prodrugs. This study reports the preclinical pharmacokinetics of a hydrophilic metabotropic glutamate 2/3 receptor antagonist, TP0178894, and its ester prodrug TP0473292, which was found to act as an oral prodrug despite being activated predominantly in the intestine. Furthermore, this study firstly reports that adamantane carboxylic acid is useful as the ester promoiety of a prodrug for increasing lipophilicity and oral bioavailability.

Prediction of cardiovascular events using myocardial strain ratio derived from 13N-ammonia positron emission tomography.

OBJECTIVES: Myocardial flow reserve (MFR), derived from ammonia N-13 positron emission tomography (NH3-PET), can predict the prognosis of patients with various heart diseases. We aimed to investigate whether myocardial strain ratio (MSR) was useful in predicting MACE and allowed for further risk stratification of cardiovascular events in patients with ischemic heart disease (IHD) in addition to MFR. METHODS: Ninety-five patients underwent NH3-PET because of IHD. MFR was determined as the ratio of hyperemic to resting myocardial blood flow (MBF). MSR was defined as the ratio of strains at stress and rest. The endpoint was major adverse cardiac events (MACE), including all-cause death, acute coronary syndrome, heart failure hospitalization, and revascularization. The ability to predict MACE was assessed using receiver operating characteristic (ROC) analysis, and the predictability of ME was analyzed using Kaplan-Meier analysis. The Cox proportional hazards regression model was used to calculate the hazard ratio (HR) with 95% confidence interval (CI). RESULTS: The ROC curve analysis demonstrated a cutoff of 0.93 for MACE with MSR (sensitivity and specificity of 77% and 71%, respectively). Patients with MSR < 0.93 displayed a significantly higher MACE rate than those with MSR ≥ 0.93 (p = 0.0036). The Cox proportional hazards regression analysis indicated that MSR was an independent marker that could predict MACE in imaging and clinical parameters (HR, 7.32; 95% CI: 1.59-33.7, p = 0.011). CONCLUSIONS: MSR was an independent predictor of MACE and was useful for further risk stratification in IHD. MSR has the potential for a new indicator of revascularization in patients with IHD. KEY POINTS: • We hypothesized that combining myocardial flow reserve (MFR) with the myocardial strain ratio (MSR) obtained by applying the feature-tracking technique to ammonia N-13 PET would make it predictive of major adverse cardiac events (MACE) compared to MFR alone. • MSR was an independent predictor of MACE, allowing for further risk stratification in addition to MFR in patients with ischemic heart disease. • MSR is a potential new indicator of revascularization.

Prolonged T-peak to T-end Interval Predicts Implantable Cardioverter Defibrillator Therapy in Patients With Cardiac Sarcoidosis.

BACKGROUND: The association between the T-peak to T-end interval (Tp-e) and ventricular arrhythmia (VA) events in cardiac sarcoidosis (CS) is unknown. The purpose of this study was to investigate whether Tp-e was associated with VA events in CS patients with implantable cardioverter defibrillators (ICDs) or cardiac resynchronization therapy defibrillators (CRT-Ds).Methods and Results: We retrospectively studied 50 patients (16 men; mean [±SD] age 56.3±10.5 years) with CS and ICD/CRT-D. The maximum Tp-e in the precordial leads recorded by a 12-lead electrocardiogram after ICD/CRT-D implantation was evaluated. The clinical endpoint was defined as appropriate ICD therapy. During a median follow-up period of 85.0 months, 22 patients underwent appropriate therapy and 10 patients died. Kaplan-Meier analysis revealed that the probability of the clinical endpoint was 28.3% at 2 years and 35.3% at 4 years. The optimal cut-off value of the Tp-e for the prediction of the clinical endpoint was 91 ms, with a sensitivity of 72.7% and a specificity of 87.0% (area under the curve=0.81). Multivariate Cox regression analysis showed that Tp-e ≥91 ms (hazard ratio [HR] 5.10; 95% confidence interval [CI] 1.99-13.1; P<0.001) and a histological diagnosis of CS (HR 3.84; 95% CI 1.28-11.5; P=0.016) were significantly associated with the clinical endpoint. CONCLUSIONS: Tp-e ≥91 ms was a significant predictor of VA events in patients with CS and ICD/CRT-D.

Drug-Coated Balloon for the Treatment of Small Vessel Coronary Artery Disease　- A Randomized Non-Inferiority Trial.

BACKGROUND: Drug-coated balloons (DCB) have shown promising results for the treatment of in-stent restenosis (ISR) and small vessel disease (SVD). However, data comparing the treatment efficacy of different DCBs are limited.Methods and Results: AGENT Japan is a prospective randomized controlled trial that compares the Agent balloon coated with a low-dose formulation of paclitaxel (2 µg/mm2) to the SeQuent Please paclitaxel-coated balloon (3 µg/mm2) for the treatment of SVD. Patients with target lesion length ≤28 mm and reference diameter between ≥2.00 and <3.00 mm were randomized 2 : 1 for treatment with Agent (n=101) or SeQuent Please (n=49). This trial also includes a separate single-arm substudy evaluating the clinical safety and effectiveness of Agent in patients with ISR. The primary endpoint of 6-month target lesion failure (TLF) was observed in 3.0% of Agent and 0.0% of SeQuent Please patients (difference=3.0%; 97.5% upper confidence bound [UCB]=9.57%, which is less than the prespecified margin of 13.2%; Pnon-inferiority=0.0012). There were no deaths or thrombosis, and angiographic and quality-of-life outcomes were comparable between groups. The AGENT Japan ISR substudy (n=30) primary endpoint was met because the one-sided 97.5% UCB for 6-month TLF (3.3%) was significantly less than the study success criterion of 15.1% (97.5% UCB=9.8%; P<0.0001). CONCLUSIONS: Data from this study demonstrate good clinical outcomes with the Agent DCB when used to treat patients with SVD or ISR.

Impact of the timing of first appropriate shock on outcomes in patients with an implantable cardioverter-defibrillator: Early versus late.

BACKGROUND: Appropriate implantable cardioverter-defibrillator (ICD) shocks are associated with an increased risk of mortality and heart failure (HF) events. The first appropriate shock may occur late after implantation. However, whether the timing of the first appropriate shock influences prognosis is unknown. This study aimed to evaluate the clinical significance of the timing of the first appropriate shock in patients with ICD. METHODS: This retrospective and observational study enrolled 565 consecutive ICD patients. Patients who received an appropriate shock were divided into the early group (first appropriate shock <1 year after ICD implantation) and late group (first appropriate shock ≥1 year after ICD implantation). All-cause mortality was compared between the two groups. RESULTS: Over a median follow-up of 5.6 years, 112 (19.8%) patients received an appropriate shock, including 32 patients (28.6%) in the early group and 80 patients (71.4%) in the late group. Comparisons of baseline characteristics at ICD implantation revealed that the late group was more likely to receive cardiac resynchronization therapy (66.3% vs. 31.3%, p < 0.001), ICD for primary prevention (60.0% vs. 31.3%, p = 0.001), and angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker treatment (88.8% vs. 71.9%, p = 0.028). Survival after shock was significantly worse in the late group than in the early group (p = 0.027). In multivariable Cox proportional hazards analysis, the late group had an increased risk of all-cause mortality compared with the early group (HR: 2.22; 95% CI 1.01-4.53; p = 0.029). In both groups, the most common cause of death was HF. CONCLUSIONS: Late occurrence of the first appropriate ICD shock was associated with a worse prognosis compared with early occurrence of the first appropriate shock. Cardiac death was the most common cause of death in patients who experienced late occurrence of the first appropriate ICD shock, resulting from HF in most cases.

Cardiovascular events in patients with deferred lesions and chronic kidney disease.

No study has reported the association between the worsening of chronic kidney disease (CKD) and cardiovascular events in patients with deferred coronary artery lesions. We included patients with deferred lesions, defined as a fractional flow reserve (FFR) value > 0.80 treated with conservative medical therapy. Patients were divided into three groups: group 1, CKD stages 1-2; group 2, CKD stages 3-5; and group 3, CKD stage 5D (hemodialysis), with the clinical outcomes compared. The primary endpoint was the first occurrence of target vessel myocardial infarction, ischemia-driven target-vessel revascularization, or all-cause death. The primary endpoint was noted in 17, 25, and 36 patients in groups 1, 2, and 3, respectively. Within the three groups, the incidence rate of deferred lesions was 7.0%, 10.4%, and 32.4%, respectively. No difference was observed in the incidence of the primary endpoint between groups 1 and 2 (log-rank p = 0.16). However, the patients in group 3 had a significantly higher risk for the primary endpoint than those in groups 1 and 2 (log-rank p < 0.0001). In the multivariate Cox proportional hazards model, the patients in group 3 exhibited a higher incidence of the primary endpoint than those in group 1 (HR: 2.14; 95% CI 1.02-4.49; p < 0.01). Careful management is needed in patients undergoing hemodialysis, even if coronary artery stenosis is considered a deferred lesion.

Left Ventricular End-Systolic Diameter May Predict Persistent Heart Failure with Reduced Ejection Fraction.

Patients with persistent heart failure (HF) with reduced ejection fraction (HFrEF) have a poorer prognosis than those with HF with improved ejection fraction (HFimpEF). However, data on the predictive value of echocardiographic parameters for persistent HFrEF are lacking. We retrospectively studied 443 patients who were diagnosed with HFrEF (EF ≤ 40%) during hospitalization and underwent echocardiography at the 1-year follow-up. We divided them into the 2 groups: HFimpEF (EF > 40%) and persistent HFrEF group at 1-year follow-up, and assessed the predictive value of echocardiographic parameters at discharge for persistent HFrEF. In total, 301/443 patients (68%) were diagnosed with persistent HFrEF and 142/443 (32%) with HFimpEF at the 1-year follow-up. Kaplan-Meier analysis revealed that the persistent HFrEF group had a poorer prognosis than the HFimpEF group (log-rank, P < 0.001). Receiver operating characteristic curve analysis revealed that left ventricular end-systolic diameter (LVESD) had the highest area under the curve (AUC) (0.70; 95% confidence interval [CI]: 0.64-0.75; cutoff value: 55 mm) among various echocardiographic parameters. LVESD was an independent predictor of persistent HFrEF at the 1-year follow-up (odds ratio: 1.07, 95%CI: 1.02-1.12) upon multivariable logistic regression analysis. The incidence of persistent HFrEF was higher in patients with an LVESD ≥ 55 mm than in those with an LVESD < 55 mm (81% versus 55%, Fisher's exact test, P < 0.001). In conclusion, an LVESD (≥ 55 mm) was associated with persistent HFrEF. Focusing on LVESD in daily practice may help clinicians with risk stratification for decision-making regarding management in patients with advanced HF refractory to guideline-directed medical therapy.

Elucidation of clearance mechanism of TP0463518, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor: does a species difference in excretion routes exist between humans and animals?

1. TP0463518, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor, is reportedly excreted predominantly through urinary excretion in an unchanged form in humans, with partial biliary excretion also possible. However, the clearance mechanisms remain unclear. The aim of this study was to investigate the clearance mechanisms in humans and to assess species differences in the excretion routes.2. TP0463518 was not metabolised in rat, dog, or human hepatocytes. TP0463518 is a substrate for human BCRP, OATP1B1, OATP1B3, and OAT3, suggesting that renal uptake by OAT3 is probably the predominant clearance route, with hepatic uptake by OATP1B1 and OATP1B3 contributing partially to clearance in humans.3. A species difference in excretion routes was observed. The unchanged urinary excretion rates in humans, male rats, female rats, dogs, and monkeys were 80.7%, 0.1%, 40.9%, 15.2%, and 72.6%, respectively. Urinary excretion was predominant in humans and monkeys, while only biliary excretion was observed in male rats. Uptake studies using hepatocytes showed that the hepatic uptake clearance in rats was 13.6-fold higher than that in humans. Therefore, not only reabsorption via renal tubules, but also hepatic uptake seems to be involved in the species differences in excretion routes between rats and humans.

Bottom-up physiologically based pharmacokinetic modelling for predicting the human pharmacokinetic profiles of the ester prodrug MGS0274 and its active metabolite MGS0008, a metabotropic glutamate 2/3 receptor agonist.

For ester prodrugs that are used to improve the gastrointestinal absorption of highly hydrophilic, pharmacologically active substances, it is challenging to predict the human pharmacokinetics (PK) of the prodrugs and their parent compounds using only preclinical data.This research was aimed at constructing a PBPK model for predicting the human PK of the ester prodrug MGS0274 and its parent compound MGS0008 after a single oral administration of MGS0274 besylate.First, we identified carboxylesterase 1 (CES1) as the major enzyme involved in the hydrolysis of MGS0274. Second, we constructed a new compartment model to estimate the passive diffusion clearance (CLpd) of MGS0008, a critical parameter for predicting the PK of highly hydrophilic compounds, based on in vivo monkey PK data. Finally, we constructed a permeability-limited liver PBPK model incorporating the CLpd assumed to be the same in humans.We confirmed that our method reliably predicted the human PK and that the estimated CLpd was comparable to that calculated retrospectively using the PBPK model, suggesting that the methodology for estimating the CLpd was valid.Our proposed methodology is expected to be helpful for human PK prediction of ester prodrugs hydrolysed by CES1 and their hydrophilic parent compounds even during the preclinical phase.

Evaluation of screening with urine dipsticks and renal ultrasonography for 3-year-olds in Chiba City over 30 years.

BACKGROUND: Urinary screening for 3-year-olds cannot adequately detect congenital anomalies of the kidney and urinary tract (CAKUT). METHODS: Urinary screening for 3-year-olds was investigated over 30 years. Dipsticks for proteinuria, hematuria, glycosuria, leukocyturia, and nitrite at first screening, and dipsticks, urinary sediments, and renal ultrasonography at second screening were performed. Screening results were evaluated. RESULTS: The positive rates of proteinuria, hematuria, leukocyturia, and nitrite relative to 218,831 children at the first screening were 1.0%, 4.6%, 2.3%, and 0.88%, respectively. Thirty-seven glomerular disease, 122 CAKUT, and 5 urological disease cases were found. We detected 6 stage 3-4 chronic kidney disease (CKD) and 3 end-stage kidney disease cases, including 3 CAKUT, comprising 2 bilateral renal hypoplasia and 1 vesicoureteral reflux (VUR), and 6 glomerular diseases, comprising 4 focal segmental glomerulosclerosis and 2 Alport syndrome. The positive rates relative to 218,831 children and CKD detection rates for each tentative diagnosis of mild hematuria, severe hematuria, proteinuria and hematuria, proteinuria, and suspected urinary tract infection were 1.4% and 0.67%, 0.11% and 3.7%, 0.01% and 28.6%, 0.02% and 45.0%, and 0.08% and 9.7%, respectively. Among 14 VUR cases with significant bacteriuria, 13 were found by leukocyturia, 12 had grade ≥ IV VUR, and 10 had severe renal scars. CONCLUSIONS: Nine stage 3-5 CKD cases comprising 3 CAKUT and 6 glomerular disease were found by urinary screening of 3-year-olds among 218,831 children. The combination of urine dipsticks including leukocyturia at the first screening and ultrasonography at the second screening appeared useful.

Increased left atrial volume index is associated with more cardiovascular events in patients with acute coronary syndrome: HIJ-PROPER study findings.

AIM: To investigate the association between the left atrial volume index (LAVI) and the incidence of cardiovascular events in patients with acute coronary syndrome (ACS) who did not have atrial fibrillation (AF). METHODS: In this sub-analysis of the HIJ-PROPER study, 226 ACS patients who did not have a history of AF were enrolled. Participants were divided into two groups according to the LAVI cut-off level calculated by receiver operating characteristic (ROC) curve analysis to predict the primary endpoint, and cardiovascular events were compared between groups. The primary endpoint was the first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure. RESULTS: ROC curve analysis for the occurrence of composite of cardiovascular events indicated a LAVI cut-off point of 34 mL/m2 . Based on this, 131 patients (58.0%) were in the LAVI < 34 mL/m2 group and 95 (42.0%) were in the LAVI ≥ 34 mL/m2 group. Over a median follow-up period of 4.0 years [interquartile range: 3.2, 5.1], cardiovascular events were noted in 7 and 15 patients in the LAVI < 34 mL/m2 and LAVI ≥ 34 mL/m2 groups, corresponding to an incidence rate of 5.3% and 15.8%, respectively. Patients with a LAVI value ≥ 34 mL/m2 had a significantly higher risk of cardiovascular events than those with a LAVI value < 34 mL/m2 (hazard ratio: 2.93; 95% confidence interval: 1.19-7.22; P = .014). The tendency was similar after adjusting for several confounders (P = .025). CONCLUSION: In ACS patients without AF, elevated LAVI was associated with increased cardiovascular events. CLINICAL TRIAL REGISTRATION: International standard randomized controlled trial (URL: https://www.umin.ac.jp; UMIN000002742).

Downregulation of CYP1A2, CYP2B6, and CYP3A4 in Human Hepatocytes by Prolyl Hydroxylase Domain 2 Inhibitors via Hypoxia-Inducible Factor-α Stabilization.

Hypoxia-inducible factor (HIF) is associated with the expression of CYP, but the underlying mechanism remains uncertain. In this study, we investigated the effect of HIF-α stabilization caused by novel prolyl hydroxylase domain (PHD) 2 inhibitors, which are HIF-α stabilizers that mimic hypoxia, on the expressions of CYP1A2, CYP2B6, and CYP3A4 in human hepatocytes. An mRNA expression analysis of human hepatocytes treated with PHD2 inhibitors for 72 hours showed the downregulation of genes encoding CYP1A2, CYP2B6, and CYP3A4. The mRNA repressions were accompanied with an increase in erythropoietin protein, a marker of HIF-α stabilization, indicating that HIF-α stabilization was involved in the downregulation of the CYP isoforms. To understand the underlying mechanisms, we assessed the relationship between the expressions of the CYP isoforms and those of their regulating transcription factors [aryl hydrocarbon receptor (AhR), AhR nuclear translocator (ARNT), constitutive androstane receptor (CAR), pregnane X receptor (PXR), and retinoid X receptor (RXR)] in human hepatocytes treated with the HIF-α stabilizers. As a result, the mRNA level of AhR did not decrease, although ARNT expression was repressed. On the other hand, the mRNA expression levels of CAR, PXR, and RXR were repressed and closely associated with those of CYP2B6 and CYP3A4. Although the underlying mechanism of the downregulation for CYP1A2 remains unclear, the presently reported results suggest that the downregulation of CYP2B6 and CYP3A4 via HIF-α stabilization is caused by a decrease in the expressions of CAR, PXR, and RXR. SIGNIFICANCE STATEMENT: We showed that hypoxia-inducible factor (HIF)-α stabilization downregulates CYP1A2, CYP2B6, and CYP3A4 using prolyl hydroxylase domain 2 inhibitors, which are HIF-α stabilizers, as a new tool to mimic hypoxia in human hepatocytes. To understand the underlying mechanisms, we assessed the relationship between the expressions of the CYP isoforms and those of their regulating transcription factors. Our findings would contribute to a better understanding of the hypoxia-triggered regulatory mechanism of drug-metabolizing enzymes in human hepatocytes.

Greater Change in the Eicosapentaenoic Acid to Arachidonic Acid Ratio Is Associated With Decreased Incidence of Cardiovascular Events in Acute Coronary Syndrome Patients With Elevated Triglyceride Levels.

BACKGROUND: This study investigated whether the percentage change (%Δ) in the eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio is associated with cardiovascular event rates among acute coronary syndrome (ACS) patients receiving contemporary lipid-lowering therapy other than polyunsaturated fatty acids (PUFAs).Methods and Results:This post hoc subanalysis of the HIJ-PROPER study included PUFA-naïve patients for whom EPA/AA ratio data were available at baseline and after 3 months. Patients were categorized into 2 groups based on the median %ΔEPA/AA ratio: Group 1, change less than the median; and Group 2, change greater than or equal to the median. The 3-year rates of the primary endpoint, a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and unstable angina pectoris, were compared between the 2 groups. The median %ΔEPA/AA ratio in Groups 1 and 2 was -26.2% (n=482 patients [49.9%]) and 42.2% (n=483 patients [50.1%]), respectively. At the 3-year follow-up, the occurrence of the primary endpoint was significantly lower in Group 2 than in Group 1 (29/483 [6.0%] vs. 53/482 [11.0%]; hazard ratio 0.53, 95% confidence interval 0.33-0.82; P=0.005). The same trend was observed after adjusting for patient factors (P=0.02). CONCLUSIONS: Among ACS patients receiving contemporary lipid-lowering therapy other than PUFAs, a greater change in the EPA/AA ratio was associated with a lower incidence of cardiovascular events.

Association between anemia and mortality in patients with acute coronary syndrome treated with percutaneous coronary intervention and contemporary lipid-lowering therapy.

Despite a clear correlation between anemia and mortality in patients with the acute coronary syndrome (ACS), anemia as a mortality predictor in patients with ACS-receiving early invasive strategy and contemporary lipid-lowering therapy has not been examined. Therefore, we aimed to evaluate the association between anemia and mortality in ACS patients treated with acute revascularization and contemporary lipid-lowering treatment. This was a post-hoc study of the Heart Institute of Japan-Proper level of Lipid-Lowering with Pitavastatin and Ezetimibe in acute coronary syndrome study, in which ACS patients with dyslipidemia were randomized to receive either pitavastatin and ezetimibe or pitavastatin monotherapy. The success rate of primary percutaneous coronary intervention (PCI) was 95.2%. Eligible patients were divided into two groups: patients with anemia (anemia group) or without anemia (non-anemia group). Anemia was defined using the World Health Organization definition hemoglobin < 12 g/dL for women and < 13 g/dL for men. We compared the mortality between the two groups using propensity scores derived from 17 baseline variables. We identified 1721 eligible patients, including 420 (24.4%) in the anemia group and 1301 (75.6%) in the non-anemia group. One-to-one propensity score-matching created 381 pairs. Both unmatched and matched analyses found significantly high mortality in the anemia group compared to the non-anemia group (unmatched 12.3% vs. 3.8%, log-rank p < 0.01; matched 11.5% vs. 6.3%, log-rank p = 0.01). In ACS patients treated with an early invasive strategy era with a high PCI success rate and concurrent contemporary lipid-lowering management, all-cause mortality was still significantly higher in anemic patients than in non-anemic patients.Trial registration: Clinical trial registration URL: http://www.umin.ac.jp/ctr . Unique identifier: UMIN00000274.

Clinical outcomes after balloon angioplasty with Crosser device for heavily calcified common femoral and popliteal artery disease.

Data on the mid-term clinical outcomes after endovascular treatment (EVT) using a Crosser catheter (C. R. Bard, Inc.) as a crossing or flossing device for a heavily calcified lesion in the common femoral artery (CFA) or popliteal artery (PA) are lacking. The aim of this study was to investigate the safety and efficacy of EVT using a Crosser catheter for isolated and heavily calcified CFA or PA disease. We retrospectively analyzed 64 consecutive patients (72 lesions; CFA 30, PA 42) who underwent EVT for heavily calcified CFA or PA lesions with Crosser catheters between April 2015 and April 2019. The primary endpoint was clinically driven target lesion revascularization (CD-TLR). The median follow-up was 18.5 months. The mean age of the study population was 70 ± 9.5 years, with a male prevalence of 73.6%. The mean Proposed Peripheral Artery Calcification Scoring System grade was 2.9 ± 0.9. Procedure success, defined as 50% or less residual stenosis without suboptimal results, was achieved in 94.4% of lesions. There were no cases of bailout stenting or target lesion-related complications. After EVT, the 1-year CD-TLR-free rate for CFA and PA lesions was 87.4 and 76.8%, respectively. The corresponding rates at 2 years were 82.2 and 62.8%, respectively. In the multivariate analysis used to define CD-TLR predictors for CFA and PA lesions, hemodialysis was the only independent predictor (HR 3.35, 95% CI 1.02-13.95, P = 0.045). EVT with a Crosser device for heavily calcified CFA and PA lesions seems to be safe and feasible.

Association between elevated left ventricular mass index and increased cardiovascular events in patients with acute coronary syndrome: A sub-analysis of the HIJ-PROPER study.

AIM: This study aimed to assess the association between left ventricular mass index (LVMI) and cardiovascular events in patients with acute coronary syndrome (ACS) under standard ACS management. METHODS AND RESULTS: This study is the sub-analysis of the HIJ-PROPER study. A total of 299 patients who had echocardiographic LVMI data were included in the current analysis. The participants were divided into four groups according to the LVMI quartile [quartile 1 (Q1), 77 (25.8%); quartile 2 (Q2), 73 (24.4%); quartile 3 (Q3), 74 (24.7%); and quartile 4 (Q4), 75 (25.1%)]. The incidence of cardiovascular events was compared among the four groups. The primary endpoint was defined as the composite endpoint of all-cause death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for heart failure. Mean LVMI in the four groups was 68.1±8.6, 86.2±3.8, 101.1±4.9, and 126.0±18.5 g/m2 , respectively. The primary endpoint was noted in 4, 4, 7, and 14 patients in Q1, Q2, Q3, and Q4, corresponding to an incidence of 5.2%, 5.5%, 9.5%, and 18.7%, respectively (p = 0.03 for difference among four groups). The cumulative incidence of the primary endpoint was significantly higher in patients in Q4 than in those in Q1 and Q2 [hazard ratio (HR) 3.75; 95% confidence interval (CI), 1.23-11.4; p = 0.02 for Q4 vs Q1; HR 3.43; 95% CI, 1.13-10.4; p = 0.03 for Q4 vs Q2]. This tendency was noted even after adjusting for patient characteristics and echocardiography parameters (p = 0.039 for Q4 vs Q1). CONCLUSION: Elevated LVMI was associated with increased cardiovascular events in patients with ACS under standard management. Adequately powered studies are warranted to validate these findings.

[Retrieval of the Ruptured Balloon during Transcatheter Aortic Valve Replacement without Complications:Report of a Case].

A 77-year-old man with a history of coronary artery bypass grafting underwent transcatheter aortic valve replacement(TAVR) via femoral artery for severe aortic stenosis(AS). Preoperative computed tomography(CT) showed there was mild calcification at the sino-tubular junction(STJ). Sapien 3 was implanted successfully, but at the end of full inflation, the balloon ruptured. The ruptured balloon was retrieved without any remnants or vascular injury. A transesophageal echocardiogram showed adequate valve deployment. TAVR with its less invasiveness has become an alternative treatment for high risk patients who cannot endure surgical aortic valve replacement(SAVR). Although there are several complications related to TAVR, they can be predicted in many cases by analysis of preoperative imaging. In this case, the rupture of the balloon was not predicted because there was no significant calcification at the STJ. Caution should be taken even though there seems to be low risk of complications by preoperative imaging modalities.