Impact of HIF prolyl hydroxylase inhibitors in heart failure patients with renal anemia.

OBJECTIVE: Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors are a new class of anti-anemia agents. We retrospectively evaluated the safety and efficacy of HIF-PH inhibitors in patients with heart failure (HF) complicated by anemia associated with chronic kidney disase. HIF-PH inhibitor treatment was initiated in 32 patients with chronic HF complicated by renal anemia and were followed up for 3 months. RESULTS: Hematocrit and hemoglobin levels markedly improved 3 months after HIF-PH inhibitor treatment. However, levels of NT-proBNP, which is an indicator of HF, did not decrease considerably. Based on the rate of change in NT-proBNP, we divided the patients into "responder" and "non-responder" groups. The results showed that considerably more patients had a ferritin level of less than 100 ng/mL in the non-responder group at baseline. There were substantially more patients with TSAT of less than 20% in the non-responder group at 1 month after HIF-PH inhibitor treatment. The cut-off values to maximize the predictive power of ferritin level at baseline and TSAT value at 1 month after treatment were 41.8 ng/ml and 20.75. HIF-PH inhibitor treatment can be expected to be effective for improving both anemia and HF if ferritin≥41.8 ng/ml at baseline or TSAT≥20.75 at 1 month after treatment.

Efficacy of azilsartan on left ventricular diastolic dysfunction compared with candesartan: J-TASTE randomized controlled trial.

Characterized by ventricular and vascular stiffness, heart failure with preserved ejection fraction (HFpEF) has led to high morbidity and mortality. As azilsartan is an angiotensin receptor blocker with the highest myocardial and vascular affinities, azilsartan may improve the left ventricular (LV) diastolic function in patients with hypertension and either HFpEF or HF with mildly reduced ejection fraction (HFmrEF) more than candesartan. In this randomized, open-label trial, we randomly assigned 193 hypertensive patients with HF and LV ejection fraction ≥ 45% to 20 mg of azilsartan (n = 95) or 8 mg of candesartan (n = 98), once daily for 48 weeks. After the initiation of treatment, changes in the doses of the study drugs were permitted based on the patient's conditions, including blood pressure (median dose at 48 weeks: azilsartan 20.0 mg/day, candesartan 8.0 mg/day). The primary endpoint was the baseline-adjusted change in the ratio of peak early diastolic transmitral flow velocity (E) to early diastolic mitral annular velocity (e') (E/e'). Adjusted least-squares mean (LSM) change in E/e' was - 0.8 (95% confidence interval [CI] - 1.49 to - 0.04) in the azilsartan group and 0.2 (95% CI - 0.49 to 0.94) in the candesartan group, providing the LSM differences of - 1.0 (95% CI - 2.01 to 0.03, P = 0.057). The median change in left atrial volume index was - 2.7 mL/m2 with azilsartan vs 1.4 mL/m2 with candesartan (P = 0.091). The frequency of adverse events related to hypotension and hyperkalemia did not differ between the groups. The current study did not provide strong evidence that azilsartan improves LV diastolic dysfunction, and further confirmatory study is required.

Efficacy and safety of atrial fibrillation ablation in heart failure patients with left ventricular ejection fraction less than 50.

INTRODUCTION: The efficacy of catheter ablation in patients with low cardiac function has been previously reported; however, only a few studies have included mid-range ejection fraction (mrEF). This study aimed to evaluate the efficacy and safety of atrial fibrillation (AF) ablation in patients with left ventricular ejection fraction (LVEF) < 50%. METHODS: This study retrospectively analyzed 79 patients (reduced ejection fraction [rEF]/mrEF, 38/41; paroxysmal/persistent, 37/42; heart failure hospitalizations within one year before ablation, 36 [45.6%]) who underwent the first ablation procedure at our hospital from April 2017 to December 2021. Radiofrequency ablation and cryoablation were performed for 69 and 10 patients, respectively. RESULTS: Complications included pacemaker implantation for postoperative sick sinus syndrome in one patient and inguinal hematoma in one patient. Regarding efficacy, there were significant postoperative improvements in echocardiographic data, blood test values, and diuretic use. After a mean follow-up of 60 months, 86.1% patients had no AF recurrence. There were 9 heart failure hospitalizations (11.4%) and 5 all-cause deaths (6.3%); no significant differences were found between the rEF and mrEF groups. No significant predictors of AF recurrence were found in preoperative patient characteristics. CONCLUSION: AF ablation in patients with LVEF <50% significantly improved cardiac and renal functions with few complications, resulting in a high non-recurrence rate and reduced heart failure.

Canagliflozin reduces proteinuria by targeting hyperinsulinaemia in diabetes patients with heart failure: A post hoc analysis of the CANDLE trial.

AIM: To investigate factors associated with proteinuria regression in patients with type 2 diabetes mellitus (T2DM) treated with canagliflozin. MATERIALS AND METHODS: This study was a post hoc analysis of the CANDLE trial (UMIN000017669), which compared the effect of 24 weeks of treatment with canagliflozin or glimepiride for changes in N-terminal pro-brain natriuretic peptide in patients with T2DM and chronic heart failure (CHF). Factors associated with regression of proteinuria at 24 weeks were evaluated with multivariate logistic models. RESULTS: The rate of regression of proteinuria was higher (28/102, 27.5% vs. 12/112, 10.7%), and that of progression was lower (9/102, 8.8% vs. 26/112, 23.2%), in the canagliflozin versus the glimepiride group (P = .0001). There were no differences in the change in the estimated glomerular filtration rate category between groups. Insulin level, homeostatic model assessment of ß-cell function, homeostatic model assessment for insulin resistance and estimated plasma volume were decreased at 24 weeks in the regression subclass but not in the progression subclass, suggesting that regression of proteinuria is associated with the declines in these values in the canagliflozin group. Higher insulin level at baseline was solely associated with proteinuria regression in the multivariate logistic regression model (baseline insulin, as per a 1-mlU/L increase, odds ratio 1.24 [1.05-1.47], P = .011). CONCLUSIONS: In patients with T2DM and CHF, regression of proteinuria with canagliflozin treatment was associated with the pretreatment insulin level. These results may provide clinicians with novel mechanistic insights into the beneficial effects of canagliflozin on renal outcomes and may warrant discussion for selecting preferred patient profiles, including pretreatment insulin levels.

Evaluation of arrhythmogenic foci using a novel automated detection algorithm and isoproterenol in persistent atrial fibrillation.

PURPOSE: The CARTOFINDER mapping system analyzes activation patterns using unipolar potentials during atrial fibrillation (AF), where isoproterenol (ISP) is conventionally used to induce non-pulmonary vein (PV) foci and confirm PV arrhythmogenicity. In 20 patients with persistent AF who underwent ablation at our hospital, arrhythmogenic foci were evaluated using both these methods. METHODS: Before pulmonary vein isolation (PVI), PV and left atrium (LA) were analyzed during AF using CARTOFINDER, and the isolation line was determined based on the results. After PVI, ISP was loaded after return of sinus rhythm and confirmation of the presence of arrhythmogenic foci. The activation site in LA was ablated at the discretion of the surgeon. RESULTS: Focal activation sites detected by CARTOFINDER correlated with the arrhythmogenic foci induced by ISP in the PVs. The results also showed that a greater number of focal activation sites in the PVs correlated to an increased response to ISP administration. In one patient, it was observed that the focal activation site identified in the PV also coincided with the site of the origin of automaticity induced by ISP after PVI. CONCLUSION: CARTOFINDER and ISP both reliably determined the presence of arrhythmogenic foci in PV, in patients with persistent AF. Knowledge of the nature of arrhythmogenic foci in non-PV is considered to be a topic for future studies, and further data collection is required.

Contrast-enhanced computed tomography for optimizing the outcomes of pulmonary vein isolation with cryoablation -the role of isolation of PVs including carina.

PURPOSE: Compared with conventional pulmonary vein isolation (PVI) with radiofrequency ablation, PVI with cryoballoon is an easier and shorter procedure without reconnection, particularly in the superior pulmonary vein. However, the durability of the cryoballoon may be reduced due to anatomical factors and the position of the pulmonary vein (PV). Further, inadequate isolation of the carina leads to recurrence of atrial fibrillation (AF). We aimed to determine whether using contrast-enhanced computed tomography (CT) for patient selection improves the early success rate and prevents the recurrence of AF in PVI with cryoballoon. METHODS: We evaluated patients who underwent ablation for paroxysmal atrial fibrillation in our hospital between July 2019 and November 2020. After excluding patients with contraindications for cryoablation, 50 patients were selected through visual inspection of the results of preoperative contrast-enhanced CT. A treatment plan was established, and the clinical course and outcomes were followed up. RESULTS: Of the 200 PVs of the 50 patients, only 8 PVs (4%) were incompletely isolated with a single cryoablation. Six of the eight PVs were successfully isolated with additional cryoablation. Only 2 patients (4%) underwent additional PVI with radiofrequency ablation. Four patients had AF recurrence within a mean follow-up period of 14.3 ± 5.1 months. The rate of sinus rhythm maintenance was 92%. PV reconnection was observed in 2 patients. None of the patients had postoperative atrial flutter. CONCLUSIONS: Selecting patients for cryoablation according to contrast-enhanced CT findings made the procedure easier to perform, leading to improved early success rates and clinical course.

Isolated bilateral external iliac artery dissections with emotional stress.

We present a patient with isolated bilateral external iliac artery dissections associated with emotional stress. The diagnosis should be kept in mind in young, fit patients presenting lower back pain occurring subsequent to emotional stress.

A case of accessory pathway mapped with ultra-high-resolution mapping led to a coronary sinus diverticulum.

Ultra-high-resolution mapping is useful in the ablation of accessory pathways. However, in patients with accessory pathways in the coronary sinus (CS) diverticulum, treatment with endocardial ablation may be challenging. Patients suspected of having subepicardial accessory pathways may require the examination of the venous anomaly using CS angiography.

Secondary Cardiac Lymphoma Presenting as Sick Sinus Syndrome and Atrial Fibrillation Which Required Leadless Pacemaker Implantation.

Cardiac involvement of malignant lymphoma is relatively common, although such a phenomenon has subclinical manifestations that are difficult to detect. We herein describe a patient with atrial fibrillation and sick sinus syndrome as the main symptoms. Computed tomography showed a mass in the right atrium extending into the superior vena cava (SVC). We implanted the patient with a leadless pacemaker. Transvenous biopsy revealed a diffuse large B-cell lymphoma. The patient was treated successfully with chemotherapy including rituximab. This case suggested that cardiac lymphoma may cause sick sinus syndrome, and leadless pacemaker implantation is a safe treatment option in patients with partial SVC obstruction.

Clinical characteristics and treatment of Spontaneous Coronary Artery Dissection in Young Women Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) has recently been recognized as a cause of acute coronary syndrome (ACS), especially in young women. However, the characteristics, optimal treatment, and prognosis of patients who experience SCAD have not been fully described. METHODS: Data were retrospectively collected from a multicenter registry. Among 187 young women less than 60 years of age who underwent percutaneous coronary intervention, 19 (10.2%) with SCAD were identified through coronary angiography. Clinical characteristics and outcomes were investigated. RESULTS: Those with SCAD less frequently exhibited coronary risk factors, such as diabetes, dyslipidemia, and smoking, than those without SCAD. Intense emotional and/or physical stress was more frequently observed as a prominent precipitating factor in cases of SCAD. All 19 SCAD patients presented with ACS, 7 of whom were treated using stents, and the other 12 treated without stents. During a median follow-up of 960 days (interquartile range, 686-1504 days), two recurrent coronary artery dissections occurred within 7 days, both of which occurred in a vessel other than that in which primary dissection occurred. There were no deaths or recurrent dissection after 1 week. CONCLUSION: SCAD was not uncommon among young Japanese women requiring percutaneous coronary intervention. Patients with SCAD exhibited fewer coronary risk factors and more precipitating factors than those without SCAD, and long-term clinical outcomes after an early period appeared to be favorable.

The appearance of a single left atrial tachycardia as two different types on preoperative surface and intracardiac ECG of pacemaker due to progressive cardiac conduction disturbance.

We treated a patient with PCCD whose single left AT appeared as two different types on preoperative surface and intracardiac ECG from a pacemaker. The diagnosis was hindered by the fact that the conduction block encompassed interatrial block and the pacemaker A-wave was captured at the right atrial appendage.

Efficacy of isoproterenol in the evaluation of dormant conduction and arrhythmogenic foci identification in atrial fibrillation ablation.

BACKGROUND: Catheter ablation for atrial fibrillation (AF) is an established therapy. However, postoperative recurrence is a serious issue caused by the reconduction of the isolated pulmonary veins (PV) and the onset of non-PV foci. The objectives of this study were to elucidate dormant conduction, confirm PV arrhythmia substrate, induce non-PV foci after PV isolation, and assess the acute efficacy of high dose isoproterenol (ISP) when administered in addition to adenosine. METHODS: The study consisted of 100 patients with drug-refractory AF (paroxysmal and persistent) who underwent ablation therapy (either radio-frequency or cryoballoon ablation) as the first-line of therapy at our hospital. All patients first underwent PV isolation (PVI) and were administered adenosine followed by ISP (6 µg × 5 min). The effects were observed, and the therapeutic strategy was evaluated. RESULTS: Persistent dormant conduction due to ISP administration was observed in 13 patients. In over half of the patients, arrhythmia substrates were identified in the PV. Ten patients presented with persistent PV firing. The ablation of non-PV foci was additionally performed in 23 patients. CONCLUSIONS: We found that dormant conduction, as a result of ISP administration, is persistent and ISP is useful when performing an ablation. In addition, ISP administration is useful for the identification of PV arrhythmia substrates and induction of non-PV foci. However, the effectiveness of ISP may be partially due to the complementary effect of adenosine, and, therefore, a combination of the two drugs seems preferable.

Comparison of Anti-factor Xa Activity Among Three Different Factor Xa Inhibitors in Non-valvular Atrial Fibrillation Patients with Renal Impairment.

BACKGROUND: Factor-Xa inhibitors (FXaIs) are widely used for the treatment of non-valvular atrial fibrillation (NVAF). Although we have previously reported the distribution of the anti-factor Xa activity (AXA) values of three different FXaIs in NVAF patients, the differences in the distribution of AXA values among the different FXaIs in patients with renal impairment (RI) have not been fully elucidated. METHODS: Trough and peak AXA values were measured in 94 patients taking rivaroxaban, 124 patients taking apixaban, and 66 patients taking edoxaban. Of them, we identified 26 patients with moderate RI [creatinine clearance (CrCl) 30-49 mL/min] and 17 patients with severe RI (CrCl 15-29 mL/min) in the rivaroxaban cohort, 37 patients with moderate RI and 17 patients with severe RI in the apixaban cohort, and 21 patients with moderate RI and 9 patients with severe RI in the edoxaban cohort. AXA values were measured using chromogenic AXA assays. Both trough and peak AXA values were compared between patients with moderate RI and those with severe RI in each cohort, and differences in the peak-to-trough ratio among the different drugs were assessed. RESULTS: In the rivaroxaban cohort, the peak AXA value was significantly higher in patients with severe RI than in those with moderate RI. In the apixaban cohort, neither the trough nor peak AXA values significantly differed between patients with moderate RI and those with severe RI. In the edoxaban cohort, the trough AXA value was significantly higher in patients with severe RI than in those with moderate RI, and peak AXA tended to be higher in patients with severe RI. The peak-to-trough ratio of AXA values was significantly lower in patients taking apixaban than in those taking rivaroxaban and edoxaban. CONCLUSION: Among Japanese NVAF patients with RI, the peak or trough AXA values were higher in patients with severe RI than in those with moderate RI when taking rivaroxaban and edoxaban, whereas both the peak and trough AXA values were similar between patients with severe RI and those with moderate RI when taking apixaban. The peak-to-trough ratio of AXA values was the lowest in patients taking apixaban.

Importance of sodium-glucose cotransporter 2 inhibitor use in diabetic patients with acute heart failure.

BACKGROUND: It is known that once heart failure occurs in older patients with diabetes, the overall prognosis is extremely poor. We investigated whether early initiation of SGLT2 inhibitor therapy after admission was beneficial for diabetic patients requiring inpatient treatment for acute heart failure. METHODS: We retrospectively assessed consecutive patients with comorbid diabetes who were admitted to the Department of Cardiology in Tosei General Hospital for treatment of acute heart failure. Patients were divided into two groups: those who initiated SGLT2 inhibitor therapy (SGLT2 inhibitor group; mean age: 73 ± 9 years) and those who did not receive the inhibitors during hospitalization (conventional treatment group; mean age: 75 ± 10 years). RESULTS: No intergroup differences were observed in the distribution of either the severity or classes of heart failure on admission. Glycosylated hemoglobin levels were significantly higher in the SGLT2 inhibitor group (HbA1c: 8.1% ± 0.8%) than in the conventional treatment group (HbA1c: 7.1% ± 0.8%) (p = 0.003). After admission, patients in both groups recovered equally well, and in almost the same period of time, before discharge. The rate of diuretics use at the time of discharge in the SGLT2 inhibitor group (n = 8, 67%) was significantly lower than that in the conventional treatment group (n = 19, 100%) (p = 0.016). In particular, the dose of loop diuretics in the conventional treatment group was 34 ± 4 mg/day while that in the SGLT2 inhibitor group was significantly lower at 13 ± 5 mg/day (p = 0.008). During hospitalization, the incidence of acute kidney injury was significantly higher in the conventional treatment group (n = 11, 58%) than in the SGLT2 inhibitor group (n = 2, 16%) (p = 0.031). CONCLUSIONS: For the treatment and management of heart failure in patients with diabetes, early initiation of SGLT2 inhibitor therapy appears to be effective.

Rationale and Design of the Multicenter Trial on Japan Working Group on the Effects of Angiotensin Receptor Blockers Selection (Azilsartan vs. Candesartan) on Diastolic Function in the Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE Trial.

BACKGROUND: Previous studies suggest that the pathophysiology of heart failure with preserved ejection fraction (HFpEF) is characterized not only by high ventricular stiffness, but also by vascular stiffness. Azilsartan has higher vascular affinity compared with other angiotensin II receptor blockers (ARBs), which were proven to have no beneficial effects on clinical outcomes in patients with HFpEF in earlier clinical trials. We aimed to test the hypothesis that azilsartan may improve left ventricular diastolic function in HFpEF patients with hypertension in this trial. METHODS: The Effects of Angiotensin Receptor Blockers on Diastolic Function in Patients Suffering from Heart Failure with Preserved Ejection Fraction: J-TASTE trial is a multicenter, randomized, open-labeled, and assessor(s)-blinded, active controlled using candesartan, parallel-group clinical trial, to compare changes in left ventricular (LV) diastolic dysfunction between HFpEF patients with hypertension who have received candesartan or azilsartan for 48 weeks. The primary endpoint is the change in early diastolic wave height/early diastolic mitral annulus velocity (E/e') assessed by echocardiography from the baseline to the end of the study (48 weeks). A total of 190 patients will be recruited into the study. CONCLUSIONS: The design of the J-TASTE trial will provide data on whether differences between the effects of the two tested drugs on LV diastolic function exist in HFpEF patients with hypertension and will improve understanding of the pathophysiological role of vascular stiffness on diastolic function.

Enhancement of Warfarin Anticoagulant Reaction in Patients with Repeated Oral Tolvaptan Administration.

The pharmacokinetics and pharmacodynamics of warfarin remained unaffected by tolvaptan during clinical trials. However, tolvaptan prolonged the prothrombin time-international normalized ratio (PT-INR) level of patients with cardiovascular disease taking warfarin. Tolvaptan was prescribed to 576 patients from December 2010 to December 2015. Of these patients, 37 underwent anticoagulant therapy. We investigated PT-INR fluctuation immediately before tolvaptan therapy was initiated. PT-INR remained unchanged in the control group and in groups administered with less than 7.5 mg/d tolvaptan, whereas it was significantly increased (p=0.03) in the group administered with more than 7.5 mg/d tolvaptan. This result indicates the possibility that tolvaptan affects the pharmacodynamics of warfarin in vivo. However, further research is necessary to clarify the mechanism of this phenomenon.

Sitagliptin on carotid intima-media thickness in type 2 diabetes patients receiving primary or secondary prevention of cardiovascular disease: A subgroup analysis of the PROLOGUE study.

BACKGROUND: Whether a dipeptidyl peptidase-4 (DPP-4) inhibitor can attenuate atherosclerosis is still controversial. Some clinical trials reported that DPP-4 inhibitors in diabetes patients without a previous history of cardiovascular (CV) events could reduce carotid intima-media thickness (IMT). However, in the PROLOGUE study, which enrolled diabetes patients both with and without previous CV events, sitagliptin failed to slow the progression of carotid IMT relative to conventional therapy. AIM AND METHODS: We hypothesized that the effect of DPP-4 inhibitors on carotid atherosclerosis might be different between the primary and secondary prevention groups. We performed a post hoc analysis of the PROLOGUE study and compared the effects of sitagliptin and conventional therapy on changes in carotid IMT in subgroups with or without previous CV events. RESULTS: No significant difference in the IMT changes between the treatment groups was found in the secondary prevention subgroup (sitagliptin, N = 102; conventional, 111). However, in the primary prevention subgroup (sitagliptin, 120; conventional, 109), we found significant inhibitory effects of sitagliptin on mean and max internal carotid artery IMT [estimated group difference: -0.096 mm (95% CI -0.175 to -0.018, p = 0.017) and -0.162 mm (95% CI -0.272 to -0.052, p = 0.004), respectively], although there was no significant difference in the common carotid artery IMT. CONCLUSIONS: Our data suggest that there is a favorable effect of DPP-4 inhibitor treatment on carotid atherosclerosis in diabetes patients without previous CV events.

Use of sodium-glucose cotransporter 2 inhibitors in older patients with type 2 diabetes mellitus.

AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that act on the proximal renal tubules to lower blood glucose levels by inhibiting glucose reabsorption and promoting urinary glucose excretion. The present study assessed the long-term use of SGLT2 inhibitors in older patients with diabetes. METHODS: A total of 117 older patients with type 2 diabetes who were given SGLT2 inhibitors were enrolled from April 2014 to March 2016. RESULTS: The mean age of the patients was 73.7 ± 10.0 years. During the follow-up period (mean 289.3 days), there was no event associated with oral administration of SGLT2 inhibitors. These drugs significantly lowered fasting blood glucose and glycosylated hemoglobin levels at 6 months, and did not affect the creatinine level, blood urea nitrogen/creatinine ratio or estimated glomerular filtration rate during treatment. Although the treatment significantly increased hemoglobin and hematocrit levels, it did not affect the ultrasonographically determined diameter of the inferior vena cava, and no signs of intravascular collapse were observed. Changes in brain natriuretic peptide levels during the follow-up period were assessed in 78 patients with a brain natriuretic peptide level exceeding the normal upper limit before treatment with SGLT2 inhibitors. The brain natriuretic peptide levels significantly decreased after 6 months of treatment. CONCLUSIONS: In older Japanese patients with diabetes, treatment with SGLT2 inhibitors for 6 months exerted a favorable hypoglycemic effect, while no sign of dehydration was observed. Geriatr Gerontol Int 2018; 18: 108-114.

Influence of proton pump inhibitors on blood dabigatran concentrations in Japanese patients with non-valvular atrial fibrillation.

BACKGROUND: Dabigatran is a direct thrombin inhibitor used to decrease the risk of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF). Its prodrug, dabigatran etexilate (DE) is often co-administrated with a proton pump inhibitor (PPI) because of its adverse effects on the gastrointestinal tract. Drug-drug interactions between DE and PPIs in daily clinical practice have not been fully elucidated. METHODS: Changes in blood dabigatran concentration (DC) were investigated using the dilute thrombin time test in a randomized, open-label, two-period crossover study including 34 Japanese patients with NVAF receiving dabigatran therapy with or without PPI. RESULTS: The average trough DC was significantly higher without PPI than with PPI (83 ± 42.3 vs. 55.5 ± 24.6 ng/mL, respectively; P < 0.001). Similarly, the average peak DC was significantly higher without PPI than with PPI (184.1 ± 107.7 vs. 124 ± 59.2 ng/mL, respectively; P = 0.0029). The average ratio of DC change at the trough and peak levels did not differ significantly among the three PPI types. CONCLUSIONS: PPI administration significantly decreased the trough and peak DCs in patients with NVAF. Therefore, when prescribing PPIs for patients with NVAF in a clinical setting, the possibility that the bioavailability of dabigatran may decrease should be considered.