Transplantation of stem/progenitor cells is a promising, emerging treatment for heart failure (HF) in the modern era. Mesenchymal stem/stromal cells (MSCs) are considered as one of the most promising cell sources for this purpose, because of their powerful secretion of reparative factors and immunomodulatory ability. To date, various sources of MSCs have been examined for the treatment of HF in preclinical or clinical studies, including adult tissues (bone marrow and adipose tissue), perinatal tissues (umbilical cord and amnion), and pluripotent stem cells (induced pluripotent stem cells and embryonic stem cells). Adult tissue-derived MSCs have been more extensively examined. Previous clinical trials have suggested the safety and feasibility of these MSCs in HF treatment, but their therapeutic effects remain arguable. Perinatal tissue-derived MSCs have the advantages of removing the necessity of invasiveness biopsy and of mass production. An increasing number of clinical studies (albeit early stage) have been conducted. Pluripotent stem cell-derived MSCs may be another promising source because of their mass-production ability underpinned by their unlimited expansion with consistent quality. However, the risk of tumorigenicity restricts their clinical application. In this review, we summarize the current information available from preclinical and clinical studies, highlighting the advantages and disadvantages of each MSC type. This will provide an insight into consideration of the best MSC source for the treatment of HF.
For more than 10 years, the Harmonization by Doing (HBD) program, a joint effort by members from academia, industry and regulators from the United States of America (USA) and Japan, has been working to increase timely regulatory approval for cardiovascular devices through the development of practical global clinical trial paradigms. Consistent with this mission and in recognition of the increasing global public health effects of critical limb ischemia (CLI), academic and government experts from the USA and Japan have developed a basic framework of global clinical trials for endovascular devices for CLI. Despite differences in medical and regulatory environments and complex patient populations in both countries, we developed a pathway for the effective design and conduct of global CLI device studies by utilizing common study design elements such as patients’ characteristics and study endpoints, and minimizing the effect of important clinical differences. Some of the key recommendations for conducting global CLI device studies are: including patients on dialysis; using a composite primary endpoint for effectiveness that includes 6-month post-procedure therapeutic success and target vessel patency; and using a 30-day primary safety endpoint of perioperative death and major adverse limb events. The proposed approach will be uniquely beneficial in facilitating both the initiation and interpretation of CLI studies and accelerating worldwide CLI device development and innovation.
Background: The ability to identify risk markers for new-onset atrial fibrillation (AF) is critical to the development of preventive strategies, but it remains unknown whether a combination of clinical, electrocardiographic, and echocardiographic parameters predicts the onset of AF. In the present study, we evaluated the predictive value of a combined score that includes these parameters.
Methods and Results: We retrospectively studied 1,040 patients without AF who underwent both echocardiography and 24-h Holter electrocardiography between May 2005 and December 2010. During a median follow-up period of 68.4 months (IQR, 49.9–93.3 months), we investigated the incidence of new-onset AF. Of the 1,040 patients, 103 (9.9%) developed AF. Patients who developed AF were older than patients who did not. Total heart beats, premature atrial contraction (PAC) count, maximum RR interval, and frequency of sinus pause quantified on 24-h electrocardiography were associated with new-onset AF. LA diameter (LAD) on echocardiography was also associated with the development of AF. On multivariate Cox analysis, age ≥58 years, PAC count ≥80 beats/day, maximum RR interval ≥1.64 s, and LAD ≥4.5 cm were independently associated with the development of AF. The incidence rate of new-onset AF significantly increased as the combined score (i.e., the sum of the risk score determined using hazard ratios) increased.
Conclusions: A combined score that includes age, PAC count, maximum RR interval, and LAD could help characterize the risk of new-onset AF.
Background: Catheter ablation is a good treatment option for atrial fibrillation (AF) in young symptomatic patients. However, there is little information on the efficacy of catheter ablation of early-onset AF between sexes.
Methods and Results: This study included 1,060 patients under the age 60 years old (837 men, 49.8±7.7 years old, 70.8% paroxysmal AF) who underwent catheter ablation for AF. Sex differences in clinical presentation and ablation outcomes were compared with and without propensity score-matching. During 24.5±18.9 months of follow-up, women showed significantly higher clinical recurrence of AF than men (log-rank, P=0.002). Female sex was independently associated with post-ablation clinical recurrence of AF (adjusted hazard ratio (HR) 2.58 [1.06–6.30], P=0.037). Women had a higher proportion of left ventricular diastolic dysfunction (E/Em, P<0.001), higher prevalence of heart failure (P=0.017), greater left atrial (LA) volume index (P=0.001), lower LA endocardial voltage (P<0.001), and higher parasympathetic nervous activity (root-mean square of differences, P<0.001; high-frequency (HF), P=0.010) than men. After a second ablation procedure (n=111), women still showed a higher clinical recurrence rate than men (log-rank, P=0.003) during 22.9±15.0 months of follow-up.
Conclusions: Among patients with early-onset AF who underwent catheter ablation, women showed poorer clinical outcomes than men after de novo and second procedures. Left ventricular dysfunction, LA remodeling, and autonomic nervous function may be potential mechanisms underlying sex differences in catheter ablation outcomes of early-onset AF.
Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) has been often misdiagnosed as long QT syndrome (LQTS) type 1 (LQT1), which phenotypically mimics CPVT but has a relatively better prognosis.
Methods and Results: The derivation and validation cohorts consisted of 146 and 21 patients, respectively, all of whom had exercise- or emotional stress-induced cardiac events. In the derivation cohort, 42 and 104 patients were first clinically diagnosed with CPVT and LQTS, respectively. Nine of 104 patient who had initial diagnosis of LQTS were found to carry RYR2 mutations. They were misdiagnosed due to 4 different reasons: (1) transient QT prolongation after cardiopulmonary arrest; (2) QT prolongation after epinephrine test; (3) absence of ventricular arrhythmia after the exercise stress test (EST); and (4) assumption of LQTS without evidence. Based on genetic results, we constructed a composite scoring system by modifying the Schwartz score: replacing the corrected QT interval (QTc) at 4 min recovery time after EST >480 ms with that at 2 min, or with ∆QTc (QTc at 2 min of recovery−QTc before exercise) >40 ms and assigning a score of −1 for ∆QTc <10 ms or documented polymorphic ventricular arrhythmias. This composite scoring yielded 100% sensitivity and specificity for the clinical differential diagnosis between LQT1 and CPVT when applied to the validation cohort.
Conclusions: The modified Schwartz score facilitated the differential diagnosis between LQT1 and CPVT.
Background: It is unclear whether renal dysfunction affects warfarin control in patients with non-valvular atrial fibrillation (NVAF).
Methods and Results: Using a dataset from the J-RHYTHM Registry, time in therapeutic range (TTR) of the international normalized ratio (INR) of prothrombin time, and creatinine clearance (CrCl) were determined in elderly patients aged ≥70 years. Target INR values were 1.6–2.6 following Japanese guidelines. Incidences of thromboembolism, major hemorrhage, and all-cause death were determined over 2 years. Of 7,406 NVAF patients enrolled in the registry, 2,782 elderly patients (mean age, 75 years) had data for CrCl measured at baseline and TTR. TTR values were lower in the lower CrCl groups (P<0.001 for trend). CrCl <30 mL/min was independently associated with TTR <65% (odds ratio, 1.49; 95% confidence interval, 1.13–1.95; P=0.004). In the multivariate analysis, TTR <65% was independently associated with thromboembolism (hazard ratio, 2.26; 95% confidence interval, 1.37–3.72; P=0.001), but CrCl was not (CrCl <30 mL/min, 1.68, 0.41–6.85, P=0.473). However, CrCl <30 mL/min and TTR <65% were independently associated with all-cause death (5.32, 1.56–18.18, P=0.008 and 1.60, 1.07–2.38, P=0.022, respectively) and the composite event (thromboembolism, major hemorrhage and all-cause death) (2.03, 1.10–3.76, P=0.024 and 1.58, 1.22–2.04, P=0.001, respectively).
Conclusions: Elderly NVAF patients with renal dysfunction had poor warfarin control, which was associated with higher risk of thromboembolism and all-cause death.
Background: The Resolute Integrity coronary drug-eluting stent (DES), the next evolution of the Resolute DES, is designed with thinner stent struts and continuous sinusoidal technology to further enhance performance. This study evaluated the performance of the Resolute Integrity DES compared with the historical performance of Xience V.
Methods and Results: We assessed the safety, efficacy, and deliverability of Resolute Integrity compared with the Xience DES, the prespecified historical control, in PROPEL, a large, real-world prospective, single-arm, open-label study. A total of 1,204 subjects were enrolled in PROPEL and treated with the Resolute Integrity DES at 76 sites in Japan. Lesion and procedural success rates were 100% and 99%, respectively. Patients were equally complex in the Resolute Integrity and Xience cohorts. At 1 year in the clinical-only cohort, the primary endpoint target lesion failure was 4.3% (34/800) in the Resolute Integrity cohort compared with 8.5% (97/1,142) in the Xience historical controls (P<0.001 for non-inferiority). Target vessel failure, major adverse cardiac events, target vessel myocardial infarction, and the composite cardiac death and target vessel myocardial infarction were all lower with Resolute Integrity compared with Xience, including in “high risk” patients.
Conclusions: In the large, prospective, multicenter PROPEL trial, the performance of the Resolute Integrity DES was non-inferior to that of the benchmark Xience DES used as a historical comparator.
Background: Embolism during percutaneous coronary intervention (PCI) causes microcirculation impairment. The aim of this study was to clarify the relationship between the pathological characteristics of tissue captured by distal protection device (DPD) and amount of tissue accumulated in DPD.
Methods and Results: A total of 671 consecutive lesions in PCI using DPD were examined. The amount of necrotic debris, fibrous tissue, calcified particle, platelet thrombus and organized thrombus in the DPD baskets was histologically evaluated. The DPD tissue amount was assessed semi-quantitatively, and the relationship between the captured DPD tissue characteristics and tissue amount was investigated. On pathology, 40.7% of the lesions had necrotic debris, 41.4% had fibrous tissue, and 18.0% had calcified particle. The prevalence of lesions in patients with acute coronary syndrome (ACS) was 62.1%. Tissue amount score distribution was as follows: score 1 (tissue invisible), 3.9%; score 2 (tissue clinging to the basket), 52.0%; score 3 (tissue accumulated at the bottom of the basket), 38.5%; and score 4 (tissue accumulated in more than half of the basket), 5.7%. On multivariate analysis, necrotic debris and fibrous tissue were associated with greater tissue amount as well as clinical presentation of ACS.
Conclusions: The presence of atherosclerotic plaque component, such as necrotic debris and fibrous tissue, might be a risk for distal embolism during PCI.
Background: Detection of yellow plaques (YP) by coronary angioscopy (CAS) 1 year after 1st-generation drug-eluting stent (DES) implantation has been related to future coronary events. However, the association between CAS findings and clinical outcomes following 2nd-generation DES implantation has not been investigated.
Methods and Results: This study included a total of 248 2nd-generation DES in 179 patients, who were examined by CAS 9±2 months after implantation. Angioscopic evaluation included dominant neointimal coverage (NIC) grade, heterogeneity of NIC, presences of YP and intrastent thrombus. The outcome measure was major adverse cardiac events (MACE) defined as a composite of cardiac death, acute myocardial infarction and any coronary revascularization. The association between the CAS findings and MACE was evaluated using the Kaplan-Meier method. A Cox proportional hazards model was used to assess the predictors of MACE. The mean follow-up duration was 1,367±843 days. Dominant NIC grade (P=0.98), heterogeneity of NIC (P=0.20) and YP (P=0.53) were not associated with the incidence of MACE. However, intrastent thrombus was significantly associated with MACE (P=0.033). Intrastent thrombus (adjusted hazard ratio: 2.22; 95% confidence interval [CI]: 1.12–4.39), acute coronary syndrome (2.83; 95% CI: 1.42–5.67) and B2/C lesion (2.13; CI: 1.12–4.05) were independent predictors of MACE.
Conclusions: Subclinical intrastent thrombus observed by CAS at 9 months after 2nd-generation DES implantation was independently associated with poor clinical outcome.
Background: Recurrent ventricular tachyarrhythmias (VTA) are “A factor” modifiers in the Interagency Registry for Mechanically Assisted Circulatory Support profile. The effect of recurrent VTA on clinical outcome, however, is controversial. We evaluated the impact of recurrent VTA on outcome in Japanese heart transplant candidates with a left ventricular assist device (LVAD).
Methods and Results: Sixty-six adult patients with advanced heart failure who were listed for heart transplantation between January 2005 and October 2017 were enrolled in the study. Recurrent VTA (modifier A status) was defined as a sustained ventricular tachycardia or fibrillation that required implantable cardioverter defibrillator shocks or an external defibrillator more than twice weekly. The primary outcome was death from any cause. The secondary outcomes were the first occurrence of VTA and recurrent VTA after LVAD implantation. Sixteen patients (24%) met the criteria for modifier A status, and 15 patients had an LVAD implanted. During a median follow-up of 1,124 days, 21 of 60 patients with an LVAD died. There was a significantly higher mortality rate in LVAD patients with modifier A status than in those who did not meet the modifier A criteria. On multivariate analysis, patients with modifier A status had an increased risk of mortality (HR, 3.43; 95% CI: 1.30–8.61, P=0.001).
Conclusions: Recurrent VTA might be a marker for worse outcome in Japanese heart transplant candidates with an LVAD.
Background: Mid-diastolic mitral forward flow (L wave) is occasionally detected in heart failure (HF), but its correlates and prognostic value are still unknown, particularly in light of the type of HF, that is, HF with preserved or with reduced ejection fraction (HFpEF, HFrEF).
Methods and Results: Of 151 patients with HF, L wave was observed in 23 of 82 HFrEF patients and in 25 of 69 HFpEF patients. Mitral early diastolic velocity (E), the ratio of E to mitral annulus velocity, and left atrial volume index were greater in the patients with L wave than in those without L wave in both subsets. Left ventricular (LV) mass index and relative wall thickness were greater in the patients with L wave than in those without L wave in the HFpEF group, but there was no difference in either parameter in the HFrEF group. Prognosis was poorer in those with L wave than in those without L wave both in the HFrEF and HFpEF groups.
Conclusions: Appearance of L wave is associated with the degree of LV diastolic dysfunction, but there was a difference in LV geometrical correlates of the appearance of L wave between the HFpEF and HFrEF groups. Detection of L wave is suggestive of poor prognosis independent of LVEF in HF.
Background: We investigated the relationship between intraprocedural angiographic and echocardiographic AR severity after TAVI, and the clinical robustness of angiographic assessment.
Methods and Results: In 74 consecutive patients, the echocardiographic circumferential extent (CE) of the paravalvular regurgitant jet was retrospectively measured and graded based on the VARC-2 cut-points; and angiographic post-TAVI AR was retrospectively quantified using contrast videodensitometry (VD) software that calculates the ratio of the contrast time-density integral in the LV outflow tract to that in the ascending aorta (LVOT-AR). Seventy-four echocardiograms immediately after TAVI were analyzable, while 51 aortograms were analyzable for VD. These 51 echocardiograms and VD were evaluated. Median LVOT-AR across the echocardiographic AR grades was as follows: none-trace, 0.07 (IQR, 0.05–0.11); mild, 0.12 (IQR, 0.09–0.15); and moderate, 0.17 (IQR, 0.15–0.22; P<0.05 for none-trace vs. mild, and mild vs. moderate). LVOT-AR strongly correlated with %CE (r=0.72, P<0.0001). At 1 year, the rate of the composite end-point of all-cause death or HF re-hospitalization was significantly higher in >mild AR patients compared with no-mild AR on intra-procedural echocardiography (41.5% vs. 12.4%, P=0.03) as well as in patients with LVOT-AR >0.17 compared with LVOT-AR ≤0.17 (59.5% vs. 16.6%, P=0.03).
Conclusions: VD (LVOT-AR) has good intra-procedural inter-technique consistency and clinical robustness. Greater than mild post-TAVI AR, but not mild post-TAVI AR, is associated with late mortality.
Background: Due to concern about bleeding complications, a maintenance dose of prasugrel 2.5 mg may be used in elderly or low-body-weight patients in Japan. There is little information, however, on the efficacy and safety of a 2.5-mg maintenance dose of prasugrel.
Methods and Results: In this single-center, prospective, open-label, cross-over study, a total of 44 elderly (≥75 years old) or low body-weight (<50 kg) Japanese patients >1 month after percutaneous coronary intervention who were treated with aspirin 81–100 mg and clopidogrel 75 mg were randomized to either prasugrel 2.5 mg or 3.75 mg instead of clopidogrel for 14 days, with a cross-over directly to the alternate treatment for another 14 days. Platelet inhibition was assessed with the VerifyNow assay (Accumetrics, San Diego, CA, USA) at 3 time points: baseline; day 14; and day 28. P2Y12 reaction units (PRU) ≤95 was defined as low on-treatment platelet reactivity (LPR), and PRU ≥262 as high on-treatment platelet reactivity (HPR). The prevalence of LPR was 2.2% in patients treated with clopidogrel, 2.2% in those with prasugrel 2.5 mg, and 22.7% in those with prasugrel 3.75 mg (P<0.001). Clopidogrel resulted in the higher prevalence of HPR compared with 2.5-mg and 3.75-mg prasugrel (40.9% vs. 18.2% vs. 6.8%, P<0.001).
Conclusions: Prasugrel 2.5 mg may be more appropriate in elderly or lower-body-weight Japanese patients.
Background: In a previous study, a low level of miR-126-3p in endothelial progenitor cells (EPCs) was linked to the outcome of ischemic cardiomyopathy (ICM) patients. However, it remains unclear whether transplantation with miR-126-3p-overexpressing EPCs (MO-EPCs) can improve the cardiac function of ICM animal models.
Methods and Results: miR-126-3p overexpression by lentiviral vector significantly increased migration and tube-like structures of EPCs from ICM patients. MO-EPCs or non-modified EPCs (NM-EPCs) were transplanted into nude rats with ICM induced by coronary artery ligation. MO-EPC transplantation increased capillary density and EPC survival rate in myocardial tissues of nude rats. Cytokines were also assessed by antibody array and real-time RT-PCR. G-CSF, VEGF-A, IL-3, IL-10, IGF-1, angiogenin, HGF, TIMP-1 and TIMP-2 were upregulated, and IL-8, MCP-1, MCP-2, TNF-α, TNF-β and MIP-1β were downregulated after miR-126-3p overexpression in EPCs. The same results were obtained in infarction tissues of nude rats after MO-EPC transplantation. Eight weeks after MO-EPC transplantation, left ventricular function improved significantly with clearly decreased infarction size, increased anterior wall thickness, and inhibition of inflammation compared with the results for NM-EPC transplantation. However, MO-EPC transplantation showed no increase in survival time of nude rats with ICM during 8 weeks of observation.
Conclusions: miR-126-3p can restore the biology of EPCs from ICM patients. Moreover, MO-EPC transplantation improves cardiac function effectively, representing a promising future treatment for ICM.
Background: Although the coronary artery calcium score (CACS) is a prognostic measurement in asymptomatic individuals, it is measured in symptomatic patients using coronary computed tomography angiography (CCTA). We aimed to examine the predictive value of the CACS for mid- to long-term cardiovascular mortality and morbidity in patients who underwent CCTA.
Methods and Results: We studied 736 patients with suspected coronary artery disease (CAD) who underwent CCTA. During a median follow-up period of 6.5 years, there were 39 primary outcomes (composite of cardiovascular disease death, non-fatal myocardial infarction, and non-fatal stroke). The estimated 10-year cumulative rates of the primary outcome were significantly increased across CACS classes (3.9%, 9.2%, 11.8%, and 18.2% in CACS of 0, 1–99, 100–399, and ≥400, respectively, P<0.001). These rates of cardiovascular disease death and stroke were also significantly increased across CACS classes. Multivariate Cox proportional hazard analysis showed that a CACS ≥100 was independently predictive for the primary outcome (hazard ratio [HR] 2.82, 95% confidence interval [CI] 1.40–6.00, P=0.003), as well as the presence of ≥50% stenosis on CCTA (HR 2.27, 95% CI 1.13–4.46, P=0.022).
Conclusions: An elevated CACS with the use of CCTA is an independent predictor of mid- to long-term cardiovascular mortality and morbidity in patients suspected of having CAD.
Background: Pulmonary arterial (PA) wall thickening evaluated by optical coherence tomography (OCT) has been reported in adults with PA hypertension. The purpose of this study was to evaluate the feasibility of OCT for preoperative assessment of the PA wall in children with congenital heart disease (CHD).
Methods and Results: Participants comprised 39 patients with ventricular septal defect, atrial septal defect, or patent ductus arteriosus. Attempts were made to evaluate vessels of various diameters using OCT. Clearly observed vessels that were optimal for evaluation were selected and classified into 4 subgroups by diameter of the lumen. Optimal depiction was obtained in 80 of 156 vessels in total, and 25 (64.1%), 34 (87.1%), 17 (43.6%), and 4 vessels (10.3%) in each of the 1.0–<2.0 mm, 2.0–<3.0 mm, 3.0–<4.0 mm, and 4.0–5.0 mm subgroups, respectively. Arterial walls in the 2.0–<3.0 mm subgroup were the most frequently delineated, and wall thickness correlated significantly with mean PA pressure, pulmonary vascular resistance index, pulmonary-to-systemic flow ratio, and PA capacitance index (r=0.56, 0.52, 0.37, and −0.49, respectively). The 3-layered appearance was delineated in 29 of 80 vessels (36.2%). This feature had no significant correlation with pulmonary hemodynamics.
Conclusions: OCT represents a promising tool for evaluating the PA wall in children with CHD.
Background: This study aimed to evaluate the long-term results of tricuspid annuloplasty using the MC3 ring for functional tricuspid regurgitation (TR).
Methods and Results: Between 2004 and 2014, 249 patients underwent tricuspid ring annuloplasty using the MC3 ring for functional TR (FTR). Main etiologies of FTR were left-sided valvular disease (n=211) and left-to-right shunt (n=34). Based on the interval between the operation and last echocardiographic scan, patients were divided into short-term and long-term follow-up groups. Mean follow-up duration was 84.4±37.1 months. Operative death occurred in 8 patients (3.2%). Predischarge echocardiography showed that both TR grade and systolic pulmonary artery pressure were significantly decreased compared with preoperative values, and these values were sustained during follow-up in both the short-term and long-term follow-up groups. There were no ring-related complications in either the postoperative or follow-up period, except for permanent pacemaker implantation in 2 patients. The freedom from TR ≥moderate and tricuspid valve (TV)-related events at 10 years were 92.1% and 92.8%, respectively. TV annular size was a risk factor for the recurrence of TR ≥moderate (P=0.001), and 42 mm was the cutoff value for predicting the recurrence of TR ≥moderate.
Conclusions: Tricuspid annuloplasty using the MC3 ring for FTR provides satisfactory early results that are sustained during long-term follow-up. Preoperative TV annular size was associated with the recurrence of TR ≥moderate.
Background: To determine the type and frequency of vascular and organ malformations in adults with thalidomide embryopathy (TE) using non-contrast magnetic resonance angiography (MRA) and to assess the effect of the observed malformations on renal function.
Methods and Results: The institutional ethics committee approved this prospective study and written informed consent was given by all 78 subjects (50 females) with TE (mean age: 55±1.1 years), who were examined by non-contrast MRA at 3T. ECG-triggered balanced turbo field echo images of the chest, abdomen and pelvis were obtained in coronal and sagittal orientations. Two observers assessed the frequency of vascular and organ malformations. Serum creatinine and estimated glomerular filtration rate (eGFR) were obtained to assess renal function. In 58 subjects, 99 vascular anomalies were observed, including 68 arterial (69%) and 31 venous anomalies (31%); 15 patients had 16 abdominal organ malformations including 12 kidney anomalies and 4 cases of gallbladder agenesis. Most vascular anomalies affected the renal vessels (n=66, 67%) or supraaortic arteries (n=28, 28%). Serum creatinine and eGFR revealed normal renal function in all subjects.
Conclusions: Vascular and organ anomalies occurred in a high number of subjects with TE without evidence of renal dysfunction. Information about the presence of malformations may be important for future surgical interventions in subjects with TE.
Background: Physical activity is associated with lower risk of coronary and cerebrovascular disease but its potential role in prevention of aortic valve stenosis (AVS) is unclear.
Methods and Results: We investigated whether physical activity influences AVS risk in a cohort of 69,288 adults. During a mean follow-up of 15.3 years, 1,238 AVS cases were diagnosed. No associations were observed between AVS and walking/bicycling (≥1 h/day vs. almost never: hazard ratio 0.92, 95% CI 0.74–1.15) or exercise (≥4 hs/week vs. <1 h/week: hazard ratio 1.18, 95% CI 0.97–1.43).
Conclusions: Physical activity did not reduce the incidence of AVS.