Balloon-expandable transcatheter heart valves for treatment of aortic valve stenosis in patients with large aortic annuli: Evaluation of deployment balloon overfilling strategies.

OBJECTIVES: Transcatheter aortic valve implantation (TAVI) using balloon-expandable (BE) transcatheter heart valves (THV) in aortic annuli above 29 mm includes particular procedural steps, mainly involving overfilling of the deployment balloon. Data on overfilling strategies in clinical daily practice is scarce. We herein aimed for a retrospective description of utilized overfilling strategies in those patients. METHODS: Between January 2016 and December 2022, 45 patients (100% male, 76.9 ± 6.1 years) received TAVI in aortic annuli above 29 mm using a BE THV. Overfilling volumina of the deployment balloon were left to operators' discretion. Clinical and multislice computed tomography data were retrospectively collected. Clinical endpoints were adjudicated in accordance with the updated standardized VARC-3 definitions. RESULTS: Profound overfilling (+4/5 mL) was used in patients with a mild calcium burden (˂750 mm³) even in aortic annuli of 29.0-30.0 mm. Nominal/slight overfilling (+1 mL) was used in aortic annuli up to 32.5 mm but an intermediate to severe calcific burden (>750-3200 mm³). Accordingly, a low calcification group (˂750 mm³, n = 17) compared to a significant calcification group (≥750 mm³, n = 28), presented with higher overfilling volumina (2.1 ± 1.4 vs. 0.8 ± 1.0; p ˂ 0.001), although aortic annulus diameter was not different (29.8 ± 0.8 vs. 29.9 ± 0.9 mm; p = 0.7). All-cause 30-day mortality was 0%. Device success was 97.8%. Transvalvular mean pressure gradient at discharge was 9.5 ± 3.6 mmHg. No case of PVL >mild was documented. CONCLUSION: Extent of overfilling of the deployment balloon largely depends on calcification burden in addition to aortic annulus diameter with significant and profound overfilling particularly in patients with a calcification burden of the aortic valve complex ˂750 mm³.

Early outcome of endoscopic mitral valve surgery in elderly patients: a high-volume single center experience.

Introduction: Despite increasing use of transcatheter approaches, endoscopic mitral valve surgery (MVS) remains an established option for treatment of mitral regurgitation (MR). Nevertheless, as perioperative risk increases with age, outcome of endoscopic MVS in elderly patients is uncertain. Methods: We retrospectively analyzed 756 consecutive patients with MR ≥2, who underwent minimally-invasive MVS at our institution between 2016 and 2022. Patients were stratified by age ≥75 (elderly-group; n = 91) or <75 years (control-group; n = 665). All patients received endoscopic MVS via right anterolateral minithoracotomy with non-rib spreading soft tissue retraction and 3D-camera visualization. Results: Overall surgical risk was increased in the elderly-group (median age of 77 (76-80) years vs. 58 (51-67) years, p < 0.001) with STS-PROM Scores of 1.9% vs. 0.4% (p < 0.001) and increased prevalence of hypertension, diabetes, coronary artery disease and atrial fibrillation (AFib). Elderly patients were also more symptomatic (NYHA class III 45.7% vs. 29.8%; p = 0.002). Axillo-femoral perfusion was more frequently used in the elderly-group (27.5% vs. 4.2%; p < 0.001). Cross-clamp and cardiopulmonary bypass times were similar. Rate of MV repair was 85.7% vs. 93.8% (p = 0.005). Closure of the left atrial appendage was more frequently performed in the elderly-group (45.1% vs. 23.9%; p < 0.001), whereas rate of concomitant tricuspid valve repair was similar (11.0% vs. 8.9%; p = 0.511). Postoperative complications including perioperative hemodialysis (3.3% vs. 2.9%; p = 0.739), low cardiac output (5.3% vs. 3.8%; p = 0.393), perioperative stroke (1.1% vs. 0.15%; p = 0.224) and myocardial infarction (0% vs. 0.15%) were favorably low in both groups. Acute mortality at 30 days was 2.2% vs. 0.4% (p = 0.112). Conclusion: Despite increased prevalence of outcome-relevant comorbidities and surgical risk, perioperative outcome of patients aged ≥75 years undergoing endoscopic MVS is favorable. Therefore, endoscopic MVS is a valuable therapeutic option for selected elderly patients and should be taken in consideration during routine heart-team discussion.

Valve-in-valve procedures for degenerated surgical and transcatheter aortic valve bioprostheses using a latest-generation self-expanding intra-annular transcatheter heart valve.

Background: Valve-in-valve (ViV) transfemoral transcatheter aortic valve implantation (TAVI) for failing aortic surgical bioprostheses or transcatheter heart valves (THV) has demonstrated a reasonable clinical and hemodynamic efficacy. Traditionally, self-expanding (SE) supra-annular THV are considered to result in superior hemodynamics compared with balloon-expandable intra-annular THV after ViV. However, so far no data are found on latest-generation intra-annular SE THV for aortic ViV procedures which might be superior with regard to coronary access or subsequent valve reintervention. Aim: We herein aim to evaluate a latest-generation SE intra-annular THV for aortic ViV procedures. Materials and methods: Between May 2022 and November 2022, five consecutive patients (4/5 female with mean age of 76.2 years and mean Society of Thoracic Surgeons predicted risk of mortality score of 2.9%) received ViV TAVI using the Navitor system (Abbott, Chicago, IL, USA) for treatment of failing surgical bioprostheses or THV. Data were retrospectively analyzed according to updated Valve Academic Research Consortium 3 (VARC-3) definitions. Results: At 30 days, absence of mortality and VARC-3 adjudicated clinical endpoints were documented. Echocardiography at 30 days revealed complete absence of paravalvular leakage and single-digit mean transvalvular gradients (mean of 6.0 mmHg) in all patients. Conclusion: The investigated intra-annular SE THV results in excellent 30-day outcomes for aortic ViV procedures for failing surgical bioprostheses or THV. Despite the intra-annular design, hemodynamic results were excellent, even in small bioprostheses. Ease of use of this valve platform is reflected by only two cycles of resheathing in five ViV procedures with hemodynamic stability during all steps of valve deployment.

Impact of Mitral Regurgitation Etiology on Mitral Surgery After Transcatheter Edge-to-Edge Repair: From the CUTTING-EDGE Registry.

BACKGROUND: Although >150,000 mitral TEER procedures have been performed worldwide, the impact of MR etiology on MV surgery after TEER remains unknown. OBJECTIVES: The authors sought to compare outcomes of mitral valve (MV) surgery after failed transcatheter edge-to-edge repair (TEER) stratified by mitral regurgitation (MR) etiology. METHODS: Data from the CUTTING-EDGE registry were retrospectively analyzed. Surgeries were stratified by MR etiology: primary (PMR) and secondary (SMR). MVARC (Mitral Valve Academic Research Consortium) outcomes at 30 days and 1 year were evaluated. Median follow-up was 9.1 months (IQR: 1.1-25.8 months) after surgery. RESULTS: From July 2009 to July 2020, 330 patients underwent MV surgery after TEER, of which 47% had PMR and 53.0% had SMR. Mean age was 73.8 ± 10.1 years, median STS risk at initial TEER was 4.0% (IQR: 2.2%-7.3%). Compared with PMR, SMR had a higher EuroSCORE, more comorbidities, lower LVEF pre-TEER and presurgery (all P < 0.05). SMR patients had more aborted TEER (25.7% vs 16.3%; P = 0.043), more surgery for mitral stenosis after TEER (19.4% vs 9.0%; P = 0.008), and fewer MV repairs (4.0% vs 11.0%; P = 0.019). Thirty-day mortality was numerically higher in SMR (20.4% vs 12.7%; P = 0.072), with an observed-to-expected ratio of 3.6 (95% CI: 1.9-5.3) overall, 2.6 (95% CI: 1.2-4.0) in PMR, and 4.6 (95% CI: 2.6-6.6) in SMR. SMR had significantly higher 1-year mortality (38.3% vs 23.2%; P = 0.019). On Kaplan-Meier analysis, the actuarial estimates of cumulative survival were significantly lower in SMR at 1 and 3 years. CONCLUSIONS: The risk of MV surgery after TEER is nontrivial, with higher mortality after surgery, especially in SMR patients. These findings provide valuable data for further research to improve these outcomes.

Early Outcomes of Endoscopic Papillary Muscle Relocation for Secondary Mitral Regurgitation Type IIIb in Patients With Severe Left Ventricular Dysfunction.

Objective: Subannular mitral valve (MV) repair techniques have been developed to address increased rates of recurrent mitral regurgitation (MR) in patients with secondary MR (SMR) type IIIb. Endoscopic papillary muscle relocation (PMR) is feasible via minithoracotomy. Nevertheless, the periprocedural outcome of patients with severe left ventricular (LV) dysfunction remains unknown. Methods: A total of 98 consecutive patients with SMR type IIIb underwent PMR at our institution. Due to concomitant coronary artery bypass grafting, 62 patients underwent sternotomy and were excluded from the current analysis, whereas 36 patients were treated by a minimally invasive technique using 3-dimensional endoscopy. Of these, 18 patients had severely depressed LV ejection fraction (LVEF) ≤35% (study group) and were compared to the remaining 18 patients with LVEF >35% (control group). Periprocedural outcome was retrospectively analyzed. Results: Although LVEF was significantly worse in the study group (30% ± 4% vs 43% ± 6%, P < 0.001), the severity of SMR and the degree of MV leaflet tethering were similar. The prevalence of concomitant procedures and the duration of surgery, cardiopulmonary bypass, and aortic cross-clamp were comparable. Periprocedural low cardiac output syndrome was favorably low in both groups (16.7% vs 5.6%, P = 0.29). Postoperative ventilation time (5.7 h [4.2 to 8.7 h] vs 6.0 h [4.6 to 9.8 h], P = 0.43) and duration of intensive care unit stay (2 days [1 to 3 days] vs 2 days [1 to 3 days], P = 0.22) were similar. There was no 30-day mortality in either group. Conclusions: Standardized endoscopic PMR resulted in favorable periprocedural outcomes in patients with severe LV dysfunction, suggesting that minimally invasive surgery can safely be extended to this patient population.

Standardized papillary muscle relocation for type IIIb secondary mitral regurgitation improves 2-year outcome.

OBJECTIVES: The major drawback of isolated annuloplasty for treatment of secondary mitral regurgitation (SMR) with restricted leaflet motion during systole (type IIIb) is the recurrence of SMR, leading to adverse clinical outcome. Additional papillary muscle relocation (PMR) specifically addresses leaflet tethering to restore mitral valve geometry. We aimed to compare the 2-year outcome of annuloplasty with additional PMR vs isolated annuloplasty. METHODS: A total of 105 consecutive type IIIb SMR patients with preoperative left ventricular (LV) ejection faction <45%, left ventricular end-diastolic diameter >55 mm and a tenting height >10 mm reached 2-year postoperative follow-up after mitral valve repair and were included in the current analysis. A total of 51 patients underwent annuloplasty and additional PMR (study group). A total of 54 patients underwent isolated annuloplasty (control group). Primary composite study end point comprised death or recurrence of mitral regurgitation ≥2 at 2 years postoperatively. RESULTS: Echocardiographic baseline variables indicating the severity of LV dysfunction and mitral leaflet tethering were similar. Procedural and periprocedural outcome was comparable in both groups. The primary composite end point was significantly improved in the study group (19.6% [10/51]) in comparison to the control group (44.4% [24/54]; P = 0.009). Two-year all-cause mortality was 7.8% [4/51] in the study group vs 18.5% [10/54] in the control group (P = 0.098). After 2 years, a significant improvement in New York Heart Association functional class as compared to the baseline values was observed in the study group. CONCLUSIONS: Additional PMR to treat SMR type IIIb resulted in an improved 2-year outcome in comparison to isolated annuloplasty. PMR specifically addressing mitral leaflet tethering represents a valid therapeutic option for heart failure patients with SMR type IIIb.

Contemporary Outcome Trends in Transcatheter Aortic Valve-in-Valve Implantation Versus Redo Aortic Valve Replacement.

As valve-in-valve (ViV) transcatheter aortic valve implantation is still an evolving method, we evaluated the development of early and midterm outcomes after ViV and conventional redo-surgical aortic valve replacement (SAVR) over the past 2 decades. In-hospital databases were retrospectively screened for patients ≥60 years treated for failing bioprosthetic aortic valves at our center. Clinical and follow-up characteristics were compared between patients who underwent ViV or redo-SAVR according to valve academic research consortium-2 (VARC-2) definitions. The comparison of outcome parameters was adjusted for baseline differences between groups. Between June 2002 and April 2020, 209 patients with ViV and 65 redo-SAVR patients met inclusion criteria. No significant differences were found in 30 days (ViV 3.8%, SAVR 3.1%, p = 0.778) or 6-month mortality (ViV 14.0%, SAVR 7.5%, p = 0.283). As patients with ViV less frequently experienced acute kidney injury (stage II or III) and life-threatening bleeding, they more frequently reached the 30-day VARC-2 combined safety end point (79.2% vs 61.5%, odds ratio [OR] 2.540, p = 0.023). Patients with ViV less frequently reached clinical efficacy (68.3% vs 84.6%, OR 0.408, p = 0.041) and device success (79.9% vs 92.3%, OR 0.311, p = 0.040) end points, because of higher frequency of postprocedural transvalvular gradients >20 mm Hg. However, over the past decade, VARC-2 clinical efficacy and device success rates continuously increased in ViV cases. In conclusion, ViV and SAVR were associated with similar acute mortality and different beneficial and adverse outcome profiles in this single-center cohort. Results after ViV procedures have continuously improved over the past years.

End-stage renal disease, calcification patterns and clinical outcomes after TAVI.

BACKGROUND: Patients with chronic hemodialysis due to end-stage renal disease (ESRD) or severely impaired kidney function (CKD) constitute a relevant share of patients undergoing trans-catheter aortic valve implantation (TAVI). However, data on specific challenges and outcomes remain limited. AIM: We aimed to characterize this patient population, evaluate clinical results and assess the significance of calcification patterns. METHODS: This retrospective single-center analysis evaluated 2,712 TAVI procedures (2012-2019) according to baseline renal function: GFR < 30 ml/min/1.73m2 (CKD; n = 210), chronic hemodialysis (ESRD; n = 119) and control (CTRL; n = 2383). Valvular and vascular calcification patterns were assessed from contrast-enhanced multi-detector computed tomography. Outcomes were evaluated in accordance with the VARC-2 definitions. RESULTS: Operative risk was higher in ESRD and CKD vs. CTRL (STS-score 8.4% and 7.6% vs. 3.9%, p < 0.001) and patients with ESRD had more severe vascular calcifications (49.1% vs. 33.9% and 29.0%, p < 0.01). Immediate procedural results were similar but non-procedure-related major/life-threatening bleeding was higher in ESRD and CKD (5.0% and 5.3% vs. 1.6%, p < 0.01). 3-year survival was impaired in patients with ESRD and CKD (33.3% and 35.3% vs. 65.4%, p < 0.001). Multivariable analysis identified ESRD (HR 1.60), CKD (HR 1.79) and vascular calcifications (HR 1.29) as predictors for 3-year and vascular calcifications (HR 1.51) for 30-day mortality. CONCLUSION: Patients with ESRD and CKD constitute a vulnerable patient group with extensive vascular calcifications. Immediate procedural results were largely unaffected by renal impairment, yielding TAVI a particularly valuable treatment option in these high-risk operative patients. Mid-term survival was determined by underlying renal disease, cardiovascular comorbidities, and vascular calcifications as a novel risk marker.

Transaxillary transcatheter ACURATE neo aortic valve implantation - The TRANSAX multicenter study.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) via transaxillary (TAx) approach with ACURATE neo valve is an off-label procedure. Our aim was to gather information on ACURATE neo cases implanted via TAx approach and report major outcomes. METHODS AND RESULTS: The TRANSAX Study (NCT04274751) retrospectively gathered patients from nine centres in Europe and North America treated with ACURATE neo valve through TAx approach up to May/2019. Follow up was pre-specified at 1-year and was obtained for all patients. A total of 75 patients (79 ± 10 years; 32% women) were included. Left axillary (72%) and conscious sedation (95.2%) were the most common setting. Risk scores were higher when right axillary artery and surgical cut-down were selected. Severe complications including valve embolization, coronary obstruction, annulus rupture, and procedural mortality did not occur. Cardiac tamponade occurred in two cases (2.7%) with one requiring conversion to open surgery (1.3%). Bail-out stenting and surgical vascular repair were required in 7 (9.3%) and 3 (4%) cases, respectively. The need for new permanent pacemaker was 8%. Procedural success (96%), in-hospital (2.7%), and 1-year mortality (8%) were comparable in all settings. Only one case (1.3%) complicated with cerebrovascular event and one (1.3%) presented moderate aortic regurgitation before discharge. CONCLUSIONS: TAx TAVR procedures with the ACURATE neo valve were presented high success rate and low in-hospital and 1-year mortality.

Prognostic value of the H2 FPEF score in patients undergoing transcatheter aortic valve implantation.

AIMS: The aim of this study was to assess the prognostic value of the H2 FPEF score in patients undergoing transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS) and preserved left ventricular ejection fraction (EF). METHODS AND RESULTS: In this multicentre study, a total of 832 patients from two German high-volume centres, who received TAVI for severe AS and preserved EF (≥50%), were identified for calculation of the H2 FPEF score. Patients were dichotomized according to low (0-5 points; n = 570) and high (6-9 points; n = 262) H2 FPEF scores. Kaplan-Meier and Cox regression analyses were applied to assess the prognostic impact of the H2 FPEF score. We observed a decrease in stroke volume index (-2.04 mL/m2 /point) and mean transvalvular gradients (-1.14 mmHg/point) with increasing H2 FPEF score translating into a higher prevalence of paradoxical low-flow, low-gradient AS among patients with high H2 FPEF score. One year after TAVI, the rates of all-cause (low vs. high H2 FPEF score: 8.0% vs. 19.4%, P < 0.0001) and cardiovascular (CV) mortality (1.9% vs. 9.0%, P < 0.0001) as well as the rate of CV mortality or rehospitalization for congestive heart failure (6.4% vs. 23.2%, P < 0.0001) were higher in patients with high H2 FPEF score compared with those with low H2 FPEF score. After multivariable analysis, a high H2 FPEF score remained independently predictive of all-cause mortality [hazard ratio 1.59 (1.28-2.35), P = 0.018] and CV mortality or rehospitalization for congestive heart failure [hazard ratio 2.92 (1.65-5.15), P < 0.001]. Among the H2 FPEF score variables, atrial fibrillation, pulmonary hypertension, and elevated left ventricular filling pressure were the strongest outcome predictors. CONCLUSIONS: The H2 FPEF score serves as an independent predictor of adverse CV and heart failure outcome among TAVI patients with preserved EF. A high H2 FPEF score is associated with the presence of paradoxical low-flow, low-gradient AS, the HFpEF in patients with AS. By identifying patients in advanced stages of HFpEF, the H2 FPEF score might be useful as a risk prediction tool in patients with preserved EF scheduled for TAVI.

TAVI for Pure Non-calcified Aortic Regurgitation Using a Self-Expandable Transcatheter Heart Valve.

Objectives: Transcatheter aortic valve implantation (TAVI) is routinely performed in patients with severe aortic stenosis (AS). For patients with pure non-calcified aortic regurgitation (AR) who are not suitable for open heart surgery no clear recommendations exist and use of TAVI has been largely off-label. We herein report a series of patients treated with the self-expandable AcurateNeo and Neo2 (Boston Scientific Co., Marlborough, MS, USA) transcatheter heart valve (THV) for pure AR. Methods: Between 05/2017 and 03/2021, 9 patients (88.8% female, 74.4 ± 7.1 years, logEuroSCORE II 5.5 ± 3.6%, STS PROM 6.2 ± 3.0%) received transfemoral (TF) TAVI for pure non-calcified AR following an adjusted valve sizing algorithm. Data were retrospectively analyzed according to updated Valve Academic Research Consortium (VARC-2) definitions. Results: Device success was 100%. Early safety was 77.7% (7/10), due to two (22.2%) cases of acute kidney injury. Thirty-day mortality was 0%, in seven (77.7%) patients no or trace paravalvular leakage (PVL) was seen and mild PVL in two (22.2%) patients at 30-day follow-up. No permanent pacemaker (PPM) was required during 30-day follow-up. Conclusion: In this series of selected patients using the Acurate neo THV for pure non-calcified AR, safety and efficacy were demonstrated. Thirty-day mortality as well as PPM implantation and PVL rates showed excellent results in this high-risk patient cohort. These results will have to be confirmed in larger patient cohorts.

TAVR for low-flow, low-gradient aortic stenosis: Prognostic impact of aortic valve calcification.

BACKGROUND: Compared to high gradient aortic stenosis (AS), patients with low-flow, low-gradient AS have higher mortality after transcatheter aortic valve replacement (TAVR), but distinct outcome predictors in this patient subset are yet to be determined. The present study investigated the prognostic impact of aortic valve calcification (AVC) in patients with low-flow, low-gradient AS undergoing TAVR. METHODS: This retrospective single-center analysis includes all patients undergoing TAVR for severe low-flow, low-gradient AS (n = 526), ie, low EF low gradient AS (LEF-LG AS; n = 290) and paradoxical low-flow, low-gradient AS (PLF-LG AS; n = 236), in whom AVC was quantified from contrast-enhanced multislice computed tomography images. AVCdensity was defined as calcium volume per annulus area. Patients were trichotomized according to sex-specific AVCdensity tertiles in both subgroups. All-cause mortality was assessed by Kaplan-Meier analyses and independent outcome predictors were determined by multivariable analyses. RESULTS: In both subgroups, patients with high AVCdensity had higher mean transvalvular gradients at baseline and higher rates of PVL after TAVR. High AVCdensity was associated with lowest 1- and 3-year mortality after TAVR in the LEF-LG AS but not in the PLF-LG AS group. According to multivariable analysis AVCdensity was independently associated with better survival in LEF-LG AS patients (HR 0.73 [0.60-0.88], P = .0011), but not in those with PLF-LG AS (HR 0.91 [0.73-1.14], P = .42). CONCLUSIONS: Quantification of AVC may not only be of diagnostic but also of prognostic value, as it facilitates the selection of LEF-LG AS patients with higher probability of beneficial outcome after TAVR.

Hepatitis delta virus persists during liver regeneration and is amplified through cell division both in vitro and in vivo.

OBJECTIVE: Hepatitis delta virus (HDV) was shown to persist for weeks in the absence of HBV and for months after liver transplantation, demonstrating the ability of HDV to persevere in quiescent hepatocytes. The aim of the study was to evaluate the impact of cell proliferation on HDV persistence in vitro and in vivo. DESIGN: Genetically labelled human sodium taurocholate cotransporting polypeptide (hNTCP)-transduced human hepatoma(HepG2) cells were infected with HBV/HDV and passaged every 7 days for 100 days in the presence of the entry inhibitor Myrcludex-B. In vivo, cell proliferation was triggered by transplanting primary human hepatocytes (PHHs) isolated from HBV/HDV-infected humanised mice into naïve recipients. Virological parameters were measured by quantitative real time polymerase chain reaction (qRT-PCR). Hepatitis delta antigen (HDAg), hepatitis B core antigen (HBcAg) and cell proliferation were determined by immunofluorescence. RESULTS: Despite 15 in vitro cell passages and block of viral spreading by Myrcludex-B, clonal cell expansion permitted amplification of HDV infection. In vivo, expansion of PHHs isolated from HBV/HDV-infected humanised mice was confirmed 3 days, 2, 4 and 8 weeks after transplantation. While HBV markers rapidly dropped in proliferating PHHs, HDAg-positive hepatocytes were observed among dividing cells at all time points. Notably, HDAg-positive cells appeared in clusters, indicating that HDV was transmitted to daughter cells during liver regeneration even in the absence of de novo infection. CONCLUSION: This study demonstrates that HDV persists during liver regeneration by transmitting HDV RNA to dividing cells even in the absence of HBV coinfection. The strong persistence capacities of HDV may also explain why HDV clearance is difficult to achieve in HBV/HDV chronically infected patients.

Binding of hepatitis B virus to its cellular receptor alters the expression profile of genes of bile acid metabolism.

UNLABELLED: Chronic hepatitis B virus (HBV) infection has been associated with alterations in lipid metabolism. Moreover, the Na+-taurocholate cotransporting polypeptide (NTCP), responsible for bile acid (BA) uptake into hepatocytes, was identified as the functional cellular receptor mediating HBV entry. The aim of the study was to determine whether HBV alters the liver metabolic profile by employing HBV-infected and uninfected human liver chimeric mice. Humanized urokinase plasminogen activator/severe combined immunodeficiency mice were used to establish chronic HBV infection. Gene expression profiles were determined by real-time polymerase chain reaction using primers specifically recognizing transcripts of either human or murine origin. Liver biopsy samples obtained from HBV-chronic individuals were used to validate changes determined in mice. Besides modest changes in lipid metabolism, HBV-infected mice displayed a significant enhancement of human cholesterol 7α-hydroxylase (human [h]CYP7A1; median 12-fold induction; P<0.0001), the rate-limiting enzyme promoting the conversion of cholesterol to BAs, and of genes involved in transcriptional regulation, biosynthesis, and uptake of cholesterol (human sterol-regulatory element-binding protein 2, human 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and human low-density lipoprotein receptor), compared to uninfected controls. Significant hCYP7A1 induction and reduction of human small heterodimer partner, the corepressor of hCYP7A1 transcription, was also confirmed in liver biopsies from HBV-infected patients. Notably, administration of Myrcludex-B, an entry inhibitor derived from the pre-S1 domain of the HBV envelope, provoked a comparable murine CYP7A1 induction in uninfected mice, thus designating the pre-S1 domain as the viral component triggering such metabolic alterations. CONCLUSION: Binding of HBV to NTCP limits its function, thus promoting compensatory BA synthesis and cholesterol provision. The intimate link determined between HBV and liver metabolism underlines the importance to exploit further metabolic pathways, as well as possible NTCP-related viral-drug interactions.