Distribution of Cerebrovascular Phenotypes According to Variants of the ENG and ACVRL1 Genes in Subjects with Hereditary Hemorrhagic Telangiectasia.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder caused, in more than 80% of cases, by mutations of either the endoglin (ENG) or the activin A receptor-like type 1 (ACVRL1) gene. Several hundred variants have been identified in these HHT-causing genes, including deletions, missense and nonsense mutations, splice defects, duplications, and insertions. In this study, we have analyzed retrospectively collected images of magnetic resonance angiographies (MRA) of the brain of HHT patients, followed at the HHT Center of our University Hospital, and looked for the distribution of cerebrovascular phenotypes according to specific gene variants. We found that cerebrovascular malformations were heterogeneous among HHT patients, with phenotypes that ranged from classical arteriovenous malformations (AVM) to intracranial aneurysms (IA), developmental venous anomalies (DVA), and cavernous angiomas (CA). There was also wide heterogeneity among the variants of the ENG and ACVRL1 genes, which included known pathogenic variants, variants of unknown significance, variants pending classification, and variants which had not been previously reported. The percentage of patients with cerebrovascular malformations was significantly higher among subjects with ENG variants than ACVRL1 variants (25.0% vs. 13.1%, p < 0.05). The prevalence of neurovascular anomalies was different among subjects with different gene variants, with an incidence that ranged from 3.3% among subjects with the c.1231C > T, c.200G > A, or c.1120C > T missense mutations of the ACVRL1 gene, to 75.0% among subjects with the c.1435C > T missense mutation of the ACVRL1 gene. Further studies and larger sample sizes are required to confirm these findings.

Combined Treatment With Carotid Endoarterectomy and Coronary Artery Bypass Grafting: A Single-Institutional Experience in 222 Patients.

INTRODUCTION: Carotid atherosclerotic disease is a known independent risk factor of post operative stroke after coronary artery bypass grafting (CABG). The best management of concomitant coronary artery disease and carotid artery disease remains debated. Current strategies include simultaneous carotid endoarterectomy (CEA) and CABG, staged CEA followed by CABG, staged CABG followed by CEA, staged transfemoral carotid artery stenting (TF-CAS) followed by CABG, simultaneous TF-CAS and CABG and transcarotid artery stenting. METHODS: We report our experience based on a cohort of 222 patients undergoing combined CEA and CABG surgery who come to our observation from 2004 to 2020. All patients with >70% carotid stenosis and severe multivessel or common truncal coronary artery disease underwent combined CEA and CABG surgery at our instituion. 30% of patients had previously remote neurological symptoms or a cerebral CT-scan with ischemic lesions. Patients with carotid stenosis >70%, either asymptomatic or symptomatic, underwent CT-scan without contrast media to assess ischemic brain injury, and in some cases, if necessary, CT-angiography of the neck and intracranial vessels. RESULTS: The overall perioperative mortality rate was 4.1% (9/222 patients). Two patients (.9%) had periprocedural ipsilateral transient ischemic attack (TIA) which completely resolved by the second postoperative day. Two patients (.9%) had an ipsilateral stroke, while 7 patients (3.2%) had a stroke of the controlateral brain hemisphere. Two patients (.9%) patients were affected by periprocedural coma caused by cerebral hypoperfusion due to perioperative heart failure. There were no statistically significant differences between patients in Extracorporeal Circulation (ECC) and Off-pump patients in the onset of perioperative stroke. CONCLUSION: Our experience reported that combined surgical treatment of CEA and CABG, possibly Off-Pump, is a feasible treatment procedure, able to minimize the risk of post-operative stroke and cognitive deficits.

Beneficial Effects of Remote Medical Care for Patients with Hereditary Hemorrhagic Telangiectasia during the COVID-19 Pandemic.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) needs high-quality care and multidisciplinary management. During the COVID-19 pandemic, most non-urgent clinical activities for HHT outpatients were suspended. We conducted an analytical observational cohort study to evaluate whether medical and psychological support, provided through remote consultation during the COVID-19 pandemic, could reduce the complications of HHT. METHODS: A structured regimen of remote consultations, conducted by either video-calls, telephone calls, or e-mails, was provided by a multidisciplinary group of physicians to a set of patients of our HHT center. The outcomes considered were: number of emergency room visits/hospitalizations, need of blood transfusions, need of iron supplementation, worsening of epistaxis, and psychological status. RESULTS: The study included 45 patients who received remote assistance for a total of eight months. During this period, 9 patients required emergency room visits, 6 needed blood transfusions, and 24 needed iron supplementation. This was not different from what was registered among the same 45 patients in the same period of the previous year. Remote care also resulted in better management of epistaxis and improved quality of life, with the mean epistaxis severity score and the Euro-Quality of Life-Visual Analogue Scale that were significantly better at the end than at the beginning of the study. DISCUSSION: Remote medical care might be a valid support for HHT subjects during periods of suspended outpatient surveillance, like the COVID-19 pandemic.

QTc Interval Prolongation and Life-Threatening Arrhythmias During Hospitalization in Patients With Coronavirus Disease 2019 (COVID-19): Results From a Multicenter Prospective Registry.

BACKGROUND: Prolonged QTc intervals and life-threatening arrhythmias (LTA) are potential drug-induced complications previously reported with antimalarials, antivirals, and antibiotics. Our objective was to evaluate the prevalence and predictors of QTc interval prolongation and incidences of LTA during hospitalization for coronavirus disease 2019 (COVID-19) among patients with normal admission QTc. METHODS: We enrolled 110 consecutive patients in a multicenter international registry. A 12-lead electrocardiograph was performed at admission, after 7, and at 14 days; QTc values were analyzed. RESULTS: After 7 days, 15 (14%) patients developed a prolonged QTc (pQTc; mean QTc increase 66 ± 20 msec; +16%; P < .001); these patients were older and had higher basal heart rates, higher rates of paroxysmal atrial fibrillation, and lower platelet counts. The QTc increase was inversely proportional to the baseline QTc level and leukocyte count and directly proportional to the basal heart rate (P < .01).We conducted a multivariate stepwise analysis including age, male gender, paroxysmal atrial fibrillation, basal QTc values, basal heart rate, and dual antiviral therapy; age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00-1.13; P < .05), basal heart rate (OR, 1.07; 95% CI, 1.02-1.13; P < .01), and dual antiviral therapy (OR, 12.46; 95% CI, 2.09-74.20; P < .1) were independent predictors of QT prolongation.The incidence rate of LTA during hospitalization was 3.6%. There was 1 patient who experienced cardiac arrest and 3 with nonsustained ventricular tachycardia. LTAs were recorded after a median of 9 days from hospitalization and were associated with 50% of the mortality rate. CONCLUSIONS: After 7 days of hospitalization, 14% of patients with COVID-19 developed pQTc; age, basal heart rate, and dual antiviral therapy were found to be independent predictors of pQTc. Life-threatening arrhythmias have an incidence rate of 3.6%, and were associated with a poor outcome.

Antithrombotic Therapy in Hereditary Hemorrhagic Telangiectasia: Real-World Data from the Gemelli Hospital HHT Registry.

Although Hereditary Hemorrhagic Telangiectasia (HHT) is characterized by an overwhelming bleeding propensity, patients with this disease may also present medical conditions that require antithrombotic therapy (AT). However, precise information on indications, dosage, duration, effectiveness, and safety of AT in HHT patients is lacking. We performed a retrospective analysis of the HHT Registry of our University Hospital and found 26 patients who received AT for a total of 30 courses (19 courses of anticoagulant therapy and 11 courses of antiplatelet therapy). Indications to treatments included: atrial fibrillation, venous thrombosis and pulmonary embolism, heart valve replacement, retinal artery occlusion, secondary prevention after either stroke or myocardial infarction, and thromboprophylaxis for surgery. The total time of exposure to antiplatelet therapy was 385 months and to anticoagulant therapy 169 months. AT was generally well tolerated, with no fatal bleedings and no significant changes in hemoglobin levels. However, we found three major bleedings, with an incidence rate of 6.5 per 100 patients per year. When only patients treated with anticoagulants were considered, the incidence rate of major bleedings increased to 21.6 per 100 patients per year. Our study indicates that major bleeding may occur in HHT patients receiving AT, with a substantially increased rate in those treated with anticoagulants. Further studies are needed to fully estimate the tolerability of antithrombotic drugs in HHT.

Safety of antithrombotic therapy in subjects with hereditary hemorrhagic telangiectasia: prospective data from a multidisciplinary working group.

Subjects with the rare autosomal dominant disease Hereditary Hemorrhagic Telangiectasia (HHT) may develop medical conditions that require antithrombotic therapy (AT). However, safety of AT is uncertain in these patients and the only data currently available derive from retrospective analyses of registries and/or databases. At the HHT Centre of the 'Fondazione Policlinico Universitario A. Gemelli IRCCS' (Rome, Italy), a prospective study is currently ongoing to evaluate the safety of AT in subjects affected by HHT. The study is enrolling subjects with a definite diagnosis of HHT who receive an AT prescription by one of the physicians of the HHT Centre. The primary outcome is the number of hemorrhagic events, distinguished in major, clinically relevant non-major (CRNM), and minor bleedings, according to the criteria of the International Society on Thrombosis and Hemostasis (ISTH). Another primary outcome is worsening of epistaxis upon initiation of AT, assessed using the internationally accepted Epistaxis Severity Score (ESS). Additional outcomes are changes in hemoglobin levels and changes in the need of blood transfusion after initiation of AT. Here, we present the results of an interim analysis, conducted on the 12 HHT subjects that have been enrolled so far. After a mean follow-up of 6.5 ± 0.8 months, no major bleedings, no CRNM bleedings, and no minor bleedings different from epistaxis were recorded. Worsening of epistaxis upon initiation of AT was documented only in one patient, but did not require discontinuation of AT. There were no significant changes in the mean ESS measured before and after initiation of AT. There were no significant changes in hemoglobin levels and need for blood transfusion after initiation of AT. Although preliminary, these are the first prospective data on the safety of AT in HHT patients. Our interim analysis suggests that, when prescribed by experienced physicians in a multidisciplinary setting, AT is well tolerated by HHT patients. More patients and a longer follow-up are needed to confirm these findings.

"Lambda-wave" ST-elevation is associated with severe prognosis in stress (takotsubo) cardiomyopathy.

BACKGROUND: Persistent ST-segment elevation in acute coronary syndrome is associated with both short and long-term complications. By contrast, there is limited information about ST-elevation and its evolution during takotsubo (stress) cardiomyopathy (TTC). AIM: To evaluate whether persistent downsloping ST-elevation in the early stages of TTC might correlate with short and long-term clinical events. METHODS: One-hundred fifty-eight consecutive subjects with TTC were prospectively enrolled and assessed by electrocardiogram. Patients were classified in two groups according to the presence of downsloping ST-elevation ≥5 mm lasting at least 24 hr ("lambda-wave" ST-elevation group vs. without downsloping ST-elevation) in at least one/two contiguous leads. RESULTS: Five (3.2%) patients, all female with a mean left ventricular ejection fraction 32 ± 5%, were included in the lambda-wave ST-elevation group. These patients were characterized by a higher prevalence of physical stressor (100% vs. 49%, p = 0.04) and higher admission and peak levels of troponin-I levels during hospitalization. Peak of ST-elevation in the lambda-wave ST-elevation group was reached 6 hr after admission and gradually decreased after 24 hr. In-hospital complications were observed in all the patients presenting lambda ST-elevation (100% vs. 23%, p = 0.03, OR: 29.1, p = 0.04); one patient presented endoventricular thrombosis and two died of cardiogenic shock. At long-term follow-up (mean 443 days), adverse events were observed in 80% of patients with lambda-wave ST-elevation (RR of adverse events at follow-up 32, p < 0.01). CONCLUSION: Persistent downsloping lambda-wave ST-elevation during the acute phase of stress cardiomyopathy may be associated with a higher risk of adverse events at short and long-term follow-up.

Improved endothelial function after short-term therapy with evolocumab.

BACKGROUND: The reduction of cholesterol levels with cholesterol-lowering therapy may improve endothelial function. Lipid-lowering therapy has been greatly enhanced by the introduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies. Less is known of the effect of PCSK9 inhibitors on endothelial function of subjects with hypercholesterolemia. OBJECTIVE: To assess whether treatment with PCSK9 inhibitors may improve endothelial function evaluated by brachial artery vasoreactivity test. METHODS: Brachial artery vasoreactivity test was performed in 14 consecutive patients with previous myocardial infarction before and after 2 months of therapy with evolocumab 140 mg twice in a month. Mean brachial artery diameter, velocity time integral, flow-mediated dilation (FMD) and low-density lipoprotein (LDL) cholesterol levels were also evaluated. RESULTS: After 2 months of treatment with evolocumab, mean total cholesterol levels decreased from 245 ± 41 to 128 ± 30 mg/dL (P < .001, -48%), and LDL levels from 176 ± 43 to 71 ± 26 mg/dL (P = .001, -59%); FMD conversely increased from 6.3 ± 4.1% to 8.8 ± 6.3% (P = .004, +40%). Improvement in FMD was proportional to reduction of LDL levels (r = 0.69, P = .006). Therapy with evolocumab increased brachial artery diameter during vasoreactivity test (peak values 0.39 ± 0.09 vs 0.36 ± 0.11 cm, P = .010; final values 0.36 ± 0.10 vs 0.34 ± 0.10 cm, P = .001), and velocity time integral (peak levels 96 ± 1 vs 85 ± 9 cm, P = .045). CONCLUSIONS: Two months of treatment with evolocumab 140 mg may improve endothelial function in subjects with increased cardiovascular risk. The improvement in endothelial function is proportional to LDL reduction.

Predictive value of very low frequency at spectral analysis among patients with unexplained syncope assessed by head-up tilt testing.

BACKGROUND: The role of heart rate variability (HRV) in the prediction of vasovagal syncope during head-up tilt testing (HUTt) is unclear. AIM: To evaluate the ability of the spectral components of HRV at rest to predict vasovagal syncope among patients with unexplained syncope referred for HUTt. METHODS: Twenty-six consecutive patients with unexplained syncope were enrolled in the study. All patients underwent HRV evaluation at rest (very low frequency [VLF], low frequency [LF], high frequency [HF] and LF/HF ratio) and during HUTt. HUTt was performed using the Westminster protocol. Continuous electrocardiogram and blood pressure monitoring were performed throughout the test. RESULTS: Eight (31%) patients developed syncope during HUTt. There were no baseline differences in terms of clinical features and HRV variables among patients who developed syncope and those who did not, except for VLF (2421 vs 896ms2; P<0.001). In the multivariable logistic regression analysis, including age and sex, VLF was the only independent variable associated with syncope during HUTt (odds ratio 1.002, 95% confidence interval 1.0003-1.0032; P=0.02). The area under the curve at rest was 0.889 for VLF, 0.674 for HF and 0.611 for LF. A value of VLF>2048ms2 was the optimal cut-off to predict syncope during HUTt (sensitivity 87.5%, specificity 72.2%). CONCLUSIONS: VLF at rest predicted the incidence of syncope during HUTt. Further studies are warranted to confirm these preliminary data.

Impact of persistent ST elevation on outcome in patients with Takotsubo syndrome. Results from the GErman Italian STress Cardiomyopathy (GEIST) registry.

BACKGROUND: Potential predictors of clinical complications of Takotsubo syndrome (TTS) are poorly known. Persistent ST-segment elevation (PSTE) may have an impact on outcome similar as previously reported in acute coronary syndrome. The aim of this study was to assess the prevalence and prognostic relevance of PSTE in patients with TTS. METHODS: Two-hundred-sixty-nine consecutive patients were enrolled in an international multicenter registry. PSTE was defined as the documentation of ST-elevation at least for the first 48h of hospitalization. Long-term mortality was evaluated in median 1.9years after the acute event. RESULTS: PSTE was found in 52 TTS patients (19%). Patients with PSTE were characterized by higher admission levels of troponin-I (23±12 vs 8±49ng/L, p<0.001), experienced a longer hospitalization (10±5 vs 8±3days, p=0.02) and a higher rate of in-hospital complications (31% vs 17% p=0.03). At multivariate analysis including PSTE, age, male sex, admission ejection fraction, PSTE (odds ratio [OR] 4.2; 95% confidence interval [CI] 1.4-13; p=0.01), age (OR 1.05; 95%CI 1.00-1.10; p=0.03) and admission ejection fraction (OR 0.93; 95%CI 0.87-0.99; p=0.02) were independent predictors of in-hospital complications. At long-term follow-up no significant differences in terms of mortality were observed between patients with and without PSTE (19% vs 15%; p=0.5). However, PSTE was a predictor of major cardiac adverse events (MACE) at follow-up (HR 2.32, 95% CI 1.02-5.31, p 0.045). CONCLUSIONS: In TTS patients, PSTE is a common finding, represents an independent predictor of in-hospital complications and could be associated with MACE at follow-up.

Dynamic changes of QTc interval and prognostic significance in takotsubo (stress) cardiomyopathy.

BACKGROUND: Prolonged QT corrected (QTc) intervals are associated with adverse cardiovascular outcomes both in healthy and high-risk populations. Our objective was to evaluate the QTc intervals during a takotsubo cardiomyopathy (TTC) episodes and their potential prognostic role. HYPOTHESIS: Dynamic changes of QTc interval during hospitalization for TTC could be associated with outcome at follow-up. METHODS: Fifty-two consecutive patients hospitalized for TTC were enrolled. Twelve-lead electrocardiogram (ECG) was performed within 3 h after admission and repeated after 3, 5, and 7 days. Patients were classified in 2 groups: group 1 presented the maximal QTc interval length at admission and group 2 developed maximal QTc interval length after admission. RESULTS: Mean admission QTc interval was 493 ± 71 ms and mean QTc peak interval was 550 ± 76 ms (P < 0.001). Seventeen (33%) patients were included in group 1 and 35 (67%) patients in group 2. There were no differences for cardiovascular risk factors and in terms of ECG findings such as ST elevation, ST depression, and inverted T waves. Rates of adverse events during hospitalization among patients of group 1 and 2 were different although not significantly (20% vs 6%, P = 0.22). After 647 days follow-up, patients of group 1 presented higher risk of cardiovascular rehospitalization (31% vs 6%, P = 0.013; log-rank, P < 0.01). At multivariate analysis, including age and gender, a prolonged QTc interval at admission was significantly associated with higher risk of rehospitalization at follow-up (hazard ratio: 1.07 every 10 ms, 95% confidence interval: 1.003-1.14, P = 0.04). CONCLUSIONS: Prolonged QTc intervals at admission during a TTC episode could be associated with a higher risk of cardiovascular rehospitalization at follow-up. Dynamic increase of QTc intervals after admission are characterized by a trend toward a better prognosis.

Relation between calcium burden, echocardiographic stent frame eccentricity and paravalvular leakage after corevalve transcatheter aortic valve implantation.

AIMS: Paravalvular aortic leakage (PVL) after transcatheter aortic valve implantation (TAVI) is a complication with potentially severe consequences. The relation between native aortic root calcium burden, stent frame eccentricity and PVL was not studied before. METHODS AND RESULTS: Two-hundred-and-twenty-three consecutive patients with severe aortic stenosis who underwent TAVI with a Medtronic CoreValve System© and who had available pre-discharge transthoracic echocardiography were studied. Echocardiographic stent inflow frame eccentricity was defined as major-minor diameter in a short-axis view >2 mm. PVL was scored according to the updated Valve Academic Research Consortium (VARC-2) recommendations. In a subgroup of 162 (73%) patients, the calcium Agatston score was available. Stent frame eccentricity was seen in 77 (35%) of patients. The correlation between the Agatston score and stent frame eccentricity was significant (ρ = 0.241, P = 0.003). Paravalvular leakage was absent in 91 cases (41%), mild in 67 (30%), moderate in 51 (23%), and severe in 14 (6%) cases. The correlation between stent frame eccentricity and PVL severity was significant (ρ = 0.525, P < 0.0001). There was a relation between particular eccentric stent frame shapes and the site of PVL. CONCLUSION: Calcification of the aortic annulus is associated with a subsequent eccentric shape of the CoreValve prosthesis. This eccentric shape results in more PVL, with the localization of PVL related to the shape of stent frame eccentricity.

Quantitative Doppler for Estimation of Paravalvular Leakage after Transcatheter Aortic Valve Implantation.

BACKGROUND: The echocardiographic grading of paravalvular aortic leakage (PVL) after transcatheter aortic valve implantation (TAVI) severity is challenging. The study aim was to assess the value of quantitative Doppler echocardiography to monitor PVL severity. METHODS: A total of 100 subjects was enrolled in the study, including 65 consecutive patients who had undergone TAVI with a CoreValve prosthesis and without valvular aortic regurgitation, and 35 normal controls. The PVL volume was calculated using the quantitative Doppler method as the difference of left and right ventricular stroke volume (SV). PVL severity was assessed both visually and quantitatively as the circumferential extent on a short-axis view (SAX). RESULTS: The inter-observer variabilities for SVs in TAVI patients were disappointing: 14 ± 11% for the left ventricular SV and 18 ± 14% for right ventricular SV. The correlation (r2) between the averaged regurgitant PVL volume and circumferential SAX extent of PVL was 0.02 (p = NS). The relationship between PVL volumes and categories, defined quantitatively by the circumferential SAX extent of PVL and qualitatively by visual assessment of severity of PVL were poor. The results improved when only patients with optimal quality images were included but were still statistically non-significant. CONCLUSIONS: The relationship between calculated PVL volume in TAVI patients and other estimates of PVL severity was poor, most likely due to intrinsic errors made in the quantitative Doppler method. Therefore, one should be prudent to include the quantitative Doppler method in TAVI patients in clinical trials and clinical decision-making, in particular in patients with reduced image quality.

Serum interleukin 6 and 10 levels in Takotsubo cardiomyopathy: Increased admission levels may predict adverse events at follow-up.

BACKGROUND AND AIMS: Systemic inflammation has been hypothesized as a possible mechanism of Takotsubo cardiomyopathy (TTC). Aim of the study was to assess the role of interleukin (IL)-6 and IL-10 in subjects with an episode of TTC. METHODS: Fifty-six consecutive subjects with TTC were prospectively enrolled in the study and followed for a mean of 178 days. Circulating levels of IL-6, IL-10, clinical condition and left ventricular ejection fraction were evaluated at admission. Incidence of death, re-hospitalization and recurrence of TTC during follow-up was also recorded. RESULTS: 23% of patients experienced in-hospital complications while 20% of patients had adverse events at follow-up. IL-6 and IL-10 serum levels at admission were higher in subjects with adverse events at follow-up (120 ± 294 vs. 22 ± 40 pg/ml, p<0.05; 13 ± 35 vs. 2 ± 3 pg/ml, p=0.05, respectively). Increased serum levels of IL-6 and IL-10 were associated with higher adverse events rates at follow-up (Log-Rank p<0.001, <0.05, hazard ratio 8.6, 5.1, respectively) and mortality rates (Log-Rank p<0.001, p<0.05, hazard ratio 20.8, 7.1, respectively). Subjects with both increased IL-6 and IL-10 levels were characterized by an increased risk of adverse events when compared to subjects with only IL-6 or IL-10 increased levels or with values below cutoff values (Log-Rank p<0.01 for any event, <0.001 for death; hazard ratio 1.20 for any event, 1.31 for death), even after correction for age, LVEF and NTproBNP levels in multivariable Cox analysis. CONCLUSIONS: Serum IL-6 and IL-10 admission levels are associated with higher risk of adverse events during follow-up.

Limitations and difficulties of echocardiographic short-axis assessment of paravalvular leakage after corevalve transcatheter aortic valve implantation.

To make assessment of paravalvular aortic leakage (PVL) after transcatheter aortic valve implantation (TAVI) more uniform the second Valve Academic Research Consortium (VARC) recently updated the echocardiographic criteria for mild, moderate and severe PVL. In the VARC recommendation the assessment of the circumferential extent of PVL in the short-axis view is considered critical. In this paper we will discuss our observational data on the limitations and difficulties of this particular view, that may potentially result in overestimation or underestimation of PVL severity.

Importance of the left ventricular outflow tract in the need for pacemaker implantation after transcatheter aortic valve replacement.

BACKGROUND: The interaction of left ventricular outflow tract (LVOT) and transcatheter heart valve (THV) is complex and may be device design specific. We sought to study LVOT characteristics and its relation with permanent pacemaker implantation (PPI) after transcatheter aortic valve replacement (TAVR). METHODS: We studied 302 patients with a median age of 81years [75-84]. Computed tomography was used to assess LVOT in terms of amount of calcium, perimeter and device size relative to LVOT. RESULTS: We implanted a Medtronic CoreValve (MCS) in 203 patients, Edwards-Sapien XT (ESV-XT) in 38, Edwards-Sapien S3 (ESV-S3) in 26 and Lotus in 35 patients. Sixty-eight patients (22.5%) received a new PPI within 30days after the index procedure. The incidence of PPI was 22.7% with MCS, 10.5% with ESV-XT, 26.9% with ESV-S3 and 31.4% with Lotus. By multivariate analysis RBBB at baseline (OR 2.9 [1.2-6.9, p=0.014), second generation valves (OR 2.1 [1.0-4.5], p=0.048), DOI (OR 1.20 per 1mm increment, [1.09-1.31], p<0.001) and LVOT sizing (OR per 1% increment 1.03 [1.01-1.07], p=0.022) were associated with need for PPI. Sensitivity analyses suggest that a lesser degree of LVOT oversizing triggers PPI with second generation THVs vs. first generation THVs. CONCLUSIONS: More LVOT oversizing is associated with a higher need for permanent pacemaker implantation after TAVR, even more so with deeper THV implants and next generation devices (ESV-S3 and Lotus). Sizing algorithms should focus more on LVOT dimensions to reduce PPI.