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Purpose To assess the prognostic value of regional quantitative myocardial flow measures as assessed by 13N-ammonia positron emission tomography (PET) myocardial perfusion imaging (MPI) in patients with suspected coronary artery disease (CAD). Methods We retrospectively included 150 consecutive patients with suspected CAD who underwent clinically indicated 13 N-ammonia PET-MPI and who did not undergo revascularization within 90 days of PET-MPI. The presence or absence of a decreased global myocardial flow reserve (i.e., MFR Results Over a median follow-up of 50 months (IQR 38–103), 30 events occurred in 29 patients. Kaplan–Meier analysis showed significantly reduced event-free and overall survival in MFR groups 2 and 3 compared to MFR group 1 (log-rank: p = 0.015 and p = 0.013). In a multivariable Cox regression analysis, decreased regional MFR was an independent predictor for MACE (adjusted HR 3.44, 95% CI 1.17–10.11, p = 0.024) and all-cause death (adjusted HR 4.72, 95% CI 1.07–20.7, p = 0.04). Conclusions A decreased regional MFR as assessed by 13 N-ammonia PET-MPI confers prognostic value by identifying patients at increased risk for future adverse cardiac outcomes and all-cause death.

Background No methodology is available to distinguish truly reduced myocardial flow reserve (MFR) in positron emission tomography myocardial perfusion imaging (PET MPI) from seemingly impaired MFR due to inadequate adenosine response. The adenosine-induced splenic switch-off (SSO) sign has been proposed as a potential marker for adequate adenosine response in cardiac magnetic resonance (CMR). We assessed the feasibility of detecting SSO in nitrogen-13 ammonia PET MPI using SSO in CMR as the standard of reference. Methods and Results Fifty patients underwent simultaneous CMR and PET MPI on a hybrid PET/MR device with co-injection of a gadolinium-based contrast agent and nitrogen-13 ammonia during rest and adenosine-induced stress. In CMR, SSO was assessed visually (positive vs negative SSO) and quantitatively by calculating the ratio of the peak signal intensity of the spleen during stress over rest (SIR). In PET MPI, the splenic signal activity ratio (SAR) was calculated as the maximal standard uptake value of the spleen during stress over rest. The median SIR was significantly lower in patients with positive versus negative SSO in CMR (0.57 [IQR 0.49 to 0.62] vs 0.89 [IQR 0.76 to 0.98]; P P Conclusion Similarly to CMR, SSO can be detected in nitrogen-13 ammonia PET MPI. This might help distinguish adenosine non-responders from patients with truly impaired MFR due to microvascular dysfunction or multivessel coronary artery disease.

The role of adipose tissue (AT) in arterial inflammation in familial dyslipidaemias is poorly studied. We investigated the relationship between AT and arterial inflammation in patients with heterozygous familial hypercholesterolemia (heFH) and familial combined hyperlipidemia (FCH). A total of 40 patients (20 heFH/20 FCH) and a subgroup of 20 of non-heFH/FCH patients were enrolled. Participants underwent blood sampling for serum adipokine measurements and Fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT imaging. Abdominal visceral (VAT) and subcutaneous (SAT) AT volumes and AT and abdominal aorta 18F-FDG uptake were quantified. FCH patients had increased VAT (pANOVA = 0.004) and SAT volumes (pANOVA = 0.003), lower VAT metabolic activity (pANOVA = 0.0047), and lower adiponectin levels (pANOVA = 0.007) compared to heFH or the control group. Log(Serum adiponectin) levels were correlated with aortic TBR (b = − 0.118, P = 0.038). In mediation analysis, VAT volume was the major determinant of circulating adiponectin, an effect partly mediated via VAT TBR. Clustering of the population of heFH/FCH by VAT volume/TBR and serum adiponectin identified two distinct patient clusters with significant differences in aortic TBR levels (2.11 ± 0.06 vs 1.89 ± 0.05, P= 0.012). VAT phenotype (increased VAT volume and/or high VAT TBR) and hypoadiponectinemia may account for the observed differences in arterial inflammation levels between heFH and FCH patients.

Objectives Coronary artery volume indexed to left myocardial mass (CAVi), derived from coronary computed tomography angiography (CCTA), has been proposed as an indicator of diffuse atherosclerosis. We investigated the association of CAVi with quantitative flow parameters and its ability to predict ischemia as derived from 13N-ammonia positron emission tomography myocardial perfusion imaging (PET-MPI). Methods Sixty patients who underwent hybrid CCTA/PET-MPI due to suspected CAD were retrospectively included. CAVi was defined as total coronary artery lumen volume over myocardial mass, both derived from CCTA. From PET-MPI, quantitative stress and rest myocardial blood flow (MBF) and myocardial flow reserve (MFR) were obtained and correlated with CAVi, and semi-quantitative perfusion images were analyzed for the presence of ischemia. Harrell’s c-statistic and net reclassification improvement (NRI) analysis were performed to evaluate the incremental value of CAVi over the CCTA model (i.e., stenosis > 50% and > 70%). Results CAVi correlated moderately with stress MBF and MFR (R = 0.50, p < 0.001, and R = 0.39, p = 0.002). Mean stress MBF and MFR were lower in patients with low (i.e., ≤ 20.2 mm3/g, n = 24) versus high (i.e., > 20.2 mm3/g, n = 36) CAVi (p < 0.001 for both comparisons). CAVi was independently associated with abnormal stress MBF (OR 0.90, 95% CI 0.82–0.998, p = 0.045). CAVi increased the predictive ability of the CCTA model for abnormal stress MBF and ischemia (c-statistic 0.763 versus 0.596, pdiff < 0.05 and 0.770 versus 0.645, pdiff < 0.05, NRI 0.84, p = 0.001 and 0.96, p < 0.001, respectively). Conclusions CAVi exhibits incremental value to predict both abnormal stress MBF and ischemia over CCTA alone. Key Points • Coronary artery volume indexed to left myocardial mass (CAVi), derived from coronary computed tomography angiography (CCTA), is correlated with myocardial blood flow indices derived from13N-ammonia positron emission tomography myocardial perfusion imaging. • CAVi is independently associated with abnormal stress myocardial blood flow. • CAVi provides incremental diagnostic value over CCTA for both abnormal stress MBF and ischemia.

The role of lipoprotein(a) (Lp[a]) as a significant and possibly causal cardiovascular disease (CVD) risk factor has been well established. Many studies, mostly experimental, have supported inflammation as a mediator of Lp(a)-induced increase in CVD risk. Lp(a), mainly through oxidized phospholipids bound to its apolipoprotein(a) part, leads to monocyte activation and endothelial dysfunction. The relationship between Lp(a) and inflammation is bidirectional as Lp(a) levels, besides being associated with inflammatory properties, are regulated by inflammatory stimuli or anti-inflammatory treatment. Reduction of Lp(a) concentration, especially by potent siRNA agents, contributes to partial reversion of the Lp(a) related inflammatory profile. This review aims to present the current pathophysiological and clinical evidence of the relationship between Lp(a) and inflammation.

The ACURATE neo transcatheter aortic valve is a self-expanding device. Several studies have investigated safety and efficacy, but meta-analysis and pooled data are lacking. We aimed to provide a comprehensive systematic review and meta-analysis on the clinical outcomes of transcatheter aortic valve implantation with the ACURATE neo valve. A systematic literature search for eligible records was conducted. The primary endpoint was device success as designated by Valve Academic Research Consortium-2 criteria. The secondary endpoints (time frame: 30 days) were all-cause mortality, stroke, myocardial infarction, need for new permanent pacemaker, major vascular complications, major bleeding, acute kidney injury stage II or III and paravalvular regurgitation grade moderate or severe (II or III). Our search yielded a total of 355 records, 20 of those (n = 5,858 ACURATE neo receivers) were included in our meta-analysis. Device success was achieved in 94.5% (95%CI: 91.4-96.5) of the patients. The 30-day all-cause mortality incidence proportion was 1.8% (95%CI: 1.3-2.4). New pacemaker implantation was required in 7.7% (95%CI: 6.4-9.2) of the patients, stroke occurred in 1.9% (95%CI: 1.6-2.3), myocardial infarction in 0.5% (95%CI: 0.3-0.7), major bleeding in 5.0% (95%CI: 3.9-6.5), major vascular complication in 5.6% (95%CI: 4.0-7.8), acute kidney injury stage ≥2 in 2.5% (95%CI: 1.8-3.4) and paravalvular leak grade ≥moderate was observed in 4.3% (95%CI: 3.0-6.2). Balloon predilatation and postdilatation incidence was 93.9% (95%CI: 87.0-97.3) and 43.2% (95%CI: 37.9-48.6) respectively. ACURATE neo appears to be safe and effective in our analysis with high device success incidence, low mortality and low new pacemaker implantations.

BACKGROUND Coronary computed tomography angiography (CCTA)-based transluminal attenuation gradient (TAG) was suggested to determine the functional significance of a stenosis. However, evidence that TAG acquired by wide-volume scanners can assess the hemodynamic significance of stenosis assessed by single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is lacking. Moreover, coronary cross-sectional area may influence TAG. Hence, we aimed at assessing the diagnostic value of TAG to predict ischemia in SPECT-MPI and the correlation between TAG and the transluminal cross-sectional area gradient (TCG). METHODS Patients undergoing CCTA and SPECT-MPI for suspected coronary artery disease were included. TAG and TCG were calculated measuring the mean vessel attenuation and the cross-sectional area along major coronary vessels at 5-mm intervals. RESULTS A total of 255 coronary arteries of 87 patients were included. TAG and TCG did not discriminate between coronary arteries with or without ischemia as assessed by SPECT-MPI (p = .44 and p = .25, respectively). The area under the curve to predict ischemia was not increased by adding TAG (0.88, 95% CI 0.83-0.92) or TCG (0.87, 95% CI 0.81-0.90) to CCTA alone (0.85, 95% CI 0.80-0.89). There was a significant correlation between TAG and TCG (r = 0.43; p

Background: Microwave radiometry (MWR) assesses non-invasive carotid artery temperatures reflecting inflammation. In the present study, we aimed to investigate the impact of hypolipidemic therapy either with simvastatin or with combination simvastatin plus ezetimibe on carotid artery temperatures of patients with familial hyperlipidemia syndromes (FHS). Methods: Consecutive patients with diagnosis of either familial heterozygous hypercholesterolemia (heFH) or familial combined hyperlipidemia (FCH) were included in the study. Patients were assigned to either simvastatin 40 mg or simvastatin 40 mg plus ezetimibe 10 mg, according to the discretion of the physician. FHS patients who refused statin therapy were used as a control group. Common carotid intima-media thickness (ccIMT) was measured and ΔΤ (maximum-minimum) temperature measurements were performed across each carotid during MWR evaluation. RESULTS: In total, 115 patients were included in the study. Of them, 40 patients received simvastatin (19 heFH and 21 FCH), 41 simvastatin + ezetimibe (31 heFH and 10 FCH), and 34 (21 heFH and 13 FCH) no statin. Carotid artery temperatures were significantly reduced at 6 months in FH patients who received hypolipidemic treatment (0.83 ± 0.34 versus 0.63 ± 0.24 °C, p = 0.004 for simvastatin, 1.00 ± 0.38 versus 0.69 ± 0.23 °C, p &lt, 0.001 for simvastatin + ezetimibe), but no change was recorded in controls (0.72 ± 0.26 versus 0.70 ± 0.26 °C, p = 0.86). Conclusions: Hypolipidemic therapy reduced carotid temperatures in FHS patients.

Introduction Transcatheter aortic valve implantation is the treatment of choice in a consistently expanding group of patients with severe aortic valve stenosis. Tricuspid and mitral annular dilatation with consequent valvular regurgitation are associated with adverse outcome. Computed tomography angiography (CTA) is routinely performed for preprocedural evaluation of vascular access and prosthesis sizing. Purpose To evaluate the impact of mitral and tricuspid annular dimensions in preprocedural CTA on prognosis of patients undergoing TAVI with a self-expanding valve. Methods CTAs of consecutive patients undergoing TAVI in a single high-volume center between 2016 and 2019 were retrospectively evaluated. Maximal septolateral tricuspid annular diameters (TAD) and mitral annular diameters (MAD) were obtained and measured from properly angulated three dimensional CTA datasets. Moreover, maximal pulmonary artery diameter perpendicular to the long axis was measured in every patient. Patients were followed up by clinical visits or telephone contacts. As clinical events were defined all-cause mortality, stroke and heart failure hospitalization. Results In total 123 patients were included in the study. The mean follow-up duration was 875±383 days and 21 clinical events were recorded. There was a moderate but statistical significant correlation between TAD and both pulmonary artery diameter (r=0.39, p Conclusions TAD and MAD were associated with heart failure rehospitalization and clinical events respectively in patients undergoing TAVI with a self-expanding valve. Further larger prospective studies are warranted to evaluate the prognostic value of these CTA markers. Funding Acknowledgement Type of funding sources: None.

Aims Paravalvular leak (PVL) remains a frequent complication after transcatheter aortic valve implantation (TAVI) and seems to affect short- and long-term survival. Purpose The aim of this study was: 1) to identify anatomical predictors of PVL after TAVI and 2) assess the impact of PVL on cumulative survival. Methods and results Patients with severe and symptomatic aortic stenosis [effective orifice area (EOA) ≤1cm2] referred for TAVI at our institution were consecutively enrolled. Prospectively collected demographic, laboratory and echocardiographic data were retrospectively analyzed. Patients were stratified into two groups according to the presence of PVL after TAVI and were followed up postoperatively with clinical and echocardiographic assessment. Primary clinical endpoint was all-cause mortality, as defined by the criteria proposed by the Valve Academic Research Consortium 2. In total, 291 patients were included (male: 50.2%, mean age: 80±7.6 years) in our study. Of these, 165 (56,8%) presented at least mild PVL after TAVI (mild: 85,5%, moderate: 13.3% and severe: 1.2%). The median follow-up period was 27.3 [min. 0, max 113 months. Two patients with severe PVL were excluded from the analysis. In the follow up period, there was no significant difference regarding all-cause mortality between patients with and those without PVL after TAVI, independently from the degree of PVL (log rank: 0.991 - Figure 1). Severe aortic annulus calcification, the presence of a bicuspid aortic valve and aortic root angulation, as assessed by computed tomography (CT), were found to associate with PVL after TAVI in univariate analysis. In the multivariate analysis, severe aortic annulus calcification was found to be the only independent predictor of mild or moderate PVL after TAVI [Exp(B): 1.540, 95% Confidence Interval: 1.067–2.224, B=0.432, p=0.021]. Conclusion The presence of mild or moderate PVL after TAVI was not found to affect cumulative survival in the 27 months of follow up period. Severe annulus calcification assessed by CT-scan, was found to be the only independent predictor of PVL after TAVI. Funding Acknowledgement Type of funding sources: None.

Background/Introduction Arterial stiffness and aortic hemodynamics are independent predictors of adverse cardiovascular events. Indications for transcatheter aortic valve implantation (TAVI) are expanding and aortic valve calcifications (AVC) are an important prognostic factor of the success of TAVI. Purpose We sought to investigate the associations between AVC and aortic vascular function/hemodynamics. Methods Fifty-two high-risk patients (mean age 80.4±8.5 years, 27 male) with severe symptomatic aortic stenosis undergoing TAVI were included. Arterial stiffness was estimated through carotid-femoral pulse wave velocity (cfPWV) and brachial-ankle pulse wave velocity (baPWV). Aortic hemodynamics (aortic pressures, aortic augmentation index corrected for heart rate [AIx@75]) were also measured. Measurements were conducted prior to the implantation and at discharge. In all patients, a native and contrast-enhanced multislice cardiac computed tomography were performed pre-interventionally. AVC were then graded semi-quantitatively as follows: grade 1 – no calcification; grade 2 – mildly calcified (small isolated spots); grade 3 – moderately calcified (multiple larger spots); grade 4 – severely calcified (extensive calcification of all cusps). Results Group 1 (subjects with none/mild AVC, n=29) did not significantly differ in age, gender and body-mass index compared to group 2 (subjects with moderate/severe AVC, n=23). As far as the traditional cardiovascular risk factors were concerned, only hypertension (p=0.008), coronary artery disease (p=0.016), atrial fibrillation (p=0.075) and insulin-dependent diabetes mellitus (p=0.068) were found to be more prevalent in group 2. Group 2 had significantly higher both cfPWV and baPWV (8.3±1.7 vs 7.2±1.2 m/s and 1750±484 cm/s vs. 2101±590 cm/s with p=0.008 and p=0.022 respectively) compared to Group 1 (Figure 1). Even after adjustment for age, gender and systolic blood pressure, aortic stiffness indices were higher in Group 2 compared to Group 1 (p=0.038 and p=0.048, respectively). There was no statistically significant difference in peripheral or aortic pressures as well as in wave reflections indices between the two groups. Conclusion Our study shows that in patients with aortic valve stenosis there is a correlation between increased aortic stiffness and a greater extent of damage of aortic valvular leaflets as well as calcifications. Funding Acknowledgement Type of funding sources: None. Figure 1. PWV and aortic valve calcifications

Objective The purpose of this study was to quantify the reduction in radiation dose achievable by using the optimal z-axis coverage in coronary computed tomography (CT) angiography (CCTA) on a latest-generation 256-slice scanner. Methods A total of 408 scans were reviewed that were performed on a wide-range detector scanner allowing up to 16-cm z-axis coverage (adjustable in 2-cm increments). For each CCTA study, we assessed the radiation dose (ie, dose-length product and volume CT dose index) and measured the minimum z-axis coverage necessary to cover the complete cardiac anatomy. We calculated the potential radiation dose savings achievable through reduction of the z-axis coverage to the minimum necessary. Results The majority of the CCTA scans were performed with a z-axis coverage of 16 cm (n = 285, 69.9%), followed by 14 cm (n = 121, 29.7%) and 12 cm (n = 2, 0.5%). In the group that was scanned with a collimation of 16 cm, radiation dose could have been reduced by 12.5% in 55 patients, 25% in 195 patients, and 37.5% in 33 patients when using optimal z-axis coverage for CCTA. In the group that was scanned with a collimation of 14 cm, radiation dose could have been reduced by 14.3% in 90 patients, and 28.6% in 30 patients, whereas in the group that was scanned with a collimation of 12 cm, dose could have been reduced by 16.7% in 2 patients. Conclusions Using correct z-axis coverage in CCTA on a latest-generation 256-slice scanner yields average dose reductions of 22.0% but may be as high as 37.5%.

The human pathophysiology of stunned, hibernating and scarred myocardium in ischemic cardiomyopathy is a subject of controversy. While the “smart heart” theory postulates that reduced myocardial blood flow (MBF) at rest is responsible for myocytes switching to a state of hibernation, other theories suggest that a reduced myocardial flow reserve (MFR) may be the cause. We included 110 patients with ischemic cardiomyopathy. Based on quantitative myocardial perfusion assessment and viability imaging with 13N-NH3 and 18F-FDG positron emission tomography, respectively, as well as wall motion assessment from echocardiography, myocardial tissue was characterized as remote (i.e., normal myocardium), stunned (i.e., dysfunctional but viable myocardium with normal rest perfusion), hibernating (i.e., dysfunctional but viable myocardium with impaired rest perfusion), or scarred myocardium (i.e., non-viable myocardium). Compared to remote myocardium, dysfunctional but viable myocardium (including stunned and hibernating) had reduced rest MBF (0.89 mL/min/g vs. 0.79 and 0.76 mL/min/g, respectively; p

Objectives The aim of this study was to compare the implantation of a self-expanding valve with or without balloon aortic valvuloplasty (BAV) in an open-label, noninferiority, randomized trial. Background There are no randomized studies comparing the implantation of a self-expanding valve with (pre-BAV) or without BAV. Methods Consecutive patients with severe aortic stenosis were randomly assigned to undergo transcatheter aortic valve replacement with the use of self-expanding prostheses with (pre-BAV) or without (no-BAV) pre-dilatation. The primary endpoint was device success according to the Valve Academic Research Consortium 2 criteria. Secondary endpoints included periprocedural mortality and stroke, new permanent pacemaker implantation, vascular complications, and 1-year mortality. The trial was scheduled to show noninferiority (Δ = 15%) of the direct versus the pre-BAV approach. Results A total of 171 patients were randomized at 4 centers. Of these, 86 underwent transcatheter aortic valve replacement with pre-dilatation and 85 without. Device success was noninferior in the no-BAV group compared with the pre-BAV group (65 of 85 [76.5%] for no-BAV vs. 64 of 86 [74.4%] for pre-BAV; mean difference 2.1%; 90% confidence interval: −8.9% to 13%). In the no-BAV group, 25 patients (29.4%) underwent post-balloon dilatation, and in the pre-BAV group, 13 patients (15.1%) underwent post-balloon dilatation (p = 0.03). Regarding major vascular complications and permanent pacemaker implantation, there was no difference between the 2 groups (log-rank p = 0.49, log-rank p = 0.54). In 1-month completed follow-up for all patients, there was 1 periprocedural stroke (0.5%), without any deaths. Conclusions Direct, without balloon pre-dilatation, transcatheter aortic valve replacement with a self-expanding prosthesis system is noninferior to the pre-dilatation procedure. Lower post-dilatation rates were encountered in the group with pre-dilatation. (The Predilatation in Transcatheter Aortic Valve Implantation Trial [DIRECT]; NCT02448927)

Purpose Misalignment between positron emission tomography (PET) datasets and attenuation correction (AC) maps is a potential source of artifacts in myocardial perfusion imaging (MPI). We assessed the impact of adenosine on the alignment of AC maps derived from magnetic resonance (MR) and PET datasets during MPI on a hybrid PET/MR scanner. Methods Twenty-eight volunteers underwent adenosine stress and rest 13N-ammonia MPI on a PET/MR. We acquired Dixon sequences for the creation of MRAC maps. After reconstruction of the original non-shifted PET images, we examined MRAC and PET datasets for cardiac spatial misalignment and, if necessary, reconstructed a second set of shifted PET images after manually adjusting co-registration. Summed rest, stress, and difference scores (SRS, SSS, and SDS) were compared between shifted and non-shifted PET images. Additionally, we measured the amount of cranial movement of the heart (i.e., myocardial creep) after termination of adenosine infusion. Results Realignment was necessary for 25 (89.3%) stress and 12 (42.9%) rest PET datasets. Median SRS, SSS, and SDS of the non-shifted images were 6 (IQR = 4–7), 12 (IQR = 7–18), and 8 (IQR = 2–11), respectively, and of the shifted images 2 (IQR = 1–6), 4 (IQR = 7–18), and 1 (IQR = 0–2), respectively. All three scores were significantly higher in non-shifted versus shifted images (all p r = 0.541, p = 0.005). Conclusion Misalignment of MRAC and PET datasets commonly occurs during adenosine stress MPI on a hybrid PET/MR device, potentially leading to an increase in false-positive findings. Our results suggest that myocardial creep may substantially account for this and prompt for a careful review and correction of PET/MRAC data.

Objective To present 1 year clinical and echocardiographic outcomes of the randomized DIRECT (Pre-dilatation in Transcatheter Aortic Valve Implantation Trial) trial. Background Intermediate-term data from randomized studies investigating the safety and efficacy of direct implantation are lacking. Methods DIRECT trial randomized 171 consecutive patients with severe aortic stenosis at four tertiary centers to undergo TAVI with the use of self-expanding prostheses with (pre-BAV) or without pre-dilatation (no-BAV). The primary endpoint was device success according to the VARC-2 criteria. All patients underwent a clinical and echocardiographic follow-up at 1 year. All-cause and cardiac mortality, stroke, heart failure hospitalization, and new pacemaker implantation were recorded. Results At 1 year, four deaths were recorded in pre-BAV group (4.7%) and three deaths in no-BAV group (3.5%). There was no difference in Kaplan-Meier plots between the two groups in all-cause mortality at 1 year (log-rank p = .72). Similarly, there was no difference in the incidence of permanent pacemaker implantation between the two groups at 1 year (27/67-40.3% in no-BAV group versus 20/69-29% in pre-BAV group, log-rank p = .24). There was no significant difference between pre-BAV and no BAV group in aortic valve area (1.84 ± 0.39 cm2 vs. 1.85 ± 0.44 cm2 , p = .90), mean aortic valve gradient (8.36 ± 5.04 vs. 8.00 ± 4.04 mmHg, p = .65) and moderate or severe paravalvular regurgitation (5-6.6 vs. 4-5.7%, respectively) at 1 year. The same applied independently from the performance of post-dilatation at baseline. Conclusions Direct, without pre-dilatation, implantation of a self-expanding valve has no impact on one-year clinical and echocardiographic outcomes, independently also from the baseline performance of post-dilatation.

Introduction The DIRECT trial (Predilatation in Transcatheter Aortic Valve Implantation Trial) evaluated in a randomized fashion the safety and efficacy of direct (without balloon pre-dilatation) implantation of a self-expanding valve in all comers undergoing TAVI. Purpose To investigate the impact of direct implantation of a self-expanding valve on one-year clinical outcomes. Methods DIRECT trial randomized consecutive patients with severe aortic stenosis at 4 tertiary centers to undergo TAVI with the use of self-expanding prostheses with (pre-BAV) or without pre-dilatation (no-BAV). The primary endpoint was device success according to the VARC-2 criteria. Secondary endpoints included periprocedural mortality and stroke, new permanent pacemaker implantation and vascular complications. All cause death, cardiac death, stroke and heart failure hospitalizations were recorded at one year and compared between the two groups using Kaplan-Meier plots. Results In total 171 patients were randomized in 4 centers. In the intention to treat analysis 86 patients were randomized to the pre-BAV group and 85 patients to the no-BAV TAVI group. The device success according to the VARC-2 criteria was non-inferior in the no-BAV group compared to the pre-BAV group (65/85 - 76.5% for no-BAV versus 64/86 – 74.4% for pre-BAV, mean difference = 2.1%, 90% CI: −8.9 to 13). In the no-BAV group 25 (29.4%) patients underwent post balloon dilatation and in the pre-BAV group 13 patients (15.1%) (p=0.03). At one year 4 deaths were recorded in pre-BAV group (4.7%) and 3 deaths in no-BAV group (3.5%). There was no difference in Kaplan-Meier plots between the two groups in all-cause mortality (log-rank p=0.72, figure). Similarly, there was no difference in one-year incidence of stroke (1 in pre-BAV and 2 in no-BAV group, log-rank p=0.55), cardiac death (log-rank p=0.66), non-cardiac death (log-rank p=0.98) and heart failure hospitalizations (1 in pre-BAV versus 3 in no-BAV group, log-rank p=0.31). Lastly, there was no difference in the incidence of permanent pacemaker implantation between the two groups at one year (27/67 in no-BAV group versus 20/69 in pre-BAV group, log-rank p=0.24) Conclusions Direct transcatheter aortic valve implantation is non-inferior to the procedure with pre-dilatation in self-expanding valve. Despite the overall low rate of events, direct procedure has no impact on clinical outcomes at one year. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Medtronic

Background Positron emission tomography myocardial perfusion imaging (PET MPI) is a robust and excellent tool for assessing ischemia. So far, however, no methodology has been established to distinguish truly reduced MFR due to microvascular dysfunction or three-vessel coronary disease (CAD) from seemingly impaired MFR due to inadequate adenosine response. Conversely, for cardiac stress magnetic resonance (CMR) the adenosine induced splenic switch-off (SSO) sign has been proposed as a potential marker for adequate adenosine response. Purpose We assessed the feasibility of detecting SSO in adenosine stress 13N-ammonia PET MPI using SSO in CMR as the standard of reference. Methods 50 patients underwent simultaneous PET MPI and CMR on a hybrid PET/MR device with co-injection of 13N-ammonia and a gadolinium-based contrast agent during rest and adenosine-induced stress. In CMR, SSO was assessed qualitatively and quantitatively by calculating the ratio of the peak signal intensity of the spleen during stress over rest (SIR). Similarly, in PET MPI the splenic signal activity ratio (SAR) was calculated as the proportion of the maximal standard uptake value of the spleen in stress and rest. Additionally, MFR was quantified in PET MPI. Results Visual SSO in CMR was present in 37 (74%) patients, whereas 13 patients had no SSO. The median SIR in CMR was significantly lower in patients with visual SSO compared to patients without visual SSO (0.57 [IQR 0.49–0.62] vs. 0.89 [IQR 0.76–0.98]; p Conclusion Similarly to CMR, SSO can be detected in 13N-ammonia PET MPI. This might help distinguish adenosine non-responders from patients with truly impaired MFR due to microvascular dysfunction or multivessel CAD. Figure 1. Splenic switch off (*) illustrated on transaxial 13N-ammonia PET MPI stress (A) compared to rest perfusion images (B) and similarly in stress (C) and rest (D) short axis CMR (**) in the same patient during adenosine induced stress and co-injection of 13N-ammonia and a gadolinium based contrast agent, acquired on a hybrid PET/MR device. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Swiss National Science Foundation (SNSF)

Introduction Transcatheter aortic valve implantation (TAVI) has become the standard of care for high-risk and inoperable surgical patients and a valid alternative in intermediate-risk patients with severe aortic stenosis.The DIRECT trial (Predilatation in Transcatheter Aortic Valve Implantation Trial) was a multicenter, randomized, clinical trial designed to evaluate the safety and efficacy of TAVI with or without balloon aortic valvuloplasty (BAV) in patients with symptomatic, severe aortic valve stenosis. Purpose To compare the one year echocardiographic findings among patients, who underwent TAVI using a self-expanding valve with or without BAV. Methods A total of 171 patients with severe aortic stenosis were randomly assigned at 4 tertiary centers to undergo TAVI with the use of self-expanding prostheses with (pre-BAV) or without pre-dilatation (no-BAV). Follow up transthoracic echocardiography was performed 1 year after TAVI. Results Of 171 patients, 86 patients were randomized to pre-BAV group and 85 to no-BAV group. One year echocardiographic follow up was available in 146 patients. In one year follow up there was no significant difference between pre-BAV and no-BAV group in aortic valve area (1.84±0.39cm2 vs. 1.85±0.44cm2, p=0.79), peak aortic valve gradient (15.95±9.97 mmHg vs. 14.51±6.60 mmHg, p=0.35), mean aortic valve gradient (8.37±5.01 mmHg vs. 7.99±4.04 mmHg, p=0.64), aortic valve peak velocity (1.90±0.51 m/s vs. 1.80±0.42m/s, p=0.24), ejection fraction (54.19±8.36% vs. 53.19±9.58%, p=0.52) and pulmonary artery systolic pressure (41.86±14.34 mmHg vs. 40.71±12.40 mmHg, p=0.64). The incidence of moderate or severe paravalvular regurgitation (PVL) in 1 year follow up was 6.2% without significant difference between the 2 study groups (5.7% in the no-BAV group vs. 6.6% in the pre-BAV group, p=0.83). Conclusions Direct transcatheter aortic valve implantation has no impact on one-year prosthesis function and PVL in patients undergoing TAVI with self-expanding valve Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Medtronic

Introduction The DIRECT trial (Predilatation in Transcatheter Aortic Valve Implantation (TAVI) Trial) was a multicenter, randomized, clinical trial designed to evaluate the safety and efficacy of TAVI with or without balloon aortic valvuloplasty (BAV) in patients with symptomatic, severe aortic valve stenosis. Purpose To investigate by echocardiography the functional changes of self-expanding prosthetic valves during the first year after TAVI with or without BAV. Methods One hundred seventy one consecutive patients with severe aortic stenosis were enrolled at 4 centers and randomized to TAVI using self-expanding prostheses with (pre-BAV) or without pre-dilatation (no-BAV). Transthoracic echocardiography was obtained at baseline, 30 days and 1 year after TAVI. Results Of 171 patients, 86 patients were randomized to pre-BAV group and 85 to no-BAV group. Over the one year, 7 (4%) patients died and in 18 (10%) there was no available paired 30 day/1 year echo. At baseline echocardiography the peak and mean aortic valve gradient and the aortic valve area (AVA) in no-BAV group were 77.31±22.56 mmHg, 47.23±14.98 mmHg and 0.69±0.16cm2 and in pre-BAV group 81.97±23.17 mmHg, 49.39±14.78 mmHg and 0.65±0.15cm2 respectively. One year after TAVI, patients in no-BAV and pre-BAV group showed stable peak and mean aortic valve gradients similar to those at 30 days (from 16.36±7.88 to 14.51±6.6 mmHg vs. 17.17±8.88 to 15.95±9.97 mmHg and from 8.87±4.23 to 7.99±4.04 mmHg vs. 9.39±4.79 to 8.38±5.02 mmHg respectively, P Conclusions In both pre-BAV and no-BAV groups the improvement in hemodynamics of self-expanding prosthetic valves remained durable during the one year echocardiographic follow up assessment. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): MEDTRONIC

Objectives The aim of this study was to investigate the prognostic and clinical value of quantitative positron emission tomographic (PET) metrics in patients with ischemic heart failure. Background Although myocardial flow reserve (MFR) is a strong predictor of cardiac risk in patients without heart failure, it is unknown whether quantitative PET metrics improve risk stratification in patients with ischemic heart failure. Methods The study included 254 patients referred for stress and rest myocardial perfusion imaging and viability testing using PET. Major adverse cardiac event(s) (MACE) consisted of death, resuscitated sudden cardiac death, heart transplantation, acute coronary syndrome, hospitalization for heart failure, and late revascularization. Results MACE occurred in 170 patients (67%) during a median follow-up of 3.3 years. In a multivariate Cox proportional hazards model including multiple quantitative PET metrics, only MFR predicted MACE significantly (p = 0.013). Beyond age, symptom severity, diabetes mellitus, previous myocardial infarction or revascularization, 3-vessel disease, renal insufficiency, ejection fraction, as well as presence and burden of ischemia, scar, and hibernating myocardium, MFR was strongly associated with MACE (adjusted hazard ratio per increase in MFR by 1: 0.63; 95% confidence interval: 0.45 to 0.91). Incorporation of MFR into a risk assessment model incrementally improved the prediction of MACE (likelihood ratio chi-square test [16] = 48.61 vs. chi-square test [15] = 39.20; p = 0.002). Conclusions In this retrospective analysis of a single-center cohort, quantitative PET metrics of myocardial blood flow all improved risk stratification in patients with ischemic heart failure. However, in a hypothesis-generating analysis, MFR appears modestly superior to the other metrics as a prognostic index.

Coronary computed tomography angiography (CCTA)-based transluminal attenuation gradient (TAG) was suggested to determine the functional significance of a stenosis. However, evidence that TAG acquired by wide-volume scanners can assess the hemodynamic significance of stenosis assessed by single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is lacking. Moreover, coronary cross-sectional area may influence TAG. Hence, we aimed at assessing the diagnostic value of TAG to predict ischemia in SPECT-MPI and the correlation between TAG and the transluminal cross-sectional area gradient (TCG).Patients undergoing CCTA and SPECT-MPI for suspected coronary artery disease were included. TAG and TCG were calculated measuring the mean vessel attenuation and the cross-sectional area along major coronary vessels at 5-mm intervals.A total of 255 coronary arteries of 87 patients were included. TAG and TCG did not discriminate between coronary arteries with or without ischemia as assessed by SPECT-MPI (p = .44 and p = .25, respectively). The area under the curve to predict ischemia was not increased by adding TAG (0.88, 95% CI 0.83-0.92) or TCG (0.87, 95% CI 0.81-0.90) to CCTA alone (0.85, 95% CI 0.80-0.89). There was a significant correlation between TAG and TCG (r = 0.43; p .001).CCTA-derived TAG and TCG do not offer any value in predicting ischemia assessed by SPECT-MPI. TAG is partly affected by differences in the coronary luminal area.

Purpose/Background/Objectives: Aortic stiffness and hemodynamics are independent predictors of adverse cardiovascular events. Transcatheter aortic valve implantation (TAVI) is growingly used in high surgical risk patients with aortic valve stenosis. We sought to investigate the effect of TAVI on aortic stiffness. Methods: Fifty-five high-risk patients (mean age 79.5 ± 8.8 years, 46% males) with severe symptomatic aortic stenosis undergoing TAVI were included. Arterial stiffness was estimated through carotid-femoral pulse wave velocity (cfPWV). Measurements were conducted prior to the implantation, at discharge and 1 year post-TAVI. Results: Prior to the implantation, cfPWV was 7.5 ± 1.4 m/s for the overall population. There was a statistically significant increase in measurements of aortic stiffness at discharge (7.5 ± 1.4 vs 8.3 ± 1.9 m/s for cfPWV with p = 0.043) without a statistically significant change in SBP (p = NS) (Figure 1). There was also a significant increase in cfPWV (8.7 ± 1.8 m/s) after 1 year compared to the pre-procedural assessment (p = 0.001). We also observed a non-significant increase in peripheral SBP at 1 year compared to SBP measurements at baseline and at discharge (153 ± 24 m/s vs 147 ± 21and 148 ± 22 m/s, respectively; p = 0.319) and these changes were independent of age and gender (Figure 1). Conclusion: Our study shows that both shortly as well as in the long-term after TAVI subjects experience an increase in aortic stiffness that is independent of changes in SBP. These findings further elucidate the hemodynamic consequences and provide evidence of a possible long-standing repercussion of TAVI. Figure 1

IntroductionMyocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in 5%–15% of all patients with acute myocardial infarction. Cardiac MR (CMR) and optical coherence tomography have been used to identify the underlying pathophysiological mechanism in MINOCA. The role of cardiac CT angiography (CCTA) in patients with MINOCA, however, has not been well studied so far. CCTA can be used to assess atherosclerotic plaque volume, vulnerable plaque characteristics as well as pericoronary fat tissue attenuation, which has not been yet studied in MINOCA.Methods and analysisMINOCA-GR is a prospective, multicentre, observational cohort study based on a national registry that will use CCTA in combination with CMR and invasive coronary angiography (ICA) to evaluate the extent and characteristics of coronary atherosclerosis and its correlation with pericoronary fat attenuation in patients with MINOCA. A total of 60 consecutive adult patients across 4 participating study sites are expected to be enrolled. Following ICA and CMR, patients will undergo CCTA during index hospitalisation. The primary endpoints are quantification of extent and severity of coronary atherosclerosis, description of high-risk plaque features and attenuation profiling of pericoronary fat tissue around all three major epicardial coronary arteries in relation to CMR. Follow-up CCTA for the evaluation of changes in pericoronary fat attenuation will also be performed. MINOCA-GR aims to be the first study to explore the role of CCTA in combination with CMR and ICA in the underlying pathophysiological mechanisms and assisting in diagnostic evaluation and prognosis of patients with MINOCA.Ethics and disseminationThe study protocol has been approved by the institutional review board/independent ethics committee at each site prior to study commencement. All patients will provide written informed consent. Results will be disseminated at national meetings and published in peer-reviewed journals.Trial registration numberNCT4186676.

Vulnerable plaque plays crucial role in prognosis of diabetes mellitus (DM). Microwave radiometry (MWR) allows measurement of the temperature of tissues, thus indirectly reflecting inflammation, a characteristic of atherosclerotic plaque stability. Aim of the study was to evaluate the relation of carotid artery inflammation with glycemic control and presence of coronary artery disease (CAD).We included 112 patients (65 ± 9 years, 30 ± 5 kg/mPatients with DM presented higher ΔTmax comparing to patients without DM (0.91 ± 0.29 vs 0.71 ± 0.25 °C, p 0.001). Glycaemia over time was associated with thermal heterogeneity of carotids (HbA1c:6.5: 0.78 ± 0.23, HbA1c: 6.5-7: 0.87 ± 0.24, HbA1c: 7-8: 0.99 ± 0.30, HbA1c:8: 1.15 ± 0.35 °C, p = 0.003). Patients with CAD presented higher ΔΤmax comparing to patients with normal CA (0.93 ± 0.24 vs 0.68 ± 0.25 °C, p 0.001) and patients that underwent coronary revascularization presented higher ΔTmax (0.95 ± 0.25 vs 0.76 ± 0.26 °C, p 0.001). A ΔTmax ≥ 0.9 (received by ROC analysis) was an independent predictor for revascularization in DM patients (odds ratio 3.29, 95% CI: 1.07-10.16; p = 0.039) when adjusted for sex, age and the established risk factors of CAD.Local inflammatory activation of carotid arteries is more pronounced in patients with DM and is associated with the glycemic control. Carotids' thermal heterogeneity is associated with need for revascularization supporting its predictive value in DM patients assessed for CAD.

Coronary computed tomography angiography (CCTA) provides critical prognostic information on plaque burden and stenosis severity of coronary arteries. We aimed to investigate the long-term prognostic value of coronary artery volume per myocardial mass as a potential new imaging parameter. Consecutive patients with suspected coronary artery disease (CAD) were included. Coronary artery volume index (CAVi) was defined as volume over myocardial mass. Additionally, obstructive CAD (≥ 70% stenosis) and segment severity score (SSS: sum of all segments scored according to lesion severity with 0 = no lesion, 1 = narrowing

Background Coronary computed tomography angiography (CCTA) provides incremental prognostic information over traditional risk factors in patients with suspected coronary artery disease. However, little is known about the long-term predictive performance of CCTA-derived coronary volumes and mid-diastolic left ventricular (LV) mass. Purpose To assess long-term prognostic value of coronary volumes and mid-diastolic LV mass as novel potential imaging predictors derived from low-dose prospectively ECG-triggered CCTA. Methods Consecutive patients with suspected or known coronary artery disease, referred for low-dose CCTA, were included. Patients with previous revascularization were excluded. The following parameters were evaluated: calcium score, segment involvement score (SIS: 1 point for each coronary segment with presence of plaque), coronary volume, mid-diastolic LV mass and coronary volume indexed to LV mass. Major adverse cardiovascular events (MACE) were defined as all-cause death, non-fatal myocardial infarction and revascularization (PCI or CABG). The association between CCTA measures and the occurrence of events was quantified using cox regression hazard and Kaplan Meier analysis. Results A total of 147 consecutive patients were included in the study. Of them, 93 (63.3%) were male and 79 (53.7%) hat one or more traditional cardiovascular risk factors. There was a weak but statistical significant inverse correlation between indexed coronary volume and both calcium score (R=-0.3, p=0.01) and SIS (R=-0.24, p=0.005). After a median follow-up of 5.8 years 30 MACE occurred in 25 patients, including 3 deaths, 26 revascularizations and 1 non-fatal myocardial infarction. In univariate cox regression hazard analysis calcium score (HR=12.69, 95% CI 2.99–53.83, p Conclusions Indexed coronary volume, derived from low-dose CCTA, independently predicts cardiovascular events. Larger studies are mandated to confirm the predictive value of this potential new biomarker.

Background Adipose tissue regulates energy balance and glucose homeostasis via the secretion of circulating molecules, termed adipokines, such as leptin and adiponectin. Excess adiposity and adipose tissue dysfunction have been involved in the pathogenesis of dyslipidemias. Positron emission tomography/computed tomography (PET/CT) with F-18-Fluorodeoxyglycose (FDG) has been used for the assessment of adiposity. Purpose To compare abdominal adipose tissue function assessed by FDG uptake with serum indices, such as plasma adipokines' levels in individuals with different subtypes of dyslipidemia and normolipidemics. Methods Seventy individuals (mean age 44±13 years, range 21–75, 43 men) with a clinical diagnosis of either heterozygous familial hypercholesterolemia (heFH) (n=38) or familial combined hyperlipidemia (FCH) (n=32), not under statins for at least one year, and 20 age and sex matched controls, were enrolled. Visceral (VAT) and subcutaneous adipose tissue metabolic activity (SAT) was assessed with FDG-PET/CT imaging and was quantified by calculating the target-to-background ratios (TBR) in consecutive axial fat images between the proximal (cephalic) end of the L1 and distal (caudal) end of the L3 vertebrae by dividing the average of the mean standard uptake value (SUV) to the mean SUV of the vena cava. Leptin and adiponectin were measured in all the subjects. Results There was no significant difference of plasma leptin values between FCH, heFH and non dyslipidemics subjects (p=0.204). FCH had reduced adiponectin values compared to heFH patients and controls [median 5.7 IQR (3.9–7.6) vs. 13.1 (9.2–23.3) vs. 10.9 (6.1–19.1) μg/mL, respectively, p Conclusions Visceral adipose tissue FDG uptake is reduced in patients with FCH compared to those with heFH and normolipidemics. In addition, serum adiponectin levels are lower in patients with FCH. These findings highlight the different pathophysiological role of visceral fat function in the two most common types of familial dyslipidemia and suggest that visceral fat could be an attractive target for the treatment of FCH.

Introduction The association of carotid plaque inflammation with cerebrovascular events is a matter of rigorous research. Microwave Radiometry (MWR) allows in vivo noninvasive measurement of the internal temperatures of tissues, reflecting inflammation. Purpose To investigate whether increased carotid temperatures in patients with documented coronary artery disease (CAD) are associated with cerebrovascular events. Methods Consecutive patients with significant CAD from three tertiary centers were included in the study. Maximum carotid plaque thickness was assessed in all carotids by ultrasound. ΔT by MWR was assigned as the temperature difference (maximal minus minimum) along the carotid artery. ΔT ≥0.90°C was assigned as high ΔT. All patients were followed-up clinically for two years and all strokes were adjudicated by an independent committee. Transient ischemic attacks were excluded. Results In total 300 patients were included in the study. High ΔT temperatures bilaterally were measured in 47 patients (15.7%). Three patients (1.0%) suffered a stroke, including one fatal. Stoke rate was 4.3% in the group with bilateral high ΔT and 0.4% in non-high ΔT group (p=0.02). In Kaplan-Meier plot patients with bilateral high ΔT showed higher stroke rate (log-rank p=0.004, figure) Conclusions Bilateral high carotid temperatures are associated with increased two-year stroke rate. The potential value of the present finding in risk stratification of intermediate carotid stenosis mandates further investigation.

Background The adipose tissue is now established as a major regulator of cardiovascular status, mediated by the secretion of several bioactive molecules, including adipocytokines. Individuals with genetic dyslipidaemias of either familial combined hyperlipidemia (FCH) or heterozygous familial hypercholesterolemia (heFH) subtype are characterized by accelerated atherosclerosis. Nonetheless, limited data exists on the relationship between adiposity and arterial inflammation, a marker of cardiovascular risk, in this setting. Purpose To investigate the relationship between adiposity indices and arterial inflammation evaluated by 18F fluorodeoxyglycose positron emission tomography (PET/CT) in patients with hereditary lipid metabolism disorders. Methods Consecutive patients with either FCH or heFH, free of statin therapy, and normolipidaemic individuals underwent PET/CT imaging. Arterial FDG uptake was estimated as the average value of target-to-background ratio (TBR) within aortic and carotid wall. Volumes of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured from CT images between the proximal (cephalic) end of the L1 and distal (caudal) end of the L3 vertebrae by selecting all voxels with attenuation between −190 and −30 Hounsfield Units (HU). Serum adiponectin and leptin levels were measured with ELISA by available commercial kits. For comparisons with arterial TBR, adiponectin and leptin concentrations above and below the 25th percentile, were stratified as high and low, respectively. Results In total, 60 individuals (20 FCH, 20 heFH and 20 controls) were included. A modest but significant correlation between SAT volume and arterial TBR (R=0.386, p=0.004) was detected. This relationship did not remain significant after controlling for VAT volume (p=0.303). A strong correlation between VAT volume and arterial TBR (R=0.621, p=0.001) was observed. This relationship remained significant after controlling for SAT volume (R=0.541, p Conclusions Abdominal adipose tissue imaging markers and serum adipocytokines correlate with arterial inflammation as assessed by PET/CT in patients with familial dyslipidaemias highlighting the role of abdominal adipose tissue for atherosclerosis progression in this population.