Association Between Omega-3 Fatty Acid Levels and Aortic Valve Calcium (from the Multi-Ethnic Study of Atherosclerosis).

Calcific aortic valve disease, a condition of chronic inflammation, is associated with increased cardiovascular events and all-cause mortality. Omega-3 fatty acids (O3FAs) reduce both acute and chronic inflammation, but their associations with aortic valve calcium (AVC) have not been studied. The Multi-Ethnic Study of Atherosclerosis is a prospective cohort study of 6,814 adults without clinical cardiovascular disease. Plasma fatty acid levels and cardiac computed tomography (CT) scans were performed at baseline, and CT scans were performed at subsequent clinical visits over a median 9-year period. We assessed whether plasma levels of O3FAs and their species correlate with the presence, severity, and progression of AVC measured by CT in Multi-Ethnic Study of Atherosclerosis. The mean age of the 6,510 included participants with baseline fatty acid levels, AVC, and covariate data was 62.1 ± 10.2 years, and 47.1% of the participants were male. Race distribution was 38.6% White, 27.2% Black, 22.1% Hispanic/Latino, and 12.1% Chinese. Among the 6,510 participants, 5,884 had a subsequent CT scan, and 3,304 had a third CT scan with AVC measurements. At baseline, 862 participants (13.2%) had prevalent AVC (Agatston score >0), and were more likely to be of older age, male, of the White race, have a lower education level, and have co-morbidities that are associated with a higher risk for AVC. Plasma tertiles of eicosapentaenoic acid, docosahexaenoic acid, and total O3FA were not associated with prevalent AVC at baseline, incident AVC, or change in AVC. In conclusion, plasma levels of O3FAs in subjects not routinely supplemented with O3FAs are not useful for predicting the presence or development of AVC. Whether high plasma O3FA levels, achievable by high-dose O3FA over-the-counter supplementation or pharmacotherapy, is associated with AVC requires further investigation.

Omega-3 fatty acids ameliorate vascular inflammation: A rationale for their atheroprotective effects.

BACKGROUND AND AIMS: Clinical trials have demonstrated reductions in major adverse cardiovascular events with purified high-dose eicosapentaenoic acid (EPA), independent of effects on lipids. We aimed to investigate whether omega-3 fatty acids reduce vascular inflammation, a critical mediator of atherosclerosis, and hypothesised that EPA is superior to docosahexaenoic acid (DHA). METHODS: In a double-blind randomised controlled trial and cell-culture study, 40 healthy volunteers were supplemented with 4 g daily of either EPA, DHA, fish oil (2:1 EPA:DHA), or placebo for 30 days. Serum was incubated with TNF-stimulated human umbilical vein endothelial cells (HUVECs), and markers of acute vascular inflammation (AVI) were measured. The effects of EPA, DHA (600 mg/kg/day), olive oil, or no treatment were also measured in preclinical models of [1] AVI using a periarterial collar (C57Bl/6J; n = 40 mice) and [2] atherosclerosis where ApoE-/- mice (n = 40) were fed a 16-week atherogenic diet. RESULTS: EPA supplementation reduced expression of C-C motif chemokine ligand 2 (CCL2) by 25% compared to placebo (p = 0.03). In the AVI model, EPA reduced vascular expression of VCAM1 by 43% (p = 0.02) and CCL2 by 41% (p = 0.03). Significant inverse correlations were observed between EPA levels and vascular expression of VCAM1 (r = -0.56, p = 0.001) and CCL2 (r = -0.56, p = 0.001). In ApoE-/- mice, EPA reduced aortic expression of Il1b by 44% (p = 0.04) and Tnf by 49% (p = 0.04), with similar inverse correlations between EPA levels and both Il1b (r = -0.63, p = 0.009) and Tnf (r = -0.50, p = 0.04). CONCLUSIONS: Supplementation with EPA, more so than DHA, ameliorates acute and chronic vascular inflammation, providing a rationale for the cardiovascular benefit observed with high dose omega-3 fatty acid administration.

Transcatheter Aortic Valve Replacement via the Right Subclavian Artery Approach: A Case Series.

The right subclavian artery (RSA) approach is an infrequently used alternative-access method for transcatheter aortic valve replacement (TAVR), which may be considered when transfemoral and left subclavian artery (LSA) access routes are contraindicated. The double arterial bend encountered along the course of the RSA to the aortic root makes advancement of the TAVR delivery system more challenging, but can be overcome using a steerable delivery system over an ultra-stiff guidewire. We report 5 cases from our institution of TAVRs performed via the RSA approach in patients with severe aortic stenosis that were unsuitable for transfemoral or LSA access. The procedures were performed under general anesthesia, using a 5-cm infraclavicular incision. In each case, an Edwards Commander Delivery System was advanced through an eSheath over an Innowi guidewire, and an Edwards SAPIEN 3 valve was successfully deployed. The mean fluoroscopy time was 19.5 ± 3.8 minutes. No aortic regurgitation (AR) was present postprocedure for 4 out of 5 cases, and 1 had mild to moderate AR. The length of hospital stay was 2 to 3 days for 4 patients. All patients had an excellent outcome at 12 months post-procedure. The RSA approach is a safe and feasible access method for TAVR, and we recommend that it be considered as the next best access method if transfemoral and LSA approaches are unsuitable.

Multimodality Tachycardia-Induced Stress Testing Predicts a Low-Risk Group for Early Cardiovascular Mortality After Renal Transplantation.

BACKGROUND: Cardiovascular events remain a major cause of death in kidney transplant recipients. The optimal noninvasive workup to prevent peritransplant cardiac mortality remains contentious. METHODS: We conducted a retrospective analysis to assess the renal transplantation cardiovascular assessment protocol within a single-center population over a 5-year period. Asymptomatic patients aged less than 45 years with no history of cigarette smoking, without diabetes mellitus, and dialysis-dependent for less than 24 months did not undergo cardiac testing before listing. All other asymptomatic patients underwent a noninvasive, tachycardia-induced stress test, where a target heart rate of 85% predicted for age and gender was required. The primary endpoints were rates of acute myocardial infarction (AMI) and cardiovascular death at 30 days after renal transplantation. RESULTS: Between 2015 and 2019, 380 recipients underwent cardiac evaluation: 79 (20.8%) were deemed low cardiovascular risk and placed on the renal transplant waitlist without further assessment; 270 (71.1%) underwent a tachycardia-induced stress test; and 31 (8.1%) were deemed high risk and proceeded directly to invasive coronary angiography (ICA). In the 5-year follow-up, 3 patients (0.8%) experienced an AMI 30 days after renal transplantation, all of which occurred in the high-risk "direct to ICA" cohort. No events were documented in the low-risk cohort or in patients who had a negative tachycardia-induced stress test. There were no cardiovascular deaths within 30 days after transplantation. CONCLUSION: A negative tachycardia-induced cardiac stress test, achieving 85% of predicted heart rate, was associated with a 0% AMI rate and no cardiovascular deaths at 30 days after renal transplantation.

Initial experience of a self-expanding transcatheter aortic valve with an outer pericardial wrap: The United Kingdom and Ireland Implanters' registry.

OBJECTIVES: The United Kingdom and Ireland Implanters' registry is a multicenter registry which reports on real-world experience with new transcatheter heart valves. BACKGROUND: The Evolut PRO (Medtronic, Minneapolis, MN) transcatheter aortic valve is a self-expanding transcatheter aortic valve with an outer pericardial wrap, designed to minimize paravalvular regurgitation. METHODS: Between July 2017 and December 2018, clinical, procedural, and 30-day outcome data were prospectively collected from all patients receiving the Evolut PRO valve across nine participating centers in the United Kingdom and Ireland. The primary efficacy outcome was the Valve Academic Research Consortium-2 (VARC-2)-defined endpoint of device success. The primary safety outcome was the VARC-2-defined composite endpoint of early safety at 30 days. RESULTS: A total of 317 patients underwent implantation. Mean age was 81.8 ± 6.4 years and Society of Thoracic Surgeons Predicted Risk of Mortality Score 5.5 ± 1.8%. Iliofemoral access was used in 99.1% of patients. Device success was 91.2%. Mean gradient was 7.6 ± 4.7 mmHg and effective orifice area 1.9 ± 0.7 cm2 . The incidence of moderate paravalvular regurgitation was 1.7% and there was no severe paravalvular regurgitation. A new permanent pacemaker was implanted in 17.8% of patients without a pacemaker at baseline. Early safety was demonstrated in 92.7%. At 30 days, all-cause mortality was 0.6%, stroke 3.8%, and major vascular complication 2.8%. CONCLUSIONS: Real-world experience of the Evolut PRO transcatheter aortic valve demonstrated favorable procedural success, safety, valve function, and incidence of new permanent pacemaker implantation.

The Extent of Aortic Atherosclerosis Predicts the Occurrence, Severity, and Recovery of Acute Kidney Injury After Transcatheter Aortic Valve Replacement.

BACKGROUND: Acute kidney injury (AKI) can be a major complication of transcatheter aortic valve replacement (TAVR). Atheroembolization of debris during catheter manipulation has been considered as a potential factor causing AKI. This study investigates the impact of aortic atheroma burden on AKI post-TAVR and evaluates the potential of preoperative multislice computed tomographic (MSCT) imaging for the assessment of AKI in these patients. METHODS AND RESULTS: Preoperative multislice computed tomographic images were analyzed in 278 patients with symptomatic severe aortic stenosis who underwent TAVR. AKI was defined as an absolute increase in serum creatinine ≥0.3 mg/dL. Aorta vessel and lumen areas in each 1-mm cross-sectional image were measured. Percent atheroma volume above (PAVabove renal arteries) and below (PAVbelow renal arteries) renal arteries were calculated by the following formula: PAV={Σ (vessel area-lumen area)/Σ(vessel area)}×100. AKI occurred in 92 patients (33.1%) after TAVR. AKI was associated with a greater PAV above (30.4±8.2 versus 21.3±5.8%; P=0.02) but not below (28.9±7.7 versus 25.8±6.1%; P=0.41) the renal arteries. Greater PAVabove renal arteries was associated directly with AKI severity ( P=0.008) and inversely with recovery in serum creatinine level from peak to discharge ( r=0.78; P=0.002). Multivariate analysis demonstrated that PAVabove renal arteries was a significant predictor of AKI ( P=0.02). Receiver-operating curve analysis identified PAVabove renal arteries >29.5% as an optimal threshold to predict AKI. CONCLUSIONS: Suprarenal aortic atheroma burden is associated with the occurrence, severity, and recovery of AKI after TAVR. This highlights the utility of preoperative assessment of aortic atherosclerosis on multislice computed tomography to identify patients at high-risk for AKI.

Effect of Serial Infusions of CER-001, a Pre-ß High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial: A Randomized Clinical Trial.

Importance: CER-001 is a negatively charged, engineered pre-ß high-density lipoprotein (HDL) mimetic containing apolipoprotein A-I and sphingomyelin. Preliminary studies demonstrated favorable effects of CER-001 on cholesterol efflux and vascular inflammation. A post hoc reanalysis of a previously completed study of intravenous infusion of CER-001, 3 mg/k, showed that the intravenous infusion in patients with a high coronary plaque burden promoted regression as assessed by intravascular ultrasonography. Objective: To determine the effect of infusing CER-001 on coronary atherosclerosis progression in statin-treated patients. Design, Setting, and Participants: A double-blind, randomized, multicenter trial evaluating the effect of 10 weekly intravenous infusions of CER-001, 3 mg/kg, (n = 135) or placebo (n = 137) in patients with an acute coronary syndrome (ACS) and baseline percent atheroma volume (PAV) greater than 30% in the proximal segment of an epicardial artery by intravascular ultrasonography. The study included 34 academic and community hospitals in Australia, Hungary, the Netherlands, and the United States in patients with ACS presenting for coronary angiography. Patients were enrolled from August 15, 2015, to November 19, 2016. Interventions: Participants were randomized to receive weekly CER-001, 3 mg/kg, or placebo for 10 weeks in addition to statins. Main Outcomes and Measures: The primary efficacy measure was the nominal change in PAV from baseline to day 78 measured by serial intravascular ultrasonography imaging. The secondary efficacy measures were nominal change in normalized total atheroma volume and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Results: Among 293 patients (mean [SD] age, 59.8 [9.4] years; 217 men [79.8%] and 261 white race/ethnicity [96.0%]), 86 (29%) had statin prior use prior to the index ACS and 272 (92.8%) had evaluable imaging at follow-up. The placebo and CER-001 groups had similar posttreatment median levels of low-density lipoprotein cholesterol (74 mg/dL vs 79 mg/dL; P = .15) and high-density lipoprotein cholesterol (43 mg/dL vs 44 mg/dL; P = .66). The primary efficacy measure, PAV, decreased 0.41% with placebo (P = .005 compared with baseline), but not with CER-001 (-0.09%; P = .67 compared with baseline; between group differences, 0.32%; P = .15). Similar percentages of patients in the placebo and CER-001 groups demonstrated regression of PAV (57.7% vs 53.3%; P = .49). Infusions were well tolerated, with no differences in clinical and laboratory adverse events observed between treatment groups. Conclusions and Relevance: Infusion of CER-001 did not promote regression of coronary atherosclerosis in statin-treated patients with ACS and high plaque burden. Trial Registration: ClinicalTrials.gov Identifier: NCT2484378.

Effect of serial infusions of reconstituted high-density lipoprotein (CER-001) on coronary atherosclerosis: rationale and design of the CARAT study.

BACKGROUND: High-density lipoprotein (HDL) is believed to have atheroprotective properties, but an effective HDL-based therapy remains elusive. Early studies have suggested that infusion of reconstituted HDL promotes reverse cholesterol transport and vascular reactivity. The CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial (CARAT) is investigating the impact of infusing an engineered pre-beta HDL mimetic containing sphingomyelin (SM) and dipalmitoyl phosphatidlyglycerol (CER-001) on coronary atheroma volume in patients with a recent acute coronary syndrome (ACS). METHODS: The CARAT is a phase 2, multicenter trial in which 292 patients with an ACS undergoing intracoronary ultrasonography and showing percent atheroma volume (PAV) greater than 30% are randomly assigned to treatment with ten infusions of CER-001 3 mg/kg or matching placebo, administered at weekly intervals. Intracoronary ultrasonography is repeated at the end of the treatment period. RESULTS: The primary endpoint is the nominal change in PAV. Safety and tolerability will also be evaluated. CONCLUSIONS: CARAT will establish whether serial 3 mg/kg infusions of an engineered pre-beta HDL mimetic containing SM and dipalmitoyl phosphatidlyglycerol (CER-001) will regress atherosclerotic plaque in patients with a recent ACS.

Aortic atheroma burden predicts acute cerebrovascular events after transcatheter aortic valve implantation: insights from volumetric multislice computed tomography analysis.

AIMS: Embolisation of atheromatous debris during catheter manipulation is considered to underlie acute cerebrovascular events (CVE) after transcatheter aortic valve implantation (TAVI). However, the relationship between aorta atheroma burden and acute CVE after TAVI has not been established. We investigated the impact of aorta atheroma burden on acute CVE. METHODS AND RESULTS: Preoperative multislice computed tomographic (MSCT) images in 278 patients receiving TAVI were analysed. Total atheroma volume (TAV) was calculated by measuring aorta vessel and lumen areas in every 1 mm cross-sectional image. Acute CVE was observed in 16 patients. Patients having acute CVE were more likely to have a prior CVE (p=0.002), and to exhibit greater TAV in the ascending aorta (12.8±3.5 vs. 7.0±2.1 cm3, p<0.001) and the aortic arch (3.1±1.6 vs. 1.2±0.2 cm3, p<0.001). TAV in the ascending aorta >10.3 cm3 and in the aortic arch >2.9 cm3 predicted acute CVE. The incidence of acute CVE was highest (36.4%) if patients had a prior CVE and TAV in the ascending aorta and the aortic arch above cut-offs. CONCLUSIONS: Patients with acute CVE after TAVI had greater aorta atheroma burden. Our findings might underscore preoperative MSCT analysis of aorta atherosclerosis to identify high-risk patients for acute CVE, who might require an embolic protection device during TAVI.

Ongoing challenges for pharmacotherapy for dyslipidemia.

INTRODUCTION: While increasing evidence has led to lipid-modifying therapy achieving an important role in the treatment guidelines for the prevention of cardiovascular disease, these agents are suboptimally used and there remains a considerable risk of clinical events. Accordingly, there is a need to develop more effective lipid-modifying approaches in many patients. AREAS COVERED: A literature search was performed of topical manuscripts focusing on factors influencing use of established therapies and new agents in development that target a range of lipid factors. EXPERT OPINION: More intensive efforts are required to ensure that statin use is maximized in higher risk patients. A range of novel therapies, including proprotein convertase subtilisin kexin-type 9 and cholesteryl ester transfer protein inhibitors, may provide additional protection, although this remains to be established by clinical trials.

Lipid pharmacotherapy for treatment of atherosclerosis.

INTRODUCTION: For more than two decades, lowering levels of low-density lipoprotein cholesterol has formed the cornerstone of management of patients with atherosclerotic cardiovascular disease. The substantial residual risk of clinical events in patients treated with statin therapy highlights the need to develop more effective strategies to reduce cardiovascular risk. AREAS COVERED: Current and future approaches targeting dyslipidemia and inflammatory factors implicated in atherosclerosis are discussed. EXPERT OPINION: Considerable efforts to further reduce levels of atherogenic lipoproteins provide additional strategies to lower cardiovascular risk. In contrast, it remains to be determined whether targeting protective lipid factors or inflammatory mediators of atherosclerosis will be clinically beneficial.