Publications by authors named "Stephen J Nicholls"

431 Publications

Omega-3 Fatty Acids Effect on Major Cardiovascular Events in Patients at High Cardiovascular Risk-Reply.

JAMA 2021 04;325(13):1334-1335

Monash Cardiovascular Research Centre, Monash University, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1001/jama.2021.0839DOI Listing
April 2021

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

Atherosclerosis 2021 Mar 17;324:27-37. Epub 2021 Mar 17.

Discipline of Medicine, University of Adelaide, Adelaide, Australia; Kolling Institute, University of Sydney, Sydney, Australia. Electronic address:

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.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.03.003DOI Listing
March 2021

BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

Cell 2021 Mar 16. Epub 2021 Mar 16.

QIMR Berghofer Medical Research Institute, Brisbane 4006, QLD, Australia. Electronic address:

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1β, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.
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http://dx.doi.org/10.1016/j.cell.2021.03.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962543PMC
March 2021

Assessing the impact of PCSK9 inhibition on coronary plaque phenotype with optical coherence tomography: rationale and design of the randomized, placebo-controlled HUYGENS study.

Cardiovasc Diagn Ther 2021 Feb;11(1):120-129

Monash Cardiovascular Research Centre, Clayton, Australia.

Background: Technological advances in arterial wall imaging permit the opportunity to visualize coronary atherosclerotic plaque with sufficient resolution to characterize both its burden and compositional phenotype. These modalities have been used extensively in clinical trials to evaluate the impact of lipid lowering therapies on serial changes in disease burden. While the findings have unequivocally established that these interventions have the capacity to either slow disease progression or promote plaque regression, depending on the degree of lipid lowering achieved, their impact on plaque phenotype is less certain. More recently optical coherence tomography (OCT) has been employed with a number of studies demonstrating favorable effects on both fibrous cap thickness (FCT) and the size of lipid pools within plaque in response to statin treatment.

Methods: The phase 3, multi-center, double-blind HUYGENS study will assess the impact of incremental lipid lowering with the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, evolocumab, on plaque features using serial OCT imaging, in statin-treated patients following an acute coronary syndrome (ACS). Subjects with non-ST-elevation ACS (n=150) will be randomized 1:1 into two groups to receive monthly injections of evolocumab 420 mg or placebo.

Results: The primary endpoint is the effect of evolocumab on coronary atherosclerotic plaques will be assessed by OCT at baseline and at week 50.

Conclusions: The HUYGENS study will determine whether intensified lipid lowering therapy with evolocumab in addition to maximally tolerated statin therapy will have incremental benefits on high-risk features of coronary artery plaques.

Trial Registration: This study was registered on Clinicaltrials.gov (NCT03570697).
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http://dx.doi.org/10.21037/cdt-20-684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944215PMC
February 2021

Clinical predictors and sequelae of computed tomography defined leaflet thrombosis following transcatheter aortic valve replacement at medium-term follow-up.

Heart Vessels 2021 Mar 4. Epub 2021 Mar 4.

Monash Cardiovascular Research Centre, Monash University, Melbourne, Australia and Monash Heart, Monash Health, Monash Heart, Monash Medical Centre, 246 Clayton Rd, Clayton, VIC, 3168, Australia.

Background: The clinical predictors and sequelae of leaflet thrombosis (LT) following transcatheter aortic valve replacement (TAVR) is still unclear. Therefore, our aim was to determine the clinical predictors and sequelae at mid-term follow-up of computed tomography (CT)-defined LT following TAVR.

Methods And Results: We performed a prospective evaluation with a 320-multislice CT following TAVR for the presence of LT, defined as hypo-attenuated leaflet thickening (HALT). Four-dimensional CT image-rendering was performed to determine the presence of reduced leaflet motion (RELM). 172 patients [89 (51.7%) male, mean age 82.8 ± 5.7 years] treated with commercially available TAVR device (Lotus 54%, CoreValve 32% and Sapien 3 14%) were included, with median CT-scan at 6.0 weeks post-TAVR. Prevalence of HALT was 14.0% (24 cases) and RELM was 9.8% (17 cases). On multivariate analysis, patients with HALT were less prescribed oral anticoagulation (OAC) (OR 9.9), received larger TAVR prostheses (OR 5.7) and higher rates of moderate-severe para-valvular regurgitation (PVR) (OR 16.3). There was no difference in clinical outcomes at a median follow-up of 2.3 years. Patients with RELM had significantly higher transvalvular gradients after discharge when compared to those without RELM.

Conclusions: Absence of OAC, large TAVR prostheses and moderate-severe PVR were predictors for LT. Transvalvular gradients were higher in patients that developed RELM but not HALT. Further studies are warranted to determine the long-term impact of LT on TAVR durability. Prevalence of different sub-types of CT-defined LT (HALT and RELM) and the clinical predictors of developing LT following TAVR. CT computed tomography, HALT hypo-attenuated leaflet thickening, LT leaflet thrombosis, RELM reduced leaflet motion, TAVR transcatheter aortic valve replacement.
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http://dx.doi.org/10.1007/s00380-021-01803-4DOI Listing
March 2021

Elevated HDL-bound miR-181c-5p level is associated with diabetic vascular complications in Australian Aboriginal people.

Diabetologia 2021 Mar 2. Epub 2021 Mar 2.

South Australian Health and Medical Research Institute, Adelaide, SA, Australia.

Aims/hypothesis: Diabetes is a major burden on Australia's Indigenous population, with high rates of disease and vascular complications. Diabetic vascular complications are associated with impaired ischaemia-driven angiogenesis. MicroRNAs (miRNAs) are key players in the regulation of angiogenesis. HDL-cholesterol (HDL-c) levels are inversely associated with the risk of developing diabetic complications and HDL can carry miRNAs. HDL-miRNA profiles differ in disease states and may present as biomarkers with the capacity to act as bioactive signalling molecules. Recent studies have demonstrated that HDL becomes dysfunctional in a diabetic environment, losing its vasculo-protective effects and becoming more pro-atherogenic. We sought to determine whether HDL-associated miRNA profiles and HDL functionality were predictive of the severity of diabetic vascular complications in Australia's Indigenous population.

Methods: HDL was isolated from plasma samples from Indigenous participants without diabetes ('Healthy'), with type 2 diabetes mellitus ('T2DM') and with diabetes-associated macrovascular complications (specifically peripheral artery disease, 'T2DM+Comp'). To assess HDL angiogenic capacity, human coronary artery endothelial cells were treated with PBS, reconstituted HDL (rHDL, positive control) or isolated HDL and then exposed to high-glucose (25 mmol/l) conditions. The expression levels of two anti-angiogenic miRNAs (miR-181c-5p and miR-223-3p) and one pro-angiogenic miRNA (miR-27b-3p) were measured in the HDL fraction, plasma and treated human coronary artery endothelial cells by quantitative real-time PCR. In vitro endothelial tubule formation was assessed using the Matrigel tubulogenesis assay.

Results: Strikingly, we found that the levels of the anti-angiogenic miRNA miR-181c-5p were 14-fold higher (1454 ± 1346%) in the HDL from Aboriginal people with diabetic complications compared with both the Healthy (100 ± 121%, p < 0.05) and T2DM (82 ± 77%, p < 0.05) groups. Interestingly, we observed a positive correlation between HDL-associated miR-181c-5p levels and disease severity (p = 0.0020). Under high-glucose conditions, cells treated with rHDL, Healthy HDL and T2DM HDL had increased numbers of tubules (rHDL: 136 ± 8%, p < 0.01; Healthy HDL: 128 ± 6%, p < 0.01; T2DM HDL: 124 ± 5%, p < 0.05) and branch points (rHDL: 138 ± 8%, p < 0.001; Healthy HDL: 128 ± 6%, p < 0.01; T2DM HDL: 127 ± 5%, p < 0.01) concomitant with elevations in mRNA levels of the key hypoxia angiogenic transcription factor HIF1A (rHDL: 140 ± 10%, p < 0.01; Healthy HDL: 136 ± 8%, p < 0.01; T2DM HDL: 133 ± 9%, p < 0.05). However, this increase in angiogenic capacity was not observed in cells treated with T2DM + Comp HDL (tubule numbers: 113 ± 6%, p = 0.32; branch points: 113 ± 5%, p = 0.28; HIF1A: 117 ± 6%, p = 0.43), which could be attributed to the increase in cellular miR-181c-5p levels (T2DM + Comp HDL: 136 ± 7% vs PBS: 100 ± 9%, p < 0.05).

Conclusions/interpretation: In conclusion, HDL from Aboriginal people with diabetic complications had reduced angiogenic capacity. This impairment is associated with an increase in the expression of anti-angiogenic miR-181c-5p. These findings provide the rationale for a new way to better inform clinical diagnosis of disease severity with the potential to incorporate targeted, personalised HDL-miRNA intervention therapies to prevent further development of, or to reverse, diabetic vascular complications in Australian Aboriginal people.
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http://dx.doi.org/10.1007/s00125-021-05414-6DOI Listing
March 2021

Long-term outcomes following endovascular and surgical revascularization for peripheral artery disease: a propensity score-matched analysis.

Eur Heart J 2021 Feb 24. Epub 2021 Feb 24.

School of Clinical Medicine, The University of Queensland, Brisbane, QLD, Australia.

Aims: Peripheral artery disease (PAD) revascularization can be performed by either endovascular or open surgical approach. Despite increasing use of endovascular revascularization, it is still uncertain which strategy yields better long-term outcomes.

Methods And Results: This retrospective cohort study evaluated patients hospitalized with PAD in Australia and New Zealand who underwent either endovascular or surgical revascularization between 2008 and 2015, and compared procedures using a propensity score-matched analysis. Hybrid interventions were excluded. The primary endpoint was mortality or major adverse limb events (MALE), defined as a composite endpoint of acute limb ischaemia, urgent surgical or endovascular reintervention, or major amputation, up to 8 years post-hospitalization using time-to-event analyses 75 189 patients fulfilled eligibility (15 239 surgery and 59 950 endovascular), from whom 14 339 matched pairs (mean ± SD age 71 ± 12 years, 73% male) with good covariate balance were identified. Endovascular revascularization was associated with an increase in combined MALE or mortality [hazard ratio (HR) 1.13, 95% confidence interval (CI): 1.09-1.17, P < 0.001]. There was a similar risk of MALE (HR 1.04, 95% CI: 0.99-1.10, P = 0.15), and all-cause urgent rehospitalizations (HR 1.01, 95% CI: 0.98-1.04, P = 0.57), but higher mortality (HR 1.16, 95% CI: 1.11-1.21, P < 0.001) when endovascular repair was compared to surgery. In subgroup analysis, these findings were consistent for both claudication and chronic limb-threatening ischaemia presentations.

Conclusion: Although the long-term risk of MALE was comparable for both approaches, enduring advantages of surgical revascularization included lower long-term mortality. This is at odds with some prior PAD studies and highlights contention in this space.
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http://dx.doi.org/10.1093/eurheartj/ehab116DOI Listing
February 2021

Combination of bempedoic acid, ezetimibe, and atorvastatin in patients with hypercholesterolemia: A randomized clinical trial.

Atherosclerosis 2021 03 31;320:122-128. Epub 2020 Dec 31.

Monash Cardiovascular Research Centre, Monash University, Clayton, Victoria, Australia. Electronic address:

Background And Aims: Many patients with hypercholesterolemia fail to achieve sufficient low-density lipoprotein cholesterol (LDL-C) lowering despite use of guideline-recommended lipid-lowering therapies. This study evaluated LDL-C lowering with the combination of bempedoic acid, ezetimibe, and atorvastatin.

Methods: This was a phase 2, randomized, double-blind, placebo-controlled study (NCT03051100). After washout of lipid-lowering drugs, patients were randomized 2:1 to triple therapy (bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg; n = 43) or placebo (n = 20) once daily for 6 weeks. The primary endpoint was percent change from baseline in LDL-C at week 6.

Results: Mean age for the 63 randomized patients was 61.2 years; baseline LDL-C was 154.8 mg/dL. At week 6, mean LDL-C lowering with triple therapy (-63.6%) was significantly greater than with placebo [-3.1%; difference, -60.5% [(95% CI, -68.0% to -53.0%); p < 0.001]. Significant reductions with triple therapy vs. placebo were also observed for non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein (p < 0.001 for all). With triple-therapy, 90% of patients achieved LDL-C <70 mg/dL and 95% of patients had ≥50% lower LDL-C from baseline to week 6; no patients in the placebo group met either goal. The majority of treatment-emergent adverse events were mild to moderate in severity. No patients experienced clinically relevant elevations in aminotransferase or creatine kinase levels.

Conclusions: Among patients with hypercholesterolemia, the combination of bempedoic acid, ezetimibe, and atorvastatin significantly lowered LDL-C, allowing more than 90% of patients in this study to reach guideline-recommended LDL-C goals.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.12.023DOI Listing
March 2021

Can CMR Elucidate the Cardiovascular Benefit of SGLT2 Inhibitors?

JACC Cardiovasc Imaging 2021 Jan 4. Epub 2021 Jan 4.

Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1016/j.jcmg.2020.11.003DOI Listing
January 2021

Cost-Effectiveness of Coronary Artery Calcium Scoring in People With a Family History of Coronary Disease.

JACC Cardiovasc Imaging 2021 Jan 7. Epub 2021 Jan 7.

Baker Heart and Diabetes Research Institute, Melbourne, Australia; Monash University, Melbourne, Australia. Electronic address:

Background: The use of coronary artery calcium scoring (CAC) to guide primary prevention statin therapy in those with a family history of premature coronary artery disease (FHCAD) is inconsistently recommended in guidelines, and usually not reimbursed by insurance. We assessed the cost-effectiveness of CAC compared with traditional risk factor-based prediction alone in those with an FHCAD.

Methods: A microsimulation model was constructed in TreeAge Healthcare Pro using data from 1,083 participants in the CAUGHT-CAD (Coronary Artery Calcium Score: Use to Guide Management of HerediTary Coronary Artery Disease) trial. Outcomes assessed were quality-adjusted life years (QALYs): cost-effectiveness was assessed over a 15-year time horizon from the perspective of the US health care sector using real-world statin prescribing, accounting for the effect of knowledge of subclinical disease on adherence to guideline-directed therapies. Costs were assessed in 2020 USD, with discounting undertaken at 3%.

Results: Statins were indicated in 45% of the cohort using the CAC strategy and 27% using American College of Cardiology/American Heart Association (2019) treatment strategies. Compared with applying a statin treatment threshold of 7.5%, the CAC strategy was more costly ($145) and more effective (0.0097 QALY) with an incremental cost-effective ratio (ICER) of $15,014/QALY. CAC ICER was driven by CAC acquisition and statin prescription cost and improved with certain patient subgroups: male, age >60 years, and 10-year risk pooled cohort equation risk ≥7.5%. CAC scanning of low-risk patients (10-year risk <5%) or those 40 to 50 years of age was not cost-effective.

Conclusion: Systematic CAC screening and treatment of those with FHCAD and subclinical disease was more cost-effective than management using statin treatment thresholds, in the US health care system.
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http://dx.doi.org/10.1016/j.jcmg.2020.11.008DOI Listing
January 2021

Apabetalone and hospitalization for heart failure in patients following an acute coronary syndrome: a prespecified analysis of the BETonMACE study.

Cardiovasc Diabetol 2021 Jan 7;20(1):13. Epub 2021 Jan 7.

Imperial Centre for Cardiovascular Disease Prevention, Imperial College, London, UK.

Background: Patients with diabetes and acute coronary syndrome (ACS) are at high risk for subsequent heart failure. Apabetalone is a selective inhibitor of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression. Preclinical data suggest that apabetalone exerts favorable effects on pathways related to myocardial structure and function and therefore could impact subsequent heart failure events. The effect of apabetalone on heart failure events after an ACS is not currently known.

Methods: The phase 3 BETonMACE trial was a double-blind, randomized comparison of apabetalone versus placebo on the incidence of major adverse cardiovascular events (MACE) in 2425 patients with a recent ACS and diabetes. This prespecified secondary analysis investigated the impact of apabetalone on hospitalization for congestive heart failure, not previously studied.

Results: Patients (age 62 years, 74.4% males, 90% high-intensity statin use, LDL-C 70.3 mg/dL, HDL-C 33.3 mg/dL and HbA1c 7.3%) were followed for an average 26 months. Apabetalone treated patients experienced the nominal finding of a lower rate of first hospitalization for heart failure (2.4% vs. 4.0%, HR 0.59 [95%CI 0.38-0.94], P = 0.03), total number of hospitalizations for heart failure (35 vs. 70, HR 0.47 [95%CI 0.27-0.83], P = 0.01) and the combination of cardiovascular death or hospitalization for heart failure (5.7% vs. 7.8%, HR 0.72 [95%CI 0.53-0.98], P = 0.04).

Conclusion: Apabetalone treatment was associated with fewer hospitalizations for heart failure in patients with type 2 diabetes and recent ACS. Future studies are warranted to define the potential for BET inhibition with apabetalone to prevent heart failure in patients with diabetes and ACS.
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http://dx.doi.org/10.1186/s12933-020-01199-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791841PMC
January 2021

Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes.

Eur Heart J 2021 Feb;42(6):700-710

Department of Cardiology (CVK), Berlin Institute of Health, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Föhrer Str. 15, 13353 Berlin, Germany.

Aims: The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF).

Methods And Results: HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were -4.0 m (-16.0, 6.0; P = 0.42) and 4.0 m (-5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported.

Conclusion: The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.
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http://dx.doi.org/10.1093/eurheartj/ehaa943DOI Listing
February 2021

Feasibility and Validity of Computed Tomography-Derived Fractional Flow Reserve in Patients With Severe Aortic Stenosis: The CAST-FFR Study.

Circ Cardiovasc Interv 2021 Jan 16;14(1):e009586. Epub 2020 Dec 16.

Monash Cardiovascular Research Centre, Monash University and MonashHeart, Monash Health, Melbourne, Australia (M.M., A.-R.I., A.C., U.T., J.D.C., L.M.M., R.P.G., S.J.N., B.S.K., A.J.B.).

Background: Coronary artery disease is common in patients with severe aortic stenosis. Computed tomography-derived fractional flow reserve (CT-FFR) is a clinically used modality for assessing coronary artery disease, however, its use has not been validated in patients with severe aortic stenosis. This study assesses the safety, feasibility, and validity of CT-FFR in patients with severe aortic stenosis.

Methods: Prospectively recruited patients underwent standard-protocol invasive FFR and coronary CT angiography (CTA). CTA images were analyzed by central core laboratory (HeartFlow, Inc) for independent evaluation of CT-FFR. CT-FFR data were compared with FFR (ischemia defined as FFR ≤0.80).

Results: Forty-two patients (68 vessels) underwent FFR and CTA; 39 patients (92.3%) and 60 vessels (88.2%) had interpretable CTA enabling CT-FFR computation. Mean age was 76.2±6.7 years (71.8% male). No patients incurred complications relating to premedication, CTA, or FFR protocol. Mean FFR and CT-FFR were 0.83±0.10 and 0.77±0.14, respectively. CT calcium score was 1373.3±1392.9 Agatston units. On per vessel analysis, there was positive correlation between FFR and CT-FFR (Pearson correlation coefficient, =0.64, <0.0001). Sensitivity, specificity, positive predictive value, and negative predictive values were 73.9%, 78.4%, 68.0%, and 82.9%, respectively, with 76.7% diagnostic accuracy. The area under the receiver-operating characteristic curve for CT-FFR was 0.83 (0.72-0.93, <0.0001), which was higher than that of CTA and quantitative coronary angiography (=0.01 and <0.001, respectively). Bland-Altman plot showed mean bias between FFR and CT-FFR as 0.059±0.110. On per patient analysis, the sensitivity, specificity, positive predictive, and negative predictive values were 76.5%, 77.3%, 72.2%, and 81.0% with 76.9% diagnostic accuracy. The per patient area under the receiver-operating characteristic curve analysis was 0.81 (0.67-0.95, <0.0001).

Conclusions: CT-FFR is safe and feasible in patients with severe aortic stenosis. Our data suggests that the diagnostic accuracy of CT-FFR in this cohort potentially enables its use in clinical practice and provides the foundation for future research into the use of CT-FFR for coronary evaluation pre-aortic valve replacement.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.120.009586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116852PMC
January 2021

Heart Disease in Women: Where Are We Now and What is The Future?

Heart Lung Circ 2021 Jan;30(1):1-2

Kolling Institute, University of Sydney, Sydney, NSW, Australia; Department of Cardiology, Royal North Shore Hospital, Sydney, NSW, Australia.

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http://dx.doi.org/10.1016/j.hlc.2020.11.001DOI Listing
January 2021

Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial.

Eur J Heart Fail 2020 12;22(12):2383-2392

Baylor University Medical Center, Dallas, TX, USA.

Aims: EMPEROR-Preserved is an ongoing trial evaluating the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). This report describes the baseline characteristics of the EMPEROR-Preserved cohort and compares them with patients enrolled in prior HFpEF trials.

Methods And Results: EMPEROR-Preserved is a phase III randomized, international, double-blind, parallel-group, placebo-controlled trial in which 5988 symptomatic HFpEF patients [left ventricular ejection fraction (LVEF) >40%] with and without type 2 diabetes mellitus (T2DM) have been enrolled. Patients were required to have elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations (i.e. >300 pg/mL in patients without and >900 pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of heart failure hospitalization. Among patients enrolled from various regions (45% Europe, 11% Asia, 25% Latin America, 12% North America), the mean age was 72 ± 9 years, 45% were women. Almost all patients had New York Heart Association class II or III symptoms (99.6%), and 23% had prior heart failure hospitalization within 12 months. Thirty-three percent of the patients had baseline LVEF of 41-50%. The mean LVEF (54 ± 9%) was slightly lower while the median NT-proBNP [974 (499-1731) pg/mL] was higher compared with previous HFpEF trials. Presence of comorbidities such as diabetes (49%) and chronic kidney disease (50%) were common. The majority of the patients were on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (80%) and beta-blockers (86%), and 37% of patients were on mineralocorticoid receptor antagonists.

Conclusion: When compared with prior trials in HFpEF, the EMPEROR-Preserved cohort has a somewhat higher burden of comorbidities, lower LVEF, higher median NT-proBNP and greater use of mineralocorticoid receptor antagonists at baseline. Results of the EMPEROR-Preserved trial will be available in 2021.
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http://dx.doi.org/10.1002/ejhf.2064DOI Listing
December 2020

The role of intracoronary imaging in translational research.

Cardiovasc Diagn Ther 2020 Oct;10(5):1480-1507

Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia.

Atherosclerotic cardiovascular disease is a key public health concern worldwide and leading cause of morbidity, mortality and health economic costs. Understanding atherosclerotic plaque microstructure in relation to molecular mechanisms that underpin its initiation and progression is needed to provide the best chance of combating this disease. Evolving vessel wall-based, endovascular coronary imaging modalities, including intravascular ultrasound (IVUS), optical coherence tomography (OCT) and near-infrared spectroscopy (NIRS), used in isolation or as hybrid modalities, have been advanced to allow comprehensive visualization of the pathological substrate of coronary atherosclerosis and accurately measure temporal changes in both the vessel wall and plaque characteristics. This has helped further our appreciation of the natural history of coronary artery disease (CAD) and the risk for major adverse cardiovascular events (MACE), evaluate the responsiveness to conventional and experimental therapeutic interventions, and assist in guiding percutaneous coronary intervention (PCI). Here we review the use of different imaging modalities for these purposes and the lessons they have provided thus far.
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http://dx.doi.org/10.21037/cdt-20-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666942PMC
October 2020

Association of Serum Lipoprotein (a) Levels and Coronary Atheroma Volume by Intravascular Ultrasound.

J Am Heart Assoc 2020 12 23;9(23):e018023. Epub 2020 Nov 23.

Cleveland Clinic Cleveland OH.

Background Lp(a) (lipoprotein (a)) is a risk factor for cardiovascular events, but the mechanism of increased risk is uncertain. This study evaluated the relationship between Lp(a) and coronary atheroma volume by intravascular ultrasound. Methods and Results This was a post hoc analysis of 6 randomized trials of coronary atheroma by intravascular ultrasound. The population was stratified into high (≥60 mg/dL) and low (<60 mg/dL) baseline serum Lp(a). The primary outcome was baseline coronary percent atheroma volume. A mixed model adjusted for baseline low density lipoprotein, ApoB (apoliporotein B100), non-high density lipoprotein, sex, age, race, history of myocardial infarction, statin use, and intravascular ultrasound study was used to provide estimates of baseline plaque burden. Of 3943 patients, 17.3% (683) had Lp(a) ≥ 60 mg/dL and 82.7% (3260) had Lp(a) < 60 mg/dL. At baseline, uncorrected low density lipoprotein level (107.7 ± 32.0 versus 99.1 ± 31.5) and statin therapy (99.0% versus 97.0%) were higher in patients with high Lp(a) levels, but low density lipoprotein corrected for Lp(a) was lower (80.6 ± 32.0 versus 94.0 ± 31.4) in patients with high Lp(a) levels. Percent atheroma volume was significantly higher in the high Lp(a) group in unadjusted (38.2% [32.8, 43.6] versus 37.1% [31.4, 43.1], =0.01) and risk-adjusted analyses (38.7%±0.5 versus 37.5%±0.5, <0.001). There was a significant association of increasing risk-adjusted percent atheroma volume across quintiles of Lp(a) (Lp(a) quintiles 1-5; 37.3 ± 0.5%, 37.2 ± 0.5%, 37.3 ± 0.5%, 38.0 ± 0.5%, 38.5 ± 0.5%, =0.002). Conclusions Elevated Lp(a) is independently associated with increased percent atheroma volume. Further work is needed to clarify the relationship of Lp(a)-lowering treatment with cardiovascular outcomes.
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http://dx.doi.org/10.1161/JAHA.120.018023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763761PMC
December 2020

Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis.

N Engl J Med 2021 01 16;384(1):31-41. Epub 2020 Nov 16.

From the Center for the Diagnosis and Treatment of Pericardial Diseases, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland (A.L.K., P.C.); University Cardiology, Cardiovascular, and Thoracic Department, Azienda Ospedaliero-Universitaria (AOU) Città della Salute e della Scienza di Torino and University of Turin, Turin (M.I.), the Department of Biomedical and Clinical Science, University of Milan, Fatebenefratelli Hospital, Milan (A.B.), and the Division of Rheumatology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome (A.I.) - all in Italy; Pauley Heart Center, Virginia Commonwealth University, Richmond (A.A.); Kiniksa Pharmaceuticals, Lexington, MA (F.F., A.P., J.F.P.); the Cardiology Unit, University of Vermont Medical Center, Burlington (M.L.); the Cardiovascular Clinical Research Institute, Lady Davis Carmel Medical Center and the Technion-Israel Institute of Technology, Haifa, Israel (B.S.L.); the Minneapolis Heart Institute, Abbott Northwestern Hospital, Minneapolis (D.L.), and the Division of Cardiovascular Ultrasound, Department of Cardiovascular Medicine, Mayo Clinic, Rochester (S.A.L.) - both in Minnesota; the Monash Cardiovascular Research Centre, Victorian Heart Institute, Monash University, Clayton, VIC, Australia (S.J.N.); and Kiniksa Pharmaceuticals, Hamilton, Bermuda (A.W.).

Background: Interleukin-1 has been implicated as a mediator of recurrent pericarditis. The efficacy and safety of rilonacept, an interleukin-1α and interleukin-1β cytokine trap, were studied previously in a phase 2 trial involving patients with recurrent pericarditis.

Methods: We conducted a phase 3 multicenter, double-blind, event-driven, randomized-withdrawal trial of rilonacept in patients with acute symptoms of recurrent pericarditis (as assessed on a patient-reported scale) and systemic inflammation (as shown by an elevated C-reactive protein [CRP] level). Patients presenting with pericarditis recurrence while receiving standard therapy were enrolled in a 12-week run-in period, during which rilonacept was initiated and background medications were discontinued. Patients who had a clinical response (i.e., met prespecified response criteria) were randomly assigned in a 1:1 ratio to receive continued rilonacept monotherapy or placebo, administered subcutaneously once weekly. The primary efficacy end point, assessed with a Cox proportional-hazards model, was the time to the first pericarditis recurrence. Safety was also assessed.

Results: A total of 86 patients with pericarditis pain and an elevated CRP level were enrolled in the run-in period. During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days. A total of 61 patients underwent randomization. During the randomized-withdrawal period, there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated; the median time to the first adjudicated recurrence in the placebo group was 8.6 weeks (95% confidence interval [CI], 4.0 to 11.7; hazard ratio in a Cox proportional-hazards model, 0.04; 95% CI, 0.01 to 0.18; P<0.001 by the log-rank test). During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group. In the run-in period, 4 patients had adverse events leading to the discontinuation of rilonacept therapy. The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections.

Conclusions: Among patients with recurrent pericarditis, rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly lower risk of pericarditis recurrence than placebo. (Funded by Kiniksa Pharmaceuticals; RHAPSODY ClinicalTrials.gov number, NCT03737110.).
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http://dx.doi.org/10.1056/NEJMoa2027892DOI Listing
January 2021

Effect of High-Dose Omega-3 Fatty Acids vs Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk: The STRENGTH Randomized Clinical Trial.

JAMA 2020 12;324(22):2268-2280

Cleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.

Importance: It remains uncertain whether the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduce cardiovascular risk.

Objective: To determine the effects on cardiovascular outcomes of a carboxylic acid formulation of EPA and DHA (omega-3 CA) with documented favorable effects on lipid and inflammatory markers in patients with atherogenic dyslipidemia and high cardiovascular risk.

Design, Setting, And Participants: A double-blind, randomized, multicenter trial (enrollment October 30, 2014, to June 14, 2017; study termination January 8, 2020; last patient visit May 14, 2020) comparing omega-3 CA with corn oil in statin-treated participants with high cardiovascular risk, hypertriglyceridemia, and low levels of high-density lipoprotein cholesterol (HDL-C). A total of 13 078 patients were randomized at 675 academic and community hospitals in 22 countries in North America, Europe, South America, Asia, Australia, New Zealand, and South Africa.

Interventions: Participants were randomized to receive 4 g/d of omega-3 CA (n = 6539) or corn oil, which was intended to serve as an inert comparator (n = 6539), in addition to usual background therapies, including statins.

Main Outcomes And Measures: The primary efficacy measure was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization.

Results: When 1384 patients had experienced a primary end point event (of a planned 1600 events), the trial was prematurely halted based on an interim analysis that indicated a low probability of clinical benefit of omega-3 CA vs the corn oil comparator. Among the 13 078 treated patients (mean [SD] age, 62.5 [9.0] years; 35% women; 70% with diabetes; median low-density lipoprotein [LDL] cholesterol level, 75.0 mg/dL; median triglycerides level, 240 mg/dL; median HDL-C level, 36 mg/dL; and median high-sensitivity C-reactive protein level, 2.1 mg/L), 12 633 (96.6%) completed the trial with ascertainment of primary end point status. The primary end point occurred in 785 patients (12.0%) treated with omega-3 CA vs 795 (12.2%) treated with corn oil (hazard ratio, 0.99 [95% CI, 0.90-1.09]; P = .84). A greater rate of gastrointestinal adverse events was observed in the omega-3 CA group (24.7%) compared with corn oil-treated patients (14.7%).

Conclusions And Relevance: Among statin-treated patients at high cardiovascular risk, the addition of omega-3 CA, compared with corn oil, to usual background therapies resulted in no significant difference in a composite outcome of major adverse cardiovascular events. These findings do not support use of this omega-3 fatty acid formulation to reduce major adverse cardiovascular events in high-risk patients.

Trial Registration: ClinicalTrials.gov Identifier: NCT02104817.
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http://dx.doi.org/10.1001/jama.2020.22258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667577PMC
December 2020

Inflammation in Coronary Atherosclerosis and Its Therapeutic Implications.

Cardiovasc Drugs Ther 2020 Nov 10. Epub 2020 Nov 10.

Department of Cardiology, Central Adelaide Local Health Network, Adelaide, Australia.

Atherosclerotic coronary artery disease has a complex pathogenesis which extends beyond cholesterol intimal infiltration. It involves chronic inflammation of the coronary artery wall driven by systemic and local activation of both the adaptive and innate immune systems, which can ultimately result in the rupture or erosion of atherosclerotic plaque, leading to thrombosis and myocardial infarction (MI). Despite current best practice care, including the widespread use of cholesterol-lowering statins, atherothrombotic cardiovascular events recur at alarming rates post-MI. To a large extent, this reflects residual inflammation that is not adequately controlled by contemporary treatment. Consequently, there has been increasing interest in the pharmacological targeting of inflammation to improve outcomes in atherosclerotic cardiovascular disease. This has comprised both novel pathway-specific agents, most notably the anti-interleukin-1 beta monoclonal antibody, canakinumab, and the repurposing of established, broad-acting drugs, such as colchicine, that are already approved for the management of other inflammatory conditions. Here we discuss the importance of inflammation in mediating atherosclerosis and its complications and provide a timely update on "new" and "old" anti-inflammatory therapies currently being investigated to target it.
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http://dx.doi.org/10.1007/s10557-020-07106-6DOI Listing
November 2020

A systematic review and meta-analysis of gender differences in long-term mortality and cardiovascular events in peripheral artery disease.

J Vasc Surg 2021 Apr 6;73(4):1456-1465.e7. Epub 2020 Nov 6.

Monash Cardiovascular Research Centre, Monash University, Melbourne, Victoria, Australia.

Objective: Individual studies of peripheral artery disease (PAD) have indicated that gender discrepancies exist in the symptoms, functional status, and treatment usage. It remains uncertain whether these discrepancies result in different long-term outcomes. We examined the potential gender differences in mortality and major adverse cardiovascular events (MACE) in patients with symptomatic PAD.

Methods: The PubMed and Embase databases were searched for studies from 2000 to January 2019. After a review of 13,582 citations, 14 articles were analyzed. The reported age-adjusted hazard ratios (HRs) for gender differences in mortality and MACE were included in the meta-analysis. The mortality outcomes were stratified according to the clinical presentation and study context.

Results: Male gender was associated with a greater risk of all-cause mortality (HR, 1.13; 95% confidence interval [CI], 1.10-1.16; P < .001) and MACE (HR, 1.10; 95% CI, 1.06-1.14; P < .001). In a stratified analysis, male gender was associated with a higher mortality risk for patients presenting with either critical limb ischemia (HR, 1.08; 95% CI, 1.05-1.10; P < .001) or mixed clinical presentations (HR, 1.16; 95% CI, 1.11-1.21; P < .001) but not for those with intermittent claudication (HR, 1.13; 95% CI, 0.98-1.30; P = .09). Elevated mortality risk was evident after revascularization (HR, 1.11; 95% CI, 1.04-1.19; P = .003), hospitalization (HR, 1.15; 95% CI, 1.08-1.22; P < .001), and amputation (HR, 1.09; 95% CI, 1.08-1.10; P < .001), although not in outpatient clinics (HR, 1.13; 95% CI, 0.97-1.32; P = .13), in men compared with women.

Conclusions: Greater mortality and MACE rates in men with PAD occurred despite other accepted gender disparities. The mechanisms underlying these gender differences in the outcomes for PAD patients require further investigation.
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http://dx.doi.org/10.1016/j.jvs.2020.09.039DOI Listing
April 2021

Good Heart: Telling Stories of Cardiovascular Protective and Risk Factors for Aboriginal Women.

Heart Lung Circ 2021 Jan 5;30(1):69-77. Epub 2020 Nov 5.

Wardliparingga Aboriginal Health Equity Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.

Background: Aboriginal and Torres Strait Islander peoples' perspectives of health and cultural wellbeing encapsulate the spiritual, social and environmental health of individuals, their communities and country. Strategies designed to reduce the cardiovascular burden of Aboriginal and Torres Strait Islander people often fail to consider their unique knowledge and worldview.

Methods: This adapted, grounded theory study sought to explore Aboriginal women's views of cardiovascular protective and risk factors.

Results: Twenty-eight (28) women from five women's groups across Central and South Australia participated. Women distinguished the heart as core to their spiritual and physical wellbeing. Women identified six attributes that keep a woman's heart strong, four that can make the heart sick, and eight socio-ecological factors which affect a woman's capacity to care for their heart. Women described having a healthy heart when able to identify as Aboriginal women, being connected to family and community, having a healthy life and body, and being engaged in their health and health care.

Conclusions: There are gaps in the provision of cardiovascular risk assessment and management, gaps in the cultural safety of primary health care services, and gaps in the communication of the sex-specific warning signs of a heart attack, all of which must be addressed.
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http://dx.doi.org/10.1016/j.hlc.2020.09.931DOI Listing
January 2021

Pericoronary adipose tissue computed tomography attenuation distinguishes different stages of coronary artery disease: a cross-sectional study.

Eur Heart J Cardiovasc Imaging 2021 Feb;22(3):298-306

Monash Cardiovascular Research Centre, Monash University and MonashHeart, Monash Health, 246 Clayton Road, Clayton, Victoria 3168, Australia.

Aims : Vascular inflammation inhibits local adipogenesis in pericoronary adipose tissue (PCAT) and this can be detected on coronary computed tomography angiography (CCTA) as an increase in CT attenuation of PCAT surrounding the proximal right coronary artery (RCA). In this cross-sectional study, we assessed the utility of PCAT CT attenuation as an imaging biomarker of coronary inflammation in distinguishing different stages of coronary artery disease (CAD).

Methods And Results: Sixty patients with acute myocardial infarction (MI) were prospectively recruited to undergo CCTA within 48 h of admission, prior to invasive angiography. These participants were matched to patients with stable CAD (n = 60) and controls with no CAD (n = 60) by age, gender, BMI, risk factors, medications, and CT tube voltage. PCAT attenuation around the proximal RCA was quantified per-patient using semi-automated software. Patients with MI had a higher PCAT attenuation (-82.3 ± 5.5 HU) compared with patients with stable CAD (-90.6 ± 5.7 HU, P < 0.001) and controls (-95.8 ± 6.2 HU, P < 0.001). PCAT attenuation was significantly increased in stable CAD patients over controls (P = 0.01). The association of PCAT attenuation with stage of CAD was independent of age, gender, cardiovascular risk factors, epicardial adipose tissue volume, and CCTA-derived quantitative plaque burden. No interaction was observed for clinical presentation (MI vs. stable CAD) and plaque burden on PCAT attenuation.

Conclusion: PCAT CT attenuation as a quantitative measure of global coronary inflammation independently distinguishes patients with MI vs. stable CAD vs. no CAD. Future studies should assess whether this imaging biomarker can track patient responses to therapies in different stages of CAD.
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http://dx.doi.org/10.1093/ehjci/jeaa224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899274PMC
February 2021

Cardiovascular bioimaging of nitric oxide: Achievements, challenges, and the future.

Med Res Rev 2021 01 19;41(1):435-463. Epub 2020 Oct 19.

Australian Research Council (ARC), Centre of Excellence for Nanoscale BioPhotonics (CNBP), Adelaide, Australia.

Nitric oxide (NO) is a ubiquitous, volatile, cellular signaling molecule that operates across a wide physiological concentration range (pM-µM) in different tissues. It is a highly diffusible messenger and intermediate in various metabolic pathways. NO plays a pivotal role in maintaining optimum cardiovascular function, particularly by regulating vascular tone and blood flow. This review highlights the need for accurate, real-time bioimaging of NO in clinical diagnostic, therapeutic, monitoring, and theranostic applications within the cardiovascular system. We summarize electrochemical, optical, and nanoscale sensors that allow measurement and imaging of NO, both directly and indirectly via surrogate measurements. The physical properties of NO render it difficult to accurately measure in tissues using direct methods. There are also significant limitations associated with the NO metabolites used as surrogates to indirectly estimate NO levels. All these factors added to significant variability in the measurement of NO using available methodology have led to a lack of sensors and imaging techniques of clinical applicability in relevant vascular pathologies such as atherosclerosis and ischemic heart disease. Challenges in applying current methods to biomedical and clinical translational research, including the wide physiological range of NO and limitations due to the characteristics and toxicity of the sensors are discussed, as are potential targets and modifications for future studies. The development of biocompatible nanoscale sensors for use in combination with existing clinical imaging modalities provides a feasible opportunity for bioimaging NO within the cardiovascular system.
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http://dx.doi.org/10.1002/med.21736DOI Listing
January 2021

Rationale and design of ApoA-I Event Reducing in Ischemic Syndromes II (AEGIS-II): A phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group study to investigate the efficacy and safety of CSL112 in subjects after acute myocardial infarction.

Am Heart J 2021 01 13;231:121-127. Epub 2020 Oct 13.

Cardiovascular Institute, Mount Sinai, New York, NY.

Acute myocardial infarction (MI) patients remain at high risk for recurrent events. Cholesterol efflux, mediated by apolipoprotein A-I, removes excess cholesterol from atherosclerotic plaque and transports it to the liver for excretion. Impaired cholesterol efflux is associated with higher cardiovascular (CV) event rates among both patients with stable coronary artery disease and recent MI. CSL112, a novel intravenous formulation of apolipoprotein A-I (human) derived from human plasma, increases cholesterol efflux capacity. AEGIS-II is a phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial investigating the efficacy and safety of CSL112 compared to placebo among high-risk acute MI participants. Eligibility criteria include age ≥ 18 years with type 1 (spontaneous) MI, evidence of multivessel stable coronary artery disease, and presence of diabetes requiring pharmacotherapy, or ≥2 of the following: age ≥ 65 years, prior MI, or peripheral artery disease. A target sample of 17,400 participants will be randomized 1:1 to receive 4 weekly infusions of CSL112 6 g or placebo, initiated prior to or on the day of discharge and within 5 days of first medical contact. The primary outcome is the time to first occurrence of the composite of CV death, MI, or stroke through 90 days. Key secondary outcomes include the total number of hospitalizations for coronary, cerebral, or peripheral ischemia through 90 days and time to first occurrence of the composite primary outcome through 180 and 365 days. AEGIS-II will be the first trial to formally test whether enhancing cholesterol efflux can reduce the rate of recurrent major adverse CV events.
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http://dx.doi.org/10.1016/j.ahj.2020.10.052DOI Listing
January 2021

The fish-oil paradox.

Curr Opin Lipidol 2020 12;31(6):356-361

Duke Clinical Research Institute, Durham, North Carolina, USA.

Purpose Of Review: Increasing interest has focused on the potential cardioprotective effects of the omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the basis of findings from epidemiology and cohort studies. This review will summarize the findings of contemporary clinical trials of omega-3 fatty acids.

Recent Findings: Although a large clinical trial performed prior to the widespread use of statins demonstrated cardiovascular benefit with fish oils, subsequent studies have failed to reproduce this result. More recent studies have demonstrated a reduction in cardiovascular risk with administration of high-dose EPA, but not a carboxylic acid formulation containing both EPA and DHA or with lower doses of omega-3 fatty acids.

Summary: Administration of omega-3 fatty acids differing in either composition or dose produce variable effects on cardiovascular outcomes. This has implications for both the public health and pharmacological approach to cardiovascular prevention.
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http://dx.doi.org/10.1097/MOL.0000000000000712DOI Listing
December 2020

Non-hyperaemic pressure ratios to guide percutaneous coronary intervention.

Open Heart 2020 10;7(2)

Monash Cardiovascular Research Centre and MonashHeart, Monash University and Monash Health, Melbourne, Victoria, Australia.

The use of fractional flow reserve (FFR) in guiding revascularisation improves patient outcomes and has been well-established in clinical guidelines. Despite this, the uptake of FFR has been limited, likely attributable to the perceived increase in procedural time and use of hyperaemic agents that can cause patient discomfort. This has led to the development of instantaneous wave-free ratio (iFR), an alternative non-hyperaemic pressure ratio (NHPR). Since its inception, the use of iFR has been supported by an increasing body of evidence and is now guideline recommended. More recently, other commercially available NHPRs including diastolic hyperaemia-free ratio and resting full-cycle ratio have emerged. Studies have demonstrated that these indices, in addition to mean distal coronary artery pressure to mean aortic pressure ratio, are mathematically analogous (with specific nuances) to iFR. Additionally, there is increasing data demonstrating the equivalent diagnostic performance of alternative NHPRs in comparison with iFR and FFR. These NHPRs are now integral within most current pressure wire systems and are commonly available in the catheter laboratory. It is therefore key to understand the fundamental differences and evidence for NHPRs to guide appropriate clinical decision-making.
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http://dx.doi.org/10.1136/openhrt-2020-001308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534727PMC
October 2020

Women With Spontaneous Coronary Artery Dissection Are at Increased Risk of Iatrogenic Coronary Artery Dissection.

Heart Lung Circ 2021 Jan 18;30(1):e23-e28. Epub 2020 Sep 18.

MonashHeart, Monash Health, Melbourne, Vic, Australia; Monash Cardiovascular Research Centre, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Vic, Australia; School of Clinical Sciences at Monash Health, Department of Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Vic, Australia. Electronic address:

Background: Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of acute coronary syndrome (ACS) that affects women disproportionately. Previous case series have found that patients with SCAD undergoing cardiac catheterisation have high rates of iatrogenic coronary damage. We formally compared the rate of iatrogenic coronary artery dissection in women with and without SCAD undergoing cardiac catheterisation over a 11-year period.

Methods: Women with SCAD were identified by a search of the cardiac catheterisation database 2007-2017 for the keywords 'SCAD', 'spontaneous coronary artery dissection', 'spontaneous coronary dissection', and 'spontaneous dissection'. For each identified case, the medical record and the coronary angiogram images were reviewed to confirm spontaneous coronary dissection. For cases of recurrent SCAD, duplicates were removed so that each patient was included only once in this analysis. For each identified case of SCAD, a control case was chosen from women aged <70 years, without SCAD, undergoing cardiac catheterisation for an ACS during the same 10-year period. One control case was chosen to match each SCAD patient as closely as possible for age and year of cardiac catheterisation. Iatrogenic coronary dissection was defined as new, proximal, flow limiting coronary artery dissection in a different coronary segment to the presenting spontaneous coronary dissection.

Results: Eighty-five (85) cases of women with SCAD were identified. Mean age was not different between SCAD and non-SCAD women (51±11 and 51±10 years, respectively). The SCAD group had lower rates of ST elevation myocardial infarction, lower rises in serum creatine kinase (CK) and troponin levels, lower rates of diabetes and smoking, and far less placement of stents during the procedure than the control group. The rate of additional iatrogenic dissection relating to the cardiac catheterisation procedure was 4 of 85 (4.7%) versus 0 of 85 (0%), p=0.04 in SCAD and control groups, respectively, despite a much lower rate of percutaneous coronary intervention in the SCAD group. No common factors could be identified regarding particular equipment or procedural factors associated with iatrogenic dissection.

Conclusion: The rate of iatrogenic dissection in women with SCAD during cardiac catheterisation is confirmed to be high and significantly higher than a contemporaneous age-matched group of women without SCAD. This observation likely indicates generalised coronary fragility in this disease, and emphasises the importance of the utmost care in the engagement, injection and intervention involving the coronary arteries in this disease. Development of a non-invasive coronary imaging modality or biomarker able to diagnose SCAD non-invasively would be a great advance in the care of patients with this condition, because it would avoid the need for invasive coronary angiography for diagnosis.
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http://dx.doi.org/10.1016/j.hlc.2020.06.028DOI Listing
January 2021

Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.

N Engl J Med 2020 10 28;383(15):1413-1424. Epub 2020 Aug 28.

From Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas (M.P.); Imperial College (M.P.) and the Department of Medical Statistics, London School of Hygiene and Tropical Medicine (S.J.P.), London, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow (N.S.), and the Department of Cardiovascular Sciences, University of Leicester and National Institute for Health Research Biomedical Research Centre, Glenfield Hospital, Leicester (I.S.) - all in the United Kingdom; the Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies, German Center for Cardiovascular Research Partner Site Berlin, Charité Universitätsmedizin, Berlin (S.D.A.), Boehringer Ingelheim International, Ingelheim (M. Brueckmann, W.J.), Faculty of Medicine Mannheim, University of Heidelberg, Mannheim (M. Brueckmann), Boehringer Ingelheim Pharma, Biberach (C.Z.), Klinik für Innere Medizin III, Saarland University, Homburg-Saar (M. Böhm), and the Department of Medicine, University Hospital of Würzburg, Würzburg (C.W.) - all in Germany; the Department of Medicine, University of Mississippi School of Medicine, Jackson (J.B.); National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens (G.F.); Washington DC Veterans Affairs Medical Center, Washington DC (P.C.); the Division of Cardiology, Harvard Medical School and Massachusetts General Hospital, Boston (J.J.); the Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, Toronto (S.V.), Boehringer Ingelheim Canada, Burlington, ON (K.K.), and the Division of Cardiology, McGill University and Health Centre, Montreal (N.G.) - all in Canada; the Department of Cardiovascular Medicine, Kyushu University, Higashi-ku, Fukuoka, Japan (H.T.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (J. Schnee, D.C.); Heart Institute, São Paulo University Medical School, São Paulo (E.B.); the Department of Medicine, Seoul National University, Seoul, South Korea (D.-J.C.); the Department of Cardiology, Max Super Speciality Hospital, Saket, New Delhi, India (V.C.); the Department of Clinical Cardiology, National Institute of Cardiology, Mexico City (E.C.); the Department of Cardiology, University Hospital Gasthuisberg of Leuven, Leuven, Belgium (S.J.); Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing (J.Z.); the Cardiology Department, University Hospital, Santiago de Compostela, Spain (J.R.G.J.); the Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles (S.K.); Maastricht Heart and Vascular Center, Maastricht, the Netherlands (H.P.B.-L.R.); the Heart and Vascular Center, Semmelweis University, Budapest, Hungary (B.M.); Victorian Heart Institute and Monash University, Melbourne, VIC, Australia (S.J.N.); Fleni Institute and Hospital El Cruce-Nestor Kirchner, Buenos Aires (S.P.); the Department of Medicine, Wayne State and Central Michigan Universities, Detroit (I.P.); the Center for Heart Diseases, Wrocław Medical University, Wrocław, Poland (P.P.); the Cardiovascular Department, Papa Giovanni XXIII Hospital, Bergamo (M.S.), and the Department of Clinical and Experimental Medicine, University of Pisa, Pisa (S.T.) - both in Italy; the Department of Cardiology, University Hospital Jean Minjoz, Besançon (M.-F.S.), and Université de Lorraine, INSERM Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Centre Hospitalier Régional Universitaire, Nancy (F.Z.) - both in France; and Internal Cardiology, University Hospital Brno, Brno, Czech Republic (J. Spinar).

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction.

Methods: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure.

Results: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin.

Conclusions: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).
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http://dx.doi.org/10.1056/NEJMoa2022190DOI Listing
October 2020

Myocardial Infarction Associates With a Distinct Pericoronary Adipose Tissue Radiomic Phenotype: A Prospective Case-Control Study.

JACC Cardiovasc Imaging 2020 11 26;13(11):2371-2383. Epub 2020 Aug 26.

Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, California. Electronic address:

Objectives: This study sought to determine whether coronary computed tomography angiography (CCTA)-based radiomic analysis of pericoronary adipose tissue (PCAT) could distinguish patients with acute myocardial infarction (MI) from patients with stable or no coronary artery disease (CAD).

Background: Imaging of PCAT with CCTA enables detection of coronary inflammation. Radiomics involves extracting quantitative features from medical images to create big data and identify novel imaging biomarkers.

Methods: In a prospective case-control study, 60 patients with acute MI underwent CCTA within 48 h of admission, before invasive angiography. These subjects were matched to patients with stable CAD (n = 60) and controls with no CAD (n = 60) by age, sex, risk factors, medications, and CT tube voltage. PCAT was segmented around the proximal right coronary artery (RCA) in all patients and around culprit and nonculprit lesions in patients with MI. PCAT segmentations were analyzed using Radiomics Image Analysis software.

Results: Of 1,103 calculated radiomic parameters, 20.3% differed significantly between MI patients and controls, and 16.5% differed between patients with MI and stable CAD (critical p < 0.0006); whereas none differed between patients with stable CAD and controls. On cluster analysis, the most significant radiomic parameters were texture or geometry based. At 6 months post-MI, there was no significant change in the PCAT radiomic profile around the proximal RCA or nonculprit lesions. Using machine learning (XGBoost), a model integrating clinical features (risk factors, serum lipids, high-sensitivity C-reactive protein), PCAT attenuation, and radiomic parameters provided superior discrimination of acute MI (area under the receiver operator characteristic curve [AUC]: 0.87) compared with a model with clinical features and PCAT attenuation (AUC: 0.77; p = 0.001) or clinical features alone (AUC: 0.76; p < 0.001).

Conclusions: Patients with acute MI have a distinct PCAT radiomic phenotype compared with patients with stable or no CAD. Using machine learning, a radiomics-based model outperforms a PCAT attenuation-based model in accurately identifying patients with MI.
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http://dx.doi.org/10.1016/j.jcmg.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996075PMC
November 2020