Reference Values for Inward Displacement in the Normal Left Ventricle: A Novel Method of Regional Left Ventricular Function Assessment.

BACKGROUND: Regional functional left ventricular (LV) assessment using current imaging techniques remains limited. Inward displacement (InD) has been developed as a novel technique to assess regional LV function via measurement of the regional displacement of the LV endocardial border across each of the 17 LV segments. Currently, normal ranges for InD are not available for clinical use. The aim of this study was to validate the normal reference limits of InD in healthy adults across all LV segments. METHODS: InD was analyzed in 120 healthy subjects with a normal LV ejection fraction, using the three standard long-axis views obtained during cardiac MRI that quantified the degree of inward endocardial wall motion towards the true LV center of contraction. For all LV segments, InD was measured in mm and expressed as a percentage of the theoretical degree of maximal segment contraction towards the true LV centerline. The arithmetic average InD was obtained for each of the 17 segments. The LV was divided into three regions, obtaining average InD at the LV base (segments 1-6), mid-cavity (segments 7-12) and apex (segments 13-17). RESULTS: Average InD was 33.4 ± 4.3%. InD was higher in basal and mid-cavity LV segments (32.8 ± 4.1% and 38.1 ± 5.8%) compared to apical LV segments (28.6 ± 7.7%). Interobserver variability correlations for InD were strong (R = 0.80, p < 0.0001). CONCLUSIONS: We provide clinically meaningful reference ranges for InD in subjects with normal LV function, which will emerge as an important screening and assessment imaging tool for a range of HFrEF therapies.

Inward Displacement: A Novel Method of Regional Left Ventricular Functional Assessment for Left Ventriculoplasty Interventions in Heart Failure with Reduced Ejection Fraction (HFrEF).

BACKGROUND: Hybrid minimally invasive left ventricular reconstruction is used to treat patients with ischemic heart failure with reduced ejection fraction (HFrEF) and antero-apical scar. Pre- and post-procedural regional functional left ventricular assessment with current imaging techniques remains limited. We evaluated 'inward displacement' as a novel technique of assessing regional left ventricular function in an ischemic HFrEF population who underwent left ventricular reconstruction with the Revivent System. METHODS: Inward displacement adopts three standard long-axis views obtained during cardiac MRI or CT and assesses the degree of inward endocardial wall motion towards the true left ventricular center of contraction. For each of the standard 17 left ventricular segments, regional inward displacement is measured in mm and expressed as a percentage of the maximal theoretical distance each segment can contract towards the centerline. The left ventricle was divided into three regions, obtaining the arithmetic average of inward displacement or speckle tracking echocardiographic strain at the left ventricular base (segments 1-6), mid-cavity (segments 7-12) and apex (segments 13-17). Inward displacement was measured using computed tomography or cardiac magnetic resonance imaging and compared pre- and post-procedurally in ischemic HFrEF patients who underwent left ventricular reconstruction with the Revivent System (n = 36). In a subset of patients who underwent baseline speckle tracking echocardiography, pre-procedural inward displacement was compared with left ventricular regional echocardiographic strain (n = 15). RESULTS: Inward displacement of basal and mid-cavity left ventricular segments increased by 27% (p < 0.001) and 37% (p < 0.001), respectively, following left ventricular reconstruction. A significant overall decrease in both the left ventricular end systolic volume index and end diastolic volume index of 31% (p < 0.001) and 26% (p < 0.001), respectively, was detected, along with a 20% increase in left ventricular ejection fraction (p = 0.005). A significant correlation between inward displacement and speckle tracking echocardiographic strain was noted within the basal (R = -0.77, p < 0.001) and mid-cavity left ventricular segments (R = -0.65, p = 0.004), respectively. Inward displacement resulted in relatively larger measurement values compared to speckle tracking echocardiography, with a mean difference of absolute values of -3.33 and -7.41 for the left ventricular base and mid-cavity, respectively. CONCLUSIONS: Obviating the limitations of echocardiography, inward displacement was found to highly correlate with speckle tracking echocardiographic strain to evaluate regional segmental left ventricular function. Significant improvements in basal and mid-cavity left ventricular contractility were demonstrated in ischemic HFrEF patients following left ventricular reconstruction of large antero-apical scars, consistent with the concept of reverse left ventricular remodeling at a distance. Inward displacement holds significant promise in the HFrEF population being evaluated pre- and post-left ventriculoplasty procedures.

Interaction Between Race and Income on Cardiac Outcomes After Percutaneous Coronary Intervention.

Background Compared with White Americans, Black Americans have a greater prevalence of cardiac events following percutaneous coronary intervention. We evaluated the association between race and neighborhood income on post-percutaneous coronary intervention cardiac events and assessed whether income modifies the effect of race on this relationship. Methods and Results Consecutive patients (n=23 822) treated with percutaneous coronary intervention from January 1, 2000, to December 31, 2016, were included. All-cause mortality and major adverse cardiac event were assessed at 3 years. Extended 10-year follow-up was performed for those residing locally (n=1285). Neighborhood income was derived using median adjusted annual gross household income reported within the patient's zip code. We compared differences in treatment and outcomes, adjusting for race, income, and their interaction. In total, 3173 (13.3%) patients self-identified as Black Americans, and 20 649 (86.7%) self-identified as White Americans. Black Americans had a worse baseline cardiac risk profile and lower neighborhood income compared with White Americans. Although risk profile improved with increasing income in White Americans, no difference was observed across incomes among Black Americans. Despite similar long-term outpatient cardiology follow-up and medication prescription, risk profiles among Black Americans remained worse. At 3 years, unadjusted all-cause mortality (18.0% versus 15.2%; P<0.001) and major adverse cardiac event (37.3% versus 34.6%; P<0.001) were greater among Black Americans and with lower income (both P<0.001); race, income, and their interaction were not significant predictors in multivariable models. At 10-year follow-up, increasing income was associated with improved outcomes only in White Americans but not Black Americans. In multivariable models for major adverse cardiac event, income (hazard ratio [HR], 0.97 [95% CI, 0.96-0.98]; P=0.005), Black race (HR, 1.77 [95% CI, 1.58-1.96]; P=0.006), and their interaction (HR, 0.98 [95% CI, 0.97-0.99]; P=0.003) were significant predictors. Similar findings were observed for cardiac death. Conclusions Early 3-year post-percutaneous coronary intervention outcomes were driven by worse risk factor profiles in both Black Americans and those with lower neighborhood income. However, late 10-year outcomes showed an independent effect of race and income, with improving outcomes with greater income limited to White Americans. These findings illustrate the importance of developing novel care strategies that address both risk factor modification and social determinants of health to mitigate disparities in cardiac outcomes.

Outcomes Following Acute Coronary Syndrome in Patients With and Without Rheumatic Immune-Mediated Inflammatory Diseases.

Background Rheumatic immune mediated inflammatory diseases (IMIDs) are associated with high risk of acute coronary syndrome. The long-term prognosis of acute coronary syndrome in patients with rheumatic IMIDs is not well studied. Methods and Results We identified Medicare beneficiaries admitted with a primary diagnosis of myocardial infarction (MI) from 2014 to 2019. Outcomes of patients with MI and concomitant rheumatic IMIDs including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, dermatomyositis, or psoriasis were compared with propensity matched control patients without rheumatic IMIDs. One-to-three propensity-score matching was done for exact age, sex, race, ST-segment-elevation MI, and non-ST-segment-elevation MI variables and greedy approach on other comorbidities. The study primary outcome was all-cause mortality. The study cohort included 1 654 862 patients with 3.6% prevalence of rheumatic IMIDs, the most common of which was rheumatoid arthritis, followed by systemic lupus erythematosus. Patients with rheumatic IMIDs were younger, more likely to be women, and more likely to present with non-ST-segment-elevation MI. Patients with rheumatic IMIDs were less likely to undergo coronary angiography, percutaneous coronary intervention or coronary artery bypass grafting. After propensity-score matching, at median follow up of 24 months (interquartile range 9-45), the risk of mortality (adjusted hazard ratio [HR], 1.15 [95% CI, 1.14-1.17]), heart failure (HR, 1.12 [95% CI 1.09-1.14]), recurrent MI (HR, 1.08 [95% CI 1.06-1.11]), and coronary reintervention (HR, 1.06 [95% CI, 1.01-1.13]) (P<0.05 for all) was higher in patients with versus without rheumatic IMIDs. Conclusions Patients with MI and rheumatic IMIDs have higher risk of mortality, heart failure, recurrent MI, and need for coronary reintervention during follow-up compared with patients without rheumatic IMIDs.

Long-Term Intracoronary Structural and Vasomotor Assessment of the ABSORB Bioresorbable Vascular Scaffold.

We systematically categorized the longer-term (≥3 years) structural and functional characteristics of the ABSORB bioresorbable vascular scaffold (BVS) using optical coherence tomography imaging and coronary vasomotor reactivity testing and further compared the functional characteristics of BVS stented versus remote coronary segments. A total of 92 patients (mean age 56.4 ± 9.7 years, 22.8% women) who underwent percutaneous coronary intervention (76% with acute coronary syndrome) using the ABSORB BVS (112 lesions) were included. Optical coherence tomography analysis (38,790 visible struts) comprised in-segment quantitative lumen/plaque and semiquantitative plaque composition analysis of the neointimal pattern. Epicardial endothelium-dependent and-independent vasomotion was defined as any vasodilatation at low/intermediate intracoronary dose of acetylcholine (ACh) and nitroglycerine, assessed using quantitative coronary angiography. At a median time of 3.2 years follow-up, 79.8% of BVS segments still demonstrated visible struts with a predominant neointimal fibrotic healing pattern in 84% of BVS segments, with 99.5% of struts demonstrating coverage with apposition. Compared with remote segments, BVS segments demonstrated less endothelium-dependent vasodilatation at low (p = 0.06) and intermediate ACh doses (p = 0.04). Hypertension, longer time interval from index percutaneous coronary intervention, and the degree of in-BVS segment neointimal volume (p <0.03 for all) were each independently associated with abnormal BVS endothelium-dependent vasomotor function. Endothelium-independent function was more likely preserved in non-BVS (remote) segments compared with BVS segments (p = 0.06). In conclusion, at 3+ years post-ABSORB BVS insertion, the rate of complete scaffold resorption was low and residual strut presence was high, with a dominant fibrous healing response contributing toward neointimal hyperplasia and endothelium-dependent and-independent vasomotor dysfunction.

Quality Assessment of Published Systematic Reviews in High Impact Cardiology Journals: Revisiting the Evidence Pyramid.

Objective: Systematic reviews are increasingly used as sources of evidence in clinical cardiology guidelines. In the present study, we aimed to assess the quality of published systematic reviews in high impact cardiology journals. Methods: We searched PubMed for systematic reviews published between 2010 and 2019 in five general cardiology journals with the highest impact factor (according to Clarivate Analytics 2019). We extracted data on eligibility criteria, methodological characteristics, bias assessments, and sources of funding. Further, we assessed the quality of retrieved reviews using the AMSTAR tool. Results: A total of 352 systematic reviews were assessed. The AMSTAR quality score was low or critically low in 71% (95% CI: 65.7-75.4) of the assessed reviews. Sixty-four reviews (18.2%, 95% CI: 14.5-22.6) registered/published their protocol. Only 221 reviews (62.8%, 95% CI: 57.6-67.7) reported adherence to the EQUATOR checklists, 208 reviews (58.4%, 95% CI: 53.9-64.1) assessed the risk of bias in the included studies, and 177 reviews (52.3%, 95% CI: 45.1-55.5) assessed the risk of publication bias in their primary outcome analysis. The primary outcome was statistically significant in 274 (79.6%, 95% CI: 75.1-83.6) and had statistical heterogeneity in 167 (48.5%, 95% CI: 43.3-53.8) reviews. The use and sources of external funding was not disclosed in 87 reviews (24.7%, 95% CI: 20.5-29.5). Data analysis showed that the existence of publication bias was significantly associated with statistical heterogeneity of the primary outcome and that complex design, larger sample size, and higher AMSTAR quality score were associated with higher citation metrics. Conclusion: Our analysis uncovered widespread gaps in conducting and reporting systematic reviews in cardiology. These findings highlight the importance of rigorous editorial and peer review policies in systematic review publishing, as well as education of the investigators and clinicians on the synthesis and interpretation of evidence.

Aortic Bioprosthetic Valve Durability: Incidence, Mechanisms, Predictors, and Management of Surgical and Transcatheter Valve Degeneration.

In recent times, there has been a considerable increase in the use of aortic bioprostheses (vs. mechanical prostheses) for treating aortic valve disease, and this tendency is likely to continue in the near future. However, the occurrence of structural valve degeneration, limiting valve durability, remains an important drawback of surgical and transcatheter bioprostheses. In this paper, we provide an overview of bioprosthetic valve durability, focusing on the definition, incidence, mechanisms, predictive factors, and management of structural degeneration of aortic bioprostheses.

Sex Differences in Nonculprit Coronary Plaque Microstructures on Frequency-Domain Optical Coherence Tomography in Acute Coronary Syndromes and Stable Coronary Artery Disease.

BACKGROUND: Numerous reports suggest sex-related differences in atherosclerosis. Frequency-domain optical coherence tomography has enabled visualization of plaque microstructures associated with disease instability. The prevalence of plaque microstructures between sexes has not been characterized. We investigated sex differences in plaque features in patients with coronary artery disease. METHODS AND RESULTS: Nonculprit plaques on frequency-domain optical coherence tomography imaging were compared between men and women with either stable coronary artery disease (n=320) or acute coronary syndromes (n=115). A greater prevalence of cardiovascular risk factors was observed in women. Nonculprit plaques in women with stable coronary artery disease were more likely to exhibit plaque erosion (8.6% versus 0.3%; P=0.03) and a smaller lipid arc (163.1±71.4° versus 211.2±71.2°; P=0.03), and less likely to harbor cholesterol crystals (17.2% versus 27.5%; P=0.01) and calcification (15.4% versus 34.4%; P=0.008), whereas fibrous cap thickness (105.2±62.1 versus 96.1±40.4 µm; P=0.57), the prevalence of thin-cap fibroatheroma (26.5% versus 25.2%; P=0.85), and microchannels (19.2% versus 20.5%; P=0.95) were comparable. In women with acute coronary syndrome, a smaller lipid arc (171.6±53.2° versus 235.8±86.4°; P=0.03), a higher frequency of plaque erosion (11.4% versus 0.6%; P=0.04), and a lower prevalence of cholesterol crystal (28.6% versus 38.2%; P=0.03) and calcification (10.0% versus 23.7%; P=0.01) were observed. These differences persisted after adjusting clinical demographics. Although thin-cap fibroatheromas in men clustered within proximal arterial segments, thin-cap fibroatheromas were evenly distributed in women. CONCLUSIONS: Despite more comorbid risk factors in women, their nonculprit plaques exhibited more plaque erosion, and less cholesterol and calcium content. This distinct phenotype suggests sex-related differences in the pathophysiology of atherosclerosis.

Impact of PCSK9 inhibition on coronary atheroma progression: Rationale and design of Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV).

BACKGROUND: Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels <70 mg/dL. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors permit LDL-C-lowering by a further 54% to 75% in statin-treated patients. The impact of achieving very low LDL-C levels with PCSK9 inhibitors on coronary atherosclerosis has not been investigated. AIMS: To test the hypothesis that incremental LDL-C lowering with the PCSK9 inhibitor, evolocumab, will result in a significantly greater change from baseline in coronary atheroma volume than placebo in subjects receiving maximally tolerated statin therapy. METHODS: A phase 3, multicenter, double-blind, randomized, placebo-controlled trial evaluating the impact of evolocumab on coronary atheroma volume as assessed by serial coronary intravascular ultrasound at baseline in patients undergoing a clinically indicated coronary angiogram with angiographic evidence of coronary atheroma, and after 78 weeks of treatment. Subjects (n = 968) were randomized 1:1 into 2 groups to receive monthly either evolocumab 420 mg or placebo subcutaneous injections. CONCLUSIONS: The GLAGOV trial will explore whether greater degrees of plaque regression are achievable with ultrahigh-intensity LDL-C lowering after combination statin-PCSK9 inhibitor therapy. GLAGOV will provide important mechanistic, safety, and efficacy data prior to the eagerly anticipated clinical outcomes trials testing the PCSK9 inhibitor hypothesis (www.clinicaltrials.gov identifier NCT01813422).

Non-invasive volumetric assessment of aortic atheroma: a core laboratory validation using computed tomography angiography.

Aortic atherosclerosis has been linked with worse peri- and post-procedural outcomes following a range of aortic procedures. Yet, there are currently no standardized methods for non-invasive volumetric pan-aortic plaque assessment. We propose a novel means of more accurately assessing plaque volume across whole aortic segments using computed tomography angiography (CTA) imaging. Sixty patients who underwent CTA prior to trans-catheter aortic valve implantation were included in this analysis. Specialized software analysis (3mensio Vascular™, Pie Medical, Maastricht, Netherlands) was used to reconstruct images using a centerline approach, thus creating true cross-sectional aortic images, akin to those images produced with intravascular ultrasonography. Following aortic segmentation (from the aortic valve to the renal artery origin), atheroma areas were measured across multiple contiguous evenly spaced (10 mm) cross-sections. Percent atheroma volume (PAV), total atheroma volume (TAV) and calcium score were calculated. In our populations (age 79.9 ± 8.5 years, male 52 %, diabetes 27 %, CAD 84 %, PVD 20 %), mean ± SD number of cross sections measured for each patient was 35.1 ± 3.5 sections. Mean aortic PAV and TAV were 33.2 ± 2.51 % and 83,509 ± 17,078 mm(3), respectively. Median (IQR) calcium score was 1.5 (0.7-2.5). Mean (SD) inter-observer coefficient of variation and agreement for plaque area among 4 different analysts was 14.1 (5.4), and the mean (95 % CI) Lin's concordance correlation coefficient was 0.79 (0.62-0.89), effectively simulating a Core Laboratory scenario. We provide an initial validation of cross-sectional volumetric aortic atheroma assessment using CTA. This proposed methodology highlights the potential for utilizing non-invasive aortic plaque imaging for risk prediction across a range of clinical scenarios.

Near-Infrared Spectroscopy Enhances Intravascular Ultrasound Assessment of Vulnerable Coronary Plaque: A Combined Pathological and In Vivo Study.

OBJECTIVES: Pathological studies demonstrate the dual significance of plaque burden (PB) and lipid composition for mediating coronary plaque vulnerability. We evaluated relationships between intravascular ultrasound (IVUS)-derived PB and arterial remodeling with near-infrared spectroscopy (NIRS)-derived lipid content in ex vivo and in vivo human coronary arteries. APPROACH AND RESULTS: Ex vivo coronary NIRS and IVUS imaging was performed through blood in 116 coronary arteries of 51 autopsied hearts, followed by 2-mm block sectioning (n=2070) and histological grading according to modified American Heart Association criteria. Lesions were defined as the most heavily diseased 2-mm block per imaged artery on IVUS. IVUS-derived PB and NIRS-derived lipid core burden index (LCBI) of each block and lesion were analyzed. Block-level analysis demonstrated significant trends of increasing PB and LCBI across more complex atheroma (Ptrend <0.001 for both LCBI and PB). Lesion-based analyses demonstrated the highest LCBI and remodeling index within coronary fibroatheroma (Ptrend <0.001 and 0.02 versus all plaque groups, respectively). Prediction models demonstrated similar abilities of PB, LCBI, and remodeling index for discriminating fibroatheroma (c indices: 0.675, 0.712, and 0.672, respectively). A combined PB+LCBI analysis significantly improved fibroatheroma detection accuracy (c index 0.77, P=0.028 versus PB; net-reclassification index 43%, P=0.003), whereas further adding remodeling index did not (c index 0.80, P=0.27 versus PB+LCBI). In vivo comparisons of 43 age- and sex-matched patients (to the autopsy cohort) undergoing combined NIRS-IVUS coronary imaging yielded similar associations to those demonstrated ex vivo. CONCLUSIONS: Adding NIRS to conventional IVUS-derived PB imaging significantly improves the ability to detect more active, potentially vulnerable coronary atheroma.

The emerging role of plasma lipidomics in cardiovascular drug discovery.

INTRODUCTION: With the rising global incidence of cardiovascular disease, the challenge for the pharmaceutical industry is to identify novel biomarkers that will allow not only for the development of the next generation of cardiometabolic therapeutics, but also to serve as a sensitive mechanism to monitor and predict drug efficacy and potential toxicity. The advent of an 'omics' (systems biological) approach has vast implications for future disease treatment and prevention. Lipidomics is the latest addition to the 'omics' family and is rapidly gaining attention due to the technological improvements in mass spectrometry, allowing for the characterization of large number of lipids (and their respective subclasses) in a short amount of time with relatively minimal preparation. AREAS COVERED: The authors discuss the various techniques involved in plasma lipidomics as well as outline the role that lipidomics will play in phenotyping disease processes and corresponding therapeutic strategies. The article was formed through comprehensive Medline search of relevant publications in this area. EXPERT OPINION: Despite the wealth of data that will emerge regarding the various lipid-molecular interactions and the functions of lipids within cells, a major challenge will be the parallel emergence of novel bioinformatics platforms in order to integrate this enormous data set with information generated from the emerging fields of genomics and proteomic analysis. Despite these challenges, lipidomics is likely to result in the reclassification of diseases from a molecular perspective and play a key role the eventuation of personalized medicine.

Cardiac magnetic resonance derived late microvascular obstruction assessment post ST-segment elevation myocardial infarction is the best predictor of left ventricular function: a comparison of angiographic and cardiac magnetic resonance derived measurements.

Microvascular obstruction (MVO) is a strong independent predictor of left ventricular remodelling and mortality following ST-segment elevation myocardial infarction (STEMI). Microvascular obstruction can be identified at angiography or with gadolinium-enhanced cardiac MRI (CMR). First-pass perfusion CMR also allows a novel quantitative evaluation of myocardial blood flow (MBF) that might provide superior predictive data in the assessment of MVO. We sought to compare angiographic and CMR derived methodologies in the assessment of MVO to determine the optimal methodology that best predicts the surrogate outcome marker of left ventricular function post STEMI. Following primary-PCI angiographic assessment of 'no-reflow' with TIMI myocardial perfusion grade (TMPG) and myocardial blush grade (MBG) were documented. Assessment of CMR derived MVO was assessed on day 3, with MVO on first-pass perfusion imaging termed 'early MVO' and on late gadolinium enhancement, 'late MVO'. Furthermore on the same day 3 CMR scan, myocardial blood flow in the infarct region was quantified at adenosine stress and rest utilizing standard perfusion imaging sequences. Assessment of remodelling, structure and function was undertaken via standard CMR imaging assessment on day 90 post-STEMI and was used as the surrogate marker for long term clinical outcome. Forty patients (age 59 ± 12 years, 84% males) were appraised. Late MVO had the strongest correlation with LVEF at 90 days compared to the CMR parameters of early MVO, stress infarct region MBF and rest infarct region MBF (r = -0.754, r = -0.588, r = 0.595 and r = 0.345 respectively). Of the angiographic parameters used to assess MVO, TMPG had the strongest relationship with MVO when assessed via CMR. Myocardial blush grade however showed no relationship to CMR derived assessment of MVO. On multivariate analysis, of all angiographic and CMR variables, late MVO was the strongest predictor of LVEF at 90 days (p = 0.004). Cardiac magnetic resonance imaging derived assessment of microvascular obstruction on late gadolinium enhancement strongly predicts left ventricular function following STEMI at 90 days.