Differential effects of anti-CD20 therapy on CD4 and CD8 T cells and implication of CD20-expressing CD8 T cells in MS disease activity.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

High-Sensitivity Cardiac Troponins I and T and Cardiovascular Outcomes: Findings from the Systolic Blood Pressure Intervention Trial (SPRINT).

BACKGROUND: Cardiac troponins are associated with adverse cardiovascular disease (CVD) outcomes. The value of high-sensitivity cardiac troponin I (hs-cTnI) independently and in concert with troponin T (hs-cTnT) in the management of hypertension has not been well studied. METHODS: We assessed the utility of hs-cTnI independently and with hs-cTnT in identifying the highest risk individuals in the Systolic Blood Pressure Intervention Trial (SPRINT). Among 8796 eligible SPRINT participants, hs-cTnI was measured at baseline and 1 year. The association of baseline level and 1-year change in hs-cTnI with CVD events and all-cause death was evaluated using adjusted Cox regression models. We further assessed the complementary value of hs-cTnI and hs-cTnT by identifying concordant and discordant categories and assessing their association with outcomes. RESULTS: hs-cTnI was positively associated with composite CVD risk [myocardial infarction, other acute coronary syndrome, stroke, or cardiovascular death: hazard ratio 1.23, 95% confidence interval 1.08-1.39 per 1-unit increase in log(troponin I)] independent of traditional risk factors, N-terminal pro-B-type natriuretic peptide, and hs-cTnT. Intensive blood pressure lowering was associated with greater absolute risk reduction (4.5% vs 1.7%) and lower number needed to treat (23 vs 59) for CVD events among those with higher baseline hs-cTnI (≥6 ng/L in men, ≥4 ng/L in women). hs-cTnI increase at 1 year was also associated with increased CVD risk. hs-cTnI and hs-cTnT were complementary, and elevations in both identified individuals with the highest risk for CVD and death. CONCLUSIONS: Baseline levels and change in hs-cTnI over 1 year identified higher-risk individuals who may derive greater cardiovascular benefit with intensive blood pressure treatment. hs-TnI and hs-TnT have complementary value in CVD risk assessment. ClinicalTrials.gov Registration Number: NCT01206062.

Intravascular Ultrasound-Guided versus Angiography-Guided Percutaneous Coronary Intervention for Stent Thrombosis Elevation Myocardial Infarction: An Updated Systematic Review and Meta-Analysis.

INTRODUCTION: Intravascular ultrasound (IVUS) provides intra-procedural guidance in optimizing percutaneous coronary interventions (PCI) and has been shown to improve clinical outcomes in stent implantation. However, current data on the benefit of IVUS during PCI in ST-elevation myocardial infarction (STEMI) patients is mixed. We performed meta-analysis pooling available data assessing IVUS-guided versus angiography-guided PCI in STEMI patients. METHODS: We conducted a systematic search on PubMed and Embase for studies comparing IVUS versus angiography-guided PCI in STEMI. Mantel-Haenszel random effects model was used to calculate risk ratios (RRs) with 95% confidence intervals (CIs) for outcomes of major adverse cardiovascular events (MACEs), death, myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis (ST) and in-hospital mortality. RESULTS: A total of 8 studies including 336,649 individuals presenting with STEMI were included for the meta-analysis. Follow-up ranged from 11 to 60 months. We found significant association between IVUS-guided PCI with lower risk for MACE (RR 0.82, 95% CI 0.76-0.90) compared with angiography-guided PCI. We also found significant association between IVUS-guided PCI with lower risk for death, MI, TVR, and in-hospital mortality but not ST. CONCLUSION: In our meta-analysis, IVUS-guided compared with angiography-guided PCI was associated with improved long-term and short-term clinical outcomes in STEMI patients.

Joint MRI T1 Unenhancing and Contrast-enhancing Multiple Sclerosis Lesion Segmentation with Deep Learning in OPERA Trials.

Background Deep learning-based segmentation could facilitate rapid and reproducible T1 lesion load assessments, which is crucial for disease management in multiple sclerosis (MS). T1 unenhancing and contrast-enhancing lesions in MS are those that enhance or do not enhance after administration of a gadolinium-based contrast agent at T1-weighted MRI. Purpose To develop deep learning models for automated assessment of T1 unenhancing and contrast-enhancing lesions; to investigate if joint training improved performance; to reproduce a known ocrelizumab treatment response; and to evaluate the association of baseline T1-weighted imaging metrics with clinical outcomes in relapsing MS clinical trials. Materials and Methods Joint and individual deep learning models (U-Nets) were developed retrospectively on multimodal MRI data sets from large multicenter OPERA trials of relapsing MS (August 2011 to May 2015). The joint model included cross-network connections and a combined loss function. Models were trained on OPERA I data sets with three-fold cross-validation. OPERA II data sets were the internal test set. Dice coefficients, lesion true-positive and false-positive rates, and areas under the receiver operating characteristic curve (AUCs) were used to evaluate model performance. Association of baseline imaging metrics with clinical outcomes was assessed with Cox proportional hazards models. Results A total of 796 patients (3030 visits; mean age, 37 years ± 9; 521 women) from the OPERA II trial were evaluated. The joint model achieved a mean Dice coefficient of 0.77 and 0.74, lesion true-positive rate of 0.88 and 0.86, and lesion false-positive rate of 0.04 and 0.19 for T1 contrast-enhancing and T1 unenhancing lesion segmentation, respectively. Joint training improved performance for smaller T1 contrast-enhancing lesions (≤0.06 mL; individual training AUC: 0.75; joint training AUC: 0.87; P < .001). A significant ocrelizumab treatment effect (P < .001) was seen in reducing the mean number of T1 contrast-enhancing lesions at 24, 48, and 96 weeks (manual assessment at 24 weeks: 10 lesions in 366 patients with ocrelizumab, 141 lesions in 355 patients with interferon, 93% reduction; manual assessment at 48 weeks: six lesions in 355 patients with ocrelizumab, 150 lesions in 317 patients with interferon, 96% reduction; manual assessment at 96 weeks: five lesions in 340 patients with ocrelizumab, 157 lesions in 294 patients with interferon, 97% reduction; joint model assessment at 24 weeks: 19 lesions in 365 patients with ocrelizumab, 128 lesions in 354 patients with interferon, 86% reduction; joint model assessment at 48 weeks: 14 lesions in 355 patients with ocrelizumab, 121 lesions in 317 patients with interferon, 90% reduction; joint model assessment at 96 weeks: 10 lesions in 340 patients with ocrelizumab, 144 lesions in 294 patients with interferon, 94% reduction) and the mean number of new T1 unenhancing lesions across all follow-up examinations (manual assessment: 504 lesions in 1060 visits for ocrelizumab-treated patients, 1438 lesions in 965 visits for interferon-treated patients, 68% reduction; joint model assessment: 205 lesions in 1053 visits for ocrelizumab-treated patients, 661 lesions in 957 visits for interferon-treated patients, 78% reduction). Baseline T1 unenhancing total lesion volume was associated with clinical outcomes (manual hazard ratio [HR]: 1.12, P = .02; joint model HR: 1.11, P = .03). Conclusion Joint architecture and training improved segmentation of MRI T1 contrast-enhancing multiple sclerosis lesions, and both deep learning models had sufficiently high performance to detect an ocrelizumab treatment response consistent with manual assessments. ClinicalTrials.gov: NCT01247324 and NCT01412333 © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Talbott in this issue.

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

Facility-Level Variation in Reported Statin-Associated Side Effects Among Patients with Atherosclerotic Cardiovascular Disease-Perspective from the Veterans Affair Healthcare System.

PURPOSE: Statin-associated side effects (SASEs) can limit statin adherence and present a potential barrier to optimal statin utilization. How standardized reporting of SASEs varies across medical facilities has not been well characterized. METHODS: We assessed facility-level variation in SASE reporting among patients with atherosclerotic cardiovascular disease receiving care across the Veterans Affairs (VA) healthcare system from October 1, 2014, to September 30, 2015. The facility rates for SASE reporting were expressed as cases per 1000 patients with ASCVD. Facility-level variation was determined using hierarchical regression analysis to calculate median rate ratios (MRR [95% confidence interval]) by first using an unadjusted model and then adjusting for patient, provider, and facility characteristics. RESULTS: Of the 1,248,158 patients with ASCVD included in our study across 130 facilities, 13.7% had at least one SASE reported. Individuals with a history of SASE were less likely to be on a statin at follow-up compared with those without SASE (72.0% vs 80.8%, p < 0.01). The median (interquartile range) facility rate of SASE reported was 140.5 (109.4-167.7) cases per 1000 patients with ASCVD. Significant facility-level variation in the rate of SASE reported was observed: MRR 1.38 (1.33-1.44) in the unadjusted model and MRR 1.56 (1.47-1.65) in the adjusted model. CONCLUSION: Significant facility-level variation in SASE reporting was found within the VA healthcare system suggesting room for improvement in standardized documentation of SASEs among medical facilities. This has the potential to lead to improvement in statin utilization.

The Meaning of Bonds: The Relationships Among Grief Rituals, Support From Relatives and Friends, and the Mental Health of Shiduers.

Previous studies have sporadically explored the effect of various bonds on the mental health of shiduers (i.e., parents who lost their only child). However, research has rarely classified different bonds to systematically describe their effects. This study administered a self-compiled questionnaire, the Center for Epidemiologic Studies Depression Scale, the Zung Self-Rating Anxiety Scale, the posttraumatic stress disorder Checklist, the Prolonged Grief Questionnaire, the Posttraumatic Growth Inventory, and the Adult Dispositional Hope Scale to 466 shiduers. The commemoration rituals that occur soon after the loss predict a lower level of posttraumatic stress disorder. Similarly, the commemoration rituals that occur on special days predict lower levels of depression and anxiety. In contrast, the continuation of commemoration rituals on ordinary days predicts higher levels of depression and prolonged grief. Support from family members and relatives, other shiduers, and nonshiduer friends are all beneficial to shiduers' mental health.

Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications.

PURPOSE: Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted. METHODS: We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record. RESULTS: Notably, 32% of patients had a genetic finding with clinical management implications, even after excluding PGx results, including 9% who were molecularly diagnosed with a Mendelian condition. Among surveyed physicians, 84% reported medical management changes based on these results, including specialist referrals, cardiac tests, and medication changes. LPA polymorphisms and high polygenic risk of CAD were found in 20% and 9% of patients, respectively, leading to diet, lifestyle, and other changes. Warfarin and simvastatin pharmacogenetic variants were present in roughly half of the cohort. CONCLUSION: Our results support the use of genetic information in routine cardiovascular health management and provide a roadmap for accompanying research.

Lipid-Lowering Biotechnological Drugs: from Monoclonal Antibodies to Antisense Therapies-a Clinical Perspective.

PURPOSE: While low density lipoprotein cholesterol (LDL-C) remains a key contributor of atherosclerotic cardiovascular disease (ASCVD), additional risk factors identified through epidemiological and genetic studies have ushered in a fertile era of drug discovery in lipid-lowering therapy. Unlike contemporary small molecule medications, many of the novel agents are biologics utilizing monoclonal antibody (mAb) or RNA interference (RNAi) technologies. This report aims to review the evidence to date, focusing on completed and ongoing clinical trials and how these new agents will impact clinical practice. METHODS: We review data from pertinent studies on lipid-lowering biologics in clinical use or have translated to human studies and are undergoing clinical trials. RESULTS: Several targets affecting lipid metabolism have been identified to be causally associated with ASCVD including proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3 (ANGPTL3), apolipoprotein C3 (APOC3), and lipoprotein (a) (Lp[a]). Biotechnological modalities that have been developed for these targets include mAb, small interfering RNA (siRNA), and anti-sense oligonucleotide (ASO) agents. Agents such as alirocumab and evolocumab have shown efficacy in risk reduction of ASCVD in cardiovascular outcome trials and have been incorporated into evidence-based practice guidelines. Other agents included in this review are in various stages of clinical trials and have shown significant efficacy in the reduction of lipid parameters. CONCLUSION: The development of new biologics targeting lipid risk factors will provide clinicians additional tools to reduce the risk for ASCVD. Important factors to consider will be cost-effectiveness and improving methods to personalize treatments to risk factors.

Association Between Omega-3 Fatty Acid Treatment and Atrial Fibrillation in Cardiovascular Outcome Trials: A Systematic Review and Meta-Analysis.

PURPOSE: Data on the relationship between omega-3 fatty acid (n-3 FA) therapy with atrial fibrillation (AF) have been inconsistent. We investigate the association between n-3 FA and risk for AF by pooling data from available large, cardiovascular outcome trials. METHODS: We performed a systematic search on PubMed and Embase for studies on n-3 FA with AF as an outcome measure. Large (≥ 1000 participants) randomized controlled trials with ≥ 1-year follow-up period were included. The association between n-3 FA and risk of AF or stroke was assessed. Mantel-Haenszel random effects model was used to calculate risk ratios (RR) with 95% confidence intervals (CI). We then performed meta-regression to evaluate effect on AF by dose of n-3 FA therapy. RESULTS: A total of 8 randomized control trials encompassing 83,112 participants were included in the meta-analysis. Of these, five trials assessed a lower dose of n-3 FA (≤ 1 g daily, n = 61,096) while 3 trials assessed a higher dose (> 1 g daily, n = 22,016). In meta-analysis, a significant association was noted between n-3 FA treatment and risk of AF (4.0% vs 3.3%; RR 1.24, 95% CI 1.11-1.38, p = 0.0002). There was a modest but still significant association in the lower dose (n-3 FA ≤ 1 g daily) sub-group (RR 1.12, 95% CI 1.04-1.21, p = 0.004) and stronger association in the higher dose (n-3 FA > 1 g daily) sub-group (RR 1.51, 95% CI 1.26-1.80, p < 0.001; p-interaction between low versus high subgroups = 0.003). There was no increase in stroke risk (RR 1.04, 95% CI 0.90-1.20). Meta-regression demonstrated a significant association between dose of n-3 FA with risk for AF events (log RR 0.103, 95% CI 0.048-0.159, p < 0.001). CONCLUSION: While overall AF event rates were low, n-3 FA treatment is associated with increased risk for AF.

Association between circulating Galectin-3 and arterial stiffness in older adults.

Background: Galectin-3 (gal-3) is a ß-galactoside-binding lectin associated tissue fibrosis and inflammation. There is limited understanding of the relationship between gal-3 and vascular health. Our aim was to assess the association between gal-3 and arterial stiffness in older adults. Methods: We conducted a cross-sectional study of 4275 participants (mean age of 75 years) from the Atherosclerosis Risk in Communities (ARIC) Study. Central arterial stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). We evaluated the association of gal-3 with cfPWV using multivariable linear regression. Results: The median (interquartile range) gal-3 concentration was 16.5 (13.8, 19.8) ng/mL and mean cfPWV was 1163±303 cm/s. Higher gal-3 concentration was associated with greater central arterial stiffness after adjustment for age, sex, race-center, heart rate, systolic blood pressure, anti-hypertensive medication use, and current smoking status (ß=36.4 cm/s change in cfPWV per log unit change in gal-3; 95% CI: 7.2, 65.5, p=0.015). The association was attenuated after adjusting for additional cardiovascular risk factors (ß=17.3, 95% CI: -14.4, 49.0). Conclusions: In community-dwelling older adults, gal-3 concentration was associated with central arterial stiffness, likely sharing common pathways with traditional cardiovascular risk factors.

The effect of autobiographical memory function on depression and anxiety in Chinese shiduers (parents who have lost their only child): The moderating role of familistic emotion.

Autobiographical memory has an important influence on the mental health of bereaved people. In this study, we conducted a questionnaire survey of 372 shiduers (parents who have lost their only child) to investigate the moderating role of familistic emotion in the effect of autobiographical memory function on depression and anxiety in shiduers. The results show that when either self-function or directive-function is the independent variable, familistic emotion plays a moderating role; however, when social function is the independent variable, familistic emotion does not play a moderating role. This article discusses the reasons for these results.

High-Sensitivity Troponin I and Incident Coronary Events, Stroke, Heart Failure Hospitalization, and Mortality in the ARIC Study.

BACKGROUND: We assessed whether plasma troponin I measured by a high-sensitivity assay (hs-TnI) is associated with incident cardiovascular disease (CVD) and mortality in a community-based sample without prior CVD. METHODS: ARIC study (Atherosclerosis Risk in Communities) participants aged 54 to 74 years without baseline CVD were included in this study (n=8121). Cox proportional hazards models were constructed to determine associations between hs-TnI and incident coronary heart disease (CHD; myocardial infarction and fatal CHD), ischemic stroke, atherosclerotic CVD (CHD and stroke), heart failure hospitalization, global CVD (atherosclerotic CVD and heart failure), and all-cause mortality. The comparative association of hs-TnI and high-sensitivity troponin T with incident CVD events was also evaluated. Risk prediction models were constructed to assess prediction improvement when hs-TnI was added to traditional risk factors used in the Pooled Cohort Equation. RESULTS: The median follow-up period was ≈15 years. Detectable hs-TnI levels were observed in 85% of the study population. In adjusted models, in comparison to low hs-TnI (lowest quintile, hs-TnI ≤1.3 ng/L), elevated hs-TnI (highest quintile, hs-TnI ≥3.8 ng/L) was associated with greater incident CHD (hazard ratio [HR], 2.20; 95% CI, 1.64-2.95), ischemic stroke (HR, 2.99; 95% CI, 2.01-4.46), atherosclerotic CVD (HR, 2.36; 95% CI, 1.86-3.00), heart failure hospitalization (HR, 4.20; 95% CI, 3.28-5.37), global CVD (HR, 3.01; 95% CI, 2.50-3.63), and all-cause mortality (HR, 1.83; 95% CI, 1.56-2.14). hs-TnI was observed to have a stronger association with incident global CVD events in white than in black individuals and a stronger association with incident CHD in women than in men. hs-TnI and high-sensitivity troponin T were only modestly correlated ( r=0.47) and were complementary in prediction of incident CVD events, with elevation of both troponins conferring the highest risk in comparison with elevation in either one alone. The addition of hs-TnI to the Pooled Cohort Equation model improved risk prediction for atherosclerotic CVD, heart failure, and global CVD. CONCLUSIONS: Elevated hs-TnI is strongly associated with increased global CVD incidence in the general population independent of traditional risk factors. hs-TnI and high-sensitivity troponin T provide complementary rather than redundant information.

Highlights from Studies in Cardiovascular Disease Prevention Presented at the Digital 2020 European Society of Cardiology Congress: Prevention Is Alive and Well.

PURPOSE OF REVIEW: The review highlights selected studies related to cardiovascular disease (CVD) prevention that were presented at the 2020 European Society of Cardiology (ESC) Congress-The Digital Experience. RECENT FINDINGS: The studies reviewed include clinical trials on novel RNA interference-based lipid-lowering therapies AKCEA-APOCIII-LRx and vupanorsen (AKCEA-ANGPTL3-LRx); the EVAPORATE trial assessing the effects of icosapent ethyl on coronary plaque volume progression; the LoDoCo2 trial evaluating the efficacy of low-dose colchicine in cardiovascular disease risk reduction among patients with chronic coronary artery disease; as well as the EMPEROR-Reduced trial evaluating cardiovascular and renal outcomes with empagliflozin in patients with heart failure and reduced ejection fraction. In addition, we review the BPLTTC analysis on blood pressure treatment across blood pressure levels and CVD status and discuss findings from the BRACE CORONA study that examined continuing versus suspending angiotensin-converting enzyme inhibitor or angiotensin receptor blockers in patients on these antihypertensive medications who were hospitalized with COVID-19 infection. The studies presented at the 2020 digital ESC Congress highlight the continuing advancements in the field of CVD prevention.

Highlights of Studies in Cardiovascular Disease Prevention Presented at the 2020 American College of Cardiology Annual Scientific Session.

PURPOSE OF REVIEW: The review highlights selected studies related to cardiovascular disease (CVD) prevention that were presented at the American College of Cardiology 2020 Virtual Scientific Session (ACC.20)/World Cardiology Congress (WCC). RECENT FINDINGS: The studies reviewed include clinical trials on the efficacy and safety of alirocumab (Study in Participants with Homozygous Familial Hypercholesterolemia [ODYSSEY HoFH]) and evinacumab in the treatment of homozygous familial hypercholesterolemia (HoFH); Evaluating the Efficacy of E-cigarettes for Smoking Cessation (E3); the use of renal denervation in the treatment of hypertension (SPYRAL HTN-OFF MED PIVOTAL); and the assessment of vericiguat in the treatment of heart failure (A Study of Vericiguat in Participants with Heart Failure with Reduce Ejection Fraction [VICTORIA]). In addition, results from the pooled analysis of phase III trials on inclisiran and secondary analysis examining eicosapentaenoic acid levels and cardiovascular outcomes from the Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) were included. Finally, we discuss studies examining the use of polygenic risk score with low density lipoprotein cholesterol (LDL-C) and systolic blood pressure (SBP) on lifetime cardiovascular risk. The studies presented at the ACC.20/WCC represent notable contributions in the field of CVD prevention.

Assessing the Validity of Echocardiographic Criteria for Left Ventricular Diastolic Dysfunction in Patients with Pulmonary Hypertension.

BACKGROUND: In patients with pulmonary hypertension (PHT), the assessment of left ventricular (LV) diastolic function by echocardiography may not be reliable. PHT can affect Doppler parameters of LV diastolic function such as mitral inflow velocities and mitral annular velocities. The current guidelines for the assessment of LV diastolic function do not recommend specific adjustments for patients with PHT. METHODS: We analyzed 36 patients from the PHT clinic that had an echocardiogram and right heart catheterization performed within 6 months of each other. Early mitral inflow velocity (E), lateral mitral annular velocity (lateral e'), septal mitral annular velocity (septal e'), tricuspid free wall annular velocity (RV e') were measured and compared to the invasively measured intracardiac pressures including pulmonary capillary wedge pressure (PCWP), mean pulmonary artery pressure, and right ventricular end-diastolic pressure. RESULTS: Among patients with PHT, the specificity of the septal e' for LV diastolic dysfunction was 0.19, and the positive predictive value was 0.13 (lower than the lateral e' or E/average e'). By receiver-operating characteristic curve analysis, the area under the curve (AUC) of lateral and septal e' was just 0.64 (p = 0.9) and 0.53 (p = 0.6), respectively, while the AUC of average E/e' was 0.94 (p < 0.001). The septal e' was paradoxically lower at 6.5 ± 1.9 cm/s for normal PCWP compared to 6.9 ± 1.7 cm/s for elevated PCWP (p = 0.04). 81 versus 40% (p = 0.017) of patients with normal versus elevated PCWP had an abnormal septal e' <7 cm/s. By linear regression, there was no correlation between the Doppler parameters of LV diastolic function and the PCWP. CONCLUSION: Our study suggests E/average e' may be the only reliable tissue Doppler parameter of LV diastolic dysfunction in patients with PHT, and that septal e' is paradoxically decreased in patients with PHT and normal left-sided filling pressures.

Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice.

There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the CNS. Here, we compared the gut microbial composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial profiles, we found a significant increase in some taxa such as Akkermansia in untreated MS twins. Furthermore, most notably, when transplanted to a transgenic mouse model of spontaneous brain autoimmunity, MS twin-derived microbiota induced a significantly higher incidence of autoimmunity than the healthy twin-derived microbiota. The microbial profiles of the colonized mice showed a high intraindividual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence. These findings provide evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS.

Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis.

OBJECTIVE: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS. METHODS: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip. RESULTS: WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27-2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18-2.10; p = 0.002). Importantly, this enrichment was not detected in RMS. INTERPRETATION: This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51-63.

Omega-3 Fatty Acid and Cardiovascular Outcomes: Insights From Recent Clinical Trials.

PURPOSE OF REVIEW: Omega-3 fatty acids (ω-3 FA) are among the most well-recognized health supplements but their cardiovascular benefits have long been controversial owing to inconsistent results from previous cardiovascular outcomes trials (CVOT). In this article, we provide a short review of existing literature followed by recent randomized clinical trial data, with a discussion of the potential clinical implications of these new findings. RECENT FINDINGS: Data from the randomized, controlled trial REDUCE-IT, when viewed within the context of other recently published trials ASCEND and VITAL, add to a growing body of evidence on the use of ω-3 FA therapies in the treatment of atherosclerotic cardiovascular disease (ASCVD). Given the different formulations, dosages, and patient populations studied, CVOTs of ω-3 FA have provided valuable insight into the use of these agents in cardioprotection. Current data suggest that higher dosages of pure eicosapentaenoic acid ω-3 FA formulations provide additional benefit in reduction of ASCVD events.

The 2018 Cholesterol Management Guidelines: Topics in Secondary ASCVD Prevention Clinicians Need to Know.

PURPOSE OF REVIEW: The 2018 ACC/AHA Multisociety blood cholesterol guidelines provide updated recommendations based on contemporary evidence on the management of serum cholesterol for the prevention of atherosclerotic cardiovascular disease (ASCVD) events. This review discusses clinically important topics in the new guidelines related to secondary ASCVD prevention. RECENT FINDINGS: Since the 2013 ACC/AHA blood cholesterol guidelines, several large randomized control trials involving ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (evolocumab and alirocumab) have been published. The trials provided evidence that these non-statin, LDL-cholesterol lowering agents are efficacious in reducing risk for ASCVD events in patients with clinical ASCVD. The 2018 guidelines incorporate these new findings into updated clinical recommendations on therapeutic strategies related to the use of ezetimibe and PCSK9 inhibitors. The guidelines also recommend risk stratification of secondary prevention patients to identify those at very high-risk of ASCVD events as these patients would derive the most absolute risk reduction from the addition of non-statin therapies. While high-intensity statins remain the first-line treatment to prevent recurrent ASCVD events in secondary prevention patients, ezetimibe and PCSK9 inhibitors are evidence-based non-statin agents that can be used when residual on top of maximally tolerated statin therapy in patients deemed to be at very-high risk of recurrent ASCVD events.