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Rates of atherosclerotic cardiovascular diseases (CVD) in the Western world have spectacularly decreased over the past 50 years. However, a substantial proportion of high-risk patients still develop heart attacks, strokes and valvular heart diseases despite benefiting from state-of-the-art treatments including lipid-lowering therapies. Over the past 10-15 years, it has become increasingly clear that Lipoprotein(a) (Lp[a]) is a critical component of this so-called residual risk. Genetic association studies revealed that Lp(a) is robustly, independently and causally associated with a broad range of cardiovascular and valvular heart diseases. Up to 1 billion people around the globe may have an Lp(a) level that places them in a high-risk category. Lp(a) is strongly associated with calcific aortic valve stenosis (CAVS), coronary artery disease (CAD), peripheral arterial disease (PAD) and to a lesser extent with ischemic stroke (IS) and heart failure (HF). Because of this strong association with cardiovascular and valvular heart diseases, Lp(a) even emerged as one of the most important genetic determinants of human lifespan and healthspan. Here, we review the evidence from the largest and most informative genetic association studies and prospective studies that have investigated the association between Lp(a) and human lifespan, healthspan, CVD, CAVS and non-cardiovascular diseases. We present Lp(a) threshold values that may be clinically relevant and identify other cardiovascular risk factors that may modulate the absolute risk of CVD in individuals with high Lp(a) levels. Finally, we identify key clinical and research questions that require further investigation to eventually and optimally reduce CVD risk in patients with high Lp(a) levels.

Despite numerous promising therapeutic targets, there are no proven medical treatments for calcific aortic stenosis (AS). Multiple stakeholders need to come together and several scientific, operational, and trial design challenges must be addressed to capitalize on the recent and emerging mechanistic insights into this prevalent heart valve disease. This review briefly discusses the pathobiology and most promising pharmacologic targets, screening, diagnosis and progression of AS, identification of subgroups that should be targeted in clinical trials, and the need to elicit the patient voice earlier rather than later in clinical trial design and implementation. Potential trial end points and tools for assessment and approaches to implementation and design of clinical trials are reviewed. The efficiencies and advantages offered by a clinical trial network and platform trial approach are highlighted. The objective is to provide practical guidance that will facilitate a series of trials to identify effective medical therapies for AS resulting in expansion of therapeutic options to complement mechanical solutions for late-stage disease.

Summary Our objectives were to determine whether autotaxin (ATX) is transported by lipoprotein(a) [Lp(a)] in human plasma and if could be used as a biomarker of calcific aortic valve stenosis (CAVS). We first found that ATX activity was higher in Lp(a) compared to low-density lipoprotein fractions in isolated fractions of 10 healthy participants. We developed a specific assay to measure ATX-Lp(a) in 88 patients with CAVS and 144 controls without CAVS. In a multivariable model corrected for CAVS risk factors, ATX-Lp(a) was associated with CAVS (p = 0.003). We concluded that ATX is preferentially transported by Lp(a) and might represent a novel biomarker for CAVS.

Background and aims Poor dietary habits contribute to the obesity pandemic and related cardiovascular diseases but the respective impact of high saturated fat versus added sugar consumption remains debated. Herein, we aimed to disentangle the individual role of dietary fat versus sugar in cardiometabolic disease progression. Methods We fed pro-atherogenic LDLr−/− ApoB100/100 mice either a low-fat/high-sucrose (LFHS) or a high-fat/low-sucrose (HFLS) diet for 24 weeks. Weekly body weight gain was registered. 16S rRNA gene-based gut microbial analysis was performed to investigate gut microbial modulations. Intraperitoneal insulin (ipITT) and oral glucose tolerance test (oGTT) were conducted to assess glucose homeostasis and insulin sensitivity. Cytokines were assessed in fasted plasma, epididymal white adipose tissue and liver lysates. Heart function was evaluated by echocardiography. Aortic atheroma lesions were quantified according to the en face technique. Results HFLS feeding increased obesity, insulin resistance and dyslipidemia compared to LFHS feeding. Conversely, high sucrose consumption decreased gut microbial diversity while augmenting inflammation and the adaptative immune defense against metabolic endotoxemia and reduced macrophage cholesterol efflux capacity. This led to more severe cardiovascular complications as revealed by remarkably high level of atherosclerotic lesions and the early development of cardiac dysfunction in LFHS vs HFLS fed mice. Conclusions We uncoupled obesity-associated insulin resistance from cardiovascular diseases and provided novel evidence that dietary sucrose, not fat, is the main driver of metabolic inflammation accelerating severe atherosclerosis in hyperlipidemic mice.

We carried out a genome-wide association analysis including 51,194 cases of hypothyroidism and 443,383 controls. In total, 139 risk loci were associated to hypothyroidism with genes involved in lymphocyte function. Candidate genes associated with hypothyroidism were identified by using molecular quantitative trait loci, colocalization, and enhancer-promoter chromatin looping. Mendelian randomization (MR) identified 42 blood expressed genes and circulating proteins as candidate causal molecules in hypothyroidism. Drug-gene interaction analysis provided evidence that immune checkpoint and tyrosine kinase inhibitors used in cancer therapy increase the risk of hypothyroidism. Hence, integrative mapping and MR support that expression of genes and proteins enriched in lymphocyte function are associated with the risk of hypothyroidism and provide genetic evidence for drug-induced hypothyroidism and identify actionable potential drug targets.

This study sought to evaluate whether a multimarker approach might identify patients with higher mortality and hospitalization rates after aortic valve replacement (AVR) for aortic stenosis (AS).The society valve guidelines include accepted triggers for AVR in patients with severe asymptomatic AS, but circulating biomarkers do not have a clear role.From a prospective registry of patients undergoing cardiac surgery between 2000 and 2012, 665 treated with surgical AVR (441 isolated) were evaluated. Seven biomarkers were measured on blood samples obtained before AVR. Biomarker levels were adjusted to account for the influence of age, sex, body mass index, and renal function; the median was used to determine an elevated value. Endpoints included all-cause mortality and all-cause and cardiovascular hospitalizations. Mean follow-up was 10.7 years and 299 (45%) died.Patients with 0 to 1, 2 to 3, 4 to 6, and 7 biomarkers elevated had 5-year mortality of 10%, 12%, 24%, and 33%, respectively, and 10-year mortality of 24%, 35%, 58%, and 71%, respectively (log-rank p 0.001). The association between an increasing number of elevated biomarkers and increased all-cause mortality was observed among those with minimal symptoms (New York Heart Association functional class I or II) and those with a low N-terminal pro-B-type natriuretic peptide (p 0.01 for both). Compared with those with 0 to 1 biomarkers elevated, patients with 4 to 6 or 7 biomarkers elevated had an increased hazard of mortality after adjustment for clinical risk scores (p 0.01) and a 2- to 3-fold higher rate of all-cause and cardiovascular rehospitalization after AVR. Similar findings were obtained when evaluating cardiovascular mortality. Among patients with no or minimal symptoms, 42% had ≥4 biomarkers elevated.Among patients with severe AS treated with surgical AVR, an increasing number of elevated biomarkers of cardiovascular stress was associated with higher all-cause and cardiovascular mortality and a higher rate of repeat hospitalization. A multimarker approach may be useful in the surveillance of asymptomatic patients with severe AS to optimize surgical timing.

Non-alcoholic fatty liver disease (NAFLD) is a complex disease linked with several chronic diseases. We aimed at identifying genetic variants associated with NAFLD and evaluate their functional consequences. We performed a genome-wide meta-analysis of four cohorts of electronic health record-documented NAFLD in participants of European ancestry (8434 cases and 770,180 controls). We identified five potential susceptibility loci for NAFLD (located at or near GCKR, TR1B1, MAU2/TM6SF2, APOE, and PNPLA3). We also report a potentially causal effect of lower LPL expression in adipose tissue on NAFLD susceptibility and an effect of the FTO genotype on NAFLD that is likely explained by obesity. Positive genetic correlations between NAFLD and cardiometabolic diseases and risk factors such as body fat accumulation/distribution, lipoprotein-lipid levels, insulin resistance and coronary artery disease and negative genetic correlations with parental lifespan, socio-economic status and acetoacetate levels were observed. Altogether, this large GWAS meta-analysis revealed new insights into the genetic architecture of NAFLD. Funding: Part of this study was supported by the European Union through the European Regional Development fund. The work of Estonian Genome Center, Univ. of Tartu has been supported by the European Regional Development Fund and grants No. GENTRANSMED (2014-2020.4.01.15-0012), MOBERA5 (Norface Network project no 462.16.107) and 2014-2020.4.01.16-0125. This study was also funded by the European Union through Horizon 2020 research and innovation programme under grant no 810645 and through the European Regional Development Fund project no. MOBEC008 and Estonian Research Council Grant PUT1660. Ethical Approval: This study and the use of data from 4119 cases and 190,120 controls was approved by the Research Ethics Committee of the University of Tartu (Approval number 288/M-18).

We carried out a genome-wide association analysis including 51,194 cases of hypothyroidism and 443,383 controls. In total, 139 risk loci were associated to hypothyroidism with genes involved in lymphocyte function. Candidate genes associated with hypothyroidism were identified by using molecular quantitative trait loci, colocalization and enhancer-promoter chromatin looping. Mendelian randomization (MR) identified 42 blood expressed genes and circulating proteins as candidate causal molecules in hypothyroidism. Association data identified alternative splicing variant rs6897932 increasing secreted IL7R (sIL7R). MR with multiple instruments showed that circulating sIL7R was positively associated with the risk of hypothyroidism. Drug-gene interaction analysis provided evidence that immune checkpoint and tyrosine kinase inhibitors used in cancer therapy increase the risk of hypothyroidism. Hence, integrative mapping and MR support that expression of genes and proteins enriched in lymphocyte function are associated with the risk of hypothyroidism and provide genetic evidence for drug-induced hypothyroidism and identify actionable potential drug targets.

PURPOSE/OBJECTIVE(S) Radiotherapy (RT) is an integral component of curative treatment of head and neck squamous cell carcinomas (HNSCC). Compromise of dysphagia/aspiration-related structures remains a clinically significant, and potentially life threatening, treatment complication. We hypothesized that treatment intensification might increase the long term risk of aspiration events, and investigated clinical factors contributing to this risk. MATERIALS/METHODS A single institution database of patients who received curative-intent RT for HNSCC from 1996 to 2018 was queried. Included patients had laryngeal/hypopharyngeal, oral cavity, or oropharyngeal cancers and did not experience locoregional failure. An aspiration event was defined as aspiration on modified barium swallow, or aspiration pneumonia, > 3 months after RT. 324 patients were eligible, with a median follow up of 42 months (range 4-195). Independent variables investigated included age, primary site, sex, T stage, N stage, overall stage, IMRT vs 3D RT, standard vs altered fractionation, prior vs never smoker, definitive vs post-operative RT, and the use of chemotherapy with RT. Univariate logistic regression was used to identify statistically significant risk factors and multivariate regression was then used to derive the final model. Kaplan Meier analysis was used to assess time to last aspiration event; significance was assessed via the log-rank test. RESULTS On univariate analysis patients who received chemotherapy (P = 0.007), were treated using 3D RT (P = 0.0009), or were prior smokers (P = 0.02) had a significantly increased risk of an aspiration event. No differences were seen with respect to age, sex, site, overall stage, T stage, N stage, postoperative vs definitive therapy, or fractionation. On multivariate analysis the use of chemotherapy [P = 0.004, OR 3.5 (95% CI 1.5 - 8.2)] and prior smoking [P = 0.03, OR 2.7 (95% CI 1.1 - 6.7)] remained significantly associated with increased risk, while use of IMRT significantly diminished risk [P = 0.001, OR 0.35 (0.19 - 0.35)]. In patients who received chemotherapy, the actuarial risk of aspiration via Kaplan Meier was 24% at five years, as opposed to 8% for RT alone (P = 0.007). Of the six patients who died secondary to aspiration pneumonia, five received chemotherapy with RT. CONCLUSION In this analysis the use of chemotherapy, prior smoking, and the use of 3D RT increased the odds of aspiration in patients receiving RT for HNSCC. Of note, use of chemotherapy increased this risk almost three-fold; this risk persisted long term, supporting the hypothesis that treatment intensification has a significant, persistent clinical impact on dysphagia-related structures. These data highlight the need to refine criteria for the use of chemotherapy with RT in the adjuvant setting, and support diminished dysphagia risk seen in de-intensification trials in HPV-associated oropharyngeal cancers.

Summary Non-alcoholic fatty liver disease (NAFLD) is a complex disease linked to several chronic diseases. We aimed at identifying genetic variants associated with NAFLD and evaluating their functional consequences. We performed a genome-wide meta-analysis of 4 cohorts of electronic health record-documented NAFLD in participants of European ancestry (8,434 cases and 770,180 controls). We identify 5 potential susceptibility loci for NAFLD (located at or near GCKR, TR1B1, MAU2/TM6SF2, APOE, and PNPLA3). We also report a potentially causal effect of lower LPL expression in adipose tissue on NAFLD susceptibility and an effect of the FTO genotype on NAFLD. Positive genetic correlations between NAFLD and cardiometabolic diseases and risk factors such as body fat accumulation/distribution, lipoprotein-lipid levels, insulin resistance, and coronary artery disease and negative genetic correlations with parental lifespan, socio-economic status, and acetoacetate levels are observed. This large GWAS meta-analysis reveals insights into the genetic architecture of NAFLD., Graphical abstract, Highlights This analysis identifies 5 genetic loci for non-alcoholic fatty liver disease Non-alcoholic fatty liver disease loci are GCKR, TR1B1, TM6SF2, APOE, and PNPLA3 Adipose tissue LPL expression may influence non-alcoholic fatty liver disease The FTO genotype may affect non-alcoholic fatty liver disease susceptibility, To gain insight into the genetic architecture of non-alcoholic fatty liver disease (NAFLD), Ghodsian et al. performed a genome-wide meta-analysis of electronic health record-documented NAFLD and identify 7 potential susceptibility loci for this disease (located at or near GCKR, TR1B1, LPL, FTO, MAU2/TM6SF2, APOE, and PNPLA3).

High levels of proprotein convertase subtilisin/kexin 9 (PCSK9) (>305 ng/ml) have been recently associated, along with insulin resistance and lipoprotein-associated phospholipase A2 activity, with aortic bioprosthesis calcification and able to predict hemodynamic valve deterioration [(1)][1].

Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle that associates with major adverse cardiovascular events (MACE). We examined relationships between Lp(a) measurements and changes in coronary atheroma volume following long-term maximally-intensive statin therapy in coronary artery disease patients.Study of coronary atheroma by intravascular ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. Baseline and follow-up Lp(a) levels were measured in 915 of the 1039 SATURN participants, and were correlated with changes in percent atheroma volume (ΔPAV).Mean age was 57.7 ± 8.6 years, 74% were men, 96% were Caucasian, with statin use prior to study enrolment occurring in 59.3% of participants. Baseline [median (IQR)] LDL-cholesterol (LDL-C) and measured Lp(a) levels (mg/dL) were 114 (99, 137) and 17.4 (7.6, 52.9) respectively; follow-up measures were 60 (47, 77), and 16.5 (6.7, 57.7) (change from baseline: p 0.001, p = 0.31 respectively). At baseline, there were 676 patients with Lp(a) levels50 mg/dL [median Lp(a) of 10.9 mg/dL], and 239 patients with Lp(a) levels ≥ 50 mg/dL [median Lp(a) of 83.2 mg/dL]. Quartiles of baseline and follow-up Lp(a) did not associate with ΔPAV. Irrespective of the achieved LDL-C (vs. ≥70 mg/dL), neither baseline nor on-treatment (vs. ≥median) Lp(a) levels significantly associated with ΔPAV. No significant differences were observed in ΔPAV in Lp(a) risers versus non-risers, nor in those patients with baseline or on-treatment Lp(a) levelsvs.50 mg/dL.In coronary artery disease patients prescribed long-term maximally intensive statin therapy with low on-treatment LDL-C levels, measured Lp(a) levels (predominantly below the 50 mg/dL threshold) do not associate with coronary atheroma progression. Alternative biomarkers may thus associate with residual cardiovascular risk in such patients.

Background and aims Lipoprotein(a) (Lp[a]) is a strong genetic risk factor for cardiovascular disease (CVD). The American Heart Association has prioritised seven cardiovascular health metrics to reduce the burden of CVD: body mass index, healthy diet, physical activity, smoking status, blood pressure, diabetes and cholesterol levels (together also known as ideal cardiovascular health). Our objective was to determine if individuals with high Lp(a) levels could derive cardiovascular benefits if characterized by ideal cardiovascular health. Methods A total of 14,051 participants of the EPIC-Norfolk study were stratified according to the cardiovascular health score (based on the number of health metrics with an ideal, intermediate or poor status). Of them, 1732 had a CVD event during a mean follow-up of 11.5 years. Cox proportional hazards models were used to describe the association between the cardiovascular health score and Lp(a) level or genotype (as estimated by the rs10455872 variant) with the risk of CVD. Results We observed little or no differences in serum Lp(a) levels across the seven cardiovascular health metric categories. Among participants with high serum Lp(a) levels ≥50 mg/dl), those in the highest (i.e. healthiest) cardiovascular health score category (10–14) had an adjusted hazard ratio for cardiovascular disease of 0.33 (95% CI = 0.17–0.63, p = 0.001) compared to participants in the lowest (i.e. unhealthiest) cardiovascular health score category(0–4). Similar results were obtained when we replaced Lp(a) with rs10455872. Conclusions Although Lp(a) levels are only slightly influenced by cardiovascular health metrics, an ideal cardiovascular health could substantially reduce CVD risk associated with high Lp(a) levels or genotype., Highlights • Elevated lipoprotein(a) levels is one of the strongest genetic risk factors for CVD. • Few health professionals routinely measure Lp(a) presumably because there are no therapeutic agents available to lower Lp(a). • Clinical and lifestyle-related factors do not appear to influence Lp(a) levels at the population level. • Individuals with high Lp(a) levels who control clinical and lifestyle-related risk factors have a lower risk of CVD. • Targeting clinical and lifestyle-related risk factors could reduce cardiovascular risk in individuals with high Lp(a) levels.

Background & Aim We developed a CAR T that recognizes the growth factor receptor form, MUC1*, does not bind full-length MUC1, hits a wide range of cancers and shows to little or no binding to normal tissues. No therapeutic has ever been tested in humans that targets the MUC1 transmembrane cleavage product – MUC1*. A 1st-in-human clinical trial of huMNC2-CAR44, NCT04020575, for metastatic breast cancers is underway at the Fred Hutchinson Cancer Research Center. We expect to have patient data by conference time. Methods, Results & Conclusion MUC1* is a Class I growth factor receptor that is activated when onco-embryonic growth factor NME7AB dimerizes its truncated extra cellular domain. The binding site for NME7AB is ectopic and is only unmasked after the tandem repeat domain of MUC1 is cleaved and shed from the cell surface. Unlike full-length MUC1, MUC1* has no sites for O-linked glycosylation, so antibodies such as 5E5 that bind to aberrant, trapped glycans cannot bind to the MUC1*. Anti-MUC1* antibody huMNC2 binds to the conformational epitope that is unmasked when MUC1 is cleaved to MUC1* by MMP9. MMP9 has now been linked to poor prognosis and metastasis. huMNC2 competes with onco-embryonic growth factor NME7AB for this same conformational epitope on MUC1*. Neither huMNC2 nor NME7AB binds to full-length MUC1. IHC studies of thousands of human tissues – both normal and cancerous – show that the tumor associated antigen is MUC1* and not full-length MUC1. Patient-match primary and metastases show that as cancer stage progresses the amount of MUC1* increases. huMNC2-scFv bound robustly to 95% of the breast cancers, 83% ovarian, 78% pancreatic and 71% of lung cancer tissues (specimens n>2,800). There was little to no staining of normal tissues. In vivo, huMNC2-CAR44 T cells inhibited or completely obliterated a variety of MUC1* positive solid tumors in NSG mice (n>400). If safety is demonstrated, we will file for INDs for next-gen CARs, including logic-gated CARs with increased in vivo persistence. Conclusions MUC1* is the predominant form of MUC1 on cancerous tissues. Antibodies that target a conformational epitope in the membrane-proximal MUC1* extra cellular domain are tumor selective. CAR T cells targeting MUC1* extra cellular domain are highly effective against solid tumors in animals. Robust staining of cancerous tissues and minimal to no staining of normal tissues predicts large therapeutic window for huMNC2-CAR44 T cell dosing.

Background: Elevated Lipoprotein(a) (Lp[a]) levels are associated with a broad range of atherosclerotic cardiovascular diseases (CVD). The impact of high Lp(a) levels on human longevity is however controversial. Our objectives were to determine whether genetically-determined Lp(a) levels are associated with parental lifespan and to assess the association between measured and genetically-determined Lp(a) levels and long-term all-cause and cardiovascular mortality. Methods: We determined the association between a genetic risk score of 26 single nucleotide polymorphisms weighted for their impact on Lp(a) levels (wGRS) and parental lifespan (at least one long-lived parent; father still alive and older than 90 or father’s age of death ≥90 or mother still alive and older than 93 or mother’s age of death ≥93) in 139,362 participants from the UK Biobank. A total of 17,686 participants were considered as having high parental lifespan. We also investigated the association between Lp(a) levels and all-cause and cardiovascular mortality in 18,720 participants from the EPIC-Norfolk study. Results: In the UK Biobank, increases in the wGRS (weighted for a 50 mg/dL increase in Lp(a) levels) were inversely associated with a high parental lifespan (odds ratio=0.92, 95% confidence interval [CI]=0.89-0.94, p=2.7x10-8). During the 20-year follow-up of the EPIC-Norfolk study, 5686 participants died (2412 from CVD-related causes). Compared to participants with Lp(a) levels