Publications

Adipocytes


Associate Professor of Medicine (Cardiovascular Medicine)

Publications

  • Hymecromone Promotes Longevity and Insulin Sensitivity in Mice. Cells Nagy, N., Czepiel, K. S., Kaber, G., Stefanovski, D., Hargil, A., Pennetzdorfer, N., Targ, R., Reghupaty, S. C., Wight, T. N., Vernon, R. B., Hull-Meichle, R. L., Marshall, P., Medina, C. O., Martinez, H., Kalinowski, A., Paladini, R. D., Garantziotis, S., Knowles, J. W., Bollyky, P. L. 2024; 13 (20)

    Abstract

    Given that the extracellular matrix polymer hyaluronan (HA) has been implicated in longevity, we asked whether 4-methylumbelliferone (4-MU), an inhibitor of HA synthesis, impacts lifespan in mice. We designed a prospective study of long-term administration of 4-MU with conventional C57BL/6J mice. We find that 4-MU extends median survival from 122 weeks (control) to 154 weeks (4-MU), an increase of 32 weeks (p < 0.0001 by Log-rank Mantel Cox test). The maximum lifespan of 4-MU treated mice increased from 159 to 194 weeks. In tandem with these effects, 4-MU enhances insulin sensitivity, a metabolic parameter known to regulate lifespan, as measured by insulin tolerance testing (ITT) as well as frequent sampling intra venous glucose tolerance tests (FSIVGTTs). We further observed that 4-MU treated mice weigh less while consuming the same amount of food, indicating that 4-MU treatment alters energy expenditure. However, we do not observe changes in tissue HA content in this model. We conclude that 4-MU promotes insulin sensitivity and longevity but that the underlying mechanism, and the contribution of HA is unclear. 4-MU, already approved in various countries for hepatobiliary conditions, is currently under investigation and clinical development as a therapy for several chronic inflammatory conditions. These data suggest that the beneficial effects of 4-MU on tissue metabolism may include effects on longevity.

    View details for DOI 10.3390/cells13201727

    View details for PubMedID 39451245

  • One-year real-world experience with mavacamten and its physiologic effects on obstructive hypertrophic cardiomyopathy FRONTIERS IN CARDIOVASCULAR MEDICINE Kim, D., Chu, E. L., Keamy-Minor, E. E., Paranjpe, I., Tang, W. L., O'Sullivan, J. W., Desai, Y. B., Liu, M. B., Munsey, E., Hecker, K., Cuenco, I., Kao, B., Bacolor, E., Bonnett, C., Linder, A., Lacar, K., Robles, N., Lamendola, C., Smith, A., Knowles, J. W., Perez, M. V., Kawana, M., Sallam, K. I., Weldy, C. S., Wheeler, M. T., Parikh, V. N., Salisbury, H., Ashley, E. A., Stanford Ctr Inherited Cardiovasc Dis 2024; 11
  • One-year real-world experience with mavacamten and its physiologic effects on obstructive hypertrophic cardiomyopathy. Frontiers in cardiovascular medicine Kim, D. S., Chu, E. L., Keamy-Minor, E. E., Paranjpe, I. D., Tang, W. L., O'Sullivan, J. W., Desai, Y. B., Liu, M. B., Munsey, E., Hecker, K., Cuenco, I., Kao, B., Bacolor, E., Bonnett, C., Linder, A., Lacar, K., Robles, N., Lamendola, C., Smith, A., Knowles, J. W., Perez, M. V., Kawana, M., Sallam, K. I., Weldy, C. S., Wheeler, M. T., Parikh, V. N., Salisbury, H., Ashley, E. A. 2024; 11: 1429230

    Abstract

    Mavacamten is a first-in-class cardiac myosin ATPase inhibitor, approved by the United States Food and Drug Administration for the treatment of hypertrophic cardiomyopathy with obstructive physiology (oHCM). Here, we present the real-world use of mavacamten in 50 patients with oHCM at a tertiary care referral center. In both our highlighted case and in our aggregate data, we report significant improvement in wall thickness, mitral regurgitation, left ventricular outflow tract obstruction and New York Heart Association symptom class. Moreover, in our center's experience, neither arrhythmia burden, nor contractility have worsened in the vast majority of patients: we note a clinically insignificant mean decrease in left ventricular ejection fraction (LVEF), with only two patients requiring temporary mavacamten discontinuance for LVEF < 50%. Adverse events were rare, unrelated to mavacamten itself, and seen solely in patients with disease too advanced to have been represented in clinical trials. Moreover, our multidisciplinary pathway enabled us to provide a large number of patients with a novel closely-monitored therapeutic within just a few months of commercial availability. These data lead us to conclude that mavacamten, as a first-in-class cardiac myosin inhibitor, is safe and efficacious in real-world settings.

    View details for DOI 10.3389/fcvm.2024.1429230

    View details for PubMedID 39314763

    View details for PubMedCentralID PMC11417615

  • A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes. Hepatology (Baltimore, Md.) Saliba-Gustafsson, P., Justesen, J. M., Ranta, A., Sharma, D., Bielczyk-Maczynska, E., Li, J., Najmi, L. A., Apodaka, M., Aspichueta, P., Björck, H. M., Eriksson, P., Schurr, T. M., Franco-Cereceda, A., Gloudemans, M., Mujica, E., den Hoed, M., Assimes, T. L., Quertermous, T., Carcamo-Orive, I., Park, C. Y., Knowles, J. W. 2024

    Abstract

    Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD.We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD.Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies.

    View details for DOI 10.1097/HEP.0000000000001066

    View details for PubMedID 39190705

  • Loss of RREB1 reduces adipogenesis and improves insulin sensitivity in mouse and human adipocytes. bioRxiv : the preprint server for biology Yu, G. Z., Krentz, N. A., Bentley, L., Zhao, M., Paphiti, K., Sun, H., Honecker, J., Nygård, M., Dashti, H., Bai, Y., Reid, M., Thaman, S., Wabitsch, M., Rajesh, V., Yang, J., Mattis, K. K., Abaitua, F., Casero, R., Hauner, H., Knowles, J. W., Wu, J. Y., Mandrup, S., Claussnitzer, M., Svensson, K. J., Cox, R. D., Gloyn, A. L. 2024

    Abstract

    There are multiple independent genetic signals at the Ras-responsive element binding protein 1 (RREB1) locus associated with type 2 diabetes risk, fasting glucose, ectopic fat, height, and bone mineral density. We have previously shown that loss of RREB1 in pancreatic beta cells reduces insulin content and impairs islet cell development and function. However, RREB1 is a widely expressed transcription factor and the metabolic impact of RREB1 loss in vivo remains unknown. Here, we show that male and female global heterozygous knockout (Rreb1 +/-) mice have reduced body length, weight, and fat mass on high-fat diet. Rreb1+/- mice have sex- and diet-specific decreases in adipose tissue and adipocyte size; male mice on high-fat diet had larger gonadal adipocytes, while males on standard chow and females on high-fat diet had smaller, more insulin sensitive subcutaneous adipocytes. Mouse and human precursor cells lacking RREB1 have decreased adipogenic gene expression and activated transcription of genes associated with osteoblast differentiation, which was associated with Rreb1 +/- mice having increased bone mineral density in vivo. Finally, human carriers of RREB1 T2D protective alleles have smaller adipocytes, consistent with RREB1 loss-of-function reducing diabetes risk.

    View details for DOI 10.1101/2024.07.30.605923

    View details for PubMedID 39131393

    View details for PubMedCentralID PMC11312556

  • X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction. Nature communications Zhang, P., Munier, J. J., Wiese, C. B., Vergnes, L., Link, J. C., Abbasi, F., Ronquillo, E., Scheker, K., Muñoz, A., Kuang, Y. L., Theusch, E., Lu, M., Sanchez, G., Oni-Orisan, A., Iribarren, C., McPhaul, M. J., Nomura, D. K., Knowles, J. W., Krauss, R. M., Medina, M. W., Reue, K. 2024; 15 (1): 5571

    Abstract

    Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

    View details for DOI 10.1038/s41467-024-49764-2

    View details for PubMedID 38956041

    View details for PubMedCentralID 6047411

  • Generation of two familial hypercholesterolemia patient-specific induced pluripotent stem cell lines harboring heterozygous mutations in the LDLR gene. Stem cell research Gao, J., Li, J., Xu, L., Yan, C. D., Knowles, J. W., Wu, J. C. 2024; 78: 103463

    Abstract

    Familial hypercholesterolemia (FH) is a genetic disorder affecting the metabolism of lipoprotein, characterized by elevated levels of plasma concentrations of low-density lipoprotein cholesterol (LDLC). The most common FH cause is mutations within the gene that encodes for the LDL receptor (LDLR) protein. Two induced pluripotent stem cell (iPSC) lines were generated from patients with FH, each carrying a single heterozygous mutation in the LDLR gene, one is a missense mutation, c.631C > T, and the other is a splice-site mutation, c.313 + 1G > A. Both iPSC lines exhibited strong expression of pluripotency markers, demonstrated the ability to differentiate into derivatives of the three germ layers, and maintained normal karyotypes. These derived iPSC lines represent powerful tools for in vitro modeling FH and offer a promising platform for therapeutic development.

    View details for DOI 10.1016/j.scr.2024.103463

    View details for PubMedID 38852422

  • Design and Pilot Results from Million Veteran Program Return Of Actionable Genetic Results (MVP-ROAR) Study. American heart journal Vassy, J. L., Brunette, C. A., Yi, T., Harrison, A., Cardellino, M. P., Assimes, T. L., Christensen, K. D., Devineni, P., Gaziano, J. M., Gong, X., Hui, Q., Knowles, J. W., Muralidhar, S., Natarajan, P., Pyarajan, S., Sears, M. G., Shi, Y., Sturm, A. C., Whitbourne, S. B., Sun, Y. V., Danowski, M. E. 2024

    Abstract

    As a mega-biobank linked to a national healthcare system, the Million Veteran Program (MVP) can directly improve the health care of participants. To determine the feasibility and outcomes of returning medically actionable genetic results to MVP participants, the program launched the MVP Return Of Actionable Results (MVP-ROAR) Study, with familial hypercholesterolemia (FH) as an exemplar actionable condition.The MVP-ROAR Study consists of a completed single-arm pilot phase and an ongoing randomized clinical trial (RCT), in which MVP participants are recontacted and invited to receive clinical confirmatory gene sequencing testing and a telegenetic counseling intervention. The primary outcome of the RCT is 6-month change in low-density lipoprotein cholesterol (LDL-C) between participants receiving results at baseline and those receiving results after 6 months.The pilot developed processes to identify and recontact participants nationally with probable pathogenic variants in low-density lipoprotein receptor (LDLR) on the MVP genotype array, invite them to clinical confirmatory gene sequencing, and deliver a telegenetic counseling intervention. Among participants in the pilot phase, 8 (100%) had active statin prescriptions after 6 months. Results were shared with 16 first-degree family members. Six-month ΔLDL-C (low-density lipoprotein cholesterol) after the genetic counseling intervention was -37 mg/dL (95% CI: -12 to -61; p=0.03). The ongoing RCT will determine between-arm differences in this primary outcome.While underscoring the importance of clinical confirmation of research results, the pilot phase of the MVP-ROAR Study marks a turning point in MVP and demonstrates the feasibility of returning genetic results to participants and their providers. The ongoing RCT will contribute to understanding how such a program might improve patient health care and outcomes.

    View details for DOI 10.1016/j.ahj.2024.04.021

    View details for PubMedID 38762090

  • Chemerin in Participants with or without Insulin Resistance and Diabetes. Biomedicines Zhao, L., Zhou, J., Abbasi, F., Fathzadeh, M., Knowles, J. W., Leung, L. L., Morser, J. 2024; 12 (4)

    Abstract

    Chemerin is a chemokine/adipokine, regulating inflammation, adipogenesis and energy metabolism whose activity depends on successive proteolytic cleavages at its C-terminus. Chemerin levels and processing are correlated with insulin resistance. We hypothesized that chemerin processing would be higher in individuals with type 2 diabetes (T2D) and in those who are insulin resistant (IR). This hypothesis was tested by characterizing different chemerin forms by specific ELISA in the plasma of 18 participants with T2D and 116 without T2D who also had their insulin resistance measured by steady-state plasma glucose (SSPG) concentration during an insulin suppression test. This approach enabled us to analyze the association of chemerin levels with a direct measure of insulin resistance (SSPG concentration). Participants were divided into groups based on their degree of insulin resistance using SSPG concentration tertiles: insulin sensitive (IS, SSPG ≤ 91 mg/dL), intermediate IR (IM, SSPG 92-199 mg/dL), and IR (SSPG ≥ 200 mg/dL). Levels of different chemerin forms were highest in patients with T2D, second highest in individuals without T2D who were IR, and lowest in persons without T2D who were IM or IS. In the whole group, chemerin levels positively correlated with both degree of insulin resistance (SSPG concentration) and adiposity (BMI). Participants with T2D and those without T2D who were IR had the most proteolytic processing of chemerin, resulting in higher levels of both cleaved and degraded chemerin. This suggests that increased inflammation in individuals who have T2D or are IR causes more chemerin processing.

    View details for DOI 10.3390/biomedicines12040924

    View details for PubMedID 38672278

    View details for PubMedCentralID PMC11048116

  • Development and utility of a clinical research informatics application for participant recruitment and workflow management for a return of results pilot trial in familial hypercholesterolemia in the Million Veteran Program. JAMIA open Brunette, C. A., Yi, T., Danowski, M. E., Cardellino, M., Harrison, A., Assimes, T. L., Knowles, J. W., Christensen, K. D., Sturm, A. C., Sun, Y. V., Hui, Q., Pyarajan, S., Shi, Y., Whitbourne, S. B., Gaziano, J. M., Muralidhar, S., Vassy, J. L. 2024; 7 (1): ooae020

    Abstract

    Objective: The development of clinical research informatics tools and workflow processes associated with re-engaging biobank participants has become necessary as genomic repositories increasingly consider the return of actionable research results.Materials and Methods: Here we describe the development and utility of an informatics application for participant recruitment and enrollment management for the Veterans Affairs Million Veteran Program Return Of Actionable Results Study, a randomized controlled pilot trial returning individual genetic results associated with familial hypercholesterolemia.Results: The application is developed in Python-Flask and was placed into production in November 2021. The application includes modules for chart review, medication reconciliation, participant contact and biospecimen logging, survey recording, randomization, and documentation of genetic counseling and result disclosure. Three primary users, a genetic counselor and two research coordinators, and 326 Veteran participants have been integrated into the system as of February 23, 2023. The application has successfully handled 3367 task requests involving greater than 95000 structured data points. Specifically, application users have recorded 326 chart reviews, 867 recruitment telephone calls, 158 telephone-based surveys, and 61 return of results genetic counseling sessions, among other available study tasks.Conclusion: The development of usable, customizable, and secure informatics tools will become increasingly important as large genomic repositories begin to return research results at scale. Our work provides a proof-of-concept for developing and using such tools to aid in managing the return of results process within a national biobank.

    View details for DOI 10.1093/jamiaopen/ooae020

    View details for PubMedID 38464744

  • Is it time for a paradigm shift? Inclusion of APOE on genetic dyslipidemia panels. Journal of genetic counseling Ison, H. E., Mowaswes, M., Durst, R., Leucker, T., Knowles, J. W., Brown, E. E. 2024

    Abstract

    APOE codes for apolipoprotein E (ApoE), which plays an important role in lipid and lipoprotein metabolism and homeostasis of tissue lipid content. Several variants in APOE have been associated with inherited dyslipidemias, and a subsequent increased risk of developing premature coronary artery disease (CAD). However, these variants and their impact on risk can be thought of on a spectrum, with some being more monogenic in nature, and others contributing in a polygenic/multifactorial manner. Despite these known associations, there is often hesitancy around ordering APOE genetic testing due to the association with Alzheimer's disease. This paper aims to catalyze discussion around APOE testing and counseling strategies, highlight the nuances around this topic, and advocate for inclusion of APOE testing on dyslipidemia panels when an inherited dyslipidemia is suspected.

    View details for DOI 10.1002/jgc4.1889

    View details for PubMedID 38549201

  • Lac-Phe mediates the effects of metformin on food intake and body weight. Nature metabolism Xiao, S., Li, V. L., Lyu, X., Chen, X., Wei, W., Abbasi, F., Knowles, J. W., Tung, A. S., Deng, S., Tiwari, G., Shi, X., Zheng, S., Farrell, L., Chen, Z. Z., Taylor, K. D., Guo, X., Goodarzi, M. O., Wood, A. C., Chen, Y. I., Lange, L. A., Rich, S. S., Rotter, J. I., Clish, C. B., Tahir, U. A., Gerszten, R. E., Benson, M. D., Long, J. Z. 2024

    Abstract

    Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin's effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts. Metformin drives Lac-Phe biosynthesis through the inhibition of complex I, increased glycolytic flux and intracellular lactate mass action. Intestinal epithelial CNDP2+ cells, not macrophages, are the principal in vivo source of basal and metformin-inducible Lac-Phe. Genetic ablation of Lac-Phe biosynthesis in male mice renders animals resistant to the effects of metformin on food intake and body weight. Lastly, mediation analyses support a role for Lac-Phe as a downstream effector of metformin's effects on body mass index in participants of a large population-based observational cohort, the Multi-Ethnic Study of Atherosclerosis. Together, these data establish Lac-Phe as a critical mediator of the body weight-lowering effects of metformin.

    View details for DOI 10.1038/s42255-024-00999-9

    View details for PubMedID 38499766

    View details for PubMedCentralID 6829283

  • Generation of two induced pluripotent stem cell lines from healthy patients of African American ancestry. Stem cell research Mullen, M., Kojic, A., Alamana, C., Canel, G., Lai, C., Knowles, J. W., Wu, J. C. 2024; 76: 103322

    Abstract

    Stem cells are a resourceful tool for investigating cardiovascular disease in the context of race and gender. Once derived from blood or skin cells, the reprogrammed induced pluripotent stem cells (iPSCs) adopt an embryonic-like pluripotent state, enabling researchers to develop drug screening or disease modeling platforms. Here, we generated two iPSC lines from peripheral blood mononuclear cells (PBMCs) of two healthy African American patients. Both lines display the usual morphology of pluripotent stem cells, demonstrate elevated expression of pluripotent markers, show normal karyotype, and differentiate into all three germ layers in vitro.

    View details for DOI 10.1016/j.scr.2024.103322

    View details for PubMedID 38359472

  • A functional genomic framework to elucidate novel causal non-alcoholic fatty liver disease genes. medRxiv : the preprint server for health sciences Saliba-Gustafsson, P., Justesen, J. M., Ranta, A., Sharma, D., Bielczyk-Maczynska, E., Li, J., Najmi, L. A., Apodaka, M., Aspichueta, P., Björck, H. M., Eriksson, P., Franco-Cereceda, A., Gloudemans, M., Mujica, E., den Hoed, M., Assimes, T. L., Quertermous, T., Carcamo-Orive, I., Park, C. Y., Knowles, J. W. 2024

    Abstract

    Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for NAFLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using NAFLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of NAFLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for NAFLD.We used the UK Biobank to explore the associations of our novel NAFLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study NAFLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of NAFLD.Complementary genetic and genomic approaches are useful for the identification of NAFLD genes. Our data supports VKORC1 as a bona fide NAFLD gene. We have established a functional genomic framework to study at scale putative novel NAFLD genes from human genetic association studies.

    View details for DOI 10.1101/2024.02.03.24302258

    View details for PubMedID 38352379

    View details for PubMedCentralID PMC10863038

  • Trends of Lipid Concentrations, Awareness, Evaluation, and Treatment in Severe Dyslipidemia in US Adults. Mayo Clinic proceedings Shetty, N. S., Gaonkar, M., Patel, N., Knowles, J. W., Natarajan, P., Arora, G., Arora, P. 2024

    Abstract

    To evaluate the contemporary trends of lipid concentrations, cholesterol evaluation, hypercholesterolemia awareness, and statin use among individuals with severe dyslipidemia (low-density lipoprotein cholesterol [LDL-C] level ≥190 mg/dL) between 2011 and 2020.This serial cross-sectional analysis included nonpregnant adults ≥20 years of age from the National Health and Nutrition Examination Survey between 2011 and 2020. Age-adjusted weighted trends of LDL-C, triglycerides, cholesterol evaluation in the past 5 years, hypercholesterolemia awareness, and documented statin use among individuals with severe dyslipidemia were estimated.Among 24,722 participants included, the prevalence of severe dyslipidemia was 5.4% (SE: 0.2%) which was stable across the study period (Ptrend=.78). Among individuals with severe dyslipidemia (mean age: 55.3 [SE: 0.7] years; 52.2% females; 68.8% non-Hispanic White), LDL-C (224.3 [SE: 4.2] mg/dL in 2011-2012 to 224.2 [SE: 4.6] mg/dL in 2017-2020; Ptrend =.83), and triglyceride (123.3 [SE: 1.1] mg/dL in 2011-2012 to 101.8 [SE: 1.1] mg/dL in 2017-2020; Ptrend=.13), levels remained stable from 2011 to 2020. The rates of cholesterol evaluation in the past 5 years (72.0% [SE: 5.7%] in 2011-2012 to 78.0% [SE: 4.8%] in 2017-2020; Ptrend=.91), hypercholesterolemia awareness (48.1% [SE: 5.5%] in 2011-2012 to 51.9% [SE: 5.8%] in 2017- 2020; Ptrend=.77), and documented statin use (34.7% [SE: 4.5%] in 2011-2012 to 33.4% [SE: 4.0%] in 2017-2020; Ptrend=.28) remained stagnant in individuals with severe dyslipidemia between 2011 and 2020.Among individuals with severe dyslipidemia, cholesterol evaluation and hypercholesterolemia awareness rates were stable at ∼75% and ∼50% in the past decade. Only ∼34% of individuals with severe dyslipidemia took statins between 2011 and 2020, which likely contributed to the stable LDL-C levels noted across the study period. Further investigations into the determinants of statin use and adherence to statins are needed.

    View details for DOI 10.1016/j.mayocp.2023.09.016

    View details for PubMedID 38189687

  • Impact of Virtual Interviewing on Cardiovascular Fellowship Applicant Diversity: Insights From 2 Academic Programs. Journal of the American Heart Association Witting, C., Knowles, J. W., DeFaria Yeh, D., Beyene, T. J., Gummipundi, S. E., Heidenreich, P. A., Yong, C. M. 2023: e030255

    View details for DOI 10.1161/JAHA.123.030255

    View details for PubMedID 38156448

  • RNA Interference Therapy Targeting Apolipoprotein C-III in Hypertriglyceridemia. NEJM evidence Gaudet, D., Clifton, P., Sullivan, D., Baker, J., Schwabe, C., Thackwray, S., Scott, R., Hamilton, J., Given, B., Melquist, S., Zhou, R., Chang, T., San Martin, J., Watts, G. F., Goldberg, I. J., Knowles, J. W., Hegele, R. A., Ballantyne, C. M. 2023; 2 (12): EVIDoa2200325

    Abstract

    APOC3-Targeting RNAi for HypertriglyceridemiaThis randomized controlled trial examined the safety and side effects of the small interfering RNA ARO-APOC3 in healthy volunteers and patients with hypertriglyceridemia and chylomicronemia. ARO-APOC3 was associated with few adverse events and no dose-limiting toxicities.

    View details for DOI 10.1056/EVIDoa2200325

    View details for PubMedID 38320498

  • USPSTF Recommendation on Screening for Lipid Disorders in Children and Adolescents. JAMA Wilemon, K., Knowles, J. W., Baum, S. J. 2023; 330 (20): 2024

    View details for DOI 10.1001/jama.2023.20446

    View details for PubMedID 38015224

  • Lac-Phe mediates the anti-obesity effect of metformin. bioRxiv : the preprint server for biology Xiao, S., Li, V. L., Lyu, X., Chen, X., Wei, W., Abbasi, F., Knowles, J. W., Deng, S., Tiwari, G., Shi, X., Zheng, S., Farrell, L., Chen, Z. Z., Taylor, K. D., Guo, X., Goodarzi, M. O., Wood, A. C., Ida Chen, Y. D., Lange, L. A., Rich, S. S., Rotter, J. I., Clish, C. B., Tahir, U. A., Gerszten, R. E., Benson, M. D., Long, J. Z. 2023

    Abstract

    Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformin's effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levels in vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformin's anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformin's effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

    View details for DOI 10.1101/2023.11.02.565321

    View details for PubMedID 37961394

    View details for PubMedCentralID PMC10635077

  • Another Use for Polygenic Risk Scores: Improving Risk Prediction for Heterozygous Familial Hypercholesterolemia. JACC. Advances Palmisano, B. T., Knowles, J. W. 2023; 2 (9): 100663

    View details for DOI 10.1016/j.jacadv.2023.100663

    View details for PubMedID 38938727

    View details for PubMedCentralID PMC11198439

  • Principles for Health Information Collection, Sharing, and Use: A Policy Statement From the American Heart Association CIRCULATION Spector-Bagdady, K., Armoundas, A. A., Arnaout, R., Hall, J. L., McSwain, B., Knowles, J. W., Price, W., Rawat, D. B., Riegel, B., Wang, T. Y., Wiley, K., Chung, M. K., Amer Heart Assoc Advocacy Coor 2023; 148 (13): 1061-1069

    Abstract

    The evolution of the electronic health record, combined with advances in data curation and analytic technologies, increasingly enables data sharing and harmonization. Advances in the analysis of health-related and health-proxy information have already accelerated research discoveries and improved patient care. This American Heart Association policy statement discusses how broad data sharing can be an enabling driver of progress by providing data to develop, test, and benchmark innovative methods, scalable insights, and potential new paradigms for data storage and workflow. Along with these advances come concerns about the sensitive nature of some health data, equity considerations about the involvement of historically excluded communities, and the complex intersection of laws attempting to govern behavior. Data-sharing principles are therefore necessary across a wide swath of entities, including parties who collect health information, funders, researchers, patients, legislatures, commercial companies, and regulatory departments and agencies. This policy statement outlines some of the key equity and legal background relevant to health data sharing and responsible management. It then articulates principles that will guide the American Heart Association's engagement in public policy related to data collection, sharing, and use to continue to inform its work across the research enterprise, as well as specific examples of how these principles might be applied in the policy landscape. The goal of these principles is to improve policy to support the use or reuse of health information in ways that are respectful of patients and research participants, equitable in impact in terms of both risks and potential benefits, and beneficial across broad and demographically diverse communities in the United States.

    View details for DOI 10.1161/CIR.0000000000001173

    View details for Web of Science ID 001072138200013

    View details for PubMedID 37646159

  • RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts. Nature medicine Watts, G. F., Schwabe, C., Scott, R., Gladding, P. A., Sullivan, D., Baker, J., Clifton, P., Hamilton, J., Given, B., Melquist, S., Zhou, R., Chang, T., San Martin, J., Gaudet, D., Goldberg, I. J., Knowles, J. W., Hegele, R. A., Ballantyne, C. M. 2023

    Abstract

    Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. Systemic absorption of ARO-ANG3 in healthy participants was rapid and sustained, with a mean Tmax of 6.0-10.5h and clearance from plasma within 24-48h after dosing with a mean t of 3.9-6.6h. In healthy participants, ARO-ANG3 treatment reduced ANGPTL3 (mean -45% to -78%) 85days after dose. Reductions in triglyceride (median -34% to -54%) and non-HDL-C (mean -18% to -29%) (exploratory endpoints) concentrations occurred with the three highest doses. These early-phase data support ANGPTL3 as a potential therapeutic target for ASCVD treatment. ClinicalTrials.gov identifier: NCT03747224.

    View details for DOI 10.1038/s41591-023-02494-2

    View details for PubMedID 37626170

  • ARO-ANG3, AN INVESTIGATIONAL RNAI THERAPEUTIC, DECREASES SERUM LDL-CHOLESTEROL, APOLIPOPROTEIN B, AND ANGIOPOIETIN-LIKE PROTEIN 3 IN PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLAEMIA Raal, F., Bergeron, J., Watts, G., Gaudet, D., Sullivan, D., Turner, T., Hegele, R., Ballantyne, C., Knowles, J., Goldberg, I., Fu, R., Alagarsamy, S., Hamilton, J., Rosenson, R. ELSEVIER IRELAND LTD. 2023
  • A single-cell CRISPRi platform for characterizing candidate genes relevant to metabolic disorders in human adipocytes. American journal of physiology. Cell physiology Bielczyk-Maczynska, E., Sharma, D., Blencowe, M., Saliba Gustafsson, P., Gloudemans, M. J., Yang, X., Carcamo-Orive, I., Wabitsch, M., Svensson, K. J., Park, C. Y., Quertermous, T., Knowles, J. W., Li, J. 2023

    Abstract

    CROP-Seq combines gene silencing using CRISPR interference with single-cell RNA sequencing. Here, we applied CROP-Seq to study adipogenesis and adipocyte biology. Human preadipocyte SGBS cell line expressing KRAB-dCas9 was transduced with a sgRNA library. Following selection, individual cells were captured using microfluidics at different timepoints during adipogenesis. Bioinformatic analysis of transcriptomic data was used to determine the knock-down effects, the dysregulated pathways, and to predict cellular phenotypes. Single-cell transcriptomes recapitulated adipogenesis states. For all targets, over 400 differentially expressed genes were identified at least at one timepoint. As a validation of our approach, the knock-down of PPARG and CEBPB (which encode key proadipogenic transcription factors) resulted in the inhibition of adipogenesis. Gene set enrichment analysis generated hypotheses regarding the molecular function of novel genes. MAFF knock-down led to downregulation of transcriptional response to proinflammatory cytokine TNF-α in preadipocytes and to decreased CXCL-16 and IL-6 secretion. TIPARP knock-down resulted in increased expression of adipogenesis markers. In summary, this powerful, hypothesis-free tool can identify novel regulators of adipogenesis, preadipocyte and adipocyte function associated with metabolic disease.

    View details for DOI 10.1152/ajpcell.00148.2023

    View details for PubMedID 37486064

  • Plasma proteomic signatures of a direct measure of insulin sensitivity in two population cohorts. Diabetologia Zanetti, D., Stell, L., Gustafsson, S., Abbasi, F., Tsao, P. S., Knowles, J. W., Zethelius, B., Ärnlöv, J., Balkau, B., Walker, M., Lazzeroni, L. C., Lind, L., Petrie, J. R., Assimes, T. L. 2023

    Abstract

    The euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC.We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R2).A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R2 0.444 [0.391, 0.497]; ULSAM to RISC R2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2.A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences.

    View details for DOI 10.1007/s00125-023-05946-z

    View details for PubMedID 37329449

    View details for PubMedCentralID 5866840

  • Single-cell transcriptome dataset of human and mouse in vitro adipogenesis models. Scientific data Li, J., Jin, C., Gustafsson, S., Rao, A., Wabitsch, M., Park, C. Y., Quertermous, T., Knowles, J. W., Bielczyk-Maczynska, E. 2023; 10 (1): 387

    Abstract

    Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on these widely used in vitro models of human and mouse adipogenesis, and on cell-to-cell variability during this process.

    View details for DOI 10.1038/s41597-023-02293-x

    View details for PubMedID 37328521

    View details for PubMedCentralID 2597101

  • Contemporary Homozygous Familial Hypercholesterolemia in the United States: Insights From the CASCADE FH Registry. Journal of the American Heart Association Cuchel, M., Lee, P. C., Hudgins, L. C., Duell, P. B., Ahmad, Z., Baum, S. J., Linton, M. F., de Ferranti, S. D., Ballantyne, C. M., Larry, J. A., Hemphill, L. C., Kindt, I., Gidding, S. S., Martin, S. S., Moriarty, P. M., Thompson, P. P., Underberg, J. A., Guyton, J. R., Andersen, R. L., Whellan, D. J., Benuck, I., Kane, J. P., Myers, K., Howard, W., Staszak, D., Jamison, A., Card, M. C., Bourbon, M., Chora, J. R., Rader, D. J., Knowles, J. W., Wilemon, K., McGowan, M. P. 2023: e029175

    Abstract

    Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.

    View details for DOI 10.1161/JAHA.122.029175

    View details for PubMedID 37119068

  • Single-cell transcriptome dataset of human and mouse in vitro adipogenesis models. bioRxiv : the preprint server for biology Li, J., Jin, C., Gustafsson, S., Rao, A., Wabitsch, M., Park, C. Y., Quertermous, T., Bielczyk-Maczynska, E., Knowles, J. W. 2023

    Abstract

    Adipogenesis is a process in which fat-specific progenitor cells (preadipocytes) differentiate into adipocytes that carry out the key metabolic functions of the adipose tissue, including glucose uptake, energy storage, and adipokine secretion. Several cell lines are routinely used to study the molecular regulation of adipogenesis, in particular the immortalized mouse 3T3-L1 line and the primary human Simpson-Golabi-Behmel syndrome (SGBS) line. However, the cell-to-cell variability of transcriptional changes prior to and during adipogenesis in these models is not well understood. Here, we present a single-cell RNA-Sequencing (scRNA-Seq) dataset collected before and during adipogenic differentiation of 3T3-L1 and SGBS cells. To minimize the effects of experimental variation, we mixed 3T3-L1 and SGBS cells and used computational analysis to demultiplex transcriptomes of mouse and human cells. In both models, adipogenesis results in the appearance of three cell clusters, corresponding to preadipocytes, early and mature adipocytes. These data provide a groundwork for comparative studies on human and mouse adipogenesis, as well as on cell-to-cell variability in gene expression during this process.

    View details for DOI 10.1101/2023.03.27.534456

    View details for PubMedID 37034809

    View details for PubMedCentralID PMC10081256

  • The relationship between insulin resistance and ion mobility lipoprotein fractions. American journal of preventive cardiology Rowland, C. M., Abbasi, F., Shiffman, D., Knowles, J. W., McPhaul, M. J. 2023; 13: 100457

    Abstract

    Objective: Insulin resistance (IR) increases risk of type 2 diabetes and atherosclerotic cardiovascular disease and is associated with lipid and lipoprotein abnormalities including high triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C). Lipoprotein size and lipoprotein subfractions (LS) have also been used to assist in identifying persons with IR. Associations of LS and IR have not been validated using both direct measures of IR and direct measures of LS. We assessed the usefulness of fasting lipoprotein subfractions (LS) by ion mobility to identify individuals with IR.Methods: Lipid panel, LS by ion mobility (LS-IM), and IR by steady-state plasma glucose (SSPG) concentration were assessed in 526 adult volunteers without diabetes. IR was defined as being in the highest tertile of SSPG concentration. LS-IM score was calculated by linear combination of regression coefficients from a stepwise regression analysis with SSPG concentration as the dependent variable. Improvement in prediction of IR was evaluated after combining LS-IM score with TG/HDL-C, TG/HDL-C and BMI as well as with TG/HDL-C, BMI, sex, race and ethnicity. IR prediction was evaluated by area under the receiver operating characteristic curve (AUC) and positive predictive value (PPV) considering the highest 5% of scores as positive test.Results: Prediction of IR was similar by LS-IM score and TG/HDL-C (AUC=0.68; PPV=0.59 and AUC=0.70; PPV=0.59, respectively) and prediction was improved when LS-IM was combined with TG/HDL-C (AUC=0.73; PPV=0.70), TG/HDL-C and BMI (AUC=0.82; PPV=0.81) and with TG/HDL-C, BMI, sex, race and ethnicity (AUC=0.84; PPV=0.89).Conclusion: For identifying individuals with IR, LS-IM score and TG/HDL-C are comparable and their combination further improves IR prediction by TG/HDL-C alone. Among patients who have undergone IM testing, the LS-IM score may assist prioritization of subjects for further evaluation and interventions to reduce IR.

    View details for DOI 10.1016/j.ajpc.2022.100457

    View details for PubMedID 36619297

  • G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis. Nature communications Bielczyk-Maczynska, E., Zhao, M., Zushin, P. H., Schnurr, T. M., Kim, H. J., Li, J., Nallagatla, P., Sangwung, P., Park, C. Y., Cornn, C., Stahl, A., Svensson, K. J., Knowles, J. W. 2022; 13 (1): 7408

    Abstract

    Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes. Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. In this work, we establish a previously unknown role of Gpr151 in the liver that provides an explanation to the lowered type 2 diabetes risk in individuals with nonsynonymous mutations in GPR151.

    View details for DOI 10.1038/s41467-022-35069-9

    View details for PubMedID 36456565

    View details for PubMedCentralID 508922

  • Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity (vol 20, pg 518, 2017) CELL STEM CELL Carcamo-Orive, I., Hoffman, G. E., Cundiff, P., Beckmann, N. D., D'Souza, S. L., Knowles, J. W., Patel, A., Hendry, C., Papatsenko, D., Abbasi, F., Reaven, G. M., Whalen, S., Lee, P., Shahbazi, M., Henrion, M. R., Zhu Kuixi, Wang, S., Roussos, P., Schadt, E. E., Pandey, G., Chang Rui, Quertermous, T., Lemischka, I. 2022; 29 (10): 1505

    View details for DOI 10.1016/j.stem.2022.08.011

    View details for Web of Science ID 000880132100009

    View details for PubMedID 36206733

  • Chronic liver disease-related mortality in diabetes before and during the COVID-19 in the United States. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver Kim, D., Alshuwaykh, O., Dennis, B. B., Cholankeril, G., Knowles, J. W., Ahmed, A. 2022

    Abstract

    BACKGROUND: Global pandemic of COVID-19 represents an unprecedented challenge. COVID-19 has predominantly targeted vulnerable populations with pre-existing chronic medical diseases, such as diabetes and chronic liver disease.AIMS: We estimated chronic liver disease-related mortality trends among individuals with diabetes before and during the COVID-19 pandemic.METHODS: Utilizing the US national mortality database and Census, we determined the quarterly age-standardized chronic liver disease-related mortality and quarterly percentage change (QPC) among individuals with diabetes.RESULTS: The quarterly age-standardized mortality for chronic liver disease and/or cirrhosis among individuals with diabetes remained stable before the COVID-19 pandemic and sharply increased during the COIVD-19 pandemic at a QPC of 8.5%. The quarterly mortality from nonalcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) increased markedly during the COVID-19 pandemic. Mortality for hepatitis C virus (HCV) infection declined with a quarterly rate of -3.3% before the COVID-19 pandemic and remained stable during the COVID-19 pandemic. While ALD- and HCV-related mortality was higher in men than in women, NAFLD-related mortality in women was higher than in men.CONCLUSIONS: The sharp increase in mortality for chronic liver disease and/or cirrhosis among individuals with diabetes during the COVID-19 pandemic was associated with increased mortality from NAFLD and ALD.

    View details for DOI 10.1016/j.dld.2022.09.006

    View details for PubMedID 36182570

  • Analysis of Insulin Resistance Among Children and Adolescents in Slovenia With Hypercholesterolemia After Treatment With Statins. JAMA network open Groselj, U., Sikonja, J., Mlinaric, M., Kotnik, P., Battelino, T., Knowles, J. W. 2022; 5 (9): e2231097

    View details for DOI 10.1001/jamanetworkopen.2022.31097

    View details for PubMedID 36094507

  • STATIN THERAPY IS NOT ASSOCIATED WITH INSULIN RESISTANCE IN CHILDREN AND ADOLESCENTS WITH FAMILIAL HYPERCHOLESTEROLAEMIA Groselj, U., Sikonja, J., Mlinaric, M., Kotnik, P., Battelino, T., Knowles, J. W. ELSEVIER IRELAND LTD. 2022: E173
  • Creation of the American Heart Association Journals' Equity, Diversity, and Inclusion Editorial Board: The Next Step to Achieving the 2024 Impact Goal. Circulation Lewis, E. F., Beaty, C., Boltze, J., Breathett, K., Clair, W. K., de Las Fuentes, L., Essien, U. R., Goodell, H., Hinson, H. E., Kershaw, K. N., Knowles, J. W., Mazimba, S., Mujahid, M., Okafor, H. E., Woo Park, K., Schultz, J. 2022: 101161CIRCULATIONAHA122061450

    View details for DOI 10.1161/CIRCULATIONAHA.122.061450

    View details for PubMedID 35862071

  • Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab. Circulation Hagström, E., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Danchin, N., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Liberopoulos, E., Marx, N., McGinniss, J., Manvelian, G., Pordy, R., Scemama, M., White, H. D., Zeiher, A. M., Schwartz, G. G. 2022: 101161CIRCULATIONAHA121057807

    Abstract

    Apolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain.The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACEs; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACEs were assessed in adjusted Cox proportional hazards and propensity score-matched models.Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9-3.6], 4.0 [95% CI, 3.6-4.5], and 5.5 [95% CI, 5.0-6.1] events per 100 patient-years in strata <75, 75-<90, ≥90 mg/dL, respectively; Ptrend<0.0001) and after adjustment for low-density lipoprotein cholesterol (Ptrend=0.035). Higher baseline apoB stratum was associated with greater relative (Ptrend<0.0001) and absolute reduction in MACEs with alirocumab versus placebo. In the alirocumab group, the incidence of MACEs after month 4 decreased monotonically across decreasing achieved apoB strata (4.26 [95% CI, 3.78-4.79], 3.09 [95% CI, 2.69-3.54], and 2.41 [95% CI, 2.11-2.76] events per 100 patient-years in strata ≥50, >35-<50, and ≤35 mg/dL, respectively). Compared with propensity score-matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB strata. Achieved apoB was predictive of MACEs after adjustment for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol but not vice versa.In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, MACEs increased across baseline apoB strata. Alirocumab reduced MACEs across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACEs, even after accounting for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol, indicating that apoB provides incremental information. Achievement of an apoB level ≤35 mg/dL may reduce lipoprotein-attributable residual risk after acute coronary syndrome.URL: https://www.gov. Unique identifier: NCT01663402.

    View details for DOI 10.1161/CIRCULATIONAHA.121.057807

    View details for PubMedID 35770629

  • Generation of two iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 and PRKAG2 variants. Stem cell research Manhas, A., Jahng, J. W., Vera, C. D., Shenoy, S. P., Knowles, J. W., Wu, J. C. 2022; 61: 102774

    Abstract

    Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder characterized by a thick left ventricular wall and an increased risk of arrhythmias, heart failure, and sudden cardiac death. The MYBPC3 and PRAKG2 are known causal genes for HCM. Here we generated two human-induced pluripotent stem cell lines from two HCM patients carrying two heterozygous mutations in MYBPC3 (c.459delC) and PRKAG2 (c.1703C > T). Both iPSC lines expressed pluripotent markers, had a normal karyotype, and were able to differentiate into three germ layers, making them potentially valuable tools for modeling HCM in vitro and investigating the pathological mechanisms related to these two variants.

    View details for DOI 10.1016/j.scr.2022.102774

    View details for PubMedID 35413566

  • Integration of genetic colocalizations with physiological and pharmacological perturbations identifies cardiometabolic disease genes. Genome medicine Gloudemans, M. J., Balliu, B., Nachun, D., Schnurr, T. M., Durrant, M. G., Ingelsson, E., Wabitsch, M., Quertermous, T., Montgomery, S. B., Knowles, J. W., Carcamo-Orive, I. 2022; 14 (1): 31

    Abstract

    BACKGROUND: Identification of causal genes for polygenic human diseases has been extremely challenging, and our understanding of how physiological and pharmacological stimuli modulate genetic risk at disease-associated loci is limited. Specifically, insulin resistance (IR), a common feature of cardiometabolic disease, including type 2 diabetes, obesity, and dyslipidemia, lacks well-powered genome-wide association studies (GWAS), and therefore, few associated loci and causal genes have been identified.METHODS: Here, we perform and integrate linkage disequilibrium (LD)-adjusted colocalization analyses across nine cardiometabolic traits (fasting insulin, fasting glucose, insulin sensitivity, insulin sensitivity index, type 2 diabetes, triglycerides, high-density lipoprotein, body mass index, and waist-hip ratio) combined with expression and splicing quantitative trait loci (eQTLs and sQTLs) from five metabolically relevant human tissues (subcutaneous and visceral adipose, skeletal muscle, liver, and pancreas). To elucidate the upstream regulators and functional mechanisms for these genes, we integrate their transcriptional responses to 21 relevant physiological and pharmacological perturbations in human adipocytes, hepatocytes, and skeletal muscle cells and map their protein-protein interactions.RESULTS: We identify 470 colocalized loci and prioritize 207 loci with a single colocalized gene. Patterns of shared colocalizations across traits and tissues highlight different potential roles for colocalized genes in cardiometabolic disease and distinguish several genes involved in pancreatic beta-cell function from others with a more direct role in skeletal muscle, liver, and adipose tissues. At the loci with a single colocalized gene, 42 of these genes were regulated by insulin and 35 by glucose in perturbation experiments, including 17 regulated by both. Other metabolic perturbations regulated the expression of 30 more genes not regulated by glucose or insulin, pointing to other potential upstream regulators of candidate causal genes.CONCLUSIONS: Our use of transcriptional responses under metabolic perturbations to contextualize genetic associations from our custom colocalization approach provides a list of likely causal genes and their upstream regulators in the context of IR-associated cardiometabolic risk.

    View details for DOI 10.1186/s13073-022-01036-8

    View details for PubMedID 35292083

  • Integration of genetic colocalizations with physiological and pharmacological perturbations identifies cardiometabolic disease genes Gloudemans, M. J., Balliu, B., Nachun, D., Durrant, M. G., Ingelsson, E., Wabitsch, M., Quertermous, T., Montgomery, S. B., Knowles, J., Carcamo-Orive, I. W B SAUNDERS CO-ELSEVIER INC. 2022: S24-S25
  • A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome medicine Marwaha, S., Knowles, J. W., Ashley, E. A. 2022; 14 (1): 23

    Abstract

    Rare diseases affect 30 million people in the USA and more than 300-400 million worldwide, often causing chronic illness, disability, and premature death. Traditional diagnostic techniques rely heavily on heuristic approaches, coupling clinical experience from prior rare disease presentations with the medical literature. A large number of rare disease patients remain undiagnosed for years and many even die without an accurate diagnosis. In recent years, gene panels, microarrays, and exome sequencing have helped to identify the molecular cause of such rare and undiagnosed diseases. These technologies have allowed diagnoses for a sizable proportion (25-35%) of undiagnosed patients, often with actionable findings. However, a large proportion of these patients remain undiagnosed. In this review, we focus on technologies that can be adopted if exome sequencing is unrevealing. We discuss the benefits of sequencing the whole genome and the additional benefit that may be offered by long-read technology, pan-genome reference, transcriptomics, metabolomics, proteomics, and methyl profiling. We highlight computational methods to help identify regionally distant patients with similar phenotypes or similar genetic mutations. Finally, we describe approaches to automate and accelerate genomic analysis. The strategies discussed here are intended to serve as a guide for clinicians and researchers in the next steps when encountering patients with non-diagnostic exomes.

    View details for DOI 10.1186/s13073-022-01026-w

    View details for PubMedID 35220969

  • Online Patient Education Materials Related to Lipoprotein(a): Readability Assessment. Journal of medical Internet research Pearson, K., Ngo, S., Ekpo, E., Sarraju, A., Baird, G., Knowles, J., Rodriguez, F. 1800; 24 (1): e31284

    Abstract

    BACKGROUND: Lipoprotein(a) (Lp(a)) is a highly proatherogenic lipid fraction that is a clinically significant risk modifier. Patients wanting to learn more about Lp(a) are likely to use online patient educational materials (OPEMs). However, the readability of OPEMs may exceed the health literacy of the public.OBJECTIVE: This study aims to assess the readability of OPEMs related to Lp(a). We hypothesized that the readability of these online materials would exceed the sixth grade level recommended by the American Medical Association.METHODS: Using an online search engine, we queried the top 20 search results from 10 commonly used Lp(a)-related search terms to identify a total of 200 websites. We excluded duplicate websites, advertised results, research journal articles, or non-patient-directed materials, such as those intended only for health professionals or researchers. Grade level readability was calculated using 5 standard readability metrics (automated readability index, SMOG index, Coleman-Liau index, Gunning Fog score, Flesch-Kincaid score) to produce robust point (mean) and interval (CI) estimates of readability. Generalized estimating equations were used to model grade level readability by each search term, with the 5 readability scores nested within each OPEM.RESULTS: A total of 27 unique websites were identified for analysis. The average readability score for the aggregated results was a 12.2 (95% CI 10.9798-13.3978) grade level. OPEMs were grouped into 6 categories by primary source: industry, lay press, research foundation and nonprofit organizations, university or government, clinic, and other. The most readable category was OPEMs published by universities or government agencies (9.0, 95% CI 6.8-11.3). The least readable OPEMs on average were the ones published by the lay press (13.0, 95% CI 11.2-14.8). All categories exceeded the sixth grade reading level recommended by the American Medical Association.CONCLUSIONS: Lack of access to readable OPEMs may disproportionately affect patients with low health literacy. Ensuring that online content is understandable by broad audiences is a necessary component of increasing the impact of novel therapeutics and recommendations regarding Lp(a).

    View details for DOI 10.2196/31284

    View details for PubMedID 35014955

  • Ultrarapid Nanopore Genome Sequencing in a Critical Care Setting. The New England journal of medicine Gorzynski, J. E., Goenka, S. D., Shafin, K., Jensen, T. D., Fisk, D. G., Grove, M. E., Spiteri, E., Pesout, T., Monlong, J., Baid, G., Bernstein, J. A., Ceresnak, S., Chang, P. C., Christle, J. W., Chubb, H., Dalton, K. P., Dunn, K., Garalde, D. R., Guillory, J., Knowles, J. W., Kolesnikov, A., Ma, M., Moscarello, T., Nattestad, M., Perez, M., Ruzhnikov, M. R., Samadi, M., Setia, A., Wright, C., Wusthoff, C. J., Xiong, K., Zhu, T., Jain, M., Sedlazeck, F. J., Carroll, A., Paten, B., Ashley, E. A. 2022

    View details for DOI 10.1056/NEJMc2112090

    View details for PubMedID 35020984

  • Interactions of physical activity, muscular fitness, adiposity, and genetic risk for NAFLD. Hepatology communications Schnurr, T. M., Katz, S. F., Justesen, J. M., O'Sullivan, J. W., Saliba-Gustafsson, P., Assimes, T. L., Carcamo-Orive, I., Ahmed, A., Ashley, E. A., Hansen, T., Knowles, J. W. 2022

    Abstract

    Genetic predisposition and unhealthy lifestyle are risk factors for nonalcoholic fatty liver disease (NAFLD). We investigated whether the genetic risk of NAFLD is modified by physical activity, muscular fitness, and/or adiposity. In up to 242,524 UK Biobank participants without excessive alcohol intake or known liver disease, we examined cross-sectional interactions and joint associations of physical activity, muscular fitness, body mass index (BMI), and a genetic risk score (GRS) with alanine aminotransferase (ALT) levels and the proxy definition for suspected NAFLD of ALT levels > 30 U/L in women and >40 U/L in men. Genetic predisposition to NAFLD was quantified using a GRS consisting of 68 loci known to be associated with chronically elevated ALT. Physical activity was assessed using accelerometry, and muscular fitness was estimated by measuring handgrip strength. We found that increased physical activity and grip strength modestly attenuate genetic predisposition to elevation in ALT levels, whereas higher BMI markedly amplifies it (all p values < 0.001). Among those with normal weight and high level of physical activity, the odds of suspected NAFLD were 1.6-fold higher in those with high versus low genetic risk (reference group). In those with high genetic risk, the odds of suspected NAFLD were 12-fold higher in obese participants with low physical activity versus those with normal weight and high physical activity (odds ratio for NAFLD = 19.2 and 1.6, respectively, vs. reference group). Conclusion: In individuals with high genetic predisposition for NAFLD, maintaining a normal body weight and increased physical activity may reduce the risk of NAFLD.

    View details for DOI 10.1002/hep4.1932

    View details for PubMedID 35293152

  • Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic Variants Independent of Clinically Observed Longitudinal Cholesterol Exposure. Circulation. Genomic and precision medicine Clarke, S. L., Tcheandjieu, C., Hilliard, A. T., Lee, M., Lynch, J., Chang, K. M., Miller, D., Knowles, J. W., O'Donnell, C., Tsao, P., Rader, D. J., Wilson, P. W., Sun, Y. V., Gaziano, M., Assimes, T. L. 2022: CIRCGEN121003501

    Abstract

    Familial hypercholesterolemia (FH) genetic variants confer risk for coronary artery disease independent of LDL-C (low-density lipoprotein cholesterol) when considering a single measurement. In real clinical settings, longitudinal LDL-C data are often available through the electronic health record. It is unknown whether genetic testing for FH variants provides additional risk-stratifying information once longitudinal LDL-C is considered.We used the extensive electronic health record data available through the Million Veteran Program to conduct a nested case-control study. The primary outcome was coronary artery disease, derived from electronic health record codes for acute myocardial infarction and coronary revascularization. Incidence density sampling was used to match case/control exposure windows, defined by the date of the first LDL-C measurement to the date of the first coronary artery disease code of the index case. Adjustments for the first, maximum, or mean LDL-C were analyzed. FH variants in LDLR, APOB, and PCSK9 were assessed by custom genotype array.In a cohort of 23 091 predominantly prevalent cases at enrollment and 230 910 matched controls, FH variant carriers had an increased risk for coronary artery disease (odds ratio [OR], 1.53 [95% CI, 1.24-1.89]). Adjusting for mean LDL-C led to the greatest attenuation of the risk estimate, but significant risk remained (odds ratio, 1.33 [95% CI, 1.08-1.64]). The degree of attenuation was not affected by the number and the spread of LDL-C measures available.The risk associated with carrying an FH variant cannot be fully captured by the LDL-C data available in the electronic health record, even when considering multiple LDL-C measurements spanning more than a decade.

    View details for DOI 10.1161/CIRCGEN.121.003501

    View details for PubMedID 35143253

  • G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis Nature Communications Bielczyk-Maczynska, E., Zhao, M., Zushin, P. H., Schnurr, T. M., Kim, H., Li, J., Sangwung, P., Nallagatla, P., Park, C., Cornn, C., Stahl, A., Svensson, K. J., Knowles, J. W. 2022
  • The Clinical Genome Resource (ClinGen) Familial Hypercholesterolemia Variant Curation Expert Panel consensus guidelines for LDLR variant classification. Genetics in medicine : official journal of the American College of Medical Genetics Chora, J. R., Iacocca, M. A., Tichy, L., Wand, H., Kurtz, C. L., Zimmermann, H., Leon, A., Williams, M., Humphries, S. E., Hooper, A. J., Trinder, M., Brunham, L. R., Costa Pereira, A., Jannes, C. E., Chen, M., Chonis, J., Wang, J., Kim, S., Johnston, T., Soucek, P., Kramarek, M., Leigh, S. E., Carrie, A., Sijbrands, E. J., Hegele, R. A., Freiberger, T., Knowles, J. W., Bourbon, M., ClinGen Familial Hypercholesterolemia Expert Panel 1800

    Abstract

    PURPOSE: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published consensus standardized guidelines for sequence-level variant classification in Mendelian disorders. To increase accuracy and consistency, the Clinical Genome Resource Familial Hypercholesterolemia (FH) Variant Curation Expert Panel was tasked with optimizing the existing ACMG/AMP framework for disease-specific classification in FH. In this study, we provide consensus recommendations for the most common FH-associated gene, LDLR, where >2300 unique FH-associated variants have been identified.METHODS: The multidisciplinary FH Variant Curation Expert Panel met in person and through frequent emails and conference calls to develop LDLR-specific modifications of ACMG/AMP guidelines. Through iteration, pilot testing, debate, and commentary, consensus among experts was reached.RESULTS: The consensus LDLR variant modifications to existing ACMG/AMP guidelines include (1) alteration of population frequency thresholds, (2) delineation of loss-of-function variant types, (3) functional study criteria specifications, (4) cosegregation criteria specifications, and (5) specific use and thresholds for in silico prediction tools, among others.CONCLUSION: Establishment of these guidelines as the new standard in the clinical laboratory setting will result in a more evidence-based, harmonized method for LDLR variant classification worldwide, thereby improving the care of patients with FH.

    View details for DOI 10.1016/j.gim.2021.09.012

    View details for PubMedID 34906454

  • Signaling defects associated with insulin resistance in non-diabetic and diabetic individuals and modification by sex. The Journal of clinical investigation Haider, N., Lebastchi, J., Jayavelu, A. K., Batista, T. M., Pan, H., Dreyfuss, J. M., Carcamo-Orive, I., Knowles, J. W., Mann, M., Kahn, C. R. 2021

    Abstract

    Insulin resistance is present in one-quarter of the general population, predisposing to a wide-range of diseases. Our aim was to identify cell-intrinsic determinants of insulin resistance in this population using IPS cell-derived myoblasts (iMyos). We found that these cells exhibited a large network of altered protein phosphorylation in vitro. Integrating these data with data from type-2-diabetic iMyos revealed critical sites of conserved altered phosphorylation in IRS-1, AKT, mTOR and TBC1D1, in addition to changes in protein phosphorylation involved in Rho/Rac signaling, chromatin organization and RNA processing. There were also striking differences in the phosphoproteome in cells from males versus females. These sex-specific and insulin resistance defects were linked to functional differences in downstream actions. Thus, there are cell-autonomous signaling alterations associated with insulin resistance within the general population and important differences in males and females, many of which are shared with diabetes, and contribute to differences in physiology and disease.

    View details for DOI 10.1172/JCI151818

    View details for PubMedID 34506305

  • Statins Are Associated With Increased Insulin Resistance and Secretion. Arteriosclerosis, thrombosis, and vascular biology Abbasi, F., Lamendola, C., Harris, C. S., Harris, V., Tsai, M., Tripathi, P., Abbas, F., Reaven, G., Reaven, P., Snyder, M. P., Kim, S. H., Knowles, J. W. 2021: ATVBAHA121316159

    Abstract

    OBJECTIVE: Statin treatment reduces the risk of atherosclerotic cardiovascular disease but is associated with a modest increased risk of type 2 diabetes, especially in those with insulin resistance or prediabetes. Our objective was to determine the physiological mechanism for the increased type 2 diabetes risk. Approach and Results: We conducted an open-label clinical trial of atorvastatin 40 mg daily in adults without known atherosclerotic cardiovascular disease or type 2 diabetes at baseline. The co-primary outcomes were changes at 10 weeks versus baseline in insulin resistance as assessed by steady-state plasma glucose during the insulin suppression test and insulin secretion as assessed by insulin secretion rate area under the curve (ISRAUC) during the graded-glucose infusion test. Secondary outcomes included glucose and insulin, both fasting and during oral glucose tolerance test. Of 75 participants who enrolled, 71 completed the study (median age 61 years, 37% women, 65% non-Hispanic White, median body mass index, 27.8 kg/m2). Atorvastatin reduced LDL (low-density lipoprotein)-cholesterol (median decrease 53%, P<0.001) but did not change body weight. Compared with baseline, atorvastatin increased insulin resistance (steady-state plasma glucose) by a median of 8% (P=0.01) and insulin secretion (ISRAUC) by a median of 9% (P<0.001). There were small increases in oral glucose tolerance test glucoseAUC (median increase, 0.05%; P=0.03) and fasting insulin (median increase, 7%; P=0.01).CONCLUSIONS: In individuals without type 2 diabetes, high-intensity atorvastatin for 10 weeks increases insulin resistance and insulin secretion. Over time, the risk of new-onset diabetes with statin use may increase in individuals who become more insulin resistant but are unable to maintain compensatory increases in insulin secretion.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02437084.

    View details for DOI 10.1161/ATVBAHA.121.316159

    View details for PubMedID 34433298

  • Genetics of Type 2 Diabetes: Opportunities for Precision Medicine: JACC Focus Seminar. Journal of the American College of Cardiology Kim, D. S., Gloyn, A. L., Knowles, J. W. 2021; 78 (5): 496-512

    Abstract

    Type 2 diabetes (T2D) is highly prevalent and is a strong contributor for cardiovascular disease. However, there is significant heterogeneity in disease pathogenesis and the risk of complications. Enormous progress has been made in our ability to catalog genetic variation associated with T2D risk and variation in disease-relevant quantitative traits. These discoveries hold the potential to shed light on tractable targets and pathways for safe and effective therapeutic development, but the promise of precision medicine has been slow to be realized. Recent studies have identified subgroups of individuals with differential risk for intermediate phenotypes (eg, lipid levels, fasting insulin, body mass index) that contribute to T2D risk, helping to account for the observed clinical heterogeneity. These "partitioned genetic risk scores" not only have the potential to identify patients at greatest risk of cardiovascular disease and rapid disease progression, but also could aid patient stratification bridging the gap toward precision medicine for T2D.

    View details for DOI 10.1016/j.jacc.2021.03.346

    View details for PubMedID 34325839

  • Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Schwartz, G. G., Szarek, M., Bittner, V. A., Diaz, R., Goodman, S. G., Jukema, J., Landmesser, U., Lopez-Jaramillo, P., Manvelian, G., Pordy, R., Scemama, M., Sinnaeve, P. R., White, H. D., Steg, P., Odyssey Outcomes Committ Invest 2021; 78 (5): 421-433

    Abstract

    Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk.In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels.ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3-74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2-111.0 mg/dL).In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [CI]: 0.52-0.90) and 1.11 (95% CI: 0.83-1.49), with treatment-lipoprotein(a) interaction on MACE (Pinteraction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43.In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

    View details for DOI 10.1016/j.jacc.2021.04.102

    View details for Web of Science ID 000679372200001

    View details for PubMedID 34325831

    View details for PubMedCentralID PMC8822604

Knowles Lab publications and collaborations