Lipoprotein Lipase Deficiency Research Articles

Prevalence, severity and management of hypertriglyceridemia-associated pancreatitis; A 7-year retrospective cohort study at Canadian quaternary care hospitals

Hypertriglyceridemia (HTG) is known as the third most common cause of acute pancreatitis (AP). To study the prevalence and outcomes of HTG-AP as well as the quality of the follow-up post HTG-AP hospitalization in Canada. This retrospective multicenter study was performed in patients admitted with AP (ICD 10 code K85) in quaternary care hospitals between 2012 and 2018. For every case of HTG-AP (TG ≥ 5.6 mmol/L on admission), two controls of biliary-AP were selected and matched for sex and age at the time of admission. Out of 1490 admitted AP patients, 40 (3%) had HTG-AP. The average TG concentration was higher in patients admitted to the ICU compared to those who were not (27.34 mmol/L vs 13.02 mmol/L). Compared to biliary-AP group, the HTG-AP patients had more frequent severe Balthazar grade (45% vs 25%) with longer duration of hospitalisation (nine versus five days) and more frequent ICU admission (38% vs 8%). Furthermore, only 35% of HTG-AP patients were referred to specialized clinics and 42.5% were left with no follow-up. Only 17% of newly discovered HTG-AP patients were started on fibrate at discharge. In comparison to biliary-AP, HTG-AP patients had a worse clinical course of pancreatitis. Furthermore, the quality of the follow-up post HTG-AP hospitalization was suboptimal. This could be explained by of the lack of knowledge of health care providers concerning the proper diagnosis and management of chylomicronemia syndromes, leading to this condition to be frequently missed or underdiagnosed.

Abstract #1183744: The challenge of unresolving chylomicronemia and recurring pancreatitis: Lessons learned on the treatment of severe hypertriglyceridemia

Severe hypertriglyceridemia (HTG) in the chylomicronemia (CM) range is associated with acute pancreatitis. Plasma exchange (PEX) has been used for the treatment of chronic CM in the setting of recurrent pancreatitis. We present a patient with multifactorial CM syndrome and recurrent pancreatitis recently started on biweekly sessions of PEX. We share lessons learned on the management of multifactorial CM syndrome and highlight the potential complications associated with chronic apheresis.

Hypertriglyceridaemia in adolescents may have serious complications

Acute pancreatitis is an often-overlooked cause of acute abdominal pain in children and adolescents. Severe hypertriglyceridaemia is an important cause of recurrent acute pancreatitis. Monogenic causes of hypertriglyceridaemia, such as familial chylomicronaemia caused by lipoprotein lipase deficiency, are more frequently encountered in children and adolescents, but remain rare. Polygenic hypertriglyceridaemia is more common, but may require a precipitant before manifesting. With the global increase in obesity and type 2 diabetes, secondary causes of hypertriglyceridaemia in children and adolescents are increasing. We report two cases of severe hypertriglyceridaemia and pancreatitis in adolescent females. Hypertriglyceridaemia improved markedly with restriction of dietary fat. An inhibitor to lipoprotein lipase was found to be the cause in one patient, while in the other limited genetic investigation excluded chylomicronaemia owing to deficiency of lipoprotein lipase, its activators and processing proteins.

Abstract 508: Combined Lipoprotein Lipase And Ldl Receptor Deficiency Increases Atherosclerosis: Hyperchylomicronemia Is Not Benign

We tested whether accumulation of chylomicrons as an addition to LDL would enhance atherosclerosis. To do this, whole body LpL deficiency was combined with LDL receptor (LDLR) deficiency. Induced global LpL deficiency (i Lpl -/- ) was created by tamoxifen injections to activate beta actin-driven cre recombinase in mice. To knock down hepatic LDLR we utilized anti-sense oligonucleotides (ASOs) or a PCSK9 expressing AAV. i Lpl -/- mice on chow diet have elevated plasma TGs, increased VLDL cholesterol, and lower LDL-C compared to control Lpl fl/fl mice. In contrast, when hepatic LDLR was knocked down, the mice displayed elevated LDL-C (~150 mg/dl), similar to the levels seen in control mice with LDLR knockdown. i Lpl -/- mice fed a Western diet for 12 weeks developed severe hypertriglyceridemia (1400-7000 mg/dl) and increased total cholesterol reaching ~1500 mg/dl. LDL-C levels were lower in iLpL -/- mice (160 mg/dl vs 359 mg/dl) and the increase in cholesterol was primarily in chylomicrons compared to the control mice with LDLR knockdown (1064 mg/dl vs 238 mg/dl). i Lpl -/- mice had bigger lesions in the brachiocephalic artery (46000 um 2 vs 13000 um 2 ) but macrophage content was lower than the control LDLR-deficient mice (24% vs 69%). Aortic root lesion size was larger (60000 um 2 vs 26000 um 2 ), due to a greater the percentage of collagen (34% vs 23%), but not macrophages (60% vs 58%) or neutral lipid content (34% vs 35%). The lack of differences in macrophage accumulation and neutral lipid content and the increase in the collagen content indicates an advanced lesion in the iLpl -/- mice. Thus, our data suggest that intact chylomicrons contribute to atherosclerosis.

The Evolving Story of Multifactorial Chylomicronemia Syndrome.

Multifactorial chylomicronemia syndrome (MCS or type V hyperlipoproteinemia) is the most frequent cause of severe hypertriglyceridemia and is associated with an increased risk of acute pancreatitis, cardiovascular disease, and non-alcoholic steatohepatitis. The estimated prevalence of MCS in the North American population is 1:600–1:250 and is increasing due to the increasing prevalence of obesity, metabolic syndrome, and type 2 diabetes. Differentiating between familial chylomicronemia syndrome and MCS is crucial due to their very different treatments. In recent years, several cohort studies have helped to differentiate these two conditions, and recent evidence suggests that MCS itself is a heterogeneous condition. This mini-review will summarize recent literature on MCS, with a specific focus on the genetic determinants of the metabolic risk and the latest developments concerning the pharmacological and non-pharmacological treatment options for these patients. Possible research directions in this field will also be discussed.

Knockout of lipoprotein lipase with CRISPR/Cas9 causes severe developmental defects and affects lipid deposition in Japanese medaka (Oryzias latipes)

In mammals, lipoprotein lipase (LPL) has been found to play an important role in lipid mentalism and deposition. LPL deficiency in humans (Homo sapiens) and mice (Mus musculus) tends to cause hypertriglyceridemia. The lpl gene is not expressed in adult mammalian liver, but is in adult fish liver. The functions provided by the lpl gene are diverse in vertebrates. Here, we knocked out the lpl gene in Japanese medaka (Oryzias latipes) with the CRISPR/Cas9 system. The lpl-knockout (KO) homozygous individuals showed severe developmental defects with an extremely emaciated and deformed body and only accounted for about 5% of the F2 fish. This is consistent with the findings in mice but disaccords with the results for zebrafish (Danio rerio). Compared with wild-type (WT) madaka, the mRNA level of lpl in lpl-KO heterozygous mutant was significantly higher in the muscle, showed no significant difference in the liver, and was significantly lower in the heart. Under lpl heterozygous deficiency, the relative area of Oil Red O and triglycerides (TG) level in the liver, heart and muscle tissue covaried with levels of lpl mRNA in medaka. The lpl heterozygous deficiency did not affect the levels of TG, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) in the plasma of medaka, which is inconsistent with the findings in mammals. In general, the lpl gene plays an important role in the growth and development and is closely related to lipid deposition of medaka.

Safety and efficacy of therapies for chylomicronemia

Introduction Primary chylomicronemia is characterized by pathological accumulation of chylomicrons in plasma causing severe hypertriglyceridemia, typically >10 mmol/L (>875 mg/dL). Patients with the ultra-rare familial chylomicronemia syndrome (FCS) subtype completely lack lipolytic capacity and respond minimally to traditional triglyceride-lowering therapies. The mainstay of treatment is a low-fat diet, which is difficult to follow and compromises quality of life. New therapies are being developed primarily to prevent episodes of life-threatening acute pancreatitis. Areas covered Antagonists of apolipoprotein (apo) C-III, such as the antisense oligonucleotide (ASO) volanesorsen, significantly reduce triglyceride levels in chylomicronemia. However, approval of and access to volanesorsen are restricted since a substantial proportion of treated FCS patients developed thrombocytopenia. Newer apo C-III antagonists, namely the ASO olezarsen (formerly AKCEA-APOCIII-LRx) and short interfering RNA (siRNA) ARO-APOC3 appear to show efficacy with less risk of thrombocytopenia. Potential utility of antagonists of angiopoietin-like protein 3 (ANGPTL3) such as evinacumab and the siRNA ARO-ANG3 in subtypes of chylomicronemia remains to be defined. Expert opinion Emerging pharmacologic therapies for chylomicronemia show promise, particularly apo C-III antagonists. However, these treatments are still investigational. Further study of their efficacy and safety in patients with both rare FCS and more common multifactorial chylomicronemia is needed.

Severe hypertriglyceridemia secondary to splice-site and missense variants in LMF1 in three patients from Ecuador

Rare pathogenic variants in the LMF1 gene, which encodes lipase maturation factor 1, are a minor cause of familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia. In this report we present three adult patients, all of them born and raised in Quito, Ecuador, with severe hypertriglyceridemia secondary to biallelic LMF1 variants. In two of the three cases (patients 1 and 3), the presentation was acute pancreatitis secondary to plasma triglycerides well above 10 mmol/L. The other case (patient 2) was a sibling of one of the initial patients, who was asymptomatic but markedly hypertriglyceridemic. Next-generation sequencing revealed a homozygous splice-site variant in exon 6 of LMF1 in patients 1 and 2 (c.897G>A, p.Gln299=), and a homozygous missense variant in exon 2 of LMF1 in patient 3 (c.233T>C, p.Leu78Pro). The finding of two disease-causing variants in three patients from the same location raises the question of whether LMF1 may be a more prevalent cause of severe hypertriglyceridemia among Latin-American patients.

Both low-fat and low-carbohydrate diets reduce triglyceride concentration in subjects with multifactorial chylomicronemia syndrome: a randomized crossover study

Multifactorial chylomicronemia syndrome (MCS) is a complex disease including a genetic component and the presence of lifestyle-related risk factors. We hypothesized that, in subjects with MCS, there would be a greater decrease in plasma triglycerides (TG) with a low-fat (F) diet than with a low-carbohydrate (C) diet. In secondary analyses, we tested the effect of both diets on TG concentration according to the presence or absence of a rare variant in the LPL gene. This randomized crossover dietary intervention included 12 adult subjects with MCS. Subjects followed 2 isocaloric diets, low-C (C, 35%; F, 45%) and low-F (F, 20%; C, 60%), in random order. Each diet lasted 3 weeks, followed by a 6-hour test meal. Diets were separated by a 2-week washout period. TG concentration in fasting subjects decreased by 55% during low-F diet (P = .002) and by 48% during low-C diet (P = .005). The difference between the 2 diets was not significant. However, we observed a more pronounced decrease in TG concentration (65% ± 17%) with the low-F diet compared with the low-C diet (46% ± 31%) (P=.06) in subjects carrying a rare variant in the LPL gene. This is the first study to show that dietary intervention is effective in MCS subjects. In addition, we highlighted the importance of the genetic profile in the choice of treatment by suggesting that subjects with a rare variant of the LPL gene have a greater reduction of TG concentration with a low-F diet than with a low-C diet.

Les traitements par ARN interférents et par oligonucléotides antisens actuellement disponibles en France : une mise au point

L’arrivée des vaccins anti Covid-19 à ARN en 2020 ne doit pas occulter le fait que nous disposons déjà depuis plusieurs années de traitements à base d’ARN interférents ou d’oligonucléotides antisens dans un certain nombre de maladies rares de pronostic très sombre telles que l’amylose à transthyrétine, la porphyrie hépatique aiguë, l’hyperoxalurie primitive, l’amyotrophie spinale ou l’hyperchylomicronémie familiale. Si leurs performances, à l’inverse de celles des vaccins, ne sont pour l’instant qualifiées que de progrès thérapeutiques modérés dans les stratégies thérapeutiques opposées à ces maladies, il y a lieu de tenir compte du fait que leur évaluation initiale a été pénalisée par un certain nombre de facteurs défavorables : des essais de petits effectifs, des modalités thérapeutiques à affiner, le manque de recul, sur leurs effets à long terme mais surtout le choix du moment de l’instauration du traitement dans l’évolution naturelle de la maladie. Ce choix n’est pas anodin car l’on imagine mal que les produits utilisés puissent, au-delà d’une simple stabilisation de la maladie installée, permettre sa régression dès lors que certaines lésions constituées sont irréversibles. C’est pourquoi leur mise en œuvre très précoce, éventuellement fondée sur un dépistage génétique, est une piste à saisir dans l’intérêt des patients. Mais, dans le contexte concurrentiel des innovations dans le domaine, ARN interférents et oligonucléotides antisens devront compter avec les thérapies géniques et l’édition du génome par la technique CRISPR-Cas 9.

Volanesorsen: A New Era in the Treatment of Severe Hypertriglyceridemia.

Introduction: Familial chylomicronemia syndrome (FCS) is a rare inherited disease, mainly due to lipoprotein lipase (LPL) gene mutations, leading to lipid abnormalities. Volanesorsen, a second-generation 2′-O-methoxyethyl (2′-MOE) chimeric antisense therapeutic oligonucleotide, can decrease plasma apolipoprotein C3 and triglycerides (TG) levels through LPL-independent pathways. The European Medicines Agency has approved volanesorsen as an adjunct to diet in adult FCS patients with an inadequate response to TG-lowering therapy. Areas covered: Available clinical data on volanesorsen efficacy and safety are presented. Furthermore, we discuss the yearly treatment with volanesorsen of a 21-year-old female FCS patient with LPL mutation. Volanesorsen was well-tolerated and decreased patient’s TG levels (from >5000 mg/dL (56 mmol/L) to 350–500 mg/dL (4–5.6 mmol/L)) at 12 months. Lipoprotein apheresis (LA) was stopped and there were no episodes of pancreatitis or abdominal pain. Expert opinion: Severe hypertriglyceridemia can potentially be fatal. Until recently, there was no specific treatment for FCS, apart from hypotriglyceridemic diet, fibrates, omega-3 fatty acids, and LA sessions. Therefore, volanesorsen represents a promising therapeutic solution for these patients. The main side effect of volanesorsen therapy is thrombocytopenia, which should be monitored and treated accordingly. Increasing evidence will further elucidate the clinical implications of volanesorsen use in daily practice.

Hypertriglyceridemia: rationale, design and implementation of the Australian Hypertriglyceridemia Registry.

Hypertriglyceridemia (HTG) is a risk factor for atherosclerotic cardiovascular disease (ASCVD), aortic stenosis, hepatic steatosis and pancreatitis. We briefly review the aetiology and treatment of HTG and familial chylomicronemia syndrome (FCS), as well as the implementation of a clinical quality registry for improving care, the Australian Hypertriglyceridemia (AUSTRIG) Registry. There is a need to improve the detection of individuals with severe HTG and FCS, who could benefit from more intense and novel treatments to prevent end-organ damage. Patient registries provide valuable data for advancing care of individuals with severe HTG at high risk of acute pancreatitis, steatohepatitis and ASCVD. However, there is a paucity of registries of such patients. We outline the design and implementation of the AUSTRIG Registry. Clinical registries can be employed in many ways for improving outcomes for patients with HTG, through the collation and analysis of data for enabling health service planning, clinical trials and audits, and for better informing and empowering registrants.

Recurrent Hypertriglyceridemia-Associated Pancreatitis in a Pregnant Woman Complicated by Severe Socioeconomic Insecurity

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis At 26 weeks gestation, a 24-year-old pregnant woman with type 2 diabetes mellitus (T2DM) and hypertriglyceridemia (HTG) was hospitalized for her second episode of acute pancreatitis (AP) associated with triglycerides (TG) > 4000 mg/dL. Medical therapy including plasma exchange resulted in dramatic improvement of TG, and the remaining hospital course was uneventful. She was discharged with plan for twice weekly plasma exchange. However, she did not have adequate childcare or transportation to enable treatment and the tunneled catheter had to be removed due to infection before she could receive any outpatient plasma exchange. This case highlights potential barriers to management of severe HTG and the need for effective therapy. Objective/Purpose To review a clinical scenario where severe inherited lipid abnormality and socioeconomic distress complicate care. Methods Laboratory testing was performed by University of Pennsylvania Health System Cernmill Laboratory. Results A 24-year-old G6P3 woman at 26 weeks gestation with T2DM presented to the hospital with intractable abdominal pain and was found to have diabetic ketoacidosis (DKA) and severe HTG causing AP (Table 1). Her medical history was notable for one prior episode of AP at age 21, during which she was first diagnosed with HTG and T2DM and treated with gemfibrozil and insulin. Subsequent medical care was disrupted by limited financial resources and housing insecurity. Follow-up lipid testing while on this regimen did not achieve TG less than 1000 mg/dl. She was admitted to the obstetrics unit for intravenous fluids and insulin and kept nill per os (NPO) resulting in resolution of the DKA. She underwent plasma exchange resulting in TG reduction and resolution of abdominal pain and elevated pancreatic enzymes. TG levels rose to >1200 mg/dL two days after plasma exchange despite clear liquid diet. A prolonged discussion about the risk of recurrent AP to her and her pregnancy, the interventions to manage HTG-associated AP, and available resources supported the role of once- or twice-weekly plasma exchange until delivery. Unfortunately, this plan was abandoned one week after discharge from the hospital because of inadequate access to appropriate childcare, transportation costs, and difficulty with safe maintenance of her tunneled IV access catheter. Present therapy includes close monitoring, dietary counseling, and combination of gemfibrozil and high dose omega-3 fatty acid supplementation. Conclusions This case illustrates a treatment dilemma stemming from the intersection of lipid biology, pregnancy, diabetes, and social determinants of health. Our patient has features of familial (FCS) and multifactorial chylomicronemia syndrome (MCS). Proper diagnosis may inform expectations from pharmacotherapy (e.g. gemfibrozil and high dose omega-3 fatty acid supplementation). In this case, the decision was made to initiate twice-weekly plasma exchange until delivery. There are no clinical trials to directly inform clinical decision-making for this rare condition. However, HTG-associated AP during pregnancy is reportedly more severe than non-pregnancy associated AP and intensive treatment is sensible given the expectation of worsening HTG in the last trimester and the high stakes for the patient and fetus. Unfortunately, our patient's socioeconomic barriers did not allow for appropriate treatment with plasma exchange and the social safety net could not solve these problems in the time required. This case serves as a reminder that our patients may face barriers to accessing complex healthcare and further highlights the need for more effective, convenient, and reliable HTG treatments for both FCS and MCS. Nothing to disclose.

Evidence of Direct Hepatic Secretion of Low density Lipoprotein (LDL) in Mice

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> National Lipid Association Junior Faculty Research Award 2020, NIH P01HL151328 and HL45095 (IJG). <h3>Background/Synopsis</h3> LDL is the major atherogenic lipoprotein causing atherosclerosis, leading to cardiovascular disease (CVD), the primary cause of morbidity and mortality in the United States. Lipoprotein lipase (LpL) is the rate limiting enzyme hydrolyzing triglyceride rich lipoproteins in the circulation. Current understanding is that LpL mediated hydrolysis of very low density lipoprotein (VLDL) generates cholesterol rich LDL particles in the circulation. However, evidence from in vitro studies as well as some human kinetic data suggest that the liver might directly secrete LDL into the circulation. <h3>Objective/Purpose</h3> In this study, we determine whether combined deficiency of lipoprotein lipase and hepatic LDL receptor (LDLR) would lead to decreased circulating LDL cholesterol (LDL-C) levels. <h3>Methods</h3> We used a mouse model of tamoxifen inducible global LpL deficiency (iLpl-/-). To knock down hepatic genes like LDLR and hepatic lipase (HL) we utilized anti sense oligonucleotides (ASOs). <h3>Results</h3> As expected, iLpl-/- mice display reduced plasma LDL-C levels compared to control mice (5 mg/dl vs 30 mg/dl). To determine whether LDL-C would increase with knock down of hepatic LDLRs, we used LDLR ASO in control and iLpl-/- mice. As anticipated, LDL-C levels increased in control mice to 150 mg/dl. Remarkably, plasma LDL-C also increased in iLpl-/- mice to levels similar to that of control mice. We then fed the mice a high cholesterol western diet for two weeks; this increased LDL-C levels equally in both mice to 300 mg/dl. When we overexpressed PCSK9 to inhibit LDLR in iLpl-/- mice, we again observed increases in LDL-C similar to control mice with PCSK9 overexpression. Further, to test if HL, another extracellular triglyceride lipase, is converting VLDL to LDL in iLpl-/- mice, we knocked down HL in control and iLpl-/- mice. HL knockdown did not alter LDL-C levels in control or iLpl-/- mice. <h3>Conclusions</h3> These data suggest the presence of direct LDL secretion from liver. We are investigating why this is apparent only with concomitant loss of LpL and LDLRs. We postulate that LDLRs have an additional gate-keeping function to halt secretion of newly synthesized LDL particles from the liver in addition to their well-established role in clearance of plasma LDL. When LDLRs are limiting or in patients with combined hyperlipidemia, direct LDL production may constitute a major source of circulating LDL. If so, this could uncover a novel approach to treat familial hypercholesterolemia.

Prophylactic therapeutic plasma exchange in pregnant woman with Familial Chylomicronemia Syndrome – A case report

ContextFamilial Chylomicronemia Syndrome (FCS) is an inherited disease where lack of lipoprotein lipase results in severe hypertriglyceridemia that frequently leads to recurrent acute pancreatitis. Pregnancy in patients with familial chylomicronemia syndrome (FCS) post a risk for mother and baby with potential complications (pancreatitis, miscarriage and death). Therapeutic approach includes strict dietary measures and plasma exchange. Despite the development of new drugs for FCS, their safety in pregnancy has not yet been confirmed. Case descriptionWe present a case of a young, pregnant female with FCS who had miscarriage in the past during one episode of acute pancreatitis. Due to the inability to achieve lower TG levels with current therapy, from 27-th week of pregnancy we have started prophylactic therapeutic plasma exchange (two times per week). Patient was followed up until the delivery of a healthy baby boy and did not experience an episode of acute pancreatitis. ConclusionsWith adequate supervision and monitoring therapeutic plasma exchange represents a safe approach in pregnant women with FCS in order to reduce TGs and prevent pancreatitis. Therefore, we prevented potential complications for both mother and child.

Eruptive Xanthomas

Eruptive Xanthomas

The Effect of a Fat-Restricted Diet in Four Patients with Familial Chylomicronemia Syndrome: A Long-Term Follow-Up Study.

(1) Background: Familial chylomicronemia syndrome (FCS) is a very rare autosomal recessive disorder characterized by severely elevated triglycerides and clinical symptoms in early childhood mainly presenting with abdominal pain, acute pancreatitis and hepatosplenomegaly. Primary treatment is a lifelong very strict low-fat diet, which might be challenging in pediatric patients. So far, data about children with FCS are rare. The aim of this study was to show the familial chylomicronemia syndrome traffic light table for pediatric patients and to assess the dietary fat intake and impact on triglycerides in children with FCS. (2) Methods: We performed a retrospective analysis in four children (50% male) affected by FCS from the Department of Pediatrics and Adolescent Medicine, Medical University of Vienna between January 2002 and September 2020. (3) Results: The four patients presented with classical FCS symptoms and showed baseline triglycerides (TG) exceeding 30,000 mg/dL in two patients, 10,000 mg/dL and 2400 mg/dL in one patient each. After diagnosis, fat percentage of total daily caloric intake was decreased and resulted immediately in triglyceride reduction. In all patients, FCS was genetically confirmed by mutations in genes encoding lipoprotein lipase. Acute pancreatitis and hepatosplenomegaly disappeared under the fat-restricted diet. A FCS traffic light table was developed as a dietary tool for affected families. (4) Conclusions: A restriction of dietary fat between 10% to 26% of the total daily caloric intake was feasible and effective in the long-term treatment of genetically confirmed FCS in children and could reduce the risk for acute pancreatitis. The dietary tool, the pediatric FCS traffic light table and the age-appropriate portion sizes for patients between 1 to 18 years, supports children and their parents to achieve and adhere to the lifelong strict low-fat diet.

LPL/AQP7/GPD2 promotes glycerol metabolism under hypoxia and prevents cardiac dysfunction during ischemia.

In the heart, fatty acid is a major energy substrate to fuel contraction under aerobic conditions. Ischemia downregulates fatty acid metabolism to adapt to the limited oxygen supply, making glucose the preferred substrate. However, the mechanism underlying the myocardial metabolic shift during ischemia remains unknown. Here, we show that lipoprotein lipase (LPL) expression in cardiomyocytes, a principal enzyme that converts triglycerides to free fatty acids and glycerol, increases during myocardial infarction (MI). Cardiomyocyte-specific LPL deficiency enhanced cardiac dysfunction and apoptosis following MI. Deficiency of aquaporin 7 (AQP7), a glycerol channel in cardiomyocytes, increased the myocardial infarct size and apoptosis in response to ischemia. Ischemic conditions activated glycerol-3-phosphate dehydrogenase 2 (GPD2), which converts glycerol-3-phosphate into dihydroxyacetone phosphate to facilitate adenosine triphosphate (ATP) synthesis from glycerol. Conversely, GPD2 deficiency exacerbated cardiac dysfunction after acute MI. Moreover, cardiomyocyte-specific LPL deficiency suppressed the effectiveness of peroxisome proliferator-activated receptor alpha (PPARα) agonist treatment for MI-induced cardiac dysfunction. These results suggest that LPL/AQP7/GPD2-mediated glycerol metabolism plays an important role in preventing myocardial ischemia-related damage.

Abstract 10357: ARO-APOC3, an Investigational RNAi Therapeutic, Shows Similar Efficacy and Safety in Genetically Confirmed FCS and Non-FCS Participants with Severe Hypertriglyceridemia

Background: Familial chylomicronemia syndrome (FCS) is an ultrarare condition caused by biallelic pathogenic DNA variants in lipolysis-associated genes, resulting in severe hypertriglyceridemia (HTG) and associated with high risk of acute pancreatitis with few therapeutic options. In a 16-week Phase 1 study (NCT03783377), subcutaneously administered ARO-APOC3 reduced serum apolipoprotein C3 (APOC3) and TG in healthy volunteers and participants (pts) with HTG and was well tolerated. Purpose: To report on the safety/pharmacodynamic (PD) effects of ARO-APOC3 in both FCS pts with biallelic pathogenic variants and pts with severely elevated TG at screening (&gt;880 mg/dL) but without biallelic pathogenic variants (chylomicronemia (MCM)). Methods: Four genetically confirmed FCS pts received 50 mg ARO-APOC3 and 26 MCM pts received 10, 25, 50, or 100 mg ARO-APOC3 on Days 1 and 29. Since similar PD responses were observed among MCM pts, results were pooled across dose levels. Safety and PD responses were examined. Maximal mean/median changes from baseline for APOC3, TG, non-HDL-C, and HDL-C were reported. Results: Baseline/demographics were comparable between groups, except for mean BMI (22.1 [FCS] and 30.5 [MCM] kg/m 2 ), and mean baseline HDL-C , which were lower in FCS pts (Table 1) (p&lt;0.0001 for both). Mean APOC3 was reduced by 98% and 96% in FCS and MCM pts, respectively. Both groups also showed similar maximum median reductions in TG of 91% and 90%, respectively. Similar to the full study, non-HDL-C was reduced and HDL-C increased with treatment in both groups (Table 1). AEs were similar between groups, suggesting a comparable safety profile. Conclusions: In patients with severe HTG, ARO-APOC3 was safe, and consistently decreased APOC3, TG, and non-HDL-C, and increased HDL-C, regardless of underlying genetic cause of HTG, and may represent a promising RNAi therapeutic for the treatment of severe HTG.

Abstract 12054: Evinacumab Reduces Atherogenic Lipids and Apolipoprotein B in Patients With Severe Hypertriglyceridemia

Background: Hypertriglyceridemia (HTG) is the consequence of elevated triglyceride-rich lipoproteins (TGRLs) containing apolipoprotein B (apoB), such as VLDL and chylomicrons. Epidemiological and genetic studies indicate that triglycerides (TGs) and the cholesterol within TGRLs causally contribute to coronary heart disease risk (CHD). Evinacumab (EVIN), an angiopoietin-like 3 inhibitor, lowers TGs by derepressing lipoprotein lipase (LPL) and endothelial lipase activity. In a Phase 2 trial in patients (pts) with severe HTG (sHTG, fasting TGs ≥500 mg/dL), EVIN was previously shown to reduce TGs in patients (pts) without familial chylomicronemia syndrome (FCS) and to be generally well tolerated (NCT03452228). This post-hoc analysis reports further details on the efficacy of EVIN in reducing atherogenic lipids/lipoproteins. Methods: Pts (N=51) were treated and assigned to cohorts based on genotype: Cohort 1 (n=17), FCS pts with bi-allelic loss-of-function (LOF) LPL pathway mutations; Cohort 2 (n=15), multifactorial chylomicronemia syndrome (MCS) pts with heterozygous LOF LPL pathway mutations; Cohort 3 (n=19), MCS pts without LPL pathway mutations. Pts were randomized (2:1) to IV EVIN 15 mg/kg or placebo every 4 weeks over a 12-week double-blind treatment (tx) period (DBTP), followed by a 12-week single-blind tx period where all pts received EVIN. Results: Of 51 pts with sHTG treated in the DBTP, 70.6% were categorized as high cardiovascular risk, and 21.6% had a history of CHD. In non-FCS pts (Cohorts 2 and 3), in addition to reducing TGs, EVIN reduced atherogenic lipids and apolipoproteins at Week (W) 12 compared with baseline (Table), including non-HDL-C, remnant cholesterol, and apoB (including apoB100 and apoB48). Overall, reductions observed at W12 were maintained through W24. Conclusions: In this post-hoc analysis, EVIN reduced atherogenic lipids and apoB, indicating it may have the potential to reduce CHD risk in pts with sHTG without genetic FCS.