Background/Synopsis Lipoprotein-X (LpX) is an abnormal, apolipoprotein B- (ApoB-)lacking lipoprotein enriched in free cholesterol and phospholipids that spuriously elevates reported low-density lipoprotein cholesterol (LDL-C). It is most often seen in cholestatic liver disease or in the rare condition lecithin-cholesterol acyltransferase (LCAT) deficiency, and even more rarely in immune-mediated cases of acquired LCAT dysfunction. Case Description A 72-year-old obese, nonsmoking man with long-standing severe high-density lipoprotein cholesterol (HDL-C) depression (3–9 mg/dL for >20 years), moderate-to-severe coronary artery calcification, and chronic kidney disease (stage 3b–4) was evaluated for persistently abnormal lipid profiles despite combination therapy including inclisiran, atorvastatin, and icosapent ethyl. Outcome Lipoprotein electrophoresis identified LpX on 2 measurements 9 months apart. Genetic testing via the Invitae Comprehensive Lipidemia Panel was negative for pathogenic variants, effectively excluding familial LCAT deficiency and other known monogenic causes. Mean total cholesterol was 148 mg/dL, triglycerides remained moderately elevated (mean 250 mg/dL), ApoB levels were controlled (mean 57 mg/dL), and LDL-C was uninterpretable in the presence of LpX. Hepatic enzymes and abdominal magnetic resonance imaging (MRI) demonstrated no evidence of cholestasis. This patient has demonstrated single-digit HDL-C for more than 2 decades, suggesting a more indolent and possibly distinct mechanism. Functional LCAT assays and autoantibody testing represent next diagnostic steps. Discussion Advanced liver disease can be associated with underlying lipid disorders and can cause dyslipidemias including extreme hypercholesterolemia. This phenotype of LpX with extreme HDL-C depression, in the absence of identifiable pathogenic genetic variants or evidence of cholestasis, raises suspicion for acquired LCAT dysfunction. Key diagnostic clues include temporal association with hepatic injury, LDL-C vs. ApoB discordance, absence of LpX, and negative genetic testing.

Background/Synopsis Familial hypercholesterolemia (FH) is characterized by severe hypercholesterolemia due to high levels of low-density lipoprotein cholesterol (LDL-C), tendon xanthomas, premature atherosclerotic cardiovascular disease (ASCVD), and strong family history of hypercholesterolemia and ASCVD. However, secondary causes such as diet-induced hypercholesterolemia can present with an FH-like phenotype but respond dramatically to dietary intervention. Case Description A 36-year-old Brazilian-born woman presented with severe hypercholesterolemia from elevated LDL-C and bilateral medial canthal xanthelasmas initially detected during pregnancy. Lipid panel obtained 6 weeks postpartum demonstrated LDL-C 339 mg/dL. Family history was significant for xanthelasmas and hypercholesterolemia in both parents and a sibling. A detailed dietary assessment revealed habitual consumption of 2–3 egg yolks daily and fatty red meat 3–4 times weekly, with dietary cholesterol estimated at approximately 600–700 mg and saturated fatty acid comprising > 15% of total daily energy. During her visit she was counseled on a Mediterranean-style dietary pattern. Outcome Comprehensive dyslipidemia genetic panel (36 genes including low-density lipoprotein receptor (LDLR), apolipoprotein B (ApoB), proprotein convertase subtilisin/kexin type 9 (PCSK9), low-density lipoprotein receptor adapter protein (LDLRAP1), ABCG5, ABCG8) was negative for pathogenic variants. Coronary artery calcium (CAC) score was zero. After 10 months of conscientious Mediterranean diet adherence, repeat lipids were greatly improved, representing a 75% reduction in LDL-C without pharmacotherapy. Xanthelasmas did not regress with lipid improvement; left-sided xanthelasma was surgically excised per patient preference. Discussion This case demonstrates an exceptional response to dietary modification in a patient with resolution of severe hypercholesterolemia (LDL-C > 300 mg/dL) and persistent xanthelasmas. The dramatic response to dietary intervention alone far exceeds the typical dietary responses reported in the literature and highlights the value of a comprehensive dietary assessment. Clinicians should evaluate diet as a cause for hypercholesterolemia in patients with severe hypercholesterolemia and counsel patients on a cardioprotective dietary pattern as part of the clinical management of this condition.Figures/Tables: 1

Background/Synopsis AB is a 40-year-old female with homozygous familial hypercholesterolemia (HoFH) found to have progressive symptomatic supra-valvular aortic stenosis. Objective/Purpose To review a clinical scenario of a patient with HoFH where regular surveillance of valvular heart disease can help optimize the treatment plan. Methods AB was seen in the office at Penn Lipid Clinic and Penn Aorta Center for further evaluation. Results AB is a 40-year-old female, diagnosed with HoFH before 1 year old, who already had tendon xanthomas present and total cholesterol level of more than 800 mg/dL. She has remained under close observation and care lifelong, and has undergone multiple cardiac catheterizations, echocardiograms, and stress tests. She receives monthly low-density lipoprotein (LDL) apheresis (since the age of 7 years), as well as rosuvastatin, evolocumab, evinacumab, and lomitapide. She undergoes yearly echocardiograms for known aortic valve stenosis. At age 37, she started developing progressive leg swelling, fatigue, and shortness of breath. Transthoracic Echocardiogram demonstrated a left ventricular ejection fraction of 71%, no segmental wall motion abnormalities, moderate to severe supravalvular aortic stenosis with elevated peak and mean gradients of 61 mmHg and 31 mmHg, respectively. Surgical planning is underway. Conclusions Homozygous Familial Hypercholesterolemia is a rare, monogenic lipid disorder characterized by severe elevations in low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic cardiovascular disease (ASCVD), aortic valve, and supra-aortic valve stenoses. Calcific aortic valve disease is the most described and earliest marker of hypercholesterolemia valvulopathy in patients with HoFH. Supravalvular aortic stenosis (SVAS) is an uncommon condition characterized by narrowing of the aorta just above the aortic valve, leading to left ventricular hypertrophy, reduced coronary blood flow, and high risk of sudden cardiac death if untreated. Early diagnosis and surveillance with timely surgical intervention are critical in such patients.

Background/Synopsis Familial Dysbetalipoproteinemia (previously known as type III hyperlipoproteinemia) is an underdiagnosed monogenic lipid disorder, characterized by potential to transform from normal to severe combined hyperlipidemia. Objective/Purpose To review a clinical scenario evaluating peripheral artery disease in a patient with Familial Dysbetalipoproteinemia. Methods Patient DL was seen in the office at Lipid Clinic at Penn for further evaluation. Results Initial lipid screen showed total cholesterol >1000 mg/dL and triglycerides >4000 mg/dL. Beta quantification after dietary modification demonstrated over 60% reduction in total cholesterol, almost 90% reduction in triglycerides, along with total cholesterol to apolipoprotein B (ApoB) ratio <10 and triglyceride to apolipoprotein B ratio >6.2, consistent with the diagnosis of familial dysbetalipoproteinemia. Due to high risk from the underlying lipid disorder and atypical foot/ankle discomfort, the patient underwent evaluation with ankle-brachial index (ABI) testing and vascular imaging, and was found to have peripheral artery disease in bilateral lower extremities. Conclusions The clinical clue for familial dysbetalipoproteinemia is combined hyperlipidemia with both total cholesterol and triglycerides typically above 300 mg/dL and roughly equal, along with disproportionately low ApoB. Peripheral artery disease (PAD) risk in these patients is over 13-fold higher than the average population, notably higher than the 3- to 5-fold increase in overall atherosclerotic cardiovascular disease (ASCVD) or the 5- to 10-fold increase in coronary artery disease (CAD) risk. Interestingly, the PAD risk in familial dysbetalipoproteinemia exceeds that in familial hypercholesterolemia (FH), primarily thought to result from beta-v low-density lipoprotein (LDL) remnant deposits in peripheral arteries. Individuals tend to be very diet-sensitive and respond favorably to both fibric acid derivatives and high-dose omega-3 fatty acids, while statin therapy can also have an impact. Making the correct diagnosis enables optimal treatment.Figures/Tables: 1

Background/Synopsis Lipoprotein(a) [Lp(a)] is a largely genetically determined, independent risk factor for atherosclerotic cardiovascular disease (ASCVD) with proatherogenic, pro-inflammatory, and prothrombotic properties. Its contribution to risk is not adequately captured by conventional lipid measures such as low-density lipoprotein cholesterol (LDL-C). Apolipoprotein B (ApoB), reflecting total atherogenic particle number, may better identify residual risk, particularly in individuals with markedly elevated Lp(a). Case Description A 71-year-old woman, never-smoker, with hypertension, hypercholesterolemia, and a strong family history of premature myocardial infarction was referred to preventive cardiology after cascade screening prompted by her son's elevated Lp(a). She was on long-term rosuvastatin 40 mg daily. Baseline lipids demonstrated total cholesterol (TC) 197 mg/dL, triglyceride (TG) 120 mg/dL, high-density lipoprotein cholesterol (HDL-C) 68 mg/dL, LDL-C 108 mg/dL, and Lp(a) 990 nmol/L. Coronary artery calcium score was 200. Coronary computed tomography (CT) angiography revealed non-obstructive but clinically significant coronary atherosclerosis, including mild-to-moderate stenosis of the left anterior descending artery with high-risk plaque features and mild plaque in the right coronary artery. Ezetimibe 10 mg daily was initiated. Outcome Follow-up testing showed LDL-C 77 mg/dL, TC 169 mg/dL, TG 112 mg/dL, HDL-C 72 mg/dL, Lp(a) 675 mg/dL, and ApoB 93 mg/dL. Despite LDL-C improvement, ApoB remained elevated, indicating persistent excess atherogenic particle burden. The patient was reclassified as very high risk due to extreme Lp(a), subclinical atherosclerosis with high-risk features, and strong familial predisposition. Escalation of therapy with a Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor was recommended, along with consideration for enrollment in an Lp(a)-targeted outcomes trial. Discussion This case illustrates the limitations of LDL-C as a sole risk marker in patients with extreme Lp(a) elevation. In such patients, the relative contribution of Lp(a) to the total ApoB pool may be substantially higher than usual, magnifying ASCVD risk beyond what LDL-C conveys. While LDL-C improved after ezetimibe addition, measurement of ApoB and Lp(a) clarified the mechanism of residual risk and altered diagnostic understanding. This case supports broader use of ApoB and Lp(a) to refine risk stratification and guide therapeutic intensity.Figures/Tables: 1

Background/Synopsis Severe hypertriglyceridemia (HTG) with mixed lipoprotein elevation can produce systemic manifestations beyond pancreatitis, including hyperviscosity-related symptoms. This case illustrates diagnostic evaluation, pathophysiologic mechanisms, and management decisions in a high-risk patient with secondary HTG. Case Description A 47-year-old male with poorly controlled type 2 diabetes mellitus (T2DM), prior HTG-induced pancreatitis, and bipolar I disorder on cariprazine, presented with atypical chest pain. Initial evaluation excluded acute pancreatitis and coronary disease. Initial lipid panels showed marked hypertriglyceridemia of 5538 mg/dL, with a high viscosity of 1.52. Advanced lipoprotein analysis demonstrated concurrent chylomicron and very low-density lipoprotein (VLDL excess, consistent with Type V hyperlipoproteinemia. Secondary contributors included uncontrolled T2DM (HbA1c 14.4%), obesity, poor dietary intake, cariprazine therapy, and excessive alcohol consumption. The care team elected to perform 3 sessions of plasmapheresis, followed by aggressive metabolic management. Outcome Prompt plasmapheresis led to rapid triglyceride reduction (314 mg/dL) and symptomatic relief. Patient was initiated on strict glycemic control, alcohol abstinence, dietary fat restriction, and long-term lipid-lowering therapy including fenofibrate, rosuvastatin, and icosapent ethyl. A heterozygous apolipoprotein (ApoE) ε2/ε4 genotype was identified. Most recent clinic follow-up labs included: triglyceride (TG) 389 mg/dL, high-density lipoprotein cholesterol (HDL-C) 28 mg/dL, low-density lipoprotein cholesterol (LDL-C) 38 mg/dL, apolipoprotein B (ApoB) 61 mg/dL. Patient denied chest symptoms on follow-up. Discussion This case emphasizes that Type V hyperlipoproteinemia, especially when driven by potent secondary triggers, can present with chest pain possibly mediated by hyperviscosity and microvascular dysfunction rather than coronary atherosclerosis. In high-risk patients with prior pancreatitis or extreme lipoprotein burden, plasmapheresis may be considered even in the absence of pancreatitis, particularly when paired with prompt metabolic correction. Accurate lipoprotein phenotyping, identification of secondary triggers, and individualized management are critical for acute stabilization and long-term risk reduction.Figures/Tables: 1

Background/Synopsis Familial dysbetalipoproteinemia (FD) is an uncommon monogenic dyslipidemia caused by variants in the apolipoprotein E (ApoE) gene. The majority of FD cases are associated with a homozygous ApoE epsilon2/epsilon2 genotype. Roughly 10–15% of these individuals develop an overt dysbetalipoproteinemia phenotype in the presence of a secondary metabolic condition. Case Description A 52-year-old female with a history of mixed hyperlipidemia, hypertension, and obesity presented with worsening dyslipidemia following a bilateral salpingo-oophorectomy at 45 years of age for metastatic cervical cancer. Family history was negative for hyperlipidemia. Physical exam was notable for palmar xanthomas and a body mass index (BMI) of 34. Lipid profile showed increased total cholesterol, triglycerides, and non-high-density-lipoprotein cholesterol (HDL-C) following surgical menopause. Further workup revealed an apolipoprotein B (ApoB) 107 mg/dL, hemoglobin A1c (HbA1c) 5.5%, and coronary artery calcium score of 25 (90–95th percentile). Genetic testing revealed a homozygous ApoE epsilon2/epsilon2 variant, establishing the diagnosis of FD. She was counseled on the importance of weight loss and dietary restriction of saturated fats and refined carbohydrates. Lipid-lowering therapy was initiated with rosuvastatin then fenofibrate, titrated to non-HDL-C. Discussion FD results from defective ApoE-mediated remnant clearance via low-density lipoprotein (LDL) receptor-related protein 1 (LRP1). The accumulation of remnant ApoB-containing lipoproteins confers a high risk of atherosclerotic cardiovascular disease (ASCVD), especially peripheral artery disease. Diagnosing FD is often difficult due to its incomplete penetrance, variable lipid profiles, and development in the presence of a secondary risk factor later in life. Management involves addressing the 'second hit' that precipitated dysbetalipoproteinemia (in this case, surgical menopause), optimizing lifestyle changes, and initiating lipid-lowering therapy titrated to non-HDL-C.Figures/Tables: 1

Background/Synopsis Extreme hypercholesterolemia typically prompts evaluation for monogenic lipid disorders such as familial hypercholesterolemia or rare mimics, including sitosterolemia and lysosomal acid lipase deficiency (LAL-D). Advanced liver disease, however, can produce a phenocopy that is managed differently. Case Description A 55-year-old woman with autoimmune hepatitis developed cirrhosis in 2023 after presenting with acute hepatocellular injury in the setting of nonsteroidal anti-inflammatory drug (NSAID) use. Following partial recovery of hepatic function, she developed progressive and extreme hypercholesterolemia characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) with normal triglycerides. Additional testing demonstrated elevation of plant sterols (sitosterol, cholestanol, and campesterol) and discordance between LDL-C and apolipoprotein B (ApoB). Lipoprotein X (LpX) was not detected. Lysosomal acid lipase (LAL) activity was mildly reduced on dried blood spot testing, likely secondary to hepatic dysfunction rather than a true enzyme deficiency. Comprehensive dyslipidemia gene panel testing revealed no pathogenic variants. Coronary computed tomography (CT) angiography showed normal coronary arteries. Low-dose rosuvastatin was initiated, followed by ezetimibe, targeting both hepatic cholesterol synthesis and intestinal sterol absorption. Discussion Advanced liver disease can be associated with underlying lipid disorders and can cause dyslipidemias including hypercholesterolemia. Key diagnostic clues include temporal association with hepatic injury, LDL-C vs ApoB discordance, absence of LpX, and negative genetic testing with a complete "dyslipidemia" panel. This case highlights the importance of considering secondary hepatic causes of extreme dyslipidemia to guide appropriate diagnosis and management.Figures/Tables: 1

Background/Synopsis Lipoprotein(a) [Lp(a)] is mostly genetically determined and relatively stable over time with modest variability reported in several conditions. Longitudinal clinical observations demonstrating large, reversible Lp(a) changes during malignancy remain limited. We report a longitudinal case of marked Lp(a) fluctuation in renal cell carcinoma. Case Description A 69-year-old male with prior myocardial infarction at age 48 was followed in preventive cardiology clinic with serial Lp(a) measurements from 2006 to 2021. Baseline Lp(a) in 2006 was 142 mg/dL (>4x upper limit of normal [ULN]). Between 2017 and 2018, the patient participated in a phase II antisense oligonucleotide (ASO) trial targeting Lp(a), and inadvertently, his on-treatment Lp(a) results were unblinded and unchanged. In April 2021, evaluation for gross hematuria revealed stage III clear cell renal cell carcinoma (ccRCC) with a 7.2 cm mass and inferior vena cava tumor thrombus; Lp(a) peaked at 616 nmol/L (>8x ULN). Outcome Following radical nephrectomy with tumor thrombectomy, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy was initiated and niacin discontinued with subsequent decline in Lp(a) to 342 nmol/L (>4x ULN), approximating historical baseline. Post-nephrectomy creatinine was 1.4 mg/dL (estimated glomerular filtration rate [eGFR] 52 mL/min/1.73 m²), consistent with new-onset chronic kidney disease (CKD) stage 3a. Discussion This case demonstrates marked elevation of Lp(a) during active renal cell carcinoma with subsequent return toward baseline following tumor resection despite eGFR reduction. The approximate 50% reduction after nephrectomy/thrombectomy suggests other physiologic factors may have contributed. These findings highlight the importance of clinical context when interpreting Lp(a) levels and support further investigation into malignancy- and thrombosis-associated modulation of Lp(a).Figures/Tables: 1

Familial hypercholesterolemia (FH) is a common genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol (LDL-C), leading to a high risk of early onset atherosclerotic cardiovascular disease (ASCVD). This document provides an update to the National Lipid Association's 2011 clinical guidance, summarizing the remarkable progress in the field. With a global prevalence of approximately 1 in 311, FH remains severely underdiagnosed. This guidance reviews current diagnostic criteria, including the expanding role of genetic testing to complement diagnosis and to facilitate cascade screening, and emphasizes a thorough differential diagnosis. It provides recommendations for universal pediatric screening and systematic cascade screening in families to improve detection. Management strategies include intensified LDL-C treatment goals for both primary and secondary prevention of ASCVD. A stepwise approach to optimal therapy is outlined, beginning with lifestyle interventions and pharmacotherapy with maximally tolerated statins and ezetimibe. This update incorporates newer agents, including proprotein convertase subtilisin/kexin type 9 inhibitors and bempedoic acid. Additional therapies, such as lomitapide and evinacumab for homozygous FH and lipoprotein apheresis for heterozygous and homozygous FH, are discussed. Further topics include cardiovascular imaging for risk stratification, management in specific populations and circumstances, such as planning for and during pregnancy and in pediatrics, and recognition of health disparities. This guidance equips clinicians with evidence-based strategies to improve the identification and care of patients with FH, ultimately reducing the high morbidity and mortality associated with this condition.

Background/Synopsis Lipodystrophy constitutes a heterogeneous group of rare acquired or inherited conditions characterized by adipose tissue deficiency, typically manifesting in hypertriglyceridemia, insulin resistance, hyperglycemia, and fatty liver. Type 2 Familial Partial Lipodystrophy (FPLD2), also known as Dunnigan variant, is an autosomal dominant disorder with onset around puberty characterized by absence of adiposity in limbs and trunk with increased face and neck fat deposition, sometimes associated with skeletal muscle hypertrophy and phlebomegaly. Here, we describe a patient with history of severe hypertriglyceridemia (HTG) and type 1 diabetes (T1DM) who developed premature multivessel coronary artery disease (CAD) and ischemic cardiomyopathy, ultimately diagnosed with FPLD2. Objective/Purpose Not applicable to this case study abstract submission. Methods Case study. Results LD is a 41-year-old female with newly diagnosed ischemic cardiomyopathy (EF 38%), triple-vessel CAD status-post drug-eluting stent to mid-LAD, severe HTG complicated by recurrent acute pancreatitis, and T1DM. Since childhood, LD reported insatiable appetite despite a thin, muscular frame disproportionate to normal activity. At 19, she was diagnosed simultaneously with T1DM, acute pancreatitis, and severe HTG. Family history was notable for a maternal aunt with similar body morphology and metabolic disease. At evaluation, her only complaint was persistent hunger, though less intense than during early adulthood. Hgb A1C was 7.0% on a continuous insulin pump at 1U/hr requiring minimal bolus dosing for meals. Physical exam was notable for absence of abdominal adiposity below the upper chest with sparing of the head and neck, muscular calf muscles, and prominent peripheral veins, consistent with FPLD2. Figure 1 reports lipid panel on high-intensity statin. She had normal serum creatinine, transaminase levels, thyroid stimulating hormone, and urine albumin-creatinine ratio. She was prescribed icosapent ethyl and introduced to a lipodystrophy patient advocacy group. Fasting leptin and genetic testing were ordered, but not completed. Conclusions Lipodystrophy is a clinical diagnosis based on physical exam, family and personal history, and metabolic features of insulin resistance and may be supported by genetic testing. Based on LD's adipose distribution, dyslipidemia, and family history, FPLD2 was diagnosed. Initial management involves targeting insulin resistance and treatment of comorbid sequelae. Metreleptin (recombinant leptin analog) is approved for severe generalized lipodystrophy and under investigation for partial lipodystrophy, while a similar leptin receptor agonist trial was terminated. LD expressed gratitude that knowing her diagnosis and connecting with others made her feel less alone and more supported. This case highlights the importance of considering lipodystrophy in the differential diagnosis of patients presenting with atypical features of classical metabolic syndrome and suggestive adipose distribution.

Background/Synopsis Lipoprotein(a) [Lp(a)] is an established causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) is 70-90% genetically determined, traditionally thought to reach steady state adult levels by age 5 in most individuals. However, certain biological states have been shown to alter Lp(a) plasma levels. Driven by adverse cardiometabolic changes in the absence of estrogen, menopause has been shown to accelerate cardiovascular risk. Population-based studies have identified an association between the menopause transition and an increase in Lp(a) levels, with a blunted response conferred by hormone replacement therapy. Here we describe a patient who developed a marked increase in Lp(a) levels after both menopause and initiation of anastrozole therapy for breast cancer (BC). Objective/Purpose To understand the effect of meno-pause on serum Lp(a). Methods Manual chart review of clinic visits. Results A 68-year-old female with estrogen receptor positive localized BC status post lumpectomy and radiation, on anastrozole maintenance therapy, 32-pack-year smoking history in remission, class I obesity, and hypercholesteremia presented to the preventive cardiology clinic for evaluation of elevated Lp(a). At age 48, her Lp(a) was 12 mg/dL. At age 53, she attained menopause after a bilateral salpingo-oophorectomy. At age 63, she was diagnosed with BC, underwent resection and 52 fractions of radiation followed by maintenance anastrozole therapy. Evaluation was notable for Lp(a) 151 mg/dL (> 4x ULN) (Figure 1) and Coronary Artery Calcium (CAC) score 64 (74th percentile for age). The patient's cardiovascular risk was addressed with the addition of aspirin to her existing regimen of high-intensity statin and ezetimibe therapy. Conclusions In this case, our patient was found to have > 12-fold increase in Lp(a) 15 years post-menopause and 5 years post initiation of anastrozole. The patient's elevated CAC is likely multifactorial, driven by her smoking history, recent radiation therapy, elevated Lp(a), and hypercholesterolemia. Limited data exists on the effect of anastrozole on Lp(a) expression. In one study of post-menopausal BC patients, anastrozole led to an increase in Lp(a) levels only in patients previously treated with tamoxifen. This effect was thought to be driven by tamoxifen withdrawal rather than directly from anastrozole itself. Further investigation is needed to elucidate the mechanism of Lp(a) expression and its association with menopause and aromatase inhibitors. This will help inform whether repeat Lp(a) testing is warranted in post-menopausal women to guide CV risk-management in this elevated risk population.

Background: ApoB-containing lipoproteins, including LDL, are well-established causes of atherosclerotic cardiovascular disease (ASCVD). While typically highly correlated, apoB and LDL-C levels can diverge due to differences in lipid composition and response to lipid-lowering therapies (LLT). Furthermore, the definition of cutpoints can influence clinically-relevant discordance between LDL-C and apoB, which may inform guideline-directed treatment. Recent proposals suggest aligning LDL-C and apoB goals using equivalent cutpoints (<55, <70, and <100 mg/dL). Clarifying the prevalence and impact of discordance has important implications for clinical care. Objectives: To quantify the prevalence of LDL-C and apoB discordance among US adults when applying equivalent LDL-C and apoB goals. Methods: We included 298,578 adults (age ≥18) with available apoB and LDL-C measurements from the Very Large Database of Lipids (VLDbL), a population-representative convenience sample with clinical lipid measurements obtained in 2015-2019. We also included 2,707 statin-treated adults from the National Health and Nutrition Examination Survey (NHANES) from 2005-2016 to assess the effects of statin use on discordance. The Martin-Hopkins equation was used to calculate LDL-C. Equivalent goals of <55, <70, and <100 mg/dL for LDL-C and apoB were applied. Results: In VLDbL (mean age 56 years, 57% female), 43.2% had apoB and LDL-C discordance ( Table 1 ). In NHANES statin-treated individuals (mean age 66 years, 47% female), 33.9% had apoB and LDL-C discordance. Among those reaching LDL-C goals of <55, <70, and <100 mg/dL, apoB was discordantly elevated in up to 33%, 12%, and 2%, respectively, for equivalent goals ( Figure 1 ). In contrast, among those reaching apoB goals of <55, <70, and <100 mg/dL, LDL-C was discordantly elevated in up to 61%, 56%, and 49%, respectively, for equivalent goals ( Figure 2 ). Conclusions: LDL-C and apoB discordance was prevalent among US adults, most often due to discordant LDL-C elevation in those reaching equivalent apoB goals, with less discordance in statin-treated adults. These results suggest that using LDL-C and apoB individually as treatment goals could lead to substantially different patient populations eligible for LLT to reduce ASCVD risk, while utilizing both as complementary goals could maximize eligibility for LLT. Taken together, these findings suggest an opportunity for an individualized approach to ASCVD risk optimization.

Introduction: Intracerebral Hemorrhage (ICH) is associated with a high case fatality and survivors of ICH are at increased risk for ICH recurrence. Roughly 20-30% of patients with ICH take a statin at the time of ICH onset. The role of statins, whether protective or deleterious, in the setting of ICH remains unclear. The SPARCL (Stroke Prevention by Aggressive Reduction of Cholesterol Level) study amongst others, have suggested that statin use may increase risk of ICH in those with prior history ICH, due to increased erythrocyte fragility and inhibition of platelet aggregation. However subsequent observational studies refuted these findings citing statins improve endothelial function and reduce oxidative stress thus theoretically. We reviewed relevant studies discussing the relationship between statin use and risk of ICH. Methods: A comprehensive search strategy utilizing the key terms “statin use” and “intracerebral hemorrhage” was performed utilizing four electronic databases: Cochrane, Embase, Google Scholar, PubMed. The search was conducted by two authors (PM and CO). Following the search, articles citing a correlation between statin use and risk of intracerebral hemorrhage were included. Below is a table citing selected studies from our review (Table 1). Discussion: There continues to be mixed evidence regarding statin use and risk of ICH. Current clinical guidelines do not provide a formal recommendation on statin use restriction in those with prior ICH. However, contrary to the SPARCL study, newer studies have suggested there is neither a statistically nor clinically significant relationship between LDL-C and ICH incidence. Our review also uncovered that one’s genetic signature may play a mediating role in this relationship as evidenced namely by the Honolulu Heart study, which analyzed a relatively monogenic study population. This implies a more nuanced relationship and we posit the burgeoning use of polygenic risk scoring may provide more utility here as well. Ultimately consideration of statin therapy should be determined by weighing one’s atherogenicity versus propensity to develop ICH. An optimal LDL-C goal has yet to be determined however many studies suggest targeting between 70-160 mg/dL is optimal. Additional studies should assess the role of other lipid lowering agents in the setting of ICH such as bempedoic acid and PCSK9 inhibitors, as well as discern optimal ranges for newer Apo-B and Lp(a) lipid biomarkers.

Background: Familial partial lipodystrophy (FPLD) is a rare genetic disorder often underrecognized in clinical practice. Given its phenotypic overlap with common metabolic disorders, its identification as an underlying clinical syndrome is often delayed. Case: A 41-year-old woman with type 1 diabetes mellitus (diagnosed following acute pancreatitis at age 19), necrobiosis lipoidica, combined hyperlipidemia, and prior triglyceride levels >1,000 mg/dL presented to the care with progressive exertional dyspnea. Physical examination revealed increased facial and nuchal adiposity with thin extremities featuring prominent veins, suggesting abnormal fat distribution. She had a recent marked improvement in her metabolic control (A1c down to 7.0% from 14.5%; triglycerides down to 112 mg/dL from 1160mg/dL) found to have NT-proBNP of 6,489 pg/mL and mildly elevated high-sensitivity troponin. Echocardiography revealed an LVEF of 38% with new regional wall motion abnormalities as well as grade 2 diastolic dysfunction. Invasive hemodynamics testing was notable for elevated bi-atrial filling pressures and subsequent coronary angiography revealed multivessel coronary artery disease. Given the patient's selective fat loss, early-onset insulin-resistant diabetes, prior hypertriglyceridemia, and now premature cardiovascular disease leading to an ischemic cardiomyopathy, a unifying diagnosis of lipodystrophy was suspected. Genetic testing confirmed a pathogenic LMNA variant, consistent with type 2 familial partial lipodystrophy, also known as Dunnigan type. Discussion: This case underscores the importance of pattern recognition in patients with atypical cardiometabolic profiles. The diagnosis of FPLD helped clarify the etiology of this patient’s cardiomyopathy and provided insight into her prior metabolic derangements. Early identification of LMNA mutations is crucial due to associated risks of arrhythmias, worsening cardiomyopathies, and sudden cardiac death. It also provided the patient with an explanation for her body morphology and the severity of her metabolic conditions, which she reported has reduced her body shame and enabled her to cope with her condition better. Conclusion: Familial partial lipodystrophy should be considered in individuals with abnormal fat distribution, severe dyslipidemia, insulin resistance, and premature cardiovascular disease. Timely genetic testing can guide management and provide answers for patients who have delays in diagnosis.

Background/Synopsis Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by very low levels of plasma low-density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB), caused by pathogenic variant in the apoB gene that results in defective apoB, and low risk for atherosclerotic cardiovascular disease (ASCVD). The defective apoB interferes with normal synthesis and export of very low-density lipoprotein (VLDL) and hepatic steatosis. Other genetic variants may result in very low LDL-C and apoB and ASCVD risk as well, but the genetic cause may impact the phenotype differently. We present a case of FHBL caused by a monoallelic PCSK9 loss-of-function mutation, associated with metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus (T2DM). Objective/Purpose To review a clinical scenario involving metabolic dysfunction and insulin resistance in the setting of an adult with PCSK9 loss-of-function gene variant. Methods Manual chart review of endocrinology and preventive cardiology outpatient clinic visits. Results A 34-year-old transgender male with history of persistent low LDL-C and apoB was found to have monoallelic loss-of-function variant (gross exon 1 deletion) of the PCSK9 gene. Medical history was notable for MASH and insulin resistance with T2DM diagnosed at 33 years of age. There was no evidence of metabolic syndrome, alcohol or substance use disorder, or family history of diabetes. He is overweight (BMI 28 kg/m2). Medications included tirzepatide. Labs were notable for a very low LDL-C and mildly elevated transaminases. Testing for type 1 diabetes mellitus, including antibodies against insulin, GAD-65, IA-2, and ZNT8 were negative. Fibrosure ultrasound demonstrated evidence of hepatic fibrosis. Workup for hepatitis, including infectious, autoimmune, and genetic etiologies was otherwise negative. Conclusions Hypobetalipoproteinemia (HBL) due to a defective APOB is associated with significant fatty liver disease attributed to the underlying mechanism. However, PCSK9 loss-of-function results in low levels of LDL-C and apoB due to enhanced LDL clearance, which should not increase liver fat significantly. We speculate the hepatic steatosis/fibrosis and diabetes are not related to the inherited low LDL syndrome in this case since enhanced hepatic LDL clearance by inherited or acquired (pharmacologic) has not been reported to have this effect previously. We introduce this case report as a novel entry in the scientific literature.

Funding Funding for this research was provided by Ionis Pharmaceuticals to Avalere Health, Daniel E. Soffer, and Seth J. Baum. Background/Synopsis Severe hypertriglyceridemia (sHTG), defined as triglyceride (TG) levels ≥ 500 mg/dL, is an important risk factor for acute pancreatitis (AP), a condition characterized by pancreatic inflammation and that typically necessitates hospitalization. While most cases of AP resolve during the acute phase of illness, long-term complications requiring ongoing care often occur. Objective/Purpose To estimate incremental levels of healthcare utilization (HCU) and healthcare expenditures (HCE) following hospital admission for AP among patients with sHTG. Methods A retrospective pre/post-cohort design and data (2015-2019) from the Merative MarketScan Research Databases (Commercial/Medicare [healthcare claims], Labs [test results]) were employed. The study population comprised adults with evidence of sHTG who were hospitalized for AP (admission date = index date), which was identified via inpatient stays with a principal diagnosis code for AP or secondary diagnosis code for AP in combination with a principal diagnosis code for an AP-related complication (e.g., sepsis, organ failure). Study measures included the characteristics and complications associated with the index AP event, 1-year risk of recurrent AP and chronic pancreatitis, as well as levels of all-cause HCU/HCE (2024 USD) during the 1-year pre/post-index periods (and corresponding differences). Study measures were annualized, as appropriate, and were summarized via means, percentages, and 95% confidence intervals (CI). Results Among the 115 patients in the study population, mean age was 46 years, 74% were male, and mean TG was 1414 mg/dL; common comorbidities included hypertension (70%) and diabetes (57%). Evidence of complications during the index admission included: necrotizing pancreatitis, 6%; organ failure, 26%; sepsis, 10%; and systemic inflammatory response syndrome, 14%. Annualized (post-index) rates of recurrent AP and chronic pancreatitis were 11% and 13%, respectively. Mean annualized levels of HCU during the post-index (vs. pre-index) period were higher by 2.0 (2.2 vs. 0.2) for hospitalizations, 11.1 (12.3 vs. 1.1) for hospital days, and 12.3 (31.5 vs. 19.2) for ambulatory encounters. Mean annualized levels of HCE were higher by $58,522 ($64,155 vs. $5,633) for hospitalizations, $7,157 ($16,421 vs. $9,264) for ambulatory encounters, and $69,110 ($90,835 vs. $21,725) on an overall basis. Conclusions Healthcare costs among hospitalized AP patients with sHTG are high, not only for initial inpatient care, but also for subsequent treatment of AP-related complications and sequelae. Interventions aimed at lowering TG levels among patients with sHTG, and thus decreasing the risk of AP, have the potential to yield significant reductions in preventable costs.

Funding Funding for this research was provided by Ionis Pharmaceuticals to Avalere Health, Daniel E. Soffer, and Seth J. Baum. Background/Synopsis Severe hypertriglyceridemia (sHTG), defined as fasting triglyceride (TG) level ≥ 500 mg/dL, is associated with increased risks of acute pancreatitis and atherosclerotic cardiovascular disease. Real-world evidence on levels of healthcare use and costs among patients with sHTG, and the marginal increase in use and costs among these patients relative to those without sHTG, is currently lacking. Such information is important for determining potential patient, public health, and economic benefits from the use of new TG-targeting therapies. Objective/Purpose To characterize levels of healthcare utilization and expenditures among patients with sHTG, and for purposes of comparison, patients without sHTG, in US clinical practice. Methods A retrospective cohort design and data from the MarketScan Research Databases (01/01/13-12/31/19) were employed. Study population comprised adults aged ≥ 18 years and was stratified based on the first observed (“index”) TG value (< 150, 150-499, 500-879, ≥ 880 mg/dL). Study measures—all-cause healthcare utilization and expenditures (2024 USD), overall and by care setting—were ascertained from the date of the index TG value to the end of the subsequent 12-month period, the date of health plan disenrollment, or last date of the study period, whichever occurred first. All-cause healthcare utilization and expenditures were annualized (i.e., adjusted for differential follow-up) and reported per patient (mean, 95% confidence intervals [CI]) within TG-specific subgroups. Results Study population totaled 1.8M adults (by index TG: < 150, N≈1.3M [73.5%]; 150-499, N≈449K [25.6%]; 500-879, N = 12,050 [0.7%]; ≥ 880, N = 3,944 [0.2%]). Mean age ranged from 48 (TG < 150) to 51 years (TG 150-499), percentage male from 41% (TG < 150) to 74% (TG 500-879), and use of lipid-lowering therapy from 16% (TG < 150) to 33% (TG ≥ 880). Mean (95% CI) annualized levels of all-cause healthcare utilization increased monotonically with increasing TG value (range, from < 150 to ≥ 880): hospitalizations, 0.07 (0.07-0.07) to 0.15 (0.13-0.16); hospital days, 0.34 (0.34-0.34) to 0.73 (0.64-0.83); ambulatory visits, 13.73 (13.70-13.76) to 16.00 (15.39-16.63). Mean (95% CI) annualized expenditures also increased monotonically—with one exception (i.e., outpatient pharmacy)—across TG values: hospitalizations, $2,154 (2,131-2,179) to $5,547 (4,759-6,465); ambulatory visits, $5,263 (5,232-5,295) to $7,253 (6,623-7,942); outpatient pharmacy, $2,327 (2,304-2,350) to $5,534 (4,692-6,528); total, $9,749 (9,695-9,803) to $18,099 (16,699-19,616). Conclusions Healthcare utilization and expenditures are substantially higher among adults with (vs. without) sHTG in US clinical practice. Strategies and interventions that more effectively manage sHTG, and thus reduce the risks of serious consequences of sHTG, have the potential to yield important patient, public health, and economic benefits.

BACKGROUND:Left ventricular outflow tract (LVOT) obstruction is a potentially fatal complication of transcatheter mitral valve replacement (TMVR), particularly in patients with anatomically high-risk features. LAMPOON (laceration of the anterior mitral leaflet to prevent outflow obstruction) is a transcatheter electrosurgical technique developed to mitigate this risk by modifying anterior mitral leaflet anatomy prior to valve deployment. OBJECTIVE:We describe our institutional experience with LAMPOON as a preventive strategy in TMVR cases with a high predicted risk for neo-LVOT obstruction. METHODS:This case series includes patients with high-risk anatomical features who underwent TMVR with LAMPOON. Variations of the LAMPOON technique, including antegrade and tip-to-base approaches using the "flying-V" electrosurgical wire configuration, were employed based on individual anatomy. CONCLUSIONS:All patients underwent successful anterior mitral leaflet laceration, with no significant LVOT obstruction. Antegrade and tip-to-base LAMPOON techniques are safe and effective adjuncts to TMVR in patients at high risk of LVOT obstruction.