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JCL Roundtable: Global Think Tank on Lipoprotein(a)

Maher, Lisa L; Tokgözoğlu, S Lale; Sanchez, Eduardo J; Underberg, James A; Guyton, John R
Lipoprotein(a) operates in causal pathways to promote atherosclerosis, arterial thrombosis, and aortic stenosis. It has been associated with rare cases of nonatherosclerotic arterial thrombotic stroke at any age. Inherited variation of lipoprotein(a) levels substantially increases cardiovascular risk in 20% of people worldwide. Recent progress in identifying the risk associated with lipoprotein(a) and in pursuing effective treatment has led to a recent Global Think Tank including representatives from the European Atherosclerosis Society, American Heart Association, Preventive Cardiovascular Nurses Association, National Lipid Association, and other groups. The need for standardized laboratory measurement in nanomoles per liter met with unanimous consensus. Atherosclerotic risk is linearly associated with plasma lipoprotein(a) levels, so that persons with the highest levels may have risk similar to other severe inherited lipoprotein disorders. Universal once-in-lifetime screening has been recommended by European and Canadian cardiovascular societies, but not by U.S. organizations. Current pharmacologic therapies are limited to 20-30% lowering of lipoprotein(a) levels, and no pharmacologic treatment for lowering lipoprotein(a) has yet been proven to reduce risk in a cardiovascular outcomes trial. Treatment for high-risk patients focuses on reducing low density lipoprotein cholesterol and other risk factors. New therapies targeting messenger RNA for apolipoprotein(a) can achieve 80-90% reduction of lipoprotein(a) levels. One such therapy using a liver-directed antisense oligonucleotide is currently being tested in a large cardiovascular outcomes trial. Increased recognition of lipoprotein(a)-associated risk and emergence of potentially effective therapy together lead to a mandate for a unified global effort on education, standardization, and clinical management.
PMID: 34144765
ISSN: 1933-2874
CID: 4924682

Characterization of PCSK9 in the Blood and Skin of Psoriasis

Garshick, Michael S; Baumer, Yvonne; Dey, Amit K; Grattan, Ryan; Ng, Qimin; Teague, Heather L; Yu, Zu-Xi; Chen, Marcus Y; Tawil, Michael; Barrett, Tessa J; Underberg, James; Fisher, Edward A; Krueger, James; Powell-Wiley, Tiffany M; Playford, Martin P; Berger, Jeffrey S; Mehta, Nehal N
Mechanisms explaining the link between psoriasis, a proinflammatory condition, and cardiovascular disease are not fully known. PCSK9 is predominantly expressed in hepatocytes as a critical regulator of lipid metabolism, and clinical trials targeting PCSK9 reduce cardiovascular disease. Independent of its role in lipid metabolism, PCSK9 levels associate with endothelial dysfunction and predict cardiovascular events. We used two separate human psoriasis cohorts and the K14-Rac1V12-/+ murine model of psoriasis to investigate PCSK9 and cardiovascular risk in psoriasis. In both psoriasis cohorts (n = 88 and n = 20), PCSK9 levels were 20% and 13% higher than in age-, sex-, and cholesterol-matched controls, respectively (P < 0.05 for each comparison) and correlated with PASI (r = 0.43, P < 0.05). Despite no difference in hepatocyte expression, K14-Rac1V12-/+ mice demonstrated skin-specific PCSK9 staining, which was confirmed in human psoriatic lesional skin. In patients with psoriasis, PCSK9 levels correlated with impaired endothelial vascular health (e.g., early atherosclerosis, β = 4.5, P < 0.01) and log converted coronary artery calcium score (β = 0.30, P = 0.01), which remained significant after adjustment for Framingham risk, body mass index, and active biologic use. Taken together, these findings suggest, independent of cholesterol, an association between circulating PCSK9 and early as well as advanced stages of atherosclerosis in psoriasis.
PMID: 32615123
ISSN: 1523-1747
CID: 4580932

New cardiovascular prevention guidelines: How to optimally manage dyslipidaemia and cardiovascular risk in 2021 in patients needing secondary prevention?

Atar, Dan; Jukema, J Wouter; Molemans, Bart; Taub, Pam R; Goto, Shinya; Mach, François; CerezoOlmos, Cesar; Underberg, James; Keech, Anthony; Tokgözoğlu, Lale; Bonaca, Marc P
Elevated low-density lipoprotein cholesterol (LDL-C) is a principally modifiable cause of atherosclerotic cardiovascular disease; accordingly, recent European and US multisociety dyslipidaemia guidelines emphasise the importance of lowering LDL-C to reduce cardiovascular risk. This review provides perspectives on established and emerging agents that reduce LDL-C to help providers synthesize the abundance of new evidence related to prevention of cardiovascular disease. We provide hypothetical cases of patients with different cardiovascular risk factors and medical histories to illustrate application of current lipid-lowering guidelines in various clinical settings. As a core focus of preventive therapy, both European and US lipid management guidelines emphasise the importance of identifying patients at very high cardiovascular risk and treating to achieve LDL-C levels as low as possible, with European guidelines setting a goal of <1.4 mmol/L (<55 mg/dL) in patients with very high-risk cardiovascular disease. The proprotein convertase subtilisin/kexin type 9 inhibitors are now included in the guidelines and may fulfil an important unmet need for very high-risk patients who are not able to achieve LDL-C goals with conventional agents. The recently approved bempedoic acid and other promising agents under development will add to the armamentarium of lipid-lowering drugs available for clinicians to help patients meet their treatment goals.
PMID: 33476944
ISSN: 1879-1484
CID: 4771612

Long-term safety and efficacy of lomitapide in patients with homozygous familial hypercholesterolemia: Five-year data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER)

Underberg, James A; Cannon, Christopher P; Larrey, Dominique; Makris, Lukas; Blom, Dirk; Phillips, Helen
BACKGROUND:Lomitapide is a lipid-lowering agent indicated as adjunct therapy for homozygous familial hypercholesterolemia (HoFH) in adults. OBJECTIVE:The Lomitapide Observational Worldwide Evaluation Registry is an international, observational registry assessing long-term safety, tolerability, and effectiveness of lomitapide. METHODS:This analysis examines 5-year data from the registry up to February 28, 2019. RESULTS:At lomitapide initiation, enrolled patients (N = 187) were a mean ± SD age of 52.2 ± 15.3 years with a mean ± SD low-density lipoprotein cholesterol (LDL-C) measurement of 232.0 ± 94.9 mg/dL. Exposure duration was up to 5.9 years (median, 1.98 years), and median dose was 10 mg (range, 5 mg QOD to 40 mg QD). After treatment, there was a mean 33% reduction in LDL-C (45% in patients remaining on lomitapide), 65.4% achieved LDL-C <100 mg/dL, and 41.1% achieved LDL-C <70 mg/dL. At year 4, the absolute mean change from baseline in LDL-C was -70.6 ± 76.21 mg/dL. Adverse events (AEs) occurred in 75.7% of patients, treatment-related AEs in 54.6%, and serious AEs in 22.2%; 23.2% of patients discontinued because of an AE. Events of special interest included gastrointestinal (13.5%), hepatic (15.1%), major adverse cardiovascular events (10.8%, resulting in 5 deaths), tumors (2.2%), and 4 pregnancies in 3 of 32 women of childbearing potential. CONCLUSION/CONCLUSIONS:The efficacy and safety of lomitapide are consistent with phase III trial data despite using a much lower median dose of 10 mg vs 40 mg in phase III. No new safety signals were identified. The incidence of AEs, serious AEs, and aminotransferase alanine transaminase elevations was lower than that seen in the phase III trial, potentially related to the lower median dose.
PMID: 33023859
ISSN: 1933-2874
CID: 4636692

Genetic testing in dyslipidemia: A scientific statement from the National Lipid Association

Brown, Emily E; Sturm, Amy C; Cuchel, Marina; Braun, Lynne T; Duell, P Barton; Underberg, James A; Jacobson, Terry A; Hegele, Robert A
The genetic basis for more than 2 dozen monogenic dyslipidemias has largely been defined. Genetic technologies, such as DNA sequencing, can detect both rare and common DNA variants underlying dyslipidemias, and these methods are increasingly available. Although patients with extreme abnormalities in low-density lipoprotein cholesterol, triglycerides, or high-density lipoprotein cholesterol may be considered for genetic testing, it is only in a minority of patients that the results will alter treatment or outcomes. Currently, there is potential clinical utility of genetic testing for familial hypercholesterolemia, familial chylomicronemia syndrome, sitosterolemia, lysosomal acid lipase deficiency, and a few other rare disorders, and this will increase the demand for reliable genetic diagnostic methods at lower cost. Clinical indications for genetic testing for most dyslipidemias are not clearly established and currently no guidelines exist. A shared decision-making model between the patient and the provider is essential as patient values and preferences play a very strong role. Potential benefits of genetic testing include providing a firm diagnosis in many cases, guiding optimal management and prevention strategies, advancing care strategies beyond currently available treatments, and contributing to overall scientific progress. Understanding the limitations and risks of genetic testing techniques is also important, as is careful interpretation of genetic test results to achieve the greatest benefit. Here we review laboratory methods, as well as technical, biological, clinical, and ethical implications and applications of genetic testing in dyslipidemias.
PMID: 32507592
ISSN: 1933-2874
CID: 4489452

Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: The CASCADE FH registry

Duell, P Barton; Gidding, Samuel S; Andersen, Rolf L; Knickelbine, Thomas; Anderson, Lars; Gianos, Eugenia; Shrader, Peter; Kindt, Iris; O'Brien, Emily C; McCann, Dervilla; Hemphill, Linda C; Ahmed, Catherine D; Martin, Seth S; Larry, John A; Ahmad, Zahid S; Kullo, Iftikhar J; Underberg, James A; Guyton, John; Thompson, Paul; Wilemon, Katherine; Roe, Matthew T; Rader, Daniel J; Cuchel, Marina; Linton, MacRae F; Shapiro, Michael D; Moriarty, Patrick M; Knowles, Joshua W
BACKGROUND AND AIMS/OBJECTIVE:There are limited data from the US on outcomes of patients in specialty care for familial hypercholesterolemia (FH). METHODS:CASCADE FH Registry data were analyzed to assess longitudinal changes in medication usage, in low density lipoprotein cholesterol (LDL-C) levels, and the rate of major adverse cardiovascular events (MACE (myocardial infarction, coronary revascularization, stroke or transient ischemic attack) in adults with FH followed in US specialty clinics. RESULTS:The cohort consisted of 1900 individuals (61% women, 87% Caucasian), with mean age of 56 ± 15 years, 37% prevalence of ASCVD at enrollment, mean pretreatment LDL-C 249 ± 68 mg/dl, mean enrollment LDL-C 145 mg/dl and 93% taking lipid lowering therapy. Over follow up of 20 ± 11 months, lipid lowering therapy use increased (mean decrease in LDL-C of 32 mg/dl (p < 0.001)). Only 48% of participants achieved LDL-C < 100 mg/dl and 22% achieved LDL-C < 70 mg/dl; ASCVD at enrollment was associated with greater likelihood of goal achievement. MACE event rates were almost 6 times higher among patients with prior ASCVD compared to those without (4.6 vs 0.8/100 patient years). Also associated with incident MACE were markers of FH severity and conventional ASCVD risk factors. CONCLUSIONS:With care in FH specialized clinics, LDL-C decreased, but LDL-C persisted >100 mg/dl in 52% of patients. High ASCVD event rates suggest that adults with FH warrant designation as having an ASCVD risk equivalent. Earlier and more aggressive therapy of FH is needed to prevent ASCVD events.
PMID: 31487564
ISSN: 1879-1484
CID: 4067662

Cardiovascular Risk Factor Control and Lifestyle Factors in Young to Middle-Aged Adults with Newly Diagnosed Obstructive Coronary Artery Disease

Garshick, Michael S; Vaidean, Georgeta D; Vani, Anish; Underberg, James A; Newman, Jonathan D; Berger, Jeffrey S; Fisher, Edward A; Gianos, Eugenia
BACKGROUND:While progress in the prevention of cardiovascular disease (CVD) has been noted over the past several decades, there are still those who develop CVD earlier in life than others. OBJECTIVE:We investigated traditional and lifestyle CVD risk factors in young to middle-aged patients compared to older ones with obstructive coronary artery disease (CAD). METHODS:A retrospective analysis of patients with a new diagnosis of obstructive CAD undergoing coronary intervention was performed. Young to middle-aged patients were defined as those in the youngest quartile (n = 281, mean age 50 ± 6 years, 81% male) compared to the other three older quartiles combined (n = 799, mean age 69 ± 7.5 years, 71% male). Obstructive CAD was determined by angiography. RESULTS:Young to middle-aged patients compared to older ones were more likely to be male (p < 0.01), smokers (21 vs. 9%, p < 0.001), and have a higher body mass index (31 ± 6 vs. 29 ± 6 kg/m2, p < 0.001). Younger patients were less likely to eat fruits, vegetables, and fish and had fewer controlled CVD risk factors (2.7 ± 1.2 vs. 3.0 ± 1.0, p < 0.001). Compared to older patients, higher levels of psychological stress (aOR 1.6, 95% CI 1.1-2.4), financial stress (aOR 1.8, 95% CI 1.3-2.5), and low functional capacity (aOR 3.3, 95% CI 2.4-4.5) were noted in the young to middle-aged population as well. CONCLUSION/CONCLUSIONS:Lifestyle in addition to traditional CVD risk factors should be taken into account when evaluating risk for development of CVD in a younger population.
PMID: 31079098
ISSN: 1421-9751
CID: 3919402

Lowering LDL-cholesterol and CV benefits: Is there a limit to how low LDL-C needs to be for optimal health benefits?

Vani, Anish; Underberg, James A
Atherosclerotic cardiovascular disease (ASCVD) is the number one cause of morbidity and mortality worldwide. Low-density lipoprotein cholesterol (LDL-C) has been implicated as one of the major risk factors causing ASCVD based on multiple hierarchical levels of evidence. The advent of powerful LDL-C lowering therapies, such as the proprotein convertase subtilisin/kexin type 9 inhibitor, have raised the question of how low to target LDL-C and whether there are any adverse safety events associated with a very low LDL-C level. The present review summarizes the available evidence and concludes that even a very low LDL-C is associated with cardiovascular benefit, although the magnitude of benefit depends on baseline ASCVD risk and the absolute change in LDL-C with pharmacologic therapy. The safety data in patients treated to very low LDL-C is reassuring, although it is inconsistent and requires longer-term follow-up.
PMID: 29882959
ISSN: 1532-6535
CID: 3144662


Underberg, James; Cannon, Christopher P.; Larrey, Dominique; Makris, Lukas; Jurecka, Agnieszka; Blom, Dirk
ISSN: 1567-5688
CID: 3156072


Vani, Anish; Hurta, Vanessa; Underberg, James
ISSN: 1567-5688
CID: 3156062