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Variation in lipoprotein(a) response to potent lipid lowering: The role of apolipoprotein (a) isoform size

Akinlonu, Adedoyin; Boffa, Michael B; Lyu, Chen; Zhong, Judy; Jindal, Manila; Fadzan, Maja; Garshick, Michael S; Schwartzbard, Arthur; Weintraub, Howard S; Bredefeld, Cindy; Newman, Jonathan D; Fisher, Edward A; Koschinsky, Marlys L; Goldberg, Ira J; Berger, Jeffrey S
BACKGROUND:Lipoprotein(a) [Lp(a)] is a driver of residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) decrease Lp(a) with significant heterogeneity in response. We investigated contributors to the heterogeneous response. METHODS:CHOlesterol Reduction and Residual Risk in Diabetes (CHORD) was a prospective study examining lipid lowering in participants with a low-density lipoprotein cholesterol (LDL-C) >100 mg/dL with and without diabetes (DM) on lipid lowering therapy (LLT) for 30-days with evolocumab 140 mg every 14 days combined with either atorvastatin 80 mg or ezetimibe 10 mg daily. Lp(a) level was measured by immunoturbidometry, and the apolipoprotein (a) [apo(a)] isoform size was measured by denaturing agarose gel electrophoresis and western blotting. We examined the change in Lp(a) levels from baseline to 30 days. RESULTS:Among 150 participants (mean age 50 years, 58% female, 50% non-White, 17% Hispanic, 50% DM), median (interquartile range) Lp(a) was 27.5 (8-75) mg/dL at baseline and 23 (3-68) mg/dL at 30 days, leading to a 10% (0-36) median reduction (P < 0.001). Among 73 (49%) participants with Lp(a) ≥30 mg/dL at baseline, there was a 15% (3-25) median reduction in Lp(a) (P < 0.001). While baseline Lp(a) level was not correlated with change in Lp(a) (r = 0.04, P = 0.59), apo(a) size directly correlated with Lp(a) reduction (P < 0.001). After adjustment for age, sex, race/ethnicity, DM, and type of LLT, apo(a) size remained positively associated with a reduction in Lp(a) (Beta 0.95, 95% confidence interval, 0.93-0.97, P < 0.001). CONCLUSION/CONCLUSIONS:Our data demonstrate variation in Lp(a) reduction with potent LLT. Change in Lp(a) was strongly associated with apo(a) isoform size.
PMID: 39828454
ISSN: 1933-2874
CID: 5777992

Statin Use and Hyperglycemia: Do Statins Cause Diabetes?

Bredefeld, Cindy L; Choi, Paula; Cullen, Tiffany; Nicolich-Henkin, Sophie J; Waters, Lauren
PURPOSE OF REVIEW/OBJECTIVE:Atherosclerotic cardiovascular disease (ASCVD) and diabetes are leading causes of morbidity and mortality in the United States and globally. Statin medications, a cornerstone of ASCVD prevention and treatment strategies, have been demonstrated to cause hyperglycemia and new onset diabetes mellitus (NODM). The purpose of this review is to summarize existing and emerging knowledge around the intersection of statins and these two important clinical problems. RECENT FINDINGS/RESULTS:Since initial reporting of statin-induced hyperglycemia and NODM, the totality of available data corroborates an association between incident diabetes and statin use. A consensus that high-intensity statin and individuals with obesity or glycemic parameters approximating diabetes thresholds constitute the majority of risk exists. Alterations in insulin signaling, glucose transport and gastrointestinal microbiota are leading hypotheses underlying the mechanisms of statin-induced hyperglycemia. The probability of NODM based on an individual's risk factors and statin specific properties can be anticipated. This risk needs to be contextualized with the risk of ASCVD. In order to effectively adjudicate the risk of NODM, improvement in formulating and ultimately conveying a comprehensive ASCVD risk assessment to patients is necessary.
PMID: 39699704
ISSN: 1534-6242
CID: 5764732

A novel mutation, Ile344Asn, in microsomal triglyceride transfer protein abolishes binding to protein disulfide isomerase

Valmiki, Swati; Bredefeld, Cindy; Hussain, M Mahmood
Microsomal triglyceride transfer protein (MTP) plays crucial roles in the assembly and secretion of apolipoprotein B-containing lipoproteins and loss of function MTP variants are associated with abetalipoproteinemia, a disease characterized by the absence of these lipoproteins. MTP is a heterodimeric protein of two subunits, MTP and protein disulfide isomerase (PDI). In this study, we report a proband with abetalipoproteinemia who was monitored annually over a period of ten years in her third decade and had very low plasma lipids and undetectable apoB-containing lipoproteins. Genetic testing revealed biallelic variants in the MTTP gene. She has a well-documented nonsense mutation Gly865* that does not interact with the PDI subunit. She also has a novel missense MTP mutation, Ile344Asn. We show that this mutation abrogates lipid transfer activity in MTP and does not support apolipoprotein B secretion. This residue is present in the central α-helical domain of MTP and the substitution of Ile with Asn at this position disrupts interactions between MTP and PDI subunits. Ile344 is away from the known MTP:PDI interacting sites identified in the crystal structure of MTP suggesting that MTP:PDI interactions are more dynamic than previously envisioned. Identification of more missense mutations will enhance our understanding about the structure-function of MTP and the role of critical residues in these interactions between the two subunits. This knowledge may guide us in developing novel treatment modalities to reduce plasma lipids and atherosclerosis.
PMID: 39672332
ISSN: 1539-7262
CID: 5761962

Abetalipoproteinemia with angioid streaks, choroidal neovascularization, atrophy, and extracellular deposits revealed by multimodal retinal imaging

Bijon, Jacques; Hussain, M Mahmood; Bredefeld, Cindy L; Boesze-Battaglia, Kathleen; Freund, K Bailey; Curcio, Christine A
PURPOSE/UNASSIGNED:Abetalipoproteinemia (ABL, MIM 200,100) is a rare autosomal recessive disorder caused by nonfunctional microsomal triglyceride transfer protein leading to absence of apolipoprotein B-containing lipoproteins in plasma and a retinitis pigmentosa-like fundus. The MTTP gene is expressed in retinal pigment epithelium (RPE) and ganglion cells of the human retina. Understanding ABL pathophysiology would benefit from new cellular-level clinical imaging of affected retinas. METHODS/UNASSIGNED:We report multimodal retinal imaging in two patients with ABL. Case 1 (67-year-old woman) exhibited a bilateral decline of vision due to choroidal neovascularization (CNV) associated with angioid streaks and calcified Bruch membrane. Optical coherence tomography were consistent with basal laminar deposits and subretinal drusenoid deposits (SDD). RESULTS/UNASSIGNED:Case 2 (46-year-old woman) exhibited unusual hyperpigmentation at the right fovea with count-fingers vision and a relatively unremarkable left fundus with 20/30 vision. The left eye exhibited the presence of nodular drusen and SDD and the absence of macular xanthophyll pigments. CONCLUSION/UNASSIGNED:We propose that mutated MTTP within the retina may contribute to ABL retinopathy in addition to systemic deficiencies of fat-soluble vitamins. This concept is supported by a new mouse model with RPE-specific MTTP deficiency and a retinal degeneration phenotype. The observed range of human pathology, including angioid streaks, underscores the need for continued monitoring in adulthood, especially for CNV, a treatable condition.
PMID: 39373891
ISSN: 1744-5094
CID: 5705902

Enhanced recovery after surgery: Preoperative carbohydrate loading and insulin management in type 2 diabetes

Bredefeld, Cindy; Patel, Amy; Islam, Shahidul; Peragallo-Dittko, Virginia
We assessed our institutional practice of individualized insulin dosing for patients with type 2 diabetes receiving preoperative carbohydrate loading (CHO-L) within an enhanced recovery after surgery (ERAS®) protocol. Patients enrolled in an ERAS® protocol with concomitant type 2 diabetes received rapid acting insulin (Novolog®[insulin aspart]) prior to 50 g CHO-L on the day of surgery. Following CHO-L and the administration of insulin, no hypoglycemic episodes occurred with preoperative POC glucose values between 6.8 and 12.3 mmol/L (123 and 221 mg/dL). Our experience demonstrates that administering rapid acting insulin prior to CHO-L in patients with type 2 diabetes is feasible and targets the potentially negative influence CHO-L may impose on preoperative glycemia in this population. Important considerations of this approach are highlighted and an insulin dosing algorithm designed for non-specialty providers is suggested.
PMCID:10920957
PMID: 38464910
ISSN: 2589-8450
CID: 5737652

Abstract 441: Relationship Between Diabetes, Glucose Control, And Vascular Health: Findings From The American Heart Association Cardiometabolic Health Strategically Focused Research Network [Meeting Abstract]

Garshick, Michael; Barrett, Tessa A; Jindal, Manila; Newman, Jonathan D; Fadzan, Maja; Bredefeld, Cindy; Levy, Natalie; Akinlonu, Adedoyin; Heguy, Adriana; Drenkova, Schlamp, Florencia; Giannarelli, Chiara; Fisher, Edward A; Goldberg, Ira J; Berger, Jeffrey
ORIGINAL:0017100
ISSN: 1524-4636
CID: 5578852

Guidance for the diagnosis and treatment of hypolipidemia disorders

Bredefeld, Cindy; Hussain, M Mahmood; Averna, Maurizio; Black, Dennis D; Brin, Mitchell F; Burnett, John R; Charrière, Sybil; Cuerq, Charlotte; Davidson, Nicholas O; Deckelbaum, Richard J; Goldberg, Ira J; Granot, Esther; Hegele, Robert A; Ishibashi, Shun; Karmally, Wahida; Levy, Emile; Moulin, Philippe; Okazaki, Hiroaki; Poinsot, Pierre; Rader, Daniel J; Takahashi, Manabu; Tarugi, Patrizia; Traber, Maret G; Di Filippo, Mathilde; Peretti, Noel
The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is "to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders". This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals.
PMID: 36243606
ISSN: 1933-2874
CID: 5361332

New Classification and Management of Abetalipoproteinemia and Related Disorders

Bredefeld, Cindy; Peretti, Noel; Hussain, M Mahmood
PMID: 33275938
ISSN: 1528-0012
CID: 5160722

Ketogenic diets, not for everyone

Goldberg, Ira J; Ibrahim, Nouran; Bredefeld, Cindy; Foo, Sandra; Lim, Vivien; Gutman, Deborah; Huggins, Lesley-Ann; Hegele, Robert A
BACKGROUND:The adoption of low-carbohydrate diets can lead to weight loss in many patients. However, these now widespread diets also have the potential to exacerbate hypercholesterolemia. OBJECTIVE:The objective of this study is to display the potentially harmful effects of the ketogenic diet on cholesterol levels in patients with or without underlying hyperlipidemia. METHODS:We describe 5 patients who developed marked increases in plasma cholesterol on ketogenic diets and assessed whether they had a well-described underlying genetic hyperlipidemia. RESULTS:Three out of 5 patients had extraordinary increases of blood cholesterol levels to over 500 mg/dL. The other 2 patients more than doubled their low-density lipoprotein cholesterol levels on a ketogenic diet. One patient had an APOE E2/E2 genotype. A higher burden of common genetic polymorphisms was found in 2 patients, with no major mutations found. No potential genetic cause was seen in a fourth patient, and the fifth patient had no genetic testing. Three patients, including the one who was most hypercholesterolemic, had a marked reduction in cholesterol after reverting to a more liberal diet. One refused to change his diet but had a satisfactory low-density lipoprotein cholesterol reduction on ezetimibe. CONCLUSION/CONCLUSIONS:These cases should serve as a caution that high-fat low-carbohydrate diets have the potential to exacerbate or cause hypercholesterolemia in patients with or without underlying genetic hyperlipidemia.
PMID: 33191194
ISSN: 1933-2874
CID: 4716282

Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes (the DEPICT-2 Study): 24-Week Results From a Randomized Controlled Trial

Mathieu, Chantal; Dandona, Paresh; Gillard, Pieter; Senior, Peter; Hasslacher, Christoph; Araki, Eiichi; Lind, Marcus; Bain, Stephen C; Jabbour, Serge; Arya, Niki; Hansen, Lars; Thoren, Fredrik; Langkilde, Anna Maria; [Bredefeld, Cindy L; et al]
OBJECTIVE:7.5-10.5%). RESEARCH DESIGN AND METHODS:= 272) plus insulin. Insulin dose was adjusted by investigators according to self-monitored glucose readings, local guidance, and individual circumstances. RESULTS:≥0.5% without severe hypoglycemia compared with placebo. Adverse events were reported for 72.7%, 67.0%, and 63.2% of patients receiving dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively. Hypoglycemia, including severe hypoglycemia, was balanced between groups. There were more adjudicated definite diabetic ketoacidosis (DKA) events with dapagliflozin: 2.6%, 2.2%, and 0% for dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo, respectively. CONCLUSIONS:Dapagliflozin as adjunct therapy to adjustable insulin in patients with type 1 diabetes was well tolerated and improved glycemic control with no increase in hypoglycemia versus placebo but with more DKA events.
PMID: 30026335
ISSN: 1935-5548
CID: 3401272