👤 Diego E Berman

Both lipoprotein(a) [Lp(a)] and peripheral artery disease (PAD) are associated with ischaemic events. We sought to assess the association between Lp(a) and major adverse cardiovascular events (MACE) and major lower extremity events (MALE) among patients with baseline PAD. The Mass General Brigham (MGB) Lp(a) registry includes all individuals with Lp(a) measured at two tertiary care centres from 2000 to 2019. Those with PAD were grouped according to Lp(a) percentile: 1st-25th [Q1, Lp(a) ≤ 14 nmol/L], 26th-50th (Q2, 14-<42 nmol/L), 51st-75th (Q3, 42-<132 nmol/L), and 76th-100th (Q4, 132-855 nmol/L). Outcomes were MACE [composite of cardiovascular (CV) death, myocardial infarction, or coronary revascularization] and MALE (composite of peripheral revascularization, acute limb ischaemia, or major lower extremity amputation). Cox proportional hazard modelling was used to assess the association between Lp(a) and the outcomes of interest after adjusting for traditional risk factors. Among 3757 individuals with PAD [39% female, median age 68 (IQR: 58-77)], individuals with Lp(a) levels in the third and fourth quartiles had a 24 and 30% increased hazard of MACE, respectively [adj. hazard ratio (HR): 1.24, P = 0.005; adj. HR: 1.30, P = 0.001] when compared with those in the first quartile. Individuals in the fourth quartile had a 19% greater hazard of MALE (adj. HR: 1.19, P = 0.043). Elevated Lp(a) in patients with PAD was associated with an increased risk of both MACE and MALE. Accordingly, measurement of Lp(a) may convey important prognostic value and allow for further risk stratification within this high-risk population. Show less

Primary prevention of incident atherosclerotic cardiovascular disease (ASCVD) as well as decreasing the risk of future events in those with established atherosclerosis is critical from a public health perspective. Management of dyslipidemias constitutes a key target in decreasing the risk of developing ASCVD events. While there have been great strides in the treatment of dyslipidemia over the last three decades, there are important recent developments and ongoing research that will expand the available therapeutic options and enable further cardiovascular risk reduction. PURPOSE OF REVIEW: The purpose of this paper is to review new developments relating to the primary prevention and management of ASCVD with a specific focus on optimizing the treatment of dyslipidemias. RECENT FINDINGS: In the realm of ASCVD risk prediction, mounting evidence over the last decade has demonstrated that coronary artery calcium testing is superior to any serum biomarker in the prediction of future ASCVD events and in discriminating future cardiovascular risk. As such, it has been incorporated into the most recent ACC/AHA primary prevention guideline to help guide management decisions in select patients. In terms of the management of dyslipidemias, PCSK9 inhibitors lower LDL-C by 50-70% and provide an additional 15% reduction in key cardiovascular events in high-risk patients with known ASCVD, as demonstrated in the ODYSSEY and FOURIER trials. Cholesteryl ester transfer protein (CETP) inhibitors, which significantly increase HDL-C levels, demonstrated mixed results in large clinical trials and have helped reframe HDL-C as a risk marker rather than a modifiable risk factor. In regard to the management of triglycerides, the REDUCE-IT trial demonstrated a nearly 5% absolute reduction in key cardiovascular events with a highly purified fish-oil derivative named icosapent ethyl in high-risk patients already on statin therapy. Finally, in regard to lipoprotein(a)-which is a strong risk factor for ASCVD-there are exciting developments in the therapeutic pipeline which reduce circulating lipoprotein(a) levels by nearly 90%. The management of dyslipidemias continues to be an exciting field with several ongoing cardiovascular outcomes trials, improvement in risk prediction models, and new therapeutic agents in the pipeline that will further mitigate residual cardiovascular risk in both primary and secondary prevention patients. Show less

In a whole-exome sequencing study of multiplex Alzheimer's disease (AD) families, we investigated three neuronal ceroid lipofuscinosis genes that have been linked to retromer, an intracellular trafficking pathway associated with AD: ceroid lipofuscinosis 3 (CLN3), ceroid lipofuscinosis 5 (CLN5), and cathepsin D (CTSD). We identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD. We find that this variant causes glycosylation defects in the expressed protein, which causes it to be retained in the endoplasmic reticulum with reduced delivery to the endolysosomal compartment, CLN5's normal cellular location. The AD-associated CLN5 variant is shown here to reduce the normal processing of cathepsin D and to decrease levels of full-length amyloid precursor protein (APP), suggestive of a defect in retromer-dependent trafficking. Show less

γ-Secretase inhibitors (GSIs) are being investigated for their potential to modify the progression of Alzheimer disease based on their ability to regulate amyloid-β (Aβ) accumulation. BMS-708163 (avagacestat) is an oral GSI designed for selective inhibition of Aβ synthesis currently in development for the treatment of mild to moderate and predementia AD. In addition to the desired effect on Aβ synthesis, GSIs affect Notch processing, which is thought to mediate some toxic adverse effects reported with this drug class. Avagacestat produced up to 190-fold greater selectivity for Aβ synthesis than Notch processing in preclinical studies and may therefore produce less toxic adverse events than other less selective compounds. Presented here are the results of the first in-human study for this new GSI compound. The goal of this study was to assess the tolerability profile, pharmacokinetic properties, and effects on pharmacodynamic markers (Aβ, trefoil factor family 3 protein, dual specificity phosphatase 6, and hairy and enhancer of split-1) of single, oral doses of avagacestat in healthy, young, male volunteers. This was a multicenter, randomized, double-blind, placebo-controlled, single-ascending dose study in 8 healthy young men (age, 18-45 years) per dosing panel. Each study participant was randomized to receive a single dose of placebo (n = 2) or avagacestat (n = 6 for each dose) as an oral solution in 1 of 9 sequential dose panels (0.3, 1.5, 5, 15, 50, 100, 200, 400, and 800 mg). For determination of avagacestat, blood samples were obtained before dosing and for up to 144 hours after dosing. For participants in the 800-mg avagacestat dose panel, additional samples were obtained at 216, 312, and 648 hours. For 40-amino acid isoform of Aβ (Aβ(1-40)) assessment, plasma samples were collected before avagacestat administration and up to 72 hours after dosing. Avagacestat concentrations peaked quickly after oral administration and then had a biphasic decrease in concentrations with a prolonged terminal phase. Exposures were proportional with doses up to 200 mg. Avagacestat was well tolerated at single oral doses up to 800 mg, with a biphasic effect on plasma Aβ(1-40). Adverse events were predominately mild to moderate in severity with no evidence of dose dependence up to 200 mg. Results from this single-ascending dose study suggest that avagacestat was tolerated at a single-dose range of 0.3 to 800 mg and suitable for further clinical development. Show less

A panel of 42 rodent X cat somatic cell hybrids segregating individual cat chromosomes in different combinations was used to assign five isozyme structural loci to cat chromosomes. The feline homolog for glutathione reductase (GSR) was mapped to chromosome C2. Adenosine deaminase (ADA) and inosine triphosphatase (ITPA) were located on chromosome A3. Lactate dehydrogenase-A (LDHA) and acid phosphatase-2 (ACP2) were reassigned to chromosome D1. Localization of these genes increases the known feline genetic map and extends the known syntenic homologies between the cat and other mammalian species. Show less