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Targeted treatment for familial hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal codominant genetic condition, which results in heightened levels of LDL-C in the blood. It is diagnosed by the presence of mutations in low-density lipoprotein receptor (LDLR), apolipoprotein (ApoB), or proprotein convertase subtilisin/kexin 9 (PCSK9), with the LDLR mutation most common. The LDLR variant results in the malfunction of LDLR and problems with the clearance of LDL-C from the blood.

The worldwide mortality rate of FH is between 1:200 and 1:300, and if left untreated, FH can lead to premature atherosclerosis and an elevated risk of cardiovascular events. Because lifestyle modification alone is insufficient to maintain decreased LDL-C concentrations in FH patients, lipid-lowering therapy is necessary. Newer treatment options include small-molecule- or antibody-based approaches.

How do you treat patients with heterozygous FH who need additional lowering of LDL-C levels than that conferred by maximally tolerated statin dosages and lifestyle intervention? How do you determine when and what agents to use based on patient type?

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Bone marrow-derived naïve B lymphocytes improve heart function after myocardial infarction: a novel cardioprotective mechanism for empagliflozin - Basic Research in Cardiology

The role of adaptive immunity in myocardial recovery post myocardial infarction (MI), particularly the immune response by B lymphocytes, remains elusive. Bone marrow immune microenvironment in response to MI is ..... see more

Source : https://link.springer.com/article/10.1007/s00395-022-00956-1



Conclusions: These findings provide new mechanistic insights into regulation of adaptive immune response post MI, and support targeting bone marrow B cell development for improved ventricular remodeling and reduced heart failure after MI.

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Novel Insights into the Management of Patients with Very High Cardiovascular Risk Eligible for PCSK9 Inhibitor Treatment: Baseline Findings from the PERI-DYS Study - Cardiovascular Drugs and Therapy

Aim The PERI-DYS study aims to characterize two groups of patients with dyslipidaemia at very high CV risk: PCSK9i receivers and patients qualifying for but not receiving PCSK9i. Methods This ..... see more

Source : https://link.springer.com/article/10.1007/s10557-022-07386-0


Conclusions: PCSK9i receivers are characterized by higher baseline LDL-C and a higher portion of statin intolerance compared to those qualified for but not-receiving PCSK9i treatment. On-treatment, LDL-C was lower in PCSK9i receivers. Ongoing follow-up will determine the prognostic importance of these findings.

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A pragmatic clinical trial of cascade testing for familial hypercholesterolemia

Genomics in public health: perspective from the Office of Public Health Genomics at the Centers for Disease Control and Prevention (CDC). : 830-837 https://doi.org/10.3390/healthcare3030830 Correction: A collaborative translational research framework ..... see more

Source : https://www.gimjournal.org/article/S1098-3600(22)00917-0/fulltext



Conclusions: New case detection rate was significantly higher in FH families with a monogenic etiology than in those without such an etiology owing to greater uptake and yield of cascade testing.

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Achilles Tendon Softness and Thickness in Patients With Hypercholesterolemia

Background Hypercholesterolemia is a condition where blood levels of cholesterol are high. It is of two types: The first type is familial hypercholesterolemia, which is hereditary, and the second one ..... see more

Source : https://www.cureus.com/articles/107840-achilles-tendon-softness-and-thickness-in-patients-with-hypercholesterolemia


Conclusions: The thickness and softness of the Achilles tendon are positively correlated with the serum total cholesterol level. Males are the group where this correlation is most significant. As a result, men have a higher risk of developing Achilles tendon thickening than women. The thickness of the Achilles tendon can therefore be one of the...

Anita Kedia, Ryan Chuang from Doctor Unite Commented on a Post
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Shared decision-making in treating hyperlipidemia

Cholesterol management has evolved to become increasingly complex and individualized. Newer guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) detail risk assessment, novel non-statin treatment options, concerns centered on patient subgroups, and the value of therapy.

Treatment plans are now highly personalized, and experts recommend shared decision-making to fulfill patient needs. When discussing cholesterol management with patients, 4 tenets to keep in mind include the following:

  1. stress the importance of a heart-healthy lifestyle spanning the patient’s life;
  2. discuss the 10-year risk of atherosclerotic cardiovascular disease per the Pooled Cohort Equations, as well as mitigating risk factors;
  3. explain that although statins are the foundation of treatment, add-on options are available for patients on maximally tolerated statins who need to further lower their LDL-C levels;
  4. address special treatment algorithms in at-risk patient subgroups.

What has worked for you when advising patients on lipid-lowering therapy? What role does shared decision-making play when caring for your patients with hyperlipidemia?

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  • September 29, 2022
    Shared decision making is critical so that patients feel empowered and are more likely to be compliant. Patients are often reluctant to try statin medications but maybe willing to Show More
  • from Doctor Unite September 28, 2022
    I'm curious what percentage of people in USA would qualify for treatment for dyslipidemia
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Lomitapide ameliorates middle cerebral artery occlusion-induced cerebral ischemia/reperfusion injury by promoting neuronal autophagy and inhibiting microglial migration - PubMed

Lomitapide is a lipid-lowering drug, and this is the first study to explore its protective effect on ischemic nerve injury in vitro and in vivo. Our results suggest that lomitapide ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/36052650/


Conclusion: Lomitapide is a lipid-lowering drug, and this is the first study to explore its protective effect on ischemic nerve injury in vitro and in vivo. Our results suggest that lomitapide can be repositioned as a potential therapeutic drug for the treatment of stroke.

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Oral Porphyromonas gingivalis and Fusobacterium nucleatum Abundance in Subjects in Primary and Secondary Cardiovascular Prevention, with or without Heterozygous Familial Hypercholesterolemia - PubMed

Greater oral Pg abundance is present in very high-risk patients with previously diagnosed ASCVD, with or without FH, suggesting a potential relationship with CV events. Future studies will assess the ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/36140246/


Conclusions: Greater oral Pg abundance is present in very high-risk patients with previously diagnosed ASCVD, with or without FH, suggesting a potential relationship with CV events. Future studies will assess the predictive value of Pg abundance measurement in ASCVD risk stratification.



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Optimization of a Protocol for Protein Extraction from Calcified Aortic Valves for Proteomics Applications: Development of a Standard Operating Procedure - PubMed

The comprehension of the pathophysiological mechanisms, the identification of druggable targets, and putative biomarkers for aortic valve stenosis can be pursued through holistic approaches such as proteomics. However, tissue homogenization ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/36136308/


Relevance:The comprehension of the pathophysiological mechanisms, the identification of druggable targets, and putative biomarkers for aortic valve stenosis can be pursued through holistic approaches such as proteomics. However, tissue homogenization and protein extraction are made difficult by tissue calcification. The reproducibility of...

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Myeloid TM6SF2 Deficiency Inhibits Atherosclerosis - PubMed

Genetic variants in transmembrane 6 superfamily member 2 ( TM6SF2 ), such as E167K, are associated with atherosclerotic cardiovascular disease (ASCVD). Chronic inflammation and lipid-laden macrophage foam cell formation are ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/36139452/



Conclusions: Myeloid TM6SF2 deficiency inhibits atherosclerosis development and is a potential therapeutic target for the treatment of atherogenesis.


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Sex-Differences in Subclinical Atherosclerosis and Systemic Immune Activation/Inflammation among People with HIV in the U.S.

AbstractBackground. August Among people with HIV (PWH), sex-differences in presentations of atherosclerotic cardiovascular disease (ASCVD) may be influenced by see more

Source : https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac767/6697021?login=false


Conclusions: Among U.S. PWH, females had a lower prevalence of plaque and NC/V-P, as well as differences in key immune/inflammatory biomarkers. Immune-plaque relationships differed by sex for D-dimer, but not other tested parameters.


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Disruption of Lipid Raft Microdomains, Regulation of CD38, TP53, and MYC Signaling, and Induction of Apoptosis by Lomitapide in Multiple Myeloma Cells

Background/Aim: Multiple myeloma (MM) is characterized by accumulation of a malignant clone of plasma cells in the bone marrow. Curative treatments are not yet available. Therefore, we undertook a drug ..... see more

Source : https://cgp.iiarjournals.org/content/19/5/540


Conclusions: Lomitapide treatment led to disruption of lipid raft domains and induction of pro-apoptotic factors and might, therefore, be considered as a potential therapeutic agent in MM.

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Approach to risk stratification of atherosclerotic cardiovascular disease

Objective To outline the 2021 Canadian Cardiovascular Society (CCS) dyslipidemia guidelines and to present the current approaches to cardiovascular risk stratification, including the incorporation of biomarkers and imaging tests. Sources ..... see more

Source : https://www.cfp.ca/content/68/9/654


Conclusions: Biomarkers and imaging tests have the potential to improve ASCVD risk stratification by reclassifying any patient whose risk has been inaccurately estimated by traditional methods. Recently published guidelines by the CCS suggest the use of biomarkers and imaging in certain patient groups.




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Racial disparity in flu vaccine uptake among Asian American Individuals: A National Health Interview Survey Study

Available online 12 September 2022, 101391 Vaccination coverage rates across Asian American subpopulations with atherosclerotic cardiovascular disease (ASCVD) and diabetes mellitus is not well-studied. We used data from the National ..... see more

Source : https://www.sciencedirect.com/science/article/abs/pii/S0146280622002882?via=ihub


Relevance: Vaccination coverage rates across Asian American subpopulations with atherosclerotic cardiovascular disease (ASCVD) and diabetes mellitus is not well-studied. We used data from the National Health Interview Survey (NHIS) from 2006-2018 and included participants with a history of ASCVD or diabetes.


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Nonproteolytic Intracellular Domain of MT1-MMP (Membrane-Type 1 Matrix Metalloproteinase) Coordinately Modulates Abdominal Aortic Aneurysm and Atherosclerosis to Mice - PubMed

Our findings show that the cytoplasmic domain of MT1-MMP safeguards from AAA and atherosclerotic plaque development through a proteolysis-independent signaling mechanism associated with Netrin-1 expression. This unexpected function of MT1-MMP ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/36073351/


Conclusions: Our findings show that the cytoplasmic domain of MT1-MMP safeguards from AAA and atherosclerotic plaque development through a proteolysis-independent signaling mechanism associated with Netrin-1 expression. This unexpected function of MT1-MMP unveils a novel mechanism of synchronous onset of AAA and atherogenesis and highlights its...

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Network Meta-Analysis of Randomized Trials Evaluating the Comparative Efficacy of Lipid-Lowering Therapies Added to Maximally Tolerated Statins for the Reduction of Low-Density Lipoprotein Cholesterol - PubMed

doi: 10.1161/JAHA.122.025551. Online ahead of print. 1 Cicarrone Center for the Prevention of Cardiovascular Disease Johns Hopkins University School of Medicine Baltimore MD. 2 Amgen Ltd Cambridge UK. 3 Amgen ..... see more

Source : https://pubmed.ncbi.nlm.nih.gov/36073669/


Conclusions: Evolocumab, 140 mg Q2W/420 mg once a month, and alirocumab, 150 mg Q2W, were consistently the most efficacious nonstatin regimens when added to maximally tolerated statins to lower LDL‐C, non–high‐density lipoprotein cholesterol, and apolipoprotein B levels and facilitate attainment of guideline‐recommended...

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Low circulating PCSK9 levels in LPL homozygous children with chylomicronemia syndrome in a syrian refugee family in Lebanon

Familial chylomicronemia syndrome is a rare autosomal recessive disorder of lipoprotein metabolism characterized by the presence of chylomicrons in fasting plasma and an important increase in plasma triglycerides (TG) levels ..... see more

Source : https://www.frontiersin.org/articles/10.3389/fgene.2022.961028/full


Conclusions:This case is crucial to raise public awareness on the risks of consanguineous marriages to decrease the emergence of inherited autosomal recessive diseases. It also highlights the importance of the early diagnosis and management of these diseases to prevent serious complications, such as recurrent pancreatitis in the case of...

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PCSK9 is minimally associated with HDL but impairs the anti-atherosclerotic HDL effects on endothelial cell activation

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates the cell-surface localization of LDL receptors in hepatocytes and is associated with LDL and lipoprotein(a) [Lp(a)] uptake, reducing blood concentrations. However, the connection ..... see more

Source : https://www.jlr.org/article/S0022-2275(22)00105-5/fulltext



Relevance: This study contributes to the elucidation of the pathophysiological role of plasma PCSK9 and highlights further the anti-atherosclerotic effect of PCSK9 inhibition.




Conclusion/Relevance: “Recommendations attempt to provide practical guidance for clinicians and patients regarding the use of nonstatin therapies to further reduce ASCVD risk in situations not covered by the guideline until such time as the scientific evidence base expands and cardiovascular outcomes trials are completed with newer agents...

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  • September 07, 2022
    This is fantastic and very timely. Note the absence of niacin and fibrates, which I am still seeing prescribed. It is good to have a gathering of data Show More
  • September 07, 2022
    Key Points • Source: Journal of the American College of Cardiology • Conclusion: “This ECDP [Expert Consensus Decision Pathway] addresses current gaps in care for LDL-C lowering to reduce ASCVD Show More
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Effect of PCSK9 Inhibitor on Contrast-Induced Acute Kidney Injury in Patients with Acute Myocardial Infarction Undergoing Intervention Therapy

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to inhibit pyroptosis and apoptosis, which play important roles in the development and progression of contrast-induced acute kidney injury (CI-AKI). ..... see more

Source : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9427281/


Conclusion/Relevance: This result indicate a significant association between the use of evolocumab and a reduction in the incidence of CI-AKI.The logistic regression analysis results revealed that evolocumab was significantly associated with CI-AKI. The use of PCSK9 inhibitors, hydration therapy, and statin administration appears promising for...