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Metabolites May 2024Coronary artery disease (CAD) and atherosclerosis pose significant global health challenges, with intricate molecular changes influencing disease progression....
Coronary artery disease (CAD) and atherosclerosis pose significant global health challenges, with intricate molecular changes influencing disease progression. Hypercholesterolemia (HC), hypertension (HT), and diabetes are key contributors to CAD development. Metabolomics, with its comprehensive analysis of metabolites, offers a unique perspective on cardiovascular diseases. This study leveraged metabolomics profiling to investigate the progression of CAD, focusing on the interplay of hypercholesterolemia, hypertension, and diabetes. We performed a metabolomic analysis on 221 participants from four different groups: (I) healthy individuals, (II) individuals with hypercholesterolemia (HC), (III) individuals with both HC and hypertension (HT) or diabetes, and (IV) patients with self-reported coronary artery disease (CAD). Utilizing data from the Qatar Biobank, we combined clinical information, metabolomic profiling, and statistical analyses to identify key metabolites associated with CAD risk. Our data identified distinct metabolite profiles across the study groups, indicating changes in carbohydrate and lipid metabolism linked to CAD risk. Specifically, levels of mannitol/sorbitol, mannose, glucose, and ribitol increased, while pregnenediol sulfate, oleoylcarnitine, and quinolinate decreased with higher CAD risk. These findings suggest a significant role of sugar, steroid, and fatty acid metabolism in CAD progression and point to the need for further research on the correlation between quinolinate levels and CAD risk, potentially guiding targeted treatments for atherosclerosis. This study provides novel insights into the metabolomic changes associated with CAD progression, emphasizing the potential of metabolites as predictive biomarkers.
PubMed: 38921428
DOI: 10.3390/metabo14060292 -
Cureus Jun 2024Cardiovascular diseases are the leading causes of global mortality and morbidity. Hyperlipidemia is a significant risk factor for atherosclerosis and subsequent... (Review)
Review
Cardiovascular diseases are the leading causes of global mortality and morbidity. Hyperlipidemia is a significant risk factor for atherosclerosis and subsequent cardiovascular diseases. Hyperlipidemia is characterized by imbalances in blood cholesterol levels, particularly elevated low-density lipoprotein cholesterol and triglycerides, and is influenced by genetic and environmental factors. Current management consists of lifestyle modifications and pharmacological interventions most commonly consisting of statins. This review paper explores pathophysiology, management strategies, and pharmacotherapies including commonly used well-established medications including statins, fibrates, and ezetimibe, exciting novel therapies including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and RNA interference therapies (inclisiran), lomitapide, and bempedoic acid, highlighting their mechanisms of action, clinical efficacy, and safety profiles. Additionally, emerging therapies under clinical trials including ApoC-III inhibitors, DGAT2 inhibitors, ACAT2 Inhibitors, and LPL gene therapies are examined for their potential to improve lipid homeostasis and cardiovascular outcomes. The evolving landscape of hyperlipidemia management underscores the importance of continued research into both established therapies and promising new candidates, offering hope for more effective treatment strategies in the future.
PubMed: 38919858
DOI: 10.7759/cureus.63078 -
International Journal of Sport... Jun 2024Dyslipidemia is a major contributor to the development of atherosclerotic cardiovascular disease. Despite high level of physical activity, athletes are not immune from...
Dyslipidemia is a major contributor to the development of atherosclerotic cardiovascular disease. Despite high level of physical activity, athletes are not immune from dyslipidemia, but longitudinal data on the variation of lipids are currently lacking. We sought to assess lipid profile changes over time in Olympic athletes practicing different sports disciplines (power, skills, endurance, and mixed). We enrolled 957 consecutive athletes evaluated from London 2012 to Beijing 2022 Olympic Games. Dyslipidemia was defined as low-density lipoprotein (LDL) ≥115 mg/dl, high-density lipoprotein (HDL) <40 mg/dl for males, or HDL <50 mg/dl for females. Hypertriglyceridemia was defined as triglycerides >150 mg/dl. At the follow-up, a variation of ±40 mg/dl for LDL, ±6 mg/dl for HDL, and ±50 mg/dl for triglycerides was considered relevant. Athletes with follow-up <10 months or taking lower lipid agents were excluded. Follow-up was completed in 717 athletes (74.9%), with a mean duration of 55.6 months. Mean age was 27.2 ± 4.8 years old, 54.6% were male (n = 392). Overall, 19.8% (n = 142) athletes were dyslipidemic at both blood tests, being older, practicing nonendurance sports, and predominantly male. In 69.3% (n = 129) of those with elevated LDL at t0, altered values were confirmed at follow-up, while the same occurred in 36.5% (n = 15) with hypo-HDL and 5.3% (n = 1) in those with elevated triglycerides. Weight and fat mass percentage modifications did not affect lipid profile variation. LDL hypercholesterolemia tends to persist over time especially among male, older, and nonendurance athletes. LDL hypercholesterolemia detection in athletes should prompt early preventive intervention to reduce the risk of future development of atherosclerotic disease.
PubMed: 38917988
DOI: 10.1123/ijsnem.2023-0266 -
Giornale Italiano Di Cardiologia (2006) Jul 2024Cardiovascular (CV) diseases account for over 4 million deaths every year in Europe and over 220 000 deaths in Italy, representing the leading cause of morbidity and...
[SIC Position paper: Treat to prevent the first event - intensive LDL cholesterol lowering in patients at very high cardiovascular risk without a previous cardiovascular event. From ESC guidelines to clinical practice].
Cardiovascular (CV) diseases account for over 4 million deaths every year in Europe and over 220 000 deaths in Italy, representing the leading cause of morbidity and mortality worldwide. The European Society of Cardiology (ESC) guidelines have visionary included in the at very high CV risk group patients without previous acute ischemic events, such as those with subclinical atherosclerosis, chronic coronary syndrome or peripheral arterial disease, familial hypercholesterolemia, diabetes mellitus with target organ damage or multiple associated risk factors, and those with high calculated CV risk score, recommending to consider them and to achieve the same LDL-cholesterol targets as for secondary prevention patients. The aim of this position paper is to provide an updated overview of ESC guidelines that focuses on these patient categories to raise awareness within the clinical community regarding CV risk reduction in this specific epidemiological context.
Topics: Humans; Cardiovascular Diseases; Cholesterol, LDL; Heart Disease Risk Factors; Practice Guidelines as Topic; Italy; Secondary Prevention; Europe; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia
PubMed: 38916469
DOI: 10.1714/4282.42641 -
The Journal of Clinical Endocrinology... Jun 2024Homozygous phytosterolaemia, is a rare autosomal recessive disorder which lead to severely elevated plasma levels of plant phytosterols causing an increased risk of...
BACKGROUND
Homozygous phytosterolaemia, is a rare autosomal recessive disorder which lead to severely elevated plasma levels of plant phytosterols causing an increased risk of coronary artery disease (CAD) and mimics the clinical presentation of familial hypercholesterolaemia(FH). Integration of the genetic variants for homozygous phytosterolaemia into the genetic panel for FH in clinical practice likely increases the detection of milder genetic forms of phytosterolaemia, of which the implications to clinical practice including cascade testing remain unclear.
RESULTS
We report three families with pathogenic loss-of-function variants in ABCG5 and/or ABCG8, in which probands were identified incidentally when genetically testing them for FH. The proband of the first family was a 35-year-old man with a homozygous ABCG5 loss-of-function variant (c.1336C > T, p.Arg446*) causing severe phytosterolaemia and premature CAD on cardiac imaging; his younger brother was heterozygous for the same variant with mildly elevated phytosterol levels. The second family included 2 sisters (31 and 29-year-old) with digenic variants in ABCG5 (c.1336C > T, p.Arg446*) and ABCG8 (c.1269G > T, p.Glu423Asp with uncertain significance) with moderately elevated plasma phytosterol levels and premature CAD on cardiac imaging. The third family referred to a 68-year-old man and his 44-year-old daughter who were both heterozygous for a pathogenic ABCG5 variant (c.1166G > A, p.Arg389His), had mild phytosterolaemia and CAD on cardiac imaging. Treatment with ezetimibe alone or in combination with colesevelam reduced elevated plasma sitosterol and campesterol concentrations by 30 to 80%.
CONCLUSION
Phytosterolaemia is specific genetic disorder that can mimic FH, cause premature atherosclerosis, and require specific pharmacotherapy. Cascade testing for pathogenic ABCG5/G8 variants can lead to earlier detection and treatment of affected family members.
PubMed: 38915260
DOI: 10.1210/clinem/dgae437 -
BioDrugs : Clinical Immunotherapeutics,... Jun 2024Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs... (Review)
Review
Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs utilize three principal modes of action (MOA). The first MOA is initiated by base-pairing between the ASO and its target mRNA, followed by RNase H-dependent mRNA degradation. The second MOA is triggered by ASOs that occlude splice acceptor sites in pre-mRNAs leading to skipping of a mutation-bearing exon. The third MOA involves ASOs that sterically hinder mRNA function, often inhibiting translation. ASOs contain a variety of modifications to the sugar-phosphate backbone and bases that stabilize the ASO or render them resistant to RNase activity. RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.].
PubMed: 38914784
DOI: 10.1007/s40259-024-00665-2 -
American Journal of Cardiovascular... Jun 2024Cardiovascular disease was the leading cause of death worldwide in 2021, with atherosclerotic cardiovascular disease, encompassing hypercholesterolemia, being a major...
BACKGROUND
Cardiovascular disease was the leading cause of death worldwide in 2021, with atherosclerotic cardiovascular disease, encompassing hypercholesterolemia, being a major contributing factor. A range of lipid-lowering medications is used for the management of hyperlipidemia, but the use of statins is considered as standard therapy. Unfortunately, some patients do not respond to this therapy, necessitating novel therapeutic approaches. Tafolecimab is a novel proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibody that inhibits the binding of PCSK9 with low-density lipoprotein receptors (LDLRs) and increases LDLR recycling, and thus it indirectly lowers circulating low-density lipoprotein cholesterol (LDL-C) levels by increasing LDL-C uptake. The primary objective of this study is to assess the efficacy of tafolecimab in reducing LDL-C levels.
METHODS
A thorough search was conducted on Medline (PubMed), Cochrane CENTRAL, Scopus, and Google Scholar from inception until December 2023. Review Manager was used for statistical analysis. The random effects model was used to calculate risk ratios (RRs), mean differences (MDs), and 95% confidence intervals (CIs). Heterogeneity was assessed using the Higgins I index. The risk of bias was assessed using Cochrane's RoB 2 tool. This review has been registered with PROSPERO (CRD42023471020).
RESULTS
A total of four Chinese studies matched the inclusion criteria and were included in this review. A total of 726 patients were included in this review, out of which 476 patients were males. Out of four, three studies that studied the efficacy of 450 mg tafolecimab every 4 weeks in patients (n = 462) as compared to placebo (n = 224) were included in the meta-analysis. According to the pooled results, tafolecimab caused a significant decrease in LDL-C levels from baseline to week 12 as compared to placebo (MD = - 63.78, 95% CI - 65.88 to - 61.68, p value < 0.00001, I = 97%). The pooled results showed that more patients achieved ≥ 50% reductions in LDL-C levels (RR = 52.33, 95% CI 18.51-147.95, p value < 0.00001, I = 0%) and LDL-C < 1.8 mmol/L (RR = 17.27, 95% CI 9.59-31.11, p value < 0.00001, I = 0%) at week 12 in the tafolecimab group than the placebo group. Additionally, tafolecimab also caused a robust decrease in non-HDL-C, apolipoprotein B, and lipoprotein(a) levels from baseline to week 12 compared to placebo. The overall risk of bias was low, as determined by the RoB 2 tool.
CONCLUSIONS
Tafolecimab showed promising lipid-lowering efficacy and a well-tolerated safety profile. Our findings suggest its potential as an innovative therapeutic option for individuals with hypercholesterolemia; however, significant heterogeneity was observed in some results, making it difficult to come to a firm conclusion. Therefore, large-scale randomized trials are required to confirm our findings, particularly exploring the most effective dosage regimens across varied populations.
REGISTRATION
PROSPERO identifier number CRD42023471020.
PubMed: 38913274
DOI: 10.1007/s40256-024-00654-4 -
Giornale Italiano Di Cardiologia (2006) Jun 2024A 60-year-old man with hypercholesterolemia and hypertension presented with acute coronary syndrome (SCA). The ECG showed lateral ischemia (T-wave inversion in V4-V6, D1...
A 60-year-old man with hypercholesterolemia and hypertension presented with acute coronary syndrome (SCA). The ECG showed lateral ischemia (T-wave inversion in V4-V6, D1 and aVL) and echocardiography showed normal left ventricular wall motion. Coronary angiography showed critical atherosclerotic lesions in the distal part of the left circumflex artery (LCx, culprit lesion), chronic total occlusion of the right coronary artery (RCA), significant but not critical stenosis in the middle part of left anterior descending artery (LAD), and a coronary artery to pulmonary artery (PA) fistula originating from the proximal part of the LAD and emptying into the PA via a coronary saccular aneurysm (12 x 12 x 10 mm). A multidetector row computed tomography angiography (CTA) confirmed the coronary artery fistula, which was treated with surgical approach. The patient underwent aneurysmorrhaphy with CAF closure and coronary artery bypass grafting on the RCA and LCx. The postoperative course was uneventful and the patient was discharged on postoperative day 14. CTA was useful for understanding the spatial relation of the CAF and the connection with the PA.
Topics: Humans; Male; Pulmonary Artery; Middle Aged; Arterio-Arterial Fistula; Coronary Aneurysm; Coronary Artery Bypass; Coronary Angiography
PubMed: 38912745
DOI: 10.1714/4287.42691 -
Cardiovascular Endocrinology &... Sep 2024Bempedoic acid (BA) has shown varied efficacy in managing hyperlipidemia. We conducted the most extensive up-to-date meta-analysis, the first to include recent studies... (Review)
Review
Efficacy and outcomes of bempedoic acid versus placebo in patients with hypercholesterolemia: an updated systematic review and meta-analysis of randomized controlled trials.
INTRODUCTION
Bempedoic acid (BA) has shown varied efficacy in managing hyperlipidemia. We conducted the most extensive up-to-date meta-analysis, the first to include recent studies by Nissen et al., which boast the largest sample size.
METHODS
Literature search was done on Medline, EMBASE, and Cochrane Library. The primary endpoint was a change in low-density lipoprotein-cholesterol (LDL-C) levels, while secondary endpoints encompassed changes in lipid parameters, clinical endpoints, and safety endpoints. The least-square mean (LSM) percent change was utilized for lipid changes, with statistical significance set at < 0.05.
RESULTS
This analysis included 12 randomized control trials with 22,249 participants. BA exhibited a substantial reduction in LDL-C levels [LSM % change, -24.34; 95% confidence interval (CI), -27.80 to -20.88; < 0.0001], total cholesterol levels (LSM % change, -16.62; 95% CI, -21.70 to -11.54; < 0.00001) and high-density lipoprotein-cholesterol (HDL-C) levels (LSM % change, -4.22; 95% CI, -5.51 to -2.92; < 0.00001) compared to the placebo.
CONCLUSIONS
BA significantly lowers LDL-C, total cholesterol, HDL-C, non-HDL-C, high sensitivity C reactive protein, and apolipoprotein levels.
PubMed: 38911912
DOI: 10.1097/XCE.0000000000000302 -
Clinical Medicine Insights. Cardiology 2024Cardiovascular illnesses (CVDs), particularly Coronary Artery Disease (CAD) and Ischemic Heart Disease (IHD), are major global health burdens, with a growing incidence...
Cardiovascular illnesses (CVDs), particularly Coronary Artery Disease (CAD) and Ischemic Heart Disease (IHD), are major global health burdens, with a growing incidence in Pakistan. The development of PCSK9 inhibitors offers encouraging advantages in lowering LDL cholesterol and lowering cardiovascular risk, even though conservative treatments are still essential. However, access to them is severely hampered by their high cost, especially in environments with little resources. The financial limitations and scarcity of healthcare resources while examining the difficulties in obtaining PCSK9 inhibitors in Pakistan is essential. In order to develop solutions for affordability and fair access, it emphasizes the urgent need for multi-stakeholder collaboration, including governmental action, healthcare sector involvement, and pharmaceutical company engagement. It also emphasizes the need for data-specific research and the use of PCSK9 inhibitors in conventional treatment protocols.
PubMed: 38911696
DOI: 10.1177/11795468241262648