Pub Date : 2025-01-01DOI: 10.1016/j.jacl.2024.11.007
Michael D. Shapiro DO, MCR , Tariq M. Haddad MD , Howard S. Weintraub MD , Seth J. Baum MD , Khaled Abdul-Nour MD , Samiha Sarwat PhD , Vadim Paluy MD , Wess Boatwright PharmD, MBA , Auris Browne MD , Imran Ayaz MD , Cheryl A. Abbas PharmD , Christie M. Ballantyne MD
BACKGROUND
Elevated lipoprotein(a) (Lp[a]) is the most common inherited dyslipidemia that is independently and causally associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. However, data from diverse populations with ASCVD are lacking.
OBJECTIVE
To evaluate Lp(a) levels in a diverse, contemporary United States (US) population with ASCVD, stratified by race, ethnicity, and sex.
METHODS
Lp(a)HERITAGE (NCT03887520) was a multicenter study that estimated the prevalence of elevated Lp(a) in adults (18–80 years) with ASCVD. US participants with Lp(a) measured in nmol/L pre- or post-enrollment were included in this subanalysis. This study was descriptive; therefore, no statistical comparisons were made.
RESULTS
Of all US participants, 14% had an Lp(a) measurement pre-enrollment. This subanalysis included 7679 US participants with Lp(a) measurements in nmol/L (80.5% White; 66.4% male; mean age 63.8 years [standard deviation ± 9.7]). Median Lp(a) was > 2.5-fold higher in Black participants (132.0 nmol/L; IQR, 57.1–239.6) vs the overall population (52.1 nmol/L; IQR, 15.7–167.8), and higher in females compared with males (69.4 nmol/L; IQR, 20.1–194.7 vs 45.6 nmol/L; IQR, 14.0–152.6, respectively). Lp(a) levels ≥ 125 nmol/L were more prevalent among Black (52.0%) and female (38.9%) participants vs the overall population (33.3%).
CONCLUSION
In US Lp(a)HERITAGE participants, only 14% had an Lp(a) measurement pre-enrollment, despite having ASCVD. One-third of participants demonstrated Lp(a) levels ≥ 125 nmol/L, the threshold for high ASCVD risk, which was higher among Black (1/2) and female (2/5) participants, suggesting a greater need for Lp(a) testing in these groups to inform ASCVD risk mitigation.
{"title":"Lipoprotein(a) levels in a population with clinical atherosclerotic cardiovascular disease in the United States: A subanalysis from the Lp(a)HERITAGE study","authors":"Michael D. Shapiro DO, MCR , Tariq M. Haddad MD , Howard S. Weintraub MD , Seth J. Baum MD , Khaled Abdul-Nour MD , Samiha Sarwat PhD , Vadim Paluy MD , Wess Boatwright PharmD, MBA , Auris Browne MD , Imran Ayaz MD , Cheryl A. Abbas PharmD , Christie M. Ballantyne MD","doi":"10.1016/j.jacl.2024.11.007","DOIUrl":"10.1016/j.jacl.2024.11.007","url":null,"abstract":"<div><h3>BACKGROUND</h3><div>Elevated lipoprotein(a) (Lp[a]) is the most common inherited dyslipidemia that is independently and causally associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. However, data from diverse populations with ASCVD are lacking.</div></div><div><h3>OBJECTIVE</h3><div>To evaluate Lp(a) levels in a diverse, contemporary United States (US) population with ASCVD, stratified by race, ethnicity, and sex.</div></div><div><h3>METHODS</h3><div>Lp(a)HERITAGE (NCT03887520) was a multicenter study that estimated the prevalence of elevated Lp(a) in adults (18–80 years) with ASCVD. US participants with Lp(a) measured in nmol/L pre- or post-enrollment were included in this subanalysis. This study was descriptive; therefore, no statistical comparisons were made.</div></div><div><h3>RESULTS</h3><div>Of all US participants, 14% had an Lp(a) measurement pre-enrollment. This subanalysis included 7679 US participants with Lp(a) measurements in nmol/L (80.5% White; 66.4% male; mean age 63.8 years [standard deviation ± 9.7]). Median Lp(a) was > 2.5-fold higher in Black participants (132.0 nmol/L; IQR, 57.1–239.6) vs the overall population (52.1 nmol/L; IQR, 15.7–167.8), and higher in females compared with males (69.4 nmol/L; IQR, 20.1–194.7 vs 45.6 nmol/L; IQR, 14.0–152.6, respectively). Lp(a) levels ≥ 125 nmol/L were more prevalent among Black (52.0%) and female (38.9%) participants vs the overall population (33.3%).</div></div><div><h3>CONCLUSION</h3><div>In US Lp(a)HERITAGE participants, only 14% had an Lp(a) measurement pre-enrollment, despite having ASCVD. One-third of participants demonstrated Lp(a) levels ≥ 125 nmol/L, the threshold for high ASCVD risk, which was higher among Black (1/2) and female (2/5) participants, suggesting a greater need for Lp(a) testing in these groups to inform ASCVD risk mitigation.</div></div>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":"19 1","pages":"Pages 28-38"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jacl.2024.10.003
Julianna West MD , Abhimanyu Garg MD
CONTEXT
Lorlatinib is an anaplastic lymphoma kinase (ALK) inhibitor, which is currently used for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). Previous reports have noticed an association between lorlatinib and hyperlipidemia, however the specific mechanisms for this side effect remain unknown. Some investigators have reported nephrotic syndrome to be the underlying cause of lorlatinib-induced hyperlipidemia.
CASE REPORT
A 59-year-old female with NSCLC presented with marked elevation of lipid levels, including total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C), after initiation of lorlatinib therapy. Despite high dose atorvastatin and ezetimibe, lipid levels remained elevated. A 24-hour urine collection revealed only 226 mg of protein excretion.
CONCLUSIONS
Lorlatinib induced a complex dyslipidemia in our patient with elevations of both LDL-C and HDL-C. The underlying mechanism of lorlatinib-induced hyperlipidemia remains unknown and is unlikely to be secondary to nephrotic syndrome in many patients.
{"title":"Complex dyslipidemia induced by lorlatinib therapy: A case study","authors":"Julianna West MD , Abhimanyu Garg MD","doi":"10.1016/j.jacl.2024.10.003","DOIUrl":"10.1016/j.jacl.2024.10.003","url":null,"abstract":"<div><h3>CONTEXT</h3><div>Lorlatinib is an anaplastic lymphoma kinase (ALK) inhibitor, which is currently used for the treatment of <em>ALK</em>-positive metastatic non-small cell lung cancer (NSCLC). Previous reports have noticed an association between lorlatinib and hyperlipidemia, however the specific mechanisms for this side effect remain unknown. Some investigators have reported nephrotic syndrome to be the underlying cause of lorlatinib-induced hyperlipidemia.</div></div><div><h3>CASE REPORT</h3><div>A 59-year-old female with NSCLC presented with marked elevation of lipid levels, including total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C), after initiation of lorlatinib therapy. Despite high dose atorvastatin and ezetimibe, lipid levels remained elevated. A 24-hour urine collection revealed only 226 mg of protein excretion.</div></div><div><h3>CONCLUSIONS</h3><div>Lorlatinib induced a complex dyslipidemia in our patient with elevations of both LDL-C and HDL-C. The underlying mechanism of lorlatinib-induced hyperlipidemia remains unknown and is unlikely to be secondary to nephrotic syndrome in many patients.</div></div>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":"19 1","pages":"Pages 178-182"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jacl.2024.09.009
Justine Cole MBChB, MMed , Patrick Couture MD, PhD , André J. Tremblay PhD , Allan D. Sniderman MD
OBJECTIVE
The importance of any enhanced atherogenicity of triglyceride (TG)-rich lipoproteins (TRLs) will depend on the relative abundance of these particles compared with low-density lipoprotein (LDL) or total apolipoprotein (apo)B. Accordingly, we determined the contribution that TRLs make to total apoB as TG or apoB concentrations increase. We also describe compositional changes in TRLs as TG or apoB increases to assess whether very low-density lipoprotein (VLDL-[C]) is a valid proxy for VLDL-apoB.
METHODS
We used sequential ultracentrifugation to separate lipoprotein fractions in plasma samples from 1940 dyslipidemic patients not on lipid-lowering medication, and measured apoB, cholesterol and TG in the plasma and in each subfraction. We analyzed these data in quartiles of TG or apoB.
RESULTS
There was wide variance in all parameters in all quartiles of both TG and apoB. Although VLDL-apoB accounted for almost all the increase in total apoB across TG quartiles, LDL-apoB still accounted for 80% of the total in TG quartile 4. In contrast, LDL-apoB accounted for 90% of the increase in apoB across apoB quartiles. As TG increases, the increase in VLDL-C is explained more by increased VLDL-C/apoB when TG is moderately elevated, and more by increased VLDL-apoB when TG is very high.
CONCLUSIONS
In conclusion, VLDL-apoB only becomes a substantial component of total apoB with extreme hypertriglyceridemia and VLDL-C is not an appropriate proxy for VLDL-apoB.
{"title":"Variance in the composition and number of VLDL and LDL particles with increasing triglyceride or increasing ApoB concentrations","authors":"Justine Cole MBChB, MMed , Patrick Couture MD, PhD , André J. Tremblay PhD , Allan D. Sniderman MD","doi":"10.1016/j.jacl.2024.09.009","DOIUrl":"10.1016/j.jacl.2024.09.009","url":null,"abstract":"<div><h3>OBJECTIVE</h3><div>The importance of any enhanced atherogenicity of triglyceride (TG)-rich lipoproteins (TRLs) will depend on the relative abundance of these particles compared with low-density lipoprotein (LDL) or total apolipoprotein (apo)B. Accordingly, we determined the contribution that TRLs make to total apoB as TG or apoB concentrations increase. We also describe compositional changes in TRLs as TG or apoB increases to assess whether very low-density lipoprotein (VLDL-[C]) is a valid proxy for VLDL-apoB.</div></div><div><h3>METHODS</h3><div>We used sequential ultracentrifugation to separate lipoprotein fractions in plasma samples from 1940 dyslipidemic patients not on lipid-lowering medication, and measured apoB, cholesterol and TG in the plasma and in each subfraction. We analyzed these data in quartiles of TG or apoB.</div></div><div><h3>RESULTS</h3><div>There was wide variance in all parameters in all quartiles of both TG and apoB. Although VLDL-apoB accounted for almost all the increase in total apoB across TG quartiles, LDL-apoB still accounted for 80% of the total in TG quartile 4. In contrast, LDL-apoB accounted for 90% of the increase in apoB across apoB quartiles. As TG increases, the increase in VLDL-C is explained more by increased VLDL-C/apoB when TG is moderately elevated, and more by increased VLDL-apoB when TG is very high.</div></div><div><h3>CONCLUSIONS</h3><div>In conclusion, VLDL-apoB only becomes a substantial component of total apoB with extreme hypertriglyceridemia and VLDL-C is not an appropriate proxy for VLDL-apoB.</div></div>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":"19 1","pages":"Pages 72-82"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Patients suffering from sitosterolemia with ABCG5/8 mutation typically present with early-onset or rapidly progressive atherosclerosis. Their kindreds with partial genetic deficiencies of ABCG5/8 are often considered healthy. However, discerning sitosterolemia from its familial kindreds and hyperlipidemia subjects has remained challenging.
METHODS
Here we retrospectively recruited 7 families including 8 individuals diagnosed with sitosterolemia subjects, and 14 kindreds carrying single gene mutations. Additionally, 17 individuals with hyperlipidemia and 130 healthy controls served as positive and negative controls, respectively. A total of 6 phytosterols combined with cholesterol absorption indices (including sitosterol, campesterol, stigmasterol, and cholestanol) and cholesterol synthesis markers (desmosterol and 7-dehydrocholesterol), was compared across the aforementioned 4 groups.
RESULTS
As expected, the sitosterolemia subjects with double mutations demonstrated significantly elevated levels of sitosterol and other cholesterol absorption indices. Meanwhile, sitosterolemia kindreds with single gene mutation showed a similar pattern of activated cholesterol-absorption ability to the hyperlipidemia group, but not as high as the double mutation group. Notably, the cholesterol-synthesis enzyme 7-dehydrocholesterol reductase displayed an increase in the hyperlipidemia group but a decrease in the sitosterolemia kindred group, suggesting a potential discriminative role of 7-dehydrocholesterol in distinguishing between these 2 groups. The combination of phytosterols was more valuable than clinical lipid index for sitosterolemia diagnosis.
CONCLUSION
Our study revealed mild disruptions of cholesterol absorption capacities in sitosterolemia kindreds with single mutations. Furthermore, the combination of 6 phytosterols proved effective in distinguishing between sitosterolemia, its single mutation carriers, and hyperlipidemia patients.
{"title":"Evaluation of plasma phytosterols in sitosterolemia, their kindreds and hyperlipidemia subjects","authors":"Xuanru Ren BS , Jun Zhang MD , Luya Wang BS , Yuxuan Zhang BS , Jialu Li BS , Hao Yu BS , Zhaohai Zheng BS , Yiqing Zhang BS , Hesong Zeng MD , Yan Chen MD , Junfang Wu PhD","doi":"10.1016/j.jacl.2024.09.002","DOIUrl":"10.1016/j.jacl.2024.09.002","url":null,"abstract":"<div><h3>BACKGROUND</h3><div>Patients suffering from sitosterolemia with <em>ABCG5/8</em> mutation typically present with early-onset or rapidly progressive atherosclerosis. Their kindreds with partial genetic deficiencies of ABCG5/8 are often considered healthy. However, discerning sitosterolemia from its familial kindreds and hyperlipidemia subjects has remained challenging.</div></div><div><h3>METHODS</h3><div>Here we retrospectively recruited 7 families including 8 individuals diagnosed with sitosterolemia subjects, and 14 kindreds carrying single gene mutations. Additionally, 17 individuals with hyperlipidemia and 130 healthy controls served as positive and negative controls, respectively. A total of 6 phytosterols combined with cholesterol absorption indices (including sitosterol, campesterol, stigmasterol, and cholestanol) and cholesterol synthesis markers (desmosterol and 7-dehydrocholesterol), was compared across the aforementioned 4 groups.</div></div><div><h3>RESULTS</h3><div>As expected, the sitosterolemia subjects with double mutations demonstrated significantly elevated levels of sitosterol and other cholesterol absorption indices. Meanwhile, sitosterolemia kindreds with single gene mutation showed a similar pattern of activated cholesterol-absorption ability to the hyperlipidemia group, but not as high as the double mutation group. Notably, the cholesterol-synthesis enzyme 7-dehydrocholesterol reductase displayed an increase in the hyperlipidemia group but a decrease in the sitosterolemia kindred group, suggesting a potential discriminative role of 7-dehydrocholesterol in distinguishing between these 2 groups. The combination of phytosterols was more valuable than clinical lipid index for sitosterolemia diagnosis.</div></div><div><h3>CONCLUSION</h3><div>Our study revealed mild disruptions of cholesterol absorption capacities in sitosterolemia kindreds with single mutations. Furthermore, the combination of 6 phytosterols proved effective in distinguishing between sitosterolemia, its single mutation carriers, and hyperlipidemia patients.</div></div>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":"19 1","pages":"Pages 146-155"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jacl.2024.10.004
Candy Bedoya PhD , Rishi Thomas DO , Anna Bjarvin BSc , Wilbur Ji DO , Hanien Samara BSc , Jody Tai DO , Laurie Green BSc , Philip H. Frost MD , Mary J. Malloy MD , Clive R. Pullinger PhD , John P. Kane MD, PhD , Miklós Péterfy PhD
BACKGROUND
The genetic basis of hypertriglyceridemia (HTG) is complex and includes variants in lipase maturation factor 1 (LMF1), an endoplasmic reticulum (ER)-chaperone involved in the post-translational activation of lipoprotein lipase (LPL).
OBJECTIVE
The objective of this study was to identify and functionally characterize biallelic LMF1 variants in patients with HTG.
METHODS
Genomic DNA sequencing was used to identify biallelic LMF1 variants in HTG patients without deleterious variants in LPL, apolipoprotein C-II (APOC2), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) or apolipoprotein A-V (APOA5). LMF1 variants were functionally evaluated by in silico analyses and assessing their impact on LPL activity, LMF1 protein expression, and specific activity in transiently transfected HEK293 cells.
RESULTS
We identified four homozygous LMF1 variants in patients with severe HTG: two novel rare variants (p.Asn147Lys and p.Pro246Arg) and two low-frequency variants (p.Arg354Trp and p.Arg364Gln) previously reported at heterozygosity. We demonstrate that all four variants reduce the secretion of enzymatically active LPL by impairing the specific activity of LMF1, whereas p.Asn147Lys also diminishes LMF1 protein expression.
CONCLUSION
This study extends the role of LMF1 as a genetic determinant in severe HTG and demonstrates that rare and low-frequency LMF1 variants can underlie this condition through distinct molecular mechanisms. The clinical phenotype of patients affected by partial loss of LMF1 function is consistent with multifactorial chylomicronemia syndrome (MCS) and suggests that secondary factors and additional genetic determinants contribute to HTG in these subjects.
{"title":"Identification and functional analysis of novel homozygous LMF1 variants in severe hypertriglyceridemia","authors":"Candy Bedoya PhD , Rishi Thomas DO , Anna Bjarvin BSc , Wilbur Ji DO , Hanien Samara BSc , Jody Tai DO , Laurie Green BSc , Philip H. Frost MD , Mary J. Malloy MD , Clive R. Pullinger PhD , John P. Kane MD, PhD , Miklós Péterfy PhD","doi":"10.1016/j.jacl.2024.10.004","DOIUrl":"10.1016/j.jacl.2024.10.004","url":null,"abstract":"<div><h3>BACKGROUND</h3><div>The genetic basis of hypertriglyceridemia (HTG) is complex and includes variants in lipase maturation factor 1 (LMF1), an endoplasmic reticulum (ER)-chaperone involved in the post-translational activation of lipoprotein lipase (LPL).</div></div><div><h3>OBJECTIVE</h3><div>The objective of this study was to identify and functionally characterize biallelic <em>LMF1</em> variants in patients with HTG.</div></div><div><h3>METHODS</h3><div>Genomic DNA sequencing was used to identify biallelic <em>LMF1</em> variants in HTG patients without deleterious variants in <em>LPL, apolipoprotein C-II (APOC2), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1)</em> or <em>apolipoprotein A-V (APOA5). LMF1</em> variants were functionally evaluated by <em>in silico</em> analyses and assessing their impact on LPL activity, LMF1 protein expression, and specific activity in transiently transfected HEK293 cells.</div></div><div><h3>RESULTS</h3><div>We identified four homozygous LMF1 variants in patients with severe HTG: two novel rare variants (p.Asn147Lys and p.Pro246Arg) and two low-frequency variants (p.Arg354Trp and p.Arg364Gln) previously reported at heterozygosity. We demonstrate that all four variants reduce the secretion of enzymatically active LPL by impairing the specific activity of LMF1, whereas p.Asn147Lys also diminishes LMF1 protein expression.</div></div><div><h3>CONCLUSION</h3><div>This study extends the role of <em>LMF1</em> as a genetic determinant in severe HTG and demonstrates that rare and low-frequency <em>LMF1</em> variants can underlie this condition through distinct molecular mechanisms. The clinical phenotype of patients affected by partial loss of LMF1 function is consistent with multifactorial chylomicronemia syndrome (MCS) and suggests that secondary factors and additional genetic determinants contribute to HTG in these subjects.</div></div>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":"19 1","pages":"Pages 95-104"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jacl.2024.10.005
Antoinette S. Birs MD , Andrew S. Kao MD , Elizabeth Silver MD , Eric D. Adler MD , Pam R. Taub MD , Michael J. Wilkinson MD
BACKGROUND
Cardiac allograft vasculopathy (CAV) is a leading cause of morbidity and mortality after heart transplantation (HTx). There are limited contemporary studies examining post-transplant lipid management and cardiometabolic health.
OBJECTIVE
We study the burden of cardiometabolic derangements post transplantation and its impact on CAV in a modern cohort of HTx recipients.
METHODS
All HTx recipients between January 2019 and December 2020, with 2 lipid assessments and angiographic surveillance were included. Logistic regression was used to assess association of lipid levels with cardiovascular outcomes and CAV.
RESULTS
Among 87 HTx recipients, atherogenic lipids were significantly elevated after Htx. Median low-density lipoprotein cholesterol increased from a baseline level of 69.5 mg/dL to 86.5 mg/dL, p = .002, non-high-density lipoprotein cholesterol (non-HDL-C) 91.5 mg/dL to 118 mg/dL, p < .001, triglycerides 94.5 mg/dL to 133 mg/dL, p < .001, and remnant cholesterol 19 mg/dL to 27 mg/dL, p < .001. Increases in non-HDL-C, triglycerides, and remnant cholesterol were significantly associated with increased risk of CAV (Stanford Grade 4 and intimal thickness). Increases in triglycerides and remnant cholesterol were associated with increased risk of composite major adverse cardiovascular events (MACE).
CONCLUSION
We demonstrate a significant increase in atherogenic lipids 2 years following transplantation with low use (20%) of high-intensity statin. Increase in atherogenic lipids was associated with increased risk of CAV and increase in triglycerides and remnant cholesterol with increased MACE. Future studies examining cardiometabolic consequences of HTx and optimal treatment strategies to reduce risk of CAV and MACE are needed.
{"title":"Burden of atherogenic lipids and association with cardiac allograft vasculopathy in heart transplant recipients","authors":"Antoinette S. Birs MD , Andrew S. Kao MD , Elizabeth Silver MD , Eric D. Adler MD , Pam R. Taub MD , Michael J. Wilkinson MD","doi":"10.1016/j.jacl.2024.10.005","DOIUrl":"10.1016/j.jacl.2024.10.005","url":null,"abstract":"<div><h3>BACKGROUND</h3><div>Cardiac allograft vasculopathy (CAV) is a leading cause of morbidity and mortality after heart transplantation (HTx). There are limited contemporary studies examining post-transplant lipid management and cardiometabolic health.</div></div><div><h3>OBJECTIVE</h3><div>We study the burden of cardiometabolic derangements post transplantation and its impact on CAV in a modern cohort of HTx recipients.</div></div><div><h3>METHODS</h3><div>All HTx recipients between January 2019 and December 2020, with 2 lipid assessments and angiographic surveillance were included. Logistic regression was used to assess association of lipid levels with cardiovascular outcomes and CAV.</div></div><div><h3>RESULTS</h3><div>Among 87 HTx recipients, atherogenic lipids were significantly elevated after Htx. Median low-density lipoprotein cholesterol increased from a baseline level of 69.5 mg/dL to 86.5 mg/dL, <em>p</em> = .002, non-high-density lipoprotein cholesterol (non-HDL-C) 91.5 mg/dL to 118 mg/dL, <em>p</em> < .001, triglycerides 94.5 mg/dL to 133 mg/dL, <em>p</em> < .001, and remnant cholesterol 19 mg/dL to 27 mg/dL, <em>p</em> < .001. Increases in non-HDL-C, triglycerides, and remnant cholesterol were significantly associated with increased risk of CAV (Stanford Grade 4 and intimal thickness). Increases in triglycerides and remnant cholesterol were associated with increased risk of composite major adverse cardiovascular events (MACE).</div></div><div><h3>CONCLUSION</h3><div>We demonstrate a significant increase in atherogenic lipids 2 years following transplantation with low use (20%) of high-intensity statin. Increase in atherogenic lipids was associated with increased risk of CAV and increase in triglycerides and remnant cholesterol with increased MACE. Future studies examining cardiometabolic consequences of HTx and optimal treatment strategies to reduce risk of CAV and MACE are needed.</div></div>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":"19 1","pages":"Pages 134-145"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Autosomal recessive hypercholesterolemia (ARH) is an ultrarare dyslipidemia caused by variants in the LDLRAP1 gene. Clinically, this condition is indistinguishable from other homozygous familial hypercholesterolemia (HoFH).
CASE
We present the cases of 2 siblings diagnosed with ARH caused by LDLRAP1 gene c.617-14C > A splicing homozygous variant. Over a 5-year treatment period, the older sibling experienced an 81% reduction in low-density lipoprotein cholesterol (LDL-C) levels with the maximal dose of pitavastatin plus ezetimibe, while the younger sibling achieved a 75% reduction. After three sessions, the older brother no longer required LDL apheresis, and the sibling never had LDL apheresis.
CONCLUSION
Our findings demonstrate a rapid and significant response to lipid-lowering therapy (LLT) in patients with ARH caused by c.617-14C > A splicing VUS variant, a condition that mimics HoFH at diagnosis. Long-term follow-up studies in large pediatric cohorts of ARH patients treated with pitavastatin plus ezetimibe from childhood are necessary to better define the risk of cardiovascular disease (CVD) development.
{"title":"Rapid lipid-lowering response in two cases of autosomal recessive hypercholesterolemia","authors":"Havva Yazıcı, Fehime Erdem, Ebru Canda, Sema Kalkan Uçar, Mahmut Çoker","doi":"10.1016/j.jacl.2024.09.003","DOIUrl":"10.1016/j.jacl.2024.09.003","url":null,"abstract":"<div><h3>BACKGROUND</h3><div>Autosomal recessive hypercholesterolemia (ARH) is an ultrarare dyslipidemia caused by variants in the <em>LDLRAP1</em> gene. Clinically, this condition is indistinguishable from other homozygous familial hypercholesterolemia (HoFH).</div></div><div><h3>CASE</h3><div>We present the cases of 2 siblings diagnosed with ARH caused by <em>LDLRAP1</em> gene c.617-14C > A splicing homozygous variant. Over a 5-year treatment period, the older sibling experienced an 81% reduction in low-density lipoprotein cholesterol (LDL-C) levels with the maximal dose of pitavastatin plus ezetimibe, while the younger sibling achieved a 75% reduction. After three sessions, the older brother no longer required LDL apheresis, and the sibling never had LDL apheresis.</div></div><div><h3>CONCLUSION</h3><div>Our findings demonstrate a rapid and significant response to lipid-lowering therapy (LLT) in patients with ARH caused by c.617-14C > A splicing VUS variant, a condition that mimics HoFH at diagnosis. Long-term follow-up studies in large pediatric cohorts of ARH patients treated with pitavastatin plus ezetimibe from childhood are necessary to better define the risk of cardiovascular disease (CVD) development.</div></div>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":"19 1","pages":"Pages 167-172"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.jacl.2024.10.008
Martine Paquette MSc , Isabelle Ruel PhD , Simon-Pierre Guay MD, PhD , Zobaida Al-Baldawi MSc , Diane Brisson PhD , Daniel Gaudet MD, PhD , Patrick Couture MD, PhD , Jean Bergeron MD, MSc , Robert A Hegele MD , Gordon A Francis MD , Mark H Sherman MD , Ruth McPherson MD, PhD , Thomas Ransom MD, MSc , Liam R Brunham MD, PhD , GB John Mancini MD , Brian W McCrindle MD MPH , Lulia Latan MD, PhD , Jacques Genest MD , Alexis Baass MD, MSc
BACKGROUND
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease of low-density lipoprotein cholesterol (LDL-C) metabolism. Despite the devastating effect of this disease on atherosclerotic cardiovascular health, the disease phenotype and severity are more heterogeneous than previously thought. The predictors of atherosclerotic cardiovascular disease (ASCVD) in HoFH patients have never been systematically studied.
OBJECTIVE
To investigate the univariate and multivariate predictors of ASCVD in HoFH patients.
METHODS
Patients from the Canadian HoFH Registry were included in the present retrospective longitudinal study. Data for these patients were collected using a standardized questionnaire between 2019 and 2022 in 19 academic sites across Canada. Predictors of ASCVD were evaluated using Cox proportional hazards models.
RESULTS
Among 48 HoFH patients, 26 (54%) of them had at least 1 ASCVD event. The average age at baseline was 19 ± 15 years and women represented 56% of the cohort. The independent predictors of ASCVD events were male sex (HR 2.57 [1.13–5.84]), diabetes (HR 16.22 [3.38–77.97]), and LDL-C above the median of 14.45 mmol/L (559 mg/dL) (HR 3.10 [1.24–7.76]). When performing subgroup analysis according to sex, the presence of LDL-C above the median was associated with a significantly higher probability of ASCVD (88% vs 43%, P = .005) in women, but not in men (100% at age 40 in both groups, P = .98).
CONCLUSION
This study reported for the first time the univariate and multivariate predictors of ASCVD in HoFH patients. We demonstrate that predictors of ASCVD in HoFH differ in males and females with respect to LDL-C levels.
{"title":"Extreme LDL-C concentration is associated with increased cardiovascular disease in women with homozygous familial hypercholesterolemia","authors":"Martine Paquette MSc , Isabelle Ruel PhD , Simon-Pierre Guay MD, PhD , Zobaida Al-Baldawi MSc , Diane Brisson PhD , Daniel Gaudet MD, PhD , Patrick Couture MD, PhD , Jean Bergeron MD, MSc , Robert A Hegele MD , Gordon A Francis MD , Mark H Sherman MD , Ruth McPherson MD, PhD , Thomas Ransom MD, MSc , Liam R Brunham MD, PhD , GB John Mancini MD , Brian W McCrindle MD MPH , Lulia Latan MD, PhD , Jacques Genest MD , Alexis Baass MD, MSc","doi":"10.1016/j.jacl.2024.10.008","DOIUrl":"10.1016/j.jacl.2024.10.008","url":null,"abstract":"<div><h3>BACKGROUND</h3><div>Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease of low-density lipoprotein cholesterol (LDL-C) metabolism. Despite the devastating effect of this disease on atherosclerotic cardiovascular health, the disease phenotype and severity are more heterogeneous than previously thought. The predictors of atherosclerotic cardiovascular disease (ASCVD) in HoFH patients have never been systematically studied.</div></div><div><h3>OBJECTIVE</h3><div>To investigate the univariate and multivariate predictors of ASCVD in HoFH patients.</div></div><div><h3>METHODS</h3><div>Patients from the Canadian HoFH Registry were included in the present retrospective longitudinal study. Data for these patients were collected using a standardized questionnaire between 2019 and 2022 in 19 academic sites across Canada. Predictors of ASCVD were evaluated using Cox proportional hazards models.</div></div><div><h3>RESULTS</h3><div>Among 48 HoFH patients, 26 (54%) of them had at least 1 ASCVD event. The average age at baseline was 19 ± 15 years and women represented 56% of the cohort. The independent predictors of ASCVD events were male sex (HR 2.57 [1.13–5.84]), diabetes (HR 16.22 [3.38–77.97]), and LDL-C above the median of 14.45 mmol/L (559 mg/dL) (HR 3.10 [1.24–7.76]). When performing subgroup analysis according to sex, the presence of LDL-C above the median was associated with a significantly higher probability of ASCVD (88% vs 43%, <em>P</em> = .005) in women, but not in men (100% at age 40 in both groups, <em>P</em> = .98).</div></div><div><h3>CONCLUSION</h3><div>This study reported for the first time the univariate and multivariate predictors of ASCVD in HoFH patients. We demonstrate that predictors of ASCVD in HoFH differ in males and females with respect to LDL-C levels.</div></div>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":"19 1","pages":"Pages 105-113"},"PeriodicalIF":3.6,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-30DOI: 10.1016/j.jacl.2024.12.016
Walter Masson, Leandro Barbagelata, Martin Lobo, Juan Patricio Nogueira, Yehuda Handelsman
Background: Obicetrapib is a next-generation, oral, selective cholesteryl ester transfer protein inhibitor known to significantly affect atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (Non-HDL-C), and lipoprotein(a) [Lp(a)].
Objective: To evaluate the lipid-lowering efficacy of obicetrapib based on available evidence.
Methods: This systematic review was drafted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search was conducted to identify randomized clinical trials assessing the lipid-lowering effects of obicetrapib compared to placebo. Fixed- and random-effects models were used.
Results: Five randomized clinical trials (n = 288 patients) were included in this analysis. Patients treated with obicetrapib exhibited significantly greater reductions in LDL-C (mean difference [MD]: 41.4% [95% CI: 45.7 to -37.1]; I²: 6%), ApoB (MD: 26.5% [95% CI: 31.3 to -21.6]; I²: 45%) and Non-HDL-C (MD: 34.5% [95% CI: 37.0 to -31.6]; I²: 80%) compared to those receiving a placebo. Additionally, HDL-C levels were significantly higher in the obicetrapib group (MD: 157.4% [95% CI: 142.2 to 172.6]; I²: 69%). While triglyceride levels did not differ significantly between the 2 groups, Lp(a) levels were notably reduced with obicetrapib treatment (MD: 39.5% [95% CI: 54.6 to -24.3]; I²: 67%).
Conclusion: Obicetrapib is associated with significant reductions in key atherogenic lipoproteins, including LDL-C, ApoB, Non-HDL-C and Lp(a). Further investigation is needed to assess its impact on cardiovascular risk.
{"title":"Lipid-lowering efficacy of obicetrapib: A comprehensive systematic review and meta-analysis.","authors":"Walter Masson, Leandro Barbagelata, Martin Lobo, Juan Patricio Nogueira, Yehuda Handelsman","doi":"10.1016/j.jacl.2024.12.016","DOIUrl":"https://doi.org/10.1016/j.jacl.2024.12.016","url":null,"abstract":"<p><strong>Background: </strong>Obicetrapib is a next-generation, oral, selective cholesteryl ester transfer protein inhibitor known to significantly affect atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (Non-HDL-C), and lipoprotein(a) [Lp(a)].</p><p><strong>Objective: </strong>To evaluate the lipid-lowering efficacy of obicetrapib based on available evidence.</p><p><strong>Methods: </strong>This systematic review was drafted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive literature search was conducted to identify randomized clinical trials assessing the lipid-lowering effects of obicetrapib compared to placebo. Fixed- and random-effects models were used.</p><p><strong>Results: </strong>Five randomized clinical trials (n = 288 patients) were included in this analysis. Patients treated with obicetrapib exhibited significantly greater reductions in LDL-C (mean difference [MD]: 41.4% [95% CI: 45.7 to -37.1]; I²: 6%), ApoB (MD: 26.5% [95% CI: 31.3 to -21.6]; I²: 45%) and Non-HDL-C (MD: 34.5% [95% CI: 37.0 to -31.6]; I²: 80%) compared to those receiving a placebo. Additionally, HDL-C levels were significantly higher in the obicetrapib group (MD: 157.4% [95% CI: 142.2 to 172.6]; I²: 69%). While triglyceride levels did not differ significantly between the 2 groups, Lp(a) levels were notably reduced with obicetrapib treatment (MD: 39.5% [95% CI: 54.6 to -24.3]; I²: 67%).</p><p><strong>Conclusion: </strong>Obicetrapib is associated with significant reductions in key atherogenic lipoproteins, including LDL-C, ApoB, Non-HDL-C and Lp(a). Further investigation is needed to assess its impact on cardiovascular risk.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-25DOI: 10.1016/j.jacl.2024.12.014
Ulrich Laufs, A Michael Lincoff, Stephen J Nicholls, Na Li, LeAnne Bloedon, William J Sasiela, Heather A Powell, Peter M Herout, Paul D Thompson, Steven E Nissen
Background: Cholesterol Lowering via bEmpedoic Acid Regimen (CLEAR) outcomes, a randomized, double-blind, placebo-controlled cardiovascular outcomes trial, and the largest prospective database of patients with statin intolerance (SI), demonstrated that bempedoic acid reduces low-density lipoprotein cholesterol and cardiovascular risk in patients at high cardiovascular risk.
Objective: Assess baseline differences in SI symptoms and whether these influenced the clinical course during CLEAR outcomes.
Methods: Symptoms and impact of SI on daily living were recorded prior to randomization. This posthoc analysis grouped patients as reporting statin-associated muscle symptoms only (SAMS), nonmuscle adverse effects only (nonSAMS), or BOTH.
Results: Of the 13,970 patients at baseline, 49% reported SAMS, 18% NonSAMS, and 33% BOTH. Moderate/severe impact on daily living was recorded for 62% SAMS, 48% NonSAMS, and 69% BOTH. Baseline lipid modifying treatment (LMT) was used in 43% SAMS, 36% nonSAMS, and 42% BOTH. Drop-in use of moderate/high-intensity statin at any time during the study was higher in the placebo group in all SI groups and higher in SAMS and BOTH vs. nonSAMS, but was not generally maintained at study end. SAMS and BOTH groups had more muscle symptoms and higher rates of treatment discontinuation vs. NonSAMS but there was no difference between treatments.
Conclusion: Patients who reported SAMS, regardless of randomization to bempedoic acid or placebo, had higher rates of discontinuation, higher rates of skeletal muscle symptoms, and a greater percentage of patients to attempt statin rechallenge. These findings indicate patients with history of SAMS may have background factors impacting their tolerance to LMT and may require more focused clinical management.
Clinicaltrials:
Gov identifier: NCT02993406.
{"title":"Characteristics and outcomes of patients with and without statin-associated muscle symptoms treated with bempedoic acid in the CLEAR Outcomes trial.","authors":"Ulrich Laufs, A Michael Lincoff, Stephen J Nicholls, Na Li, LeAnne Bloedon, William J Sasiela, Heather A Powell, Peter M Herout, Paul D Thompson, Steven E Nissen","doi":"10.1016/j.jacl.2024.12.014","DOIUrl":"https://doi.org/10.1016/j.jacl.2024.12.014","url":null,"abstract":"<p><strong>Background: </strong>Cholesterol Lowering via bEmpedoic Acid Regimen (CLEAR) outcomes, a randomized, double-blind, placebo-controlled cardiovascular outcomes trial, and the largest prospective database of patients with statin intolerance (SI), demonstrated that bempedoic acid reduces low-density lipoprotein cholesterol and cardiovascular risk in patients at high cardiovascular risk.</p><p><strong>Objective: </strong>Assess baseline differences in SI symptoms and whether these influenced the clinical course during CLEAR outcomes.</p><p><strong>Methods: </strong>Symptoms and impact of SI on daily living were recorded prior to randomization. This posthoc analysis grouped patients as reporting statin-associated muscle symptoms only (SAMS), nonmuscle adverse effects only (nonSAMS), or BOTH.</p><p><strong>Results: </strong>Of the 13,970 patients at baseline, 49% reported SAMS, 18% NonSAMS, and 33% BOTH. Moderate/severe impact on daily living was recorded for 62% SAMS, 48% NonSAMS, and 69% BOTH. Baseline lipid modifying treatment (LMT) was used in 43% SAMS, 36% nonSAMS, and 42% BOTH. Drop-in use of moderate/high-intensity statin at any time during the study was higher in the placebo group in all SI groups and higher in SAMS and BOTH vs. nonSAMS, but was not generally maintained at study end. SAMS and BOTH groups had more muscle symptoms and higher rates of treatment discontinuation vs. NonSAMS but there was no difference between treatments.</p><p><strong>Conclusion: </strong>Patients who reported SAMS, regardless of randomization to bempedoic acid or placebo, had higher rates of discontinuation, higher rates of skeletal muscle symptoms, and a greater percentage of patients to attempt statin rechallenge. These findings indicate patients with history of SAMS may have background factors impacting their tolerance to LMT and may require more focused clinical management.</p><p><strong>Clinicaltrials: </strong></p><p><strong>Gov identifier: </strong>NCT02993406.</p>","PeriodicalId":15392,"journal":{"name":"Journal of clinical lipidology","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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