Excess Apolipoprotein B and Cardiovascular Risk in Women and Men.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) are highly correlated measures of atherogenic lipoproteins. OBJECTIVES: The study investigators hypothesized that excess apoB is associated with an increased risk of myocardial infarction (MI), atherosclerotic cardiovascular disease (ASCVD), and all-cause mortality. METHODS: The study included 53,484 women and 41,624 men not taking statins from the Copenhagen General Population Study. Associations of excess apoB with the risk of MI, ASCVD, and all-cause mortality were estimated by Cox proportional hazards regressions with 95% CIs. Excess apoB was defined as measured levels of apoB minus expected levels of apoB from LDL-C alone; expected levels were defined by linear regressions of LDL-C levels vs apoB levels in individuals with triglycerides ≤1 mmol/L (89 mg/dL). RESULTS: During a median follow-up of 9.6 years, 2,048 MIs, 4,282 ASCVD events, and 8,873 deaths occurred. There was a dose-dependent association between excess apoB and the risk of MI and ASCVD in both women and men, as well as an association with the risk of all-cause mortality in women. For ASCVD in women compared with those with excess apoB <11 mg/dL, the multivariable adjusted HR was 1.08 (95% CI: 0.97-1.21) for excess apoB 11 to 25 mg/dL, 1.30 (95% CI: 1.14-1.48) for 26 to 45 mg/dL, 1.34 (95% CI: 1.14-1.58) for 46 to 100 mg/dL, and 1.75 (95% CI: 1.08-2.83) for excess apoB >100 mg/dL. Corresponding HRs in men were 1.14 (95% CI: 1.02-1.26), 1.41 (95% CI: 1.26-1.57), 1.41 (95% CI: 1.25-1.60), and 1.52 (95% CI: 1.13-2.05), respectively. Results were robust across the entire LDL-C spectrum. CONCLUSIONS: Excess apoB (ie, the value of apoB above that contributed by LDL-C levels alone) is associated dose-dependently with an increased risk of MI and ASCVD in women and men. This finding demonstrates that apoB provides important predictive value beyond LDL-C across the entire LDL-C spectrum.

Worldwide Increasing Use of Nonfasting Rather Than Fasting Lipid Profiles.

BACKGROUND: Historically, lipids and lipoproteins were measured in the fasting state for cardiovascular risk prediction; however, since 2009 use of nonfasting lipid profiles has increased substantially worldwide. For patients, nonfasting lipid profiles are convenient and avoid any risk of hypoglycemia. For laboratories, blood sampling in the morning and extra visits for patients who have not fasted are avoided. For patients, clinicians, hospitals, and society, nonfasting sampling allows same-day visits with first blood sampling followed by a short wait for test results before clinical consultation. Therefore, nonfasting compared to fasting lipid profiles will save money and time and may improve patient compliance with cardiovascular prevention programs. CONTENT: We report on the progression of endorsement and implementation of nonfasting lipid profiles for cardiovascular risk prediction worldwide and summarize the recommendations from major medical societies and health authorities in different countries. We also describe practical advantages and disadvantages for using nonfasting lipid profiles. Further, we include a description of why fasting has been the standard historically, the barriers against implementation of nonfasting lipid profiles, and finally we suggest the optimal content of a nonfasting lipid profile. SUMMARY: Lipid, lipoprotein, and apolipoprotein concentrations vary minimally in response to normal food intake and nonfasting lipid profiles are equal or superior to fasting profiles for cardiovascular risk prediction. Major guidelines and consensus statements in Europe, the United States, Canada, Brazil, Japan, India, and Australia now endorse use of nonfasting lipid profiles in some or all patients; however, there are still gaps in endorsement and implementation of nonfasting lipid profiles worldwide.

Remnant cholesterol, LDL cholesterol, and apoB absolute mass changes explain results of the PROMINENT trial.

BACKGROUND AND AIMS: The PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. We tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B explain the results of the PROMINENT trial. METHODS: Among 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT. RESULTS: In the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (-0.18 mmol/L; -18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) LDL cholesterol, and +5 mg/dL (+0.05 g/L; +5 %) apolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 (95 % confidence interval: 0.94-0.99) for a -7 mg/dL (-0.18 mmol/L) change in remnant cholesterol, 1.04 (1.01-1.07) for a +10 mg/dL (+0.26 mmol/L) change in LDL cholesterol, and 1.02 (1.01-1.03) for a +5 mg/dL (+0.05 g/L) change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 (0.96-1.14) in the CGPS mimicking PROMINENT compared to 1.03 (0.91-1.15) in the PROMINENT trial. CONCLUSIONS: Absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL (0.05 g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm.

Novel Therapies for Lipoprotein(a): Update in Cardiovascular Risk Estimation and Treatment.

PURPOSE OF REVIEW: Lipoprotein(a) is an important causal risk factor for cardiovascular disease but currently no available medication effectively reduces lipoprotein(a). This review discusses recent findings regarding lipoprotein(a) as a causal risk factor and therapeutic target in cardiovascular disease, it reviews current clinical recommendations, and summarizes new lipoprotein(a) lowering drugs. RECENT FINDINGS: Epidemiological and genetic studies have established lipoprotein(a) as a causal risk factor for cardiovascular disease and mortality. Guidelines worldwide now recommend lipoprotein(a) to be measured once in a lifetime, to offer patients with high lipoprotein(a) lifestyle advise and initiate other cardiovascular medications. Clinical trials including antisense oligonucleotides, small interfering RNAs, and an oral lipoprotein(a) inhibitor have shown great effect on lowering lipoprotein(a) with reductions up to 106%, without any major adverse effects. Recent clinical phase 1 and 2 trials show encouraging results and ongoing phase 3 trials will hopefully result in the introduction of specific lipoprotein(a) lowering drugs to lower the risk of cardiovascular disease.

Lipoproteins, Cholesterol, and Atherosclerotic Cardiovascular Disease in East Asians and Europeans.

One fifth of the world population live in East Asia comprising Japan, Korea, and China where ischemic heart disease, a major component of atherosclerotic cardiovascular disease (ASCVD), is the second most frequent cause of death. Each of low-density lipoproteins (LDL), remnant lipoproteins, and lipoprotein(a), summarized as non-high-density lipoproteins (non-HDL) or apolipoprotein B (apoB) containing lipoproteins, causes ASCVD. However, a significant proportion of the evidence on lipoproteins and lipoprotein cholesterol with risk of ASCVD came from White people mainly living in Europe and North America and not from people living in East Asia or of East Asian descent. With a unique biological, geohistorical, and social background in this world region, East Asians have distinctive characteristics that might have potential impact on the association of lipoproteins and lipoprotein cholesterol with risk of ASCVD. Considering the movement across national borders in the World, understanding of lipoprotein and lipoprotein cholesterol evidence on ASCVD in East Asia is important for both East Asian and non-East Asian populations wherever they live in the World.In this review, we introduce the biological features of lipoproteins and lipoprotein cholesterol and the evidence for their association with risk of ASCVD in East Asian and European populations. We also provide an overview of guideline recommendations for prevention of ASCVD in these two different world regions. Finally, specific preventive strategies and future perspectives are touched upon.

Hypertriglyceridemia-Associated Pancreatitis: New Concepts and Potential Mechanisms.

BACKGROUND: Triglycerides are a major source of energy, while high plasma triglycerides are a risk factor for various diseases and premature death. Severely elevated plasma triglycerides are a well-established cause of acute pancreatitis with high mortality, likely due to the presence of elevated levels of chylomicrons and large very low-density lipoproteins in plasma. As markedly elevated levels of these very large lipoproteins are not generally found in mild to moderate hypertriglyceridemia, this was previously not regarded as a cause or marker of increased risk of acute pancreatitis. However, mild to moderate hypertriglyceridemia may identify individuals who at a later timepoint develop severe hypertriglyceridemia and acute pancreatitis. CONTENT: We describe measurement of plasma triglycerides and studies on plasma triglycerides and risk of acute pancreatitis. Further, we summarize current European and American guidelines for the prevention of acute pancreatitis and, finally, the potential for future prevention of acute pancreatitis through lowering of plasma triglycerides. SUMMARY: Recent observational and genetic studies indicate that mild to moderate hypertriglyceridemia is causally related to increased risk of acute pancreatitis, most likely as a marker of future severe hypertriglyceridemia. Current guidelines do not mention individuals with mild to moderate hypertriglyceridemia, even though newer evidence suggests an unmet medical need. Treatment could include plasma triglyceride-lowering therapy targeting the pathway for lipoprotein lipase as the main triglyceride degrading enzyme in plasma. Angiopoietin-like 3 and apolipoproteinC-III are inhibitors of lipoprotein lipase, and blocking of these 2 inhibitors is showing promising results in relation to marked triglyceride-lowering and could perhaps be used to prevent acute pancreatitis in the future.

Dual elevated remnant cholesterol and C-reactive protein in myocardial infarction, atherosclerotic cardiovascular disease, and mortality.

BACKGROUND AND AIMS: Elevated remnant cholesterol and low-grade inflammation each cause atherosclerotic cardiovascular disease (ASCVD); however, it is unknown whether joint elevation of both factors confers the highest risk. We tested the hypothesis that dual elevated remnant cholesterol and low-grade inflammation marked by elevated C-reactive protein is associated with the highest risk of myocardial infarction, ASCVD, and all-cause mortality. METHODS: The Copenhagen General Population Study randomly recruited white Danish individuals aged 20-100 years in 2003-2015 and followed them for a median 9.5 years. ASCVD was cardiovascular mortality, myocardial infarction, stroke, and coronary revascularization. RESULTS: In 103,221 individuals, we observed 2,454 (2.4%) myocardial infarctions, 5,437 (5.3%) ASCVD events, and 10,521 (10.2%) deaths. The hazard ratios increased with each of stepwise higher remnant cholesterol and stepwise higher C-reactive protein. In individuals with the highest tertile of both remnant cholesterol and C-reactive protein compared to individuals with the lowest tertile of both, the multivariable adjusted hazard ratios were 2.2 (95%CI:1.9-2.7) for myocardial infarction, 1.9 (1.7-2.2) for ASCVD, and 1.4 (1.3-1.5) for all-cause mortality. Corresponding values for only the highest tertile of remnant cholesterol were 1.6 (1.5-1.8), 1.4 (1.3-1.5), and 1.1 (1.0-1.1), and those for only the highest tertile of C-reactive protein were 1.7 (1.5-1.8), 1.6 (1.5-1.7), and 1.3 (1.3-1.4), respectively. There was no statistical evidence for interaction between elevated remnant cholesterol and elevated C-reactive protein on risk of myocardial infarction (p = 0.10), ASCVD (p = 0.40), or all-cause mortality (p = 0.74). CONCLUSIONS: Dual elevated remnant cholesterol and C-reactive protein confers the highest risk of myocardial infarction, ASCVD, and all-cause mortality, that is, compared to either of these two factors individually.

Can remnant cholesterol (triglyceride-rich lipoproteins) reclassify estimated risk of atherosclerotic cardiovascular disease?

PURPOSE OF REVIEW: To summarize recent studies analyzing reclassification of estimated risk of myocardial infarction (MI) and ischemic heart disease (IHD) by inclusion of remnant cholesterol (= cholesterol content in triglyceride-rich lipoproteins) in primary and secondary prevention settings. RECENT FINDINGS: For individuals in a primary prevention setting with remnant cholesterol levels at least 95th percentile (≥1.6 mmol/l, 61 mg/dl), 23% of MI and 21% of IHD events developed later were reclassified correctly from below to above 5% for 10-year occurrence when remnant cholesterol levels were added to models based on conventional risk factors, whereas no events were reclassified incorrectly. Overall improved reclassification of MI was also observed for remnant cholesterol levels as low as at least 50th percentile (≥0.6 mmol/l, 25 mg/dl); however, the addition of remnant cholesterol over the entire concentration range yielded insignificant improvements of NRI for MI but slightly improved reclassification of NRI for IHD. In a secondary prevention setting, addition of remnant cholesterol over the entire concentration range to a conventional risk model improved reclassification. SUMMARY: Elevated remnant cholesterol levels considerably improves reclassification of individuals who later develop MI and IHD, in primary as well as in secondary prevention settings.

Small Dense Low-Density Lipoprotein Cholesterol and Ischemic Stroke.

OBJECTIVE: For decades, it has been suggested that small dense low-density lipoprotein (sdLDL) may be particularly atherogenic. High levels of sdLDL are associated with an increased risk of ischemic heart disease; however, the association of sdLDL with ischemic stroke has not been explored in a large prospective study on the general population. We tested the hypothesis that high sdLDL cholesterol levels are associated with an increased risk of ischemic stroke. METHODS: This prospective study included 38,319 individuals from the Copenhagen General Population Study with fresh sample measurements of sdLDL cholesterol. Median follow-up time was 3.1 years. We observed 302 and 74 ischemic and hemorrhagic strokes from baseline in 2013 to 2017 to the end of follow-up in 2018. For comparison, we included estimates for large buoyant LDL cholesterol and total LDL cholesterol. RESULTS: Higher levels of sdLDL cholesterol were log-linearly associated with increased risk of ischemic stroke. Compared with individuals with sdLDL cholesterol in the lowest tertile (≤0.60 mmol/l; ≤23 mg/dl) the multivariable adjusted hazard ratio for ischemic stroke was 1.79 (95% confidence interval = 1.31-2.43) for the highest tertile (≥0.86 mmol/l; ≥33 mg/dl). Multivariable adjusted hazard ratios for ischemic stroke per 1 mmol/l (38.7 mg/dl) higher levels were 1.69 (1.28-2.22) for sdLDL cholesterol, 0.95 (0.78-1.16) for large buoyant LDL cholesterol, and 1.08 (0.93-1.25) for total LDL cholesterol. Hazard ratios were similar when further adjusting for body mass index (BMI) and diabetes mellitus in the biological pathway in combination with related lipids and lipoproteins. INTERPRETATION: Higher sdLDL cholesterol levels were robustly associated with increased risk of ischemic stroke. ANN NEUROL 2023;93:952-964.

Elevated LDL Triglycerides and Atherosclerotic Risk.

BACKGROUND: It is unclear whether elevated low-density lipoprotein (LDL) triglycerides are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). OBJECTIVES: This study tested the hypothesis that elevated LDL triglycerides are associated with an increased risk of ASCVD and of each ASCVD component individually. METHODS: The study investigators used the Copenhagen General Population Study, which measured LDL triglycerides in 38,081 individuals with a direct automated assay (direct LDL triglycerides) and in another 30,208 individuals with nuclear magnetic resonance (NMR) spectroscopy (NMR LDL triglycerides). Meta-analyses aggregated the present findings with previously reported results. RESULTS: During a median follow-up of 3.0 and 9.2 years, respectively, 872 and 5,766 individuals in the 2 cohorts received a diagnosis of ASCVD. Per 0.1 mmol/L (9 mg/dL) higher direct LDL triglycerides, HRs were 1.26 (95% CI: 1.17-1.35) for ASCVD, 1.27 (95% CI: 1.16-1.39) for ischemic heart disease, 1.28 (95% CI: 1.11-1.48) for myocardial infarction, 1.22 (95% CI: 1.08-1.38) for ischemic stroke, and 1.38 (95% CI: 1.21-1.58) for peripheral artery disease. Corresponding HRs for NMR LDL triglycerides were 1.26 (95% CI: 1.20-1.33), 1.33 (95% CI: 1.25-1.41), 1.41 (95% CI: 1.31-1.52), 1.13 (95% CI: 1.05-1.23), and 1.26 (95% CI: 1.10-1.43), respectively. The foregoing results were not entirely statistically explained by apolipoprotein B levels. In meta-analyses for the highest quartile vs the lowest quartile of LDL triglycerides, random-effects risk ratios were 1.50 (95% CI: 1.35-1.66) for ASCVD (4 studies; 71,526 individuals; 8,576 events), 1.62 (95% CI: 1.37-1.93) for ischemic heart disease (6 studies; 107,538 individuals; 9,734 events), 1.30 (95% CI: 1.13-1.49) for ischemic stroke (4 studies; 78,026 individuals; 4,273 events), and 1.53 (95% CI: 1.29-1.81) for peripheral artery disease (4 studies; 107,511 individuals; 1,848 events). CONCLUSIONS: Elevated LDL triglycerides were robustly associated with an increased risk of ASCVD and of each ASCVD component individually in 2 prospective cohort studies and in meta-analyses of previous and present studies combined.

Smoking as the most important risk factor for chronic pancreatitis in the general population.

We tested the hypothesis that six toxic risk factors from the TIGAR-O classification system are equally important for risk of chronic pancreatitis, at the level of the individual patient and in the general population. 108,438 women and men aged 20-100 years participating in the Copenhagen General Population Study from 2003 to 2015 were included. Associations of smoking, alcohol intake, waist/hip ratio, kidney function, plasma triglycerides, plasma Ca2+, and diseases within the causal pathway with risk of chronic pancreatitis, and corresponding population attributable risks were estimated. Information on chronic pancreatitis was from national Danish health registries. During median 9 years (range: 0-15) of follow-up, 313 individuals had a first diagnosis of chronic pancreatitis; the incidence of chronic pancreatitis per 10,000 person-years were 3.1 overall, 2.8 in women, and 3.5 in men. Of the six toxic risk factors and relative to individuals with low values, individuals in the top 5% had hazard ratios for chronic pancreatitis of 3.1(95% CI 2.1-4.5) for pack-years smoked, 2.5(1.5-4.0) for alcohol intake, and 1.6(1.1-2.6) for plasma triglycerides. Corresponding values versus those without the baseline disease were 12.6 (7.9-20.2) for acute pancreatitis, 1.9 (1.2-2.8) for gallstone disease, and 1.9 (1.3-2.7) for diabetes mellitus. The highest population attributable fractions were for women (1) ever smoking (31%), (2) gallstone disease (5%), and (3) diabetes mellitus (4%), and for men (1) ever smoking (38%), (2) acute pancreatitis (7%)/high alcohol intake (7%), and (3) high plasma triglycerides (5%). Smoking is the most important risk factor for chronic pancreatitis in the general population.

Equivalent Impact of Elevated Lipoprotein(a) and Familial Hypercholesterolemia in Patients With Atherosclerotic Cardiovascular Disease.

BACKGROUND: Genetically elevated plasma lipoprotein(a) and familial hypercholesterolemia each result in premature atherosclerotic cardiovascular disease (ASCVD); however, a direct comparison in the same population is needed of these 2 genetic traits on the risk of ASCVD. OBJECTIVES: We determined the level of plasma lipoprotein(a) that is equivalent to low-density lipoprotein (LDL) cholesterol in clinically and genetically diagnosed familial hypercholesterolemia on risk of myocardial infarction and ASCVD. METHODS: We examined the CGPS (Copenhagen General Population Study) with determination of lipoprotein(a) and familial hypercholesterolemia in 69,644 individuals followed for 42 years, during which time, 4,166 developed myocardial infarction and 11,464, ASCVD. RESULTS: For risk of myocardial infarction, the plasma lipoprotein(a) level equivalent to LDL cholesterol in clinical familial hypercholesterolemia was 67 mg/dL (142 nmol/L) for MEDPED (Make Early Diagnosis to Prevent Early Death), 110 mg/dL (236 nmol/L) for Simon Broome, 256 mg/dL (554 nmol/L) for possible DLCN (Dutch Lipid Clinic Network), and 402 mg/dL (873 nmol/L) for probable+definite DLCN, whereas it was 180 mg/dL (389 nmol/L) for genetic familial hypercholesterolemia. Corresponding values for ASCVD were 130 mg/dL (280 nmol/L), 150 mg/dL (323 nmol/L), 227 mg/dL (491 nmol/L), 391 mg/dL (849 nmol/L), and 175 mg/dL (378 nmol/L), respectively. Individuals with both elevated lipoprotein(a) and either familial hypercholesterolemia or a family history of premature myocardial infarction had a higher risk of myocardial infarction and ASCVD compared with individuals with only 1 of these genetic traits, with the highest HRs being for lipoprotein(a) upper 20% vs lower 50% of 14.0 (95% CI: 9.15-21.3) for myocardial infarction and 5.05 (95% CI: 3.41-7.48) for ASCVD. CONCLUSIONS: Lipoprotein(a) levels equivalent to LDL cholesterol in clinical and genetic familial hypercholesterolemia were 67 to 402 mg/dL and 180 mg/dL, respectively, for myocardial infarction and 130 to 391 mg/dL and 175 mg/dL, respectively, for ASCVD.

Lipoprotein(a) during COVID-19 hospitalization: Thrombosis, inflammation, and mortality.

BACKGROUND AND AIMS: High levels of lipoprotein(a) could worsen the outcome of COVID-19 due to prothrombotic and proinflammatory properties of lipoprotein(a). We tested the hypotheses that during COVID-19 hospitalization i) increased thrombotic activity and inflammation are associated with lipoprotein(a) levels, and ii) lipoprotein(a) levels are associated with rate of hospital death and discharge. METHODS: We studied 211 patients admitted to Copenhagen University Hospital in 2020 with COVID-19, that is, prior to any vaccination. Thrombotic activity was marked by elevated D-dimer while inflammation was marked by elevated interleukin-6, C-reactive protein, and procalcitonin. Patients were followed until death (N = 36) or discharge (N = 175). RESULTS: A 2-fold higher D-dimer was associated with 14% (95%CI: 8.1-20%) higher lipoprotein(a). Conversely, 2-fold higher interleukin-6, C-reactive protein, and procalcitonin were associated with respectively 4.3% (0.62-7.8%), 5.7% (0.15-5.2%), and 8.7% (5.2-12%) lower lipoprotein(a). For hospital death, the multivariable adjusted hazard ratio per 2-fold higher lipoprotein(a) was 1.26 (95%CI:0.91-1.73). Corresponding hazard ratios per 2-fold higher biomarker were 0.93 (0.75-1.16) for D-dimer, 1.42 (1.17-1.73) for interleukin-6, 1.44 (0.95-2.17) for C-reactive protein, and 1.44 (1.20-1.73) for procalcitonin. For hospital discharge, the multivariable adjusted hazard ratio per 2-fold higher lipoprotein(a) was 0.91 (95%CI:0.79-1.06). Corresponding hazard ratios per 2-fold higher biomarker were 0.86 (0.75-0.98) for D-dimer, 0.84 (0.76-0.92) for interleukin-6, 0.80 (0.71-0.90) for C-reactive protein, and 0.76 (0.67-0.88) for procalcitonin. CONCLUSIONS: In COVID-19 patients, thrombotic activity marked by elevated D-dimer was associated with higher lipoprotein(a) while elevated inflammatory biomarkers of interleukin-6, C-reactive protein, and procalcitonin were associated with lower lipoprotein(a); however, elevated lipoprotein(a) was not associated with rate of hospital death or discharge.

Sex differences of lipoprotein(a) levels and associated risk of morbidity and mortality by age: The Copenhagen General Population Study.

BACKGROUND AND AIMS: Lipoprotein(a) is a well-known causal risk factor for cardiovascular morbidity and mortality. Little is known about the effect of age and sex on lipoprotein(a) levels, and it is largely unknown if the same elevation in lipoprotein(a) confers the same increase in risk in women and men. We investigated whether lipoprotein(a) levels and lipoprotein(a) associated risks of morbidity and mortality by age are similar in women and men. METHODS: We included 37,545 women and 32,497 men from the Copenhagen General Population Study. RESULTS: Plasma lipoprotein(a) increased with age, and in women we found an additional increase around age 50 (age by sex interaction p = 8∙10-7). In women, levels were 27% higher after menopause (p = 4∙10-61) and 12% lower during hormone replacement therapy (p = 2∙10-19). Adjustment for estimated Glomerular Filtration Rate in both sexes and plasma estradiol in women resulted in attenuated sex differences in lipoprotein(a) levels. In sex and age stratified multivariable adjusted models, lipoprotein(a) >40 mg/dL(83 nmol/L) versus <10 mg/dL(18 nmol/L) was associated with increased risk of myocardial infarction, ischemic heart disease, aortic valve stenosis, and heart failure (men only), but not statistically significant with risk of ischemic stroke, cardiovascular mortality, or all-cause mortality. CONCLUSIONS: Lipoprotein(a) levels increased modestly around age 50 selectively in women; however, risk of morbidity and mortality for high lipoprotein(a) was similar in women and men above age 50. This implies that elevated lipoprotein(a) above age 50 is a relatively more common cardiovascular risk factor in women, pointing toward repeat measurements in women above age 50.

Elevated Remnant Cholesterol Reclassifies Risk of Ischemic Heart Disease and Myocardial Infarction.

BACKGROUND: Elevated remnant cholesterol causes ischemic heart disease. OBJECTIVES: We tested the hypothesis that the inclusion of elevated remnant cholesterol will lead to appropriate reclassification of individuals who later experience myocardial infarction and ischemic heart disease. METHODS: For >10 years we followed up 41,928 white Danish individuals from the Copenhagen General Population Study without a history of ischemic cardiovascular disease, diabetes, and statin use. Using predefined cut points for elevated remnant cholesterol, we calculated net reclassification index (NRI) from below to above 5%, 7.5%, and/or 10% 10-year occurrence of myocardial infarction and ischemic heart disease defined as a composite of death from ischemic heart disease, myocardial infarction, and coronary revascularization. RESULTS: For individuals with remnant cholesterol levels ≥95th percentile (≥1.6 mmol/L, 61 mg/dL), 23% (P < 0.001) of myocardial infarction and 21% (P < 0.001) of ischemic heart disease were reclassified correctly from below to above 5% for 10-year occurrence when remnant cholesterol levels were added to models based on conventional risk factors, whereas no events were reclassified incorrectly. Consequently, the addition of remnant cholesterol levels yielded NRI of 10% (95% CI: 1%-20%) for myocardial infarction and 5% (95% CI: -3% to 13%) for ischemic heart disease. Correspondingly, when reclassifications were combined from below to above 5%, 7.5%, and 10% risk of events, 42% (P < 0.001) of individuals with myocardial infarction and 41% (P < 0.001) with ischemic heart disease were reclassified appropriately, leading to NRI of respectively 20% (95% CI: 9%-31%) and 11% (95% CI: 2%-21%). CONCLUSIONS: Elevated remnant cholesterol levels considerably improve myocardial infarction and ischemic heart disease risk prediction.

ApoB and Non-HDL Cholesterol Versus LDL Cholesterol for Ischemic Stroke Risk.

OBJECTIVE: Conflicting results have been reported on the association between lipids and risk of ischemic stroke. We tested the hypothesis that the burden of ischemic stroke attributable to either elevated apolipoprotein B (apoB) or non-high-density lipoprotein (non-HDL) cholesterol is higher than that attributable to elevated low-density lipoprotein (LDL) cholesterol. METHODS: We included 104,618 individuals from an ongoing cohort study, the Copenhagen General Population Study. The associations of quintiles of apoB, non-HDL cholesterol, and LDL cholesterol with risk of ischemic stroke were estimated by Cox proportional hazards regressions with 95% confidence intervals. With 1st quintile as reference, the proportion of ischemic stroke attributable to the 2nd , 3rd , 4th , and 5th quintiles of apoB, non-HDL cholesterol, and LDL cholesterol were estimated by population attributable fractions. RESULTS: Higher quintiles of apoB and non-HDL cholesterol were associated with increased risk of ischemic stroke (both trends: p < 0.0001), whereas for LDL cholesterol this association was somewhat attenuated (trend: p = 0.0005). A similar pattern was seen for population attributable fraction values. Compared to individuals in the 1st quintile, the combined proportion of ischemic stroke attributable to individuals in the 2nd to 5th quintiles was 16.3% for apoB (levels >82 mg/dL), 14.7% for non-HDL cholesterol (>3.0 mmol/L; >117 mg/dL), and 6.8% for LDL cholesterol (>2.4 mmol/L; >94 mg/dL). INTERPRETATION: The proportion of ischemic stroke attributable to either elevated apoB or non-HDL cholesterol was double that attributable to elevated LDL cholesterol. ANN NEUROL 2022;92:379-389.

Lipoprotein(a) as Part of the Diagnosis of Clinical Familial Hypercholesterolemia.

PURPOSE OF REVIEW: Individuals with familial hypercholesterolemia have very high risk of cardiovascular disease due to lifelong elevations in LDL cholesterol. Elevated lipoprotein(a) is a risk factor for cardiovascular diseases such as myocardial infarction and aortic valve stenosis. It has been proposed to include elevated lipoprotein(a) in the diagnosis of clinical familial hypercholesterolemia. RECENT FINDINGS: Lipoprotein(a) is co-measured in LDL cholesterol, and up to one-quarter of all diagnoses of clinical familial hypercholesterolemia are due to high levels of lipoprotein(a). Further, individuals with both familial hypercholesterolemia and elevated lipoprotein(a) have an extremely high risk of myocardial infarction. We discuss the background for familial hypercholesterolemia and elevated lipoprotein(a) as risk factors for cardiovascular disease and the consequences of the fact that LDL cholesterol measurements/calculations include the cholesterol present in lipoprotein(a). Finally, we discuss the potential of including lipoprotein(a) as part of the diagnosis of familial hypercholesterolemia and in consequence possible treatments.

Lipoprotein(a) and Body Mass Compound the Risk of Calcific Aortic Valve Disease.

BACKGROUND: High plasma lipoprotein(a) and high body mass index are both causal risk factors for calcific aortic valve disease. OBJECTIVES: This study sought to test the hypothesis that risk of calcific aortic valve disease is the highest when both plasma lipoprotein(a) and body mass index are extremely high. METHODS: From the Copenhagen General Population Study, we used information on 69,988 randomly selected individuals recruited from 2003 to 2015 (median follow-up 7.4 years) to evaluate the association between high lipoprotein(a) and high body mass index with risk of calcific aortic valve disease. RESULTS: Compared with individuals in the 1st to 49th percentiles for both lipoprotein(a) and body mass index, the multivariable adjusted HRs for calcific aortic valve disease were 1.6 (95% CI: 1.3-1.9) for the 50th to 89th percentiles of both (16% of all individuals) and 3.5 (95% CI: 2.5-5.1) for the 90th to 100th percentiles of both (1.1%) (P for interaction = 0.92). The 10-year absolute risk of calcific aortic valve disease increased with higher lipoprotein(a), body mass index, and age, and was higher in men than in women. For women and men 70-79 years of age with body mass index ≥30.0 kg/m2, 10-year absolute risks were 5% and 8% for lipoprotein(a) ≤42 mg/dL (88 nmol/L), 7% and 11% for 42-79 mg/dL (89-169 nmol/L), and 9% and 14% for lipoprotein(a) ≥80 mg/dL (170 nmol/L), respectively. CONCLUSIONS: Extremely high lipoprotein(a) levels and extremely high body mass index together conferred a 3.5-fold risk of calcific aortic valve disease. Ten-year absolute risk of calcific aortic valve disease by categories of lipoprotein(a) levels, body mass index, age, and sex ranged from 0.4% to 14%.