Small LDL subfractions are associated with coronary atherosclerosis despite no differences in conventional lipids.

Lipoprotein subfractions currently represent a new source of cardiovascular disease (CVD) risk markers that may provide more information than conventional lipid measures. We aimed to investigate whether lipoprotein subfractions are associated with coronary atherosclerosis in patients without prior known CVD. Fasting serum samples from 60 patients with suspected coronary artery disease (CAD) were collected before coronary angiography and analyzed by nuclear magnetic resonance (NMR) spectroscopy. The severity of coronary atherosclerosis was quantified by the Gensini score (≤20.5 = nonsignificant coronary atherosclerosis, 20.6-30.0 = intermediate coronary atherosclerosis, ≥30.1 = significant CAD). Differences in lipoprotein subfractions between the three Gensini groups were assessed by two-way ANOVA, adjusted for statin use. Despite no differences in conventional lipid measures between the three Gensini groups, patients with significant CAD had higher apolipoprotein-B/apolipoprotein-A1 ratio, 30% more small and dense low-density lipoprotein 5 (LDL-5) particles, and increased levels of cholesterol, triglycerides, and phospholipids within LDL-5 compared with patients with nonsignificant coronary atherosclerosis and intermediate coronary atherosclerosis (P ≤ 0.001). In addition, the low-density lipoprotein (LDL) cholesterol/high-density lipoprotein cholesterol ratio, and triglyceride levels of LDL 4 were significantly increased in patients with significant CAD compared with patients with nonsignificant coronary atherosclerosis. In conclusion, small and dense lipoprotein subfractions were associated with coronary atherosclerosis in patients without prior CVD. Additional studies are needed to explore whether lipoprotein subfractions may represent biomarkers offering a clinically meaningful improvement in the risk prediction of CAD.

Effect of 5 years of exercise training on the cardiovascular risk profile of older adults: the Generation 100 randomized trial.

AIMS: The aim of this study was to compare the effects of 5 years of supervised exercise training (ExComb), and the differential effects of subgroups of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT), with control on the cardiovascular risk profile in older adults. METHODS AND RESULTS: Older adults aged 70-77 years from Trondheim, Norway (n = 1567, 50% women), able to safely perform exercise training were randomized to 5 years of two weekly sessions of HIIT [∼90% of peak heart rate (HR), n = 400] or MICT (∼70% of peak HR, n = 387), together forming ExComb (n = 787), or control (instructed to follow physical activity recommendations, n = 780). The main outcome was a continuous cardiovascular risk score (CCR), individual cardiovascular risk factors, and peak oxygen uptake (VO2peak). CCR was not significantly lower [-0.19, 99% confidence interval (CI) -0.46 to 0.07] and VO2peak was not significantly higher (0.39 mL/kg/min, 99% CI -0.22 to 1.00) for ExComb vs. control. HIIT showed higher VO2peak (0.76 mL/kg/min, 99% CI 0.02-1.51), but not lower CCR (-0.32, 99% CI -0.64 to 0.01) vs. control. MICT did not show significant differences compared to control or HIIT. Individual risk factors mostly did not show significant between-group differences, with some exceptions for HIIT being better than control. There was no significant effect modification by sex. The number of cardiovascular events was similar across groups. The healthy and fit study sample, and contamination and cross-over between intervention groups, challenged the possibility of detecting between-group differences. CONCLUSIONS: Five years of supervised exercise training in older adults had little effect on cardiovascular risk profile and did not reduce cardiovascular events. REGISTRATION: ClinicalTrials.gov: NCT01666340.

High levels of lipoprotein(a) - assessment and treatment. / Høyt nivå av lipoprotein(a) ­ utredning og behandling.

Approximately 5 % of the population have highly elevated levels of lipoprotein(a) (Lp(a)), which is a genetically determined risk factor for cardiovascular disease. Measuring lipoprotein(a) can improve cardiovascular risk stratification and have consequences for preventive measures. Treatment is targeted at reducing modifiable cardiovascular risk factors, but Lp(a)-lowering drugs are being trialled. This article reviews the management of lipoprotein(a) in clinical practice.

Completeness and correctness of acute myocardial infarction diagnoses in a medical quality register and an administrative health register.

Aims: Health registers are used for administrative purposes, disease surveillance, quality assessment, and research. The value of the registers is entirely dependent on the quality of their data. The aim of this study was to investigate and compare the completeness and correctness of the acute myocardial infarction (AMI) diagnosis in the Norwegian Myocardial Infarction Register and in the Norwegian Patient Register. Methods: All Norwegian patients admitted directly to St Olavs hospital, Trondheim University Hospital, Trondheim University Hospital from 1 July to 31 December 2012 and who had plasma levels of cardiac troponin T measured during their hospitalization (n=4835 unique individuals, n=5882 hospitalizations) were identified in the hospital biochemical database. A gold standard for AMI was established by evaluation of maximum troponin T levels and by review of the information in the medical records. Cases of AMI in the registers were classified as true positive, false positive, true negative, and false negative according to the gold standard. We calculated sensitivity, positive predictive value (PPV), specificity, and negative predictive value (NPV). Results: The Norwegian Myocardial Infarction Register had a sensitivity of 86.0% (95% confidence interval (CI) 82.8-89.3%), PPV of 97.9% (96.4-99.3%), and specificity of 99.9% and NPV of 98.9% (98.6-99.2%) (99.8-100%). The corresponding figures for the Norwegian Patient Register were 85.8% (95% CI 82.5-89.1%), 95.1% (92.9-97.2%), and 99.7% (99.5-99.8%) and 98.9% (98.6-99.2%), respectively. Both registers had a sensitivity higher than 95% when compared to hospital discharge diagnoses. The results were similar for men and women and for cases below and above 80 years of age. Conclusions: The Norwegian Myocardial Infarction Register and the Norwegian Patient Register are adequately complete and correct for administrative purposes, disease surveillance, quality assessment, and research.

Peak oxygen uptake and incident coronary heart disease in a healthy population: the HUNT Fitness Study.

AIMS: The majority of previous research on the association between cardiorespiratory fitness (CRF) and cardiovascular disease (CVD) is based on indirect assessment of CRF in clinically referred predominantly male populations. Therefore, our aim was to examine the associations between VO2peak measured by the gold-standard method of cardiopulmonary exercise testing and fatal and non-fatal coronary heart disease (CHD) in a healthy and fit population. METHODS AND RESULTS: Data on VO2peak from 4527 adults (51% women) with no previous history of cardiovascular or lung disease, cancer, and hypertension or use of antihypertensive medications participating in a large population-based health-study (The HUNT3 Study), were linked to hospital registries and the cause of death registry. Average VO2peak was 36.0 mL/kg/min and 44.4 mL/kg/min among women and men, and 83.5% had low 10-year risk of CVD at baseline. Average follow-up was 8.8 years, and 147 participants reached the primary endpoint. Multi-adjusted Cox-regression showed 15% lower risk for the primary endpoint per one-MET (metabolic equivalent task) higher VO2peak [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.93], with similar results across sex. The highest quartile of VO2peak had 48% lower risk of event compared with the lowest quartile (multi-adjusted HR 0.52, 95% CI 0.33-0.82). Oxygen pulse and ventilatory equivalents of oxygen and carbon dioxide also showed significant predictive value for the primary endpoint. CONCLUSION: VO2peak was strongly and inversely associated with CHD across the whole fitness continuum in a low-risk population sample. Increasing VO2peak may have substantial benefits in reducing the burden of CHD.

High-intensity interval training induces beneficial effects on coronary atheromatous plaques: a randomized trial.

AIMS: Coronary atheroma volume is associated with risk of coronary events in coronary artery disease (CAD). Exercise training is a cornerstone in primary and secondary prevention of CAD, but the effect of exercise on coronary atheromatous plaques is largely unknown. We assessed the effect of 6 months supervised high-intensity interval training (HIIT) on coronary plaque geometry using intravascular ultrasound in patients with stable CAD following percutaneous coronary intervention (PCI). METHODS AND RESULTS: Sixty patients were randomized to two sessions of weekly supervised HIIT at 85-95% of peak heart rate (n = 30) or to follow contemporary preventive guidelines (control group, n = 30). The study endpoints were change in percent atheroma volume (PAV) and total atheroma volume (TAV) normalized for segment length (TAVnorm) at 6-month follow-up. The change in average PAV for matched coronary segments from baseline to follow-up showed a significant between-group difference (-1.4, 95% CI: -2.7 to -0.1, P = 0.036). There was a significant reduction in the HIIT group (-1.2, 95% CI: -2.1 to -0.2, P = 0.017) while not in the control group (0.2, 95% CI: -0.7 to 1.1, P = 0.616). TAVnorm was reduced (-9 mm3, 95% CI: -14.7 to -3.4, P = 0.002) after HIIT, with a significant between-group difference (-12.0 mm3, 95% CI: -19.9 to -4.2, P = 0.003). CONCLUSION: In patients with established CAD, a regression of atheroma volume was observed in those undergoing 6 months of supervised HIIT compared with patients following contemporary preventive guidelines. Our study indicates that HIIT counteracts atherosclerotic coronary disease progression and reduces atheroma volume in residual coronary atheromatous plaques following PCI.

The association between circulating lipoprotein subfractions and lipid content in coronary atheromatous plaques assessed by near-infrared spectroscopy.

Background: Lipid content in coronary atheromatous plaques, measured by near-infrared spectroscopy (NIRS), can predict the risk of future coronary events. Biomarkers that reflect lipid content in coronary plaques may therefore improve coronary artery disease (CAD) risk assessment. Purpose: We aimed to investigate the association between circulating lipoprotein subfractions and lipid content in coronary atheromatous plaques in statin-treated patients with stable CAD undergoing percutaneous coronary intervention. Methods: 56 patients with stable CAD underwent three-vessel imaging with NIRS when feasible. The coronary artery segment with the highest lipid content, defined as the maximum lipid core burden index within any 4 mm length across the entire lesion (maxLCBI4mm), was defined as target segment. Lipoprotein subfractions and Lipoprotein a (Lp(a)) were analyzed in fasting serum samples by nuclear magnetic resonance spectroscopy and by standard in-hospital procedures, respectively. Penalized linear regression analyses were used to identify the best predictors of maxLCBI4mm. The uncertainty of the lasso estimates was assessed as the percentage presence of a variable in resampled datasets by bootstrapping. Results: Only modest evidence was found for an association between lipoprotein subfractions and maxLCBI4mm. The lipoprotein subfractions with strongest potential as predictors according to the percentage presence in resampled datasets were Lp(a) (78.1 % presence) and free cholesterol in the smallest high-density lipoprotein (HDL) subfractions (74.3 % presence). When including established cardiovascular disease (CVD) risk factors in the regression model, none of the lipoprotein subfractions were considered potential predictors of maxLCBI4mm. Conclusion: In this study, serum levels of Lp(a) and free cholesterol in the smallest HDL subfractions showed the strongest potential as predictors for lipid content in coronary atheromatous plaques. Although the evidence is modest, our study suggests that measurement of lipoprotein subfractions may provide additional information with respect to coronary plaque composition compared to traditional lipid measurements, but not in addition to established risk factors. Further and larger studies are needed to assess the potential of circulating lipoprotein subfractions as meaningful biomarkers both for lipid content in coronary atheromatous plaques and as CVD risk markers.

Associations between circulating microRNAs and lipid-rich coronary plaques measured with near-infrared spectroscopy.

Lipid-rich coronary atherosclerotic plaques often cause myocardial infarction (MI), and circulating biomarkers that reflect lipid content may predict risk of MI. We investigated the association between circulating microRNAs (miRs) are lipid-rich coronary plaques in 47 statin-treated patients (44 males) with stable coronary artery disease undergoing percutaneous coronary intervention. We assessed lipid content in non-culprit coronary artery lesions with near-infrared spectroscopy and selected the 4 mm segment with the highest measured lipid core burden index (maxLCBI4mm). Lipid-rich plaques were predefined as a lesion with maxLCBI4mm ≥ 324.7. We analyzed 177 circulating miRs with quantitative polymerase chain reaction in plasma samples. The associations between miRs and lipid-rich plaques were analyzed with elastic net. miR-133b was the miR most strongly associated with lipid-rich coronary plaques, with an estimated 18% increase in odds of lipid-rich plaques per unit increase in miR-133b. Assessing the uncertainty by bootstrapping, miR-133b was present in 82.6% of the resampled dataset. Inclusion of established cardiovascular risk factors did not attenuate the association. No evidence was found for an association between the other analyzed miRs and lipid-rich coronary plaques. Even though the evidence for an association was modest, miR-133b could be a potential biomarker of vulnerable coronary plaques and risk of future MI. However, the prognostic value and clinical relevance of miR-133b needs to be assessed in larger cohorts.

CENIT (Impact of Cardiac Exercise Training on Lipid Content in Coronary Atheromatous Plaques Evaluated by Near-Infrared Spectroscopy): A Randomized Trial.

Background The effect of physical exercise on lipid content of coronary artery plaques is unknown. With near infrared spectroscopy we measured the effect of high intensity interval training (HIIT) on lipid content in coronary plaques in patients with stable coronary artery disease following percutaneous coronary intervention. Methods and Results In CENIT (Impact of Cardiac Exercise Training on Lipid Content in Coronary Atheromatous Plaques Evaluated by Near-Infrared Spectroscopy) 60 patients were randomized to 6 months supervised HIIT or to a control group. The primary end point was change in lipid content measured as maximum lipid core burden index at 4 mm (maxLCBI4mm). A predefined cutoff of maxLCBI4mm >100 was required for inclusion in the analysis. Forty-nine patients (HIIT=20, usual care=29) had maxLCBI4mm >100 at baseline. Change in maxLCBI4mm did not differ between groups (-1.2, 95% CI, -65.8 to 63.4, P=0.97). The estimated reduction in maxLCBI4mm was -47.7 (95% CI, -100.3 to 5.0, P=0.075) and -46.5 (95% CI, -87.5 to -5.4, P=0.027) after HIIT and in controls, respectively. A negative correlation was observed between change in peak oxygen uptake (VO2peak) and change in lipid content (Spearman's correlation -0.44, P=0.009). With an increase in VO2peak above 1 metabolic equivalent task, maxLCBI4mm was on average reduced by 142 (-8 to -262), whereas the change was -3.2 (154 to -255) with increased VO2peak below 1 metabolic equivalent task. Conclusions Six months of HIIT following percutaneous coronary intervention did not reduce lipid content in coronary plaques compared with usual care. A moderate negative correlation between increase in VO2peak and change in lipid content generates the hypothesis that exercise with a subsequent increase in fitness may reduce lipid content in coronary atheromatous plaques. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02494947.

The Long-term Effect of Different Exercise Intensities on High-Density Lipoprotein Cholesterol in Older Men and Women Using the Per Protocol Approach: The Generation 100 Study.

OBJECTIVE: To examine whether 5 years of high-intensity interval training (HIIT) increases high-density lipoprotein cholesterol (HDL-C) concentration more than moderate-intensity continuous training (MICT) and control (CON) in older men and women. METHODS: A total of 1567 older adults (790 [50.4%] women) were randomized (2:1:1) to either CON (n=780; asked to follow the national recommendations for physical activity) or 2 weekly sessions of HIIT (10-minute warm-up followed by 4×4-minute intervals at ∼90% of peak heart rate) or MICT (50 minutes of continuous work at ∼70% of peak heart rate). Serum HDL-C concentration was measured by standard procedures at baseline and at 1 year, 3 years, and 5 years. The study took place between August 21, 2012, and June 31, 2018. Linear mixed models were used to determine between-group differences during 5 years using the per protocol approach. RESULTS: Men in HIIT had a smaller reduction in HDL-C (-1.2%) than men in CON (-6.9%) and MICT (-7.8%) after 5 years (P=.01 and P=.03 for CON vs HIIT and MICT vs HIIT, respectively). No effect of exercise intensity on HDL-C was seen in women. Changes in peak oxygen uptake were associated with changes in HDL-C in both men and women, whereas changes in body weight and fat mass were not. CONCLUSION: In men, HIIT seems to be the best strategy to prevent a decline in HDL-C during a 5-year period. No effect of exercise intensity was seen for older women. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01666340.

Loss of statin treatment years during pregnancy and breastfeeding periods in women with familial hypercholesterolemia.

BACKGROUND AND AIMS: Women with heterozygous familial hypercholesterolemia (FH) are recommended to initiate statin treatment at the same age as men (from 8 to 10 years of age). However, statins are contraindicated when pregnancy is planned, during pregnancy and breastfeeding. The aim of the study was to determine the duration of pregnancy-related off-statin periods and breastfeeding in FH women. METHODS: A cross-sectional study using an anonymous online self-administered questionnaire was conducted. Women with FH were recruited through Lipid Clinics in Norway and Netherlands and national FH patient organizations. RESULTS: 102 women with FH (n = 70 Norwegian and n = 32 Dutch) were included in the analysis. Total length of pregnancy-related off-statin periods was estimated for 80 women where data were available, and was median (min-max) 2.3 (0-14.2) years. Lost statin treatment time was estimated for 67 women where data were available, and was median (min-max) 18 (0-100)% at mean (SD) age of 31 (4.3) years at last pregnancy. More women breastfed in Norway (83%) and for longer time [8.5 [1-42] months] compared to the Netherlands [63%, p = 0.03; 3.6 (0-14) months, p < 0.001]. Eighty-six percent of the women reported need for more information on pregnancy and breastfeeding in relation to FH. CONCLUSIONS: Young FH women lose years of treatment when discontinuing statins in relation to pregnancy and breastfeeding periods and should be closely followed up to minimize the duration of these off-statin periods. Whether these periods of interrupted treatment increase the cardiovascular risk in FH women needs to be further elucidated.