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.

Insight into the relationship between resting heart rate and atrial fibrillation: a Mendelian randomization study.

AIMS: A low resting heart rate (RHR) implies a more efficient heart function and a lower risk of cardiovascular disease. However, observational studies have reported a U-shaped association between RHR and atrial fibrillation (AF). In contrast, Mendelian randomization (MR) studies have found an inverse causal association between RHR and AF. Hence, the causal nature of the relationship is not clear. The aim is to investigate the causal association and its shape between RHR on AF using linear and non-linear MR (NLMR). METHODS AND RESULTS: Linear and non-linear MR were performed on individual-level data in the Trøndelag Health Study (HUNT) and UK Biobank (UKB). HUNT consists of 69 155 individuals with 7,062 AF cases, while UKB provides data on 431 852 individuals with 20 452 AF cases. The linear MR found an inverse relationship between RHR and AF with an OR = 0.95 [95% confidence interval (CI): 0.93-0.98] and OR = 0.96 (95% CI: 0.95-0.97) per unit decrease in RHR in HUNT and UKB, respectively. The NLMR was supportive of an inverse linear relationship in both HUNT and UKB for RHR values <90 beats per minute (bpm). Several sensitivity analyses were also consistent. CONCLUSION: In contrast with the current observational knowledge of RHR and AF, an inverse causal association between RHR and AF was demonstrated in both linear and non-linear MR for RHR values up to 90 bpm. Further exploring the underlying mechanisms of the genetic instrument for RHR may shed light on whether pleiotropy is biasing this association.

Associations between circulating microRNAs and coronary plaque characteristics: potential impact from physical exercise.

microRNAs (miRs) are involved in different steps in the development of atherosclerosis and are proposed as promising biomarkers of coronary artery disease (CAD). We hypothesized that circulating levels of miRs were associated with coronary plaque components assessed by radiofrequency intravascular ultrasound (RF-IVUS) before and after aerobic exercise intervention. Thirty-one patients with CAD treated with percutaneous coronary intervention (PCI) previously included in a randomized trial with aerobic interval training (AIT) or moderate continuous training (MCT) as post-PCI intervention were included. Coronary plaque characteristics by grayscale and RF-IVUS and predefined circulating candidate miRs in plasma were analyzed at baseline and follow-up. Associations between miRs and coronary plaque composition, and the potential effect from exercise, were analyzed using linear regression. Circulating levels of miR-15a-5p, miR-30e-5p, miR-92a-3p, miR-199a-3p, miR-221-3p, and miR-222-3p were associated with baseline coronary necrotic core volume. Following exercise intervention, decreased levels of miR-15a-5p, miR-93-5p, and miR-451a, and increased levels of miR-146a-5p were associated with an observed regression of coronary plaque burden. A mirPath prediction tool identified that genes regulated by miR-15a-5p, miR-199a-3p, and miR-30e-5p were significantly overrepresented in pathways related to fatty acid biosynthesis and fatty acid metabolism. This exploratory study demonstrated six miRs associated with coronary necrotic core, a marker of plaque vulnerability. In addition, changes in four miRs were associated with a regression of coronary plaque burden following exercise intervention. These novel findings may identify potential future biomarkers of CAD and coronary plaque composition.

Reproducibility of grayscale and radiofrequency IVUS data acquisition in stented coronary arteries.

OBJECTIVES: Variability in data acquisition from intervened coronary arteries could represent a source of error that has implications for the design of serial stent studies. We assessed inter-pullback reproducibility of volumetric grayscale and radiofrequency intravascular ultrasound (IVUS) data in stented coronary arteries. DESIGN: Fifteen patients with coronary artery lesions treated with stent implantation were included and examined with two separate pullbacks using the Eagle Eye Gold-phased array 20 MHz IVUS catheter (Volcano). The arteries were divided into five segments, giving a total of 150 sub-segments for analyses. Matching of frames was performed using landmarks that were clearly visible in coronary angiography and intravascular pullbacks. Data were analyzed off-line at an independent Corelab. RESULTS: The inter-pullback reproducibility of geometrical data was very good for non-stented segments with relative differences less than 5% between pullbacks for lumen-, vessel-, and plaque volumes. For stented segments reproducibility was poorer with relative differences between pullbacks in the range of 5-10%. The inter-pullback reproducibility of compositional data demonstrated large standard deviations of relative differences, indicating a weaker agreement. CONCLUSIONS: Agreements between pullbacks were weaker in stented than those in non-stented segments. Based on our data, future longitudinal IVUS studies in intervened vessels should account for a variability of 5-10% attributed to the acquisition of images.

Sex-specific and polygenic effects underlying resting heart rate and associated risk of cardiovascular disease.

AIMS: Resting heart rate (RHR) is associated with cardiovascular disease (CVD) and mortality. This study aimed to identify genetic loci associated with RHR, develop a genome-wide polygenic risk score (PRS) for RHR, and assess associations between the RHR PRS and CVD outcomes, to better understand the biological mechanisms linking RHR to disease. Sex-specific analyses were conducted to potentially elucidate different pathways between the sexes. METHODS: We performed a genome-wide meta-analysis of RHR (n=550,467) using two independent study populations, The Trøndelag Health Study (HUNT) and the UK Biobank (UKB), comprising 69,155 and 481,312 participants, respectively. We also developed a genome-wide PRS for RHR using UKB and tested for association between the PRS and 13 disease outcomes in HUNT. RESULTS: We identified 403, 253, and 167 independent single nucleotide polymorphisms (SNPs) significantly associated with RHR in the total population, women, and men, respectively. The sex-specified analyses indicated differences in the genetic contribution to RHR and revealed loci significantly associated with RHR in only one of the sexes. The SNPs were mapped to genes enriched in heart tissue and cardiac conduction pathways, as well as disease-pathways, including dilated cardiomyopathy. The PRS for RHR was associated with increased risk of hypertension and dilated cardiomyopathy, and decreased risk of atrial fibrillation. CONCLUSION: Our findings provide insight into the pleiotropic effects of the RHR variants, contributing towards an improved understanding of mechanisms linking RHR and disease. In addition, the sex-specific results might contribute to a more refined understanding of RHR as a risk factor for the different diseases.

We conducted a genome-wide meta-analysis on resting heart rate (RHR), created a polygenic risk score for RHR and examined the associations to cardiovascular disease outcomes. Sex-specific analyses indicated differences in the genetic contribution to RHR between men and women.High genetically predicted RHR was associated with increased risk of dilated cardiomyopathy and hypertension, and decreased risk of atrial fibrillation.

Risk of acute myocardial infarction: dyslipidemia more detrimental for men than women.

BACKGROUND: Endogenous estrogens prevent lipid peroxidation, which is pivotal in atherogenesis. Dyslipidemia may therefore be more dangerous for men than for women as a risk factor for acute myocardial infarction (AMI). A differential effect by sex has not been empirically established. METHODS: In a prospective population-based cohort study of 23,525 women and 20,725 men younger than 60 years of age at baseline, we followed participants for 12 years for a first AMI. By calculating the proportion of AMI among men with dyslipidemia attributable to the synergism between male sex and dyslipidemia, we assessed the degree to which dyslipidemia is more detrimental for men than for women. RESULTS: Dyslipidemia and male sex enhanced the effect of one another in relation to AMI risk. The proportion of AMI cases among men with dyslipidemia attributable to this synergism alone was 0.46 (95% confidence interval = 0.35 to 0.57) for high total serum cholesterol, 0.23 (0.05 to 0.41) for low high-density lipoprotein (HDL) cholesterol, and 0.52 (0.42 to 0.62) for high non-HDL cholesterol. In contrast, obesity and hypertension were equally detrimental for men and women in relation to AMI risk, with a corresponding attributable proportion of 0.02 (-0.21 to 0.25) and -0.01 (-0.27 to 0.24), respectively. CONCLUSIONS: Current clinical guidelines of dyslipidemia management do not distinguish between men and women in relation to primary prevention of AMI. Our results suggest that in middle age, dyslipidemia is much more detrimental for men than for women, and that preventing dyslipidemia has a greater potential to reduce the occurrence of AMI among men.

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.

Abnormal glucose regulation and gender-specific risk of fatal coronary artery disease in the HUNT 1 study.

OBJECTIVES: To assess fatal coronary artery disease (CAD) by gender and glucose regulation status. DESIGN: 47,951 people were followed up according to fatal CAD identified in the National Cause of Death Registry. Gender-effects of fatal CAD in people with impaired glucose regulation (IGR), newly diagnosed diabetes (NDM) or known diabetes (KDM) compared with people with normal glucose regulation (NGR) were calculated using Cox regression. RESULTS: Using NGR as reference, the hazard ratios (HR, 95% confidence intervals) associated with IGR was 1.2 (0.8-1.9) for women and 1.2 (0.9-1.6) for men. The corresponding HRs were 1.6 (1.2-2.2) and 1.4 (1.1.-1.9) for NDM, and 2.5 (2.1-2.8) and 1.8 (1.6-2.1) for KDM. The gender-difference in mortality varied by category (P(interaction) = 0.003). Using women as the reference, the HRs for men were 2.1 (2.0-2.3) for NGR, 1.8 (1.0-3.3) for IGR, 1.6 (1.0-2.5) for NDM, and 1.2 (1.0-1.5) for KDM. CONCLUSIONS: Diabetes mellitus, but not IGR, was associated with fatal CAD in both genders. The known gender-difference in CAD mortality was attenuated in people with abnormal glucose regulation, evident already in people with IGR.

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.

Genome-Wide Association Study Identifies New Genetic Determinants of Cardiorespiratory Fitness: The Trøndelag Health Study.

PURPOSE: Low cardiorespiratory fitness (CRF) is a major risk factor for cardiovascular disease (CVD) and a stronger predictor of CVD morbidity and mortality than established risk factors. The genetic component of CRF, quantified as peak oxygen uptake (V̇O 2peak ), is estimated to be ~60%. Unfortunately, current studies on genetic markers for CRF have been limited by small sample sizes and using estimated CRF. To overcome these limitations, we performed a large-scale systematic screening for genetic variants associated with V̇O 2peak . METHODS: A genome-wide association study was performed with BOLT-LMM including directly measured V̇O 2peak from 4525 participants in the HUNT3 Fitness study and 14 million single-nucleotide polymorphisms (SNP). For validation, similar analyses were performed in the United Kingdom Biobank (UKB), where CRF was assessed through a submaximal bicycle test, including ~60,000 participants and ~60 million SNP. Functional mapping and annotation of the genome-wide association study results was conducted using FUMA. RESULTS: In HUNT, two genome-wide significant SNP associated with V̇O 2peak were identified in the total population, two in males, and 35 in females. Two SNP in the female population showed nominally significant association in the UKB. One of the replicated SNP is located in PIK3R5 , shown to be of importance for cardiac function and CVD. Bioinformatic analyses of the total and male population revealed candidate SNP in PPP3CA , previously associated with CRF. CONCLUSIONS: We identified 38 novel SNP associated with V̇O 2peak in HUNT. Two SNP were nominally replicated in UKB. Several interesting genes emerged from the functional analyses, among them one previously reported to be associated with CVD and another with CRF.

Stent edge vascular response and in-stent geometry after aerobic exercise.

The purpose of the present study was to investigate the edge vascular response in patients treated with second-generation drug-eluting stents (DES) after 3 months of aerobic exercise intervention. Thirty-two patients with significant coronary artery disease underwent percutaneous coronary intervention with DES implantation prior to randomization to aerobic interval training (AIT, 14 patients) versus moderate continuous training (MCT, 18 patients). Plaque changes were assessed using grayscale and radiofrequency intravascular ultrasound at baseline and follow-up. The main endpoints were changes in plaque burden and necrotic core content in the 5-mm proximal and distal stent edges. Plaque burden in the distal stent edges decreased significantly in both groups (AIT: - 3.3%; MCT: - 0.4%, p = 0.01 for both), and more in the AIT group (p = 0.048). Necrotic core content decreased significantly in the distal stent edges in both groups (- 2.1 mm3 in AIT, - 0.3 mm3 in MCT, p = 0.01 for both), and more in the AIT group (p = 0.03). There were no significant changes in proximal stent edges or in in-stent geometry at follow-up. In this small study of patients treated with DES implantation, 3 months of aerobic exercise training demonstrated decreased plaque burden and necrotic core content in the distal stent edges, with larger reductions in the AIT group.

Inflammation Is Strongly Associated With Cardiorespiratory Fitness, Sex, BMI, and the Metabolic Syndrome in a Self-reported Healthy Population: HUNT3 Fitness Study.

OBJECTIVE: To investigate whether C-reactive protein (CRP, a general marker of inflammation), neopterin (activated macrophages), lactoferrin (activated neutrophils), and endothelial function (flow-mediated vasodilation [FMD]) are associated with cardiorespiratory fitness (peak oxygen uptake [VO2peak]), sex, body mass index (BMI), and the metabolic syndrome (MetSyn) in a healthy adult population. PATIENTS AND METHODS: This was a cross-sectional association study based on the population-based HUNT3 Fitness Study performed from May 15, 2007, through June 23, 2008. Seven hundred forty self-reported healthy respondents (327 women) identified as having the MetSyn were age- and sex-matched with 692 controls (307 women) from the same cohort. Associations between the inflammatory biomarkers and VO2peak, FMD, and the MetSyn were analyzed by multivariate linear regression. RESULTS: The CRP level was negatively associated with VO2peak (P<.001), positively associated with the MetSyn (with a stronger effect in men) (P<.001) and BMI (with a stronger effect in women) (P<.01), but not with FMD (P=.34). Lactoferrin was positively associated with the MetSyn (P<.001), but neither neopterin nor lactoferrin were associated with VO2peak or FMD. CONCLUSION: The CRP level was strongly associated with VO2peak and the MetSyn, but not with FMD. The associations among inflammation, VO2peak, and the MetSyn were strongly influenced by sex and BMI. These data support that low cardiorespiratory fitness should be considered an etiologic factor contributing to systemic inflammation and that reducing body weight and improving VO2peak are methods that may positively affect CRP levels.

Repeated image analyses improves accuracy in assessing arterial flow-mediated dilatation.

OBJECTIVES: A high degree of variability has been reported regarding the ultrasound-based assessment of flow-mediated dilatation. We wanted to investigate the variability and find out how it might be reduced most efficiently. DESIGN: Brachial artery flow-mediated dilatation was measured by high-resolution ultrasound in 22 healthy adults on two consecutive days. Two observers analysed all images twice. The total variance was split into variance components and estimated hierarchically using the method of restricted maximum likelihood. RESULTS: The relative proportional contributions from intraobserver (residual), interobserver, interpatient and interday variance components, with percentage dilatation as outcome variable, were 0.41, 0.18, 0.25, and 0.15, respectively. CONCLUSIONS: The major source of variability when assessing flow-mediated dilatation was found to be intraobserver variability. The simplest way to reduce total variability is for the observer to average results from repeated image analyses. We suggest that three repetitions are sufficient. This will reduce the total variance by 30%.

Predictors of Beneficial Coronary Plaque Changes after Aerobic Exercise.

PURPOSE: It has been demonstrated that aerobic exercise induces beneficial changes in coronary atherosclerosis via reduced necrotic core and plaque burden. Clinical factors that may be associated with favorable exercise-induced intracoronary effects are unknown. METHODS: This study used post hoc analysis of associations between baseline clinical variables and reductions in coronary necrotic core and plaque burden after aerobic exercise intervention. Coronary plaque characteristics were measured with grayscale and radiofrequency intravascular ultrasound in 36 patients (median age, 58.5 yr; seven women) with stable CAD (SCAD) or non-ST elevation acute coronary syndrome (NSTE-ACS). Screening of clinical variables was performed with random forest analysis followed by multivariate linear regression. RESULTS: The only significant clinical variable for necrotic core reduction was clinical presentation of disease (SCAD vs NSTE-ACS, P = 0.011). The changes in necrotic core after exercise were -4.94 mm3 (-10.33; -1.33) in patients with SCAD and 1.03 mm3 (-4.29; 3.71) in patients with NSTE-ACS (P = 0.01). Necrotic core was reduced in 17 patients (94%) with SCAD and eight patients (44%) with NSTE-ACS (P = 0.01). R2 for the model including baseline clinical presentation and baseline necrotic core volume was 0.90. There were no significant explanatory variables for plaque burden reduction. CONCLUSIONS: Exercise-induced plaque stabilization via reduced coronary necrotic core may be strongly dependent on clinical presentation of CAD. We hypothesized that an increased proinflammatory load renders patients with NSTE-ACS more resistant to exercise-induced plaque stabilization than patients with SCAD. Furthermore, aerobic exercise may have a particular potential for inducing beneficial effects on coronary atherosclerosis in patients with SCAD compared with patients in the early phase after an acute coronary syndrome.

Peak oxygen uptake after cardiac rehabilitation: a randomized controlled trial of a 12-month maintenance program versus usual care.

BACKGROUND: Exercise capacity is a strong predictor of survival in patients with coronary artery disease (CAD). Exercise capacity improves after cardiac rehabilitation exercise training, but previous studies have demonstrated a decline in peak oxygen uptake after ending a formal rehabilitation program. There is a lack of knowledge on how long-term exercise adherence can be achieved in CAD patients. We therefore assessed if a 12-month maintenance program following cardiac rehabilitation would lead to increased adherence to exercise and increased exercise capacity compared to usual care. MATERIALS AND METHODS: Two-centre, open, parallel randomized controlled trial with 12 months follow-up comparing usual care to a maintenance program. The maintenance program consisted of one monthly supervised high intensity interval training session, a written exercise program and exercise diary, and a maximum exercise test every third month during follow-up. Forty-nine patients (15 women) on optimal medical treatment were included following discharge from cardiac rehabilitation. The primary endpoint was change in peak oxygen uptake at follow-up; secondary endpoints were physical activity level, quality of life and blood markers of cardiovascular risk. RESULTS: There was no change in peak oxygen uptake from baseline to follow-up in either group (intervention group 27.9 (±4.7) to 28.8 (±5.6) mL·kg (-1) min (-1), control group 32.0 (±6.2) to 32.8 (±5.8) mL·kg (-1) min (-1), with no between-group difference, p = 0.22). Quality of life and blood biomarkers remained essentially unchanged, and both self-reported and measured physical activity levels were similar between groups after 12 months. CONCLUSIONS: A maintenance exercise program for 12 months did not improve adherence to exercise or peak oxygen uptake in CAD patients after discharge from cardiac rehabilitation compared to usual care. This suggests that infrequent supervised high intensity interval training sessions are inadequate to improve peak oxygen uptake in this patient group. TRIAL REGISTRATION: ClinicalTrials.gov NCT01246570.

The higher the better? Interval training intensity in coronary heart disease.

OBJECTIVES: Peak oxygen uptake (VO2 peak) increases more after high intensity interval training compared to isocaloric moderate exercise in patients with coronary heart disease (CHD). We assessed the impact of exercise intensity during high intensity intervals on the increase in VO2 peak. DESIGN/METHODS: We included 112 patients with coronary heart disease who had participated in randomized trials of interval training consisting of four times four minutes intervals at 85-95% of heart rate maximum (HRmax) for 12 weeks. Exercise intensity was calculated for each patient using HR during the two last minutes of each interval, expressed as percentage of HRmax. We used a univariate general linear model with VO2 peak increase as the dependent variable and percentage of HRmax, age, number of exercise sessions, and baseline VO2 peak as covariates. Exercise intensity was also divided into three categories; <88%, 88-92%, and >92% of HRmax, and these categories were used as a fixed factor in the model. RESULTS: VO2 peak increased by 3.9 (SD 3.1) mL kg(-1)min(-1), equal to 11.9% after 23.4 exercise sessions. Percentage of HRmax had a significant effect on increase in VO2 peak, both as a continuous (p=0.019) and categorical variable (p=0.020). The estimated marginal means and 95% confidence intervals of the increase in VO2 peak for the three intensity categories were 3.1 (2.0, 4.2), 3.6 (2.8, 4.4), and 5.2 (4.1, 6.3) for the <88%, the 88-92%, and the >92% category, respectively. CONCLUSIONS: Even within the high intensity training zone, exercise intensity was an important determinant for improving VO2 peak in patients with coronary heart disease.

Coronary atheroma regression and plaque characteristics assessed by grayscale and radiofrequency intravascular ultrasound after aerobic exercise.

The aim of the present study was to investigate effects of aerobic interval training (AIT) versus moderate continuous training (MCT) on coronary atherosclerosis in patients with significant coronary artery disease on optimal medical treatment. Thirty-six patients were randomized to AIT (intervals at ≈ 90% of peak heart rate) or MCT (continuous exercise at ≈ 70% of peak heart rate) 3 times a week for 12 weeks after intracoronary stent implantation. Grayscale and radiofrequency intravascular ultrasounds (IVUS) were performed at baseline and follow-up. The primary end point was the change in plaque burden, and the secondary end points were change in necrotic core and plaque vulnerability. Separate lesions were classified using radiofrequency IVUS criteria. We demonstrated that necrotic core was reduced in both groups in defined coronary segments (AIT -3.2%, MCT -2.7%, p <0.05) and in separate lesions (median change -2.3% and -0.15 mm(3), p <0.05). Plaque burden was reduced by 10.7% in separate lesions independent of intervention group (p = 0.06). No significant differences in IVUS parameters were found between exercise groups. A minority of separate lesions were transformed in terms of plaque vulnerability during follow-up with large individual differences between and within patients. In conclusion, changes in coronary artery plaque structure or morphology did not differ between patients who underwent AIT or MCT. The combination of regular aerobic exercise and optimal medical treatment for 12 weeks induced a moderate regression of necrotic core and plaque burden in IVUS-defined coronary lesions.