Pre-Participation Screenings Frequently Miss Occult Cardiovascular Conditions in Apparently Healthy Male Middle-Aged First-Time Marathon Runners.

INTRODUCTION: The optimal pre-participation screening strategy to identify athletes at risk for exercise-induced cardiovascular events is unknown. We therefore aimed to compare the American College of Sports Medicine (ACSM) and European Society of Cardiology (ESC) pre-participation screening strategies against extensive cardiovascular evaluations in identifying high-risk individuals among 35-50-year-old apparently healthy men. METHODS: We applied ACSM and ESC pre-participation screenings to 25 men participating in a study on first-time marathon running. We compared screening outcomes against medical history, physical examination, electrocardiography, blood tests, echocardiography, cardiopulmonary exercise testing, and magnetic resonance imaging. RESULTS: ACSM screening classified all participants as "medical clearance not necessary." ESC screening classified two participants as "high-risk." Extensive cardiovascular evaluations revealed ≥1 minor abnormality and/or cardiovascular condition in 17 participants, including three subjects with mitral regurgitation and one with a small atrial septal defect. Eleven participants had dyslipidaemia, six had hypertension, and two had premature atherosclerosis. Ultimately, three (12%) subjects had a serious cardiovascular condition warranting sports restrictions: aortic aneurysm, hypertrophic cardiomyopathy (HCM), and myocardial fibrosis post-myocarditis. Of these three participants, only one had been identified as "high-risk" by the ESC screening (for dyslipidaemia, not HCM) and none by the ACSM screening. CONCLUSION: Numerous occult cardiovascular conditions are missed when applying current ACSM/ESC screening strategies to apparently healthy middle-aged men engaging in their first high-intensity endurance sports event.

Dobutamine stress echocardiography during transcatheter edge-to-edge mitral valve repair predicts residual mitral regurgitation.

OBJECTIVES: The current study sought to determine whether low-dose dobutamine stress echocardiography (DSE) during transcatheter edge-to-edge mitral valve repair (TMVR) can predict residual mitral regurgitation (MR) at discharge. BACKGROUND: In most patients, TMVR can successfully reduce MR from severe to mild or moderate. However, general anesthesia during the intervention affects hemodynamics and MR assessment. At discharge transthoracic echocardiogram residual MR (>moderate) is present in 10%-30% of patients which is associated with worse clinical outcome. METHODS: In consecutive patients the severity of MR was determined at baseline, immediately after TMVR clip implantation and subsequently during low-dose DSE (both under general anesthesia) and at discharge. RESULTS: A total of 39 patients were included (mean age 76.1 ± 8.1 years, 39% male, 56% functional MR, 41% left ventricular ejection fraction < 45%). An increase of MR during DSE was seen in 11 patients, of whom 6 (55%) showed >moderate MR at discharge. None of the 28 patients without an increase of MR during DSE showed >moderate MR at discharge. The diagnostic performance of the test could be established at a sensitivity of 100% and a specificity of 85% in unselected patients. CONCLUSIONS: DSE during TMVR is a useful tool to predict residual MR at discharge. It could support procedural decision making, including implantation of additional clips and thus potentially improve clinical outcome.

Non-invasive stereotactic arrhythmia radiotherapy for ventricular tachycardia: results of the prospective STARNL-1 trial.

AIMS: Stereotactic arrhythmia radiotherapy (STAR) is suggested as potentially effective and safe treatment for patients with therapy-refractory ventricular tachycardia (VT). However, the current prospective knowledge base and experience with STAR is limited. In this study we aimed to prospectively evaluate the efficacy and safety of STAR. METHODS AND RESULTS: The StereoTactic Arrhythmia Radiotherapy in the Netherlands no.1 was a pre-post intervention study to prospectively evaluate efficacy and safety of STAR. In patients with therapy-refractory VT, the pro-arrhythmic region was treated with a 25 Gy single radiotherapy fraction. The main efficacy measure was a reduction in the number of treated VT-episodes by ≥50%, comparing the 12 months before and after treatment (or end of follow-up, excluding a 6-week blanking period). The study was deemed positive when ≥50% of patients would meet this criterion. Safety evaluation included left ventricular ejection fraction, pulmonary function, and adverse events. Six male patients with an ischaemic cardiomyopathy were enrolled, and median age was 73 years (range 54-83). Median left ventricular ejection fraction was 38% (range 24-52). The median planning target volume was 187 mL (range 93-372). Four (67%) patients completed the 12-month follow-up, and two patients died (not STAR related) during follow-up. The main efficacy measure of ≥50% reduction in treated VT-episodes at the end of follow-up was achieved in four patients (67%). The median number of treated VT-episodes was reduced by 87%. No reduction in left ventricular ejection fraction or pulmonary function was observed. No treatment related serious adverse events occurred. CONCLUSIONS: STAR resulted in a ≥ 50% reduction in treated VT-episodes in 4/6 (67%) patients. No reduction in cardiac and pulmonary function nor treatment-related serious adverse events were observed during follow-up. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register-NL7510.

A comparison of myocardial magnetic resonance extracellular volume mapping at 3 T against histology of tissue collagen in severe aortic valve stenosis and obstructive hypertrophic cardiomyopathy.

OBJECTIVE: Quantitative extracellular volume fraction (ECV) mapping with MRI is commonly used to investigate in vivo diffuse myocardial fibrosis. This study aimed to validate ECV measurements against ex vivo histology of myocardial tissue samples from patients with aortic valve stenosis or hypertrophic cardiomyopathy. MATERIALS AND METHODS: Sixteen patients underwent MRI examination at 3 T to acquire native T1 maps and post-contrast T1 maps after gadobutrol administration, from which hematocrit-corrected ECV maps were estimated. Intra-operatively obtained myocardial tissue samples from the same patients were stained with picrosirius red for quantitative histology of myocardial interstitial fibrosis. Correlations between in vivo ECV and ex vivo myocardial collagen content were evaluated with regression analyses. RESULTS: Septal ECV was 30.3% ± 4.6% and correlated strongly (n = 16, r = 0.70; p = 0.003) with myocardial collagen content. Myocardial native T1 values (1206 ± 36 ms) did not correlate with septal ECV (r = 0.41; p = 0.111) or with myocardial collagen content (r = 0.32; p = 0.227). DISCUSSION: We compared myocardial ECV mapping at 3 T against ex vivo histology of myocardial collagen content, adding evidence to the notion that ECV mapping is a surrogate marker for in vivo diffuse myocardial fibrosis.

Sex-specific associations between potassium intake, blood pressure, and cardiovascular outcomes: the EPIC-Norfolk study.

AIMS: A potassium replete diet is associated with lower blood pressure (BP) and lower risk of cardiovascular disease (CVD). Whether these associations differ between men and women and whether they depend on daily sodium intake is unknown. METHODS AND RESULTS: An analysis was performed in 11 267 men and 13 696 women from the EPIC-Norfolk cohort. Twenty-four hour excretion of sodium and potassium, reflecting intake, was estimated from sodium and potassium concentration in spot urine samples using the Kawasaki formula. Linear and Cox regression were used to explore the association between potassium intake, systolic BP (SBP), and CVD events (defined as hospitalization or death due to CVD). After adjustment for confounders, interaction by sex was found for the association between potassium intake and SBP (P < 0.001). In women, but not in men, the inverse slope between potassium intake and SBP was steeper in those within the highest tertile of sodium intake compared with those within the lowest tertile of sodium intake (P < 0.001 for interaction by sodium intake). Both in men and women, higher potassium intake was associated with a lower risk of CVD events, but the hazard ratio (HR) associated with higher potassium intake was lower in women than in men [highest vs. lowest potassium intake tertile: men: HR 0.93, 95% confidence interval (CI) 0.87-1.00; women: HR 0.89, 95% CI 0.83-0.95, P = 0.033 for interaction by sex]. CONCLUSION: The association between potassium intake, SBP, and CVD events is sex specific. The data suggest that women with a high sodium intake in particular benefit most from a higher potassium intake with regard to SBP.

Lipoprotein(a) is associated with the onset but not the progression of aortic valve calcification.

AIM: Lipoprotein(a) [Lp(a)] is a potential causal factor in the pathogenesis of aortic valve disease. However, the relationship of Lp(a) with new onset and progression of aortic valve calcium (AVC) has not been studied. The purpose of the study was to assess whether high serum levels of Lp(a) are associated with AVC incidence and progression. METHODS AND RESULTS: A total of 922 individuals from the population-based Rotterdam Study (mean age 66.0±4.2 years, 47.7% men), whose Lp(a) measurements were available, underwent non-enhanced cardiac computed tomography imaging at baseline and after a median follow-up of 14.0 [interquartile range (IQR) 13.9-14.2] years. New-onset AVC was defined as an AVC score >0 on the follow-up scan in the absence of AVC on the first scan. Progression was defined as the absolute difference in AVC score between the baseline and follow-up scan. Logistic and linear regression analyses were performed to evaluate the relationship of Lp(a) with baseline, new onset, and progression of AVC. All analyses were corrected for age, sex, body mass index, smoking, hypertension, dyslipidaemia, and creatinine. AVC progression was analysed conditional on baseline AVC score expressed as restricted cubic splines. Of the 702 individuals without AVC at baseline, 415 (59.1%) developed new-onset AVC on the follow-up scan. In those with baseline AVC, median annual progression was 13.5 (IQR = 5.2-37.8) Agatston units (AU). Lipoprotein(a) concentration was independently associated with baseline AVC [odds ratio (OR) 1.43 for each 50 mg/dL higher Lp(a); 95% confidence interval (CI) 1.15-1.79] and new-onset AVC (OR 1.30 for each 50 mg/dL higher Lp(a); 95% CI 1.02-1.65), but not with AVC progression (ß: -71 AU for each 50 mg/dL higher Lp(a); 95% CI -117; 35). Only baseline AVC score was significantly associated with AVC progression (P < 0.001). CONCLUSION: In the population-based Rotterdam Study, Lp(a) is robustly associated with baseline and new-onset AVC but not with AVC progression, suggesting that Lp(a)-lowering interventions may be most effective in pre-calcific stages of aortic valve disease.

Higher anticholinergic burden from medications is associated with significant increase in markers of inflammation in the EPIC-Norfolk prospective population-based cohort study.

BACKGROUND: Higher medication anticholinergic burden is associated with increased risk of cardiovascular disease and cognitive decline. A mechanistic pathway has not been established. We aimed to determine whether inflammation may mediate these associations. METHODS: Participants were drawn from the European Prospective Investigation into Cancer, Norfolk cohort (40-79 years at baseline). Anticholinergic burden score (ACB) was calculated at first (1HC) (1993/97) and second (2HC) (1998/2000) health checks. Fibrinogen and C-reactive protein (CRP) were measured during 1HC and tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) during 2HC. Cross-sectional associations between ACB and inflammatory markers were examined for both health checks. Prospective associations were also examined between 1HC ACB and 2HC inflammatory markers. Models were adjusted for age, sex, lifestyle factors, comorbidities and medications. RESULTS: In total, 17 678 and 22 051 participants were included in cross-sectional analyses for CRP, and fibrinogen, respectively. Furthermore, 5101 participants with data on TNF-α and IL-6 were included in the prospective analyses. Cross-sectionally, compared to ACB = 0, ACB ≥ 4 was associated with higher fibrinogen, beta (95% confidence interval) = 0.134 g/L (0.070, 0.199), CRP 1.175 mg/L (0.715, 1.634), IL-6 0.593 pg/mL (0.254, 0.932) and TNF-α 0.137 pg/mL (0.033, 0.241). In addition, a point increase in ACB was associated with higher levels of all markers. Prospectively, compared to ACB = 0, ACB ≥ 4 was associated with higher IL-6(pg/mL) of 0.019 (-0.323, 0.361) and TNF-α (pg/mL) of 0.202% (0.81, 0.323). A unit increase in ACB was associated with a significantly higher TNF-α and IL-6. CONCLUSION: Higher ACB was associated with higher inflammatory markers. Inflammation may mediate the relationship between anticholinergic medications and adverse outcomes.

Impact of cholesterol on proinflammatory monocyte production by the bone marrow.

AIM: Preclinical work indicates that low-density lipoprotein cholesterol (LDL-C) not only drives atherosclerosis by directing the innate immune response at plaque level but also augments proinflammatory monocyte production in the bone marrow (BM) compartment. In this study, we aim to unravel the impact of LDL-C on monocyte production in the BM compartment in human subjects. METHODS AND RESULTS: A multivariable linear regression analysis in 12 304 individuals of the EPIC-Norfolk prospective population study showed that LDL-C is associated with monocyte percentage (ß = 0.131 [95% CI: 0.036-0.225]; P = 0.007), at the expense of granulocytes (ß = -0.876 [95% CI: -1.046 to -0.705]; P < 0.001). Next, we investigated whether altered haematopoiesis could explain this monocytic skewing by characterizing CD34+ BM haematopoietic stem and progenitor cells (HSPCs) of patients with familial hypercholesterolaemia (FH) and healthy normocholesterolaemic controls. The HSPC transcriptomic profile of untreated FH patients showed increased gene expression in pathways involved in HSPC migration and, in agreement with our epidemiological findings, myelomonocytic skewing. Twelve weeks of cholesterol-lowering treatment reverted the myelomonocytic skewing, but transcriptomic enrichment of monocyte-associated inflammatory and migratory pathways persisted in HSPCs post-treatment. Lastly, we link hypercholesterolaemia to perturbed lipid homeostasis in HSPCs, characterized by lipid droplet formation and transcriptomic changes compatible with increased intracellular cholesterol availability. CONCLUSIONS: Collectively, these data highlight that LDL-C impacts haematopoiesis, promoting both the number and the proinflammatory activation of circulating monocytes. Furthermore, this study reveals a potential contributory role of HSPC transcriptomic reprogramming to residual inflammatory risk in FH patients despite cholesterol-lowering therapy.

Plasma trimethylamine N-oxide (TMAO) levels predict future risk of coronary artery disease in apparently healthy individuals in the EPIC-Norfolk prospective population study.

BACKGROUND: Recent studies show a mechanistic link between gut microbiota-dependent formation of the atherosclerosis- and thrombosis-promoting metabolite trimethylamine N-oxide (TMAO) and cardiovascular disease (CVD). The clinical utility of TMAO in apparently healthy subjects for predicting incident CVD risks is unclear. METHODS AND RESULTS: In the EPIC-Norfolk community-based study, we examined baseline fasting levels of TMAO and two of its nutrient precursors, choline and betaine, in a case:control design study comparing apparently European healthy middle-aged participants who subsequently develop CVD (Cases, n = 908) vs those who did not (Controls, n = 1,273) over an ensuing average follow-up period of 8 years. In participants who developed CVD vs controls, higher plasma TMAO (3.70 [IQR 2.50-6.41]µM vs 3.25 [IQR 2.19-52,1.15]µM; P < .001) and choline levels (9.09 [IQR 7.87-10.53]µM vs 8.89 [IQR 7.66-10.13]µM; P = .001) were observed. Following adjustments for traditional risk factors, elevated TMAO (adjusted odds ratio (OR) 1.58 [95% confidence interval (CI) 1.21-2.06], P < .001) and choline levels (adjusted OR 1.31 [95%CI 1.00-1.72], P < .05) remained predictive of incident CVD development. The clinical prognostic utility of TMAO remained significant and essentially unchanged regardless of the level of cutoff chosen between 1.5 uM (10%ile) to 10.5 uM (90%ile). CONCLUSION: In apparently healthy participants of the community-based middle-aged EPIC-Norfolk population, elevated plasma levels of the gut microbe-dependent metabolite TMAO, and its nutrient precursor choline, predict incident risk for CVD development independent of traditional risk factors.

Retrospective Camera-Based Respiratory Gating in Clinical Whole-Heart 4D Flow MRI.

BACKGROUND: Respiratory gating is generally recommended in 4D flow MRI of the heart to avoid blurring and motion artifacts. Recently, a novel automated contact-less camera-based respiratory motion sensor has been introduced. PURPOSE: To compare camera-based respiratory gating (CAM) with liver-lung-navigator-based gating (NAV) and no gating (NO) for whole-heart 4D flow MRI. STUDY TYPE: Retrospective. SUBJECTS: Thirty two patients with a spectrum of cardiovascular diseases. FIELD STRENGTH/SEQUENCE: A 3T, 3D-cine spoiled-gradient-echo-T1-weighted-sequence with flow-encoding in three spatial directions. ASSESSMENT: Respiratory phases were derived and compared against each other by cross-correlation. Three radiologists/cardiologist scored images reconstructed with camera-based, navigator-based, and no respiratory gating with a 4-point Likert scale (qualitative analysis). Quantitative image quality analysis, in form of signal-to-noise ratio (SNR) and liver-lung-edge (LLE) for sharpness and quantitative flow analysis of the valves were performed semi-automatically. STATISTICAL TESTS: One-way repeated measured analysis of variance (ANOVA) with Wilks's lambda testing and follow-up pairwise comparisons. Significance level of P ≤ 0.05. Krippendorff's-alpha-test for inter-rater reliability. RESULTS: The respiratory signal analysis revealed that CAM and NAV phases were highly correlated (C = 0.93 ± 0.09, P < 0.01). Image scoring showed poor inter-rater reliability and no significant differences were observed (P ≥ 0.16). The image quality comparison showed that NAV and CAM were superior to NO with higher SNR (P = 0.02) and smaller LLE (P < 0.01). The quantitative flow analysis showed significant differences between the three respiratory-gated reconstructions in the tricuspid and pulmonary valves (P ≤ 0.05), but not in the mitral and aortic valves (P > 0.05). Pairwise comparisons showed that reconstructions without respiratory gating were different in flow measurements to either CAM or NAV or both, but no differences were found between CAM and NAV reconstructions. DATA CONCLUSION: Camera-based respiratory gating performed as well as conventional liver-lung-navigator-based respiratory gating. Quantitative image quality analysis showed that both techniques were equivalent and superior to no-gating-reconstructions. Quantitative flow analysis revealed local flow differences (tricuspid/pulmonary valves) in images of no-gating-reconstructions, but no differences were found between images reconstructed with camera-based and navigator-based respiratory gating. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Quantification of Myocardial Creatine and Triglyceride Content in the Human Heart: Precision and Accuracy of in vivo Proton Magnetic Resonance Spectroscopy.

BACKGROUND: Proton magnetic resonance spectroscopy (1 H-MRS) of the human heart is deemed to be a quantitative method to investigate myocardial metabolite content, but thorough validations of in vivo measurements against invasive techniques are lacking. PURPOSE: To determine measurement precision and accuracy for quantifications of myocardial total creatine and triglyceride content with localized 1 H-MRS. STUDY TYPE: Test-retest repeatability and measurement validation study. SUBJECTS: Sixteen volunteers and 22 patients scheduled for open-heart aortic valve replacement or septal myectomy. FIELD STRENGTH/SEQUENCE: Prospectively ECG-triggered respiratory-gated free-breathing single-voxel point-resolved spectroscopy (PRESS) sequence at 3 T. ASSESSMENT: Myocardial total creatine and triglyceride content were quantified relative to the total water content by fitting the 1 H-MR spectra. Precision was assessed with measurement repeatability. Accuracy was assessed by validating in vivo 1 H-MRS measurements against biochemical assays in myocardial tissue from the same subjects. STATISTICAL TESTS: Intrasession and intersession repeatability was assessed using Bland-Altman analyses. Agreement between 1 H-MRS measurements and biochemical assay was tested with regression analyses. RESULTS: The intersession repeatability coefficient for myocardial total creatine content was 41.8% with a mean value of 0.083% ± 0.020% of the total water signal, and 36.7% for myocardial triglyceride content with a mean value of 0.35% ± 0.13% of the total water signal. Ex vivo myocardial total creatine concentrations in tissue samples correlated with the in vivo myocardial total creatine content measured with 1 H-MRS: n = 22, r = 0.44; P < 0.05. Likewise, ex vivo myocardial triglyceride concentrations correlated with the in vivo myocardial triglyceride content: n = 20, r = 0.50; P < 0.05. DATA CONCLUSION: We validated the use of localized 1 H-MRS of the human heart at 3 T for quantitative assessments of in vivo myocardial tissue metabolite content by estimating the measurement precision and accuracy. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.

Tricuspid regurgitation after transcatheter mitral valve repair: Clinical course and impact on outcome.

OBJECTIVES: The aim of this study was to determine the course of tricuspid regurgitation (TR) after transcatheter mitral valve repair (TMVR), identify predictors for severe TR after TMVR and determine the association of severe TR after TMVR with outcome. BACKGROUND: TR is often present in patients with symptomatic mitral regurgitation (MR) and is associated with increased morbidity and mortality. The clinical course of TR after TMVR has not been clearly determined. METHODS: Patients that underwent TMVR between 2009 and 2017 were included. Clinical data were compared between patients with and without severe TR at 6 months after TMVR. Multivariate logistic regression analysis was performed to identify predictors for severe TR after TMVR. Survival analysis was done for both groups, using the Kaplan-Meier method. RESULTS: A total of 146 patients were included (mean age 76 years, 51% male, 79% New York Heart Association class ≥3 and 29% severe TR at baseline). Advanced age, atrial fibrillation (AF), right ventricular (RV) dysfunction, and limited procedural MR reduction were revealed as independent predictors for severe TR after TMVR. Survival of patients with severe TR after TMVR was 58% after 2 years compared to 82% for those with non, mild or moderate TR. CONCLUSIONS: Severe TR after TMVR is common in patients at advanced age, those with AF, RV dysfunction and limited MR reduction during TMVR and is associated with impaired survival. As the associated parameters are indicators of longstanding MR, research investigating the benefits of earlier intervention in MR should be initiated.

Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke: Meta-Analysis of Population-Based Studies Involving 17 180 Individuals.

Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02-1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.

Association between serum secretory phospholipase A2 and risk of ischaemic stroke.

BACKGROUND AND PURPOSE: Previous literature has demonstrated an association between high serum levels of type II secretory phospholipase A2 (sPLA2) concentration and an increased risk of coronary artery disease. However, such association has not been established in terms of ischaemic stroke risk. The aim was to evaluate the association between both sPLA2 concentration and activity as continuous variables with risk of future ischaemic stroke. METHODS: A nested case-control study was conducted using data from the European Prospective Investigation into Cancer-Norfolk study. Cases (n = 145) in the current study were participants who developed ischaemic stroke during follow-up, with controls (n = 290) matched in a 2:1 ratio based on age and sex. Statistical analyses were performed using SPSS (version 25.0) software. Logistic regression was used to determine odds ratios (OR) and corresponding 95% confidence intervals (95% CIs) for ischaemic stroke. RESULTS: After adjusting for a wide array of cardiovascular confounders, sPLA2 activity was found to be associated with an increased risk of ischaemic stroke using both multiple imputations with chained equations and complete case analysis: OR 1.20 (95% CI 1.01-1.43) and OR 1.23 (95% CI 1.01-1.49), respectively. However, sPLA2 concentration was not found to be associated with increased risk of ischaemic stroke. CONCLUSIONS: The activity of sPLA2, but not sPLA2 concentration, is associated with an increased risk of future ischaemic stroke. This finding may be significant in risk group stratification, allowing targeted prophylactic treatment, or the development of novel therapeutic agents.

Fully quantitative mapping of abnormal aortic velocity and wall shear stress direction in patients with bicuspid aortic valves and repaired coarctation using 4D flow cardiovascular magnetic resonance.

BACKGROUND: Helices and vortices in thoracic aortic blood flow measured with 4D flow cardiovascular magnetic resonance (CMR) have been associated with aortic dilation and aneurysms. Current approaches are semi-quantitative or when fully quantitative based on 2D plane placement. In this study, we present a fully quantitative and three-dimensional approach to map and quantify abnormal velocity and wall shear stress (WSS) at peak systole in patients with a bicuspid aortic valve (BAV) of which 52% had a repaired coarctation. METHODS: 4D flow CMR was performed in 48 patients with BAV and in 25 healthy subjects at a spatiotemporal resolution of 2.5 × 2.5 × 2.5mm3/ ~ 42 ms and TE/TR/FA of 2.1 ms/3.4 ms/8° with k-t Principal Component Analysis factor R = 8. A 3D average of velocity and WSS direction was created for the normal subjects. Comparing BAV patient data with the 3D average map and selecting voxels deviating between 60° and 120° and > 120° yielded 3D maps and volume (in cm3) and surface (in cm2) quantification of abnormally directed velocity and WSS, respectively. Linear regression with Bonferroni corrected significance of P < 0.0125 was used to compare abnormally directed velocity volume and WSS surface in the ascending aorta with qualitative helicity and vorticity scores, with local normalized helicity (LNH) and quantitative vorticity and with patient characteristics. RESULTS: The velocity volumes > 120° correlated moderately with the vorticity scores (R ~ 0.50, P < 0.001 for both observers). For WSS surface these results were similar. The velocity volumes between 60° and 120° correlated moderately with LNH (R = 0.66) but the velocity volumes > 120° did not correlate with quantitative vorticity. For abnormal velocity and WSS deviating between 60° and 120°, moderate correlations were found with aortic diameters (R = 0.50-0.70). For abnormal velocity and WSS deviating > 120°, additional moderate correlations were found with age and with peak velocity (stenosis severity) and a weak correlation with gender. Ensemble maps showed that more than 60% of the patients had abnormally directed velocity and WSS. Additionally, abnormally directed velocity and WSS was higher in the proximal descending aorta in the patients with repaired coarctation than in the patients where coarctation was never present. CONCLUSION: The possibility to reveal directional abnormalities of velocity and WSS in 3D provides a new tool for hemodynamic characterization in BAV disease.

Improved cardiovascular risk prediction using targeted plasma proteomics in primary prevention.

AIMS: In the era of personalized medicine, it is of utmost importance to be able to identify subjects at the highest cardiovascular (CV) risk. To date, single biomarkers have failed to markedly improve the estimation of CV risk. Using novel technology, simultaneous assessment of large numbers of biomarkers may hold promise to improve prediction. In the present study, we compared a protein-based risk model with a model using traditional risk factors in predicting CV events in the primary prevention setting of the European Prospective Investigation (EPIC)-Norfolk study, followed by validation in the Progressione della Lesione Intimale Carotidea (PLIC) cohort. METHODS AND RESULTS: Using the proximity extension assay, 368 proteins were measured in a nested case-control sample of 822 individuals from the EPIC-Norfolk prospective cohort study and 702 individuals from the PLIC cohort. Using tree-based ensemble and boosting methods, we constructed a protein-based prediction model, an optimized clinical risk model, and a model combining both. In the derivation cohort (EPIC-Norfolk), we defined a panel of 50 proteins, which outperformed the clinical risk model in the prediction of myocardial infarction [area under the curve (AUC) 0.754 vs. 0.730; P < 0.001] during a median follow-up of 20 years. The clinically more relevant prediction of events occurring within 3 years showed an AUC of 0.732 using the clinical risk model and an AUC of 0.803 for the protein model (P < 0.001). The predictive value of the protein panel was confirmed to be superior to the clinical risk model in the validation cohort (AUC 0.705 vs. 0.609; P < 0.001). CONCLUSION: In a primary prevention setting, a proteome-based model outperforms a model comprising clinical risk factors in predicting the risk of CV events. Validation in a large prospective primary prevention cohort is required to address the value for future clinical implementation in CV prevention.

Subclinical effects of long-chain fatty acid ß-oxidation deficiency on the adult heart: A case-control magnetic resonance study.

Cardiomyopathy can be a severe complication in patients with long-chain fatty acid ß-oxidation disorders (LCFAOD), particularly during episodes of metabolic derangement. It is unknown whether latent cardiac abnormalities exist in adult patients. To investigate cardiac involvement in LCFAOD, we used proton magnetic resonance imaging (MRI) and spectroscopy (1 H-MRS) to quantify heart function, myocardial tissue characteristics, and myocardial lipid content in 14 adult patients (two with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD); four with carnitine palmitoyltransferase II deficiency (CPT2D); and eight with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD)) and 14 gender-, age-, and BMI-matched control subjects. Examinations included cine MRI, MR tagging, native myocardial T1 and T2 mapping, and localized 1 H-MRS at 3 Tesla. Left ventricular (LV) myocardial mass (P = .011) and the LV myocardial mass-to-volume ratio (P = .008) were higher in patients, while ejection fraction (EF) was normal (P = .397). LV torsion was higher in patients (P = .026), whereas circumferential shortening was similar compared with controls (P = .875). LV hypertrophy was accompanied by high myocardial T1 values (indicative of diffuse fibrosis) in two patients, and additionally a low EF in one case. Myocardial lipid content was similar in patients and controls. We identified subclinical morphological and functional differences between the hearts of LCFAOD patients and matched control subjects using state-of-the-art MR methods. Our results suggest a chronic cardiac disease phenotype and hypertrophic LV remodeling of the heart in LCFAOD, potentially triggered by a mild, but chronic, energy deficiency, rather than by lipotoxic effects of accumulating lipid metabolites.

Outcomes of cardiac surgery after mediastinal radiation therapy: A single-center experience.

BACKGROUND: Mediastinal radiation therapy (MRT) is a widely used therapy for thoracic malignancies. This therapy has the potential to cause cardiovascular injuries, which may require surgery. The primary aim of this study is to identify the perioperative outcomes of cardiac surgery in patients with a history of MRT. Second, potential predictors of mortality and adverse events were identified. METHODS: A retrospective study was conducted among 59 patients with prior MRT who underwent cardiac surgery between December 2009 and March 2015. Included surgeries consisted of procedures through median- and ministernotomy. Baseline, perioperative, and follow-up data were obtained and analyzed. RESULTS: The majority of patients had a history of breast cancer (n = 43), followed by Hodgkin lymphoma (n = 10) and non-Hodgkin lymphoma (n = 3). Preoperative estimated mortality with the Euroscore II was 3.4%. Overall 30-day mortality was 6.8% (n = 4), with a total in-hospital mortality of 10.2% (n = 6). Postoperatively, nine rethoracotomies (15.3%) had to be performed. During a mean follow-up of 53 months, an additional 10 patients (16.9%) died, of which 60% (n = 6) as a result of cancer-related events. Cox proportional modeling showed no differences in mortality between primary malignancies (P > .05). CONCLUSION: This study shows that cardiac surgery after mediastinal radiotherapy is associated with increased short- and long-term mortality when compared to preoperative mortality risks predicted by the Euroscore II. Surgery-related events caused all short-term mortality cases, while malignancy-related events were the main cause of death during the follow-up. Mortality was higher in patients with a previous stroke and a lower estimated glomerular filtration rate.

Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the TNT Trial.

BACKGROUND: Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets). METHODS: Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C <130 mg/dL entered the randomized phase with ATV10 (n=5006) versus atorvastatin 80 mg/d (ATV80, n=4995). The primary end point was coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke (major adverse cardiovascular events [MACE]). TRL-C was calculated as total cholesterol minus high-density lipoprotein cholesterol minus LDL-C. The effect of atorvastatin on TRL-C was assessed during the run-in phase (ATV10) and randomized phase (ATV80 versus ATV10). The risk of MACE was assessed across quintiles (Q) of baseline TRL-C (and, for comparison, by baseline triglycerides and non-high-density lipoprotein cholesterol) during the randomized period. Last, the association between TRL-C changes with atorvastatin and cardiovascular risk was assessed by multivariate Cox regression. RESULTS: ATV10 reduced TRL-C 10.7% from an initial TRL-C of 33.9±16.6 mg/dL. ATV80 led to an additional 15.4% reduction. Cardiovascular risk factors positively correlated with TRL-C. Among patients receiving ATV10, higher TRL-C was associated with higher 5-year MACE rates (Q1=9.7%, Q5=13.8%; hazard ratio Q5-versus-Q1, 1.48; 95% confidence interval, 1.15-1.92; P-trend<0.0001). ATV80 (versus ATV10) did not significantly alter the risk of MACE in Q1-Q2, but significantly reduced risk in Q3-Q5 (relative risk reduction, 29%-41%; all P<0.0250), with evidence of effect modification ( P-homogeneity=0.0053); results were consistent for triglycerides ( P-homogeneity=0.0101) and directionally similar for non-high-density lipoprotein cholesterol ( P-homogeneity=0.1387). Last, in adjusted analyses, a 1 SD percentage reduction in TRL-C with atorvastatin resulted in a significant lower risk of MACE (hazard ratio, 0.93; 95% confidence interval, 0.86-1.00; P=0.0482) independent of the reduction in LDL-C and of similar magnitude to that per 1 SD lowering in LDL-C (hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; P=0.0008). CONCLUSIONS: The present post hoc analysis from TNT shows that increased TRL-C levels are associated with an increased cardiovascular risk and provides evidence for the cardiovascular benefit of lipid lowering with statins among patients who have coronary heart disease with high TRL-C. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00327691.

Effect of Losartan on Right Ventricular Dysfunction: Results From the Double-Blind, Randomized REDEFINE Trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) in Adults With Repaired Tetralogy of Fallot.

BACKGROUND: The effect of angiotensin II receptor blockers on right ventricular (RV) function is still unknown. Angiotensin II receptor blockers are beneficial in patients with acquired left ventricular dysfunction, and recent findings have suggested a favorable effect in symptomatic patients with systemic RV dysfunction. The current study aimed to determine the effect of losartan, an angiotensin II receptor blocker, on subpulmonary RV dysfunction in adults after repaired tetralogy of Fallot. METHODS: The REDEFINE trial (Right Ventricular Dysfunction in Tetralogy of Fallot: Inhibition of the Renin-Angiotensin-Aldosterone System) is an investigator-initiated, multicenter, prospective, 1:1 randomized, double-blind, placebo-controlled study. Adults with repaired tetralogy of Fallot and RV dysfunction (RV ejection fraction [EF] <50%) but without severe valvular dysfunction were eligible. Patients were randomly assigned between losartan (150 mg daily) and placebo with target treatment duration between 18 and 24 months. The primary outcome was RV EF change, determined by cardiovascular MRI in intention-to-treat analysis. RESULTS: Of 95 included patients, 47 patients received 150 mg losartan daily (age, 38.0±12.4 years; 74% male), and 48 patients received placebo (age, 40.6±11.4 years; 63% male). Overall, RV EF did not change in patients allocated to losartan (n=42) (44.4±5.1% to 45.2±5.0%) and placebo (n=46) (43.2±6.3% to 43.6±6.9%). Losartan did not significantly improve RV EF in comparison with placebo (+0.51%; 95% confidence interval, -1.0 to +2.0; P=0.50). No significant treatment effects were found on secondary outcomes: left ventricular EF, peak aerobic exercise capacity, and N-terminal pro-brain natriuretic peptide (P>0.30 for all). In predefined subgroup analyses, losartan did not have a statistically significant impact on RV EF in subgroups with symptoms, restrictive RV, RV EF<40%, pulmonary valve replacement, or QRS fragmentation. However, in a post hoc analysis, losartan was associated with improved RV EF in a subgroup (n=30) with nonrestrictive RV and incomplete remodeling (QRS fragmentation and previous pulmonary valve replacement) (+2.7%; 95% confidence interval, +0.1 to +5.4; P=0.045). CONCLUSIONS: Losartan had no significant effect on RV dysfunction or secondary outcome parameters in repaired tetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02010905.