Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1,2,3,4,5,6,7. This detailed knowledge of the genetic... Show moreGenome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1,2,3,4,5,6,7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8,9,10,11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases. Show less
To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of... Show moreTo date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases. Show less
BACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can... Show moreBACKGROUND: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors. Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system using mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (MACE).METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the PCSK9 inhibitor alirocumab with placebo in patients with recent acute coronary syndrome. We compared risk of a MACE in the placebo group and MACE risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by Siemens N-latex nephelometric immunoassay (IA-mass; mg/dL), Roche Tina-Quant turbidimetric immunoassay (IA-molar; nmol/L), and a noncommercial mass spectrometry-based test (MS; nmol/L). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay.RESULTS: Among 11 970 trial participants with results from all 3 tests, baseline median (Q1, Q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/ L for IA-mass, IA-molar, and MS, respectively. The strongest correlation was between IA-molar and MS (r=0.990), with nominally weaker correlations between IA-mass and MS (r=0.967) and IA-mass and IA-molar (r=0.972). Relationships of lipoprotein(a) with MACE risk in the placebo group were nearly identical with each test, with estimated cumulative incidences differing by <= 0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol levels (all spline P <= 0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the 3 tests, with estimated treatment hazard ratios differing by <= 0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all 3 tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles.CONCLUSIONS: In patients with recent acute coronary syndrome, 3 lipoprotein(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level. Show less
Driest, F.Y. van; Broersen, A.; Geest, R.J. van der; Jukema, J.W.; Scholte, A.J.H.A.; Dijkstra, J. 2023
Introduction: The use of serial coronary computed tomography angiography (CCTA) allows for the early assessment of coronary plaque progression, a crucial factor in averting major adverse cardiac... Show moreIntroduction: The use of serial coronary computed tomography angiography (CCTA) allows for the early assessment of coronary plaque progression, a crucial factor in averting major adverse cardiac events (MACEs). Traditionally, serial CCTA is assessed using anatomical landmarks to match baseline and follow-up scans. Recently, a tool has been developed that allows for the automatic quantification of local plaque thickness differences in serial CCTA utilizing plaque contour delineation.The aim of this study was to determine thresholds of plaque thickness differences that define whether there is plaque progression and/or regression. These thresholds depend on the contrast-to-noise ratio (CNR). Methods: Plaque thickness differences between two scans acquired at the same moment in time should always be zero. The negative and positive differences in plaque contour delineation in these scans were used along with the CNR in order to create calibration graphs on which a linear regression analysis was performed. This analysis was conducted on a cohort of 50 patients referred for a CCTA due to chest complaints. A total of 300 coronary vessels were analyzed. First, plaque contours were semi-automatically determined for all major epicardial coronary vessels. Second, manual drawings of seven regions of interest (ROIs) per scan were used to quantify the scan quality based on the CNR for each vessel. Results: A linear regression analysis was performed on the CNR and negative and positive plaque contour delineation differences. Accounting for the standard error of the estimate, the linear regression analysis revealed that above 1.009 - 0.002 9 CNR there is an increase in plaque thickness (progression), and below - 1.638 ? 0.012 9 CNR there is a decrease in plaque thickness (regression). Conclusion: This study demonstrates the feasibility of developing vessel-specific, qualitybased thresholds for visualizing local plaque thickness differences evaluated by serial CCTA. These thresholds have the potential to facilitate the early detection of atherosclerosis progression. Show less
Polomski, E.A.S.; Heemelaar, J.C.; Graaf, M.A. de; Krol, A.D.G.; Louwerens, M.; Stöger, J.L.; ... ; Antoni, M.L. 2023
Simple Summary: This study compares the presence of coronary artery calcium on coronary computed tomography angiography in relation to cardiovascular events between Hodgkin lymphoma (HL) survivors... Show moreSimple Summary: This study compares the presence of coronary artery calcium on coronary computed tomography angiography in relation to cardiovascular events between Hodgkin lymphoma (HL) survivors treated with thoracic radiotherapy and a matched non-cancer control group. HL survivors have a higher prevalence of coronary artery calcium more than ten years after irradiation. However, HL patients with a coronary artery calcium score of zero still have an increased risk of future cardiovascular events, possibly due to rapid progression of atherosclerosis in the coronary arteries following irradiation. Timely treatment with statins should be considered to prevent rapid acceleration of pre-existing atherosclerosis. Background: Thoracic radiotherapy is one of the corner stones of HL treatment, but it is associated with increased risk of cardiovascular events. As HL is often diagnosed at a young age, long-term follow-up including screening for coronary artery disease (CAD) is recommended. Objectives: This study aims to evaluate the presence of coronary artery calcium score (CACS) in relation to cardiovascular events in HL patients treated with thoracic radiotherapy compared to a non-cancer control group. Methods: Consecutive HL patients who underwent evaluation for asymptomatic CAD with coronary computed tomography angiography > 10 years after thoracic irradiation were included. The study population consisted of 97 HL patients matched to 97 non-cancer patients on gender, age, cardiovascular risk factors, and statin use. Results: Mean age during CT scan in the HL population was 45.5 +/- 9.9 and in the non-cancer population 45.5 +/- 10.3 years. CACS was elevated (defined as >0) in 49 (50.5%) HL patients and 30 (30.9%) control patients. HL survivors had an odds ratio of 2.28 [95% CI: 1.22-4.28] for having a CACS > 0 compared to the matched population (p = 0.006). Prevalence of CACS > 90th percentile differed significantly: 17.1% in HL survivors vs. 4.6% in the matched population (p = 0.009). Non-obstructive coronary artery stenosis was more prevalent in the HL population than in the control population (45.7% vs. 28.4%, respectively, p = 0.01). During follow-up of 8.5 [5.3; 9.9] years, nine HL patients experienced an event including two patients with a CACS of zero. No events occurred in the control population. Conclusion: In a matched study population, HL survivors have a higher prevalence of a CACS > 0 and an increased risk of cardiovascular events after thoracic irradiation compared to a matched non-cancer control group. Show less
Verheijen, D.B.H.; Engele, L.J.; Egorova, A.; Stöger, J.L.; Mertens, B.J.A.; Palen, R.L.F. van der; ... ; Kies, P. 2023
BackgroundAfter the arterial switch operation (ASO) for transposition of the great arteries (TGA), neo-aortic dilatation and coronary arterial anomalies, especially an interarterial course and acute .Show moreBackgroundAfter the arterial switch operation (ASO) for transposition of the great arteries (TGA), neo-aortic dilatation and coronary arterial anomalies, especially an interarterial course and acute coronary artery take-off angle, are commonly found. Long-term follow-up data after ASO is scarce. Aim of this study was to determine the prevalence of neo-aortic dilatation and coronary abnormalities, with special emphasis on acute coronary take-off angle, in adult TGA-ASO patients.MethodsIn this retrospective cohort study, all adult TGA-ASO patients with ≥1 CT-angiography (CTA) at the age of ≥16 years were included.ResultsEighty-one patients, 69 % male and median age 21.0 [18.5–22.8] years, were included. At baseline, maximum neo-aortic diameter was 39.2 ± 5.3 mm; 35 (43 %) patients had neo-aortic dilatation (neo-aortic diameter of >40 mm), 22 (27 %) patients had an acute coronary take-off angle (<30°), and 5 (6 %) patients had an interarterial course of the RCA (2 %) or LCA (4 %). Neo-aortic or coronary artery re-intervention occurred in 10 (12 %) patients. All 10 patients had neo-aortic dilatation or coronary take-off angle of <30° on baseline CTA.ConclusionThis study reports a prevalence of 43 % of neo-aortic dilatation, 6 % of interarterial coronary course and 27 % for acute coronary take-off angle (<30°) at a median term of 21.0 years post ASO. All patients with a neo-aortic re-intervention or coronary artery re-intervention during follow-up had a maximum neo-aortic diameter of >40 mm or a coronary take-off angle of <30° at baseline CTA. This hypothesis generating study suggests that an active surveillance in patients with neo-aortic dilation and/or an acute angulation of < 30° post ASO might be considered and requires prospective evaluation. Show less
Spoel, E. van der; Vliet, N.A. van; Poortvliet, R.K.E.; Puy, R.S. du; Elzen, W.P.J. den; Quinn, T.J.; ... ; Heemst, D. van 2023
ContextWith age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown.ObjectiveTo investigate incidence and... Show moreContextWith age, the prevalence of subclinical hypothyroidism rises. However, incidence and determinants of spontaneous normalization remain largely unknown.ObjectiveTo investigate incidence and determinants of spontaneous normalization of TSH levels in older adults with subclinical hypothyroidism.DesignPooled data were used from the (1) pretrial population and (2) in-trial placebo group from 2 randomized, double-blind, placebo-controlled trials (Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism Trial and Institute for Evidence-Based Medicine in Old Age thyroid 80-plus thyroid trial).SettingCommunity-dwelling 65+ adults with subclinical hypothyroidism from the Netherlands, Switzerland, Ireland, and the United Kingdom.ParticipantsThe pretrial population (N = 2335) consisted of older adults with biochemical subclinical hypothyroidism, defined as ≥1 elevated TSH measurement (≥4.60 mIU/L) and a free T4 within the laboratory-specific reference range. Individuals with persistent subclinical hypothyroidism, defined as ≥2 elevated TSH measurements ≥3 months apart, were randomized to levothyroxine/placebo, of which the in-trial placebo group (N = 361) was included.Main Outcome MeasuresIncidence of spontaneous normalization of TSH levels and associations between participant characteristics and normalization.ResultsIn the pretrial phase, TSH levels normalized in 60.8% of participants in a median follow-up of 1 year. In the in-trial phase, levels normalized in 39.9% of participants after 1 year of follow-up. Younger age, female sex, lower initial TSH level, higher initial free T4 level, absence of thyroid peroxidase antibodies, and a follow-up measurement in summer were independent determinants for normalization.ConclusionBecause TSH levels spontaneously normalized in a large proportion of older adults with subclinical hypothyroidism (also after confirmation by repeat measurement), a third measurement may be recommended before considering treatment. Show less
Schiele, F.; Catapano, A.L.; Caterina, R. de; Laufs, U.; Jukema, J.W.; Zaman, A.; Sionis, A. 2023
AimsWe performed quality control of lipid-lowering therapy (LLT) in patients with acute coronary syndrome (ACS), with a view to proposing corrective actions.Methods and resultsUsing a Define... Show moreAimsWe performed quality control of lipid-lowering therapy (LLT) in patients with acute coronary syndrome (ACS), with a view to proposing corrective actions.Methods and resultsUsing a Define Measure Analysis Improve Control (DMAIC) approach applied to data from the ACS EuroPath IV survey, we measured attainment of two quality indicators (QIs) related to lipid-lowering treatment: (i) prescription of high-intensity statins (or equipotent treatment) before discharge, and (ii) proportion with LDL-cholesterol <55 mg/dL (1.4 mmol/L) during follow-up. A total of 530 European cardiologists responded and provided data for up to 5 patients from their centre, for acute and follow-up phases. Corrective measures are proposed to increase the rate of attainment of both QIs. Attainment of the first QI was measured in 929 acute-phase patients, 99% had LLT prescribed at discharge and 75% of patients fulfilled the first QI. Attainment of the second QI was assessed in 1721 patients with follow-up. The second QI was reached in 31% of patients. The DMAIC approach yielded 10 potential changes in prescription, 3 for the first and 7 for the second QI. The overall strategy is ‘Fire to Target’, i.e. early intensification of the LLT using statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type-9 inhibitors, and is presented as an algorithm for routine application.ConclusionQuality control for LLT, based on the ACS EuroPath IV survey, detected 10 potential changes in prescription that could enhance attainment of 2 QIs. Whether the Fire to Target strategy will be adopted and effective needs to be assessed in further steps of the EuroPath Quality programme. Show less
Steg, P.G.; Szarek, M.; Valgimigli, M.; Islam, S.; Zeiher, A.M.; Bhatt, D.L.; ... ; ODYSSEY OUTCOMES Investigators 2023
BackgroundMany patients require revascularization after index acute coronary syndrome (ACS). Lipoprotein(a) is thought to play a pathogenic role in atherothrombosis. In ODYSSEY OUTCOMES, alirocumab... Show moreBackgroundMany patients require revascularization after index acute coronary syndrome (ACS). Lipoprotein(a) is thought to play a pathogenic role in atherothrombosis. In ODYSSEY OUTCOMES, alirocumab reduced major adverse cardiovascular events after ACS, with greater reduction among those with higher lipoprotein(a) levels. We explored whether risk of revascularization after ACS was modified by the level of lipoprotein(a) and treatment with alirocumab or placebo.MethodsIn ODYSSEY OUTCOMES alirocumab was compared with placebo in 18,924 patients with ACS and elevated atherogenic lipoprotein levels despite optimized statin treatment. In this post hoc analysis, treatment effects are summarized using competing risks proportional hazard models.ResultsA total of 1559 (8.2%) patients had coronary, 204 (1.1%) had limb, and 40 (0.2%) had carotid revascularization. Alirocumab reduced coronary revascularization (2.8 vs 3.2 events per 100 patient-years; hazard ratio [HR], 0.88 [95% confidence interval (CI), 0.80-0.97]; P = 0.01) and any revascularization (3.2 vs 3.7 events per 100 patient-years; HR, 0.85 [95% CI, 0.78-0.94]; P = 0.001). Baseline lipoprotein(a) quartile was directly associated with risk of coronary or any revascularization in the placebo arm and inversely related to treatment HRs (all P for trend < 0.01). Alirocumab produced the greatest reduction of coronary revascularizationin patients with baseline lipoprotein(a) in the top quartile (≥ 59.6 mg/dL; HR, 0.69 [95% CI, 0.57-0.84]), but no apparent reduction in the bottom quartile (HR, 1.00 [95% CI, 0.82-1.22]). Findings were similar for the effect of alirocumab on any revascularization.ConclusionsAlirocumab reduced revascularization rates after ACS. The risk of revascularization and reduction in that risk with alirocumab were greatest in patients with elevated lipoprotein(a) at baseline. Show less
BackgroundEarly aspirin withdrawal, also known as P2Y12-inhibitor monotherapy, following percutaneous coronary intervention (PCI) for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) can... Show moreBackgroundEarly aspirin withdrawal, also known as P2Y12-inhibitor monotherapy, following percutaneous coronary intervention (PCI) for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) can reduce bleeding without a trade-off in efficacy. Still the average daily bleeding risk is highest during the first months and it remains unclear if aspirin can be omitted immediately following PCI.MethodsThe LEGACY study is an open-label, multicenter randomized controlled trial evaluating the safety and efficacy of immediate P2Y12-inhibitor monotherapy versus dual antiplatelettherapy (DAPT) for 12 months in 3,090 patients. Patients are randomized immediately following successful PCI for NSTE-ACS to 75-100 mg aspirin once daily versus no aspirin. The primary hypothesis is that immediately omitting aspirin is superior to DAPT with respect to major or minor bleeding defined as Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, while maintaining noninferiority for the composite of all-cause mortality, myocardial infarction and stroke compared to DAPT.ConclusionsThe LEGACY study is the first randomized study that is specifically designed to evaluate the impact of immediately omitting aspirin, and thus treating patients with P2Y12-inhibitor monotherapy, as compared to DAPT for 12 months on bleeding and ischemic events within 12 months following PCI for NSTE-ACS. Show less
Vegte, Y. van de; Eppinga, R.N.; Ende, M.Y. van der; Hagemeijer, Y.; Mahendran, Y.V.; Salfati, E.Y.; ... ; DCCT EDIC Res Grp 2023
The genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher... Show moreThe genetics and clinical consequences of resting heart rate (RHR) remain incompletely understood. Here, the authors discover new genetic variants associated with RHR and find that higher genetically predicted RHR decreases risk of atrial fibrillation and ischemic stroke.Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development. Show less
Polomski, E.A.S.; Graaf, M.A. de; Jukema, J.W.; Antoni, M.L. 2023
Background: Major improvements in cancer therapies have significantly contributed to increased survival rates of Hodgkin lymphoma (HL) survivors, outweighing cardiovascular side effects and the... Show moreBackground: Major improvements in cancer therapies have significantly contributed to increased survival rates of Hodgkin lymphoma (HL) survivors, outweighing cardiovascular side effects and the risks of radiation-induced heart disease. Non-invasive screening for coronary artery disease (CAD) starting five years after irradiation is recommended, as plaque development and morphology may differ in this high-risk population. Due to rapid plaque progression and a possibly higher incidence of non-calcified plaques, coronary artery calcium scoring may not be sufficient as a screening modality in HL survivors treated with thoracic radiotherapy. Case summary: A 42-year-old man with a history of HL treated with thoracic radiotherapy presented at the emergency department 20 years after cancer treatment with an ST-elevation myocardial infarction, in the absence of cardiovascular risk factors, for which primary percutaneous coronary intervention of the left anterior descending artery was performed. Four months prior to acute myocardial infarction, invasive coronary angiography only showed wall irregularities. Two years earlier, the Agatston calcium score was zero. Discussion: In HL survivors treated with thoracic radiotherapy, a calcium score of zero may not give the same warranty period for cardiac event-free survival compared to the general population. Coronary computed tomography angiography can be a proper diagnostic tool to detect CAD at an early stage after mediastinal irradiation, as performing calcium scoring may not be sufficient in this population to detect non-calcified plaques, which may show rapid progression and lead to acute coronary syndrome. Also, intensive lipid-lowering therapy should be considered in the presence of atherosclerosis in this patient population. Show less
AimsGiven the compelling evidence on the effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the conventional heart failure population, SGLT2i deserve exploration in systemic... Show moreAimsGiven the compelling evidence on the effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the conventional heart failure population, SGLT2i deserve exploration in systemic right ventricular (sRV) failure. The initial experience with dapagliflozin in sRV failure patients is described, with a focus on tolerability and short-term effects on clinical outcomes.Methods and resultsTen patients (70% female, median age 50 years [46.5-52]) with symptomatic sRV failure who received dapagliflozin 10 mg per day on top of optimal medical therapy between 04-2021 and 01-2023 were included. Within 4 weeks, no significant changes in blood pressure, electrolytes, or serum glucose occurred. Creatinine and estimated glomerular filtration rate (eGFR) showed a slight decline (88 & PLUSMN; 17 to 97 & PLUSMN; 23 & mu;mol/L, p = 0.036, and 72 & PLUSMN; 14 vs. 66 & PLUSMN; 16 ml/min/1.73m(2), p = 0.020, respectively). At 6 months follow-up (n = 8), median NT-proBNP decreased significantly from 736.6 [589.3-1193.3] to 531.6 [400.8-1018] ng/L (p = 0.012). Creatinine and eGFR recovered to baseline levels. There were no significant changes in echocardiographic systolic sRV or left ventricular function. New York Heart Association class improved significantly in 4 out of 8 patients (p = 0.046), who also showed an improvement in the 6-minute walk test or bicycle exercise test performance. One female patient developed an uncomplicated urinary tract infection. No patients discontinued treatment.ConclusionDapagliflozin was well-tolerated in this small cohort of sRV failure patients. While the early results on the reduction of NT-proBNP and clinical outcome parameters are encouraging, large-scale prospective studies are warranted to thoroughly evaluate the effects of SGLT2i in the growing sRV failure population. Show less
BackgroundSome data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors... Show moreBackgroundSome data suggest that low levels of low-density lipoprotein cholesterol (LDL-C) are associated with risk of cataracts. Proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors reduce LDL-C below levels achieved with statins alone. We determined whether the incidence of cataracts was influenced by treatment with the PCSK9 inhibitor alirocumab versus placebo, and whether that incidence was affected by achieved LDL-C levels.MethodsThe ODYSSEY OUTCOMES trial (NCT01663402) compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome receiving high-intensity or maximum-tolerated statin. Incident cataracts were pre-specified events of interest. In multivariable analysis using propensity score-matching on characteristics including cataract risk factors, incident cataracts were compared in the alirocumab and placebo groups according to LDL-C levels achieved with alirocumab.ResultsOver median follow-up of 2.8 years (interquartile range 2.3 − 3.4), the incidence of cataracts was similar with alirocumab (127/9462 [1.3%]) versus placebo (134/9462 [1.4%]); hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74 − 1.20). In patients treated with alirocumab with ≥ 2 LDL-C values < 25 mg/dL (0.65 mmol/L), the incidence of cataracts was 71/4305 (1.6%), versus 60/4305 (1.4%) in propensity score-matched patients from the placebo group (HR 1.10, CI 95% 0.78 − 1.55). In patients treated with alirocumab with ≥ 2 LDL-C values < 15 mg/dL (0.39 mmol/L), the incidence of cataracts was 13/782 (1.7%), versus 36/2346 (1.5%) in matched patients from the placebo group (HR 1.03, CI 95% 0.54 − 1.94).ConclusionTreatment with alirocumab versus placebo, added to statin, did not influence the incidence of cataracts, even when achieved LDL-C levels on alirocumab were very low. Longer follow-up studies might be necessary to exclude the long-term effects on the incidence or progression of cataracts. Show less
BackgroundPregnancy is a known trigger of novel and pre-existing supraventricular tachyarrhythmias. We present a case of a stable pregnant patient presenting with atrioventricular nodal reentry... Show moreBackgroundPregnancy is a known trigger of novel and pre-existing supraventricular tachyarrhythmias. We present a case of a stable pregnant patient presenting with atrioventricular nodal reentry tachycardia (AVNRT) and application of the ‘facial ice immersion technique’.Case summaryA 37-year-old pregnant woman presented with recurrent AVNRT. Due to unsuccessful attempts of conventional vagal manoeuvres (VMs) and refusal of pharmacological agents, we successfully performed a non-conventional VM with the ‘facial ice immersion technique’. This technique was applied successfully at repeated clinical presentation.DiscussionThe role of non-pharmacological interventions remains pivotal and may lead to desired therapeutical effects without the use of any costly pharmacological agents with possible adverse events. However, non-conventional VMs such as the ‘facial ice immersion technique’ are less commonly known but appear to be easy and a safe option for both mother and foetus in the management of AVNRT during pregnancy. Clinical awareness and understanding of treatment options are imperative in contemporary patient care. Show less
Noordam, R.; Brochard, T.A.G.; Drewes, Y.M.; Gussekloo, J.; Mooijaart, S.P.; Dijk, K.W. van; ... ; Heemst, D. van 2023
Background and aims: Mendelian randomization confirmed multiple risk factors for primary events of coronary artery disease (CAD), but no such studies have been performed on recurrent major coronary... Show moreBackground and aims: Mendelian randomization confirmed multiple risk factors for primary events of coronary artery disease (CAD), but no such studies have been performed on recurrent major coronary events despite interesting insights derived from other designs. We examined the associations between genetically-influenced classical cardiovascular risk factors and the risk of recurrent major coronary events in a cohort of CAD patients. Methods: We included all first-time CAD cases (defined as angina pectoris, chronic ischemic heart disease or acute myocardial infarction) of European ancestry from the UK Biobank. Cases were followed till the end of follow-up, death or when they developed a recurrent major coronary event (chronic ischemic heart disease or acute myocardial infarction). Standardized weighted genetic risk scores were calculated for body mass index (BMI), systolic blood pressure, LDL cholesterol and triglycerides. Results: From a total of 22,949 CAD patients (mean age at first diagnosis 59.8 (SD 7.3) years, 71.1% men), 12,539 (54.6%) reported a recurrent major coronary event within a period of maximum 17.8 years. One standard de-viation higher genetically-determined LDL cholesterol was associated with a higher risk of a recurrent major coronary event (odds ratio: 1.08 [95% confidence interval: 1.05, 1.11]). No associations were observed for genetically-influenced BMI (1.00 [0.98, 1.03]), systolic blood pressure (1.01 [0.98, 1.03]) and triglycerides (1.02 [0.995, 1.05]). Conclusions: Despite the use risk-reducing medications following a first coronary event, this study provided ge-netic evidence that, of the classical risk factors, mainly high LDL cholesterol was associated with a higher risk of developing recurrent major coronary events. Show less
Christen, T.; Mutsert, R. de; Smit, R.A.; Dijk, K.W. van; Lamb, H.J.; Rosendaal, F.R.; ... ; Trompet, S. 2023
Background and aims: Leptin has been associated with adverse effects on cardiovascu-lar disease, but the effect of confounding by body fat in these associations remains unclear. To investigate... Show moreBackground and aims: Leptin has been associated with adverse effects on cardiovascu-lar disease, but the effect of confounding by body fat in these associations remains unclear. To investigate associations between leptin and heart function and subclinical cardiovascular disease adjusted for total body fat, and to investigate the causal relation between leptin and cardiovas-cular disease using Mendelian randomisation.Methods and results: Leptin concentrations, total body fat and diverse measures of subclinical car-diovascular disease were determined in participants of the Netherlands Epidemiology of Obesity study. Linear regression between leptin concentration and measures of heart function, ECG mea-sures, and carotid intima media thickness as a measure of subclinical atherosclerosis was adjusted for potential confounding factors, and additionally including total body fat. We analysed the combined effects of genetic variants from a GWAS on leptin concentrations in publicly-available summary statistics of coronary heart disease GWAS (CARDIoGRAMplusC4D, n Z 184,305). As many as 6107 men and women, mean (SD) age 56 (6) years, BMI 26 (4) kg/ m2, and median leptin concentration 12.1 mg (IQR: 6.7-22.6) were included.In observational analyses, leptin was weakly associated with heart function and subclinical cardiovascular disease, but these associations attenuated when adjusting for total body fat. A doubling of genetically-determined leptin concentration was associated with an odds ratio of cardiovascular disease of 0.69 (0.37, 1.27).Conclusion: Observational associations between leptin and subclinical measures of cardiovascu-lar disease were largely explained by differences in total body fat. Results of analyses of genetically-determined leptin and coronary heart disease risk were inconclusive due to a large confidence interval. 2023 The Authors. Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Ital-ian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Patients with metabolic syndrome are often prescribed statins to prevent the development of cardiovascular disease. Conversely, data on their effects on non-alcoholic steatohepatitis (NASH) are... Show morePatients with metabolic syndrome are often prescribed statins to prevent the development of cardiovascular disease. Conversely, data on their effects on non-alcoholic steatohepatitis (NASH) are lacking. We evaluated these effects by feeding APOE*3-Leiden mice a Western-type diet (WTD) with or without atorvastatin to induce NASH and hepatic fibrosis. Besides the well-known plasma cholesterol lowering (−30%) and anti-atherogenic effects (severe lesion size −48%), atorvastatin significantly reduced hepatic steatosis (−22%), the number of aggregated inflammatory cells in the liver (−80%) and hepatic fibrosis (−92%) compared to WTD-fed mice. Furthermore, atorvastatin-treated mice showed less immunohistochemically stained areas of inflammation markers. Atorvastatin prevented accumulation of free cholesterol in the form of cholesterol crystals (−78%). Cholesterol crystals are potent inducers of the NLRP3 inflammasome pathway and atorvastatin prevented its activation, which resulted in reduced expression of the pro-inflammatory cytokines interleukin (IL)-1β (−61%) and IL-18 (−26%). Transcriptome analysis confirmed strong reducing effects of atorvastatin on inflammatory mediators, including NLRP3, NFκB and TLR4. The present study demonstrates that atorvastatin reduces hepatic steatosis, inflammation and fibrosis and prevents cholesterol crystal formation, thereby precluding NLRP3 inflammasome activation. This may render atorvastatin treatment as an attractive approach to reduce NAFLD and prevent progression into NASH in dyslipidemic patients. Show less
The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is... Show moreThe 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N=118,780) and 11 for the frontal QRS-T angle (N=159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction. The spatial and frontal QRS-T angles are electrocardiographic (ECG) predictors for arrhythmia. This work used genetic analyses to identify associated loci and pathways, and explore their relationships with other ECG traits and cardiovascular disease. Show less
