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ABSTRACT: JAK2 V617F (JAK2VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD). We assessed the impact of Jak2VF CH on arterial thrombosis and explored the underlying mechanisms. A meta-analysis of 3 large cohort studies confirmed the association of JAK2VF with CVD and with platelet counts and adjusted mean platelet volume (MPV). In mice, 20% or 1.5% Jak2VF CH accelerated arterial thrombosis and increased platelet activation. Megakaryocytes in Jak2VF CH showed elevated proplatelet formation and release, increasing prothrombogenic reticulated platelet counts. Gp1ba-Cre-mediated expression of Jak2VF in platelets (VFGp1ba) increased platelet counts to a similar level as in 20% Jak2VF CH mice while having no effect on leukocyte counts. Like Jak2VF CH mice, VFGp1ba mice showed enhanced platelet activation and accelerated arterial thrombosis. In Jak2VF CH, both Jak2VF and wild-type (WT) platelets showed increased activation, suggesting cross talk between mutant and WT platelets. Jak2VF platelets showed twofold to threefold upregulation of COX-1 and COX-2, particularly in young platelets, with elevated cPLA2 activation and thromboxane A2 production. Compared with controls, conditioned media from activated Jak2VF platelets induced greater activation of WT platelets that was reversed by a thromboxane receptor antagonist. Low-dose aspirin ameliorated carotid artery thrombosis in VFGp1ba and Jak2VF CH mice but not in WT control mice. This study shows accelerated arterial thrombosis and platelet activation in Jak2VF CH with a major role of increased reticulated Jak2VF platelets, which mediate thromboxane cross talk with WT platelets and suggests a potential beneficial effect of aspirin in JAK2VF CH.
Subject(s)
Clonal Hematopoiesis , Thrombosis , Animals , Humans , Mice , Aspirin/pharmacology , Aspirin/therapeutic use , Blood Platelets/metabolism , Mice, Knockout , Platelet Activation , Thrombosis/genetics , Thrombosis/metabolismABSTRACT
BACKGROUND: Premature menopause is a risk factor for accelerated cardiovascular aging, but underlying mechanisms remain incompletely understood. This study investigated the role of leukocyte telomere length (LTL), a marker of cellular aging and genomic instability, in the association of premature menopause with cardiovascular disease. METHODS: Participants from the UK Biobank and Women's Health Initiative with complete reproductive history and LTL measurements were included. Primary analyses tested the association between age at menopause and LTL using multivariable-adjusted linear regression. Secondary analyses stratified women by history of gynecologic surgery. Mendelian randomization was used to infer causal relationships between LTL and age at natural menopause. Multivariable-adjusted Cox regression and mediation analyses tested the joint associations of premature menopause and LTL with incident coronary artery disease. RESULTS: This study included 130â 254 postmenopausal women (UK Biobank: n=122â 224; Women's Health Initiative: n=8030), of whom 4809 (3.7%) had experienced menopause before age 40. Earlier menopause was associated with shorter LTL (meta-analyzed ß=-0.02 SD/5 years of earlier menopause [95% CI, -0.02 to -0.01]; P=7.2×10-12). This association was stronger and significant in both cohorts for women with natural/spontaneous menopause (meta-analyzed ß=-0.04 SD/5 years of earlier menopause [95% CI, -0.04 to -0.03]; P<2.2×10-16) and was independent of hormone therapy use. Mendelian randomization supported a causal association of shorter genetically predicted LTL with earlier age at natural menopause. LTL and age at menopause were independently associated with incident coronary artery disease, and mediation analyses indicated small but significant mediation effects of LTL in the association of menopausal age with coronary artery disease. CONCLUSIONS: Earlier age at menopause is associated with shorter LTL, especially among women with natural menopause. Accelerated telomere shortening may contribute to the heightened cardiovascular risk associated with premature menopause.
Subject(s)
Coronary Artery Disease , Menopause, Premature , Adult , Female , Humans , Coronary Artery Disease/epidemiology , Coronary Artery Disease/genetics , Leukocytes , Menopause/genetics , Postmenopause/genetics , Telomere/geneticsABSTRACT
BACKGROUND AND AIMS: Low birth weight is a common pregnancy complication, which has been associated with higher risk of cardiometabolic disease in later life. Prior Mendelian randomization (MR) studies exploring this question do not distinguish the mechanistic contributions of variants that directly influence birth weight through the foetal genome (direct foetal effects), vs. variants influencing birth weight indirectly by causing an adverse intrauterine environment (indirect maternal effects). In this study, MR was used to assess whether birth weight, independent of intrauterine influences, is associated with cardiovascular disease risk and measures of adverse cardiac structure and function. METHODS: Uncorrelated (r2 < .001), genome-wide significant (P < 5 × 10-8) single nucleotide polymorphisms were extracted from genome-wide association studies summary statistics for birth weight overall, and after isolating direct foetal effects only. Inverse-variance weighted MR was utilized for analyses on outcomes of atrial fibrillation, coronary artery disease, heart failure, ischaemic stroke, and 16 measures of cardiac structure and function. Multiple comparisons were accounted for by Benjamini-Hochberg correction. RESULTS: Lower genetically-predicted birth weight, isolating direct foetal effects only, was associated with an increased risk of coronary artery disease (odds ratio 1.21, 95% confidence interval 1.06-1.37; P = .031), smaller chamber volumes, and lower stroke volume, but higher contractility. CONCLUSIONS: The results of this study support a causal role of low birth weight in cardiovascular disease, even after accounting for the influence of the intrauterine environment. This suggests that individuals with a low birth weight may benefit from early targeted cardiovascular disease prevention strategies, independent of whether this was linked to an adverse intrauterine environment during gestation.
Subject(s)
Brain Ischemia , Coronary Artery Disease , Stroke , Pregnancy , Female , Humans , Birth Weight/genetics , Genome-Wide Association Study , Brain Ischemia/genetics , Mendelian Randomization Analysis , Polymorphism, Single Nucleotide/geneticsABSTRACT
BACKGROUND AND AIMS: Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias. METHODS: UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested. RESULTS: This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04-1.18; P = .001] and 1.13 (95% CI 1.05-1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01-1.19; P = .031) and 1.13 (95% CI 1.03-1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00-1.34; P = .049) and 1.22 (95% CI 1.03-1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07-1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR. CONCLUSIONS: CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment.
Subject(s)
Atrial Fibrillation , Heart Arrest , Heart Failure , Humans , Clonal Hematopoiesis , BradycardiaABSTRACT
PURPOSE OF REVIEW: To summarize the contemporary evidence on decongestion strategies in patients with acute heart failure (AHF). RECENT FINDINGS: While loop diuretic therapy has remained the backbone of decongestive treatment in AHF, multiple randomized clinical trials suggest that early combination with other diuretic classes or molecules with diuretic properties should be considered. Mineralocorticoid receptor antagonists and sodium-glucose co-transporter-2 inhibitors are disease-modifying drugs in heart failure that favourably influence prognosis early on, advocating their start as soon as possible in the absence of any compelling contraindications. Short-term upfront use of acetazolamide in adjunction to intravenous loop diuretic therapy relieves congestion faster, avoids diuretic resistance, and may shorten hospitalization length. Thiazide-like diuretics remain a good option to break diuretic resistance. Currently, ultrafiltration in AHF remains mainly reserved for patient with an inadequate response to pharmacological treatment. SUMMARY: In most patients with AHF, decongestion can be achieved effectively and safely through combination diuretic therapies. Appropriate diuretic therapy may shorten hospitalization length and improve quality of life, but has not yet proven to reduce death or heart failure readmissions. Ultrafiltration currently has a limited role in AHF, mainly as bail-out strategy, but evidence for a more upfront use remains inconclusive.
Subject(s)
Heart Failure , Sodium Potassium Chloride Symporter Inhibitors , Humans , Sodium Potassium Chloride Symporter Inhibitors/therapeutic use , Ultrafiltration , Quality of Life , Diuretics/therapeutic use , Heart Failure/drug therapy , Acute DiseaseABSTRACT
AIMS: To support decision-making in children undergoing aortic valve replacement (AVR), by providing a comprehensive overview of published outcomes after paediatric AVR, and microsimulation-based age-specific estimates of outcome with different valve substitutes. METHODS AND RESULTS: A systematic review of published literature reporting clinical outcome after paediatric AVR (mean age <18 years) published between 1/1/1990 and 11/08/2021 was conducted. Publications reporting outcome after paediatric Ross procedure, mechanical AVR (mAVR), homograft AVR (hAVR), and/or bioprosthetic AVR were considered for inclusion. Early risks (<30d), late event rates (>30d) and time-to-event data were pooled and entered into a microsimulation model. Sixty-eight studies, of which one prospective and 67 retrospective cohort studies, were included, encompassing a total of 5259 patients (37 435 patient-years; median follow-up: 5.9 years; range 1-21 years). Pooled mean age for the Ross procedure, mAVR, and hAVR was 9.2 ± 5.6, 13.0 ± 3.4, and 8.4 ± 5.4 years, respectively. Pooled early mortality for the Ross procedure, mAVR, and hAVR was 3.7% (95% CI, 3.0%-4.7%), 7.0% (5.1%-9.6%), and 10.6% (6.6%-17.0%), respectively, and late mortality rate was 0.5%/year (0.4%-0.7%/year), 1.0%/year (0.6%-1.5%/year), and 1.4%/year (0.8%-2.5%/year), respectively. Microsimulation-based mean life-expectancy in the first 20 years was 18.9 years (18.6-19.1 years) after Ross (relative life-expectancy: 94.8%) and 17.0 years (16.5-17.6 years) after mAVR (relative life-expectancy: 86.3%). Microsimulation-based 20-year risk of aortic valve reintervention was 42.0% (95% CI: 39.6%-44.6%) after Ross and 17.8% (95% CI: 17.0%-19.4%) after mAVR. CONCLUSION: Results of paediatric AVR are currently suboptimal with substantial mortality especially in the very young with considerable reintervention hazards for all valve substitutes, but the Ross procedure provides a survival benefit over mAVR. Pros and cons of substitutes should be carefully weighed during paediatric valve selection.
Subject(s)
Heart Valve Prosthesis Implantation , Heart Valve Prosthesis , Humans , Child , Adolescent , Aortic Valve/surgery , Heart Valve Prosthesis Implantation/methods , Retrospective Studies , Prospective Studies , Treatment OutcomeABSTRACT
OBJECTIVE: The objective of this study was to evaluate the available data on long-term kidney dysfunction, hypertension, and mortality after cardiac surgery-associated acute kidney injury (AKI) in the pediatric population. STUDY DESIGN: PubMed/MEDLINE, Embase, Scopus, and reference lists of relevant articles were searched for eligible studies published from inception through March 2022. Long-term outcomes after pediatric cardiac surgery complicated by AKI and those without were investigated. RESULTS: We identified 14 studies published between 2013 and 2022 that included a total of 6701 patients (AKI: 1376 patients; no AKI: 5325 patients). These studies used different well-established classifications to define AKI. All the studies suggested that AKI after heart surgery is common in the pediatric patient population and reported a potential link between cardiac surgery-associated AKI and important clinical outcomes. However, only 4 out of 11 studies found a strong association between (absence of recovery from) cardiac surgery-associated AKI and risk of developing chronic kidney disease, and 3 out of 5 studies found a significant increase in mortality rates for pediatric patients who developed AKI after cardiac surgery. Only 1 out of 4 studies found an association between AKI and hypertension at 12 months postoperatively, but found no association at later follow-up times. CONCLUSIONS: Although there is a trend, evidence on the long-term consequences of cardiac surgery-associated AKI in the pediatric population is mixed. Genetic syndromes, preexisting kidney disease, univentricular or cyanotic heart conditions, and/or high-complexity surgery may be more important for the development of kidney dysfunction by adolescence and early adulthood. Regardless, these children may benefit from a long-term kidney follow-up.
Subject(s)
Acute Kidney Injury , Cardiac Surgical Procedures , Hypertension , Renal Insufficiency, Chronic , Adolescent , Child , Humans , Adult , Postoperative Complications/epidemiology , Cardiac Surgical Procedures/adverse effects , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Renal Insufficiency, Chronic/complications , Hypertension/complications , Risk Factors , Retrospective StudiesABSTRACT
OBJECTIVE: To assess the effects of preterm birth on cardiac structure and function and transplant-free survival in patients with hypoplastic left heart syndrome and associated anomalies throughout the staged palliation process. STUDY DESIGN: Data from the Single Ventricle Reconstruction trial were used to assess the impact of prematurity on echocardiographic measures at birth, Norwood, Stage II, and 14 months in 549 patients with a single functional right ventricle. Medical history was recorded once a year using medical records or telephone interviews. Cox regression models were applied to analyze transplant-free survival to age 6 years. Causal mediation analysis was performed to estimate the mediating effect of birth weight within this relationship. RESULTS: Of the 549 participants, 64 (11.7%) were born preterm. Preterm-born participants had lower indexed right ventricle end-diastolic volumes at birth but higher volumes than term-born participants by age 14 months. Preterm-born participants had an increased risk of death or heart transplantation from birth to age 6 years, with an almost linear increase in the observed risk as gestational age decreased below 37 weeks. Of the total effect of preterm birth on transplant-free survival, 27.3% (95% CI 2.5-59.0%) was mediated through birth weight. CONCLUSIONS: Preterm birth is associated with adverse right ventricle remodeling and worse transplant-free survival throughout the palliation process, in part independently of low birth weight. Further investigation into this vulnerable group may allow development of strategies that mitigate the impact of prematurity on outcomes in patients with hypoplastic left heart syndrome.
Subject(s)
Hypoplastic Left Heart Syndrome , Norwood Procedures , Premature Birth , Univentricular Heart , Female , Humans , Infant, Newborn , Child , Infant , Hypoplastic Left Heart Syndrome/surgery , Birth Weight , Heart Ventricles/abnormalities , Ventricular Remodeling , Treatment OutcomeABSTRACT
PURPOSE OF REVIEW: Acute kidney injury (AKI) affects up to 35% of all critically ill children and is associated with substantial short-term morbidity and mortality. However, the link between paediatric AKI and long-term adverse outcomes remains incompletely understood. This review highlights the most recent clinical data supporting the role of paediatric AKI as a risk factor for long-term kidney and cardiovascular consequences. In addition, it stresses the need for long-term surveillance of paediatric AKI survivors. RECENT FINDINGS: Recent large-scale studies have led to an increasing understanding that paediatric AKI is a significant risk factor for adverse outcomes such as hypertension, cardiovascular disease and chronic kidney disease (CKD) over time. These long-term sequelae of paediatric AKI are most often observed in vulnerable populations, such as critically ill children, paediatric cardiac surgery patients, children who suffer from severe infections and paediatric cancer patients. SUMMARY: A growing body of research has shown that paediatric AKI is associated with long-term adverse outcomes such as CKD, hypertension and cardiovascular disease. Although therapeutic pathways tailored to individual paediatric AKI patients are yet to be validated, we provide a framework to guide monitoring and prevention in children at the highest risk for developing long-term kidney dysfunction.
Subject(s)
Acute Kidney Injury , Cardiovascular Diseases , Hypertension , Renal Insufficiency, Chronic , Humans , Child , Cardiovascular Diseases/complications , Critical Illness/therapy , Acute Kidney Injury/diagnosis , Acute Kidney Injury/epidemiology , Acute Kidney Injury/etiology , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/diagnosis , Hypertension/complications , Hypertension/therapy , Risk FactorsABSTRACT
Acute kidney injury (AKI) occurs frequently after cardiac surgery in children. Although current diagnostic criteria rely on serum creatinine and urine output, changes occur only after considerable loss of kidney function. This meta-analysis aimed to synthesize the knowledge on novel biomarkers and compare their ability to predict AKI. PubMed/MEDLINE, Embase, Scopus, and reference lists were searched for relevant studies published by March 2021. Diagnostic accuracy parameters were extracted and analyzed using hierarchical summary receiver operating characteristic (HSROC) method. Pooled estimates of the area under the curve (AUC) were calculated using conventional random-effects meta-analysis. Fifty-six articles investigating 49 biomarkers in 8617 participants fulfilled our eligibility criteria. Data from 37 studies were available for meta-analysis. Of the 10 biomarkers suitable for HSROC analysis, urinary neutrophil gelatinase-associated lipocalin (uNGAL) to creatinine (Cr) ratio yielded the highest diagnostic odds ratio (91.0, 95% CI 90.1-91.9), with a sensitivity of 91.3% (95% CI 91.2-91.3%) and a specificity of 89.7% (95% CI 89.6-89.7%). These results were confirmed in pooled AUC analysis, as uNGAL-to-Cr ratio and uNGAL were the only elaborately studied biomarkers (> 5 observations) with pooled AUCs ≥ 0.800. Liver fatty acid-binding protein (L-FABP), serum cystatin C (sCysC), serum NGAL (sNGAL), and interleukin-18 (IL-18) all had AUCs ≥ 0.700. CONCLUSION: A variety of biomarkers have been proposed as predictors of cardiac surgery-associated AKI in children, of which uNGAL was the most prominent with excellent diagnostic qualities. However, more consolidatory evidence will be required before these novel biomarkers may eventually help realize precision medicine in AKI management. WHAT IS KNOWN: ⢠Acute kidney injury (AKI) occurs in about 30-60% of children undergoing cardiac surgery and is associated with increased in-hospital mortality and adverse short-term outcomes. However, in current clinical practice, AKI definitions and detection often rely on changes in serum creatinine and urine output, which are late and insensitive markers of kidney injury. ⢠Although various novel biomarkers have been studied for the diagnosis of AKI in children after cardiac surgery, it remains unclear how these compare to one another in terms of diagnostic accuracy. WHAT IS NEW: ⢠Pooled analyses suggest that for the diagnosis of AKI in children who underwent cardiac surgery, NGAL is the most accurate among the most frequently studied biomarkers. ⢠A number of other promising biomarkers have been reported, although they will require further research into their diagnostic accuracy and clinical applicability.
Subject(s)
Acute Kidney Injury , Cardiac Surgical Procedures , Acute Kidney Injury/diagnosis , Acute Kidney Injury/etiology , Biomarkers , Cardiac Surgical Procedures/adverse effects , Child , Creatinine , Diagnostic Tests, Routine , Female , Humans , Lipocalin-2/urine , MaleABSTRACT
BACKGROUND: The clinical significance of isolated diastolic hypertension defined by the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guidelines remains inconsistent. We examined whether long-term diastolic burden predicts the first major adverse cardiovascular event in participants with sustained and untreated normal systolic BP. METHODS: The Mass General Brigham Biobank is a New England health care-based cohort recruited between 2010 and 2021. A total of 15â 979 participants aged 18 to 64 years and without prior cardiovascular disease, antihypertensives, or high systolic BP were studied. The cumulative diastolic burden was determined as the area under the curve for diastolic BP (DBP) ≥80 mmâ Hg over 5 years before enrollment. Major adverse cardiovascular event was defined as a composite of first incident ischemic heart disease, stroke, heart failure, or all-cause death. RESULTS: Of the 15â 979 participants, mean (SD) age at enrollment was 47.6 (14.3) years, 11â 950 (74.8%) were women, and the mean (SD) systolic BP and DBP were 118.0 (12.9) and 72.2 (9.3) mmâ Hg, respectively. Over a median (interquartile range) follow-up of 3.5 (1.8-5.4) years, 2467 (15.4%) major adverse cardiovascular events occurred. Using Cox proportional hazards regression, each SD increase in cumulative DBP was independently associated with a hazard ratio (95% CI) of 1.06 (1.02-1.10) without effect modification by sex (P=0.65), age (P=0.46), or race/ethnicity (P=0.24). In addition to traditional risk factors, cumulative DBP modestly improved the discrimination C index (95% CI) from 0.74 (0.72-0.75) to 0.75 (0.74-0.76; likelihood ratio test, P=0.037). CONCLUSIONS: Among individuals with normal systolic BP, cumulative DBP may augment cardiovascular disease risk stratification beyond a single DBP measure and traditional risk factors.
Subject(s)
Cardiovascular Diseases , Heart Failure , Hypertension , Humans , Female , Male , Cardiovascular Diseases/drug therapy , Blood Pressure/physiology , Hypertension/drug therapy , Hypertension/epidemiology , Hypertension/complications , Heart Failure/drug therapy , Antihypertensive Agents/therapeutic use , Antihypertensive Agents/pharmacology , Risk FactorsABSTRACT
During the Renaissance, Leonardo Da Vinci was the first person to successfully detail the anatomy of the aortic root and its adjacent structures. Ever since, novel insights into morphology, function, and their interplay have accumulated, resulting in advanced knowledge on the complex functional characteristics of the aortic valve (AV) and root. This has shifted our vision from the AV as being a static structure towards that of a dynamic interconnected apparatus within the aortic root as a functional unit, exhibiting a complex interplay with adjacent structures via both humoral and mechanical stimuli. This paradigm shift has stimulated surgical treatment strategies of valvular disease that seek to recapitulate healthy AV function, whereby AV disease can no longer be seen as an isolated morphological pathology which needs to be replaced. As prostheses still cannot reproduce the complexity of human nature, treatment of diseased AVs, whether stenotic or insufficient, has tremendously evolved, with a similar shift towards treatments options that are more hemodynamically centered, such as the Ross procedure and valve-conserving surgery. Native AV and root components allow for an efficient Venturi effect over the valve to allow for optimal opening during the cardiac cycle, while also alleviating the left ventricle. Next to that, several receptors are present on native AV leaflets, enabling messenger pathways based on their interaction with blood and other shear-stress-related stimuli. Many of these physiological and hemodynamical processes are under-acknowledged but may hold important clues for innovative treatment strategies, or as potential novel targets for therapeutic agents that halt or reverse the process of valve degeneration. A structured overview of these pathways and their implications for cardiothoracic surgeons and cardiologists is lacking. As such, we provide an overview on embryology, hemodynamics, and messenger pathways of the healthy and diseased AV and its implications for clinical practice, by relating this knowledge to current treatment alternatives and clinical decision making.
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Background: Neoaortic root dilatation (NeoARD) and neoaortic regurgitation (NeoAR) are common sequelae following the arterial switch operation (ASO) for transposition of the great arteries. Objectives: The authors aimed to estimate the cumulative incidence of NeoAR, assess whether larger neoaortic root dimensions were associated with NeoAR, and evaluate factors associated with the development of NeoAR during long-term follow-up. Methods: Electronic databases were systematically searched for articles that assessed NeoAR and NeoARD after ASO, published before November 2022. The primary outcome was NeoAR, classified based on severity categories (trace, mild, moderate, and severe). Cumulative incidence was estimated from Kaplan-Meier curves, neoaortic root dimensions using Z-scores, and risk factors were evaluated using random-effects meta-analysis. Results: Thirty publications, comprising a total of 6,169 patients, were included in this review. Pooled estimated cumulative incidence of ≥mild NeoAR and ≥moderate NeoAR at 30-year follow-up were 67.5% and 21.4%, respectively. At last follow-up, neoaortic Z-scores were larger at the annulus (mean difference [MD]: 1.17, 95% CI: 0.52-1.82, P < 0.001; MD: 1.38, 95% CI: 0.46-2.30, P = 0.003) and root (MD: 1.83, 95% CI: 1.16-2.49, P < 0.001; MD: 1.84, 95% CI: 1.07-2.60, P < 0.001) in patients with ≥mild and ≥moderate NeoAR, respectively, compared to those without NeoAR. Risk factors for the development of any NeoAR included prior pulmonary artery banding, presence of a ventricular septal defect, aorto-pulmonary mismatch, a bicuspid pulmonary valve, and NeoAR at discharge. Conclusions: The risks of NeoARD and NeoAR increase over time following ASO surgery. Identified risk factors for NeoAR may alert the clinician that closer follow-up is needed. (Risk factors for neoaortic valve regurgitation after arterial switch operation: a meta-analysis; CRD42022373214).
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Background: Despite advances in managing traditional risk factors, coronary artery disease (CAD) remains the leading cause of mortality. Circulating hematopoietic cells influence risk for CAD, but the role of a key regulating organ, spleen, is unknown. The understudied spleen is a 3-dimensional structure of the hematopoietic system optimally suited for unbiased radiologic investigations toward novel mechanistic insights. Methods: Deep learning-based image segmentation and radiomics techniques were utilized to extract splenic radiomic features from abdominal MRIs of 42,059 UK Biobank participants. Regression analysis was used to identify splenic radiomics features associated with CAD. Genome-wide association analyses were applied to identify loci associated with these radiomics features. Overlap between loci associated with CAD and the splenic radiomics features was explored to understand the underlying genetic mechanisms of the role of the spleen in CAD. Results: We extracted 107 splenic radiomics features from abdominal MRIs, and of these, 10 features were associated with CAD. Genome-wide association analysis of CAD-associated features identified 219 loci, including 35 previously reported CAD loci, 7 of which were not associated with conventional CAD risk factors. Notably, variants at 9p21 were associated with splenic features such as run length non-uniformity. Conclusions: Our study, combining deep learning with genomics, presents a new framework to uncover the splenic axis of CAD. Notably, our study provides evidence for the underlying genetic connection between the spleen as a candidate causal tissue-type and CAD with insight into the mechanisms of 9p21, whose mechanism is still elusive despite its initial discovery in 2007. More broadly, our study provides a unique application of deep learning radiomics to non-invasively find associations between imaging, genetics, and clinical outcomes.
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BACKGROUND: Preeclampsia is a leading cause of maternal and perinatal morbidity and mortality. However, the current understanding of its underlying biological pathways remains limited. METHODS: In this study, we performed a cross-platform proteome- and transcriptome-wide genetic analysis aimed at evaluating the causal relevance of >2000 circulating proteins with preeclampsia, supported by data on the expression of over 15â 000 genes across 36 tissues leveraging large-scale preeclampsia genetic association data from women of European ancestry. RESULTS: We demonstrate genetic associations of 18 circulating proteins with preeclampsia (SULT1A1, SH2B3, SERPINE2, RGS18, PZP, NOTUM, METAP1, MANEA, jun-D, GDF15 [growth/differentiation factor 15], FGL1, FGF5, FES, APOBR, ANP, ALDH-E2, ADAMTS13, and 3MG), among which 11 were either directly or indirectly supported by gene expression data, 9 were supported by Bayesian colocalization analyses, and 5 (SERPINE2, PZP, FGF5, FES, and ANP) were supported by all lines of evidence examined. Protein interaction mapping identified potential shared biological pathways through natriuretic peptide signaling, blood pressure regulation, immune tolerance, and thrombin activity regulation. CONCLUSIONS: This investigation identified multiple targetable proteins linked to cardiovascular, inflammatory, and coagulation pathways, with SERPINE2, PZP, FGF5, FES, and ANP identified as pivotal proteins with likely causal roles in the development of preeclampsia. The identification of these potential targets may guide the development of targeted therapies for preeclampsia.
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OBJECTIVES: The potential risk of autograft dilatation and homograft stenosis after the Ross procedure mandates lifelong follow-up. This retrospective cohort study aimed to determine long-term outcome of the Ross procedure, investigating autograft and homograft failure patterns leading to reintervention. METHODS: All adults who underwent the Ross procedure between 1991 and 2018 at the University Hospitals Leuven were included, with follow-up data collected retrospectively. Autograft implantation was performed using the full root replacement technique. The primary end-point was long-term survival. Secondary end-points were survival free from any reintervention, autograft or homograft reintervention-free survival, and evolution of autograft diameter, homograft gradient and aortic regurgitation grade over time. RESULTS: A total of 173 adult patients (66% male) with a median age of 32 years (range 18-58 years) were included. External support at both the annulus and sinotubular junction was used in 38.7% (67/173). Median follow-up duration was 11.1 years (IQR, 6.4-15.9; 2065 patient-years) with 95% follow-up completeness. There was one (0.6%) perioperative death. Kaplan-Meier estimate for 15-year survival was 91.1% and Ross-related reintervention-free survival was 75.7% (autograft: 83.5%, homograft: 85%). Regression analyses demonstrated progressive neoaortic root dilatation (0.56 mm/year) and increase in homograft gradient (0.72 mmHg/year). CONCLUSIONS: The Ross procedure has the potential to offer excellent long-term survival and reintervention-free survival. These long-term data further confirm that the Ross procedure is a suitable option in young adults with aortic valve disease which should be considered on an individual basis.
Subject(s)
Aortic Valve , Humans , Adult , Male , Female , Retrospective Studies , Middle Aged , Young Adult , Adolescent , Follow-Up Studies , Aortic Valve/surgery , Treatment Outcome , Heart Valve Prosthesis Implantation/methods , Heart Valve Prosthesis Implantation/statistics & numerical data , Heart Valve Prosthesis Implantation/mortality , Reoperation/statistics & numerical data , Aortic Valve Insufficiency/surgery , Pulmonary Valve/transplantation , Pulmonary Valve/surgery , Autografts , Aortic Valve Disease/surgeryABSTRACT
AIMS: Current guidelines advise against the use of lipid-lowering drugs during pregnancy. This is based only on previous observational evidence demonstrating an association between statin use and congenital malformations, which is increasingly controversial. In the absence of clinical trial data, we aimed to use drug-target Mendelian randomization to model the potential impact of fetal LDL-lowering, overall and through PCSK9 drug targets, on congenital malformations. METHODS AND RESULTS: Instrumental variants influencing LDL levels overall and through PCSK9-inhibitor drug targets were extracted from genome-wide association study (GWAS) summary data for LDL on 1 320 016 individuals. Instrumental variants influencing circulating PCSK9 levels (pQTLs) and liver PCSK9 gene expression levels (eQTLs) were extracted, respectively, from a GWAS on 10 186 individuals and from the genotype-tissue expression project. Gene-outcome association data was extracted from the 7th release of GWAS summary data on the FinnGen cohort (n = 342 499) for eight categories of congenital malformations affecting multiple systems. Genetically proxied LDL-lowering through PCSK9 was associated with higher odds of malformations affecting multiple systems [OR 2.70, 95% confidence interval (CI) 1.30-5.63, P = 0.018], the skin (OR 2.23, 95% CI 1.33-3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal, and limb association (VACTERL) (OR 1.51, 95% CI 1.16-1.96, P = 0.007). An association was also found with obstructive defects of the renal pelvis and ureter, but this association was suggestive of horizontal pleiotropy. Lower PCSK9 pQTLs were associated with the same congenital malformations. CONCLUSION: These data provide genetic evidence supporting current manufacturer advice to avoid the use of PCSK9 inhibitors during pregnancy.
Using genetic techniques to mimic the effects of PCSK9-inhibitors, a group of lipid-lowering medications, this study provides evidence to support recommendations to avoid the use of these medications in pregnancy due to potential risk of multiple malformations in the newborn.This study provides genetic evidence to support potential associations of PCSK9-inhibitor medications with newborn malformations affecting multiple organ systems, the skin, and a cluster of structural defects simultaneously affecting the spine, anus/rectum, heart, throat, kidneys, arms and legs.There was also weaker evidence of an association of PCSK9-inhibitor medications with newborn malformations resulting in blockages of the kidneys and urine system, though the evidence was less certain for these than for the other malformations.