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Caristo Diagnostics, an Oxford University spinout company, has been launched to commercialise a new coronary CT image analysis technology that can flag patients at risk of deadly heart attacks years before they occur.
Evaluation and Management of Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2024 Clinical Practice Guideline.
DESCRIPTION: The Kidney Disease: Improving Global Outcomes (KDIGO) organization updated its existing clinical practice guideline in 2024 to provide guidance on the evaluation, management, and treatment of chronic kidney disease (CKD) in adults and children who are not receiving kidney replacement therapy. METHODS: The KDIGO CKD Guideline Work Group defined the scope of the guideline and determined topics for systematic review. An independent Evidence Review Team systematically reviewed the evidence and graded the certainty of evidence for each of the review topics. Latest searches of the English-language literature were done in July 2023. Final modification of the guideline was informed by a public review process during summer of 2023 involving registered stakeholders. RECOMMENDATIONS: The full guideline included 28 recommendations and 141 practice points. This synopsis focuses on the recommendations that have the greatest evidence. Practice points reflect the expert opinion of the group where evidence is not that strong. Recommendations include greater emphasis on cystatin C for assessment of glomerular filtration rate, point-of-care testing in remote areas, a shift to an individualized risk-based approach to predict kidney failure, sodium-glucose cotransporter-2 inhibitors for some patients with CKD with and without diabetes, and statin use for adults older than 50 years and CKD. Together the recommendations and practice points provide guidance for how to evaluate and manage persons with CKD.
Associations of total, domain-specific, and intensity-specific physical activity with all-cause and cause-specific mortality in China: A population-based cohort study.
BACKGROUND: Evidence of an association between physical activity (PA) and mortality has mainly focused on leisure-time physical activity (LTPA) and moderate-to-vigorous-intensity physical activity (MVPA). We aimed to assess the associations of total, domain-specific, and intensity-specific PA with all-cause and cause-specific mortality. METHODS: We used baseline PA data from the China Kadoorie Biobank, including 482,067 participants aged 30-79 years from 10 areas in China. PA via self-report was quantified as a metabolic equivalent of task hours per day. Total PA was calculated by summing occupational, commuting, household, and leisure-time PA, and domain- and intensity-specific PAs were also calculated. Cox regression was used to estimate the associations of quintiles of different types of PA with all-cause and cause-specific mortality and adjust for potential confounders. Cause-specific mortalities were also examined in a competing risk analysis. RESULTS: During a median follow-up of 12.1 years, 47,281 deaths occurred. Total PA was inversely associated with the risk of all-cause mortality, with a hazard ratio (HR) (95% confidence interval [95% CI]) of 0.69 (0.67-0.71) in the highest quintile as compared with the lowest quintile. Similar associations were observed for disease-specific mortality risks from cardiovascular disease, cancer, respiratory disease, diabetes, and nervous system disease, with HR (95% CI) for top vs. bottom quintile of PA of 0.68 (0.64-0.71), 0.80 (0.76-0.83), 0.39 (0.35-0.44), 0.44 (0.35-0.55), and 0.52 (0.38-0.73), respectively. In addition, the risk of all-cause mortality was lowered by 34%, 13%, 17%, and 30% for occupational PA, non-occupational PA, low-intensity PA, and MVPA, respectively, when comparing the highest quintile with the lowest quintile. CONCLUSIONS: PA was inversely associated with the risk of all-cause and cause-specific mortality, regardless of domain and intensity. Any PA can bring long-term beneficial health effects.
Polygenic risk scores for pan-cancer risk prediction in the Chinese population: A population-based cohort study based on the China Kadoorie Biobank.
BACKGROUND: Polygenic risk scores (PRSs) have been extensively developed for cancer risk prediction in European populations, but their effectiveness in the Chinese population remains uncertain. METHODS AND FINDINGS: We constructed 80 PRSs for the 13 most common cancers using seven schemes and evaluated these PRSs in 100,219 participants from the China Kadoorie Biobank (CKB). The optimal PRSs with the highest discriminatory ability were used to define genetic risk, and their site-specific and cross-cancer associations were assessed. We modeled 10-year absolute risk trajectories for each cancer across risk strata defined by PRSs and modifiable risk scores and quantified the explained relative risk (ERR) of PRSs with modifiable risk factors for different cancers. More than 60% (50/80) of the PRSs demonstrated significant associations with the corresponding cancer outcomes. Optimal PRSs for nine common cancers were identified, with each standard deviation increase significantly associated with corresponding cancer risk (hazard ratios (HRs) ranging from 1.20 to 1.76). Compared with participants at low genetic risk and reduced modifiable risk scores, those with high genetic risk and elevated modifiable risk scores had the highest risk of incident cancer, with HRs ranging from 1.97 (95% confidence interval (CI): 1.11-3.48 for cervical cancer, P = 0.020) to 8.26 (95% CI: 1.92-35.46 for prostate cancer, P = 0.005). We observed nine significant cross-cancer associations for PRSs and found the integration of PRSs significantly increased the prediction accuracy for most cancers. The PRSs contributed 2.6%-20.3%, while modifiable risk factors explained 2.3%-16.7% of the ERR in the Chinese population. CONCLUSIONS: The integration of existing evidence has facilitated the development of PRSs associated with nine common cancer risks in the Chinese population, potentially improving clinical risk assessment.
Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management.
Balancing the risk of major bleeding against vascular disease risk in people without atherosclerotic disease.
BACKGROUND AND AIMS: In the primary prevention setting, low-dose aspirin reduces major vascular events (MVEs) by approximately 11% but increases major bleeding (MB) by 40-50%, implying that net benefit will be most evident when the MVE-to-MB ratio is >4. This study aimed to derive cross-validated risk scores for MB and MVE and use the MVE-to-MB ratio to identify groups who may derive differing net benefits from treatment. METHODS: 431 167 UK Biobank participants without known atherosclerotic cardiovascular disease at baseline were followed through record linkage for incident MVEs (myocardial infarction, non-haemorrhagic stroke, transient ischaemic attack, arterial revascularisation or vascular death) and MB (gastrointestinal and intracranial bleeds with hospital admission for ≥2 days). Risk scores were derived for MVE and MB using Cox proportional hazards models with cross-validation. Ratios of observed MVE-to-MB rates were calculated across risk categories. RESULTS: During a median follow-up of 12 years, 18 310 participants suffered an MVE and 5352 an MB. MB risk was highest among participants with frailty, prior bleeds, cancer, liver disease or renal dysfunction, with a 4.3-fold difference in risk between the highest and lowest fifths of MB risk (HR 4.3, 95% CI 3.87 to 4.77). The MVE-to-MB ratio was ≤2.6 in the highest MB risk groups and ≥4 in lower MB risk categories. CONCLUSIONS: The derived models using routinely available disease history and laboratory measurements improved distinction of the MVE-to-MB ratio compared with using conventional models for MB risk including vascular risk factors. Such models can help identify those with moderate MVE risk but low MB risk who may benefit from low-dose aspirin.
Fabry Disease: Insights into Pathophysiology and Novel Therapeutic Strategies
Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by deficiency of α-galactosidase A (α-GalA), leading to the accumulation of glycosphingolipids and multi-organ dysfunction, particularly affecting the cardiovascular and renal systems. Disease-modifying treatments such as enzyme replacement therapy (ERT) and oral chaperone therapy (OCT) have limited efficacy, particularly in advanced disease, prompting a need for innovative therapeutic approaches targeting underlying molecular mechanisms beyond glycosphingolipid storage alone. Recent insights into the pathophysiology of FD highlights chronic inflammation and mitochondrial, lysosomal, and endothelial dysfunction as key mediators of disease progression. Adjunctive therapies such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRAs) demonstrate significant cardiovascular and renal benefits in conditions including heart failure and chronic kidney disease. These drugs also modulate pathways involved in the pathophysiology of FD, such as autophagy, oxidative stress, and pro-inflammatory cytokine signaling. While theoretical foundations support their utility, dedicated trials are necessary to confirm efficacy in the FD-specific population. This narrative review highlights the importance of expanding therapeutic strategies in FD, advocating for a multi-faceted approach involving evidence-based adjunctive treatments to improve outcomes. Tailored research focusing on diverse FD phenotypes, including females and non-classical variants of disease, will be critical to advancing care and improving outcomes in this complex disorder.
Generation of a human iPSC-derived cardiomyocyte/fibroblast engineered heart tissue model
Animal models have proven integral to broadening our understanding of complex cardiac diseases but have been hampered by significant species-dependent differences in cellular physiology. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have shown great promise in the modelling of cardiac diseases despite limitations in functional and structural maturity. 3D stem cell-derived cardiac models represent a step towards mimicking the intricate microenvironment present in the heart as an in vitro model. Incorporation of non-myocyte cell types, such as cardiac fibroblasts, into engineered heart tissue models (EHTs) can help better recapitulate the cell-to-cell and cell-to-matrix interactions present in the human myocardium. Integration of human-induced pluripotent stem cell-derived cardiac fibroblasts (hiPSC-CFs) and hiPSC-CM into EHT models enables the generation of a genetically homogeneous modelling system capable of exploring the abstruse structural and electrophysiological interplay present in cardiac pathophysiology. Furthermore, the construction of more physiologically relevant 3D cardiac models offers great potential in the replacement of animals in heart disease research. Here we describe efficient and reproducible protocols for the differentiation of hiPSC-CMs and hiPSC-CFs and their subsequent assimilation into EHTs. The resultant EHT consists of longitudinally arranged iPSC-CMs, incorporated alongside hiPSC-CFs. EHTs with both hiPSC-CMs and hiPSC-CFs exhibit slower beating frequencies and enhanced contractile force compared to those composed of hiPSC-CMs alone. The modified protocol may help better characterise the interplay between different cell types in the myocardium and their contribution to structural remodelling and cardiac fibrosis.
A call to action on pregnancy-related lifestyle interventions to reduce cardiovascular risk in the offspring. A Scientific Statement of the European Association of Preventive Cardiology of the ESC.
Adverse pregnancy outcomes, such as gestational diabetes, hypertensive disorders of pregnancy, fetal growth restriction, and prematurity, can increase the risk of future cardiovascular disease (CVD) in the offspring. This document aims to raise recognition of the impact of maternal health on offspring cardiometabolic health and to highlight research gaps on how to mitigate this risk via pregnancy-related lifestyle interventions. Lifestyle interventions initiated before, during, or after pregnancy hold great promise to prevent and manage adverse maternal outcomes. Still, there is limited evidence for the effect of such interventions on CVD-related outcomes in the offspring. In this document, we "Call for action" concerning research investigating how pregnancy-related lifestyle interventions can reduce CVD risk in the offspring. There is a need to overcome barriers to recruit individuals who need such interventions the most, to better design strategies for increased adherence, and to include relevant measurements in children.
Benchmarking Photon-Counting Computed Tomography Angiography Against Invasive Assessment of Coronary Stenosis: Implications for Severely Calcified Coronaries.
BACKGROUND: Clinical guidelines do not recommend coronary computed tomographic angiography (CTA) in elderly patients or in the presence of heavy coronary calcification. Photon-counting coronary computed tomographic angiography (PCCTA) introduces ultrahigh in-plane resolution and multienergy imaging, but the ability of this technology to overcome these limitations is unclear. OBJECTIVES: The authors evaluate the ability of PCCTA to quantitatively assess coronary luminal stenosis in the presence and absence of calcification, comparing both the ultrahigh-resolution (UHR)-PCCTA and the multienergy standard-resolution (SR)-PCCTA with the criterion-standard 3-dimensional invasive quantitative coronary angiography (3D QCA). METHODS: The authors included 100 patients who had both PCCTA and invasive coronary angiography (ICA). They comparatively evaluated luminal diameter stenosis with PCCTA and 3D QCA, anatomic disease severity (according to CAD-RADS [Coronary Artery Disease-Reporting and Data System]) and the diagnostic performance of PCCTA in identifying coronary arteries with ≥50% diameter stenosis on 3D QCA requiring invasive hemodynamic severity evaluation and/or revascularization. RESULTS: The authors analyzed 257 vessels and 343 plaques. UHR-PCCTA luminal evaluation relative to 3D QCA was more precise than SR-PCCTA (median difference: 3% [Q1-Q3: 1%-6%] vs 6% [Q1-Q3: 2%-11%]; P < 0.001), particularly in severely calcified arteries (median difference 3% [Q1-Q3: 1%-6%] vs 6% [Q1-Q3: 3%-13%]; P = 0.002). Per-vessel agreement for CAD-RADS between UHR-PCCTA and 3D QCA was near-perfect (κ = 0.90 [Q1-Q3: 0.84-0.95]; P < 0.001), and it was substantial for SR-PCCTA (κ = 0.63 [Q1-Q3: 0.54-0.71]; P < 0.001), especially in severely calcified arteries: κ = 0.90 (Q1-Q3: 0.83-0.97; P < 0.001) and κ = 0.67 (Q1-Q3: 0.56-0.77; P < 0.001), respectively. Per-vessel diagnostic performance of SR- and UHR-PCCTA was excellent: AUC: 0.94 (95% CI: 0.91-0.98; P < 0.001) and 0.99 (95% CI: 0.98-1.00; P < 0.001), respectively. UHR-PCCTA diagnostically outperformed SR-PCCTA: ΔAUC: 0.05 (95% CI: 0.01-0.08; P = 0.01). CONCLUSIONS: PCCTA compares favorably with ICA for lumen assessment and anatomic disease severity classification in patients presenting with acute coronary syndrome or patients referred for ICA. UHR-PCCTA luminal evaluation is superior to SR-PCCTA, especially in patients with heavy coronary calcification. UHR-PCCTA has excellent diagnostic performance in identifying coronary arteries with ≥50% luminal stenosis on 3D QCA, outperforming standard-resolution imaging.
Metabolic flexibility and reverse remodelling of the failing human heart.
BACKGROUND AND AIMS: Cardiac resynchronization therapy (CRT) produces long-term reverse remodelling which requires greater adenosine triphosphate delivery to the contractile machinery. Whilst the heart retains some metabolic flexibility in non-ischaemic cardiomyopathy, whether this correlates with reverse remodelling is unknown. This study investigated whether CRT acutely changes cardiac substrate uptake, and whether this translates to favourable reverse remodelling. METHODS: The effect of CRT on cardiac substrate uptake was assessed via direct coronary flow and arteriovenous measurements, with metabolomic/lipidomic analysis on infusions of insulin/glucose and intralipid. Cardiac function was assessed with left ventricular pressure-volume loops during implantation, and cardiac magnetic resonance before and 6 months following CRT, with and without biventricular pacing. RESULTS: Regardless of substrate infusion, CRT acutely improved stroke work without increasing O2 uptake on both insulin/glucose (by 34%, P = .05) and intralipid (by 36%, P = .03). This was followed by increased fatty acid (FA) uptake on insulin/glucose (R = 0.89, P = .03) and increased β-hydroxybutyrate uptake (R = 0.81, P = .05) during intralipid infusion. After 6 months, there was a 48% (P < .001) reduction in left ventricular end diastolic volume, beyond that achievable by acutely shortening or lengthening QRS duration. Reverse remodelling significantly correlated with increased FA uptake with CRT on insulin/glucose (R = 0.71, P = .05) driven by long and medium chain uptake, and increased ketone uptake with CRT on intralipid (R = 0.79, P = .05). CONCLUSIONS: CRT acutely alters the metabolic phenotype of non-ischaemic cardiomyopathy towards a more physiological picture of FA uptake which correlates with reverse remodelling. Retained metabolic flexibility may therefore be critical for subsequent reverse remodelling.
Integrating the environmental and genetic architectures of aging and mortality.
Both environmental exposures and genetics are known to play important roles in shaping human aging. Here we aimed to quantify the relative contributions of environment (referred to as the exposome) and genetics to aging and premature mortality. To systematically identify environmental exposures associated with aging in the UK Biobank, we first conducted an exposome-wide analysis of all-cause mortality (n = 492,567) and then assessed the associations of these exposures with a proteomic age clock (n = 45,441), identifying 25 independent exposures associated with mortality and proteomic aging. These exposures were also associated with incident age-related multimorbidity, aging biomarkers and major disease risk factors. Compared with information on age and sex, polygenic risk scores for 22 major diseases explained less than 2 percentage points of additional mortality variation, whereas the exposome explained an additional 17 percentage points. Polygenic risk explained a greater proportion of variation (10.3-26.2%) compared with the exposome for incidence of dementias and breast, prostate and colorectal cancers, whereas the exposome explained a greater proportion of variation (5.5-49.4%) compared with polygenic risk for incidence of diseases of the lung, heart and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and incidence of common age-related diseases, suggesting that the exposome shapes distinct patterns of disease and mortality risk, irrespective of polygenic disease risk.
Evaluation of polygenic scores for hypertrophic cardiomyopathy in the general population and across clinical settings.
Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality, with pathogenic variants found in about a third of cases. Large-scale genome-wide association studies (GWAS) demonstrate that common genetic variation contributes to HCM risk. Here we derive polygenic scores (PGS) from HCM GWAS and genetically correlated traits and test their performance in the UK Biobank, 100,000 Genomes Project, and clinical cohorts. We show that higher PGS significantly increases the risk of HCM in the general population, particularly among pathogenic variant carriers, where HCM penetrance differs 10-fold between those in the highest and lowest PGS quintiles. Among relatives of HCM probands, PGS stratifies risks of developing HCM and adverse outcomes. Finally, among HCM cases, PGS strongly predicts the risk of adverse outcomes and death. These findings support the broad utility of PGS across clinical settings, enabling tailored screening and surveillance and stratification of risk of adverse outcomes.
Comparative analysis of the Mexico City Prospective Study and the UK Biobank identifies ancestry-specific effects on clonal hematopoiesis.
The impact of genetic ancestry on the development of clonal hematopoiesis (CH) remains largely unexplored. Here, we compared CH in 136,401 participants from the Mexico City Prospective Study (MCPS) to 416,118 individuals from the UK Biobank (UKB) and observed CH to be significantly less common in MCPS compared to UKB (adjusted odds ratio = 0.59, 95% confidence interval (CI) = [0.57, 0.61], P = 7.31 × 10-185). Among MCPS participants, CH frequency was positively correlated with the percentage of European ancestry (adjusted beta = 0.84, 95% CI = [0.66, 1.03], P = 7.35 × 10-19). Genome-wide and exome-wide association analyses in MCPS identified ancestry-specific variants in the TCL1B locus with opposing effects on DNMT3A-CH versus non-DNMT3A-CH. Meta-analysis of MCPS and UKB identified five novel loci associated with CH, including polymorphisms at PARP11/CCND2, MEIS1 and MYCN. Our CH study, the largest in a non-European population to date, demonstrates the power of cross-ancestry comparisons to derive novel insights into CH pathogenesis.