Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

Influenza-Associated Hospitalizations and Risk of Subsequent Heart Failure Hospital Admissions: A 20-Year Territorywide Registry Study in Hong Kong, China.

Little is known about the risk of hospitalization for cardiovascular disease after influenza infection in younger adults. In a territorywide Hong Kong, China, study using clinical registry data for 1997-2017, we examined the association between influenza-associated hospitalizations and the risk of subsequent hospitalization for heart failure (HHF) in 3 age groups: 18-44 years, 45-65 years, and >65 years. Exposure was defined as any infection with influenzavirus as a primary principal diagnosis for hospitalization, whereas the nonexposed control group comprised persons with hospitalizations for elective orthopedic surgery. Logistic regression was used to determine the risk of HHF within 12 months of hospital discharge for the exposed group versus the nonexposed group. Results showed that influenza-associated hospitalization in the preceding 12 months was associated with increased risk of subsequent HHF in all age groups (all P values < 0.001). Notably, the age group 18-44 years was found to have the highest elevated risk of HHF (adjusted odds ratio = 14.90, 95% confidence interval: 4.48, 49.58). In view of the relatively small number of subsequent HHF episodes in this age group, future studies are needed to confirm the elevated risk in this group and to explore the role of age in the relationship between influenza-associated hospitalization and subsequent HHF.

Dual deficiency of angiotensin-converting enzyme-2 and Mas receptor enhances angiotensin II-induced hypertension and hypertensive nephropathy.

Angiotensin-converting enzyme-2 (ACE2) and Mas receptor are the major components of the ACE2/Ang 1-7/Mas axis and have been shown to play a protective role in hypertension and hypertensive nephropathy individually. However, the effects of dual deficiency of ACE2 and Mas (ACE2/Mas) on Ang II-induced hypertensive nephropathy remain unexplored, which was investigated in this study in a mouse model of hypertension induced in either ACE2 knockout (KO) or Mas KO mice and in double ACE2/Mas KO mice by subcutaneously chronic infusion of Ang II. Compared with wild-type (WT) animals, mice lacking either ACE2 or Mas significantly increased blood pressure over 7-28 days following a chronic Ang II infusion (P < .001), which was further exacerbated in double ACE2/Mas KO mice (P < .001). Furthermore, compared to a single ACE2 or Mas KO mice, mice lacking ACE2/Mas developed more severe renal injury including higher levels of serum creatinine and a further reduction in creatinine clearance, and progressive renal inflammation and fibrosis. Mechanistically, worsen hypertensive nephropathy in double ACE2/Mas KO mice was associated with markedly enhanced AT1-ERK1/2-Smad3 and NF-κB signalling, thereby promoting renal fibrosis and renal inflammation in the hypertensive kidney. In conclusion, ACE2 and Mas play an additive protective role in Ang II-induced hypertension and hypertensive nephropathy. Thus, restoring the ACE2/Ang1-7/Mas axis may represent a novel therapy for hypertension and hypertensive nephropathy.

Circulating branched-chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register.

AIM: Levels of branched-chain amino acids (BCAAs, namely, isoleucine, leucine, and valine) are modulated by dietary intake and metabolic/genetic factors. BCAAs are associated with insulin resistance and increased risk of type 2 diabetes (T2D). Although insulin resistance predicts heart failure (HF), the relationship between BCAAs and HF in T2D remains unknown. METHODS: In this prospective observational study, we measured BCAAs in fasting serum samples collected at inception from 2139 T2D patients free of cardiovascular-renal diseases. The study outcome was the first hospitalization for HF. RESULTS: During 29 103 person-years of follow-up, 115 primary events occurred (age: 54.8 ± 11.2 years, 48.2% men, median [interquartile range] diabetes duration: 5 years [1-10]). Patients with incident HF had 5.6% higher serum BCAAs than those without HF (median 639.3 [561.3-756.3] vs 605.2 [524.8-708.7] µmol/L; P = .01). Serum BCAAs had a positive linear association with incident HF (per-SD increase in logarithmically transformed BCAAs: hazard ratio [HR] 1.22 [95% CI 1.07-1.39]), adjusting for age, sex, and diabetes duration. The HR remained significant after sequential adjustment of risk factors including incident coronary heart disease (1.24, 1.09-1.41); blood pressure, low-density lipoprotein cholesterol, and baseline use of related medications (1.31, 1.14-1.50); HbA1c , waist circumference, triglyceride, and baseline use of related medications (1.28, 1.11-1.48); albuminuria and estimated glomerular filtration rate (1.28, 1.11-1.48). The competing risk of death analyses showed similar results. CONCLUSIONS: Circulating levels of BCAAs are independently associated with incident HF in patients with T2D. Prospective cohort analysis and randomized trials are needed to evaluate the long-term safety and efficacy of using different interventions to optimize BCAAs levels in these patients.

C-reactive protein and ageing.

Increasing evidence shows that C-reactive protein (CRP) is not only an inflammatory biomarker but also an important risk factor associated with ageing-related diseases including cardiovascular disease, hypertension, diabetes mellitus, and kidney disease. Recent studies have demonstrated that CRP is pathogenic in a number of diseases including hypertensive cardiovascular and kidney complications, diabetic nephropathy, and acute and chronic kidney diseases. It is well known that CRP binds its receptor, CD32/CD64, to induce the process of inflammation by activating the NF-κB signalling pathway. In addition, CRP mediates tissue fibrosis in a number of cardiovascular and kidney diseases by activating TGF-ß/Smad signalling via TGF-ß1-dependent and independent mechanisms. Furthermore, CRP is able to activate mTOR signalling in the diabetic conditions. Our recent studies also revealed that CRP impairs cell regeneration by causing the G1 cell cycle arrest and promotes ageing via a Smad3-dependent p21/p27 mechanism. In this review, we discuss the roles of CRP in ageing, with a focus on its function and mechanisms in physiological or "healthy" ageing, in ageing-related diseases, and in cell signalling.

The incidence, risk factors and in-hospital mortality of acute kidney injury in patients after abdominal aortic aneurysm repair surgery.

BACKGROUND: Acute kidney injury (AKI) is a severe complication associated with abdominal aortic aneurysm (AAA) repair. In this study, we evaluated the incidence, risk factors and in-hospital mortality of AKI in patients after the AAA repair surgery. METHODS: A total of 314 Chinese AAA patients who underwent endovascular aneurysm repair (EVAR) or open aneurysm repair (OPEN) were enrolled in this study. AKI was diagnosed according to the 2012 KDIGO criteria. Logistic regression modeling was used to explore risk factors of AKI, while risk factors associated with in-hospital mortality in AKI patients were investigated using Cox proportional hazards model and Kaplan-Meier analysis, respectively. Multicollinearity analysis was performed to identify the collinearity between the variables before logistic regression analysis and Cox proportional hazards analysis. RESULTS: Among 314 patients, 94 (29.9%) developed AKI after AAA repair surgery. Severity of AKI and ruptured AAA were independently associated with an increase in in-hospital mortality in AKI patients after AAA repair. Kaplan-Meier analysis identified severity of AKI as being negatively associated with hospital survival in AKI patients. Risk factors associated with AKI included cardiovascular disease (OR 3.169, 95% confidence interval (CI) 1.538 to 6.527, P = 0.002), decreased eGFR (OR 0.965, 95%CI 0.954 to 0.977, P < 0.001), ruptured AAA (OR 2.717, 95%CI 1.320 to 5.592, P = 0.007), renal artery involvement (OR 2.903, 95%CI 1.219 to 6.912, P = 0.016) and OPEN (OR 2.094, 95%CI 1.048 to 4.183, P = 0.036). Further subgroup analysis identified OPEN as an important risk factor of AKI in ruptured AAA patients but not in ruptured AAA patients. The incidence of AKI was significantly lower in EVAR than in OPEN (27.1% vs. 42.8%) and, similarly lower in nonruptured AAA than in ruptured AAA (26.2% vs. 48.1%). CONCLUSION: One-third of AAA patients developed AKI after repair surgery. Severity of AKI was associated with reduced survival rate in AAA patients who developed postoperative AKI. Decreased preoperative creatinine clearance, cardiovascular disease, ruptured AAA and OPEN were independent risk factors for postoperative AKI in all 314 AAA patients. Although a lower rate of incident AKI was observed in EVAR compared with OPEN, subgroup analysis of ruptured AAA versus nonruptured AAA showed that EVAR was an independent protective factor for AKI only in ruptured AAA patients but not in nonruptured AAA patients.

Infant locomotive development and its association with adult blood pressure.

UNLABELLED: Evidence from animal models suggests that locomotion and blood pressure share common neurophysiological regulatory systems. As a result of this common regulation, we hypothesized that the development of locomotion in human infants would be associated with blood pressure levels in adulthood. The study sample comprised 4,347 individuals with measures of locomotive and non-locomotive neuromotor development in infancy and adult blood pressure levels within a longitudinal birth cohort study, the Northern Finland Birth Cohort 1966. Later development in all three stages of locomotive development during infancy was associated with higher systolic and diastolic blood pressure levels at age 31. For age of walking without support, 0.34 (95 % CI 0.07 to 0.60)-mm Hg higher SBP and 0.38 (95 % CI 0.15 to 0.62)-mm Hg higher DBP were estimated for each month of later achievement (P = 0.012 for SBP; P = 0.001 for DBP). No association was identified for non-locomotive neuromotor development. CONCLUSION: These results highlight the positive sequelae of advanced locomotive development during infancy, suggesting that the common regulatory systems between locomotion and blood pressure may influence the development of raised blood pressure over time.

Early Metabolomic and Immunologic Biomarkers as Prognostic Indicators for COVID-19.

This prospective study in Hong Kong aimed at identifying prognostic metabolomic and immunologic biomarkers for Coronavirus Disease 2019 (COVID-19). We examined 327 patients, mean age 55 (19-89) years, in whom 33.6% were infected with Omicron and 66.4% were infected with earlier variants. The effect size of disease severity on metabolome outweighed others including age, gender, peak C-reactive protein (CRP), vitamin D and peak viral levels. Sixty-five metabolites demonstrated strong associations and the majority (54, 83.1%) were downregulated in severe disease (z score: -3.30 to -8.61). Ten cytokines/chemokines demonstrated strong associations (p < 0.001), and all were upregulated in severe disease. Multiple pairs of metabolomic/immunologic biomarkers showed significant correlations. Fourteen metabolites had the area under the receiver operating characteristic curve (AUC) > 0.8, suggesting a high predictive value. Three metabolites carried high sensitivity for severe disease: triglycerides in medium high-density lipoprotein (MHDL) (sensitivity: 0.94), free cholesterol-to-total lipids ratio in very small very-low-density lipoprotein (VLDL) (0.93), cholesteryl esters-to-total lipids ratio in chylomicrons and extremely large VLDL (0.92);whereas metabolites with the highest specificity were creatinine (specificity: 0.94), phospholipids in large VLDL (0.94) and triglycerides-to-total lipids ratio in large VLDL (0.93). Five cytokines/chemokines, namely, interleukin (IL)-6, IL-18, IL-10, macrophage inflammatory protein (MIP)-1b and tumour necrosis factor (TNF)-a, had AUC > 0.8. In conclusion, we demonstrated a tight interaction and prognostic potential of metabolomic and immunologic biomarkers enabling an outcome-based patient stratification.

The Asian Fabry Cardiomyopathy High-Risk Screening Study 2 (ASIAN-FAME-2): Prevalence of Fabry Disease in Patients with Left Ventricular Hypertrophy.

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder that commonly manifests cardiovascular complications. We aimed to assess the prevalence of FD in a Chinese population with left ventricular hypertrophy (LVH) whilst implementing a gender-specific screening approach. Methods: Patients with LVH, defined as a maximum thickness of the left ventricular septal/posterior wall ≥ 13 mm, were considered eligible. All patients with hypertrophic cardiomyopathy (HCM) were excluded. Plasma α-galactosidase (α-GLA) enzyme activity was assessed using a dried blood spot test. Males with low enzyme activity underwent genetic testing to confirm a diagnosis of FD whereas females were screened for both α-GLA and globotriaosylsphingosine concentration and underwent genetic analysis of the GLA gene only if testing positive for ≥1 parameter. Results: 426 unrelated patients (age = 64.6 ± 13.0 years; female: male = 113:313) were evaluated. FD was diagnosed in 3 unrelated patients (age = 69.0 ± 3.5 years, female: male = 1:2) and 1 related female subject (age = 43 years). Genetic analyses confirmed the late-onset cardiac variant GLA c.640-801G>A (n = 3) and the missense variant c.869T>C associated with classic FD (n = 1). Cardiac complications were the only significant findings associated with the late-onset c.640-801G>A mutation, manifesting as mild or severe concentric LVH. In contrast, the classic c.869T>C mutation FD exhibited multisystemic manifestations in addition to severe concentric LVH. Conclusions: The prevalence of FD is lower in Chinese patients with LVH when HCM is excluded. The pathological variant c.640-801G>A remains the most common cause of late-onset FD, while the detection of FD in females can be improved by utilizing a gender-specific screening method.

Towards clinical application of GlycA and GlycB for early detection of inflammation associated with (pre)diabetes and cardiovascular disease: recent evidence and updates.

Cardiometabolic diseases are associated with low-grade inflammation early in life and persists into old age. The long latency period presents opportunities for early detection, lifestyle modification and intervention. However, the performance of conventional biomarker assays to detect low-grade inflammation has been variable, particularly for early-stage cardiometabolic disorder including prediabetes and subclinical atherosclerotic vascular inflammation. During the last decade, the application of nuclear magnetic resonance (NMR) spectroscopy for metabolic profiling of biofluids in translational and epidemiological research has advanced to a stage approaching clinical application. Proton (1H)-NMR profiling induces no destructible physical changes to specimens, and generates quantitative signals from deconvoluted spectra that are highly repeatable and reproducible. Apart from quantitative analysis of amino acids, lipids/lipoproteins, metabolic intermediates and small proteins, 1H-NMR technology is unique in being able to detect composite signals of acute-phase and low-grade inflammation indicated by glycosylated acetyls (GlycA) and N-acetylneuraminic acid (sialic acid) moieties (GlycB). Different from conventional immunoassays that target epitopes and are susceptible to conformational variation in protein structure and binding, GlycA and GlycB signals are stable over time, and maybe complementary as well as superior to high-sensitivity C-reactive protein and other inflammatory cytokines. Here we review the physicochemical principles behind 1H-NMR profiling of GlycA and GlycB, and the available evidence supporting their potential clinical application for the prediction of incident (pre)diabetes, cardiovascular disease, and adverse outcomes.

Divergent Survival Outcomes Associated with Elevated Branched-Chain Amino Acid Levels among Older Adults with or without Hypertension and Diabetes: A Validated, Prospective, Longitudinal Follow-Up Study.

Branched-chain amino acids are critical metabolic intermediates that can indicate increased risk of cardiometabolic disease when levels are elevated or, alternatively, suggest sufficient mitochondrial energy metabolism and reserve in old age. The interpretation of BCAA levels can be context-dependent, and it remains unclear whether abnormal levels can inform prognosis. This prospective longitudinal study aimed to determine the interrelationship between mortality hazard and fasting serum BCAA levels among older men and women aged ≥65 years with or without hypertension and diabetes mellitus. At baseline (0Y), fasting serum BCAA concentration in 2997 community-living older men and women were measured. Approximately 14 years later (14Y), 860 study participants returned for repeat measurements. Deaths were analysed and classified into cardiovascular and non-cardiovascular causes using International Classification of Diseases codes. Survival analysis and multivariable Cox regression were performed. During a median follow-up of 17Y, 971 (78.6%) non-cardiovascular and 263 (21.4%) cardiovascular deaths occurred among 1235 (41.2%) deceased (median age, 85.8 years [IQR 81.7-89.7]). From 0Y to 14Y, BCAA levels declined in both sexes, whereas serum creatinine concentration increased (both p < 0.0001). In older adults without hypertension or diabetes mellitus, the relationship between mortality hazard and BCAA level was linear and above-median BCAA levels were associated with improved survival, whereas in the presence of cardiometabolic disease the relationship was U-shaped. Overall, adjusted Cox regression determined that each 10% increment in BCAA concentration was associated with a 7% (p = 0.0002) and 16% (p = 0.0057) reduction in mortality hazard estimated at 0Y and 14Y, respectively. Our findings suggested that abnormally high or low (dyshomeostatic) BCAA levels among older adults with hypertension and/or diabetes mellitus were associated with increased mortality, whereas in those with neither disease, increased BCAA levels was associated with improved survival, particularly in the oldest-old.

Assessing and managing frailty in advanced heart failure: An International Society for Heart and Lung Transplantation consensus statement.

Frailty is increasingly recognized as a salient condition in patients with heart failure (HF) as previous studies have determined that frailty is highly prevalent and prognostically significant, particularly in those with advanced HF. Definitions of frailty have included a variety of domains, including physical performance, sarcopenia, disability, comorbidity, and cognitive and psychological impairments, many of which are common in advanced HF. Multiple groups have recently recommended incorporating frailty assessments into clinical practice and research studies, indicating the need to standardize the definition and measurement of frailty in advanced HF. Therefore, the purpose of this consensus statement is to provide an integrated perspective on the definition of frailty in advanced HF and to generate a consensus on how to assess and manage frailty. We convened a group of HF clinicians and researchers who have expertise in frailty and related geriatric conditions in HF, and we focused on the patient with advanced HF. Herein, we provide an overview of frailty and how it has been applied in advanced HF (including potential mechanisms), present a definition of frailty, generate suggested assessments of frailty, provide guidance to differentiate frailty and related terms, and describe the assessment and management in advanced HF, including with surgical and nonsurgical interventions. We conclude by outlining critical evidence gaps, areas for future research, and clinical implementation.

Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin.

The genes encoding the cytochrome P450 2C9 enzyme (CYP2C9) and vitamin K-epoxide reductase complex unit 1 (VKORC1) are major determinants of anticoagulant response to warfarin. Together with patient demographics and clinical information, they account for approximately one-half of the warfarin dose variance in individuals of European descent. Recent prospective and randomized controlled trial data support pharmacogenetic guidance with their use in warfarin dose initiation and titration. Benefits from pharmacogenetics-guided warfarin dosing have been reported to extend beyond the period of initial dosing, with supportive data indicating benefits to at least 3 months. The genetic effects of VKORC1 and CYP2C9 in African and Asian populations are concordant with those in individuals of European ancestry; however, frequency distribution of allelic variants can vary considerably between major populations. Future randomized controlled trials in multiethnic settings using population-specific dosing algorithms will allow us to further ascertain the generalizability and cost-effectiveness of pharmacogenetics-guided warfarin therapy. Additional genome-wide association studies may help us to improve and refine dosing algorithms and potentially identify novel biological pathways.

Early risk of acute myocardial infarction following hospitalization for severe influenza infection in the middle-aged population of Hong Kong.

INTRODUCTION: Despite evidence suggesting an association between influenza infection and increased risk of acute myocardial infarction (AMI) in the older adult population (aged 65 years or above), little is known about its near-term risks in middle-aged adults (aged 45 to 64 years). This study aims to estimate the risks of and association between severe influenza infection requiring hospitalization and subsequent AMI within 12 months in middle-aged adults. METHOD: This is a retrospective case-control analysis of territorywide registry data of people aged 45 to 64 years admitting from up to 43 public hospitals in Hong Kong during a 20-year period from January 1997 to December 2017. The exposure was defined as severe influenza infection documented as the principal diagnosis using International Classification of Diseases codes and non-exposure as hospitalization for orthopedic surgery. Logistic regression was used to analyze the risk of subsequent hospitalization for AMI within 12 months following the exposure. RESULTS: Among 30,657 middle-aged adults with an indexed hospitalization, 8,840 (28.8%) had an influenza-associated hospitalization. 81 (0.92%) were subsequently rehospitalized with AMI within 12 months after the indexed hospitalization. Compared with the control group, the risk of subsequent hospitalization for AMI was significantly increased (odds ratio [OR]: 2.54, 95% confidence interval [CI]: 1.64-3.92, p<0.001). The association remained significant even after adjusting for potential confounders (adjusted OR: 1.81, 95% CI: 1.11-2.95, p = 0.02). Patients with a history of hypertension, but not those with diabetes mellitus, dyslipidemia or atrial fibrillation/flutter, were at increased risk (adjusted OR: 5.01, 95% CI: 2.93-8.56, p<0.001). CONCLUSION: Subsequent hospitalization for AMI within 12 months following an indexed respiratory hospitalization for severe influenza increased nearly two-fold compared with the non-cardiopulmonary, non-exposure control. Recommendation of influenza vaccination extending to middle-aged adult population may be justified for the small but significant increased near-term risk of AMI.

Major Adverse Cardiovascular Events and Mortality Prediction by Circulating GDF-15 in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Background: Growth differentiation factor 15 (GDF-15) is a homeostatic cytokine that regulates neural and cardio-metabolic functions, and its release is increased in response to stress, injury, and inflammation. In patients with coronary artery disease and heart failure (HF), three separate meta-analyses have found that elevated circulating GDF-15 was predictive of major adverse cardiovascular events (MACE), but none has evaluated its effects on incident MACE including HF and mortality hazard in type 2 diabetes. Methods: MEDLINE, EMBASE, and Scopus databases were queried. Articles that met the predefined eligibility criteria, including prospective studies that reported adjusted hazard ratios (aHRs), were selected according to the Cochrane Handbook and PRISMA guidelines. Study endpoints were (1) MACE including HF, and (2) all-cause mortality. Different GDF-15 concentration measurements were harmonized using a validated mathematical approach to express log2-transformed values in per standard deviation (SD). Study heterogeneity (I2), quality, and bias were assessed. Results: 19354 patients in 8 prospective studies were included. In 7 studies that reported 4247 MACE among 19200 participants, the incident rate was 22.1% during a median follow-up of 5.6 years. It was found that four of eight studies included HF decompensation or hospitalization as a component of MACE. In 5 studies that reported all-cause mortality, 1893 of 13223 patients died, at an incidence rate of 15.1% over 5.0 years. Of note, each 1 SD increase of log2[GDF-15] was associated with aHRs of 1.12 (1.09−1.15, I2 = 5%, p < 0.000001) and 1.27 (1.11−1.46, I2 = 86%, p = 0.00062) and for MACE and all-cause mortality, respectively. Conclusion: Elevated circulating level of GDF-15 was robustly predictive of MACE in patients with T2D but its prognostic significance in the prediction of mortality requires further studies.

Towards early risk biomarkers: serum metabolic signature in childhood predicts cardio-metabolic risk in adulthood.

BACKGROUND: Cardiovascular diseases may originate in childhood. Biomarkers identifying individuals with increased risk for disease are needed to support early detection and to optimise prevention strategies. METHODS: In this prospective study, by applying a machine learning to high throughput NMR-based metabolomics data, we identified circulating childhood metabolic predictors of adult cardiovascular disease risk (MetS score) in a cohort of 396 females, followed from childhood (mean age 11·2 years) to early adulthood (mean age 18·1 years). The results obtained from the discovery cohort were validated in a large longitudinal birth cohort of females and males followed from puberty to adulthood (n = 2664) and in four cross-sectional data sets (n = 6341). FINDINGS: The identified childhood metabolic signature included three circulating biomarkers, glycoprotein acetyls (GlycA), large high-density lipoprotein phospholipids (L-HDL-PL), and the ratio of apolipoprotein B to apolipoprotein A-1 (ApoB/ApoA) that were associated with increased cardio-metabolic risk in early adulthood (AUC = 0·641‒0·802, all p<0·01). These associations were confirmed in all validation cohorts with similar effect estimates both in females (AUC = 0·667‒0·905, all p<0·01) and males (AUC = 0·734‒0·889, all p<0·01) as well as in elderly patients with and without type 2 diabetes (AUC = 0·517‒0·700, all p<0·01). We subsequently applied random intercept cross-lagged panel model analysis, which suggested bidirectional causal relationship between metabolic biomarkers and cardio-metabolic risk score from childhood to early adulthood. INTERPRETATION: These results provide evidence for the utility of a circulating metabolomics panel to identify children and adolescents at risk for future cardiovascular disease, to whom preventive measures and follow-up could be indicated. FUNDING: This study was financially supported by the Academy of Finland, Ministry of Education of Finland and University of Jyv€askyl€a, the National Nature Science Foundation of China (Grant 31571219), the 111 Project (B17029), the Shanghai Jiao Tong University Zhiyuan Foundation (Grant CP2014013), China Postdoc Scholarship Council (201806230001), the Food and Health Bureau of Hong Kong SAR's Health and Medical Research Fund (HMRF grants 15162161 and 07181036) and the CUHK Direct Grants for Research (2016¢033 and 2018¢034), and a postdoctoral fellowship from K. Carole Ellison (to T.W.). The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. NFBC1966 received financial support from University of Oulu Grant no. 24000692, Oulu University Hospital Grant no. 24301140, ERDF European Regional Development Fund Grant no. 539/2010 A31592. This work was supported by European Union's Horizon 2020 research and innovation programme LongITools 874739.

High Prevalence of Late-Onset Fabry Cardiomyopathy in a Cohort of 499 Non-Selective Patients with Left Ventricular Hypertrophy: The Asian Fabry Cardiomyopathy High-Risk Screening Study (ASIAN-FAME).

Left ventricular hypertrophy (LVH) caused by cardiac variant Fabry disease (FD) is typically late-onset and may mimic LVH caused by abnormal loading conditions. We aimed to determine the prevalence of FD in a non-selective patient population of everyday practice presenting with LVH, including those with hypertension and valve disease. We measured plasma alpha-galactosidase A activity using dried blood spot tests in 499 (age = 66 ± 13 years; 336 men) Hong Kong Chinese patients with LVH defined as maximal LV septal/posterior wall thickness ≥13 mm on echocardiography. Patients with low enzyme activity underwent mutation analysis of the GLA gene. Eight (age = 53-74 years; all men) unrelated patients (1.6%) had low plasma alpha-galactosidase A activity (0.57 ± 0.27 µmol/L wb/hr) and all were confirmed to have the GLA IVS4 + 919G > A mutation. FD patients presented with heart failure (n = 5), heart block (n = 2), ventricular tachycardia (n = 1), chest pain (n = 3), and/or murmur (n = 1). Uncontrolled hypertension (n = 4) and/or severe mitral/aortic valve pathology (n = 2) were frequent. Ethnic subgroups included Teochew (n = 5), Canton (n = 2), and Wenzhou (n = 1). Endomyocardial biopsy (n = 6) revealed hypertrophic myocytes with vacuolization and dense lamellar bodies. Late-onset IVS4 + 919G > A FD is prevalent among Chinese LVH patients, and should be considered as a cause of LVH in adult patients even when hypertension and/or valve pathology are present.

Characterising frailty, metrics of continuous glucose monitoring, and mortality hazards in older adults with type 2 diabetes on insulin therapy (HARE): a prospective, observational cohort study.

BACKGROUND: To our knowledge, no previous study has examined the inter-relationship between frailty, dysglycaemia, and mortality in frail older adults with type 2 diabetes who are on insulin therapy. We used continuous glucose monitors (CGMs) to profile this patient population and determine the prognostic value of CGM metrics. We hypothesised that incremental frailty was associated with increased hypoglycaemia or time below range (TBR). METHODS: HARE was a multicentre, prospective, observational cohort study with mortality hazard analysis carried out in four hospitals in Hong Kong. Eligible participants were community-living adults aged 70 years and older; had had type 2 diabetes for 5 years or more; were on insulin therapy; were frail; and were not hospitalised at the time of frailty assessment and CGM recording. Glucose control was characterised according to the Advanced Technologies and Treatments for Diabetes 2019 international consensus clinical targets. Frailty index was computed, and comprehensive frailty assessments and targeted serum metabolic profiling were performed. The Jonckheere-Terpstra test for trend was used to analyse frailty index tertiles and variables. Inter-relationships between CGM metrics and frailty, glycated haemoglobin A1c (HbA1c), and serum albumin were characterised using adjusted regression models. Survival analysis and Cox proportional hazard modelling were performed. FINDINGS: Between July 25, 2018, and Sept 27, 2019, 225 participants were recruited, 222 of whom had CGMs fitted and 215 of whom had analysable CGM data (190 were frail, 25 were not frail). Incremental frailty was associated with older age, greater HbA1c, worse renal function, and history of stroke. Eight of 11 CGM metrics were significantly associated with frailty. Decreased time in range (TIR; glucose concentration 3·9-10·0 mmol/L) and increased time above range (TAR) metrics were strongly correlated with increased frailty and hyperglycaemia, whereas TBR metrics were marginally or not different between frailty levels. Glucose-lowering agents did not significantly affect regression estimates. In patients with HbA1c of 7·5% or more, reduced serum albumin was associated with level 2 TAR (glucose concentration >13·9 mmol/L) and dysglycaemia. During a median follow-up of 28·0 months (IQR 25·3-30·4), increased level 2 TAR was predictive of mortality explainable by frailty in the absence of detectable interaction. Each 1% increment of level 2 TAR was associated with 1·9% increase in mortality hazard. INTERPRETATION: In older adults with type 2 diabetes who are on insulin therapy, incremental frailty was associated with increased dysglycaemia and hyperglycaemia rather than hypoglycaemia. Mortality hazard was increased with severe hyperglycaemia. Future clinical studies and trials targeting actionable CGM metrics highlighted in this study could translate into improved care and outcomes. FUNDING: Health and Medical Research Fund, Food and Health Bureau, The Government of the Hong Kong Special Administrative Region of China.