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AIMS: Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF. METHODS AND RESULTS: ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt-1 or PlGF levels were genotyped. sFlt-1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All-cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt-1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt-1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt-1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57-16.1; p < 0.001) in PEOPLE, independent of age, NT-proBNP, ischaemic aetiology, diabetic status and beta-blocker therapy. CONCLUSIONS: Plasma sFlt-1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF.
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Biomarcadores , Insuficiencia Cardíaca , Factor de Crecimiento Placentario , Polimorfismo de Nucleótido Simple , Proteínas Gestacionales , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Humanos , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/mortalidad , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Femenino , Masculino , Factor de Crecimiento Placentario/sangre , Proteínas Gestacionales/sangre , Proteínas Gestacionales/genética , Anciano , Persona de Mediana Edad , Biomarcadores/sangre , Pronóstico , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/genética , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Genotipo , Ensayo de Inmunoadsorción EnzimáticaRESUMEN
Mass spectrometry is a powerful technique for investigating renal pathologies and identifying biomarkers, and efficient protein extraction from kidney tissue is essential for bottom-up proteomic analyses. Detergent-based strategies aid cell lysis and protein solubilization but are poorly compatible with downstream protein digestion and liquid chromatography-coupled mass spectrometry, requiring additional purification and buffer-exchange steps. This study compares two well-established detergent-based methods for protein extraction (in-solution sodium deoxycholate (SDC); suspension trapping (S-Trap)) with the recently developed sample preparation by easy extraction and digestion (SPEED) method, which uses strong acid for denaturation. We compared the quantitative performance of each method using label-free mass spectrometry in both sheep kidney cortical tissue and plasma. In kidney tissue, SPEED quantified the most unique proteins (SPEED 1250; S-Trap 1202; SDC 1197). In plasma, S-Trap produced the most unique protein quantifications (S-Trap 150; SDC 148; SPEED 137). Protein quantifications were reproducible across biological replicates in both tissue (R2 = 0.85-0.90) and plasma (SPEED R2 = 0.84; SDC R2 = 0.76, S-Trap R2 = 0.65). Our data suggest SPEED as the optimal method for proteomic preparation in kidney tissue and S-Trap or SPEED as the optimal method for plasma, depending on whether a higher number of protein quantifications or greater reproducibility is desired.
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Detergentes , Espectrometría de Masas en Tándem , Animales , Ovinos , Detergentes/química , Espectrometría de Masas en Tándem/métodos , Proteómica/métodos , Reproducibilidad de los Resultados , ProteínasRESUMEN
BACKGROUND: Individuals born very low birthweight (VLBW) are at increased risk of impaired cardiovascular and respiratory function in adulthood. To identify markers to predict future risk for VLBW individuals, we analyzed DNA methylation at birth and at 28 years in the New Zealand (NZ) VLBW cohort (all infants born < 1500 g in NZ in 1986) compared with age-matched, normal birthweight controls. Associations between neonatal methylation and cardiac structure and function (echocardiography), vascular function and respiratory outcomes at age 28 years were documented. RESULTS: Genomic DNA from archived newborn heel-prick blood (n = 109 VLBW, 51 controls) and from peripheral blood at ~ 28 years (n = 215 VLBW, 96 controls) was analyzed on Illumina Infinium MethylationEPIC 850 K arrays. Following quality assurance and normalization, methylation levels were compared between VLBW cases and controls at both ages by linear regression, with genome-wide significance set to p < 0.05 adjusted for false discovery rate (FDR, Benjamini-Hochberg). In neonates, methylation at over 16,400 CpG methylation sites differed between VLBW cases and controls and the canonical pathway most enriched for these CpGs was Cardiac Hypertrophy Signaling (p = 3.44E-11). The top 20 CpGs that differed most between VLBW cases and controls featured clusters in ARID3A, SPATA33, and PLCH1 and these 3 genes, along with MCF2L, TRBJ2-1 and SRC, led the list of 15,000 differentially methylated regions (DMRs) reaching FDR-adj significance. Fifteen of the 20 top CpGs in the neonate EWAS showed associations between methylation at birth and adult cardiovascular traits (particularly LnRHI). In 28-year-old adults, twelve CpGs differed between VLBW cases and controls at FDR-adjusted significance, including hypermethylation in EBF4 (four CpGs), CFI and UNC119B and hypomethylation at three CpGs in HIF3A and one in KCNQ1. DNA methylation GrimAge scores at 28 years were significantly greater in VLBW cases versus controls and weakly associated with cardiovascular traits. Four CpGs were identified where methylation differed between VLBW cases and controls in both neonates and adults, three reversing directions with age (two CpGs in EBF4, one in SNAI1 were hypomethylated in neonates, hypermethylated in adults). Of these, cg16426670 in EBF4 at birth showed associations with several cardiovascular traits in adults. CONCLUSIONS: These findings suggest that methylation patterns in VLBW neonates may be informative about future adult cardiovascular and respiratory outcomes and have value in guiding early preventative care to improve adult health.
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Metilación de ADN , Epigénesis Genética , Recién Nacido , Humanos , Adulto Joven , Adulto , Recién Nacido de muy Bajo Peso , Fenotipo , Evaluación de Resultado en la Atención de Salud , Islas de CpG , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Proteínas Represoras/genética , Proteínas Reguladoras de la Apoptosis/genéticaRESUMEN
OBJECTIVE: The Multi-Ethnic New Zealand Study of Acute Coronary Syndromes (MENZACS) was established to investigate the drivers of secondary events after first-time acute coronary syndrome (ACS), including addressing inequitable outcomes by ethnicity. Herein, the first clinical outcomes and prognostic modelling approach are reported. METHODS: First, in 28 176 New Zealanders with first-time ACS from a national registry, a clinical summary score for predicting 1-year death/cardiovascular readmission was created using Cox regression of 20 clinical variables. This score was then calculated in the 2015 participant MENZACS study to represent clinical risk. In MENZACS, Cox regression was used to assess N-terminal pro-B-type natriuretic peptide (NT-proBNP) as a prognostic marker for death/cardiovascular readmission in four models, adjusting for (1) age and sex; (2) age, sex, ethnicity; (3) clinical summary score; (4) clinical summary score and ethnicity. RESULTS: Of the 2015 MENZACS participants (mean age 61 years, 79% male, 73% European, 14% Maori, 5% Pacific people), 2003 were alive at discharge. Of the 2003, 416 (20.8%) experienced all-cause death/cardiovascular readmission over a median of 3.5 years. In a simple model, age, male sex, Maori ethnicity and NT-proBNP levels were significant predictors of outcome. After adjustment for the clinical summary score, which includes age and sex, NT-proBNP and ethnicity were no longer statistically significant: log2(NT-proBNP) hazard ratio (HR) 1.03, 95% confidence interval (95% CI) 0.98 to 1.08, p=0.305; Maori ethnicity HR 1.26, 95% CI 0.97 to 1.62, p=0.084. CONCLUSIONS: In 2015 patients with first-time ACS, recurrent events were common (20.8%). Increasing NT-proBNP levels and Maori ethnicity were predictors of death/cardiovascular readmission, but not after adjustment for the 20 clinical risk factors represented by the clinical summary score. TRIAL REGISTRATION NUMBER: ACTRN12615000676516.
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Síndrome Coronario Agudo , Humanos , Masculino , Persona de Mediana Edad , Femenino , Pronóstico , Síndrome Coronario Agudo/diagnóstico , Síndrome Coronario Agudo/terapia , Biomarcadores , Pueblo Maorí , Nueva Zelanda/epidemiología , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Factores de Riesgo , Medición de RiesgoRESUMEN
The enzyme cytochrome P450 2D6 (CYP2D6) metabolises approximately 25% of commonly prescribed drugs, including analgesics, anti-hypertensives, and anti-depressants, among many others. Genetic variation in drug metabolising genes can alter how an individual responds to prescribed drugs, including predisposing to adverse drug reactions. The majority of research on the CYP2D6 gene has been carried out in European and East Asian populations, with many Indigenous and minority populations, such as those from Oceania, greatly underrepresented. However, genetic variation is often population specific and analysis of diverse ethnic groups can reveal differences in alleles that may be of clinical significance. For this reason, we set out to examine the range and frequency of CYP2D6 variants in a sample of 202 Maori and Pacific people living in Aotearoa (New Zealand). We carried out long PCR to isolate the CYP2D6 region before performing nanopore sequencing to identify all variants and alleles in these samples. We identified twelve variants which have previously not been reported in the PharmVar CYP2D6 database, three of which were exonic missense variations. Six of these occurred in single samples and one was found in 19 samples (9.4% of the cohort). The remaining five variants were identified in two samples each. Identified variants formed twelve new CYP2D6 suballeles and four new star alleles, now recorded in the PharmVar database. One striking finding was that CYP2D6*71, an allele of uncertain functional status which has been rarely observed in previous studies, occurs at a relatively high frequency (8.9%) within this cohort. These data will help to ensure that CYP2D6 genetic analysis for pharmacogenetic purposes can be carried out accurately and effectively in this population group.
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Advances in RNA sequencing (RNA-Seq) have facilitated transcriptomic analysis of plasma for the discovery of new diagnostic and prognostic markers for disease. We aimed to develop a short-read RNA-Seq protocol to detect mRNAs, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in plasma for the discovery of novel markers for coronary artery disease (CAD) and heart failure (HF). Circulating cell-free RNA from 59 patients with stable CAD (half of whom developed HF within 3 years) and 30 controls was sequenced to a median depth of 108 paired reads per sample. We identified fragments from 3986 messenger RNAs (mRNAs), 164 long non-coding RNAs (lncRNAs), 405 putative novel lncRNAs and 227 circular RNAs in plasma. Circulating levels of 160 mRNAs, 10 lncRNAs and 2 putative novel lncRNAs were altered in patients compared with controls (absolute fold change >1.2, p < 0.01 adjusted for multiple comparisons). The most differentially abundant transcripts were enriched in mRNAs encoded by the mitochondrial genome. We did not detect any differences in the plasma RNA profile between patients who developed HF compared with those who did not. In summary, we show that mRNAs, lncRNAs and circular RNAs can be reliably detected in plasma by deep RNA-Seq. Multiple coding and non-coding transcripts were altered in association with CAD, including several mitochondrial mRNAs, which may indicate underlying myocardial ischaemia and oxidative stress. If validated, circulating levels of these transcripts could potentially be used to help identify asymptomatic individuals with established CAD prior to an acute coronary event.
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Ácidos Nucleicos Libres de Células , Enfermedad de la Arteria Coronaria , ARN Largo no Codificante , Humanos , ARN Circular , ARN Largo no Codificante/genética , Enfermedad de la Arteria Coronaria/genética , Ácidos Nucleicos Libres de Células/genética , Análisis de Secuencia de ARN , BiomarcadoresRESUMEN
Hydrogen sulfide (H2S) and substance P (SP) are known from animal models and in vitro studies as proinflammatory mediators. In this study, peripheral blood concentrations of H2S and SP were measured in patients with Escherichia coli or Klebsiella pneumoniae bacteraemia. Fifty patients were recruited from general wards at Christchurch Hospital, during 2020-2021. Samples from age- and sex-matched healthy subjects previously recruited as controls for studies of cardiovascular disease were used as controls. The concentrations of H2S were higher than controls on day 0, day 1, and day 2, and SP was higher than controls on all 4 days. The concentrations of H2S were highest on day 0, whereas SP concentrations were higher on day 2 than other days. Interleukin-6 and C-reactive protein were significantly higher on day 0 and day 1, respectively. The concentrations of H2S and SP did not differ between 15 non-septic (SIRS 0-1) and the 35 septic subjects (SIRS ≥ 2). Substance P concentrations were higher in subjects with abdominal infection than urinary tract infections on day 0 (p = 0.0002) and day 1 (p = 0.0091). In conclusion, the peak H2S concentrations precede the SP peak in patients with Gram-negative bacteraemia, but this response varies with the site of infection.
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Bacteriemia , Infecciones por Escherichia coli , Sulfuro de Hidrógeno , Animales , Escherichia coli/metabolismo , Humanos , Sulfuro de Hidrógeno/metabolismo , Klebsiella pneumoniae/metabolismo , Sustancia PRESUMEN
Background: The knowledge of factors influencing disease progression in patients with established coronary heart disease (CHD) is still relatively limited. One potential pathway is related to peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A), a transcription factor linked to energy metabolism which may play a role in the heart function. Thus, its associations with subsequent CHD events remain unclear. We aimed to investigate the effect of three different SNPs in the PPARGC1A gene on the risk of subsequent CHD in a population with established CHD. Methods: We employed an individual-level meta-analysis using 23 studies from the GENetIcs of sUbSequent Coronary Heart Disease (GENIUS-CHD) consortium, which included participants (n = 80,900) with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. Three variants in the PPARGC1A gene (rs8192678, G482S; rs7672915, intron 2; and rs3755863, T528T) were tested for their associations with subsequent events during the follow-up using a Cox proportional hazards model adjusted for age and sex. The primary outcome was subsequent CHD death or myocardial infarction (CHD death/myocardial infarction). Stratified analyses of the participant or study characteristics as well as additional analyses for secondary outcomes of specific cardiovascular disease diagnoses and all-cause death were also performed. Results: Meta-analysis revealed no significant association between any of the three variants in the PPARGC1A gene and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline: rs8192678, hazard ratio (HR): 1.01, 95% confidence interval (CI) 0.98-1.05 and rs7672915, HR: 0.97, 95% CI 0.94-1.00; rs3755863, HR: 1.02, 95% CI 0.99-1.06. Similarly, no significant associations were observed for any of the secondary outcomes. The results from stratified analyses showed null results, except for significant inverse associations between rs7672915 (intron 2) and the primary outcome among 1) individuals aged ≥65, 2) individuals with renal impairment, and 3) antiplatelet users. Conclusion: We found no clear associations between polymorphisms in the PPARGC1A gene and subsequent CHD events in patients with established CHD at baseline.
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BACKGROUND: Plasma cardiac markers may assist in prediction of incident cardiovascular disease. METHODS: The incremental value of cardiac Troponins (T and I) and NT-proBNP added to risk factors in the PREDICT score for incident cardiovascular disease (CVD) in primary care, was assessed in 4102 asymptomatic participants in a randomised controlled trial of Vitamin D (ViDA). Findings were corroborated in 2528 participants in a separate community-based observational registry of CVD-free volunteers (HVOLS). FINDINGS: Hazard ratios for first cardiovascular events adjusted for PREDICT risk factors, comparing fifth to first quintiles of marker plasma concentrations, were 2.57 (95% CI 1.47-4.49); 3.01 (1.66-5.48) and 3.38 (2.04-5.60) for hs-cTnI, hs-cTnT and NT-proBNP respectively. The C statistic for discrimination of the primary endpoint increased from 0.755 to 0.771 (+0.016, p = 0.01). Cardiac marker data correctly reclassified risk upwards in 6.7% of patients and downwards in 3.3%. These findings were corroborated by results from HVOLS. INTERPRETATION: Increments in plasma cardiac biomarkers robustly and reproducibly predicted increased hazard of incident CVD, independent of established risk factors, in two community-dwelling populations. Cardiac markers may augment risk assessment for onset of CVD in primary care. FUNDING: ViDA was funded by the Health Research Council of New Zealand (grant 10/400) and the Accident Compensation Corporation. HVOLS was funded by the Health Research Council of NZ Programme Grants (grants 02/152 and 08/070) and by grants from the Heart Foundation of NZ and the Christchurch Heart Institute Trust. Roche Diagnostics provided in-kind support for NT-proBNP and hs-cTnT assays and Abbott Laboratories for hs-cTnI assays.
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Enfermedades Cardiovasculares , Troponina T , Biomarcadores , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Humanos , Vida Independiente , Laboratorios , Péptido Natriurético Encefálico , Fragmentos de Péptidos , Medición de Riesgo/métodos , Factores de Riesgo , Troponina I , Vitamina DRESUMEN
One-quarter of patients with acute decompensated heart failure (ADHF) experience acute kidney injury (AKI)-an abrupt reduction or loss of kidney function associated with increased long-term mortality. There is a critical need to identify early and real-time markers of AKI in ADHF; however, to date, no protein biomarkers have exhibited sufficient diagnostic or prognostic performance for widespread clinical uptake. We aimed to identify novel protein biomarkers of AKI associated with ADHF by quantifying changes in protein abundance in the kidneys that occur during ADHF development and recovery in an ovine model. Relative quantitative protein profiling was performed using sequential window acquisition of all theoretical fragment ion spectra-mass spectrometry (SWATH-MS) in kidney cortices from control sheep (n = 5), sheep with established rapid-pacing-induced ADHF (n = 8), and sheep after ~4 weeks recovery from ADHF (n = 7). Of the 790 proteins quantified, we identified 17 candidate kidney injury markers in ADHF, 1 potential kidney marker of ADHF recovery, and 2 potential markers of long-term renal impairment (differential abundance between groups of 1.2-2.6-fold, adjusted p < 0.05). Among these 20 candidate protein markers of kidney injury were 6 candidates supported by existing evidence and 14 novel candidates not previously implicated in AKI. Proteins of differential abundance were enriched in pro-inflammatory signalling pathways: glycoprotein VI (activated during ADHF development; adjusted p < 0.01) and acute phase response (repressed during recovery from ADHF; adjusted p < 0.01). New biomarkers for the early detection of AKI in ADHF may help us to evaluate effective treatment strategies to prevent mortality and improve outcomes for patients.
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Lesión Renal Aguda/diagnóstico , Biomarcadores/metabolismo , Insuficiencia Cardíaca/metabolismo , Proteómica/métodos , Lesión Renal Aguda/sangre , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/orina , Animales , Biomarcadores/sangre , Biomarcadores/orina , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/sangre , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/orina , Humanos , Glicoproteínas de Membrana Plaquetaria/metabolismo , Glicoproteínas de Membrana Plaquetaria/orina , Pronóstico , OvinosRESUMEN
BACKGROUND: Long noncoding RNAs (lncRNAs) have been implicated in the pathogenesis of cardiovascular diseases. We aimed to identify novel lncRNAs associated with the early response to ischemia in the heart. METHODS AND RESULTS: RNA sequencing data gathered from 81 paired left ventricle samples from patients undergoing cardiopulmonary bypass was collected before and after a period of ischemia. Novel lncRNAs were validated with Oxford Nanopore Technologies long-read sequencing. Gene modules associated with an early ischemic response were identified and the subcellular location of selected lncRNAs was determined with RNAscope. A total of 2446 mRNAs, 270 annotated lncRNAs and one novel lncRNA differed in response to ischemia (adjusted p < 0.001, absolute fold change >1.2). The novel lncRNA belonged to a gene module of highly correlated genes that also included 39 annotated lncRNAs. This module associated with ischemia (Pearson correlation coefficient = -0.69, p = 1 × 10-23) and activation of cell death pathways (p < 6 × 10-9). A further nine novel cardiac lncRNAs were identified, of which, one overlapped five cis-eQTL eSNPs for the gene RWD Domain-Containing Sumoylation Enhancer (RWDD3) and was itself correlated with RWDD3 expression (Pearson correlation coefficient -0.2, p = 0.002). CONCLUSION: We have identified 10 novel lncRNAs, one of which was associated with myocardial ischemia and may have potential as a novel therapeutic target or early marker for myocardial dysfunction.
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Isquemia Miocárdica/genética , Isquemia Miocárdica/metabolismo , ARN Largo no Codificante/metabolismo , Bases de Datos Genéticas , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Ventrículos Cardíacos/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Miocardio/metabolismo , ARN Mensajero/metabolismo , Análisis de Secuencia de ARNRESUMEN
BACKGROUND: Development of a competent collateral circulation in established coronary artery disease is cardio-protective. The vascular endothelial growth factor (VEGF) system plays a key role in this process. We investigated the prognostic performance of circulating VEGF-A and three genetic variants in the VEGFA gene in a clinical coronary cohort. METHODS AND RESULTS: The Coronary Disease Cohort Study (CDCS) recruited 2,140 patients, with a diagnosis of acute coronary syndrome (ACS), after admission to Christchurch or Auckland City Hospitals between July 2002 and January 2009. We present data for 1927 patients from the cohort genotyped for three SNPs in the VEGF-A gene, rs699947 (C-2578A), rs2010963 (C405G) and rs3025039 (C936T). Plasma VEGF-A concentrations were assayed in a subgroup (n = 550) of CDCS patients (geometric mean 36.6 [34.7-38.5] pg/ml). VEGF-A levels correlated with patient heart rate at baseline (p = 0.034). None of rs699947, rs3025039, nor rs2010963 genotypes were significantly associated with VEGF-A levels, but rs3025039 genotype was positively associated with collateral vessels perfusion according to the Rentrop classification (p = 0.01) and baseline natriuretic peptide levels (p<0.05). Survival in the CDCS cohort was independently associated with baseline VEGF-A levels and (in males) with rs699947 genotype. CONCLUSIONS: This study is strongly suggestive that VEGF-A levels have value as a prognostic biomarker in coronary heart disease patients and SNPs in VEGF-A deserve further investigation as prognostic markers and indicators of angiogenic potential influencing the formation of collateral circulation.
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Síndrome Coronario Agudo , Factor A de Crecimiento Endotelial Vascular , Estudios de Cohortes , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido SimpleRESUMEN
Historically marginalized racial and ethnic groups and Indigenous peoples are burdened by significant health inequities that are compounded by their underrepresentation in genetic and genomic research. Of all genome-wide association study participants, ≈79% are of European descent, despite this group constituting only 16% of the global population. For underrepresented populations, polygenic risk scores derived from these studies are less accurate in predicting disease phenotypes, novel population-specific genetic variations may be misclassified as potentially pathogenic, and there is a lack of understanding of how different populations metabolize drugs. Although inclusion of marginalized racial and ethnic groups and Indigenous peoples in genetic and genomic research is crucial, scientific studies must be guided by ethical principles of respect, honesty, justice, reciprocity, and care for individuals and communities. Special considerations are needed to support research that benefits the scientific community as well as Indigenous peoples and marginalized groups. Before a project begins, collaboration with community leaders and agencies can lead to successful implementation of the study. Throughout the study, consideration must be given to issues such as implications of informed consent for individuals and communities, dissemination of findings through scientific and community avenues, and implications of community identity for data governance and sharing. Attention to these issues is critical, given historical harms in biomedical research that marginalized groups and Indigenous peoples have suffered. Conducting genetic and genomic research in partnership with Indigenous peoples and marginalized groups guided by ethical principles provides a pathway for scientific advances that will enhance prevention and treatment of cardiovascular disease for everyone.
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Enfermedades Cardiovasculares , Estudio de Asociación del Genoma Completo/ética , Genómica/ética , Inequidades en Salud , Pueblos Indígenas/genética , Consentimiento Informado , American Heart Association , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/etnología , Enfermedades Cardiovasculares/genética , Humanos , Pruebas de Farmacogenómica , Guías de Práctica Clínica como Asunto , Estados UnidosRESUMEN
AIMS: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1ß can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. METHODS AND RESULTS: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. CONCLUSION: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target.
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Enfermedades Cardiovasculares/mortalidad , Inflamasomas , Inflamación , Proteína con Dominio Pirina 3 de la Familia NLR , Humanos , Inflamasomas/genética , Inflamación/genética , Leucocitos Mononucleares , Proteína con Dominio Pirina 3 de la Familia NLR/genéticaRESUMEN
Circular RNAs (circRNAs) are an evolutionarily conserved form of noncoding RNA with covalently closed loop structures. Initial studies established a functional role for circRNAs as potent microRNA sponges and many other studies have focussed solely on this. However, the biological functions of most circRNAs are still undetermined and other functional roles are gaining traction. These include protein sponges and regulators, and coding for proteins with an alternative mechanism of translation, potentially opening up a whole new transcriptome. The first step to gaining insight into circRNA function is accurate identification and various software platforms have been developed. Specialized detection software has now evolved into whole bioinformatics pipelines that can be used for detection, de novo identification, functional prediction, and validation of circRNAs. However, few cardiovascular circRNA studies have utilized these tools. This review summarizes current knowledge of circRNA biogenesis, bioinformatic detection tools and the emerging role of circRNAs in cardiovascular disease.
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Enfermedades Cardiovasculares/genética , Biología Computacional/métodos , ARN Circular/genética , Regulación de la Expresión Génica , Humanos , MicroARNs/genética , Programas InformáticosRESUMEN
To identify circulating proteins predictive of acute cardiovascular disease events in the general population, we performed a proteomic screen in plasma from asymptomatic individuals. A "Discovery cohort" of 25 individuals who subsequently incurred a cardiovascular event within 3 years (median age = 70 years, 80% male) was matched to 25 controls remaining event-free for > 5 years (median age = 72 years, 80% male). Plasma proteins were assessed by data independent acquisition mass spectrometry (DIA-MS). Associations with cardiovascular events were tested using Cox regression, adjusted for the New Zealand Cardiovascular Risk Score. Concentrations of leading protein candidates were subsequently measured with ELISAs in a larger (n = 151) independent subset. In the Discovery cohort, 76 plasma proteins were robustly quantified by DIA-MS, with 8 independently associated with cardiovascular events. These included (HR = hazard ratio [95% confidence interval] above vs below median): fibrinogen alpha chain (HR = 1.84 [1.19-2.84]); alpha-2-HS-glycoprotein (also called fetuin A) (HR = 1.86 [1.19-2.93]); clusterin isoform 2 (HR = 1.59 [1.06-2.38]); fibrinogen beta chain (HR = 1.55 [1.04-2.30]); hemoglobin subunit beta (HR = 1.49 [1.04-2.15]); complement component C9 (HR = 1.62 [1.01-2.59]), fibronectin isoform 3 (HR = 0.60 [0.37-0.99]); and lipopolysaccharide-binding protein (HR = 1.58 [1.00-2.49]). The proteins for which DIA-MS and ELISA data were correlated, fibrinogen and hemoglobin, were analyzed in an Extended cohort, with broader inclusion criteria and longer time to events, in which these two proteins were not associated with incident cardiovascular events. We have identified eight candidate proteins that may independently predict cardiovascular events occurring within three years in asymptomatic, low-to-moderate risk individuals, although these appear not to predict events beyond three years.
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Enfermedades Cardiovasculares/sangre , Fibrinógeno/análisis , Hemoglobinas/análisis , Anciano , Enfermedades Cardiovasculares/diagnóstico , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Masculino , Espectrometría de Masas , Valor Predictivo de las Pruebas , Modelos de Riesgos ProporcionalesRESUMEN
Acute decompensated heart failure (ADHF) is associated with a high incidence of acute kidney injury (AKI), an abrupt loss of kidney function associated with a near doubling of mortality at 1 year. In addition to the direct threat acute HF itself poses to kidney function, the beneficial effects of commonly prescribed HF treatments must be weighed against their potentially adverse effects on glomerular perfusion. Consequently, there is an urgent need to identify early markers for AKI in ADHF to facilitate timely implementation of supportive measures to minimize kidney damage and improve outcomes. The recent recognition of the diagnostic potential of circulating microRNAs presents the potential to address this gap if microRNAs specific for AKI can be identified in serial plasma, serum and/or urine samples from well-phenotyped cohorts of ADHF patients, including a proportion with AKI. This review summarizes emerging circulating diagnostic and prognostic microRNA biomarkers (serum, plasma or urine) in HF and AKI.
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Lesión Renal Aguda , Insuficiencia Cardíaca , MicroARNs , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/epidemiología , Biomarcadores , Insuficiencia Cardíaca/diagnóstico , Humanos , IncidenciaRESUMEN
Hydrogen sulfide (H2S) is recognized as an endogenous gaseous signaling molecule generated by cystathionine γ-lyase (CSE) in cardiovascular tissues. H2S up-regulation has been shown to reduce ischemic injury, and H2S donors are cardioprotective in rodent models when administered concurrent with myocardial ischemia. We evaluated the potential utility of H2S therapy in ameliorating cardiac remodeling with administration delayed until 2 h post-infarction in mice with or without cystathionine γ-lyase gene deletion (CSE-/-). The slow-release H2S donor, GYY4137, was administered from 2 h after surgery and daily for 28 days following myocardial infarction (MI) induced by coronary artery ligation, comparing responses in CSE-/- with wild-type (WT) mice (n = 5-10/group/genotype). Measures of cardiac function and expression of key genes associated with cardiac hypertrophy, fibrosis, and apoptosis were documented in atria, ventricle, and kidney tissues. Post-MI GYY4137 administration reduced infarct area and restored cardiac function, accompanied by reduction of the elevated ventricular expression of genes mediating cardiac remodeling to near-normal levels. Few differences between WT and CSE-/- mice were observed, except CSE-/- mice had higher blood pressures, and higher atrial Mir21a expression across all treatment groups. These findings suggest endogenous CSE gene deletion does not substantially exacerbate the long-term response to MI. Moreover, the H2S donor GYY4137 administered after onset of MI preserves cardiac function and protects against adverse cardiac remodeling in both WT and CSE-deficient mice.
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Cistationina gamma-Liasa/genética , Sulfuro de Hidrógeno/metabolismo , Morfolinas/administración & dosificación , Infarto del Miocardio/tratamiento farmacológico , Compuestos Organotiofosforados/administración & dosificación , Animales , Modelos Animales de Enfermedad , Pruebas de Función Cardíaca/efectos de los fármacos , Masculino , Ratones , Ratones Noqueados , MicroARNs/genética , Morfolinas/farmacología , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/fisiopatología , Compuestos Organotiofosforados/farmacología , Recuperación de la Función , Regulación hacia ArribaRESUMEN
Natriuretic Peptides (NP) are important in maintaining normal cardiac and metabolic status and have been used to predict cardiovascular events. Whether plasma concentrations of NP products within the normal range reflect cardio-metabolic health is unknown. Plasma NTproANP, NTproBNP and NTproCNP and their bioactive counterparts were measured in a random sample of 348 community dwellers aged 49-51 yr without heart disease and associations sought with established vascular risk factors, echocardiographic indices and a genetic variant previously linked with BNP. Stratified by sex, each of ten vascular risk factors were positively associated with NTproCNP whereas associations with NTproBNP and NTproANP were all negative. In both sexes, higher plasma NTproCNP was associated with higher arterial elastance, lower LV stroke volume and lower LV end diastolic volume. Exactly opposite associations were found with plasma NTproBNP or NTproANP. Sex specific differences were identified: positive association of NTproBNP with LV end systolic volume and the negative association with LV elastance were found only in males. The genetic variant rs198358 was independently associated with NTproBNP but not with NTproANP. In conclusion, higher NTproCNP is likely to be an adaptive response to impaired LV relaxation whereas genetic factors likely contribute to higher NTproBNP and improved cardio-metabolic health at midlife.
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Factor Natriurético Atrial/sangre , Cardiopatías/sangre , Péptido Natriurético Encefálico/sangre , Péptido Natriurético Tipo-C/sangre , Fragmentos de Péptidos/sangre , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patología , Femenino , Cardiopatías/epidemiología , Cardiopatías/patología , Humanos , Masculino , Persona de Mediana Edad , Péptidos Natriuréticos/sangre , Factores de Riesgo , Caracteres SexualesRESUMEN
BACKGROUND: Clinicians need improved tools to better identify nonacute heart failure with preserved ejection fraction (HFpEF). OBJECTIVES: The purpose of this study was to derive and validate circulating microRNA signatures for nonacute heart failure (HF). METHODS: Discovery and validation cohorts (N = 1,710), comprised 903 HF and 807 non-HF patients from Singapore and New Zealand (NZ). MicroRNA biomarker panel discovery in a Singapore cohort (n = 546) was independently validated in a second Singapore cohort (Validation 1; n = 448) and a NZ cohort (Validation 2; n = 716). RESULTS: In discovery, an 8-microRNA panel identified HF with an area under the curve (AUC) 0.96, specificity 0.88, and accuracy 0.89. Corresponding metrics were 0.88, 0.66, and 0.77 in Validation 1, and 0.87, 0.58, and 0.74 in Validation 2. Combining microRNA panels with N-terminal pro-B-type natriuretic peptide (NT-proBNP) clearly improved specificity and accuracy from AUC 0.96, specificity 0.91, and accuracy 0.90 for NT-proBNP alone to corresponding metrics of 0.99, 0.99, and 0.93 in the discovery and 0.97, 0.96, and 0.93 in Validation 1. The 8-microRNA discovery panel distinguished HFpEF from HF with reduced ejection fraction with AUC 0.81, specificity 0.66, and accuracy 0.72. Corresponding metrics were 0.65, 0.41, and 0.56 in Validation 1 and 0.65, 0.41, and 0.62 in Validation 2. For phenotype categorization, combined markers achieved AUC 0.87, specificity 0.75, and accuracy 0.77 in the discovery with corresponding metrics of 0.74, 0.59, and 0.67 in Validation 1 and 0.72, 0.52, and 0.68 in Validation 2, as compared with NT-proBNP alone of AUC 0.71, specificity 0.46, and accuracy 0.62 in the discovery; with corresponding metrics of 0.72, 0.44, and 0.57 in Validation 1 and 0.69, 0.48, and 0.66 in Validation 2. Accordingly, false negative (FN) (81% Singapore and all NZ FN cases were HFpEF) as classified by a guideline-endorsed NT-proBNP ruleout threshold, were correctly reclassified by the 8-microRNA panel in the majority (72% and 88% of FN in Singapore and NZ, respectively) of cases. CONCLUSIONS: Multi-microRNA panels in combination with NT-proBNP are highly discriminatory and improved specificity and accuracy in identifying nonacute HF. These findings suggest potential utility in the identification of nonacute HF, where clinical assessment, imaging, and NT-proBNP may not be definitive, especially in HFpEF.