C-Reactive Protein Gene Variants Are Associated with Postoperative C-reactive Protein Levels After Coronary Artery Bypass Surgery

Background: Elevated baseline C-reactive protein (CRP) levels are associated with increased risk for developing cardiovascular disease. Several CRP gene variants have been associated with altered baseline CRP levels in ambulatory populations. However, the influence of CRP gene variants on CRP levels during inflammatory states, such as surgery, is largely unexplored. We describe the association between candidate CRP gene variants and postoperative plasma CRP levels in patients undergoing primary, elective coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB). Methods: Using a multicenter candidate gene association study design, we examined the association between seventeen candidate CRP single nucleotide polymorphisms (SNPs) and inferred haplotypes, and altered postoperative CRP levels in 604 patients undergoing CABG surgery with CPB. Perioperative CRP levels were measured immediately prior to surgery, post-CPB and on postoperative days (POD) 1–4. Results: CRP levels were significantly elevated at all postoperative time points when compared with preoperative levels (P < 0.0001). After adjusting for clinical covariates, the minor allele of the synonymous coding SNP, rs1800947 was associated with lower peak postoperative CRP levels ($P = 2.4 × 10^{-4}$) and lower CRP levels across all postoperative time points ($P = 4.8 × 10^{-5}$). rs1800947 remained highly significant after Bonferroni adjustment for multiple comparisons. Conclusion: We identified a CRP gene SNP associated with lower postoperative CRP levels in patients undergoing CABG surgery with CPB. Further investigation is needed to clarify the significance of this association between CRP gene variants and the acute-phase rise in postoperative CRP levels with regard to the risk of adverse postoperative outcomes

The Long Noncoding RNA Landscape of the Ischemic Human Left Ventricle

Background—The discovery of functional classes of long noncoding RNAs (lncRNAs) has expanded our understanding of the variety of RNA species that exist in cells. In the heart, lncRNAs have been implicated in the regulation of development, ischemic and dilated cardiomyopathy, and myocardial infarction. Nevertheless, there is a limited description of expression profiles for these transcripts in human subjects. Methods and Results—We obtained left ventricular tissue from human patients undergoing cardiac surgery and used RNA sequencing to describe a lncRNA profile. We then identified a list of lncRNAs that were differentially expressed between pairs of samples before and after the ischemic insult of cardiopulmonary bypass. The expression of some of these lncRNAs correlates with ischemic time. Coding genes in close proximity to differentially expressed lncRNAs as well as coding genes that have coordinated expression with these lncRNAs are enriched in functional categories related to myocardial infarction including: heart function, metabolism, the stress response, and the immune system. Conclusions—We describe a list of lncRNAs that are differentially expressed after ischemia in the human heart. These genes are predicted to function in pathways consistent with myocardial injury. As a result, lncRNAs may serve as novel diagnostic and therapeutic targets for ischemic heart disease

Association of Factor V Leiden with Subsequent Atherothrombotic Events:A GENIUS-CHD Study of Individual Participant Data

BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population

Subsequent Event Risk in Individuals with Established Coronary Heart Disease:Design and Rationale of the GENIUS-CHD Consortium

BACKGROUND: The "GENetIcs of sUbSequent Coronary Heart Disease" (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators

Genome-wide analysis yields new loci associating with aortic valve stenosis

Aortic valve stenosis (AS) is the most common valvular heart disease, and valve replacement is the only definitive treatment. Here we report a large genome-wide association (GWA) study of 2,457 Icelandic AS cases and 349,342 controls with a follow-up in up to 4,850 cases and 451,731 controls of European ancestry. We identify two new AS loci, on chromosome 1p21 near PALMD (rs7543130; odds ratio (OR) = 1.20, P = 1.2 × 10−22) and on chromosome 2q22 in TEX41 (rs1830321; OR = 1.15, P = 1.8 × 10−13). Rs7543130 also associates with bicuspid aortic valve (BAV) (OR = 1.28, P = 6.6 × 10−10) and aortic root diameter (P = 1.30 × 10−8), and rs1830321 associates with BAV (OR = 1.12, P = 5.3 × 10−3) and coronary artery disease (OR = 1.05, P = 9.3 × 10−5). The results implicate both cardiac developmental abnormalities and atherosclerosis-like processes in the pathogenesis of AS. We show that several pathways are shared by CAD and AS. Causal analysis suggests that the shared risk factors of Lp(a) and non-high-density lipoprotein cholesterol contribute substantially to the frequent co-occurence of these diseases

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec

The value of symptoms and signs in the emergent diagnosis of acute coronary syndromes

Patient history and physical examination are widely accepted as cornerstones of diagnosis in modern medicine. We aimed to assess the value of individual historical and examination findings for diagnosing acute myocardial infarction (AMI) and predicting adverse cardiac events in undifferentiated Emergency Department (ED) patients with chest pain. We prospectively recruited patients presenting to the ED with suspected cardiac chest pain. Clinical features were recorded using a custom-designed report form. All patients were followed up for the diagnosis of AMI and the occurrence of adverse events (death, AMI or urgent revascularization) within 6 months.AMI was diagnosed in 148 (18.6%) of the 796 patients recruited. Following adjustment for age, sex and ECG changes, the following characteristics made AMI more likely (adjusted odds ratio, 95% confidence intervals): pain radiating to the right arm (2.23, 1.24–4.00), both arms (2.69, 1.36–5.36), vomiting (3.50, 1.81–6.77), central chest pain (3.29, 1.94–5.61) and sweating observed (5.18, 3.02–8.86). Pain in the left anterior chest made AMI significantly less likely (0.25, 0.14–0.46). The presence of rest pain (0.67, 0.41–1.10) or pain radiating to the left arm (1.36, 0.89–2.09) did not significantly alter the probability of AMI.Our results challenge many widely held assertions about the value of individual symptoms and signs in ED patients with suspected acute coronary syndromes. Several ‘atypical’ symptoms actually render AMI more likely, whereas many ‘typical’ symptoms that are often considered to identify high-risk populations have no diagnostic value

The value of symptoms and signs in the emergent diagnosis of acute coronary syndromes

Patient history and physical examination are widely accepted as cornerstones of diagnosis in modern medicine. We aimed to assess the value of individual historical and examination findings for diagnosing acute myocardial infarction (AMI) and predicting adverse cardiac events in undifferentiated Emergency Department (ED) patients with chest pain. We prospectively recruited patients presenting to the ED with suspected cardiac chest pain. Clinical features were recorded using a custom-designed report form. All patients were followed up for the diagnosis of AMI and the occurrence of adverse events (death, AMI or urgent revascularization) within 6 months.AMI was diagnosed in 148 (18.6%) of the 796 patients recruited. Following adjustment for age, sex and ECG changes, the following characteristics made AMI more likely (adjusted odds ratio, 95% confidence intervals): pain radiating to the right arm (2.23, 1.24–4.00), both arms (2.69, 1.36–5.36), vomiting (3.50, 1.81–6.77), central chest pain (3.29, 1.94–5.61) and sweating observed (5.18, 3.02–8.86). Pain in the left anterior chest made AMI significantly less likely (0.25, 0.14–0.46). The presence of rest pain (0.67, 0.41–1.10) or pain radiating to the left arm (1.36, 0.89–2.09) did not significantly alter the probability of AMI.Our results challenge many widely held assertions about the value of individual symptoms and signs in ED patients with suspected acute coronary syndromes. Several ‘atypical’ symptoms actually render AMI more likely, whereas many ‘typical’ symptoms that are often considered to identify high-risk populations have no diagnostic value

Quantification of calcified particles in human valve tissue reveals asymmetry of calcific aortic valve disease development

Recent studies indicated that small calcified particles observable by scanning electron microcopy (SEM) may initiate calcification in cardiovascular tissues. We hypothesized that if the calcified particles precede gross calcification observed in calcific aortic valve disease (CAVD), they would exhibit a regional asymmetric distribution associated with CAVD development, which always initiates at the base of aortic valve leaflets adjacent to the aortic outflow in a region known as the fibrosa. Testing this hypothesis required counting the calcified particles in histological sections of aortic valve leaflets. SEM images, however, do not provide high contrast between components within images, making the identification and quantification of particles buried within tissue extracellular matrix difficult. We designed a new unique pattern matching-based technique to allow for flexibility in recognizing particles by creating a gap zone in the detection criteria that decreased the influence of non-particle image clutter in determining whether a particle was identified. We developed this flexible pattern particle labeling (FpPL) technique using synthetic test images and human carotid artery tissue sections. A conventional image particle counting method (pre-installed in ImageJ) did not properly recognize small calcified particles located in noisy images that include complex extracellular matrix structures, and other commonly used pattern matching methods failed to detect the wide variation in size, shape and brightness exhibited by the particles. Comparative experiments with the ImageJ particle counting method demonstrated that our method detected significantly more p<2*10-7 particles than the conventional method with significantly fewer p<0.0003 false positives and false negatives p<0.0003. We then applied the FpPL technique to CAVD leaflets and showed a significant increase in detected particles in the fibrosa at the base of the leaflets (p<0.0001), supporting our hypothesis. The outcomes of this study are two-fold: 1) development of a new image analysis technique that can be adapted to a wide range of applications; 2) acquisition of new insight on potential early mediators of calcification in CAVD

Rapid Exclusion of Acute Myocardial Infarction in Patients With Undetectable Troponin Using a High-Sensitivity Assay

ObjectivesThis paper sought to evaluate whether high sensitivity troponin (hs-cTnT) can immediately exclude acute myocardial infarction (AMI) at a novel ‘rule out' cut-off.BackgroundSubgroup analysis of recent evidence suggests that undetectable hs-cTnT may exclude AMI at presentation.MethodsIn a cohort study, we prospectively enrolled patients with chest pain, evaluating them with standard troponin T and testing for hs-cTnT (Roche Diagnostics, Basel, Switzerland) at presentation. The primary outcome was a diagnosis of AMI. We also followed up patients for adverse events within 6 months. After subsequent clinical implementation of hs-cTnT, we again evaluated whether initially undetectable hs-cTnT ruled out a subsequent rise.ResultsOf 703 patients in the cohort study, 130 (18.5%) had AMI, none of whom initially had undetectable hs-cTnT (sensitivity: 100.0%, 95% confidence interval [CI]: 95.1% to 100.0%, negative predictive value: 100.0%, 95% CI: 98.1% to 100.0%). This strategy would rule out AMI in 27.7% of patients, 2 (1.0%) of whom died or had AMI within 6 months (1 periprocedural AMI, 1 noncardiac death). We evaluated this approach in an additional 915 patients in clinical practice. Only 1 patient (0.6%) with initially undetectable hs-cTnT had subsequent elevation (to 17 ng/l), giving a sensitivity of 99.8% (95% CI: 99.1% to 100.0%) and a negative predictive value of 99.4% (95% CI: 96.6% to 100.0%).ConclusionsUndetectable hs-cTnT at presentation has very high negative predictive value, which may be considered to rule out AMI, identifying patients at low risk of adverse events. Pending further validation, this strategy may reduce the need for serial testing and empirical treatment, enabling earlier reassurance for patients and fewer unnecessary evaluations and hospital admissions