The life history of 21 breast cancers.

Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis.

Mutational processes molding the genomes of 21 breast cancers.

All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.

An analysis of long-term clinical outcome following the use of excimer laser coronary atherectomy in a large UK PCI center.

BACKGROUND: Excimer laser atherectomy (ELCA) is an established adjunctive technique to facilitate acute success in percutaneous coronary intervention (PCI). Despite this there are a lack of contemporary outcome data, particulary longer-term, forpatients treated with ELCA PCI. AIMS: To evaluate the contemporary use ofELCA in PCI, the frequency of periprocedural complications and the longer-term outcomes associated with ELCA PCI. METHODS: This was a retrospective study that included all patients undergoing PCI (with or without ELCA) between April 2005 and May 2021. Relevant features from all cases were downloaded from the patient record and matched to hospital data on mortality on November 22, 2022. Kaplan Meier curves were used to compare mortality between the ELCA PCI and non-ELCA PCI cohorts with a landmark at 1 year. Multivariable Cox regression was performed to assess whether ELCA PCI was independently associated with long-term mortality. RESULT: There were 21,256 patients in this analysis, of which 448 (2.1%) were treated with ELCA PCI. ELCA PCI was associated with a higher frequency of any periprocedural complication. Median follow-up was 2812 days (IQR, 1577-4245 days) with higher mortality in ELCA PCI (38.2% vs. 29.0%, p < 0.001). However, on multivariable analysis, ELCA PCI was not independently associated with long-term mortality. The TVR frequency in ELCA PCI was 16.7% but TVR was significantly higher for cases of in-stent restenosis (ISR) (29.5%). CONCLUSION: Despite ELCA PCI being used in higher risk populations with complex coronary artery disease there was no long-term increased mortality associated with the use of this device. ELCA PCI for ISR is highly effective and safe although TVR in this cohort remains high in long-term follow-up.

Novel application of intravascular lithotripsy in stent under-expansion: A single-center experience.

INTRODUCTION: Stent under-expansion due to calcification is associated with a less durable result. The development of intravascular lithotripsy (IVL) has provided clinicians with a readily available, simple-to-use treatment option for coronary calcification, but the use of IVL within a previously stented segment is currently off-license. There are, however, developing data suggesting that the use of IVL can be an effective treatment option for patients with calcific stent under-expansion. METHOD: This was a single-center study of all patients treated with IVL for calcific stent under-expansion between January 2019 and June 2021. The impact of IVL on quantitative coronary angiography (QCA) stenosis and on the minimal stent area (MSA) derived from intracoronary imaging were recorded. The presence of periprocedural complications and adverse cardiovascular events was obtained from the clinical record during the study timeframe. RESULTS: Thirty-nine patients underwent IVL for calcific stent under-expansion during the study time frame with one patient treated with more than one lesion in the same session. In all lesions, there was an improvement in the QCA stenosis with 37 (92.5%) having a residual stenosis of ≤30%. The mean QCA stenosis pre-IVL was 68 ± 21% and following IVL the mean QCA was 18 ± 9% (p < 0.001). In all lesions, there was an improvement in the MSA, with 26 (92.9%) achieving an MSA of more than 4.5 mm2 . The mean MSA pre-IVL was 3.88 ± 1.51 mm2 and following IVL the mean MSA was 7.41 ± 2.34 mm2 (p < 0.001). There were no major procedural complications. Over a mean follow-up of 506 ± 277 days, one patient died from ventricular arrhythmia but there were no other major adverse cardiovascular events. CONCLUSION: This single-center study demonstrates that IVL is a safe and effective treatment for calcific stent under-expansion with good medium-term results.

Distribution of High-Sensitivity Troponin Taken Without Conventional Clinical Indications in Critical Care Patients and Its Association With Mortality.

OBJECTIVES: To describe the distribution of high-sensitivity troponin in a consecutive cohort of patients in critical care units, regardless of clinical indication, and its association with clinical outcomes. DESIGN: Prospective observational study. SETTING: Single-center teaching hospital. PATIENTS: Consecutive patients admitted to two adult critical care units (general critical care unit and neuroscience critical care unit) over a 6-month period. INTERVENTIONS: All patients had high-sensitivity troponin tests performed at admission and tracked throughout their critical care stay, regardless of whether the supervising team felt there was a clinical indication. The results were not revealed to patients or clinicians unless clinically requested. MEASUREMENTS AND MAIN RESULTS: There were 1,033 patients in the study cohort (general critical care unit 750 and neuroscience critical care unit 283). The median high-sensitivity troponin was 21 ng/L (interquartile range, 7-86 ng/L), with 560 patients (54.2%) above the upper limit of normal as defined by the manufacturer. Admission high-sensitivity troponin concentrations above the upper limit of normal in general critical care unit and neuroscience critical care unit were associated with increasing age, comorbidity, markers of illness severity, and the need for organ support. On adjusted analysis, the high-sensitivity troponin concentration remained an independent predictor of critical care mortality in general critical care unit and neuroscience critical care unit. CONCLUSIONS: High-sensitivity troponin elevation, taken outside the context of conventional clinical indications, was common in the critically ill. Such elevations were associated with increasing age, comorbidity, illness severity, and the need for organ support. Admission high-sensitivity troponin concentration is an independent predictor of critical care mortality and as such may represent a novel prognostic biomarker at admission.

Cardiogenic shock due to acute severe ischemic mitral regurgitation.

The reduction in patients presenting with ST-elevation myocardial infarction (STEMI) during the COVID19 crisis could have resulted from fears about developing COVID-19 infection in hospital. Patients who delay presenting with STEMI are more likely to develop mechanical complications, including acute ischemic mitral regurgitation (MR). We present a 69-year-old women with an inferior STEMI and cardiogenic shock due to acute ischemic MR who delayed presenting to hospital due to the fear of COVID-19. Early identification of this mechanical complication using transthoracic echocardiography in the Emergency Department enabled the team to target her optimisation. Ultimately these patients require urgent surgery to repair the mitral valve and revascularize the myocardium but they are often too unwell to undergo surgery and even when it is feasible the outcomes are poor.

Twelve-month outcomes of patients unsuitable for prolonged DAPT presenting with an acute coronary syndrome and treated with polymer-free biolimus A9 drug-coated stents.

INTRODUCTION: Prolonged dual anti-platelet therapy (DAPT) is undesirable in certain patients. The biolimus-A9 drug-coated stent (BA9-DCS) has a rapid drug-elution profile allowing shortened DAPT. METHODS: The demographics, procedural data, and clinical outcomes for 505 patients presenting with an ACS to three UK centres and treated with a BA9-DCS stent (PCI-DCS) were collected, and compared to a consecutive ACS cohort of unselected patients treated in the same period with drug-eluting stents (PCI-DES). RESULTS: PCI-DCS patients were older, more often female with hypertension, chronic kidney disease, severe LV dysfunction, and peripheral vascular disease more frequent than the PCI-DES cohort. PCI-DCS patients had a much higher Mehran bleed risk score (21.5 ± 7.7 vs. 15.9 ± 7.7, P < 0.0001). Baseline disease burden was greater in the PCI-DCS cohort with more left main and three vessel disease. During PCI, more stents (1.91 ± 1.1 vs. 1.57 ± 0.94, P < 0.0001), total stent length (38.2 ± 20.8 vs. 31.4 ± 20.3, P < 0.0001) and longer stents (38.2 ± 20.8 vs. 31.4 ± 20.3 mm, P < 0.0001) were used in the PCI-DCS cohort with rotational atherectomy also used more frequently. Physician-recommended DAPT duration was 2.9 ± 3.9 months for PCI-DCS patients and 11.3 ± 2.4 months for PCI-DES patients (P < 0.0001). At 12-month follow-up, definite stent thrombosis (0.6% vs. 1.1%) and TLR (3.2% vs. 2.7%) rates were similar between the two groups. After adjustment for baseline differences, there were no statistically significant differences in death and combined MACE rates at 12 months. CONCLUSIONS: The outcomes of patients treated with polymer-free BA9 drug-coated stent who present with an ACS and who were deemed unsuitable for prolonged DAPT are encouraging. Further studies are warranted.

The landscape of cancer genes and mutational processes in breast cancer.

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.

Artificial Intelligence for the Interventional Cardiologist: Powering and Enabling OCT Image Interpretation.

Intravascular optical coherence tomography (IVOCT) is a form of intra-coronary imaging that uses near-infrared light to generate high-resolution, cross-sectional, and 3D volumetric images of the vessel. Given its high spatial resolution, IVOCT is well-placed to characterise coronary plaques and aid with decision-making during percutaneous coronary intervention. IVOCT requires significant interpretation skills, which themselves require extensive education and training for effective utilisation, and this would appear to be the biggest barrier to its widespread adoption. Various artificial intelligence-based tools have been utilised in the most contemporary clinical IVOCT systems to facilitate better human interaction, interpretation and decision-making. The purpose of this article is to review the existing and future technological developments in IVOCT and demonstrate how they could aid the operator.

Derivation and validation of a novel functional FFRCT score incorporating the burden of coronary stenosis severity and flow impairment to predict clinical events.

BACKGROUND: A score combining the burden of stenosis severity on coronary computed tomography angiography (CCTA) and flow impairment by fractional flow reserve derived from computed tomography (FFRCT) may be a better predictor of clinical events than either parameter alone. METHODS: The Functional FFRCT Score (FFS) combines CCTA and FFRCT parameters in an allocated point-based system. The feasibility of the FFS was assessed in cohort of 72 stable chest pain patients with matched CCTA and FFRCT datasets. Validation was performed using 2 cohorts: (a) 4468 patients from the ADVANCE Registry to define its association with revascularization and major adverse cardiovascular events (MACE); (b) 212 patients from the FORECAST trial to determine predictors of MACE. RESULTS: The median calculation time for the FFS was 10 (interquartile range 6-17) seconds, with strong intra-operator and inter-operator agreement (Cohen's Kappa 0.89 (±0.37, p â€‹< â€‹0.001) and 0.83 (±0.04, p â€‹< â€‹0.001, respectively). The FFS correlated strongly with both the CT-SYNTAX and the Functional CT-SYNTAX scores (rS â€‹= â€‹0.808 for both, p â€‹< â€‹0.001). In the ADVANCE cohort the FFS had good discriminatory abilities for revascularization with an area under the curve of 0.82, 95 â€‹% confidence interval (CI) 0.81-0.84, p â€‹< â€‹0.001. Patients in the highest FFS tertile had significantly higher rates of revascularization (61 â€‹% vs 5 â€‹%, p â€‹< â€‹0.001) and MACE (1.9 â€‹% vs 0.5 â€‹%, p â€‹= â€‹0.001) compared with the lowest FFS tertile. In the FORECAST cohort the FFS was an independent predictor of MACE at 9-month follow-up (hazard ratio 1.04, 95 â€‹% CI 1.01-1.08, p â€‹< â€‹0.01). CONCLUSION: The FFS is a quick-to-calculate and reproducible score, associated with revascularization and MACE in two distinct populations of stable symptomatic patients.

Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms.

In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.

Systematic coronary physiology improves level of agreement in diagnostic coronary angiography.

OBJECTIVE: The training of interventional cardiologists (ICs), non-interventional cardiologists (NICs) and cardiac surgeons (CSs) differs, and this may be reflected in their interpretation of invasive coronary angiography (ICA) and management plan. Availability of systematic coronary physiology might result in more homogeneous interpretation and management strategy compared with ICA alone. METHODS: 150 coronary angiograms from patients with stable chest pain were presented independently to three NICs, three ICs and three CSs. By consensus, each group graded (1) coronary disease severity and (2) management plan, using options: (a) optimal medical therapy alone, (b) percutaneous coronary intervention, (c) coronary artery bypass graft or (d) more investigation required. Each group was then provided with fractional flow reserve (FFR) from all major vessels and asked to repeat the analysis. RESULTS: There was only 'fair' level of agreement of management plan among ICs, NICs and CSs (kappa 0.351, 95% CI 0.295-0.408, p<0.001) based on ICA alone (complete agreement in 35% of cases), which almost doubled to 'good' level (kappa 0.635, 95% CI 0.572-0.697, p<0.001) when comprehensive FFR was available (complete agreement in 66% of cases). Overall, the consensus management plan changed in 36.7%, 52% and 37.3% of cases for ICs, NICs and CSs, respectively, when FFR data were available. CONCLUSIONS: Compared with ICA alone, the availability of systematic FFR of all major coronary arteries produced a significantly more concordant interpretation and more homogeneous management plan among IC, NIC and CS specialists. Comprehensive physiological assessment may be of value in routine care for Heart Team decision-making. TRIAL REGISTRATION NUMBER: NCT01070771.

Is high sensitivity troponin, taken regardless of a clinical indication, associated with 1 year mortality in critical care patients?

The aim of this study was to assess whether high sensitivity troponin (hs-cTnI) is associated with 1 year mortality in critical care (CC). One year mortality data were obtained from NHS Digital for a consecutive cohort of patients admitted to general CC unit (GCCU) and neuroscience CC unit (NCCU) who had hs-cTnI tests performed throughout their CC admission, regardless of whether the test was clinically indicated. Cox proportional hazards were used to estimate the risk of 1-year mortality. A landmark analysis was undertaken to assess whether any relationship at 1 year was driven by mortality within the first 30 days. A total of 1033 consecutive patients were included. At 1 year 254 (24.6%) patients had died. The admission log(10)hs-cTnI concentration in the entire cohort (HR 1.35 (95% CI 1.05-1.75) p = 0.009 with a bootstrap of 1000 samples) was independently associated with 1 year mortality. On landmark analysis the association with 1 year mortality was driven by 30 day mortality. These results indicate that admission hs-cTnI concentration is independently associated with 1 year mortality in CC and this relationship may be driven by differences in mortality at 30 days.

Association between troponin level and medium-term mortality in 20 000 hospital patients.

INTRODUCTION: Cardiac troponin (cTn) concentrations above the manufacturer recommended upper limit of normal (ULN) are frequently seen in hospital patients without a clinical presentation consistent with type 1 myocardial infarction, and the significance of this is uncertain. The aim of this study was to assess the relationship between medium-term mortality and cTn concentration in a large consecutive hospital population, regardless of whether there was a clinical indication for performing the test. METHOD: This prospective observational study included 20 000 consecutive in-hospital and outpatient patients who had a blood test for any reason at a large teaching hospital, and in whom a hs-cTnI assay was measured, regardless of the original clinical indication. Mortality was obtained via NHS Digital. RESULTS: A total of 20 000 patients were included in the analysis and 18 282 of these (91.4%) did not have a clinical indication for cardiac troponin I (cTnI) testing. Overall, 2825 (14.1%) patients died at a median of 809 days. The mortality was significantly higher if the cTnI concentration was above the ULN (45.3% vs 12.3% p<0.001 log rank). Multivariable Cox analysis demonstrated that the log10 cTnI concentration was independently associated with mortality (HR 1.76 (95% CI 1.65 to 1.88)). Landmark analysis, excluding deaths within 30 days, showed the relationship between cTnI concentration and mortality persisted. CONCLUSION: In a large, unselected hospital population, in 91.4% of whom there was no clinical indication for testing, cTnI concentration was independently associated with medium-term cardiovascular and non-cardiovascular mortality in the statistical model tested.

Atheroma or ischemia: which is more important for managing patients with stable chest pain?

In the evaluation and management of patients with stable chest pain/chronic coronary syndrome, cardiologists need to be able to weigh up the relative merits of managing these patients using either optimal therapy alone or optimal therapy plus revascularization. These decisions rely on an understanding of both the presence and the degree of coronary atheroma and myocardial ischemia, and the impact that these have on patients' symptoms and their prognosis. In this review the authors examine the relative impact of the anatomical and physiological assessment of patients with chronic coronary syndrome and how it can be used to achieve optimal and tailored therapy.

There are a large number of patients with stable chest pain in the community who are not having a heart attack. This review looks at the relative merits of different investigation strategies that assess whether a patient has either coronary artery disease or a blood supply problem related to coronary disease.

Incidence and 1-year outcome of periprocedural myocardial infarction following cardiac surgery: are the Universal Definition and Society for Cardiovascular Angiography and Intervention criteria fit for purpose?

OBJECTIVES: The diagnosis and clinical implications of periprocedural myocardial infarction (PPMI) following coronary artery bypass grafting (CABG) are contentious, especially the importance of PPMI in the interpretation of trial data. METHODS: Consecutive patients admitted to a cardiothoracic critical care unit over a 6-month period following open cardiac surgery had high-sensitivity cardiac troponin I assay performed on admission and every day for 48 h, regardless of whether there was a request by the supervising clinical team. Patients were categorized as PPMI using both the Universal Definition of Myocardial Infarction (UDMI) and Society of Cardiovascular Angiography and Interventions (SCAI) criteria. Multivariable Cox regression analysis was performed to assess whether any relationships between PPMI diagnoses and 1-year mortality were independent. RESULTS: There were 2 groups of consecutive patients: (i) after CABG (n = 245) and (ii) after non-CABG surgery (n = 243). Of the CABG patients, 20.4% met criteria for UDMI PPMI and 87.6% for SCAI PPMI. The diagnosis of UDMI PPMI was independently associated with 1-year mortality on multivariable Cox regression analysis [hazard ratio 4.16 (95% confidence interval 1.28-13.49)]. Of 243 patients who had non-CABG cardiac surgery, 11.4% met criteria for UDMI PPMI and 85.2% for SCAI PPMI but neither were associated with 1-year mortality. CONCLUSIONS: The incidence of SCAI PPMI in a real-world cohort of cardiac surgery patients is so high as to be of limited clinical value. In contrast, a diagnosis of UDMI PPMI post-CABG is independently associated with 1-year mortality, so may have clinical (and research) utility.

Analysis of conflicts of interest among authors and researchers of European clinical guidelines in cardiovascular medicine.

OBJECTIVES: We aimed to assess the frequency and nature of financial conflicts of interest among both the guideline committee authors and the authors of research studies used to support the European Society of Cardiology (ESC) guidelines. DESIGN: We evaluated the competing interests of the doctors that write five of the key ESC clinical practice guidelines (CPG): valvular heart disease (VHD), atrial fibrillation (AF), pericardial diseases (PD), heart failure (HF) and myocardial revascularisation (IHD). In addition, we examined the funding sources of studies cited in the recommendations that were related to pharmaceutical agents. If a study was sponsored by industry, the disclosures of all authors were reviewed to assess whether there was a financial conflict of interest with the study funder. RESULTS: In total, there were 603 recommendations (PD 112, VHD 111, HF 169, IHD 97 and AF 114) across the five guidelines, of which, 271 (45% (PD 26, VHD 23, HF 72, IHD 84 and AF 66)) related to pharmaceutical agents. At least 80% of guideline committee authors, except for the PD guidelines, had a relevant financial conflict of interest, with the most frequent being a direct personal payment (68-82%). Industry support for studies varied across the guidelines from 5% (PD) to 65% (IHD). If a study was funded by industry, authors were frequently (55-90%) conflicted with the industry sponsor. CONCLUSIONS: The majority of the doctors that write clinical guidelines have a relevant financial conflict of interest. In addition, industry sponsorship of studies is frequent, and authors are often conflicted with the study funder. We propose that physicians that write clinical guidelines should be free of such financial conflicts of interest to maintain scientific integrity and independence in the clinical guidelines.

Fractional flow reserve derived from coronary computed tomography: where are we now and where are we heading?

Computed tomography coronary angiography is emerging as the preferred diagnostic tool for patients with chest pain. Additional knowledge of the extent and distribution of myocardial ischemia enables tailored patient management. Computed tomography-derived fractional flow reserve (FFRCT) employs computed tomography coronary angiography raw data processed via complex computational fluid dynamics and produces a surrogate of the invasive fractional flow reserve (FFR) thus delivering anatomical and physiological assessment in a single test. FFRCT has been extensively validated against invasive FFR and observational clinical studies have consistently demonstrated its utility as gatekeeper to invasive angiography while also reducing downstream clinical events and costs. Novel workstation-based models of estimating FFR are now being tested. Ongoing and future research results will define their role in clinical practice.

Relation of High-Sensitivity Troponin to 1 Year Mortality in 20,000 Consecutive Hospital Patients Undergoing a Blood Test for Any Reason.

This was an observational study of the 1-year outcomes of the 20,000 patients included in the original CHARIOT study. The aim of the study was to assess the association between high sensitivity troponin I (hs-cTnI) concentration and 1 year mortality in this cohort. The original CHARIOT study included a consecutive cohort of in- and out-patients undergoing blood tests for any reason. Hs-cTnI concentrations were measured regardless of whether the clinician requested them. These results were nested and not revealed to the team unless requested for clinical reasons. One year mortality data was obtained from NHS Digital as originally planned. Overall, 1782 (8.9%) patients had died at 1 year. Multivariable Cox regression analysis showed that a hs-cTnI concentration above the upper limit of normal was independently associated with the hazard of mortality (HR 2.23; 95% confidence intervals 1.97 to 2.52). Furthermore, the log (10) hs-cTnI concentration was independently associated with the hazard of 1 year mortality (HR 1.77; 95% confidence intervals 1.64 to 1.91). In conclusion, in a large, unselected hospital population of both in- and out-patients, in 18,282 (91.4%) of whom there was no clinical indication for testing, hs-cTnI concentration was associated with 1 year mortality.

Is the true clinical value of high-sensitivity troponins as a biomarker of risk? The concept that detection of high-sensitivity troponin 'never means nothing'.

INTRODUCTION: High-sensitivity troponin (hs-cTn) assays are central to the diagnosis of myocardial infarction (MI). Their increased sensitivity has facilitated rapid pathways for the exclusion of MI. However, hs-cTn is now more readily detectable in patients without symptoms typical of MI, in whom a degree of myocardial injury is assumed. Recently, the practice of using the 99th centile of hs-cTn as a working 'upper reference limit' has been challenged. There is increasing evidence that hs-cTn may provide useful prognostic information, regardless of any suspicion of MI, and as such these assays may have potential as a general biomarker for mortality. This raises the concept that detection of hs-cTn 'never means nothing.' AREAS COVERED: In this review, we will evaluate the evidence for the use of hs-cTn assays outside their common clinical indication to rule out or diagnose acute MI. EXPERT OPINION: The data presented suggest that hs-cTn testing may in the future have a generalized role as a biomarker of mortality risk and may be used less as a test for ruling in acute MI, but will remain a frontline test to exclude that diagnosis in ED. Further, the data suggest that the detection of hs-cTn 'never means nothing.'