Long-term prognosis of low high-sensitivity cardiac troponin T in the emergency department compared with the general population.

BACKGROUND: Long-term prognosis associated with low-high-sensitivity cardiac troponin T (hs-cTnT) concentrations in patients with chest pain is unknown. We investigated these prognostic implications compared with the general population. METHODS: All first visits to seven emergency departments (ED)s in Sweden were included from 9 December 2010 to 31 August, 2017 by patients presenting with chest pain and at least one hs-cTnT measured. Patients with myocardial injury (any hs-cTnT >14 ng/L), including patients with myocardial infarction (MI) were excluded. Standardised mortality ratios (SMRs) and standardised incidence ratios (SIRs) were calculated as the ratio of the number of observed to expected events. The expected number was computed by multiplying the 1-year calendar period-specific, age-specific and sex-specific follow-up time in the cohort with the corresponding incidence in the general population. HRs were calculated for all-cause mortality and major adverse cardiovascular events (MACE), defined as acute MI, heart failure hospitalisation, cerebrovascular stroke or cardiovascular death, between patients with undetectable (<5 ng/L) and low (5-14 ng/L) hs-cTnT. RESULTS: A total of 1 11 916 patients were included, of whom 69 090 (62%) and 42 826 (38%) had peak hs-cTnT concentrations of <5 and 5-14 ng/L. Patients with undetectable peak hs-cTnT had a lower mortality risk compared with the general Swedish population (SMR 0.83, 95% CI 0.79 to 0.87), with lower risks observed in all patients ≥65 years of age, but a slightly higher risk of being diagnosed with a future MI (SIR 1.39, 95% CI 1.32 to 1.47). The adjusted risk of a first MACE associated with low versus undetectable peak hs-cTnT was 1.6-fold (HR 1.61, 95% CI 1.53 to 1.70). CONCLUSION: Patients with chest pain and undetectable hs-cTnT have an overall lower risk of death compared with the general population, with risks being highly age dependent. Detectable hs-cTnT concentrations are still associated with increased long-term cardiovascular risks.

Application of the Universal Definition of Myocardial Infarction in Clinical Practice in Scotland and Sweden.

Importance: Whether the diagnostic classifications proposed by the universal definition of myocardial infarction (MI) to identify type 1 MI due to atherothrombosis and type 2 MI due to myocardial oxygen supply-demand imbalance have been applied consistently in clinical practice is unknown. Objective: To evaluate the application of the universal definition of MI in consecutive patients with possible MI across 2 health care systems. Design, Setting, and Participants: This cohort study used data from 2 prospective cohorts enrolling consecutive patients with possible MI in Scotland (2013-2016) and Sweden (2011-2014) to assess accuracy of clinical diagnosis of MI recorded in hospital records for patients with an adjudicated diagnosis of type 1 or type 2 MI. Data were analyzed from August 2022 to February 2023. Main Outcomes and Measures: The main outcome was the proportion of patients with a clinical diagnosis of MI recorded in the hospital records who had type 1 or type 2 MI, adjudicated by an independent panel according to the universal definition. Characteristics and risk of subsequent MI or cardiovascular death at 1 year were compared. Results: A total of 50 356 patients were assessed. The cohort from Scotland included 28 783 (15 562 men [54%]; mean [SD] age, 60 [17] years), and the cohort from Sweden included 21 573 (11 110 men [51%]; mean [SD] age, 56 [17] years) patients. In Scotland, a clinical diagnosis of MI was recorded in 2506 of 3187 patients with an adjudicated diagnosis of type 1 MI (79%) and 122 of 716 patients with an adjudicated diagnosis of type 2 MI (17%). Similar findings were observed in Sweden, with 970 of 1111 patients with adjudicated diagnosis of type 1 MI (87%) and 57 of 251 patients with adjudicated diagnosis of type 2 MI (23%) receiving a clinical diagnosis of MI. Patients with an adjudicated diagnosis of type 1 MI without a clinical diagnosis were more likely to be women (eg, 336 women [49%] vs 909 women [36%] in Scotland; P < .001) and older (mean [SD] age, 71 [14] v 67 [14] years in Scotland, P < .001) and, when adjusting for competing risk from noncardiovascular death, were at similar or increased risk of subsequent MI or cardiovascular death compared with patients with a clinical diagnosis of MI (eg, 29% vs 18% in Scotland; P < .001). Conclusions and Relevance: In this cohort study, the universal definition of MI was not consistently applied in clinical practice, with a minority of patients with type 2 MI identified, and type 1 MI underrecognized in women and older persons, suggesting uncertainty remains regarding the diagnostic criteria or value of the classification.

Improving Risk Stratification for Patients With Type 2 Myocardial Infarction.

BACKGROUND: Despite poor cardiovascular outcomes, there are no dedicated, validated risk stratification tools to guide investigation or treatment in type 2 myocardial infarction. OBJECTIVES: The goal of this study was to derive and validate a risk stratification tool for the prediction of death or future myocardial infarction in patients with type 2 myocardial infarction. METHODS: The T2-risk score was developed in a prospective multicenter cohort of consecutive patients with type 2 myocardial infarction. Cox proportional hazards models were constructed for the primary outcome of myocardial infarction or death at 1 year using variables selected a priori based on clinical importance. Discrimination was assessed by area under the receiving-operating characteristic curve (AUC). Calibration was investigated graphically. The tool was validated in a single-center cohort of consecutive patients and in a multicenter cohort study from sites across Europe. RESULTS: There were 1,121, 250, and 253 patients in the derivation, single-center, and multicenter validation cohorts, with the primary outcome occurring in 27% (297 of 1,121), 26% (66 of 250), and 14% (35 of 253) of patients, respectively. The T2-risk score incorporating age, ischemic heart disease, heart failure, diabetes mellitus, myocardial ischemia on electrocardiogram, heart rate, anemia, estimated glomerular filtration rate, and maximal cardiac troponin concentration had good discrimination (AUC: 0.76; 95% CI: 0.73-0.79) for the primary outcome and was well calibrated. Discrimination was similar in the consecutive patient (AUC: 0.83; 95% CI: 0.77-0.88) and multicenter (AUC: 0.74; 95% CI: 0.64-0.83) cohorts. T2-risk provided improved discrimination over the Global Registry of Acute Coronary Events 2.0 risk score in all cohorts. CONCLUSIONS: The T2-risk score performed well in different health care settings and could help clinicians to prognosticate, as well as target investigation and preventative therapies more effectively. (High-Sensitivity Troponin in the Evaluation of Patients With Suspected Acute Coronary Syndrome [High-STEACS]; NCT01852123).

Statin Therapy and Intensity: Prognosis in Patients with Myocardial Injury.

BACKGROUND: No guideline-directed pharmacological therapy has been established for patients with myocardial injury without type 1 myocardial infarction. We investigated the impact of statin treatment in patients with myocardial injury. METHODS: Patients with myocardial injury (nonischemic acute and chronic myocardial injury), type 2 myocardial infarction, and type 1 myocardial infarction with at least 1 emergency department visit for chest pain from 2011 to 2014 were included. Dispensed prescriptions of all types of statins with dosage within 180 days from the index visit were collected. In total, 2054 patients were divided into 3 groups: 1) acute myocardial injury (type 2 myocardial infarction, acute nonischemic myocardial injury), 2) chronic myocardial injury, and 3) type 1 myocardial infarction. We estimated the adjusted hazard ratio with 95% confidence interval for death with low- (reference), moderate-, and high-intensity statin therapy. RESULTS: The mean follow-up was 4.2 ± 1.8 years. Only 13% of patients with acute and chronic myocardial injury and 30% with type 1 myocardial infarction were treated with high-intensity statins. Adjusted mortality rates were higher in patients with acute and chronic myocardial injury than in those with type 1 myocardial infarction across all statin intensity categories. In patients with type 1 myocardial infarction, the adjusted mortality risk was 20% (hazard ratio, 0.80; 95% confidence interval, 0.36-1.77) lower in patients with high-intensity therapy. Point estimates in the adjusted models indicated similar associations between statin intensity and mortality risk in patients with acute and chronic myocardial injury. CONCLUSION: Patients with myocardial injury may benefit from high-intensity statin treatment, but the associations were not statistically significant when adjusting for confounders.

Treatment With Cardiovascular Medications: Prognosis in Patients With Myocardial Injury.

Background There is no clinical guidance on treatment in patients with non-ischemic myocardial injury and type 2 myocardial infarction (T2MI). Methods and Results In a cohort of 22 589 patients in the emergency department at Karolinska University Hospital in Sweden during 2011 to 2014 we identified 3853 patients who were categorized into either type 1 myocardial infarction, T2MI, non-ischemic acute and chronic myocardial injury. Data from all dispensed prescriptions within 180 days of the visit to the emergency department were obtained concerning ß-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, statins, and platelet inhibitors. We estimated adjusted hazard ratios (HR) with 95% CI for all-cause mortality in relationship to the number of medications (categorized into 0-1 [referent], 2-3 and 4 medications) in the groups of myocardial injury. In patients with T2MI, treatment with 2 to 3 and 4 medications was associated with a 50% and 56% lower mortality, respectively (adjusted HR [95% CI], 0.50 [0.25-1.01], and 0.43 [0.19-0.96]), while corresponding associations in patients with acute myocardial injury were 24% and 29%, respectively (adjusted HR [95% CI], 0.76 [0.59-0.99] and 0.71 [0.5-1.02]), and in patients with chronic myocardial injury 27% and 37%, respectively (adjusted HR [95% CI], 0.73 [0.58-0.92] and 0.63 [0.46-0.87]). Conclusions Patients with T2MI and non-ischemic acute or chronic myocardial injury are infrequently prescribed common cardiovascular medications compared with patients with type 1 myocardial infarction. However, treatment with guideline recommended drugs in patients with T2MI and acute or chronic myocardial injury is associated with a lower risk of death after adjustment for confounders.

Performance of the GRACE 2.0 score in patients with type 1 and type 2 myocardial infarction.

AIMS: The Global Registry of Acute Coronary Events (GRACE) score was developed to evaluate risk in patients with myocardial infarction. However, its performance in type 2 myocardial infarction is uncertain. METHODS AND RESULTS: In two cohorts of consecutive patients with suspected acute coronary syndrome from 10 hospitals in Scotland (n = 48 282) and a tertiary care hospital in Sweden (n = 22 589), we calculated the GRACE 2.0 score to estimate death at 1 year. Discrimination was evaluated by the area under the receiver operating curve (AUC), and compared for those with an adjudicated diagnosis of type 1 and type 2 myocardial infarction using DeLong's test. Type 1 myocardial infarction was diagnosed in 4981 (10%) and 1080 (5%) patients in Scotland and Sweden, respectively. At 1 year, 720 (15%) and 112 (10%) patients died with an AUC for the GRACE 2.0 score of 0.83 [95% confidence interval (CI) 0.82-0.85] and 0.85 (95% CI 0.81-0.89). Type 2 myocardial infarction occurred in 1121 (2%) and 247 (1%) patients in Scotland and Sweden, respectively, with 258 (23%) and 57 (23%) deaths at 1 year. The AUC was 0.73 (95% CI 0.70-0.77) and 0.73 (95% CI 0.66-0.81) in type 2 myocardial infarction, which was lower than for type 1 myocardial infarction in both cohorts (P < 0.001 and P = 0.008, respectively). CONCLUSION: The GRACE 2.0 score provided good discrimination for all-cause death at 1 year in patients with type 1 myocardial infarction, and moderate discrimination for those with type 2 myocardial infarction. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01852123.

Causes of death in relation to stable troponin levels including chronic myocardial injury.

BACKGROUND: Many patients presenting with chest pain in the emergency department have stable concentrations of high-sensitivity cardiac troponin T (hs-cTnT) without any acute medical condition. Stable hs-cTnT levels are associated with a high risk of death. This study aimed to investigate causes of death in relation to hs-cTnT concentrations. METHODS: In a cohort of 19,460 patients with chest pain and stable hs-cTnT levels measured 2011-2014, of whom 1528 (7.9%) had chronic myocardial injury, we included all patients who died during follow-up (4.0 ± 1.3 years). Rates of cause-specific death were calculated for hs-cTnT concentrations and adjusted odds ratios (OR) estimated for causes of death at hs-cTnT 5-14 ng/l and >14 ng/l (referent hs-cTnT < 5 ng/l). RESULTS: The study cohort comprised 1577 patients (8.1%), of whom 684 (43%) had chronic myocardial injury (hs-cTnT > 14 ng/l). Annual cardiovascular and non-cardiovascular death rates increased with increasing hs-cTnT from 0.07% and 0.4% (<5 ng/l) to 17% and 15% (≥50 ng/l), respectively. The ratio of cardiovascular to non-cardiovascular death increased with higher hs-cTnT. Patients with hs-cTnT 5-14 ng/l were 87% more likely to die from cardiovascular causes than those with hs-cTnT < 5 ng/l (adjusted OR: 1.87, 95% CI: 1.24-2.80). The association was similar for patients with chronic myocardial injury. CONCLUSIONS: Hs-cTnT concentrations of 5-14 ng/l and >14 ng/l are associated with an almost twofold risk of cardiovascular death, whereas cardiovascular death almost never occurs in patients with undetectable troponin. Only with hs-cTnT concentrations ≥ 50 ng/l were cardiovascular diseases the predominant cause of death.

Causes of Death in Patients With Acute and Chronic Myocardial Injury.

BACKGROUND: Information about causes of death in patients with myocardial injury is limited. The purpose of this study was to explore causes of death in patients with myocardial injury. METHODS: In a cohort of 22,589 patients, 3853 patients with myocardial injury were identified and categorized into: type 1 myocardial infarction, type 2 myocardial infarction, and nonischemic acute and chronic myocardial injury. We included all 1466/3853 (38%) patients who died during follow-up (3.9 ± 2 years). We estimated rates and adjusted odds ratio (OR) with 95% confidence interval (CI) for causes of death in the 4 categories of myocardial injury using patients without myocardial injury 819/17,932 (4.6%) who died as reference. RESULTS: The study cohort included 2285 patients. The proportion of cardiovascular deaths was higher in patients with type 1 myocardial infarction (48%), acute (43%), and chronic (45%) myocardial injury and type 2 myocardial infarction (39%) compared with patients without myocardial injury (25%). Adjusted rates for cardiovascular death were similar in patients with myocardial injury. Type 1 myocardial infarction, acute, and chronic myocardial injury was associated with a 77% (OR: 1.77, 95% CI 1.29-2.41), 40% (OR: 1.40, 95% CI: 1.07-1.84), and 36% (OR: 1.36, 95% CI: 1.05-1.76) higher risk of cardiovascular death. CONCLUSIONS: Patients with type 1 myocardial infarction and acute or chronic myocardial injury have similar proportions and high risks for cardiovascular death. We believe that these findings stress the need for investigating patients without known heart diseases who present with nonischemic myocardial injury, or type 2 myocardial infarction.

Acute versus chronic myocardial injury and long-term outcomes.

OBJECTIVE: There is a paucity of data regarding prognosis in patients with acute versus chronic myocardial injury for long-term outcomes. We hypothesised that patients with chronic myocardial injury have a similar long-term prognosis as patients with acute myocardial injury. METHODS: In an observational cohort study of 22 589 patients who had high-sensitivity cardiac troponin T (hs-cTnT) measured in the emergency department during 2011-2014, we identified all patients with level >14 ng/L and categorised them as acute myocardial injury, type 1 myocardial infarction (T1MI), type 2 myocardial infarction (T2MI) or chronic myocardial injury through adjudication. We estimated adjusted HRs with 95% CIs for the primary outcome all-cause mortality and secondary outcomes MI, and heart failure in patients with acute myocardial injury, T1MI and T2MI compared with chronic myocardial injury. RESULTS: In total, 3853 patients were included. During 3.9 (±2) years of follow-up, 48%, 24%, 44% and 49% of patients with acute myocardial injury, T1MI, T2MI and chronic myocardial injury died, respectively. Patients with acute myocardial injury had higher adjusted risks of death (1.21, 95% CI 1.08 to 1.36) and heart failure (1.24, 95% CI 1.07 to 1.43), but a similar risk for myocardial infarction (MI) compared with the reference group. Patients with T1MI had a lower adjusted risk of death (0.86, 95% CI 0.74 to 1.00) and higher risk of MI (2.09, 95% CI 1.62 to 2.68), but a similar risk of heart failure. Patients with T2MI had a higher adjusted risk of death (1.46, 95% CI 1.18 to 1.80) and heart failure (1.30, 95% CI 1.00 to 1.69) compared with patients with chronic myocardial injury. CONCLUSIONS: Absolute long-term risks for death are similar, and adjusted risks are slightly higher, among patients with acute myocardial injury and T2MI, respectively, compared with chronic myocardial injury. The lowest risk of long-term mortality was found in patients with T1MI. Both acute and chronic myocardial injury are associated with very high risks of adverse outcomes.

Interleukin-35 administration counteracts established murine type 1 diabetes--possible involvement of regulatory T cells.

The anti-inflammatory cytokine IL-35 is produced by regulatory T (Treg) cells to suppress autoimmune and inflammatory responses. The role of IL-35 in type 1 diabetes (T1D) remains to be answered. To elucidate this, we investigated the kinetics of Treg cell response in the multiple low dose streptozotocin induced (MLDSTZ) T1D model and measured the levels of IL-35 in human T1D patients. We found that Treg cells were increased in MLDSTZ mice. However, the Treg cells showed a decreased production of anti-inflammatory (IL-10, IL-35, TGF-ß) and increased pro-inflammatory (IFN-γ, IL-2, IL-17) cytokines, indicating a phenotypic shift of Treg cells under T1D condition. IL-35 administration effectively both prevented development of, and counteracted established MLDSTZ T1D, seemingly by induction of Eos expression and IL-35 production in Treg cells, thus reversing the phenotypic shift of the Treg cells. IL-35 administration reversed established hyperglycemia in NOD mouse model of T1D. Moreover, circulating IL-35 levels were decreased in human T1D patients compared to healthy controls. These findings suggest that insufficient IL-35 levels play a pivotal role in the development of T1D and that treatment with IL-35 should be investigated in treatment of T1D and other autoimmune diseases.