Sofia Sederholm Lawesson

Th1-like dominance in high-risk first-degree relatives of Type I diabetic patients

Aims/hypothesis. The humoral part of the immune system, including autoantibodies, is known to predict manifest Type I (insulin-dependent) diabetes mellitus in first-degree relatives but the cell-mediated immune process preceding the manifest disease still is not known. The aim of this investigation was to estimate the immunological balance of Th-like lymphocytes (Th1/Th2) in high-risk first-degree relatives of Type I diabetic children.¶Methods. Peripheral blood mononuclear cells (PBMC) from 21 healthy high-risk first-degree relatives (ICA ≥ 20) were examined and compared with the response seen in PBMC from children with newly diagnosed Type I diabetes and healthy control subjects of similar age, sex and HLA-type. Expression of interleukin-4 (IL-4) and interferon-γ (IFN-γ) mRNA were determined by RT-PCR and as protein by ELISPOT after stimulation with specific epitopes of GAD65 (a. a. 247–279, 509–528, 524–543), bovine serum albumin, the ABBOS peptide (a. a. 152–169) and insulin.¶Results. High-risk relatives had a high ratio of IFN-γ:IL-4 compared with both diabetic children (p = 0.0005) and healthy control subjects (p = 0.004). Production of IFN-γ seen in high-risk relatives was negatively correlated to production of GADA (r = –0.44, p = 0.05). The high concentration of IFN-γ from high-risk relatives, decreased after stimulation with peptides of GAD65, the ABBOS peptide, BSA and insulin. Increased secretion of IL-4 was observed after stimulation with two peptides of GAD65 (a. a. 509–528 and 524–543), the ABBOS peptide and insulin.¶Conclusion/interpretation. Overwhelming production of IFN-γ seen in peripheral blood mononuclear cells from high-risk first-degree relatives of children with Type I diabetes suggests a Th1-like immune deviation in the prediabetic phase. [Diabetologia (2000) 43: 742–749]

Time trends in STEMI—improved treatment and outcome but still a gender gap: a prospective observational cohort study from the SWEDEHEART register

Objective In ST elevation myocardial infarction women received less evidence-based medicine and had worse outcome during the fibrinolytic era. With the shift to primary percutaneous coronary intervention (pPCI) as preferred reperfusion strategy, the authors aimed to investigate whether these gender differences has diminished. Design, setting and participants Cohort study including consecutive ST elevation myocardial infarction patients registered 1998–2000 (n=15 697) and 2004–2006 (n=14 380) in the Register of Information and Knowledge about Swedish Heart Intensive care Admissions. Outcome measures 1. Use of evidence-based medicine such as reperfusion therapy (pPCI or fibrinolysis) and evidence-based drugs at discharge. 2. Inhospital and 1-year mortality. Results Of those who got reperfusion therapy, pPCI was the choice in 9% in the early period compared with 68% in the late period. In the early period, reperfusion therapy was given to 63% of women versus 71% of men, p<0.001. Corresponding figures in the late period were 64% vs 75%, p<0.001. After multivariable adjustments, the ORs (women vs men) were 0.86 (95% CI 0.78 to 0.94) in the early and 0.80 (95% CI 0.73 to 0.89) in the late period. As regards evidence-based secondary preventive drugs at discharge in hospital survivors (platelet inhibitors, statins, ACE inhibitors/angiotensin receptor blockers and β-blockers), there were small gender differences in the early period. In the late period, women had 14%–25% less chance of receiving these drugs, OR 0.75 (95% CI 0.68 to 0.81) through 0.86 (95% CI 0.73 to 1.00). In both periods, multivariable-adjusted inhospital mortality was higher in women, OR 1.18 (95% CI 1.02 to 1.36) and 1.21 (1.00 to 1.46). One-year mortality was gender equal, HR 0.95 (95% CI 0.87 to 1.05) and 0.96 (0.86 to 1.08), after adding evidence-based medicine to the multivariable adjustments. Conclusion In spite of an intense gender debate, focus on guideline adherence and the change in reperfusion strategy, the last decade gender differences in use of reperfusion therapy and evidence-based therapy at discharge did not decline during the study period, rather the opposite. Moreover, higher mortality in women persisted.

Gender perspective on risk factors, coronary lesions and long-term outcome in young patients with ST-elevation myocardial infarction

Objective Previous data on young patients with acute coronary syndrome (ACS) have indicated higher rates of normal coronary angiograms but higher mortality in women than men. However, ST-elevation myocardial infarction (STEMI) differs from non-ST-elevation ACS in many aspects. We elucidated sex differences in risk factors, angiographic findings and outcome in consecutive STEMI patients below 46 years of age. Design Retrospective cohort study. Setting The Swedish registers for CCU care and coronary angioplasty; RIKS-HIA and SCAAR. Patients 2132 STEMI patients below 46 years of age admitted to intensive coronary care units in Sweden between 1995 and 2006 and followed for at least 1 year. Main outcome measures Angiographic findings and short-term and long-term mortality. Results Risk factors were more common in women. Significant coronary lesions were equally common (92.1% vs 93.1%, p=0.64) while single vessel disease was more common (72.9% vs 59.3%; p<0.001) in women. Women had higher multivariable adjusted in-hospital mortality, OR 2.85 (95% CI 1.31 to 6.19) while long-term mortality was the same, HR 0.93 (95% CI 0.60 to 1.45). The catch-up of mortality in men might be related to a higher occurrence of re-infarctions, HR 1.82 (95% CI 1.25 to 2.65). Conclusions STEMI below age 46 is a more rare condition in women than in men and more often related to cardiovascular risk factors. More than 90% of both men and women had coronary lesions, in women more often single vessel lesions. Female sex is associated with higher in-hospital mortality, while long-term mortality is low without difference between genders.

A gender perspective on short- and long term mortality in ST-elevation myocardial infarction — A report from the SWEDEHEART register

BACKGROUND Previous studies of patients admitted for ST-elevation myocardial infarction [STEMI] have indicated that women have a higher risk of early mortality than do men. These studies have presented limited information on gender related differences in the short term and almost no information on the long term. METHODS AND RESULTS We analysed a prospective, consecutively included STEMI population consisting of 54,146 patients (35% women). This population consists of almost all patients hospitalised in Sweden between January 1, 1995 and December 31, 2006 as recorded in the SWEDEHEART register (formerly RIKS-HIA). Follow-up time ranged from one to 13 years (mean 4.6). Women had a lower probability of being given reperfusion therapy, odds ratio [OR] 0.83 (95% confidence interval [CI] 0.79-0.88). During the time these STEMI patients were in the hospital, 13% of the women and 7% of men died, multivariable adjusted OR 1.21 (95% CI 1.11-1.32). During the follow up period, 46% of the women died as compared with 32% of the men. There was, however, no gender difference in age-adjusted risk of long term mortality (hazard ratio [HR] 0.98, 95% CI 0.95-1.01) whereas the multivariable adjusted risk was lower in women (HR 0.92, 95% CI 0.89-0.96). The long term risk of re-infarction was the same in men and women (HR 0.98, 95% CI 0.93-1.03) whereas men in the youngest group had a higher risk than women in that age group (HR 0.82, 95% CI 0.72-0.94). CONCLUSION In STEMI, women had a higher risk of in-hospital mortality but the long-term risk of death was higher in men. More studies are needed in the primary percutaneous coronary intervention (pPCI) era that are designed to determine why women fare worse than men after STEMI during the first phase when they are in hospital.

Gender difference in prevalence and prognostic impact of renal insufficiency in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention

Objective To evaluate if female gender is associated with renal insufficiency in patients with ST-elevation myocardial infarction (STEMI) and if there is a gender difference in the prognostic importance of renal insufficiency in STEMI. Design Single-centre observational study. Setting One tertiary cardiac centre. Patients All consecutive patients with STEMI planned for primary percutaneous coronary intervention in one Swedish county in 2005 (98 women and 176 men). Main outcome measures Logistic regression analyses were conducted to evaluate the predictors of renal insufficiency, associations between estimated glomerular filtration rate (eGFR) and outcome in each gender and a possible interaction between gender and eGFR regarding outcome. Results Renal insufficiency was defined as eGFR less than 60 ml/min per 1.73 m2. 67% of women had renal insufficiency compared with 26% of men, OR 5.06 (95% CI 2.66 to 9.59) after multivariable adjustment. In women each 10 ml/min per 1.73 m2 increment of eGFR was associated with a 63% risk reduction for 1-year mortality, OR 0.37 (95% CI 0.15 to 0.89). No such association was found in men, OR 1.05 (95% CI 0.63 to 1.76). A trend towards a significant interaction between gender and eGFR regarding 1-year mortality was found, OR 2.05 (95% CI 0.93 to 4.50). Conclusions A considerable gender difference in the prevalence of renal insufficiency in STEMI was found and renal insufficiency seemed to be a more important prognostic marker in women. These results are important as previous STEMI studies have shown higher multivariable adjusted mortality in women than in men but renal function has seldom been taken into consideration.

Prevalence and prognostic impact of chronic kidney disease in STEMI from a gender perspective: data from the SWEDEHEART register, a large Swedish prospective cohort

Objectives Gender differences in prevalence and prognostic impact of chronic kidney disease (CKD) in ST segment elevation myocardial infarction (STEMI) have been poorly evaluated. In STEMI, female gender has been independently associated with an increased risk of mortality. CKD has been found to be an important prognostic marker in myocardial infarction. The aim of this study was to evaluate gender differences in prevalence and prognostic impact of CKD on short-term and long-term mortality. Design Prospective observational cohort study. Setting The national quality register SWEDEHEART was used. In the beginning of the study period, 94% of the Swedish coronary care units contributed data to the register, which subsequently increased to 100%. The glomerular filtration rate was estimated (eGFR) according to Modification of Diet in Renal Disease Study (MDRD) and Cockcroft-Gault (CG). Participants All patients with STEMI registered in SWEDEHEART from the years 2003–2009 were included (37 991 patients, 66% men). Main results Women had 1.6 (MDRD) to 2.2 (CG) times higher multivariable adjusted risk of CKD. Half of the women had CKD according to CG. CKD was associated with 2–2.5 times higher risk of in-hospital mortality and approximately 1.5 times higher risk of long-term mortality in both genders. Each 10 mL/min decline of eGFR was associated with an increased risk of in-hospital and long-term mortality (22–33% and 9–16%, respectively) and this did not vary significantly by gender. Both in-hospital and long-term mortality were doubled in women. After multivariable adjustment including eGFR, there was no longer any gender difference in early outcome and the long-term outcome was better in women. Conclusions Among patients with STEMI, female gender was independently associated with CKD. Reduced eGFR was a strong independent risk factor for short-term and long-term mortality without a significant gender difference in prognostic impact and seems to be an important reason why women have higher mortality than men with STEMI.

First medical contact in patients with STEMI and its impact on time to diagnosis; an explorative cross-sectional study

Objective It is unknown into what extent patients with ST-elevation myocardial infarction (STEMI) utilise a joint service number (Swedish Healthcare Direct, SHD) as first medical contact (FMC) instead of Emergency Medical Services (EMS) and how this impact time to diagnosis. We aimed to (1) describe patients’ FMC; (2) find explanatory factors influencing their FMC (ie, EMS and SHD) and (3) explore the time interval from symptom onset to diagnosis. Setting Multicentred study, Sweden. Methods Cross-sectional, enrolling patients with consecutive STEMI admitted within 24 h from admission. Results We included 109 women and 336 men (mean age 66±11 years). Although 83% arrived by ambulance to the hospital, just half of the patients (51%) called EMS as their FMC. Other utilised SHD (21%), contacted their primary healthcare centre (14%), or went directly to the emergency room (14%). Reasons for not contacting EMS were predominantly; (1) my transport mode was faster (40%), (2) did not consider myself sick enough (30%), and (3) it was easier to be driven or taking a taxi (25%). Predictors associated with contacting SHD as FMC were female gender (OR 1.92), higher education (OR 2.40), history of diabetes (OR 2.10), pain in throat/neck (OR 2.24) and pain intensity (OR 0.85). Predictors associated with contacting EMS as FMC were history of MI (OR 2.18), atrial fibrillation (OR 3.81), abdominal pain (OR 0.35) and believing the symptoms originating from the heart (OR 1.60). Symptom onset to diagnosis time was significantly longer when turning to the SHD instead of the EMS as FMC (1:59 vs 1:21 h, p<0.001). Conclusions Using other forms of contacts than EMS, significantly prolong delay times, and could adversely affect patient prognosis. Nevertheless, having the opportunity to call the SHD might also, in some instances, lower the threshold for taking contact with the healthcare system, and thus lowers the number that would otherwise have delayed even longer.

Sex Differences in Treatments, Relative Survival, and Excess Mortality Following Acute Myocardial Infarction: National Cohort Study Using the SWEDEHEART Registry

Background This study assessed sex differences in treatments, all‐cause mortality, relative survival, and excess mortality following acute myocardial infarction. Methods and Results A population‐based cohort of all hospitals providing acute myocardial infarction care in Sweden (SWEDEHEART [Swedish Web System for Enhancement and Development of Evidence‐Based Care in Heart Disease Evaluated According to Recommended Therapies]) from 2003 to 2013 was included in the analysis. Excess mortality rate ratios (EMRRs), adjusted for clinical characteristics and guideline‐indicated treatments after matching by age, sex, and year to background mortality data, were estimated. Although there were no sex differences in all‐cause mortality adjusted for age, year of hospitalization, and comorbidities for ST‐segment–elevation myocardial infarction (STEMI) and non‐STEMI at 1 year (mortality rate ratio: 1.01 [95% confidence interval (CI), 0.96–1.05] and 0.97 [95% CI, 0.95–0.99], respectively) and 5 years (mortality rate ratio: 1.03 [95% CI, 0.99–1.07] and 0.97 [95% CI, 0.95–0.99], respectively), excess mortality was higher among women compared with men for STEMI and non‐STEMI at 1 year (EMRR: 1.89 [95% CI, 1.66–2.16] and 1.20 [95% CI, 1.16–1.24], respectively) and 5 years (EMRR: 1.60 [95% CI, 1.48–1.72] and 1.26 [95% CI, 1.21–1.32], respectively). After further adjustment for the use of guideline‐indicated treatments, excess mortality among women with non‐STEMI was not significant at 1 year (EMRR: 1.01 [95% CI, 0.97–1.04]) and slightly higher at 5 years (EMRR: 1.07 [95% CI, 1.02–1.12]). For STEMI, adjustment for treatments attenuated the excess mortality for women at 1 year (EMRR: 1.43 [95% CI, 1.26–1.62]) and 5 years (EMRR: 1.31 [95% CI, 1.19–1.43]). Conclusions Women with acute myocardial infarction did not have statistically different all‐cause mortality, but had higher excess mortality compared with men that was attenuated after adjustment for the use of guideline‐indicated treatments. This suggests that improved adherence to guideline recommendations for the treatment of acute myocardial infarction may reduce premature cardiovascular death among women. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02952417.

Chewed ticagrelor tablets provide faster platelet inhibition compared to integral tablets: The inhibition of platelet aggregation after administration of three different ticagrelor formulations (IPAAD-Tica) study, a randomised controlled trial

AIMS To provide pharmacodynamic data of crushed and chewed ticagrelor tablets, in comparison with standard integral tablets. METHODS Ninety nine patients with stable angina were randomly assigned, in a 3:1:1 fashion, to one of the following 180mg ticagrelor loading dose (LD) formulations: A) Integral B) Crushed or C) Chewed tablets. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60min after LD. High residual platelet reactivity (HRPR) was defined as >208 P2Y12 reaction units (PRU). RESULTS There was no significant difference in PRU values at baseline. PRU 20min after LD were 237 (182-295), 112 (53-238) and 84 (29-129) and 60min after LD, 56 (15-150), 51 (18-85) and 9 (7-34) in integral, crushed and chewed ticagrelor LD, respectively (p<0.01 for both). Chewed ticagrelor tablets resulted in significantly lower PRU values compared to crushed or integral tablets at 20 and 60min. Crushed ticagrelor LD resulted in significantly lower PRU values compared to integral tablets at 20min whereas no difference was observed at 60min. At 20min, no patients had HRPR with chewed ticagrelor compared to 68% with integral and 30% with crushed ticagrelor LD (p<0.01). CONCLUSION With crushed or chewed ticagrelor tablets a more rapid platelet inhibition may be achieved, compared to standard integral tablets. We also show that administration of chewed tablets is feasible and provides faster inhibition than either crushed or integral tablets. CLINICAL TRIAL REGISTRATION European Clinical Trial Database (EudraCT number 2014-002227-96).

Glomerular filtration rate (GFR) during and after STEMI: a single-centre, methodological study comparing estimated and measured GFR

Objectives To validate the performance of the most commonly used formulas for estimation of glomerular filtration rate (GFR) against measured GFR during the index hospitalisation for ST-elevation myocardial infarction (STEMI). Setting Single centre, methodological study. Participants 40 patients with percutaneous coronary intervention-treated STEMI were included between November 2011 and February 2013. Patients on dialysis, cardiogenic shock or known allergy to iodine were excluded. Outcome measures Creatinine and cystatin C were determined at admission and before discharge in 40 patients with STEMI. Clearance of iohexol was measured (mGFR) before discharge. We evaluated and compared the Cockcroft-Gault (CG), the Modification of Diet in Renal Disease (MDRD-IDMS), the Chronic Kidney Disease Epidemiology (CKD-EPI) and the Grubb relative cystatin C (rG-CystC) with GFR regarding correlation, bias, precision and accuracy (P30). Agreement between eGFR and mGFR to discriminate CKD was assessed by Cohens κ statistics. Results MDRD-IDMS and CKD-EPI demonstrated good performance to estimate GFR (correlation 0.78 vs 0.81%, bias −1.3% vs 1.5%, precision 17.9 vs 17.1 mL/min 1.73 m2 and P30 82.5% vs 82.5% for MDRD-IDMS vs CKD-EPI). CKD was best classified by CKD-EPI (κ 0.83). CG showed the worst performance (correlation 0.73%, bias −1% to 3%, precision 22.5 mL/min 1.73 m2 and P30 75%). The rG-CystC formula had a marked bias of −17.8% and significantly underestimated mGFR (p=0.03). At arrival, CKD-EPI and rG-CystC had almost perfect agreement in CKD classification (κ=0.87), whereas at discharge agreement was substantially lower (κ=0.59) and showed a significant discrepancy in CKD classification (p=0.02). Median cystatin C concentration increased by 19%. Conclusions In acute STEMI, CKD-EPI showed the best CKD-classification ability followed by MDRD-IDMS, whereas CG performed the worst. STEMI altered the performance of the cystatin C equation during the acute phase, suggesting that other factors might be involved in the rise of cystatin C.