Inter-relationships between cardiovascular, renal and metabolic diseases: Underlying evidence and implications for integrated interdisciplinary care and management.

Cardiovascular, renal and metabolic (CaReMe) diseases are individually among the leading global causes of death, and each is associated with substantial morbidity and mortality. However, as these conditions commonly coexist in the same patient, the individual risk of mortality and morbidity is further compounded, leading to a considerable healthcare burden. A number of pathophysiological pathways are common to diseases of the CaReMe spectrum, including neurohormonal dysfunction, visceral adiposity and insulin resistance, oxidative stress and systemic inflammation. Because of the shared pathology and common co-occurrence of the CaReMe diseases, the value of managing these conditions holistically is increasingly being realized. A number of pharmacological and non-pharmacological approaches have been shown to offer simultaneous metabolic, cardioprotective and renoprotective benefits, leading to improved patient outcomes across the CaReMe spectrum. In addition, increasing value is being placed on interdisciplinary team-based and coordinated care models built on greater integration between specialties to increase the rate of early diagnosis and adherence to practice guidelines, and improve clinical outcomes. This interdisciplinary approach also facilitates integration between primary and specialty care, improving the patient experience, optimizing resources, and leading to efficiencies and cost savings. As the burden of CaReMe diseases continues to increase, implementation of innovative and integrated care delivery models will be essential to achieve effective and efficient chronic disease management and to ensure that patients benefit from the best care available across all three disciplines.

Statin Treatment Intensity, Discontinuation, and Long-Term Outcome in Patients With Acute Myocardial Infarction and Impaired Kidney Function.

ABSTRACT: Statin dosage in patients with acute myocardial infarction (AMI) and concomitant kidney dysfunction is a clinical dilemma. We studied discontinuation during the first year after an AMI and long-term outcome in patients receiving high versus low-moderate intensity statin treatment, in relation to kidney function. For the intention-to-treat analysis (ITT-A), we included all patients admitted to Swedish coronary care units for a first AMI between 2005 and 2016 that survived in-hospital, had known creatinine, and initiated statin therapy (N = 112,727). High intensity was initiated in 38.7% and low-moderate in 61.3%. In patients with estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 , 25% discontinued treatment the first year; however, the discontinuation rate was similar regardless of the statin intensity. After excluding patients who died, changed therapy, or were nonadherent during the first year, 84,705 remained for the on-treatment analysis (OT-A). Patients were followed for 12.6 (median 5.6) years. In patients with eGFR 30-59 mL/min, high-intensity statin was associated with lower risk for the composite death, reinfarction, or stroke both in ITT-A (hazard ratio [HR] 0.93; 95% confidence interval, 0.87-0.99) and OT-A (HR 0.90; 0.83-0.99); the interaction test for OT-A indicated no heterogeneity for the eGFR < 60 mL/min group ( P = 0.46). Similar associations were seen for all-cause mortality. We confirm that high-intensity statin treatment is associated with improved long-term outcome after AMI in patients with reduced kidney function. Most patients with reduced kidney function initiated on high-intensity statins are persistent after 1 year and equally persistent as patients initiated on low-moderate intensity.

Helicobacter pylori and Pro-Inflammatory Protein Biomarkers in Myocardial Infarction with and without Obstructive Coronary Artery Disease.

Myocardial infarction (MI) with obstructive coronary artery disease (MI-CAD) and MI in the absence of obstructive coronary artery disease (MINOCA) affect different populations and may have separate pathophysiological mechanisms, with greater inflammatory activity in MINOCA compared to MI-CAD. Helicobacter pylori (Hp) can cause systemic inflammation and has been associated with cardiovascular disease (CVD). We aimed to investigate whether Hp infection is associated with concentrations of protein biomarkers of inflammation and CVD. In a case-control study, patients with MINOCA (n = 99) in Sweden were included, complemented by matched subjects with MI-CAD (n = 99) and controls (n = 100). Protein biomarkers were measured with a proximity extension assay in plasma samples collected 3 months after MI. The seroprevalence of Hp and cytotoxin-associated gene A (CagA) was determined using ELISA. The associations between protein levels and Hp status were studied with linear regression. The prevalence of Hp was 20.2%, 19.2%, and 16.0% for MINOCA, MI-CAD, and controls, respectively (p = 0.73). Seven proteins were associated with Hp in an adjusted model: tissue plasminogen activator (tPA), interleukin-6 (IL-6), myeloperoxidase (MPO), TNF-related activation-induced cytokine (TRANCE), pappalysin-1 (PAPPA), soluble urokinase plasminogen activator receptor (suPAR), and P-selectin glycoprotein ligand 1 (PSGL-1). Hp infection was present in one in five patients with MI, irrespective of the presence of obstructive CAD. Inflammatory proteins were elevated in Hp-positive subjects, thus not ruling out that Hp may promote an inflammatory response and potentially contribute to the development of CVD.

Antiphospholipid antibodies in patients with myocardial infarction with and without obstructive coronary arteries.

BACKGROUND: Recent studies demonstrate that prothrombotic antiphospholipid antibodies (aPL) are overrepresented in patients with myocardial infarction (MI) due to coronary artery disease (MICAD). However, it is not known whether aPL differ between the two subsets of MI: MICAD and MI with nonobstructive coronary arteries (MINOCA). OBJECTIVES: To determine whether aPL are associated with MINOCA or MICAD, or with hypercoagulability as assessed by activated protein C-protein C inhibitor (APC-PCI) complex. METHODS: Well-characterized patients with MINOCA (n = 98), age- and gender-matched patients with MICAD (n = 99), and healthy controls (n = 100) were included in a cross-sectional case-control study. Autoantibodies (IgA/G/M) targeting cardiolipin and ß2 glycoprotein-I and specific nuclear antigens were analyzed by multiplexed bead technology. The concentration of APC-PCI was determined as a measure of hypercoagulability by an immunofluorometric sandwich assay. RESULTS: Both prevalence and titers of aPL of the IgG isotype (anti-cardiolipin and/or anti-ß2 glycoprotein-I) were higher in patients with MINOCA and MICAD than in controls. aPL IgG positivity was twice as frequent among patients with MICAD than MINOCA (11% vs. 6%, nonsignificant). We observed no group differences regarding aPL IgA/M or antibodies targeting specific nuclear antigens. Levels of APC-PCI were elevated in aPL IgG-positive compared to aPL IgG-negative MICAD patients. CONCLUSIONS: aPL IgG, but not IgA/M, are enriched particularly in patients with MICAD but also in patients with MINOCA, as compared to controls. Interestingly, signs of hypercoagulability-measured by increased levels of the APC-PCI complex-were present in aPL IgG-positive MICAD patients, indicating an association with functional disturbances of the coagulation system.

User experience of self-reported computerized medical history taking for acute chest pain: The Clinical Expert Operating System Chest Pain Danderyd Study.

BACKGROUND AND OBJECTIVE: Chest pain is one of the most common complaints in emergency departments (EDs). Self-reported computerized history taking (CHT) programmes can be used for interpretation of the clinical significance of medical information coming directly from patients. The adoption of CHT in clinical practice depends on reactions and attitudes to the technology from patients and their belief that the technology will have benefits for their medical care. The study objective was to explore the user experience of the self-reported CHT programme Clinical Expert Operating System (CLEOS) in the setting of patients visiting an ED for acute chest pain. METHODS: This qualitative interview study is part of the ongoing CLEOS-Chest Pain Danderyd Study. A subset (n = 84) of the larger sample who had taken part in self-reported history taking during waiting times at the ED were contacted by telephone and n = 54 (64%) accepted participation. An interview guide with open-ended questions was used and the text was analysed using directed content analysis. RESULTS: The patients' experiences of the CLEOS programme were overall positive although some perceived it as extensive. The programme was well accepted and despite the busy environment, patients were highly motivated and deemed it helpful to make a diagnosis. Six categories of user experience emerged: The clinical context, The individual context, Time aspect, Acceptability of the programme, Usability of the programme and Perceptions of usefulness in a clinical setting. CONCLUSIONS: The programme was well accepted by most patients in the stressful environment at ED although some found it difficult to answer all the questions. Adjustments to the extent of an interview to better suit the context of the clinical use should be a future development of the programme. The findings suggest that CHT programmes can be integrated as a standard process for collecting self-reported medical history data in the ED setting.

Aortic stiffness and aortic-brachial stiffness mismatch as markers of renal dysfunction in hypertension.

PURPOSE: The dismal combination of hypertension and chronic kidney disease potentiates both cardiovascular disease and loss of renal function. Research points to the importance of arterial and left ventricular stiffening in this process but few studies have compared aspects of central and peripheral hemodynamics in relation to renal function in hypertension. MATERIALS AND METHODS: We investigated 107 hypertensive individuals with renal function ranging from normal to severe dysfunction with pulse wave analysis to obtain central blood pressures (BP), augmentation index, carotid-femoral and carotid-radial pulse wave velocity (cfPWV, crPWV), aortic-to-brachial stiffness mismatch (cfPWV/crPWV), endothelial function by forearm flow-mediated vasodilation and myocardial microvascular function by subendocardial viability ratio, and indices of left ventricular structure (left ventricular mass index and relative wall thickness, RWT) and diastolic function (left atrial volume index, E/A, and E/é). RESULTS: Mean age was 58 years, BP 149/87 mm Hg, 9% had cardiovascular disease, and 31% were on antihypertensive treatment. Mean estimated glomerular filtration rate (eGFR) was 74 (range 130-21) ml/min × 1.73 m2. Whereas cfPWV and cfPWV/crPWV were independently related to eGFR (r = -0.20, p = 0.002, r = -0.16, p = 0.01), central diastolic BP (r = 0.21, p = 0.04), RWT (r = -0.34, p = 0.001), E/é (r = -0.39, p < 0.001) and E/A (r = 0.27, p = 0.01) were related to eGFR in bivariate correlations, but these findings were not retained in multivariate analyses. Remaining markers of hypertensive heart disease and measures of microvascular function were not related to eGFR. CONCLUSION: Increased aortic stiffness and aortic-to-brachial stiffness mismatch are independently related to reduced eGFR in hypertensive patients, suggesting an important role for aortic stiffness in the evolution of hypertension-mediated renal dysfunction. Aortic stiffness and aortic-brachial stiffness mismatch may be useful early markers to find hypertensive patients at risk for decline in renal function.

Use of Self-Reported Computerized Medical History Taking for Acute Chest Pain in the Emergency Department - the Clinical Expert Operating System Chest Pain Danderyd Study (CLEOS-CPDS): Prospective Cohort Study.

BACKGROUND: Chest pain is one of the most common chief complaints in emergency departments (EDs). Collecting an adequate medical history is challenging but essential in order to use recommended risk scores such as the HEART score (based on history, electrocardiogram, age, risk factors, and troponin). Self-reported computerized history taking (CHT) is a novel method to collect structured medical history data directly from the patient through a digital device. CHT is rarely used in clinical practice, and there is a lack of evidence for utility in an acute setting. OBJECTIVE: This substudy of the Clinical Expert Operating System Chest Pain Danderyd Study (CLEOS-CPDS) aimed to evaluate whether patients with acute chest pain can interact effectively with CHT in the ED. METHODS: Prospective cohort study on self-reported medical histories collected from acute chest pain patients using a CHT program on a tablet. Clinically stable patients aged 18 years and older with a chief complaint of chest pain, fluency in Swedish, and a nondiagnostic electrocardiogram or serum markers for acute coronary syndrome were eligible for inclusion. Patients unable to carry out an interview with CHT (eg, inadequate eyesight, confusion or agitation) were excluded. Effectiveness was assessed as the proportion of patients completing the interview and the time required in order to collect a medical history sufficient for cardiovascular risk stratification according to HEART score. RESULTS: During 2017-2018, 500 participants were consecutively enrolled. The age and sex distribution (mean 54.3, SD 17.0 years; 213/500, 42.6% women) was similar to that of the general chest pain population (mean 57.5, SD 19.2 years; 49.6% women). Common reasons for noninclusion were language issues (182/1000, 18.2%), fatigue (158/1000, 15.8%), and inability to use a tablet (152/1000, 15.2%). Sufficient data to calculate HEART score were collected in 70.4% (352/500) of the patients. Key modules for chief complaint, cardiovascular history, and respiratory history were completed by 408 (81.6%), 339 (67.8%), and 291 (58.2%) of the 500 participants, respectively, while 148 (29.6%) completed the entire interview (in all 14 modules). Factors associated with completeness were age 18-69 years (all key modules: Ps<.001), male sex (cardiovascular: P=.04), active workers (all key modules: Ps<.005), not arriving by ambulance (chief complaint: P=.03; cardiovascular: P=.045), and ongoing chest pain (complete interview: P=.002). The median time to collect HEART score data was 23 (IQR 18-31) minutes and to complete an interview was 64 (IQR 53-77) minutes. The main reasons for discontinuing the interview prior to completion (n=352) were discharge from the ED (101, 28.7%) and tiredness (95, 27.0%). CONCLUSIONS: A majority of patients with acute chest pain can interact effectively with CHT on a tablet in the ED to provide sufficient data for risk stratification with a well-established risk score. The utility was somewhat lower in patients 70 years and older, in patients arriving by ambulance, and in patients without ongoing chest pain. Further studies are warranted to assess whether CHT can contribute to improved management and prognosis in this large patient group. TRIAL REGISTRATION: ClinicalTrials.gov NCT03439449; https://clinicaltrials.gov/ct2/show/NCT03439449. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2019-031871.

Designing a Web-Based Psychological Intervention for Patients With Myocardial Infarction With Nonobstructive Coronary Arteries: User-Centered Design Approach.

BACKGROUND: The involvement of patient research partners (PRPs) in research aims to safeguard the needs of patient groups and produce new interventions that are developed based on patient input. Myocardial infarction with nonobstructive coronary arteries (MINOCA), unlike acute myocardial infarction (MI) with obstructive coronary arteries, is presented with no significant obstructive coronary artery disease. Patients with this diagnosis are a subset of those diagnosed with traditional MI and often need more psychological support, something that is presently not established in the current treatment scheme in Swedish health care or elsewhere, to our knowledge. An internet-delivered intervention might offer patients with MINOCA the opportunity to access a psychological treatment that is tailored to their specific needs after MINOCA and could therefore supplement the existing medical care in an easily accessible format. OBJECTIVE: This paper aims to describe the development of a therapist-guided, internet-delivered psychological intervention designed specifically for patients with MINOCA. METHODS: The study used a participatory design that involved 7 PRPs diagnosed with MINOCA who collaborated with a team consisting of researchers, cardiologists, and psychologists. Intervention content was developed iteratively and presented to the PRPs across several prototypes, each continually adjusted and redesigned according to the feedback received. The intervention and experience of it were discussed by PRPs in a final meeting and then presented to a panel of 2 clinical psychologists and a cardiologist for further input. RESULTS: The outcome of the collaboration between PRPs and the research group produced a web-based psychological 9-step program focusing on stress, worry, and valued action. The input from PRPs contributed substantially to the therapy content, homework tasks, interactive activities, multimedia, and design presentation. CONCLUSIONS: Working with PRPs to develop an intervention for people with MINOCA produced a web-based intervention that can be further evaluated with the goal of offering a new psychological treatment option to a patient group currently without one. Direct contribution from PRPs enabled us to obtain relevant, insightful, and valuable feedback that was put towards the overall design and content of the intervention.

Increased Inflammatory Activity in Patients 3 Months after Myocardial Infarction with Nonobstructive Coronary Arteries.

BACKGROUND: Around 5%-10% of patients with myocardial infarction (MI) present with nonobstructive coronary arteries (MINOCA). We aimed to assess pathophysiological mechanisms in MINOCA by extensively evaluating cardiovascular biomarkers in the stable phase after an event, comparing MINOCA patients with cardiovascular healthy controls and MI patients with obstructive coronary artery disease (MI-CAD). METHODS: Ninety-one biomarkers were measured with a proximity extension assay 3 months after MI in 97 MINOCA patients, 97 age- and sex-matched MI-CAD patients, and 98 controls. Lasso analyses (penalized logistic regression models) and adjusted multiple linear regression models were used for statistical analyses. RESULTS: In the Lasso analysis (MINOCA vs MI-CAD), 8 biomarkers provided discriminatory value: P-selectin glycoprotein ligand 1, C-X-C motif chemokine 1, TNF-related activation-induced cytokine, and pappalysin-1 (PAPPA) with increasing probabilities of MINOCA, and tissue-type plasminogen activator, B-type natriuretic peptide, myeloperoxidase, and interleukin-1 receptor antagonist protein with increasing probabilities of MI-CAD. Comparing MINOCA vs controls, 7 biomarkers provided discriminatory value: N-terminal pro-B-type natriuretic peptide, renin, NF-κ-B essential modulator, PAPPA, interleukin-6, and soluble urokinase plasminogen activator surface receptor with increasing probabilities of MINOCA, and agouti-related protein with increasing probabilities of controls. Adjusted multiple linear regression analyses showed that group affiliation was associated with the concentrations of 7 of the 8 biomarkers in the comparison MINOCA vs MI-CAD and 5 of the 7 biomarkers in MINOCA vs controls. CONCLUSIONS: Three months after the MI, the biomarker concentrations indicated greater inflammatory activity in MINOCA patients than in both MI-CAD patients and healthy controls, and a varying degree of myocardial dysfunction among the 3 cohorts.

Increased concentrations of platelet- and endothelial-derived microparticles in patients with myocardial infarction and reduced renal function- a descriptive study.

BACKGROUND: Patients with chronic kidney disease (CKD) have a high risk of recurring thrombotic events following acute myocardial infarction (AMI). Microparticles (MPs) are circulating small vesicles shed from various cells. Platelet microparticles (PMPs) reflect platelet activation and endothelial microparticles (EMPs) reflect endothelial activation or dysfunction. Both increase following AMI, and may mediate important biological effects. We hypothesized that AMI patients with CKD have further elevated PMPs and EMPs compared with non-CKD patients, despite concurrent antithrombotic treatment. METHODS: We performed a descriptive study of patients with AMI. Fasting blood samples were acquired from 47 patients on dual antiplatelet treatment. Patients were stratified by renal function: normal (H; n = 19) mean eGFR 88; moderate CKD (CKD3; n = 15) mean eGFR 47, and severe CKD (CKD4-5; n = 13) mean eGFR 20 mL/min/1.73 m2. MPs were measured by flow-cytometry and phenotyped according to size (< 1.0 µm) and expression of CD41 (GPIIb; PMPs) and CD62E (E-selectin; EMPs). In addition, expression of platelet activation markers P-selectin (CD62P) and CD40ligand (CD154) were also investigated. RESULTS: PMPs expressing CD40 ligand were higher in CKD4-5: 210 /µl (174-237); median and interquartile range; vs. group H; 101 /µl (71-134; p < 0.0001) and CKD 3: 142 /µl (125-187; p = 0.006). PMPs expressing P-selectin were higher in CKD4-5 compared with H, but not in CKD3. EMPs were higher in CKD4-5; 245 /µl (189-308) compared with H; 83 /µl (53-140; p < 0.0001) and CKD3; 197 /µl (120-245; p < 0.002). CONCLUSIONS: In AMI patients, PMPs and EMPs from activated platelets and endothelial cell are further elevated in CKD patients. This indicate impaired endothelial function and higher platelet activation in CKD patients, despite concurrent antiplatelet treatment.

Changes in microparticle profiles by vitamin D receptor activation in chronic kidney disease - a randomized trial.

BACKGROUND: Microparticles (MPs) are biomarkers and mediators of disease through their expression of surface receptors, reflecting activation or stress in their parent cells. Endothelial markers, ICAM-1 and VCAM-1, are implicated in atherosclerosis and associated with cardiovascular risk. Chronic kidney disease (CKD) patients have endothelial dysfunction and high levels of endothelial derived MPs. Vitamin D treatment has been reported to ameliorate endothelial function in CKD patients. We aimed to examine cell specific MP profiles and concentrations of MPs expressing the atherosclerotic markers ICAM-1 and VCAM-1 after treatment with paricalcitol in patients with CKD stage 3-4. METHODS: Sub-study of the previously reported SOLID trial where 36 patients were randomly assigned to placebo, 1 or 2 µg paricalcitol, for 12 weeks. MPs were measured by flow cytometry after labelling with antibodies against endothelial (CD62E), platelet (CD62P, CD41, CD154) leukocyte (CD45) and vascular (CD54, CD106) markers. RESULTS: Patients had a mean age of 65 years with a mean eGFR of 40 mL/min/1.73m2. Concentrations of ICAM-1 positive MPs were significantly reduced by treatment (repeated measures ANOVA p = 0.04). Repeated measures MANOVA of concentrations of endothelial, platelet and leukocyte MPs showed sustained levels in the 2 µg treatment group (p = 0.85) but a decline in the 1 µg (p = 0.04) and placebo groups (p = 0.005). CONCLUSIONS: Treatment with paricalcitol reduces concentrations of ICAM-1 positive MPs. This is accompanied by sustained concentrations of all cell specific MPs in the 2 µg group, and decreasing concentrations in the other groups, possibly due to a more healthy and reactive endothelium with paricalcitol treatment.

Treating endothelial dysfunction with vitamin D in chronic kidney disease: a meta-analysis.

BACKGROUND: Vitamin D deficiency is common in patients with chronic kidney disease (CKD), and is associated with endothelial dysfunction and cardiovascular disease. We performed a meta-analysis to assess the effect of vitamin D treatment on flow mediated vasodilation (FMD) in CKD patients. METHODS: PubMed/Medline, Web of Science, Embase and Cochrane trials and reviews were searched systematically for randomized controlled trials (RCT:s) using any vitamin D compound, at any stage of CKD, with FMD as outcome. Fixed and random effects models were performed using the standardized mean difference effect size post treatment for each trial. Heterogeneity was assessed by I2 statistics. RESULTS: 4 trials were included, comprising 305 patients. One used both 1 and 2 µg for two intervention groups and was therefore split in two during the analysis. Patients in the included trials had a mean age of 44-65 years and were all in CKD 3 to 4. One study used cholecalciferol, the others all used paricalcitol as treatment. Study duration was 12-16 weeks. Intervention with vitamin D was associated with ameliorated FMD (STANDmean ES 0.78, 95% CI 0.55-1.01) in a fixed model. Heterogeneity was substantial (I2 = 84%). Secondary analysis with random model analysis also showed significant results. CONCLUSIONS: Short term intervention with vitamin D is associated with improvements in endothelial function, as measured by FMD. This indicates positive effects of vitamin D on vascular disease in CKD. Limitations of this meta-analysis are the small number of studies performed, and the short duration of intervention.

Kidney function is associated with short-term, mid-term and long-term clinical outcome after coronary angiography and intervention.

BACKGROUND: Patients with kidney dysfunction are at risk of developing ischaemic heart disease. We investigated the association between eGFR and early-, mid- and long-term clinical outcome in patients undergoing coronary angiography and intervention. METHODS: Retrospective study on 4968 patients with complete data on eGFR, 65% male and aged 32-80 years, admitted to Danderyd University Hospital, Stockholm, Sweden for coronary angiography and intervention from 2006 to 2008. Data were censored at 0-30 days, 31-365 days and 366-1825 days of follow-up. RESULTS: Baseline eGFR was strongly associated with all-cause mortality at all three time periods studied with each 10 ml/min per 1.73 m2 increase in eGFR being associated with a ∼30% (p < .001), 25% (p = .002) and 20% (p < .001) decrease in all-cause mortality at 30, 365 and 1825 days respectively. Each 10 ml/min per 1.73 m2 increase in eGFR was associated with a ∼21% (p < .001) decrease in re-hospitalisation for MI at 365 days and a 6% decrease (p = .03) at day 30 for re-vascularisation. CONCLUSIONS: We report a strong association between kidney function and all-cause mortality at both early, mid- and long-term follow-up in patients undergoing coronary angiography and intervention, with eGFR significantly associated with MI-related mortality after one month of follow-up. Kidney function was also shown to be associated with risk for re-vascularisation at one month, indicating mostly procedural-related risk and with new MI at mid-term follow-up. Further research is warranted to explore the mechanisms linking kidney function and cardiovascular disease to improve both the short- and long-term care of these patients.

Quantitation of 87 Proteins by nLC-MRM/MS in Human Plasma: Workflow for Large-Scale Analysis of Biobank Samples.

A multiple reaction monitoring (MRM) assay was developed for precise quantitation of 87 plasma proteins including the three isoforms of apolipoprotein E (APOE) associated with cardiovascular diseases using nanoscale liquid chromatography separation and stable isotope dilution strategy. The analytical performance of the assay was evaluated and we found an average technical variation of 4.7% in 4-5 orders of magnitude dynamic range (≈0.2 mg/L to 4.5 g/L) from whole plasma digest. Here, we report a complete workflow, including sample processing adapted to 96-well plate format and normalization strategy for large-scale studies. To further investigate the MS-based quantitation the amount of six selected proteins was measured by routinely used clinical chemistry assays as well and the two methods showed excellent correlation with high significance (p-value < 10e-5) for the six proteins, in addition for the cardiovascular predictor factor, APOB: APOA1 ratio (r = 0.969, p-value < 10e-5). Moreover, we utilized the developed assay for screening of biobank samples from patients with myocardial infarction and performed the comparative analysis of patient groups with STEMI (ST- segment elevation myocardial infarction), NSTEMI (non ST- segment elevation myocardial infarction) and type-2 AMI (type-2 myocardial infarction) patients.

Long-term versus short-term dual antiplatelet therapy was similarly associated with a lower risk of death, stroke, or infarction in patients with acute coronary syndrome regardless of underlying kidney disease.

Scarce and conflicting evidence exists on whether clopidogrel is effective and whether dual antiplatelet treatment (DAPT) is safe in patients with acute coronary syndrome and chronic kidney disease (CKD). To study this, we performed an observational, prospective, multicenter cohort study of 36,001 patients of the SWEDEHEART registry. The exposure was DAPT prolonged after 3 months versus DAPT stopped at 3 months in consecutive patients with acute coronary syndrome and known serum creatinine. DAPT duration with clopidogrel and aspirin was assessed by dispensed tablets. CKD stages were classified according to estimated glomerular filtration rate (eGFR). Study outcomes were 1) the composite of death, myocardial infarction, or ischemic stroke; 2) bleeding; or 3) the aggregate of these two outcomes within day 111 and 365 from discharge. A longer DAPT duration, as compared with 3-month DAPT, was associated with lower hazard ratios for outcome one in each CKD stratum (eGFR over 60, adjusted hazard ratio [95% confidence interval] 0.76 [0.67-0.85]; eGFR 60 and less, 0.84 [0.73-0.96], of which eGFR between 45 and 60, 0.85 [0.70-1.05], eGFR between 30 and 45, 0.78 [0.62-0.97]; eGFR 30 and less ml/min/1.73 m2, 0.93 [0.70-1.24]. Bleeding (outcome 2) was in general more common in the longer DAPT group of each aforementioned CKD stratum. Aggregated outcome analysis (outcome 3) similarly favored longer DAPT in each stratum. There was no interaction between DAPT duration and CKD strata for any of the study outcomes. Thus, a prolonged as compared with three-month DAPT was similarly associated with a lower risk of death, stroke, or reinfarction regardless of underlying CKD.

Vitamin D receptor activation reduces inflammatory cytokines and plasma MicroRNAs in moderate chronic kidney disease - a randomized trial.

BACKGROUND: Chronic kidney disease (CKD) is a major risk factor for cardiovascular disease (CVD), partly due to endothelial dysfunction and chronic inflammation. Vitamin D treatment in end stage renal disease is suggested to modulate the immune system and lead to improved outcomes. We and others have demonstrated that treatment with vitamin D or activated vitamin D analogues protects the endothelial function in less severe renal disease as well. Since the endothelial protection might be mediated by vitamin D effects on inflammation, we assessed levels of pro-inflammatory cytokines and micro RNAs (miRs) in patients with moderate CKD, treated with an active vitamin D analogue (paricalcitol). METHODS: Thirty-six patients with moderate CKD were randomized to 12 weeks treatment with placebo, 1 µg, or 2 µg paricalcitol daily. Cytokines were measured by Milliplex 26-plex. Total RNA was isolated from plasma and miRs were determined by quantitative reverse transcription PCR analysis. RESULTS: Selected pro-inflammatory cytokines decreased significantly following treatment, while no change was observed in the placebo group. The micro RNAs; miR 432-5p, miR 495-3p, and miR 576-5p were significantly downregulated in the active treated groups, compared to the placebo group. CONCLUSION: Paricalcitol treatment for 12 weeks in patients with moderate CKD reduces cytokines and micro RNAs involved in atherosclerosis and inflammation. The potentially protective role of vitamin D receptor activation in the inflammatory processes regarding the long-term outcomes in CKD patients warrants further studies. TRIAL REGISTRATION: SOLID study; NCT01204528 , April 27, 2010.

Paricalcitol, Microvascular and Endothelial Function in Non-Diabetic Chronic Kidney Disease: A Randomized Trial.

BACKGROUND: Vitamin D deficiency, sympathetic activation and endothelial dysfunction are associated with increased cardiovascular risk in patients with chronic kidney disease (CKD). Studies have so far failed to establish the role of vitamin D and vitamin D receptor activator (VDRA) treatment in moderate CKD. This trial was designed to assess whether VDRA treatment can ameliorate sympathetic activation and macro- and microvascular dysfunction in non-diabetic patients with moderate CKD. METHODS: We conducted a randomized controlled double-blind trial using placebo, 1 or 2 µg of paricalcitol, a VDRA, for 3 months. We assessed muscle sympathetic nerve activity (MSNA) by microneurography, pulse wave velocity (PWV) by tonometry, flow mediated vasodilatation (FMD) by brachial ultrasound, skin microcirculation assessed by iontophoresis and capillary blood velocity (CBV) by videophotometric capillaroscopy. RESULTS: Thirty-six patients with a mean age of 65 years and mean estimated glomerular filtration rate of 40 ml/min/1.73 m2 were included. We found a significant decline in endothelial function after 3 months, except in the group receiving 2 µg of paricalcitol. The higher dose (2 µg) seemed to attenuate the decline in microvascular endothelial function, assessed by iontophoresis of acetylcholine (p=0.06 for all groups, p=0.65 for the 2 µg group) and for FMD (p=0.006 for all groups, p=0.54 for the 2 µg group). We found a borderline significance (p=0.05) for improved CBV in the treated groups. We found no significant changes between treatments in MSNA, PWV or albuminuria. CONCLUSIONS: Endothelial function declined significantly over 3 months in patients with moderate CKD, and this decline could be ameliorated by VDRA treatment (NCT01204528).

Association between the use of fondaparinux vs low-molecular-weight heparin and clinical outcomes in patients with non-ST-segment elevation myocardial infarction.

IMPORTANCE: Fondaparinux was associated with reduced major bleeding events and improved survival compared with low-molecular-weight heparin (LMWH) in a large randomized clinical trial involving patients with non-ST-segment elevation myocardial infarction (NSTEMI). Large-scale experience of the use of fondaparinux vs LMWH in a nontrial setting is lacking. OBJECTIVE: To study the association between the use of fondaparinux vs LMWH and outcomes in patients with NSTEMI in Sweden. DESIGN, SETTING, AND PATIENTS: Prospective multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies registry involving 40,616 consecutive patients with NSTEMI who received fondaparinux or LMWH between September 1, 2006, through June 30, 2010, with the last follow-up on December 31, 2010. EXPOSURES: In-hospital treatment with fondaparinux or LMWH during the hospital stay. MAIN OUTCOMES AND MEASURES: In-hospital severe bleeding events and death and 30- and 180-day death, MI, stroke, and major bleeding events. Logistic regression models adjusted for calendar time, admitting hospital, baseline characteristics, and in-hospital revascularization. RESULTS: In total, 14,791 patients (36.4%) were treated with fondaparinux and 25,825 (63.6%) with LMWH. One hundred sixty-five patients (1.1%) in the fondaparinux group vs 461 patients (1.8%) in the LMWH group experienced in-hospital bleeding events (adjusted odds ratio [OR], 0.54; 95% CI, 0.42-0.70). A total of 394 patients (2.7%) in the fondaparinux group died while in the hospital vs 1022 (4.0%) in the LMWH group (adjusted OR, 0.75; 95% CI, 0.63-0.89). The differences in major bleeding events and mortality between the 2 treatments were similar at 30 and 180 days. There were no significant differences in the number of recurrent MI and stroke events at 30 or 180 days among the 2 treatment groups. CONCLUSIONS AND RELEVANCE: In routine clinical care of patients with NSTEMI, fondaparinux was associated with lower odds than LMWH of major bleeding events and death both in-hospital and up to 180 days afterward.

Warfarin, kidney dysfunction, and outcomes following acute myocardial infarction in patients with atrial fibrillation.

IMPORTANCE: Conflicting evidence exists regarding the association between warfarin treatment, death, and ischemic stroke incidence in patients with advanced chronic kidney disease (CKD) and atrial fibrillation. OBJECTIVE: To study outcomes associated with warfarin treatment in relation to kidney function among patients with established cardiovascular disease and atrial fibrillation. DESIGN, SETTING, AND PARTICIPANTS: Observational, prospective, multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry (2003-2010), which includes all Swedish hospitals that provide care for acute cardiac diseases. Participants included consecutive survivors of an acute myocardial infarction (MI) with atrial fibrillation and known serum creatinine (N = 24,317), including 21.8% who were prescribed warfarin at discharge. Chronic kidney disease stages were classified according to estimated glomerular filtration rate (eGFR). MAIN OUTCOMES AND MEASURES: (1) Composite end point analysis of death, readmission due to MI, or ischemic stroke; (2) bleeding (composite of readmission due to hemorrhagic stroke, gastrointestinal bleeding, bleeding causing anemia, and others); or (3) the aggregate of these 2 outcomes within 1 year from discharge date. RESULTS: A total of 5292 patients (21.8%) were treated with warfarin at discharge, and 51.7% had manifest CKD (eGFR <60 mL/min/1.73 m2 [eGFR<60]). Compared with no warfarin use, warfarin was associated with a lower risk of the first composite outcome (n = 9002 events) in each CKD stratum for event rates per 100 person-years: eGFR>60 event rate, 28.0 for warfarin vs 36.1 for no warfarin; adjusted hazard ratio (HR), 0.73 (95% CI, 0.65 to 0.81); eGFR>30-60: event rate, 48.5 for warfarin vs 63.8 for no warfarin; HR, 0.73 (95% CI, 0.66 to 0.80); eGFR>15-30: event rate, 84.3 for warfarin vs 110.1 for no warfarin; HR, 0.84 (95% CI, 0.70-1.02); eGFR≤15: event rate, 83.2 for warfarin vs 128.3 for no warfarin; HR, 0.57 (95% CI, 0.37-0.86). The risk of bleeding (n = 1202 events) was not significantly higher in patients treated with warfarin in any CKD stratum for event rates per 100 person-years: eGFR>60 event rate, 5.0 for warfarin vs 4.8 for no warfarin; HR, 1.10 (95% CI, 0.86-1.41); eGFR>30-60 event rate, 6.8 for warfarin vs 6.3 for no warfarin; HR, 1.04 (95% CI, 0.81-1.33); eGFR>15-30 event rate, 9.3 for warfarin vs 10.4 for no warfarin; HR, 0.82 (95% CI, 0.48-1.39); eGFR≤15 event rate, 9.1 for warfarin vs 13.5 for no warfarin; HR, 0.52 (95% CI, 0.16-1.65). Warfarin use in each CKD stratum was associated with lower hazards of the aggregate outcome (n = 9592 events) for event rates per 100 person-years: eGFR>60 event rate, 32.1 for warfarin vs 40.0 for no warfarin; HR, 0.76 (95% CI, 0.69-0.84); eGFR>30-60 event rate, 53.6 for warfarin vs 69.0 for no warfarin; HR, 0.75 (95% CI, 0.68-0.82); eGFR>15-30 event rate, 90.2 for warfarin vs 117.7 for no warfarin; HR, 0.82 (95% CI, 0.68-0.99); eGFR≤15 event rate, 86.2 for warfarin vs 138.2 for no warfarin; HR, 0.55 (95% CI, 0.37-0.83). CONCLUSIONS AND RELEVANCE: Warfarin treatment was associated with a lower 1-year risk for the composite outcome of death, MI, and ischemic stroke without a higher risk of bleeding in consecutive acute MI patients with atrial fibrillation. This association was not related to the severity of concurrent CKD.

Assessment of aortic stiffness during atrial fibrillation: solutions and considerations.

Background: Methods to assess aortic stiffness are not validated during ongoing atrial fibrillation (AF) We aimed to determine whether aortic stiffness can be assessed reliably in patients during AF. Methods and results: Carotid-to-femoral and aortic pulse wave velocity (cf/aoPWV), central blood pressure (BP), and augmentation index (AIx) were assessed by a two-site applanation method and a one-site cuff-based oscillometric method in 40 patients with persistent AF and repeated after cardioversion to SR. Mean age was 63 ± 8 years, 73% male, 50% hypertensive. For the two-site method, cfPWV values were slightly higher in AF than in SR (9.3 ± 1.8 vs. 8.5 ± 1.6 m/s, p < 0.001), whereas the one-site method provided similar values in AF and SR (10.1 ± 1.5 vs. 10.0 ± 1.8 m/s).The variability indices from the device was higher in AF for the two-site method (SD 2.5 ± 1.7 vs. 1.0 ± 0.5 m/s, p < 0.001) but similar in AF and SR with the one-site method (SD 0.7 ± 0.2 vs. 0.6 ± 0.2 m/s). Both methods yielded higher central BP (+4.8/+6.6 and +4.1/+5.7 mm Hg) and lower Aix (-6.8 and -9.1 mm Hg) in AF. Conclusions: Aortic stiffness can be assessed during AF. Both methods yielded higher central BP and lower AIx in AF, but similar results for PWV in AF and SR, also when adjusted for BP changes. The two-site method showed high variability necessitating repeated measurements. The one-site method showed lower device-calculated variability and needed fewer repeated measurements.