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Background and Objective AZD5718, a 5-lipoxygenase-activating protein (FLAP) inhibitor, is in clinical development for treatment of coronary artery disease (CAD) and chronic kidney disease (CKD). This study evaluated AZD5718 pharmacokinetics, pharmacodynamics, and tolerability in healthy male Japanese subjects. Methods Four cohorts of eight Japanese subjects were randomized to receive oral doses of AZD5718 (60, 180, 360, and 600 mg) or matching placebo administered as a single dose on Day 1 and as once-daily doses from Day 3 to Day 10 in fasted conditions. Pharmacokinetic, pharmacodynamic, and safety data were collected. Results The pharmacokinetics characteristics of AZD5718 in Japanese male subjects were similar to those reported in a previous study, and the pharmacokinetics were characterized as rapid absorption with median time to reach maximum concentration (Tmax) of 1–2 h Creatine-normalized urine maximum concentration (Cmax) with mean half-lives ranging from 8 to 21 h, and supra-proportional increase in exposure over the 60–600 mg dose range evaluated. Also, an increase in steady-state area under the concentration-time curve (AUC) compared to the first dose was observed. After both single and multiple doses of AZD5718, a clear dose/concentration-effect relationship was shown for urinary leukotriene E4 (LTE4) versus AZD5718 exposure with > 80 % inhibition at plasma concentrations in the lower nM range. No clinically relevant safety and tolerability findings were observed. Conclusions The observed pharmacokinetics and pharmacodynamics were similar to reported data for non-Japanese healthy subjects, which support further evaluation of AZD5718 at similar doses/exposures in Japanese and non-Japanese subjects for future evaluation in patients with CAD and CKD. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-021-01078-7.

Background: Leukotrienes are pro-inflammatory vasoactive lipid mediators implicated in the pathophysiology of atherosclerotic cardiovascular disease. We studied the effect of the 5-lipoxygenase-activating protein inhibitor AZD5718 on leukotriene biosynthesis and coronary microvascular function in a single-blind, phase 2a study. Methods: Patients 7–28 days after myocardial infarction (±ST elevation), with 4 (uLTE4) was the primary endpoint, and coronary flow velocity reserve (CFVR; via echocardiography) was the key secondary endpoint. Results: Of 129 randomized patients, 128 received treatment (200 mg, n = 52; 50 mg, n = 25; placebo, n = 51). Statistically significant reductions in uLTE4 levels of >80% were observed in both AZD5718 groups versus the placebo group at 4 and 12 weeks. No significant changes in CFVR were observed for AZD5718 versus placebo. Adverse events (AEs) occurred in 12/18, 3/6 and 6/13 patients receiving 200 mg, 50 mg and placebo, respectively, in the 4-week cohort, and in 27/34, 14/19 and 24/38 patients, respectively, in the 12-week cohort. Serious AEs in seven patients receiving AZD5718 and four receiving placebo were not treatment-related, and there were no deaths. Conclusions: In patients with recent myocardial infarction, AZD5718 was well tolerated, and leukotriene biosynthesis was dose-dependently inhibited. No significant changes in CFVR were detected. ClinicalTrials.gov identifier: NCT03317002.

Background The mechanisms underlying rupture of a coronary atherosclerotic plaque and development of myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI) remain unresolved. Increased arginase 1 activity leads to reduced nitric oxide (NO) production and increased formation of reactive oxygen species due to uncoupling of the NO-producing enzyme endothelial NO synthase (eNOS). This contributes to endothelial dysfunction, plaque instability and increased susceptibility to ischemia-reperfusion injury in acute myocardial infarction. Objective The purpose of this study was to test the hypothesis that arginase gene and protein expression are upregulated in patients with STEMI. Methods Two cohorts of patients with STEMI were included. In the first cohort (n = 51), expression of arginase and NO-synthases as well as arginase 1 protein levels were determined and compared to a healthy control group (n = 45). In a second cohort (n = 68) plasma arginase 1 levels and infarct size were determined using cardiac magnetic resonance imaging. Results Expression of the gene encoding arginase 1 was significantly elevated at admission and 24-48 hours after STEMI but not three months post STEMI, in comparison with the control group. Expression of the genes encoding arginase 2 and endothelial NO synthase (NOS3) were unaltered. Arginase 1 protein levels were elevated at admission, 24 hours post STEMI and remained elevated for up to six months. No significant correlation between plasma arginase 1 protein levels and infarct size was observed. Conclusion The markedly increased gene and protein expression of arginase 1 already at admission indicates a role of arginase 1 in the development of STEMI. This article is protected by copyright. All rights reserved.

Background Despite extensive research in atherosclerosis, the mechanisms of coronary atherothrombosis in ST-elevation myocardial infarction (STEMI) patients are undetermined. Objectives Our aim was to find candidate genes involved in STEMI by analysing leucocyte gene expression in STEMI patients, without the influence of secondary inflammation from innate immunity, which was assumed to be a consequence rather than the cause of coronary atherothrombosis. Methods Fifty-one patients were included at coronary angiography because of STEMI. Arterial blood was sampled in the acute phase (P1), at 24-48 h (P2) and at 3 months (P3). Leucocyte RNA was isolated and gene expression analysis was performed by Affymetrix Human Transcriptome Array 2.0. By omission of up- or downregulated genes at P2, secondary changes from innate immunity were excluded. Genes differentially expressed in P1 when compared to the convalescent sample in P3 were determined as genes involved in STEMI. Results Three genes were upregulated at P1 compared to P3; ABCG1 (P = 5.81 × 10-5 ), RAB20 (P = 3.69 × 10-5 ) and TMEM2 (P = 7.75 × 10-6 ) whilst four were downregulated; ACVR1 (P = 9.01 × 10-5 ), NFATC2IP (P = 8.86 × 10-5 ), SUN1 (P = 3.87 × 10-5 ) and TTC9C (P = 7.18 × 10-6 ). These genes were also highly expressed in carotid atherosclerotic plaques. Conclusions We found seven genes involved in STEMI. The study is unique regarding the blood sampling in the acute phase and omission of secondary expressed genes from innate immunity. However, the results need to be replicated by future studies.

Background Persistent, low-grade inflammation likely participates in the pathophysiology of both atherosclerosis and kidney disease. Although high-sensitivity C-reactive protein (hsCRP) predicts future cardiovascular risk in patients with chronic kidney disease (CKD), it is unknown whether hsCRP levels predict adverse renal outcomes in patients with cardiovascular disease.Methods We studied all myocardial infarction (MI) survivors undergoing hsCRP testing >30 days after their MI during routine health care in Stockholm, Sweden (2006-2011), with available information on estimated glomerular filtration rate (eGFR). HsCRP tests measured during hospitalization/emergency room visits, followed by antibiotics or indicative of acute illness, were excluded, together with patients with ongoing/recent cancer, chronic infections, or immunosuppression. Inflammation was defined over a 3-month baseline window. Study outcomes were CKD progression (composite of doubling plasma creatinine, renal replacement therapy, or renal death) and acute kidney injury (AKI, acute creatinine peaks according to Kidney Disease: Improving Global Outcomes criteria). Multivariable Cox regression was used to adjust for age, sex, eGFR, hemoglobin, time since MI, comorbidities, undertaken procedures, and medications.Results A total of 12,905 patients (62% men, mean age 73 years and 3 years since MI) were included, of whom 35% had an eGFR= 2 mg/L were at higher risk of both CKD progression (adjusted hazard ratio 1.42; 95% CI 1.21-1.66) and AKI (1.29; 1.13-1.47) compared to those with hsCRP 10 mg/L). Results were robust across subgroups of patients and after exclusion of events occurring during the first 6-12 months.Conclusions In post-MI patients undergoing routine health care, elevated hsCRP was associated with subsequent risk of AKI and progression of CKD, irrespective of baseline kidney function.

Heart failure (HF) is associated with pathological activation of arginine vasopressin, measured in plasma by the pre-hormone fragment copeptin. We hypothesised that copeptin is elevated and associated with worse prognosis in HF, and that left ventricular assist device (LVAD) therapy and heart transplantation (HTx) are associated with lower levels of copeptin.We measured copeptin in groups of 49 patients with advanced HF, 13 patients one year post-LVAD and 22 patients one year post-HTx and correlated with clinical data and cardiac output. In HF we also assessed the prognostic role of copeptin with Kaplan-Meier analysis and multivariate Cox regression.In HF, median (interquartile range) copeptin was 28 (18-45) pmol/L, after LVAD 16 (6-27) pmol/L, and after HTx 12 (5-20) pmol/L (p overall0.001). In HF, copeptin was an independent predictor of death, LVAD or HTx (hazard ratio for log copeptin, 3.28 [95% confidence interval: 1.66-6.50], p=0.001).Copeptin was elevated in, and independently predicted prognosis in, HF. Copeptin was progressively lower after LVAD and HTx. This suggests that improvement in cardiac output with LVAD and HTx may induce progressively reduced activation of vasopressin, which may be a marker for the beneficial effects of LVAD and HTx.

Background and purpose Excessive MR activation is implicated in the pathogenesis of cardiovascular disease. MR antagonists (MRA) are effective and key guideline-directed therapy in patients with heart failure (HF) with reduced ejection fraction. However, clinical adverse events due to hyperkalaemia and a decline in renal function significantly restricts the treatment. AZD9977 is a novel, non-steroidal selective MR modulator that, compared with MRA, displays a differentiated MR-binding pattern and cofactor recruitment profile, and exerts similar organ protective effects to eplerenone with minimal effects on urinary electrolyte handling. Methods We performed a randomized, placebo-controlled, single-blind phase 1 study to evaluate the safety, tolerability and pharmacokinetics of oral AZD9977 in healthy men. Three sequential ascending dose cohorts were evaluated, and participants received either AZD9977 (n=6) or placebo (n=3) for 8 days. AZD9977 target doses of 50mg bid, 150mg bid and 300mg bid were explored based on a model predicted dose range comparable to and exceeding the target receptor occupancy levels achieved with approved MRA drugs. The dose of AZD9977 50mg bid is predicted to be equipotent to spironolactone 25mg daily. Results 27 healthy male subjects aged 23–45 years completed the study. All doses of AZD9977 were well tolerated with no safety concerns identified. A total of 7 adverse events occurred in 4 participants (22.2%) receiving AZD9977 and 8 events occurred in 6 participants (66.7%) receiving placebo, none severe or resulting in withdrawal from the study. Rapid absorption of AZD9977 was observed with median Tmax values ranging from 0.5 to 0.8-hours post-dose and approximate dose proportional kinetics between 50 to 300 mg twice daily, as measured by AUCτ and Cmax. Steady-state levels in plasma were generally reached within 3–4 days. Target engagement was confirmed by a robust dose-dependent rise in mean serum aldosterone levels between Day −1 and Day 7 (Placebo = 43±172pmol/L, AZD9977 50mg bid = 132±83pmol/L, 150mg bid = 447±242pmol/L, 300mg bid = 808±330pmol/L; Figure 1). AZD9977 had no effect on blood pressure or heart rate and did not alter serum electrolyte levels, urinary Na+ excretion, log urinary Na+/K+ ratio (Figure 2), estimated GFR, or urine volumes when compared to placebo-treated subjects. Figure 1 and Figure 2 Conclusion These observations in humans are consistent with pre-clinical studies, demonstrating robust MR-receptor engagement without changes in serum K+ and renal electrolyte handling. These characteristics could potentially realise the therapeutic benefit of MR blockade with a low risk of hyperkalaemia. This hypothesis is currently being tested clinically in a head-to-head trial of AZD9977 versus spironolactone in patients with HF and impaired renal function (NCT03682497). Acknowledgement/Funding The study was Sponsored and funded by AstraZeneca

Background The mechanisms underlying rupture of a coronary atherosclerotic plaque and development of myocardial ischemia-reperfusion injury in ST-elevation myocardial infarction (STEMI) remain unknown. Increased arginase-1 activity leads to reduced nitric oxide production and increased formation of reactive oxygen species due to uncoupling of the endothelial nitric oxide synthase (eNOS). These events lead to endothelial dysfunction, plaque instability and increased susceptibility to ischemia-reperfusion injury in acute myocardial infarction. Experimental studies have shown that arginase-1 expression and activity are increased in atherosclerosis and during myocardial ischemia-reperfusion. Accordingly, inhibition of arginase-1 reduces atherosclerotic lesion development and limits the extent of infarct size during ischemia-reperfusion via an eNOS-dependent mechanism. Furthermore, arginase-1 inhibition improves endothelial function in patients with coronary artery disease but the potential role of arginase-1 in patients with STEMI is poorly understood. Purpose The purpose of the current study was to test the hypothesis that arginase-1 is upregulated and correlate to infarct size in STEMI patients. Methods and results Two independent cohorts of STEMI patients were included. In cohort 1, plasma and buffy coat leukocytes were collected from 53 STEMI patients at the time of arterial puncture for percutaneous coronary intervention, at 24–48 hours post STEMI and at 3 months post STEMI. Gene expression in leukocytes was determined in 51 patients with Affymetrix Human Transcriptome Array 2.0. In cohort 2, plasma was collected from 82 STEMI patients at admission and at 6 months for determination of plasma arginase-1. These patients underwent cardiac magnetic resonance imaging performed at day 4–7 and at 6 months post STEMI. Plasma arginase-1 levels were quantified with ELISA. Control blood samples were collected from 56 healthy age matched subjects. In cohort 1, ARG1 gene expression was four-fold higher in STEMI patients at admission compared to controls (Figure A). This expression returned to control levels within 3 months. Plasma arginase-1 levels were two times higher in STEMI patients at admission compared to controls, and remained elevated at 24–48 hours and at 3 months post STEMI (Figure B). The increase in plasma arginase-1 in STEMI patients was confirmed in cohort 2 (Figure C). Arginase-1 levels did not correlate with infarct size. Conclusions STEMI patients demonstrate increased gene expression and plasma levels of arginase-1 in the acute setting. In contrast to gene expression plasma arginase-1 levels remain significantly elevated over time. The markedly increased expression of arginase-1 already at admission may suggest a mechanistic role of arginase-1 in the development of STEMI. Further studies are needed to elucidate whether increased expression, induction and activity of arginase-1 are contributing factors for the development of STEMI.

Background Fractalkine is a chemokine that mediates recruitment and extravasation of CX3CR1-expressing subsets of leukocytes and monocytes and has been implicated in the inflammation-driven pathology of cardiovascular disease. More specifically, fractalkine signaling has been proposed to contribute to increased infarct size and enhanced atherosclerotic plaque vulnerability in patients and experimental models. Blocking fractalkine/CX3CR1 signaling is suggested as a promising anti-inflammatory strategy for the treatment of both acute and chronic cardiovascular disease. KAND567 is a small molecule, selective, non-competitive, allosteric antagonist of the fractalkine receptor CX3CR1, that is under preparation for a clinical phase IIa study in AMI patients. Purpose To explore the therapeutic effects of the short and long term administration of KAND567 in experimental rodent models of acute myocardial infarction and atherosclerosis, respectively. Methods Myocardial infarction was induced in Wistar rats (N=6–8 per group) by ligation of the left anterior descending (LAD) coronary artery for 30 minutes followed by 2 h of reperfusion. The drug or vehicle infusion started either 5 min before or 30 min after start of reperfusion and continued during the remainder of the experiment. Hearts were collected and subjected to triphenyl tetrazolium chlorine (TTC) staining and the infarction area/area at risk of the left ventricle was determined by planimetry and compared against vehicle group. Atherosclerosis-prone LDL-receptor deficient mice on a high-cholesterol diet, (N=15–25 per group) were treated with KAND567 for 15–23 weeks. Atherosclerotic plaque development in the thoracic arch was determined by ultrasound imaging and histology. Immunohistochemistry was used to follow changes in the cellular composition in the atherosclerotic lesions. Results In the acute myocardial infarction study, the infusion of KAND567 before the start of reperfusion significantly reduced infarcted/risk area (by up to 50%) as compared to the vehicle group. However, the infusion had no effect on the infarct size when administration was initiated 30 min after start of reperfusion. In the atherogenesis study, oral treatment with KAND567 significantly reduced vascular macrophage infiltration by 50% and reduced intima media thickness. Furthermore, reduced plaque volume and a more stable plaque phenotype was noted following treatment with KAND567. KAND567 experimental results Conclusion Specific inhibition of fractalkine-driven inflammation by KAND567 provides cardioprotective, anti-atherosclerotic and plaque stabilizing effects via mechanisms related to immune cell infiltration, in rodent models. Further studies should be initiated to test if KAND567 is a potential candidate drug, targeting the excessive inflammatory injury associated with ischemia/reperfusion in myocardial infarction and providing plaque stabilization by reducing inflammatory risk for recurrent coronary events.

Background Beyond the controlled setting of trials, scarce information exists on the burden, predictors, and outcomes associated with elevated hs CRP (high‐sensitivity C‐reactive protein) in “real‐world” patients with myocardial infarction ( MI ). Methods and Results We included all‐coming MI survivors undergoing hs CRP testing >30 days after an MI during routine health care in Stockholm, Sweden (2006–2011). hs CRP tests measured during hospitalization/emergency department visits, followed by antibiotics or indicative of acute illness, were excluded, together with patients with ongoing/recent cancer, chronic infections, or immunosuppression. Inflammation was defined over a 3‐month baseline window and associated with subsequent death and major adverse cardiovascular events (composite of MI, ischemic stroke, or cardiovascular death). Included were 17 464 patients (63% men; mean age, 72.6 years) with a median hs CRP level of 2.2 (interquartile range, 1.0–6.0) mg/L and a median of 2.2 (interquartile range, 0.8–4.9) years since their MI . Most (66%) had hs CRP ≥2 mg/L, and 40% had hs CRP >3 mg/L. Lower hemoglobin, lower estimated glomerular filtration rate, and comorbidities (eg, heart failure, peripheral vascular disease, stroke, atrial fibrillation, diabetes mellitus, and rheumatoid diseases) were associated with higher odds of hs CRP ≥2 mg/L. Conversely, previous percutaneous coronary intervention, ongoing renin‐angiotensin blockade, and statins were associated with lower hs CRP ≥2 mg/L odds. Patients with hs CRP ≥2 mg/L were at higher risk of major adverse cardiovascular events (n=3900; adjusted hazard ratio, 1.28; 95% CI, 1.18–1.38) and death (n=4138; adjusted hazard ratio, 1.42; 95% CI, 1.31–1.53). Results were robust across subgroups of patients and after exclusion of events occurring during the first 6 to 12 months. On a continuous scale, the association between hs CRP and outcomes was linear until hs CRP >5 mg/L, plateauing thereafter. Conclusions Most patients with MI exhibit elevated hs CRP levels. Besides identifying populations at high‐inflammatory risk, this study extends the prognostic validity of this biomarker from trial evidence to real‐world healthcare settings.

Background and aims Endothelin-1 (ET-1) and arginase are both suggested to be involved in the inflammatory processes and development of endothelial dysfunction in atherosclerosis. However, information regarding the roles of ET-1 and arginase, as well as the interactions between the two in human atherosclerosis, is scarce. We investigated the expression of ET-1 and its receptors, ETA and ETB, as well as arginase in human carotid atherosclerotic plaques and determined the functional interactions between ET-1 and arginase in endothelial cells and THP-1-derived macrophages. Methods Carotid plaques and blood samples were retreived from patients undergoing surgery for symptomatic or asymptomatic carotid stenosis. Plaque gene and protein expression was determined and related to clinical characteristics. Functional interactions between ET-1 and arginase were investigated in endothelial cells and THP-1 cells. Results Expression of ET-1 and ETB receptors was increased in plaques from patients with symptomatic carotid artery disease. ET-1 was co-localized with arginase 1 and arginase 2 in the necrotic core, together with macrophage markers CD163 and CD68. Arginase 2, ET-1 and ETB receptors were expressed in endothelial cells as well as in smooth muscle cells in the fibrous cap. ET-1 increased arginase 2 mRNA expression and arginase activity in endothelial cells and arginase activity in macrophages. Moreover, ET-1 stimulated formation of reactive oxygen species (ROS) in THP-1-derived macrophages via an arginase-dependent mechanism. Conclusions This is the first study that demonstrates co-localization of ET-1 and arginase 2 in human atherosclerotic plaques. ET-1 stimulated arginase 2 expression and activity in endothelial cells, as well as arginase activity and ROS formation in macrophages via an arginase-dependent mechanism. These results indicate an important interaction between the ET pathway and arginase in human atherosclerotic plaques.

Background Embolism from unstable atheromas in the carotid bifurcation is a major cause of stroke. Here, we analysed gene expression in endarterectomies from patients with symptomatic (S) and asymptomatic (AS) carotid stenosis to identify pathways linked to plaque instability. Methods Microarrays were prepared from plaques (n = 127) and peripheral blood samples (n = 96) of S and AS patients. Gene set enrichment, pathway mapping and network analyses of differentially expressed genes were performed. Results These studies revealed upregulation of haemoglobin metabolism (P = 2.20E-05) and bone resorption (P = 9.63E-04) in S patients. Analysis of subgroups of patients indicated enrichment of calcification and osteoblast differentiation in S patients on statins, as well as inflammation and apoptosis in plaques removed >1 month compared to

Cardiac sarcoidosis (CS) is a potentially life-threatening condition. Early detection of CS is therefore important. The aim of this study was to eludicate the usefulness of different investigations in a subgroup of patients with sarcoidosis regarded as having an increased risk for cardiac involvement.42 sarcoidosis patients, who had an abnormal resting electrocardiogram (ECG) and/or symptoms indicating possible cardiac involvement (i.e. palpitations, pre-syncope or syncope), were included in the study. They were identified in a consecutive manner among patients followed-up at outpatient clinics for respiratory disorders. Holter monitoring, exercise test, transthoracic echocardiogram (TTE), cardiovascular magnetic resonance (CMR) and analysis of N-terminal pro B-type natriuretic peptide (NT-pro-BNP) in serum were performed. Note, that the role of FDG-PET was not investigated in this study.In the group with a pathologic ECG 11/25 (44%) were ultimately diagnosed with CS (all with pathologic CMR). However, in the group with only symptoms but a normal ECG just 1/17 got the diagnosis CS (p0.05). This patient had a pathologic Holter monitoring. The risk for CS was increased if serum NT-pro-BNP was elevated (i.e. NT-pro-BNP125 ng/L), sensitivity 78% (p0.05), specificity 67%. By adding a pathologic ECG to an elevated NT-pro-BNP increased specificity to 93% and sensitivity remained at 78%.Our findings indicate that CMR should be performed at an early stage in sarcoidosis patients with an abnormal resting ECG. Holter monitoring and elevated levels of NT-pro-BNP may enhance the diagnostic accuracy whereas exercise testing and TTE in this study had less impact on the identification of CS.

Arterial wall remodeling is a central multifactorial process in the development and progression of cardiovascular diseases. We employed an approach aimed at observing genetic variants associated with the progression of carotid intima-media thickness (cIMT) in order to identify novel pathways effecting vessel remodeling. This was achieved by conducting gene-centric analysis of 400,000 variants in 3,042 subjects with repeated cIMT measurements. Rs16997464 on chr22 intergenic between neutrophil cytosolic factor-4 ( NCF4) and colony stimulating factor 2 receptor beta ( CSF2RB ) was associated with cIMT progression at array-wide significance (p -7 ). The potential causative genes within this locus were investigated using a human vascular and non-vascular tissue biobank. Expression of 9 genes near rs16997464, were analyzed with the most significant association being with NCF4 in aortic adventitia. The effect of the variant on the function of the NCF4 gene product was further analyzed by comparing the oxidative burst capacity of neutrophils from subjects with different rs16997464 genotypes. We observed that neutrophils homozygous for the minor T allele, associated with slower cIMT progression, produced more extracellular ROS than neutrophils homozygous for the G allele, indicating a functional effect of rs16997464 on the NCF4 gene product p40 phox , a component of the NADPH oxidase 2 complex (NOX2). In parallel, we investigated if the chr22 locus also influenced the cellular composition of the atherosclerotic plaque, by utilizing data from the Athero-Express Biobank. Here we found that the minor T allele associated with a higher smooth muscle cell (SMC) content in the plaque. Finally, using a partial ligation model in mice where ncf4 is mutated, resulting in a reduced but not absent NOX2-associated ROS formation, we observed a reduced neointima formation in the ncf4 -mutated strain compared with wild-type littermates. Thus, this study identified rs16997464 in the NCF4-CSF2RB locus as a novel genetic determinant of cIMT progression, and provides evidence suggesting that NCF4 is involved in SMC proliferation and alteration of vessel wall pathophysiology.

Background: C-reactive protein can be measured by a high-sensitivity assay (hsCRP) to detect persistent low grade vascular inflammation predictive of cardiovascular (CV) risk in patients with history of myocardial infarction (MI). However, the real-world use of hsCRP testing among patient with history of MI, and hence the contemporary usage to address residual inflammatory risk, is unknown Methods: Patients with ≥1 claim with an inpatient, primary diagnosis for MI (ICD-9-CM code: 410.xx) between 01 October 2011 to 30 September 2014 (the most recent set as an index) in MarketScan and 1 year continuous enrolment pre- and post-hospital admission were included Results: A total of 71,071 patients (mean age 63.6 years, 67.6% males) were included. The hsCRP measurement was performed in 3.3% patients (CCAE: 4.7%; Medicare: 1.3%) with a mean time of 4.3 months after the index MI; 81.7% of patients were tested ≥30 days after the index MI. Patient characteristics and resource uses were similar among hsCRP tested and non-tested patients (Table 1) Conclusion: hsCRP testing with a potential to evaluate residual inflammatory CV risk is not used widely in routine clinical practice in US patients with history of MI. No systematic effect of hsCRP testing was observed with respect to patient characteristics and resource use. Further research is warranted to understand and describe the real-world usage of hsCRP testing to evaluate residual inflammatory risk and the associated patient characteristics, outcomes and burden of disease

Genetic factors influence the risk for disease as well as the clinical picture seen in sarcoidosis and especially the genes localized to the human leukocyte antigen (HLA) region on chromosome 6 are of importance. The aim of this study was to further investigate associations between HLA-DRB1 alleles and the risk for extra-pulmonary manifestations (EPMs), i.e. engagement of the skin, superficial lymph nodes, eyes, nervous system, kidneys, hypercalcemia, parotid and salivary glands, heart, liver, spleen and bone marrow in Scandinavian sarcoidosis patients. One thousand patients with together with a group of 2000 healthy individuals, matched for sex and age. HLA-DRB1 alleles were determined for all patients and controls. Excluding erythema nodosum and ankle arthritis, we found 288 of 1000 patients to have EPMs. There were 383 patients with Lofgren's syndrome (LS), and among them EPM were relatively uncommon and diagnosed in only 31 (8.1%) of the patients. In contrast, among the 617 non-LS patients, 257 (41.6%) had EPM (P

Heart transplantation (HTx) and left ventricular assist devices (LVADs) improve symptoms and survival in patients with severe heart failure (HF). LVADs are used mainly as a bridge to transplantation (BTT), but with improving outcomes with continuous-flow devices, they are increasingly used as permanent destination therapy (DT). However, patients with advanced HF are believed to be underserved by HTx and LVAD. Cardiac resynchronization therapy (CRT) and

Background The role of adiponectin as a risk factor for mortality and recurrent ischemic cardiovascular events in patients with carotid artery disease is unknown. Methods Consecutive patients ( n = 292) undergoing carotid endarterectomy for symptomatic and asymptomatic carotid stenosis were included in the study. Mortality and cardiovascular ischemic events were recorded during a median follow-up of 5.2 years. Baseline plasma concentrations of adiponectin were measured. Cox regression models stratified for gender were used for estimation of risk of events. Results Fifty-two patients died and 73 had an ischemic event (ischemic stroke, n = 52 and/or MI, n = 28) during follow-up. In univariate analyses, adiponectin was associated with mortality, hazard ratio (HR) per standard deviation (SD) increase of adiponectin, 1.46 (95% confidence interval [CI], 1.14–1.86). In multivariate analysis age, type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), plasma interleukin-6 (IL-6) and plasma adiponectin (HR per SD increase of adiponectin, 1.73 [95% CI, 1.29–2.32]) were independently associated with mortality. T2DM, CHD, fibrinogen, contralateral carotid artery stenosis, systolic blood pressure, symptomatic carotid artery stenosis were independently associated with ischemic events, whereas plasma adiponectin was not (HR per SD increase of adiponectin, 0.96 [95% CI, 0.75–1.23]). Conclusions High plasma adiponectin concentration is associated with mortality in patients with established atherosclerosis undergoing surgery for carotid artery stenosis. Further studies to determine the role for adiponectin as a biomarker are warranted.

Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants associated with increased risk of coronary artery disease (CAD) and myocardial infarction (MI) by 10% to 30%. The authors state that these loci explain only a small proportion of the predicted genetic risk and that all of the current loci for CAD and MI by GWAS have been discovered in European populations. The authors hypothesized that discovery of new susceptibility loci of smaller effect sizes would be aided by conducting much larger studies in addition to an emphasis on early-onset CAD and clearly defined clinical end points. Therefore, they assembled the Coronary Artery Disease (C4D) Genetics Consortium.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 4 large GWAS of CAD, 2 of European ancestry (PROCARDIS and HPS) and 2 of South Asian ancestry (PROMIS and LOLLIPOP), with ≈575 000 genotyped single-nucleotide polymorphisms (SNPs) in a discovery data set comprising 15 420 individuals with CAD (cases) (8424 Europeans and 6996 South Asians) and 15 062 control subjects. They observed little evidence for ancestry-specific associations, supporting the use of combined analyses. Furthermore, the authors state that because all individuals were genotyped on the same platform (whole-genome Illumina BeadChips), a meta-analysis of actual genotypes rather than imputed data enabled analysis of low-frequency variants (1% to 5%), which have been excluded from GWAS either because of sample size or because imputation has been required to combine data from different genotyping platforms. After the meta-analysis, they selected 59 SNPs from 50 loci that showed potential new associations from the meta-analysis of the European and South Asian studies (41 SNPs; P

A total of 75 cardiovascular patients were investigated for levels of the circulating miR-486-3P. The objective was to find out if any miRNA could distinguish patients with unstable plaque from patients with stable plaque after acute coronary syndrome., Easily accessible biomarkers are needed to diagnose cardiovascular disease precisely—particularly, to distinguish between disease subtypes that are encountered in clinical practice. Per the hypothesis that plasma miRNA is valuable for this purpose, we performed complete transcriptional profiling of an miRNA discovery-set in 14 samples: three patients with ST-elevated acute myocardial infarction (STEMI) at baseline and after three months of follow-up, four with stable ischaemic heart disease (stable-IHD) and four healthy age-matched volunteers. Our aim was to determine whether we could distinguish patients with unstable plaques from stable patients following a STEMI event. After analysing miRNA profiles, we conducted a validation study comparing three-month STEMI (n=40) with stable-IHD (n=35), which confirmed that miR-486-3P differentiates patients with three-month STEMI from those with stable-IHD (P=0.019).

Continuous-flow left ventricular assist devices/systems (LVADs/LVASs) reduce symptoms and mortality in severe heart failure. The impeller or centrifugal designs provide challenges in assessing and titrating pump speed (revolutions per minute [RPM]), flow, and native heart pulsatility, and contribution to cardiac output. The Thoratec HeartMate II (HM II) LVAS is the most commonly used LVAD worldwide. The user sets the RPM and the monitor provides online data on RPM, power consumption, flow, and pulsatility. These parameters are routinely used by clinicians to assess native heart function and to optimize pump settings. However, little is known about their reliability, reproducibility, and variability. Therefore, we assessed HM II controller parameters and concurrent echocardiography during titrations of RPM to low and high values. We found that data displayed on the monitor and logged in the controller are consistent for power consumption and for flow at settings above 8,000 RPM but inconsistent and unreliable for flow at or below 8,000 RPM and for pulsatility throughout a range of common settings and specifically at 9,000 RPM. These findings have implications for clinicians attempting to optimize settings and assess pump and native heart function.

INTRODUCTION:The inflammatory marker C-reactive protein (CRP) can be measured by a high-sensitivity assay (hsCRP) specific to vascular inflammation. We aimed to identify published literature on prevalence of elevated hsCRP and associated clinical, economic, and humanistic burden in patients with a history of myocardial infarction (MI).METHODS:A comprehensive literature search was performed for publications in English between January 2000 and February 2016 in MEDLINE, EMBASE, and MEDLINE In-Process. Search terms were variations on ‘Post myocardial infarction’, ‘CRP’, ‘epidemiology’ and ‘burden’. Clinical and real-world studies reporting baseline CRP levels in patients with a history of MI were included in the analysis.RESULTS:Ten studies (prevalence: two; burden: two; both: six) were included. Cut-off points in hsCRP assays varied from >2 mg/L to ≥5.9 mg/L. Prevalence of hsCRP levels >2, >2.3, ≥2.37 and ≥2.9 mg/L were reported in 36 percent, 49 percent, 50 percent and 33 percent of patients, respectively (one publication each). Two publications reported >3 mg/L levels in 27.6 percent and 53.7 percent of patients. Levels of ≥3.3, ≥3.8, ≥4.2 and ≥5.9 mg/L were found in 38.8 percent, 25 percent, 25 percent and 24.7 percent respectively (one publication each). Of six studies reported CV events, four studies found elevated hsCRP levels to be predictive of future risk. Elevated hsCRP levels independently predicted all-cause mortality in four studies and CV mortality in three studies. Three publications included data on comorbidities: Diabetes was associated with elevated hsCRP in two of three analyses; hypertension in one out of two. No consistent associations between elevated hsCRP levels and hyperlipidaemia (one study), stroke or angina pectoris (one study) were found. No study reported economic, resource use or quality-of-life burden.CONCLUSIONS:Due to limited evidence on prevalence of elevated hsCRP and associated burden of illness in patients with a history of MI, further research is warranted. Variations in findings, cut-off points and methods between studies make generalisations difficult.

Lipoxygenase (ALOX) enzymes are implicated in both pro- and anti-atherogenic processes. The aim of this study was to investigate mRNA expression of 12- and 15-lipoxygenases (ALOX12, ALOX12B, ALOX15, ALOX15B) and the atypical ALOXE3 in human carotid atherosclerotic lesions, in relation to cerebrovascular symptoms and risk factors. The Biobank of Karolinska Endarterectomies (BiKE) collection of human carotid plaque tissue and associated clinical data was utilized (n=132). Lesion mRNA levels were analyzed by TaqMan qPCR (n=132) and microarray hybridization (n=77). Of the investigated mRNAs, only ALOX15B (15-LOX-2; epidermis-type 15-LOX) was readily detected in all plaque samples by qPCR, and thus suitable for quantitative statistical evaluation. ALOX12, ALOX12B, ALOX15 and ALOXE3 were detected with lower frequency and at lower levels, or virtually undetected. Microarray analysis confirmed ALOX15B as the most abundant 12- or 15-lipoxygenase mRNA in carotid lesions. Comparing plaques with or without attributable cerebrovascular symptoms (amaurosis fugax, transient ischemic attack, or stroke), ALOX15B mRNA levels were higher in symptomatic than asymptomatic plaques (1.31 [1.11-1.56], n=102; and 0.79 [0.55-1.15], n=30, respectively; p=0.008; mean [95% CI], arbitrary units). Multiple regression analysis confirmed symptomatic/asymptomatic status as a significant determinant of ALOX15B mRNA levels, independently of potentially confounding factors. Immunohistochemical analyses showed abundant ALOX15B expression in macrophage-rich areas of carotid lesions, and lipidomic analyses demonstrated the presence of typical ALOX15B products in plaque tissue. In summary, we observed associations between high ALOX15B expression in carotid lesions and a history of cerebrovascular symptoms. These findings suggest a link between ALOX15B and atherothrombotic events that merits further investigation.

Agardh HE, Folkersen L, Ekstrand J, Marcus D, Swedenborg J, Hedin U, Gabrielsen A, Paulsson-Berne G (Department of Medicine, Experimental Cardiovascular Research, Karolinska Institutet; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden). Expression of fatty acid–binding protein 4/aP2 is correlated with plaque instability in carotid atherosclerosis. J Intern Med 2011; 269: 200–210. Objective. The molecular basis for atherosclerotic plaque vulnerability with high risk of plaque rupture and thromboembolism is complex. We investigated whether clinical estimates of plaque stability correlate with differentially expressed mRNA transcripts within the lesion. Methods and results. Endarterectomy samples from patients undergoing surgery for symptomatic and asymptomatic carotid stenosis were prospectively collected and clinical parameters recorded in the Biobank of Karolinska Carotid Endarterectomies. mRNA expression profiling (n = 40) and quantitative RT-PCR (n = 105) revealed increased levels of fatty acid–binding protein 4 (FABP4/aP2) in lesions from patients with recent symptoms of plaque instability compared to asymptomatic patients (array: FC = 2, P

Background— Population-based genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with cardiovascular disease or its risk factors. Genes in close proximity to these risk-SNPs are often thought to be pathogenetically important based on their location alone. However, the actual connections between SNPs and disease mechanisms remain largely unknown. Methods and Results— To identify novel susceptibility genes, we investigated how 166 SNPs previously found to be associated with increased cardiovascular risk and/or predisposing metabolic traits relate to the expression of nearby genes. Gene expression in 577 samples of aorta, liver, mammary artery, and carotid atherosclerotic plaque was measured using expression arrays. For 47 SNPs, the expression levels of proximal genes (located within 200 kb) were affected ( P Conclusions— This study demonstrates several instances of association between risk-SNPs and genes immediately adjacent to them. It also demonstrates instances in which the associated gene is not the immediately proximal and obvious candidate gene for disease. This shows the necessity of careful studies of genetic marker data as a first step toward application of genome-wide association studies findings in a clinical setting.

Objectives The aim of this study was to investigate gene expression networks related to cardiovascular disease in radiated human arteries. Background Recent epidemiological studies have shown that radiotherapy is associated with cardiovascular disease years after treatment. However, the molecular mechanisms underlying late effects of radiation are poorly described. Methods Arterial biopsies from radiated and nonradiated human conduit arteries, from the same patient, were simultaneously harvested during microvascular free tissue transfer for cancer-reconstruction in 13 patients, 4 to 500 weeks from radiation treatment. Radiated and nonradiated arteries were compared, with Affymetrix (Santa Clara, California) microarrays on a subset of the material to generate candidate genes. A Taqman (Applied Biosystems, Foster City, California) low-density array of 45 selected genes was designed for analysis of the whole material. Results Thirteen genes were synchronously expressed in all patients (p = 0.0015), including CCL8, CCL3, CXCL2, DUSP5, FGFR2, HMOX1, HOXA9, IL-6, MMP-1, PTX3, RDH10, SOD2, and TNFAIP3. A majority of differentially regulated genes related to the nuclear factor-kappa B (NF-κB) signaling pathway and were dysregulated even years after radiation. The NF-κB activation was confirmed by immunohistochemistry and immunofluorescence. Conclusions In the present study, we found sustained inflammation due to NF-κB activation in human radiated arteries. The results are supported by previous in vitro findings suggesting that deoxyribonucleic acid injury, after radiation, activates NF-κB. We also suggest that HOXA9 might be involved in the regulation of NF-κB activation. The observed sustained inflammatory response can explain cardiovascular disease years after radiation.

Systems biology offers the potential to provide new insights into our understanding of the pathogenesis of complex diseases such as atherosclerosis. It seeks to comprehend the system properties of the non-linear interactions of the multiple biomolecular components that characterize a living organism. An important component of this research approach is identifying the biological networks that connect the differing elements of a system and in the process describe the characteristics that define a shift in equilibrium from a healthy to a diseased state. The utility of this method becomes clear when applied to multifactorial diseases with complex etiologies such as inflammatory-related diseases, herein exemplified by cardiovascular disease. In this study, the application of network theory to systems biology is described in detail and an example is provided using data from a clinical biobank database of carotid endarterectomies from the Karolinska University Hospital (Biobank of Karolinska Endarterectomies, BiKE). Data from 47 microarrays were examined using a combination of Bioconductor modules and the Cytoscape resource with several associated plugins to analyze the transcriptomics data and create a combined gene association and correlation network of atherosclerosis. The methodology and workflow are described in detail, with a total of 43 genes found to be differentially expressed on a gender-specific basis, of which 15 were not directly linked to the sex chromosomes. In particular, the APOC1 gene was 2.1-fold down-regulated in plaques in women relative to men and was selected for further analysis based upon a purported role in cardiovascular disease. The resulting network was identified as a scale-free network that contained specific sub-networks related to immune function and lipid biosynthesis. These sub-networks link atherosclerotic-related genes to other genes that may not have previously known roles in disease etiology and only evidence small alterations, which are challenging to find by statistical and comparison-based methods. A number of Gene Ontology (GO), BioCarta and KEGG pathways involved in the atherosclerotic process were identified in the constructed sub-network, with 19 GO pathways related to APOC1 of which 'phospholipid efflux' evidenced the strongest association. The utility and functionality of network analysis and the different Cytoscape plugins employed are discussed. Lastly, the applications of these methods to cardiovascular disease are discussed with focus on the current limitations and future visions of this emerging field.

Objective— Based on the emerging importance of the wingless (Wnt) pathways in inflammation and vascular biology, we hypothesized a role for Dickkopf-1 (DKK-1), a major modulator of Wnt signaling, in atherogenesis and plaque destabilization. Methods and Results— We report increased levels of DKK-1 in experimental (ApoE −/− mice) and clinical (patients with coronary artery disease [n=80] and patients with carotid plaque [n=47]) atherosclerosis, both systemically (serum) and within the lesion, with particularly high levels in advanced and unstable disease. We identified platelets as an important cellular source of DKK-1 as shown by in vitro experiments and by immunostaining of thrombus material obtained at the site of plaque rupture in patients with acute ST-elevation myocardial infarction, with strong immunoreactivity in platelet aggregates. Our in vitro experiments identified a role for platelet- and endothelial-derived DKK-1 in platelet-dependent endothelial activation, promoting enhanced release of inflammatory cytokines. These inflammatory effects of DKK-1 involved inhibition of the Wnt/β-catenin pathway and activation of nuclear factor κB. Conclusion— Our findings identify DKK-1 as a novel mediator in platelet-mediated endothelial cell activation. The demonstration of enhanced DKK-1 expression within advanced carotid plaques may suggest that this DKK-1-driven inflammatory loop could be operating within the atherosclerotic lesion.

YKL-40 is involved in remodelling and angiogenesis in non-cardiac inflammatory diseases. Aim was to quantitate plasma YKL-40 in patients with ST-elevation myocardial infarction (STEMI) or stable chronic coronary artery disease (CAD), and YKL-40 gene activation in human myocardium.We included 73 patients: I) 20 patients with STEMI; II) 28 patients with stable CAD; III) 15 CAD patients referred for coronary by-pass surgery. YKL-40 mRNA expression was measured in myocardium subtended by stenotic or occluded arteries and areas with no apparent disease; and IV) 10 age-matched healthy controls. Plasma YKL-40 was significantly increased in patients with STEMI (88 microg/l, median) and CAD (66 microg/l) compared to controls (16 microg/l, p0.01 for both). Plasma YKL-40 correlated with CRP at baseline in STEMI (r=0.53, p=0.02) and CAD patients (r=0.41, p=0.031).YKL-40 gene expression was similar in ischemic and non-ischemic myocardium.Plasma YKL-40 was significantly increased in patients with STEMI and stable CAD. Further studies will define the role of YKL-40 as a clinically useful marker for myocardial ischemia, remodelling and maybe prognosis.

Objective—Neutrophil gelatinase-associated lipocalin (NGAL) modulates the activity of matrix metalloproteinase (MMP) 9, an important mediator of vascular remodeling and plaque instability in atherosclerosis. This study aimed to analyze the expression of NGAL in atherosclerotic plaques and myocardial infarction (MI).Methods and Results—Atherosclerotic apolipoprotein E (apoE)−/−× low-density lipoprotein receptor (LDLR)−/−and C57BL/6J control mice were exposed to brief hypoxic stress (10 minutes of 10% oxygen). Expression of the mouse NGAL homolog (24p3) and MMP-9 was analyzed 48 hours later by quantitative RT-PCR, immunohistochemistry, and zymography. Hypoxic stress increased NGAL/24p3 mRNA in the cardiac vasculature. NGAL/24p3 was also increased in atherosclerotic plaques of apolipoprotein E−/−× LDLR−/−mice compared with C57BL/6J mice. Mice developing MI exhibited the highest plaque mRNA expression of NGAL/24p3 and MMP-9. Zymography revealed strong proteolytic activity in areas rich in 24p3 and MMP-9 protein. Immunohistochemistry performed on human carotid endarterectomy specimens and control tissue from the internal mammary artery showed colocalization of MMP-9 and NGAL with macrophages in the atherosclerotic plaques.Conclusions—NGAL/24p3 is increased in atherosclerotic plaques and MI. Colocalization with MMP-9 in areas with high-proteolytic activity suggests a role for NGAL/24p3 in modulating the MMP-9-mediated remodeling of plaques and infarcted hearts.

The hypothesis was tested that suppression of generation of ANG II is one of the mechanisms of the water immersion (WI)-induced natriuresis in humans. In one protocol, eight healthy young males were subjected to 3 h of 1) WI (WI + placebo), 2) WI combined with ANG II infusion of 0.5 ng · kg−1· min−1(WI + ANG II-low), and 3) a seated time control (Con). In another almost identical protocol, 7–10 healthy young males were investigated to delineate the tubular site(s) of action of ANG II by the lithium clearance method (CLi) and were on an additional fourth study day subjected to infusion of ANG II at a rate of 1.5 ng · kg−1· min−1(WI + ANG II-high). During WI + placebo, plasma concentration of ANG II decreased from 16 ± 2 to 8 ± 1 pg/ml ( P < 0.05) and renal sodium excretion increased from 104 ± 15 to 294 ± 27 μmol/min ( P < 0.05). During WI + ANG II-low, plasma ANG II was not suppressed by WI, and the natriuresis was blunted by 52 ± 13% ( P < 0.05). During WI + ANG II-low and WI + ANG II-high, an increase in CLiwas prevented that was otherwise observed during WI, and fractional distal reabsorption of sodium was facilitated. In conclusion, maintaining plasma concentration of ANG II unchanged at the level of control attenuates the natriuresis of WI considerably in humans. Therefore, suppression of generation of ANG II is an important mechanism of the natriuresis of WI in humans. Furthermore, infusion of ANG II during WI prevents an otherwise induced increase in CLiand facilitates the fractional distal reabsorption of sodium, probably via an effect on aldosterone release.

We tested the hypothesis that atrial distension (stimulation of cardiopulmonary baroreceptors) is not the single pivotal stimulus for the acute suppression of renin release during water immersion in humans and that immersion-induced haemodilution constitutes an important additional stimulus. In nine healthy male subjects, identical increases in atrial distension were induced by two immersion procedures (of 30 min each); one without (WI) and one with attenuation (WI + cuff) of the concomitant haemodilution (estimated from changes in plasma protein concentration) by inflating thigh cuffs during immersion. During WI, central venous pressure (CVP) and left atrial diameter (LAD) increased (P < 0.05) by 5.5 +/- 0.4 mmHg and 4.6 +/- 0.5 mm, respectively, and plasma protein concentration and plasma renin activity (PRA) progressively decreased (P < 0.05) by 4.8 +/- 0.5 g L(-1) and 1.6 +/- 0.2 ng mL(-1) h(-1) (to 49 +/- 4% of baseline values), respectively. The WI + cuff caused similar atrial distension as WI (CVP and LAD increased by 6.9 +/- 0.5 mmHg and 5.5 +/- 0.5 mm, respectively), attenuated haemodilution (plasma protein concentration decreased by 1.9 +/- 0.4 g L(-1), P < 0.05 vs. WI), and markedly inhibited suppression of PRA, which decreased by 0.4 +/- 0.1 ng mL(-1) h(-1) (to 87 +/- 4% of baseline values, P < 0.05 vs. WI). Differences in renin release could not be accounted for by differences in mean arterial pressure. In conclusion, baroreceptor stimulation induced by atrial distension is not the single pivotal stimulus for the acute suppression of renin release in response to intravascular volume expansion by water immersion in humans. Haemodilution constitutes a significant and conceivably the principal stimulus for the acute immersion-induced suppression of renin-angiotensin system activity.

International audience; Background/objectives - In heart failure (HF), activation of brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP) and adrenomedullin (ADM) is adaptive. The activation of these peptides in relation to different HF phenotypes such as HF with preserved ejection fraction (HFpEF), reduced ejection fraction (HFrEF) and after left ventricular assist device (LVAD) and heart transplantation (HTx) remains poorly characterized. Methods - We measured and compared N-terminal (NT)-proBNP, mid-regional (MR)-proANP and mid-regional (MR)-proADM in 86 patients with HFpEF, 49 patients with HFrEF, 13 patients one year post-LVAD and 22 patients one year post-HTx. We assessed their prognostic impact using Kaplan-Meier analysis and multivariable Cox regression. Results - In HFpEF, HFrEF, LVAD and HTx, NT-proBNP, median (inter-quartile range), was 1000 (465-2335), 3145 (1475-5190), 1430 (986-2570), and 208 (127-353) pmol/L, p < 0.001. MR-proANP was 313 (192-381), 449 (325-596), 276 (216-305), and 118 (96-163) pmol/L, p < 0.001. MR-proADM was 1.2 (0.9-1.6), 1.3 (0.9-2.0), 0.9 (0.7-1.4), and 0.7 (0.6-0.9) nmol/L, p < 0.001 overall and p = 0.212 HFpEF versus HFrEF. In both HFpEF and HFrEF, NT-proBNP and MR-proANP predicted survival free from HTx or LVAD, independent of age, gender, NYHA class and eGFR, whereas MR-proADM did not. Conclusions - Patterns of the cardiomyocyte stress hormones NT-proBNP and MR-proANP suggest that compared to HFrEF, HFpEF may represent milder disease and LVAD and HTx may represent progressive resolution of HF severity. NT-proBNP and MR-proANP independently predicted prognosis in both HFpEF and HFrEF. In contrast, MR-proADM did not distinguish between HFpEF and HFrEF, did not predict prognosis in either, and may be more non-specific in HF.

Embolism from atherosclerotic plaques in the carotid artery is a major cause of stroke, disability and death. The aim of this project was to explore gene expression signatures and clinical parameters of carotid plaque instability in the Biobank of Karolinska Endarterectomies (BiKE). Whole transcriptome profiling by microarrays was performed on n=127 plaques from n=40 asymptomatic (AS) and n=87 symptomatic (S) patients, and on n=10 normal arteries. After normalization and gender adjustments, differential gene expression was assessed by multiple t-tests with Bonferroni correction. Gene set enrichment and pathway analyses were done using DAVID software. Genes significantly upregulated between S and AS plaques were associated with oxidative stress, immune system activation, exopeptidases, lipoprotein particle clearance and bone resorption, Transcription factors and markers of smooth muscle cells were downregulated in this comparison. When S patients with transitory ischemic attacks and minor stroke were compared with amaurosis fugax , most enriched GO terms were angiogenesis, oxidoreductases and inflammation. Patients on statins showed enrichment of calcification, osteoblast differentiation and negative regulation of angiogenesis. Prolonged immune response, lymphocyte activation and apoptosis were processes ongoing in plaques obtained >1 month compared to 0.90, p In conclusion, analysis of the largest existing global transcriptome database of carotid atherosclerosis reveals novel genes and pathways related to patient phenotype, confirms the important role of inflammation and lipid metabolism, and highlights the role of repair processes and lymphocyte activation in human atherosclerosis.

Extracorporeal and implantable mechanical circulatory support devices are increasingly used for refractory cardiogenic shock. We describe a patient with a continuous-flow left ventricular assist device (LVAD) who developed refractory ventricular fibrillation (VF) and deteriorating right ventricular function, requiring emergency implantation of venoarterial extracorporeal membrane oxygenation (ECMO), which supported the patient for 23 days of continuous VF until urgent transplantation. We illustrate challenges in managing parallel competing flows in the 2 circuits (Figure). Figure. Schematic illustration of parallel extracorporeal membrane oxygenation (ECMO) and left ventricular assist device (LVAD). The ECMO flow bypasses the lungs and LVAD. The LVAD flow consists of pulmonary venous return and aortic regurgitant flow (illustration AB Typofom). The patient is a 45-year-old man with dilated cardiomyopathy and a HeartMate II (Thoratec, Pleasanton, CA) as a bridge to …

During prolonged, static carotid baroreceptor stimulation by neck suction (NS) in seated humans, heart rate (HR) decreases acutely and thereafter gradually increases. This increase has been explained by carotid baroreceptor adaptation and/or buffering by aortic reflexes. During a posture change from seated to supine (Sup) with similar carotid stimulation, however, the decrease in HR is sustained. To investigate whether this discrepancy is caused by changes in central blood volume, we compared ( n = 10 subjects) the effects of 10 min of seated NS (adjusted to simulate carotid stimulation of a posture change), a posture change from seated to Sup, and the same posture change with left atrial (LA) diameter maintained unchanged by lower body negative pressure (Sup + LBNP). During Sup, the prompt decreases in HR and mean arterial pressure (MAP) were sustained. HR decreased similarly within 30 s of NS (65 ± 2 to 59 ± 2 beats/min) and Sup + LBNP (65 ± 2 to 58 ± 2 beats/min) and thereafter gradually increased to values of seated. MAP decreased similarly within 5 min during Sup + LBNP and NS (by 7 ± 1 to 9 ± 1 mmHg) and thereafter tended to increase toward values of seated subjects. Arterial pulse pressure was increased the most by Sup, less so by Sup + LBNP, and was unchanged by NS. LA diameter was only increased by Sup. In conclusion, static carotid baroreceptor stimulation per se causes the acute (

We hypothesized that the more-pronounced hypotensive and bradycardic effects of an antiorthostatic posture change from seated to supine than water immersion are caused by hydrostatic carotid baroreceptor stimulation. Ten seated healthy males underwent five interventions of 15-min each of 1) posture change to supine, 2) seated water immersion to the Xiphoid process (WI), 3) seated neck suction (NS), 4) WI with simultaneous neck suction (−22 mmHg) adjusted to simulate the carotid hydrostatic pressure increase during supine (WI + NS), and 5) seated control. Left atrial diameter increased similarly during supine, WI + NS, and WI and was unchanged during control and NS. Mean arterial pressure (MAP) decreased the most during supine (7 ± 1 mmHg, P < 0.05) and less during WI + NS (4 ± 1 mmHg) and NS (3 ± 1 mmHg). The decrease in heart rate (HR) by 13 ± 1 beats/min ( P < 0.05) and the increase in arterial pulse pressure (PP) by 17 ± 4 mmHg ( P< 0.05) during supine was more pronounced ( P < 0.05) than during WI + NS (10 ± 2 beats/min and 7 ± 2 mmHg, respectively) and WI (8 ± 2 beats/min and 6 ± 1 mmHg, respectively, P < 0.05). Plasma vasopressin decreased only during supine and WI, and plasma norepinephrine, in addition, decreased during WI + NS ( P < 0.05). In conclusion, WI + NS is not sufficient to decrease MAP and HR to a similar extent as a 15-min seated to supine posture change. We suggest that not only static carotid baroreceptor stimulation but also the increase in PP combined with low-pressure receptor stimulation is a possible mechanism for the more-pronounced decrease in MAP and HR during the posture change.

The hypothesis that graded expansion of central blood volume by water immersion to the xiphoid process and neck would elicit a graded decrease in forearm vascular resistance was tested. Central venous pressure increased (P < 0.05) by 4.2 +/- 0.4 mmHg (mean +/- SEM) during xiphoid immersion and by 10.4 +/- 0.5 mmHg during neck immersion. Plasma noradrenaline was gradually suppressed (P < 0.05) by 62 +/- 8 and 104 +/- 11 pg mL-1 during xiphoid and neck immersion, respectively, indicating a graded suppression of sympathetic nervous activity. Plasma concentrations of arginine vasopressin were suppressed by 1.5 +/- 0.5 pg mL-1 (P < 0.05) during xiphoid immersion and by 2.0 +/- 0.5 pg mL-1 during neck immersion (P < 0.05 vs. xiphoid immersion). Forearm subcutaneous vascular resistance decreased to the same extent by 26 +/- 9 and 28 +/- 4% (P < 0.05), respectively, during both immersion procedures, whereas forearm skeletal muscle vascular resistance declined only during neck immersion by 27 +/- 6% (P < 0.05). In conclusion, graded central blood volume expansion initiated a graded decrease in sympathetic nervous activity and AVP-release. Changes in forearm subcutaneous vascular resistance, however, were not related to the gradual withdrawal of the sympathetic and neuroendocrine vasoconstrictor activity. Forearm skeletal muscle vasodilatation exhibited a more graded response with a detectable decrease only during immersion to the neck. Therefore, the forearm subcutaneous vasodilator response reaches saturation at a lower degree of central volume expansion than that of forearm skeletal muscle.