[Show abstract][Hide abstract] ABSTRACT: Background:
There is increasing interest in measurements of cardiovascular (CV) biomarker concentrations for risk prediction in the general population. We investigated the prognostic utility of a panel of novel CV biomarkers and their changes over time.
We measured concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional proadrenomedullin, high-sensitivity cardiac troponin I, growth-differentiation factor-15 (GDF-15), soluble ST2 (sST2), and galectin-3 at baseline and 5 years later in 1016 elderly individuals participating in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Assessed outcomes included all-cause mortality and fatal and nonfatal CV events (in participants without CV disease at baseline) during 10 years of follow-up.
GDF-15 exhibited the strongest association with all-cause mortality (n = 158) with a hazard ratio (HR) per 1-SD increase in standardized ln GDF-15 of 1.68 (95% CI, 1.44-1.96). NT-proBNP was the only biomarker to predict CV events (n = 163; HR 1.54 [95% CI, 1.30-1.84]). GDF-15 and NT-proBNP also improved metrics of discrimination and reclassification of the respective outcomes. Changes in GDF-15 concentrations between 70 and 75 years predicted all-cause mortality whereas changes in NT-proBNP predicted both outcomes. The other biomarkers and their temporal changes provided only moderate prognostic value apart from sST2 which had a neutral relationship with adverse events.
Evaluation of temporal changes in GDF-15 and NT-proBNP concentrations improves risk prediction in an elderly population. These findings are of considerable interest given the emphasis on biomarkers as tools to identify and monitor at-risk individuals with preclinical and potentially modifiable stages of CV disease.
Full-text · Article · Jan 2016 · Clinical Chemistry
[Show abstract][Hide abstract] ABSTRACT: Objectives:
An assay for molecular imaging of myocardial CXCR4 expression was evaluated, in order to obtain mechanistic insights noninvasively based on quantitative positron emission tomography (PET).
The chemokine receptor CXCR4 has emerged as a therapeutic target after acute myocardial infarction (AMI), because of its role in inflammatory and progenitor cell recruitment.
PET with the specific CXCR4 ligand, gallium-68 ((68)Ga)-pentixafor, was performed in mice (n = 53) and compared with ex vivo autoradiography, immunohistochemistry, and left ventricular flow cytometry. In addition, 12 patients were imaged at 2 to 8 days after AMI.
In mice, (68)Ga-pentixafor identified regional CXCR4 upregulation in the infarct region, peaking at 3 days (infarct/remote [I/R] ratio 1.5 ± 0.2 at 3 days vs. 1.2 ± 0.3 at 7 days; p = 0.03), corresponding to a flow cytometry-based peak of CD45+ leukocytes and immunohistochemical detection of CD68+ macrophages and Ly6G+ granulocytes. Blockade with the CXCR4 antagonist AMD3100 abolished the signal. No specific uptake was found in sham-operated or control animals. Long-term treatment with oral enalapril attenuated the CXCR4 signal (I/R 1.2 ± 0.2 at 3 days and 1.0 ± 0.0.1 at 7 days; p = 0.01 vs. untreated). Patients showed variable degrees of CXCR4 upregulation in the infarct region. No single clinical parameter allowed for prediction of CXCR4 signal strength. At multivariate analysis, a combination of infarct size and time after reperfusion predicted the CXCR4 infarct signal (rmultiple = 0.73; p = 0.03). Infarct signal in the myocardium was paralleled by elevated pentixafor uptake in bone marrow (r = 0.61; p = 0.04), which highlighted systemic interactions.
Targeted PET imaging with (68)Ga-pentixafor identifies the global and regional CXCR4 expression pattern in myocardium and systemic organs. CXCR4 upregulation after AMI coincides with inflammatory cell infiltration, but shows interindividual variability in patients. This may have implications for the response to CXCR4- or other inflammation-targeted therapy, and for subsequent ventricular remodeling.
No preview · Article · Nov 2015 · JACC. Cardiovascular imaging
[Show abstract][Hide abstract] ABSTRACT: Purpose: The outcome of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF) has improved by computed tomography (CT) or magnetic resonance (MR) for the characterization of left atrium (LA) anatomy before the procedure. However, no comparative data between CT and MR have been described regarding to the impact of different imaging modality. The aim of this study is to compare the procedural characteristics, overall radiation exposure and clinical outcomes between RFCA guided by image integration with CCT versus CMR.
Methods: Four hundred consecutive patients with drug-refractory paroxysmal or persistent AF were randomized to CT (Group 1; N: 200; mean age 61.6±10.9 yo; male:155) or MR (Group 2; N: 200; mean age 59.7±10.4 yo; male:166) for evaluation of LA before RFCA. CT was performed with 64-slices scanner and MR was performed with 1.5-T scanner using a non-triggered contrast enhancement magnetic resonance angiography sequence. All patients were subsequently treated by image integration-supported RFCA. Left atrium diameter, left atrium volume, variant of pulmonary veins anatomy, pulmonary veins ostial dimensions, procedural characteristics, overall radiation exposure and rate of AF recurrence were measured and compared between the two groups.
Results: The two groups were homogeneous in terms of demographic characteristics, cardiovascular risk factors, prevalence of persistent AF, medical therapy and echocardiographic characteristics. The mean follow-up was similar (557±302 vs. 523±265 days, respectively, p:0.24). Group 1 showed higher LA volume versus group 2 (117±46 vs. 101±40 mL, p<0.001). The procedural characteristics [fluoroscopy time (32.6±16.0 vs. 35.0±16.6 min, p:0.15); procedural duration (180.2±59.0 vs. 182.8±53.5, p:0.65, pulmonary veins identified (4±0.1 vs. 3.9±0.2, p:0.08); pulmonary veins targeted (3.9±0.4 vs. 3.9±0.4, p: 053); pulmonary veins isolated (3.9±0.4 vs. 3.9±0.4, p:0.9)] and the rate of AF recurrence (29% vs. 26%, p:0.5) were similar between the two groups. Group 1 showed a higher overall cumulative radiation exposure (40.4±23.7 vs. 32.8±23.5, p<0.005). and LA volume measured by MR was the most robust independent predictor of AF recurrence at multivariate analysis [(HR: 1.08 (1.01–1.15), p:0.02]
Conclusions: CT and MR appear to provide similar information before RFCA. However, MR integration- supported RFCA procedure seems to be associated with a lower overall cumulative radiation despite similar outcome in comparison with CT-guided RFCA.
No preview · Article · May 2015 · European Heart Journal Cardiovascular Imaging
[Show abstract][Hide abstract] ABSTRACT: Background: While area detector computed tomography (ADCT) is a useful tool for coronary artery disease (CAD) evaluation, myocardial perfusion imaging (MPI) with single photon emission computed tomography is a well-established method of predicting functional relevance of CAD. Purpose: We assess the usefulness for decision making using both ADCT and MPI and discussed from the standpoint of cost for diagnostic work-up and contrast agent. Method: Between January, 2013 to September, 2014, 78 patients underwent both ADCT and MPI within two months were analyzed their therapeutic strategy. From ADCT, severity of stenosis was divided non-significant(less than 50%), moderate (over or equal to 50% and less than 75%) and severe (over or equal to 75%). Summed difference score of MPI was judged as ischemia positive.
Result: Table showed the result and executed treatment strategy. Patients with significant stenosis by ADCT were 40 patients (51.3%) and patients with ischemia positive were 25 patients (33.8%). Invasive revasculization was performed higher (82.3%, p<0.01) for the patients with significant stenosis and ischemia than moderate stenosis with ischemia (25%) or significant stenosis without ischemia (39.1%). Before taking invasive therapy, examination with ADCT and MPI saved 63700 yen and about 100ml of contrast agent in each case based study as it was compared with the case with ADCT and coronary angiography without MPI in spite of slightly higher radiation dose (4mSv). Conclusion: The combined use of ADCT and MPI could choose effectively treatment strategy of CAD with a reduction of cost and contrast agent.
[Show abstract][Hide abstract] ABSTRACT: Background:
Up to 50% of the patients still die or have to be rehospitalized during the first year after transcatheter aortic valve replacement (TAVR). This emphasizes the need for more strategic patient selection. The aim of this prospective observational cohort study was to compare the prognostic value of risk scores and circulating biomarkers to predict all-cause mortality and rehospitalization in patients undergoing TAVR.
We calculated the hazard ratios and C-statistics (area under the curve [AUC]) of 4 risk scores (logistic European System for Cardiac Operative Risk Evaluation [EuroSCORE], EuroSCORE II, Society of Thoracic Surgeons predicted risk of mortality, and German aortic valve score) and 5 biomarkers of inflammation and/or myocardial dysfunction (high-sensitivity C-reactive protein, growth differentiation factor (GDF)-15, interleukin-6, interleukin-8, and N-terminal pro-B-type natriuretic peptide) for the risk of death (n = 80) and the combination of death or rehospitalization (n = 132) during the first year after TAVR in 310 consecutive TAVR patients.
The EuroSCORE II and GDF-15 had the strongest predictive value for 1-year mortality (EuroSCORE II, AUC 0.711; GDF-15, AUC 0.686) and for the composite end point (EuroSCORE II, AUC 0.690; GDF-15, AUC 0.682). When added to the logistic EuroSCORE and EuroSCORE II, GDF-15 enhanced the prognostic performance of the score and enabled substantial reclassification of patients. Combinations of increasing tertiles of the logistic EuroSCORE or EuroSCORE II and GDF-15 allowed the stratification of the patients into subgroups with mortality rates ranging from 4.0% to 49.1% and death/rehospitalization rates ranging from 15.3% to 68.4%.
Our study identified GDF-15 in addition to the logistic EuroSCORE and the EuroSCORE II as the most promising predictors of a poor outcome after TAVR.
Full-text · Article · Mar 2015 · Journal of the American College of Cardiology
[Show abstract][Hide abstract] ABSTRACT: Manic depression is searching my soul, I know what I want, but I just don’t know, honey, how to go about getting it. Jimi Hendrix Infusion of autologous bone marrow mononuclear cells (BMMCs) into the infarct-related coronary artery has been shown in clinical trials to improve systolic function in patients with a large ST-segment elevation myocardial infarction (STEMI).1 Based on these results, it was hoped that BMMC infusions may represent a new strategy to protect this vulnerable patient population that continues to be at high risk of developing chronic heart failure. Trial results have been rather heterogeneous, however, and the latest clinical trials—timing in myocardial infarction evaluation (TIME) and SWiss Multicenter Intracoronary Stem Cells Study in Acute Myocardial Infarction (SWISS-AMI)—did not confirm a significant impact of BMMCs on LVEF after STEMI.S1 S2 To make matters worse, a hotly debated meta-analysis by Francis and colleagues has cast doubt on the scientific integrity of the available trial evidence. This study examined reports (abstracts and final publications) of all available BMMC trials for discrepancies in design, methods or results and reported a positive correlation between the number of discrepancies and the magnitude of LVEF improvement.S3 Given these recent developments, it has been argued that the clinical validation process of BMMC therapy may approach a dead end,S4 and that physicians need to reconsider whether BMMC therapies should be pursued at all.S5 It seems, the field has fallen into a state of depression and it is uncertain whether it will ever recover. Contrast this with the stem cell mania at the turn of the century, when a report that bone marrow-derived stem cells can generate de novo myocardium,S6 a claim that has been refuted since,S7 S8 electrified cardiologists around the globe (including this editorialist) and stimulated the first … [Full text of this article]
No preview · Article · Jan 2015 · Heart (British Cardiac Society)
[Show abstract][Hide abstract] ABSTRACT: Paracrine-acting proteins are emerging as a central mechanism by which bone marrow cell-based therapies improve tissue repair and heart function after myocardial infarction (MI). We carried out a bioinformatic secretome analysis in bone marrow cells from patients with acute MI to identify novel secreted proteins with therapeutic potential. Functional screens revealed a secreted protein encoded by an open reading frame on chromosome 19 (C19orf10) that promotes cardiac myocyte survival and angiogenesis. We show that bone marrow-derived monocytes and macrophages produce this protein endogenously to protect and repair the heart after MI, and we named it myeloid-derived growth factor (MYDGF). Whereas Mydgf-deficient mice develop larger infarct scars and more severe contractile dysfunction compared to wild-type mice, treatment with recombinant Mydgf reduces scar size and contractile dysfunction after MI. This study is the first to assign a biological function to MYDGF, and it may serve as a prototypical example for the development of protein-based therapies for ischemic tissue repair.
[Show abstract][Hide abstract] ABSTRACT: Coronary heart disease is one of the main causes of death in the developed world, and treatment success remains modest, with high mortality rates within 1 year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases, including heart disease. Here we address the potential of telomerase (Tert) activation in prevention of heart failure after MI in adult mice. We use adeno-associated viruses for cardiac-specific Tert expression. We find that upon MI, hearts expressing Tert show attenuated cardiac dilation, improved ventricular function and smaller infarct scars concomitant with increased mouse survival by 17% compared with controls. Furthermore, Tert treatment results in elongated telomeres, increased numbers of Ki67 and pH3-positive cardiomyocytes and a gene expression switch towards a regeneration signature of neonatal mice. Our work suggests telomerase activation could be a therapeutic strategy to prevent heart failure after MI.
Full-text · Article · Dec 2014 · Nature Communications
[Show abstract][Hide abstract] ABSTRACT: Purpose
Myocardial inflammation is an emerging target for novel therapies and thus for molecular imaging. Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) has been employed, but requires an approach for suppression of cardiomyocyte uptake. We tested clinically viable strategies for their suitability in mouse models in order to optimize preclinical imaging protocols.
C57BL/6 mice (n = 56) underwent FDG PET under various conditions. In healthy animals, the effect of low-dose (5 units/kg) or high-dose (500 units/kg, 15 min prior) intravenous heparin, extended fasting (18 h) and the impact of conscious injection with limited, late application of isoflurane anaesthesia after 40 min of conscious uptake were examined in comparison to ketamine/xylazine anaesthesia. Conscious injection/uptake strategies were further evaluated at 3 days after permanent coronary artery occlusion.
Under continuous isoflurane anaesthesia, neither heparin administration nor extended fasting significantly impacted myocardial 18F-FDG accumulation. Injection with 40 min uptake in awake mice resulted in a marked reduction of global myocardial 18F-FDG uptake compared to standard isoflurane anaesthesia (5.7 ± 1.1 %ID/g vs 30.2 ± 7.9 %ID/g, p
No preview · Article · Nov 2014 · European journal of nuclear medicine and molecular imaging
[Show abstract][Hide abstract] ABSTRACT: Background:
The American Heart Association Cardiovascular Health score (CVH score) is inversely associated with cardiovascular disease (CVD) incidence, but the mechanisms underlying this association warrant exploration.
Methods and results:
We related the CVH score to circulating biomarkers and prevalent subclinical CVD (defined as ≥1 of the following: increased carotid intima-media thickness or stenosis, left ventricular hypertrophy [by ECG or echocardiography], left ventricular systolic dysfunction, microalbuminuria, and a reduced ankle-brachial index) in 2680 Framingham Study participants (mean age, 58 years; 55% women). After adjustment for age and sex, an ideal CVH score (nonsmoking status, ideal body mass index, regular physical activity, healthy diet, and an optimal profile of serum cholesterol, blood pressure, and glucose; 1 point for each) was associated with higher circulating concentrations of natriuretic peptides (N-terminal pro-atrial natriuretic peptide and B-type natriuretic peptide) and lower blood concentrations of plasminogen activator inhibitor-1, aldosterone, C-reactive protein, D-dimer, fibrinogen, homocysteine, and growth differentiation factor-15 levels (P<0.001 for all), as well as lower odds of subclinical disease (odds ratio, 0.74 per 1-unit increase in CVH score; 95% confidence interval, 0.68-0.80). The incidence of CVD (267 events over 16 years) was inversely associated with the CVH score in age- and sex-adjusted models (hazard ratio, 0.77 per 1-unit increase in CVH score; 95% confidence interval, 0.70-0.86), which was slightly attenuated upon adjustment for biomarkers and subclinical disease (hazard ratio, 0.87; 95% confidence interval, 0.78-0.97).
In our prospective community-based study, the inverse association between an ideal cardiovascular health score and CVD incidence was partly attributable to its favorable impact on CVD biomarker levels and subclinical disease.
[Show abstract][Hide abstract] ABSTRACT: Background:
Biomarkers of cardiovascular stress have been associated with incident cardiovascular outcomes. Their relations with measures of subclinical atherosclerosis, as assessed by carotid intima-media thickness, have not been well described.
We measured plasma growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) in 3111 Framingham Offspring participants who also underwent carotid ultrasonography during the sixth examination (1995-1998, mean age 58 years, 54% women). Carotid measurements included maximal internal carotid artery (ICA) intima-media thickness (IMT), plaque presence (defined as ICA IMT >1.5 mm), and mean common carotid artery IMT. We carried out multivariable regressions for carotid measurements vs biomarkers using linear and logistic models; P < 0.0056 was deemed statistically significant.
Maximal ICA IMT was significantly associated with plasma GDF-15 [β-estimate 0.04 per 1-U increase in log(GDF-15), SE 0.01, P < 0.0001]. Similarly, the odds of having carotid plaque increased 33% [odds ratio 1.33 per 1-U increase in log(GDF-15), 95% CI 1.20-1.48, P < 0.0001]. In contrast, there was no significant association of maximal ICA IMT or plaque presence with sST2 or hsTnI, and none of the 3 biomarkers was significantly associated with mean CCA IMT. GDF-15 was a stronger predictor of maximal ICA thickness and plaque presence compared with BNP and CRP when these conventional biomarkers were tested together.
Increased GDF-15 concentrations are associated with subclinical atherosclerosis, including maximal ICA IMT and carotid plaque presence. Future studies investigating the role of GDF-15 for screening and management of patients with subclinical atherosclerosis are warranted.
No preview · Article · Sep 2014 · Clinical Chemistry
[Show abstract][Hide abstract] ABSTRACT: Maladaptive remodelling of the arterial wall after mechanical injury (e. g. angioplasty) is characterised by inflammation, neointima formation and media hypertrophy, resulting in narrowing of the affected artery. Moreover, mechanical injury of the arterial wall causes loss of the vessel protecting endothelial cell monolayer. Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), a major downstream target of p38 MAPK, regulates inflammation, cell migration and proliferation, essential processes for vascular remodelling and reendothelialisation. Therefore, we investigated the role of MK2 in remodelling and reendothelialisation after arterial injury in genetically modified mice in vivo. Hypercholesterolaemic low-density-lipoprotein-receptor-deficient mice (ldlr-/-) were subjected to wire injury of the common carotid artery. MK2-deficiency (ldlr-/-/mk2-/-) nearly completely prevented neointima formation, media hypertrophy, and lumen loss after injury. This was accompanied by reduced proliferation and migration of MK2-deficient smooth muscle cells. In addition, MK2-deficiency severely reduced monocyte adhesion to the arterial wall (day 3 after injury, intravital microscopy), which may be attributed to reduced expression of the chemokine ligands CCL2 and CCL5. In line, MK2-deficiency significantly reduced the content of monocytes, neutrophiles and lymphocytes of the arterial wall (day 7 after injury, flow cytometry). In conclusion, in a model of endothelial injury (electric injury), MK2-deficiency strongly increased proliferation of endothelial cells and improved reendothelialisation of the arterial wall after injury. Deficiency of MK2 prevents adverse remodelling and promotes endothelial healing of the arterial wall after injury, suggesting that MK2-inhibition is a very attractive intervention to prevent restenosis after percutaneous therapeutic angioplasty.
Full-text · Article · Aug 2014 · Thrombosis and Haemostasis
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
Imaging of inflammation early after myocardial infarction (MI) is a promising approach to the guidance of novel molecular interventions that support endogenous healing processes. (18)F-FDG PET has been used, but may be complicated by physiological myocyte uptake. We evaluated the potential of two alternative imaging targets: lactoferrin binding by (68)Ga-citrate and somatostatin receptor binding by (68)Ga-DOTATATE.
C57Bl/6 mice underwent permanent coronary artery ligation. Serial PET imaging was performed 3 - 7 days after MI using (68)Ga-citrate, (68)Ga-DOTATATE, or (18)F-FDG with ketamine/xylazine suppression of myocyte glucose uptake. Myocardial perfusion was evaluated by (13)N-ammonia PET and cardiac geometry by contrast-enhanced ECG-gated CT.
Mice exhibited a perfusion defect of 30 - 40% (of the total left ventricle) with apical anterolateral wall akinesia and thinning on day 7 after MI. (18)F-FDG with ketamine/xylazine suppression demonstrated distinct uptake in the infarct region, as well as in the border zone and remote myocardium. The myocardial standardized uptake value in MI mice was significantly higher than in healthy mice under ketamine/xylazine anaesthesia (1.9 ± 0.4 vs. 1.0 ± 0.1). (68)Ga images exhibited high blood pool activity with no specific myocardial uptake up to 90 min after injection (tissue-to-blood contrast 0.9). (68)Ga-DOTATATE was rapidly cleared from the blood, but myocardial SUV was very low (0.10 ± 0.03).
Neither (68)Ga nor (68)Ga-DOTATATE is a useful alternative to (18)F-FDG for PET imaging of myocardial inflammation after MI in mice. Among the three tested approaches, (18)F-FDG with ketamine/xylazine suppression of cardiomyocyte uptake remains the most practical imaging marker of post-infarct inflammation.
No preview · Article · Aug 2014 · European journal of nuclear medicine and molecular imaging
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Mineralocorticoid antagonists improve survival among patients with chronic, severe systolic heart failure and heart failure after myocardial infarction. We evaluated the effects of eplerenone in patients with chronic systolic heart failure and mild symptoms. METHODS: In this randomized, double-blind trial, we randomly assigned 2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. RESULTS: The trial was stopped prematurely, according to prespecified rules, after a median follow-up period of 21 months. The primary outcome occurred in 18.3% of patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (hazard ratio, 0.76; 95% CI, 0.62 to 0.93; P=0.008); 10.8% and 13.5%, respectively, died of cardiovascular causes (hazard ratio, 0.76; 95% CI, 0.61 to 0.94; P=0.01). Hospitalizations for heart failure and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group (P<0.001). CONCLUSIONS: Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. (Funded by Pfizer; ClinicalTrials.gov number, NCT00232180.).