Emergency Heart failure Mortality Risk Grade may help to reduce heart failure admissions.

INTRODUCTION: Hospital admissions for heart failure (HF) are frequent and pose a heavy burden on health care resources. Currently, the decision to hospitalise is based on clinical judgement rather than on prognostic risk stratification. The Emergency Heart failure Mortality Risk Grade (EHMRG) was recently developed to identify high-risk HF patients in the emergency department (ED). OBJECTIVE: To assess the ability of the EHMRG to predict 30-day mortality in Dutch HF patients visiting the ED and to evaluate whether the EHMRG could help to reduce the number of hospital admissions for decompensated HF. METHODS: Patients visiting the ED for decompensated HF were included. The decision to hospitalise or discharge was based on clinical judgement. The EHMRG was calculated retrospectively. Based on their EHMRG, patients were stratified as very low risk, low risk, intermediate risk, high risk and very high risk. RESULTS: In 227 patients (age 73 ± 12 years, 69% male) 30-day mortality was 11%. Mortality differed significantly among the EHMRG risk groups at 7­day (p = 0.012) and 30-day follow-up (p < 0.01). Based on clinical judgement, 76% of patients were hospitalised. If decision-making had been based on EHMRG, the hospitalisation rate could have been reduced to 66% (p < 0.01), particularly by reducing hospitalisations in patients at low risk of death. Mortality in discharged patients, whether the decision was based on EHMRG or clinical judgement, was 0%. CONCLUSION: The EHMRG accurately differentiates between high- and low-risk decompensated HF patients visiting the ED, making it a promising tool to safely reduce the number of HF admissions.

Intramyocardial bone marrow cell injection does not lead to functional improvement in patients with chronic ischaemic heart failure without considerable ischaemia.

BACKGROUND: It has been suggested that bone marrow cell injection may have beneficial effects in patients with chronic ischaemic heart disease. However, previous trials have led to discrepant results of cell-based therapy in patients with chronic heart failure. The aim of this study was to evaluate the efficacy of intramyocardial injection of mononuclear bone marrow cells in patients with chronic ischaemic heart failure with limited stress-inducible myocardial ischaemia. METHODS AND RESULTS: This multicentre, randomised, placebo-controlled trial included 39 patients with no-option chronic ischaemic heart failure with a follow-up of 12 months. A total of 19 patients were randomised to autologous intramyocardial bone marrow cell injection (cell group) and 20 patients received a placebo injection (placebo group). The primary endpoint was the group difference in change of left ventricular ejection fraction, as determined by single-photon emission tomography. On follow-up at 3 and 12 months, change of left ventricular ejection fraction in the cell group was comparable with change in the placebo group (P = 0.47 and P = 0.08, respectively). Also secondary endpoints, including left ventricle volumes, myocardial perfusion, functional and clinical parameters did not significantly change in the cell group as compared to placebo. Neither improvement was demonstrated in a subgroup of patients with stress-inducible ischaemia (P = 0.54 at 3­month and P = 0.15 at 12-month follow-up). CONCLUSION: Intramyocardial bone marrow cell injection does not improve cardiac function, nor functional and clinical parameters in patients with severe chronic ischaemic heart failure with limited stress-inducible ischaemia. CLINICAL TRIAL REGISTRATION: NTR2516.

Redesigning healthcare: The 2.4 billion euro question? : Connecting smart technology to improve outcome of patients.

Although it has been possible to transfer electrocardiograms via a phone line for more than 100 years, use of internet-based patient monitoring and communication systems in daily care is uncommon. Despite the introduction of numerous health-monitoring devices, and despite most patients having internet access, the implementation of individualised healthcare services is still limited. On the other hand, hospitals have invested heavily in massive information systems offering limited value for money and connectivity. However, the consumer market for personal healthcare devices is developing rapidly and with the current healthcare-related investments by tech companies it can be expected that the way healthcare is provided will change dramatically. Although a variety of initiatives under the banner of 'e-Health' are deployed, most are characterised by either industry-driven developments without proven clinical effectiveness or individual initiatives lacking the embedding within the traditional organisations. However, the introduction of numerous smart devices and internet-based technologies facilitates the fundamental redesign of healthcare based on the principle of achieving the best possible care for the individual patient at the lowest possible cost. Conclusion The way healthcare is delivered will change, but to what degree healthcare professionals together with patients will be able to redesign healthcare in a structured manner is still a question.

Polycistronic lentivirus induced pluripotent stem cells from skin biopsies after long term storage, blood outgrowth endothelial cells and cells from milk teeth.

The generation of human induced pluripotent stem cells (hiPSCs) requires the collection of donor tissue, but clinical circumstances in which the interests of patients have highest priority may compromise the quality and availability of cells that are eventually used for reprogramming. Here we compared (i) skin biopsies stored in standard physiological salt solution for up to two weeks (ii) blood outgrowth endothelial cells (BOECs) isolated from fresh peripheral blood and (iii) children's milk teeth lost during normal replacement for their ability to form somatic cell cultures suitable for reprogramming to hiPSCs. We derived all hiPSC lines using the same reprogramming method (a conditional (FLPe) polycistronic lentivirus) and under similar conditions (same batch of virus, fetal calf serum and feeder cells). Skin fibroblasts could be reprogrammed robustly even after long-term biopsy storage. Generation of hiPSCs from juvenile dental pulp cells gave similar high efficiencies, but that of BOECs was lower. In terms of invasiveness of biopsy sampling, biopsy storage and reprogramming efficiencies skin fibroblasts appeared best for the generation of hiPSCs, but where non-invasive procedures are required (e.g., for children and minors) dental pulp cells from milk teeth represent a valuable alternative.

Treatment options in end-stage heart failure: where to go from here?

Chronic heart failure is a major healthcare problem associated with high morbidity and mortality. Despite significant progress in treatment strategies, the prognosis of heart failure patients remains poor. The golden standard treatment for heart failure is heart transplantation after failure of medical therapy, surgery and/or cardiac resynchronisation therapy. In order to improve patients' outcome and quality of life, new emerging treatment modalities are currently being investigated, including mechanical cardiac support devices, of which the left ventricular assist device is the most promising treatment option. Structured care for heart failure patients according to the most recent international heart failure guidelines may further contribute to optimal decision-making. This article will review the conventional and novel treatment modalities of heart failure.

Young at heart. An update on cardiac regeneration.

Cardiovascular disease remains one of the most important causes of mortality. Over the past decades important advances have been made in prevention and treatment of acute complications after myocardial infarction (MI). As a result, the number of patients that acutely die from MI has been reduced. Current treatments can not prevent the loss of cardiac contractility caused by cardiomyocyte death, and therefore patients that do survive MI are prone to develop progressive impaired cardiac function, which may lead to heart failure. Cell-based therapy has been proposed as a potential new therapy to prevent progression to end-stage heart failure by (re)generating contractile tissue in the damaged heart. During the last years many different cell sources have been studied extensively for their cardiomyogenic differentiation capacity in vitro and in vitro. These cells include several populations of cardiac-derived progenitor cells as well as mesenchymal stem cells derived from different sources. It has become clear that not only the origin, but also the "age" of a cell is an important determinant of its plasticity. Therefore, special attention is paid to the difference in developmental state of the cell sources and the consequences for their differentiation capacity and therapeutic applicability. Furthermore, we provide future perspectives for several aspects of cell-based therapy that could be optimized in order to enhance the regeneration of the heart.

Standardised pre-hospital care of acute myocardial infarction patients: MISSION! guidelines applied in practice.

Background. To improve acute myocardial infarction (AMI) care in the region 'Hollands-Midden' (the Netherlands), a standardised guideline-based care program was developed (MISSION!). This study aimed to evaluate the outcome of the pre-hospital part of the MISSION! program and to study potential differences in pre-hospital care between four areas of residency.Methods. Time-to-treatment delays, AMI risk profile, cardiac enzymes, hospital stay, in-hospital mortality, and pre-AMI medication was evaluated in consecutive AMI patients (n=863, 61±13years, 75% male) transferred to the Leiden University Medical Center for primary percutaneous coronary intervention (PCI).Results. Median time interval between onset of symptoms and arrival at the catheterisation laboratory was 150 (interquartile range [IQR] 101-280) minutes. The alert of emergency services to arrival at the hospital time was 48 (IQR 40-60) minutes and the door-to-catheterisation laboratory time was 23 (IQR 13-42) minutes. Despite significant regional differences in ambulance transportation times no difference in total time from onset of symptoms to arrival at the catheterisation room was found. Peak troponin T was 3.33 (IQR 1.23-7.04) µg/l, hospital stay was 2 (IQR 2-3) days and in-hospital mortality was 2.3%. Twelve percent had 0 known risk factors, 30% had one risk factor, 45% two to three risk factors and 13% had four or more risk factors. No significant differences were observed for AMI risk profiles and medication pre-AMI. Conclusions. This study shows that a standardised regional AMI treatment protocol achieved optimal and uniformly distributed pre-hospital performance in the region 'Hollands-Midden', resulting in minimal time delays regardless of area of residence. Hospital stay was short and in-hospital mortality low. Of the patients, 88% had ≥1 modifiable risk factor. (Neth Heart J 2010;18:408-15.).

Novel approaches to treat experimental pulmonary arterial hypertension: a review.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by an increase in pulmonary artery pressure leading to right ventricular (RV) hypertrophy, RV failure, and ultimately death. Current treatments can improve symptoms and reduce severity of the hemodynamic disorder but gradual deterioration in their condition often necessitates a lung transplant. METHODS AND RESULTS: In experimental models of PAH, particularly the model of monocrotaline-induced pulmonary hypertension, efficacious treatment options tested so far include a spectrum of pharmacologic agents with actions such as anti-mitogenic, proendothelial function, proangiogenic, antiinflammatory and antioxidative. Emerging trends in PAH treatment are gene and cell therapy and their combination, like (progenitor) cells enriched with eNOS or VEGF gene. More animal data should be collected to investigate optimal cell type, in vitro cell transduction, route of administration, and number of cells to inject. Several recently discovered and experimentally tested interventions bear potential for therapeutic purposes in humans or have been shown already to be effective in PAH patients leading to improved life expectation and better quality of life. CONCLUSION: Since many patients remain symptomatic despite therapy, we should encourage research in animal models of PAH and implement promising treatments in homogeneous groups of PAH patients.

Integrin stimulation-induced hypertrophy in neonatal rat cardiomyocytes is NO-dependent.

Prolonged myocardial stretch typically leads to hypertrophy of cardiomyocytes. As integrins are cellular receptors of stretch, we hypothesize that integrin stimulation induces cardiomyocyte hypertrophy. Integrins of neonatal rat cardiomyocytes (NRCMs) were stimulated with a peptide containing the Arg-Gly-Asp (RGD) sequence for 24 h. For comparison, alpha(1)-adrenergic stimulation by phenylephrine (PE) for 24 h was applied. Saline-treated NRCMs were used as control. The hypertrophic response was quantified by measuring cell surface area (CSA). Phosphorylation of NO-synthase-1 (NOS1) was assessed by immunocytochemistry. CSA was increased by 38% (IQR 31-44%) with RGD and by 68% (IQR 64-84%) with PE versus control (both P < 0.001). NOS-1 phosphorylation was increased by 61% with RGD and by 21% with PE versus control (both P < 0.01). A general NOS-inhibitor (L-NAME) inhibited RGD-induced hypertrophy completely, but had no significant effect on PE-induced hypertrophy. Administration of NO-donor to NRCMs co-incubated with RGD + L-NAME partly restored hypertrophy (to 62% of the hypertrophic effect of RGD alone), but had no effect if incubated with PE + L-NAME. Ryanodine and BAPTA-AM inhibited RGD-induced hypertrophy completely but not that induced by PE. Integrin stimulation of NRCMs by RGD leads to hypertrophy, likely by activation of NOS-1. Abrogation of RGD-induced hypertrophic response upon NOS-inhibition and rescue of this hypertrophic effect by NO-donor suggest that integrin stimulation-induced hypertrophy of NRCMs is NO-dependent.

Effect of intramyocardial bone marrow cell injection on left ventricular dyssynchrony and global strain.

OBJECTIVE: To evaluate the effect of bone marrow cell injection on global strain and left ventricular (LV) dyssynchrony. METHODS: In 14 patients with severe postinfarction heart failure, 93 (14) x 10(6) autologous bone marrow cells were percutaneously injected in the infarction border zone. LV ejection fraction (LVEF), LV dyssynchrony and echocardiographic global strain were assessed at baseline and 3 months in patients and in a non-randomised control group of 10 patients with a history of infarction who developed heart failure and were treated medically. RESULTS: No periprocedural complications occurred during bone marrow cell injection. At 3 months mean (SD) LVEF increased from 23 (8)% to 27 (9)% (p = 0.02) and global strain improved from -7.7 (4.7)% to -8.5 (4.9)% (p = 0.04). In patients with > or =5% improvement in LVEF after bone marrow cell injection, global strain improved from -8.7 (4.6)% to -10.6 (4.5)% (p<0.01). Global strain remained unchanged in patients with <5% improvement in LVEF (-6.6 (4.9)% vs -6.4 (4.5)%, p = NS). The relation between the increase in LVEF and improvement in global strain was significant (r = 0.84, p<0.01). In patients with > or =5% improvement in LVEF, LV dyssynchrony decreased from 173 (64) ms to 116 (64) ms (p = 0.01). In patients with <5% improvement in LVEF, LV dyssynchrony remained unchanged (155 (67) ms vs 177 (81) ms, p = NS). The correlation between improvement in LVEF and reduction in LV dyssynchrony was good (r = -0.77, p<0.01). In the control group, LVEF, global strain and LV dyssynchrony did not improve. CONCLUSIONS: Bone marrow cell injection improves LVEF in patients with severe postinfarction heart failure. The improvement in LVEF was related to reduced LV dyssynchrony and increased global strain.

Reduced leucocyte cholesteryl ester transfer protein expression in acute coronary syndromes.

OBJECTIVE: Cholesterol ester transfer protein (CETP) plays an important role in HDL cholesterol metabolism. Leucocytes, including monocyte-derived macrophages in the arterial wall synthesize and secrete CETP, but its role in atherosclerosis is unclear. The aim of the current study was to investigate the effect of acute coronary syndromes (ACS) on leucocyte CETP expression. RESEARCH DESIGN: Peripheral blood mononuclear cells (PBMCs) were freshly isolated from hospitalized ACS patients displaying Braunwald class IIIB unstable angina pectoris (UAP) on admission (t = 0) and at 180 days post inclusion (t = 180) for analysis of CETP expression. In addition, to prove the potential correlation between leucocyte CETP and ACS the effect of acute myocardial infarction on leucocyte CETP expression was studied in CETP transgenic mice. RESULTS: Upon admission, UAP patients displayed approximately 3-6 fold (P < 0.01) lower CETP mRNA and nearly absent CETP protein expression in PBMCs, as compared to healthy age-/sex-matched controls. Interestingly, CETP mRNA and protein levels were significantly elevated in PBMCs isolated from UAP patients (both stabilized and refractory) at t = 180 as compared to t = 0 (P < 0.01), which was correlated with a reduced inflammatory status after medical treatment. In agreement with the data obtained in UAP patients, markedly down-regulated leucocyte CETP mRNA expression was observed after coronary artery ligation in CETP transgenic mice, which also correlated with increased serum amyloid A levels. CONCLUSIONS: We are the first to report that episodes of UAP in humans and myocardial infarction in CETP transgenic mice are associated with reduced leucocyte CETP expression. We propose that the impairment in leucocyte CETP production is associated with an enhanced inflammatory status, which could be clinically relevant for the pathogenesis of ACS.

Release kinetics of intact and degraded troponin I and T after irreversible cell damage.

PURPOSE: We characterized the release kinetics of cardiac troponin I and T in relation to lactate dehydrogenase (LDH) from cardiomyocytes before and after the transition from reversible to irreversible cell damage. METHODS: Cardiomyocytes were exposed to mild metabolic inhibition (1 mmol/L sodium azide) to induce a necrotic cell death process that is characterized by a reversible (0-12 h) and irreversible phase (12-30 h). At various time intervals cells and media were collected and analyzed for LDH activity, intact cTnI and cTnT, and their degradation products. RESULTS: During the first 12 h of metabolic inhibition, cell viability was unchanged with no release of intact cTnI and cTnT nor their degradation products. Between 12 and 30 h of azide treatment, cardiomyocytes showed progressive cell death accompanied by release of intact cTnI (29 kDa), intact cTnT (39 kDa), four cTnI degradation products of 26, 20, 17 and 12 kDa, and three cTnT degradation products of 37, 27 and 14 kDa. Possibly due to degradation, there is progressive loss of cTnI and cTnT protein that is obviously undetected by the antibodies used. CONCLUSIONS: Metabolic inhibition of cardiomyocytes induces a parallel release of intact cTnI and cTnT and their degradation products, starting only after onset of irreversible cardiomyocyte damage.

Left ventricular function in the post-infarct failing mouse heart by magnetic resonance imaging and conductance catheter: a comparative analysis.

AIM: Murine myocardial infarction (MI) models are increasingly used in heart failure studies. Magnetic resonance imaging (MRI) and pressure-volume loops by conductance catheter (CC) enable physiological phenotyping. We performed a comparative analysis of MRI vs. CC to assess left ventricular (LV) function in the failing mouse heart. METHODS: MI was created by LAD ligation. MRI (day 14) and CC (day 15) were used to determine LV end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF). RESULTS: Pooled data yielded moderate-to-strong linear correlations: EDV: R = 0.61; ESV: R = 0.72; EF: R = 0.81. We analysed three groups, no MI (sham, n = 10), small MI (<30% of LV, n = 14) and large MI (>30%, n = 20). Volumes and EF were consistently lower by CC than by MRI, but group differences were evident for both techniques. Receiver-operating characteristic analysis indicated good sensitivity and specificity for both techniques, with superior results for MRI. CONCLUSIONS: CC and MRI are highly valuable for evaluation of LV volume and function. MRI is recommended for longitudinal studies, accurate absolute volumes and anatomical information. Unique features of CC are its online signal with high temporal resolution, and advanced analysis of LV function and energetics.

Development of a new test for the global fibrinolytic capacity in whole blood.

BACKGROUND: The development of global tests for the fibrinolytic capacity in blood is hampered by the low base-line fibrinolytic activity in blood, by the involvement of both plasmatic components and blood cells in the fibrinolytic system and by the loss of fibrinolytic activity as a result of the action of plasminogen activator inhibitor-1 (PAI-1). OBJECTIVE: To develop a new test for the global fibrinolytic capacity (GFC) of whole blood samples. METHODS AND RESULTS: Collection of blood in thrombin increased the subsequent generation of fibrin degradation products. This was ascribed to rapid clot formation and concomitant reduction of in vitro neutralization of tissue-type plasminogen activator (tPA) by PAI-1. On the basis of this observation, the following test was designed: blood samples were collected in thrombin with and without aprotinin and clots were incubated for 3 h at 37 degrees C. The GFC was assessed from the difference between the fibrin degradation products in the two sera. The assay was applied to blood samples from patients and healthy subjects. Other hemostasis parameters were determined in plasma samples taken simultaneously. The GFC varied considerably (normal range 0.13-13.6 microg mL(-1)); physical exercise strongly increased the GFC. Statistically significant correlations were found with tPA activity, PAI-1 activity and fibrinogen level. A mixture of antibodies against tPA and urokinase-type plasminogen activator (uPA) completely inhibited the GFC. An inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFI) accelerated fibrinolysis 8-fold. CONCLUSION: The new test represents a global assessment of the main fibrinolytic factors in plasma and potentially those associated with blood cells.

Release of cardiac troponin I from viable cardiomyocytes is mediated by integrin stimulation.

Elevated cardiac troponin-I (cTnI) levels have been demonstrated in serum of patients without acute coronary syndromes, potentially via a stretch-related process. We hypothesize that this cTnI release from viable cardiomyocytes is mediated by stimulation of stretch-responsive integrins. Cultured cardiomyocytes were treated with (1) Gly-Arg-Gly-Asp-Ser (GRGDS, n = 22) to stimulate integrins, (2) Ser-Asp-Gly-Arg-Gly (SDGRG, n = 8) that does not stimulate integrins, or (3) phosphate-buffered saline (control, n = 38). Cells and media were analyzed for intact cTnI, cTnI degradation products, and matrix metalloproteinase (MMP)-2. Cell viability was examined by assay of lactate dehydrogenase (LDH) activity and by nuclear staining with propidium iodide. GRGDS-induced integrin stimulation caused increased release of intact cTnI (9.6 +/- 3.0%) as compared to SDGRG-treated cardiomyocytes (4.5 +/- 0.8%, p < 0.001) and control (3.0 +/- 3.4%, p < 0.001). LDH release from GRGDS-treated cardiomyocytes (15.9 +/- 3.8%) equalled that from controls (15.2 +/- 2.3%, p = n.s.), indicating that the GRGDS-induced release of cTnI is not due to cell necrosis. This result was confirmed by nuclear staining with propidium iodide. Integrin stimulation increased the intracellular and extracellular MMP2 activity as compared to controls (both p < 0.05). However, despite the ability of active MMP2 to degrade cTnI in vitro, integrin stimulation in cardiomyocytes was not associated with cTnI degradation. The present study demonstrates that intact cTnI can be released from viable cardiomyocytes by stimulation of stretch-responsive integrins.

Preservation of left ventricular function and attenuation of remodeling after transplantation of human epicardium-derived cells into the infarcted mouse heart.

BACKGROUND: Proper development of compact myocardium, coronary vessels, and Purkinje fibers depends on the presence of epicardium-derived cells (EPDCs) in embryonic myocardium. We hypothesized that adult human EPDCs might partly reactivate their embryonic program when transplanted into ischemic myocardium and improve cardiac performance after myocardial infarction. METHODS AND RESULTS: EPDCs were isolated from human adult atrial tissue. Myocardial infarction was created in immunodeficient mice, followed by intramyocardial injection of 4x10(5) enhanced green fluorescent protein-labeled EPDCs (2-week survival, n=22; 6-week survival, n=15) or culture medium (n=24 and n=18, respectively). Left ventricular function was assessed with a 9.4T animal MRI unit. Ejection fraction was similar between groups on day 2 but was significantly higher in the EPDC-injected group at 2 weeks (short term), as well as after long-term survival at 6 weeks. End-systolic and end-diastolic volumes were significantly smaller in the EPDC-injected group than in the medium-injected group at all ages evaluated. At 2 weeks, vascularization was significantly increased in the EPDC-treated group, as was wall thickness, a development that might be explained by augmented DNA-damage repair activity in the infarcted area. Immunohistochemical analysis showed massive engraftment of injected EPDCs at 2 weeks, with expression of alpha-smooth muscle actin, von Willebrand factor, sarcoplasmic reticulum Ca2+-ATPase, and voltage-gated sodium channel (alpha-subunit; SCN5a). EPDCs were negative for cardiomyocyte markers. At 6-weeks survival, wall thickness was still increased, but only a few EPDCs could be detected. CONCLUSIONS: After transplantation into ischemic myocardium, adult human EPDCs preserve cardiac function and attenuate ventricular remodeling. Autologous human EPDCs are promising candidates for clinical application in infarcted hearts.

[Intramyocardial injection of autologous bone-marrow stem cells in a 74-year-old man with untreatable angina pectoris and demonstrated myocardial ischaemia]. / Intramyocardiale injectie van autologe stamcellen bij een 74-jarige man met onbehandelbare angina pectoris en bewezen myocardischemie.

For a 74-year-old man with angina pectoris and demonstrated myocardial ischaemia, optimal medical treatment was insufficient. He was ineligible for coronary revascularization. To improve myocardial perfusion, autologous bone-marrow stem cells were injected into the ischaemic myocardium. During the months following the injection, the frequency of angina attacks decreased and myocardial perfusion and cardiac function improved.

Genetic programme of cardiogenesis: implications for therapeutic application.

It has become accepted that new cardiomyocytes can be derived from stem cells. Although the potential for therapeutic application is evident, the reported efficiency of differentiation varies greatly from 0.02 to 54%. To obtain clinically relevant numbers of newly differentiated cardiac cells, stem cell differentiation should be as efficient as possible. A plausible way to increase the efficiency of differentiation of stem cells into cardiomyocytes is through the introduction of cardiac specific regulatory genes in the stem cells. This review summarises the role of several key transcription factors in cardiogenesis.