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Introduction Milrinone is an inotrope widely used for treatment of cardiac failure. Because previous meta-analyses had methodological flaws, we decided to conduct a systematic review of the effect of milrinone in critically ill adult patients with cardiac dysfunction. Methods This systematic review was performed according to The Cochrane Handbook for Systematic Reviews of Interventions. Searches were conducted until November 2015. Patients with cardiac dysfunction were included. The primary outcome was serious adverse events (SAE) including mortality at maximum follow-up. The risk of bias was evaluated and trial sequential analyses were conducted. The quality of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation criteria. Results A total of 31 randomised clinical trials fulfilled the inclusion criteria, of which 16 provided data for our analyses. All trials were at high risk of bias, and none reported the primary composite outcome SAE. Fourteen trials with 1611 randomised patients reported mortality data at maximum follow-up (RR 0.96; 95% confidence interval 0.76–1.21). Milrinone did not significantly affect other patient-centred outcomes. All analyses displayed statistical and/or clinical heterogeneity of patients, interventions, comparators, outcomes, and/or settings and all featured missing data. Discussion The current evidence on the use of milrinone in critically ill adult patients with cardiac dysfunction suffers from considerable risks of both bias and random error and demonstrates no benefits. The use of milrinone for the treatment of critically ill patients with cardiac dysfunction can be neither recommended nor refuted. Future randomised clinical trials need to be sufficiently large and designed to have low risk of bias. Electronic supplementary material The online version of this article (doi:10.1007/s00134-016-4449-6) contains supplementary material, which is available to authorized users.

Renal dysfunction in heart failure with preserved ejection fraction (HFpEF) is common and is associated with increased mortality. Impaired renal function is also a risk factor for developing HFpEF. A new paradigm for HFpEF, proposing a sequence of events leading to myocardial remodelling and dysfunction in HFpEF, was recently introduced, involving inflammatory, microvascular, and cardiac components. The kidney might play a key role in this systemic process. Renal impairment causes metabolic and systemic derangements in circulating factors, causing an activated systemic inflammatory state and endothelial dysfunction, which may lead to cardiomyocyte stiffening, hypertrophy, and interstitial fibrosis via cross-talk between the endothelium and cardiomyocyte compartments. Here, we review the role of endothelial dysfunction and inflammation to explain the link between renal dysfunction and HFpEF, which allows for identification of new early risk markers, prognostic factors, and unique targets for intervention.

Renal dysfunction in heart failure with preserved ejection fraction (HFpEF) is common and is associated with increased mortality. Impaired renal function is also a risk factor for developing HFpEF. A new paradigm for HFpEF, proposing a sequence of events leading to myocardial remodelling and dysfunction in HFpEF, was recently introduced, involving inflammatory, microvascular, and cardiac components. The kidney might play a key role in this systemic process. Renal impairment causes metabolic and systemic derangements in circulating factors, causing an activated systemic inflammatory state and endothelial dysfunction, which may lead to cardiomyocyte stiffening, hypertrophy, and interstitial fibrosis via cross-talk between the endothelium and cardiomyocyte compartments. Here, we review the role of endothelial dysfunction and inflammation to explain the link between renal dysfunction and HFpEF, which allows for identification of new early risk markers, prognostic factors, and unique targets for intervention.

Introduction: The revised Ghent nosology presents the classical features of Marfan syndrome. However, behind its familiar face, Marfan syndrome hides less well-known features. Areas covered: The German Marfan Organization listed unusual symptoms and clinical experts reviewed the literature on clinical features of Marfan syndrome not listed in the Ghent nosology. Thereby we identified the following features: (1) bicuspid aortic valve, mitral valve prolapse, pulmonary valve prolapse, tricuspid valve prolapse, (2) heart failure and cardiomyopathy, (3) supraventricular arrhythmia, ventricular arrhythmia, and abnormal repolarization, (4) spontaneous coronary artery dissection, anomalous coronary arteries, and atherosclerotic coronary artery disease, tortuosity-, aneurysm-, and dissection of large and medium-sized arteries, (5) restrictive lung disease, parenchymal lung disease, and airway disorders, (6) obstructive- and central sleep apnea, (7) liver and kidney cysts, biliary tract disease, diaphragmatic hernia, and adiposity, (8) premature labor, and urinary incontinence, (9) myopathy, reduced bone mineral density, and craniofacial manifestations, (10) atrophic scars, (11) caries, and craniomandibular dysfunction, (12) headache from migraine and spontaneous cerebrospinal fluid leakage, (13) cognitive dysfunction, schizophrenia, depression, fatigue, and pain, (14) and activated fibrinolysis, thrombin, platelets, acquired von Willebrand disease, and platelet dysfunction. Expert commentary: Future research, nosologies, and guidelines may consider less well-known features of Marfan syndrome.

Targeted HFpEF therapy based on matchmaking of human and animal models. Am J Physiol Heart Circ Physiol 315: H1670-H1683, 2018. First published September 21, 2018; doi:10.1152/ajpheart.00024.2018. The diversity in clinical phenotypes and poor understanding of the underlying pathophysiology of heart failure with preserved ejection fraction (HFpEF) is the main reason why no effective treatments have been found yet. Targeted, instead of one size fits all, treatment seems the only promising approach for treating 1114pE14. To be able to design a targeted, phenotype-specific HFpEF treatment, the matrix relating clinical phenotypes and underlying pathophysiological mechanisms has to be clarified. This review discusses the opportunities for additional evaluation of the underlying pathophysiological processes, e.g., to evaluate biological phenotypes on top of clinical routine, to guide us toward a phenotype specific HFpEF treatment. Moreover, a translational approach with matchmaking of animal models to biological HFpEF phenotypes will be a valuable step to test the effectiveness of novel, targeted interventions in IIFpEF.

Peripartum cardiomyopathy is an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause for heart failure is identified. Outcome varies from full recovery to residual left ventricular systolic dysfunction and even death. Many women return to their physician to acquire information on their long- term prognosis, to seek medical advice regarding contraception, or when planning a subsequent pregnancy. This position paper summarizes current evidence for long-term outcome, risk stratification of further pregnancies and overall management. Based on the best available evidence, as well as the clinical experience of the European Society of Cardiology Study Group on Peripartum Cardiomyopathy members, a consensus on pre- and postpartum management algorithms for women undergoing a subsequent pregnancy is presented.

Background Obesity is associated with cardiac dysfunction, atherosclerosis, and increased cardiovascular risk. It can be lead to obesity cardiomyopathy and severe heart failure, which in turn raise morbidity and mortality while carrying a negative impact on quality of life. There is increasing clinical and mechanistic evidence on the metabolic and weight loss effects of bariatric surgery on improving cardiac structure and function in obese patients. Objectives The objective of this study was to quantify the effects of bariatric surgery on cardiac structure and function by appraising cardiac imaging changes before and after metabolic operations. Methods This is a comprehensive systematic review of studies reporting pre-operative and post-operative echocardiographic or magnetic resonance cardiac indices in obese patients undergoing bariatric surgery. Studies were quality scored, and data were meta-analyzed using random effects modeling. Results Bariatric surgery is associated with significant improvements in the weighted incidence of a number of cardiac indices including a decrease in left ventricular mass index (11.2 %, 95 % confidence intervals (CI) 8.2–14.1 %), left ventricular end-diastolic volume (13.28 ml, 95 % CI 5.22–21.34 ml), and left atrium diameter (1.967 mm, 95 % CI 0.980–2.954). There were beneficial increases in left ventricular ejection fraction (1.198 %, 95 %CI −0.050–2.347) and E/A ratio (0.189 %, 95 %CI −0.113–0.265). Conclusions Bariatric surgery offers beneficial cardiac effects on diastolic function, systolic function, and myocardial structure in obese patients. These may derive from surgical modulation of an enterocardiac axis. Future studies must focus on higher evidence levels to better identify the most successful bariatric approaches in preventing and treating the broad spectrum of obesity-associated heart disease while also enhancing treatment strategies in the management of obesity cardiomyopathy.

Aims: Interleukin-6 receptor (IL-6R) signalling has been suggested to play a causal role in the development and outcome of coronary heart disease (CHD). The aim of this study was to investigate the association of sIL-6R levels with myocardial reperfusion after percutaneous coronary intervention (PCI) for acute ST-elevated myocardial infarction (STEMI).Methods: Blood was sampled from 70 patients presenting with STEMI at 6 different time-points (baseline, post-PCI, t = 1 h, t = 6 h, t = 24 h, t = 2w). Coronary angiograms post-PCI were analysed for myocardial blush grade (MBG) as indicator of myocardial reperfusion. Serum IL-6 and sIL-6R were measured using IL-6 and sIL-6R enzyme-linked immunosorbent assays (ELISA).Results: sIL-6R levels fluctuated biphasic during the two weeks after STEMI. Reduced MBG was associated with a larger change in sIL-6R levels between baseline and post-PCI compared to optimal MBG (-13.40; SEM 2.78 ng/ml vs -1.99; SEM 2.35 ng/ml, respectively; p Conclusions: sIL-6R levels fluctuate biphasic during the two weeks after MI with larger changes and increased IL-6/sIL-6R ratio in patients with reduced MBG. Further research is needed to increase our understanding of the possible causality of these associations. (C) 2015 Elsevier Ltd. All rights reserved.

OBJECTIVES This study evaluated a biochemical validation of patient-reported symptom onset time in patients with ST-segment elevation myocardial infarction (STEMI).BACKGROUND Symptom onset time is an important metric but has never been formally validated. METHODS The Mayo Clinic Percutaneous Coronary Intervention (PCI) Registry was interrogated to obtain baseline, procedural, and outcome data on 607 STEMI patients undergoing primary PCI. Biochemical onset time was determined by backward extrapolation of serial increasing cardiac troponin T (cTnT) measurements.RESULTS The median patient-reported onset time was 12 min later than the calculated time of first cTnT increase and was therefore estimated to be 4.2 h later than the biochemical onset time (interquartile range: 1.9 to 11.1 h; p CONCLUSIONS Although our point estimate should be interpreted with caution, our study indicates that the actual onset of STEMI is likely to be earlier than the patient-reported onset time. Recalculation of ischemic time with biochemical onset time greatly enhanced its prognostic value. Underestimation of ischemic time by patient-reported onset time occurred more often in high-risk patients. (C) 2015 by the American College of Cardiology Foundation.

Levosimendan is a calcium sensitizer and ATP-dependent potassium channel opener which exerts sustained hemodynamic, symptomatic and organ-protective effects. It is registered for the treatment of acute heart failure, and when inotropic support is considered appropriate. In the past fifteen years, levosimendan has been widely used in clinical practice, and has also been tested in clinical trials to stabilize at-risk patients undergoing cardiac surgery. Recently, three randomized, placebo-controlled, multicenter studies (LICORN, CHEETAH and LEVO-CTS) have been published reporting on the peri-operative use of levosimendan in patients with compromised cardiac ventricular function. Taken together, many smaller trials conducted in the past suggested beneficial outcomes with levosimendan in peri-operative settings. In contrast, the latest three studies were neutral or inconclusive. In order to understand the reasons for such dissimilarity, a group of experts from Austria, Belgium, Finland, France, Germany, Italy, Switzerland, and Russia, including investigators from the three most recent studies, met to discuss the study results in the light of both the previous literature and current clinical practice. Despite the fact that the null hypothesis could not be ruled out in the recent multicenter trials, we conclude that levosimendan can still be viewed as a safe and effective inodilator in cardiac surgery.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Item does not contain fulltext OBJECTIVES: This study reports the long-term follow-up of the randomised controlled HEBE trial. The HEBE study is a multicentre trial that randomised 200 patients with large first acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention to either intracoronary infusion of bone marrow mononuclear cells (BMMCs) (n=69), peripheral blood mononuclear cells (PBMCs) (n=66) or standard therapy (n=65). METHODS: In addition to 3-5 days, and 4 months after AMI, all patients underwent cardiac MRI after 2 years. A follow-up for 5 years after AMI was performed to assess clinical adverse events, including death, myocardial reinfarction and hospitalisation for heart failure. RESULTS: Of the 200 patients enrolled, 9 patients died and 12 patients were lost to follow-up at 5 years after AMI. BMMC group showed less increase in LV end-diastolic volume (LVEDV) (3.5+/-16.9 mL/m(2)) compared with (11.2+/-19.8 mL/m(2), p=0.03) in the control group, with no difference between the PBMC group (9.2+/-20.9 mL/m(2)) and controls (p=0.69). Moreover, the BMMC group showed a trend for decrease in LV end systolic volume (-1.8+/-15.0 mL/m(2)) as compared with controls (3.0+/-16.3 mL/m(2), p=0.07), with again no difference between PBMC (3.3+/-18.8 mL/m(2)) and controls (p=0.66). The combined endpoint of death and hospitalisation for heart failure was non-significantly less frequent in the BMMC group compared with the control group (n=4 vs n=1, p=0.20), with no difference between PBMC and controls (n=6 vs n=4, p=0.74). The composite endpoint of death or recurrent myocardial infarction was significantly higher in the PBMC group compared with controls (14 patients vs 3 patients, p=0.008), with no difference between the BMMC group and controls (2 vs 3 patients, p=0.67). CONCLUSIONS: Long-term follow-up of the HEBE trial showed that increase in LVEDV was lower in the BMMC group. This study supports the long-term safety of intracoronary BMMC therapy. However, major clinical cardiovascular adverse events were significantly more frequent in the PBMC group. TRIAL REGISTRATION NUMBER: The Netherlands Trial Register #NTR166 (http://www.trialregister.nl) and the International Standard Randomised Controlled Trial, #ISRCTN95796863 (http://isrctn.org).

Purpose: To assess the benefits and harms of levosimendan for low cardiac output syndrome in critically ill patients. Methods: We conducted a systematic review with meta-analyses and trial sequential analyses (TSA) of randomised clinical trials comparing levosimendan with any type of control. Two reviewers independently assessed studies for inclusion. The Cochrane Collaboration methodology was used. Random-effects risk ratios (RR) and 95 % confidence intervals (CI) were derived for the principal primary outcome mortality at maximal followup. Results: A total of 88 trials were included in the systematic review and 49 trials (6,688 patients) in the meta-analysis. One trial had low risk of bias and nine trials (2,490 patients) were considered lower risk of bias. Trials compared levosimendan with placebo, control interventions, and other inotropes. Pooling all trials including heterogenous populations was considered inappropriate. Pooled analysis of 30 trials including critically ill patients not having cardiac surgery showed an association between levosimendan and mortality (RR 0.83, TSA-adjusted 95 % CI 0.59-0.97), while trials with lower risk of bias showed no significant difference (RR 0.83, TSA-adjusted 95 % CI 0.48-1.55). Conventional meta-analysis of all 14 trials including cardiac surgery patients showed an association, while lower risk of bias trials showed no association between levosimendan and mortality (RR 0.52, 95 % CI 0.37-0.73 versus RR 1.02, 95 % CI 0.48-2.16). Conclusions: The available evidence is inconclusive whether or not levosimendan may have a beneficial effect on mortality due to risks of systematic errors and random errors. Further well-designed randomised trials are needed.

BackgroundStem cell therapy to improve cardiac function after myocardial infarction is hampered by poor cell retention, while it may also increase the risk of arrhythmias by providing an arrhythmogenic substrate. We previously showed that porcine adipose tissue-derived-stromal cells (pASC) induce conduction slowing through paracrine actions, whereas rat ASC (rASC) and human ASC (hASC) induce conduction slowing by direct coupling. We postulate that biomaterial microspheres mitigate the conduction slowing influence of pASC by interacting with paracrine signaling.AimTo investigate the modulation of ASC-loaded recombinant human collagen-based microspheres, on the electrophysiological behavior of neonatal rat ventricular myocytes (NRVM).MethodUnipolar extracellular electrograms, derived from microelectrode arrays (8x8 electrodes) containing NRVM, co-cultured with ASC or ASC loaded microspheres, were used to determine conduction velocity (CV) and conduction heterogeneity. Conditioned medium (Cme) of (co)cultures was used to assess paracrine mechanisms.ResultsMicrospheres did not affect CV in control (NRVM) monolayers. In co-cultures of NRVM and rASC, hASC or pASC, CV was lower than in controls (14.4±1.0, 13.0±0.6 and 9.0± 1.0 vs. 19.5±0.5 cm/s respectively, pConclusionThe application of recombinant human collagen-based microspheres mitigates indirect paracrine conduction slowing through interference with a secondary autocrine myocardial factor.

Recent studies have reported on circadian variation in infarct size in ST-elevation myocardial infarction (STEMI) patients. Controversy remains as to whether this finding indicates circadian dependence of myocardial tolerance to ischemia/reperfusion injury or that it can simply be explained by confounding factors such as baseline profile and ischemic time. We assessed the clinical impact and independent association between symptom onset time and infarct size, accounting for possible subgroup differences. From a multicenter registry, 6799 consecutive STEMI patients undergoing primary percutaneous coronary intervention (PCI) between 2004 and 2010 were included. Infarct size was measured using peak creatine kinase (CK). Infarct size exhibited circadian variation with largest infarct size in patients with symptom onset around 03:00 at night (estimated peak CK 1322 U/l; 95% confidence interval (CI): 1217–1436) and smallest infarct size around 11:00 in the morning (estimated peak CK 1071 U/l; 95% CI: 1001–1146; relative reduction 19%; p = 0.001). Circadian variation in infarct size followed an inverse pattern in patients with prior myocardial infarction (p-interaction p = 0.081). In conclusion, there is substantial circadian variation in infarct size, which cannot be fully explained by variations in baseline profile or ischemic time. Our results lend support to the hypothesis of circadian myocardial ischemic tolerance and suggest a different mechanism in patients with prior myocardial infarction.

Purpose: To assess the benefits and harms of levosimendan for low cardiac output syndrome in critically ill patients. Methods: We conducted a systematic review with meta-analyses and trial sequential analyses (TSA) of randomised clinical trials comparing levosimendan with any type of control. Two reviewers independently assessed studies for inclusion. The Cochrane Collaboration methodology was used. Random-effects risk ratios (RR) and 95 % confidence intervals (CI) were derived for the principal primary outcome mortality at maximal followup. Results: A total of 88 trials were included in the systematic review and 49 trials (6,688 patients) in the meta-analysis. One trial had low risk of bias and nine trials (2,490 patients) were considered lower risk of bias. Trials compared levosimendan with placebo, control interventions, and other inotropes. Pooling all trials including heterogenous populations was considered inappropriate. Pooled analysis of 30 trials including critically ill patients not having cardiac surgery showed an association between levosimendan and mortality (RR 0.83, TSA-adjusted 95 % CI 0.59-0.97), while trials with lower risk of bias showed no significant difference (RR 0.83, TSA-adjusted 95 % CI 0.48-1.55). Conventional meta-analysis of all 14 trials including cardiac surgery patients showed an association, while lower risk of bias trials showed no association between levosimendan and mortality (RR 0.52, 95 % CI 0.37-0.73 versus RR 1.02, 95 % CI 0.48-2.16). Conclusions: The available evidence is inconclusive whether or not levosimendan may have a beneficial effect on mortality due to risks of systematic errors and random errors. Further well-designed randomised trials are needed.

Cardiac dysfunction leads to decreased organ perfusion. We aimed to measure cardiac and renal perfusion simultaneously with the use of N-13-NH3-microPET in different rat models. Ten male Wistar rats underwent sham surgery (n = 5) or permanent coronary artery ligation to induce myocardial infarction (MI, n = 5). Eleven weeks later N-13-NH3-microPET scan was performed to study the cardiac and renal perfusion. Cardiac perfusion was significantly reduced in MI group, directly correlated with ejection fraction and inversely correlated with MI size (r = 0.89; p

Digoxin is the oldest cardiac drug still in contemporary use, yet its role in the management of patients with heart failure (HF) remains controversial. A purified cardiac glycoside derived from the foxglove plant, digoxin increases ejection fraction, augments cardiac output, and reduces pulmonary capillary wedge pressure without causing deleterious increases in heart rate or decreases in blood pressure. Moreover, it is also a neurohormonal modulator at low doses. In the pivotal DIG (Digitalis Investigation Group) trial, digoxin therapy was shown to reduce all-cause and HF-specific hospitalizations but had no effect on survival. With the discovery of neurohormonal blockers capable of reducing mortality in HF with reduced ejection fraction, the results of the DIG trial were viewed as neutral, and the use of digoxin declined precipitously. Although modern drug and device-based therapies have dramatically improved the survival of ambulatory patients with HF, outcomes for patients with worsening chronic HF, defined as deteriorating signs and symptoms on standard therapy often leading to unscheduled clinic or emergency department visits or hospitalization, have largely remained unchanged over the past 2 decades. The available data suggest that a therapeutic trial of digoxin may be appropriate in patients with worsening chronic heart failure who remain symptomatic. (C) 2014 by the American College of Cardiology Foundation

Increased myocardial infarct (MI) size is associated with higher risk of developing left ventricular dysfunction, heart failure and mortality. Experimental studies have suggested that metformin treatment reduces MI size after induced ischaemia but human data is lacking. We aimed to investigate the effect of metformin on MI size in patients presenting with an acute MI.All consecutive patients (n = 3,288) presenting to our hospital with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI between January 2004 and December 2010 were included in this retrospective analysis. Patients with diabetes were divided according to metformin versus non-metformin based pharmacotherapy. MI size was estimated using peak values of serum creatine kinase (CK), myocardial band of CK (CK-MB), and troponin-T.We identified 677 (20.6 %) patients with diabetes, of whom 189 (27.9 %) were treated with metformin. Chronic metformin treatment was associated with lower peak levels of CK (1,101 vs. 1,422 U/L, P = 0.005), CK-MB (152 vs. 182 U/L, P = 0.018) and troponin-T (2.5 vs. 4.0 ng/L, P = 0.021) compared to non-metformin using diabetics. After adjustment for age, sex, TIMI flow post PCI, and previous MI, the use of metformin treatment remained an independent predictor of smaller MI size. Patient with diabetes treated with metformin had even smaller MI size than patients without diabetes.Chronic metformin treatment is associated with reduced MI size compared to non-metformin based strategies in diabetic patients presenting with STEMI. Metformin might have additional beneficial effects beyond glucose lowering efficacy.

Background— Treatments that reduce mortality and morbidity in patients with heart failure with reduced ejection fraction, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), β-blockers (BB), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor–neprilysin inhibitors (ARNI), have not been studied in a head-to-head fashion. This network meta-analysis aimed to compare the efficacy of these drugs and their combinations regarding all-cause mortality in patients with heart failure with reduced ejection fraction. Methods and Results— A systematic literature review identified 57 randomized controlled trials published between 1987 and 2015, which were compared in terms of study and patient characteristics, baseline risk, outcome definitions, and the observed treatment effects. Despite differences identified in terms of study duration, New York Heart Association class, ejection fraction, and use of background digoxin, a network meta-analysis was considered feasible and all trials were analyzed simultaneously. The random-effects network meta-analysis suggested that the combination of ACEI+BB+MRA was associated with a 56% reduction in mortality versus placebo (hazard ratio 0.44, 95% credible interval 0.26–0.66); ARNI+BB+MRA was associated with the greatest reduction in all-cause mortality versus placebo (hazard ratio 0.37, 95% credible interval 0.19–0.65). A sensitivity analysis that did not account for background therapy suggested that ARNI monotherapy is more efficacious than ACEI or ARB monotherapy. Conclusions— The network meta-analysis showed that treatment with ACEI, ARB, BB, MRA, and ARNI and their combinations were better than the treatment with placebo in reducing all-cause mortality, with the exception of ARB monotherapy and ARB plus ACEI. The combination of ARNI+BB+MRA resulted in the greatest mortality reduction.

Aims: The purpose of this study is to describe disease presentation, co-morbidities, diagnosis and initial therapeutic management of patients with peripartum cardiomyopathy (PPCM) living in countries belonging to the European Society of Cardiology (ESC) vs. non-ESC countries. Methods and results: Out of 500 patients with PPCM entered by 31 March 2016, we report on data of the first 411 patients with completed case record forms (from 43 countries) entered into this ongoing registry. There were marked differences in socio-demographic parameters such as Human Development Index, GINI index on inequality, and Health Expenditure in PPCM patients from ESC vs. non-ESC countries (P < 0.001 each). Ethnicity was Caucasian (34%), Black African (25.8%), Asian (21.8%), and Middle Eastern backgrounds (16.4%). Despite the huge disparities in socio-demographic factors and ethnic backgrounds, baseline characteristics are remarkably similar. Drug therapy initiated post-partum included ACE inhibitors/ARBs and mineralocorticoid receptor antagonists with identical frequencies in ESC vs. non-ESC countries. However, in non-ESC countries, there was significantly less use of beta-blockers (70.3% vs. 91.9%) and ivabradine (1.4% vs. 17.1%), but more use of diuretics (91.3% vs. 68.8%), digoxin (37.0% vs. 18.0%), and bromocriptine (32.6% vs. 7.1%) (P < 0.001). More patients in non-ESC vs. ESC countries continued to have symptomatic heart failure after 1 month (92.3% vs. 81.3%, P < 0.001). Venous thrombo-embolic events, arterial embolizations, and cerebrovascular accidents were documented in 28 of 411 patients (6.8%). Neonatal death rate was 3.1%. Conclusion: PPCM occurs in women from different ethnic backgrounds globally. Despite marked differences in socio-economic background, mode of presentation was largely similar. Embolic events and persistent heart failure were common within 1 month post-diagnosis and required intensive, multidisciplinary management.

Contains fulltext : 182443.pdf (Publisher’s version ) (Closed access) OBJECTIVE: The aim of this systematic review and meta-analysis was to describe comprehensively the pattern of cardiac remodeling during normotensive human singleton pregnancy and to compare it with that of pregnancy complicated by hypertension. METHODS: We performed a meta-analysis of the current literature on cardiac remodeling during normotensive and complicated pregnancies. Literature was retrieved from PubMed (NCBI) and EMBASE (Ovid) databases. Included studies needed to report a reference measurement (matched non-pregnant control group, prepregnancy or postpartum) and measurements made during predetermined gestational-age intervals. Mean differences between reference and pregnancy data were calculated using the random-effects model described by DerSimonian and Laird. RESULTS: Forty-eight studies were included in the meta-analysis, with publication dates ranging from 1977 to 2016. During normotensive pregnancy, most geometric indices started to increase in the second trimester. Left ventricular mass (LVM) increased by 28.36 (95% CI, 19.73-37.00) g (24%), and relative wall thickness (RWT) increased by 0.03 (95% CI, 0.02-0.05) (10%) compared with those in the reference group. During hypertensive pregnancy, LVM and RWT increased more than during normotensive pregnancy (92 (95% CI, 75.46-108.54) g (95%) and 0.14 (95% CI, 0.09-0.19) (56%), respectively). CONCLUSIONS: During normotensive pregnancy, most cardiac geometric indices change from the second trimester onwards. Both LVM and RWT increase, by 20% and 10%, respectively, consistent with concentric rather than eccentric remodeling. Cardiac adaptation in hypertensive pregnancy deviates from that in healthy pregnancy by a greater change in LVM (95% increase from reference) and RWT (56% increase from reference). Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd.

IntroductionDiastolic dysfunction is an important predictor of poor outcome after myocardial infarction. Metformin treatment improved diastolic function in animal models and patients with diabetes. Whether metformin improves diastolic function in patients presenting with ST-segment elevation myocardial infarction (STEMI) is unknown.MethodsThe GIPS-III trial randomized STEMI patients, without known diabetes, to metformin or placebo initiated directly after PCI. The previously reported primary endpoint was left ventricular ejection fraction at 4 months, which was unaffected by metformin treatment. This is a predefined substudy to determine an effect of metformin on diastolic function. For this substudy trans-thoracic echocardiography was performed during hospitalization and after 4 months. Diastolic dysfunction was defined as having the combination of a functional alteration (i.e. decreased tissue velocity: mean of septal e' and lateral e') and a structural alteration (i.e. increased left atrial volume index (LAVI)). In addition, left ventricular mass index and transmitral flow velocity (E) to mean e' ratio (E/e') were measured to determine an effect of metformin on individual echocardiographic markers of diastolic function.ResultsIn 237 (63%) patients included in the GIPS-III trial diastolic function was measured during hospitalization as well as at 4 months. Diastolic dysfunction was present in 11 (9%) of patients on metformin and 11 (9%) patients on placebo treatment (P = 0.98) during hospitalization. After 4 months 22 (19%) of patients with metformin and 18 (15%) patients with placebo (P = 0.47) had diastolic dysfunction. In addition, metformin did not improve any of the individual echocardiographic markers of diastolic function.ConclusionsIn contrast to experimental and observational data, our randomized placebo controlled trial did not suggest a beneficial effect of short-term metformin treatment on diastolic function in STEMI patients.

Background Both papillary muscle infarction (PMI) and chronic ischemic mitral regurgitation (CIMR) are associated with reduced survival after myocardial infarction. The influence of PMI on CIMR and factors influencing both entities are incompletely understood. Objectives We sought to determine the influence of PMI on CIMR after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) and to define independent predictors of PMI and CIMR. Methods Between January 2011 and May 2013, 263 patients (mean age 57.8 ± 11.5 years) underwent late gadolinium-enhanced cardiac magnetic resonance imaging and transthoracic echocardiography 4 months after PCI for STEMI. Infarct size, PMI, and mitral valve and left ventricular geometric and functional parameters were assessed. Univariate and multivariate analyses were performed to identify predictors of PMI and CIMR (≥grade 2+). Results PMI was present in 61 patients (23 %) and CIMR was present in 86 patients (33 %). In patients with PMI, 52 % had CIMR, and in patients without PMI, 27 % had CIMR (P

International audience; Most human tissues do not regenerate spontaneously, which is why "cell therapy" are promising alternative treatments. The Principe is simple: patients' or donors' cells are collected and introduced into the injured tissues or organs directly or in a porous 3D material, with or without modification of their properties. This concept of regenerative medicine is an emerging field which can be defined as "the way to improve health and quality of life by restoring, maintaining, or enhancing tissue and organ functions".There is an extraordinarily wide range of opportunities for clinical applications: artheropathies, diabetes, cartilage defects, bone repair, burns, livers or bladder regeneration, organs reconstruction (lung, heart, liver...) neurodegenerative disorders, sepsis...Different stem cells (SC) with different potential can be used and characterised (totipotent, mesenchymal of different origins, especially those present in tissues...). Today it is undeniable that cells like bone marrow, adipose tissue or Wharton Jelly stem cells, are of potential interest for clinical applications because they are easily separated and prepared and no ethical problems are involved in their use.In this paper some potential clinical applications in the vascular field are considered: peripheral arteriopathy in diabetic patients, cardiac insufficiency, traitment of erectile dysfunction, or organ regeneration with liver as example. But the regeneration of tissue or organ is and will remain a challenge for the future development of cell therapy. Many problems remain to be solved that could lead to the development of innovative strategies to facilitate cell differentiation, increase the yield of cells and ensure a standardised product, overcome the risks of teratogenic effects and/or immune reactions, enable grafting via direct cell or biotissue transplantation and avoid legal issues involved in national regulations.

HFA practical guidance

Ischaemic heart disease (IHD) remains the leading cause of death and disability in Europe and worldwide. A major cause of morbidity and mortality in IHD patients is an acute ST-segment elevation myocardial infarction (STEMI), which despite prompt reperfusion by primary percutaneous coronary intervention (PPCI) has significant mortality (7% death at 1 year) and morbidity (22% prolonged or new hospitalization for heart failure at 1 year) in patients with large infarcts.1 When high-risk STEMI patients presenting with cardiogenic shock are not excluded, mortality at 1 year is even higher, at 12% after 1 year.2 As such, there remains an urgent need to discover novel therapies which can be given prior to or at the time of PPCI to reduce myocardial infarct (MI) size in order to preserve left ventricular (LV) systolic function, prevent the onset of heart failure, and improve survival in reperfused STEMI patients. In patients presenting with STEMI, rapid access to the emergency medical services and timely reperfusion by PPCI minimize the total ischaemic time, a major determinant of MI size. Although myocardial reperfusion is essential to salvage myocardium following a STEMI, the process of restoring coronary blood flow to the ischaemic tissue can, in itself, induce myocardial injury and cardiomyocyte death, a phenomenon which is known as ‘myocardial reperfusion injury’.3,4 Crucially, there is currently no effective therapy for reducing myocardial reperfusion injury in STEMI patients, and therefore, it remains a valid target for cardioprotection. However, the search for an effective therapy capable of targeting myocardial reperfusion injury and reducing MI size has been quite challenging, with a large number of failures to translate novel cardioprotective therapies into the …

Background Left ventricular dysfunction and the development of heart failure is a frequent and serious complication of myocardial infarction. Recent animal experimental studies suggested that metformin treatment reduces myocardial injury and preserves cardiac function in non-diabetic rats after experimental myocardial infarction. We will study the efficacy of metformin with the aim to preserve left ventricular ejection fraction in non-diabetic patients presenting with ST elevation myocardial infarction (STEMI). Methods The Glycometabolic Intervention as adjunct to Primary percutaneous intervention in ST elevation myocardial infarction (GIPS)-III trial is a prospective, single center, double blind, randomized, placebo-controlled trial. Three-hundred-and-fifty patients, without diabetes, requiring primary percutaneous coronary intervention (PCI) for STEMI will be randomized to metformin 500 mg twice daily or placebo treatment and will undergo magnetic resonance imaging (MRI) after 4 months. Major exclusion criteria were prior myocardial infarction and severe renal dysfunction. The primary efficacy parameter is left ventricular ejection fraction 4 months after randomization. Secondary and tertiary efficacy parameters include major adverse cardiac events, new onset diabetes and glycometabolic parameters, and echocardiographic diastolic function. Safety parameters include renal function deterioration and lactic acidosis. Conclusions The GIPS-III trial will evaluate the efficacy of metformin treatment to preserve left ventricular ejection fraction in STEMI patients without diabetes.

OBJECTIVE. This article reviews the CT-based approaches aimed at the assessment of myocardial infarction, ischemia, and viability described in the recent literature.CONCLUSION. Rapid advances in CT technology not only have improved visualization of coronary arteries but also increasingly enable noncoronary myocardial applications, including analysis of wall motion and the state of the myocardial blood supply. These advancements hold promise for eventually accomplishing the goal of comprehensively evaluating coronary heart disease with a single noninvasive modality.

The use of coronary computed tomography angiography (cCTA) is growing rapidly, in large part because of fast-paced technical innovations that have increased diagnostic accuracy while providing new opportunities for radiation dose reduction. cCTA using recent generation CT scanners has been repeatedly shown to have excellent negative predictive value for ruling out significant coronary stenosis in comparison with invasive coronary angiography (ICA) and is now accepted for this use in selected populations. Current work is increasingly focused on evaluating and optimising radiation dose reduction techniques, the cost-effectiveness of cCTA implementation, and the impact of cCTA on patient management and outcomes. In addition, the potential value of emerging applications, such as atherosclerotic plaque characterisation and myocardial perfusion and viability assessment, are undergoing intense investigation.

Heart failure is still a large medical problem, and the European Journal of Heart Failure remains dedicated to further investigating its pathophysiology and diagnosis, as well as alleviating the symptoms and improving outcome for patients with this disorder.(1) In 2010, a large number of important studies have been published, many with exciting results. In this overview, we discuss the results of many of these studies, which have been conducted in a broad range of areas, ranging from pre-clinical research, to co-morbidities, new insights in the genetics of heart failure, and novel guidelines in the field of device therapy.

Heart failure is still a large medical problem, and the European Journal of Heart Failure remains dedicated to further investigating its pathophysiology and diagnosis, as well as alleviating the symptoms and improving outcome for patients with this disorder.(1) In 2010, a large number of important studies have been published, many with exciting results. In this overview, we discuss the results of many of these studies, which have been conducted in a broad range of areas, ranging from pre-clinical research, to co-morbidities, new insights in the genetics of heart failure, and novel guidelines in the field of device therapy.

We present use of a synthetic, injectable matrix metalloproteinase (MMP)- responsive, bioactive hydrogel as an in situ forming scaffold to deliver thymosin beta 4 (T beta 4), a pro-angiogenic and pro-survival factor, along with vascular cells derived from human embryonic stem cells (hESC) in ischemic injuries to the heart in a rat model. The gel was found to substitute the degrading extracellular matrix in the infarcted myocardium of rats and to promote structural organization of native endothelial cells, while some of the delivered hESC-derived vascular cells formed de novo capillaries in the infarct zone. Magnetic resonance imaging (MRI) revealed that the microvascular grafts effectively preserved contractile performance 3 d and 6 wk after myocardial infarction, attenuated left ventricular dilation, and decreased infarct size as compared to infarcted rats treated with PBS injection as a control (3 d ejection fraction, + similar to 7%, P < 0.001; 6 wk ejection faction, + similar to 12%, P < 0.001). Elevation in vessel density was observed in response to treatment, which may be due in part to elevations in human (donor)-derived cytokines EGF, VEGF and HGF (1 d). Thus, a clinically relevant matrix for dual delivery of vascular cells and drugs may be useful in engineering sustained tissue preservation and potentially regenerating ischemic cardiac tissue. (c) 2010 Elsevier Ltd. All rights reserved.

In Idiopathic Dilated Cardiomyopathy (IDC) an imbalance between myocardial oxygen consumption and supply has been postulated. The ensuing subclinical myocardial ischemia may contribute to progressive deterioration of LV function. beta-blocker is the therapy of choice in these patients. However, not all patients respond to the same extent. The aim of this study was to elucidate whether differences between responders and non-responders can be identified with respect to regional myocardial perfusion reserve (MPR) and contractile performance.Patients with newly diagnosed IDC underwent Positron Emission Tomography (PET) scanning using both (13)N-ammonia as a perfusion tracer (baseline and dipyridamole stress), and (18)F-fluoro-deoxyglucose as a metabolism tracer, and a dobutamine stress MRI. MRI and PET were repeated 6 months after maximal beta-blocker therapy. MPR (assessed by PET) as well as wall motion score (WMS, assessed by MRI) were evaluated in a 17 segment-model. Functional response to beta-blocker therapy was assigned as a stable or improved LVEF or diminished LVEF.Sixteen patients were included (age 47.9 +/- A 11.5 years; 12 males, LVEF 28.6 +/- A 8.4%). Seven patients showed improved LVEF (9.7 +/- A 3.1%), and nine patients did not show improved LVEF (-3.4 +/- A 3.9%). MPR improved significantly in responders (1.56 +/- A .23 to 1.93 +/- A .49, P = .049), and MPR decreased in non-responders; however, not significantly (1.98 +/- A .70 to 1.61 +/- A .28, P = .064), but was significantly different between both groups (P = .017) after beta-blocker therapy. A significant correlation was found between change in perfusion reserve and change in LVEF: a decrease in perfusion reserve was associated with a decrease in LVEF and vice versa. Summed rest score of wall motion in responders improved from 26 to 21 (P = .022) whereas in non-responders no change was observed from 26 to 25) (P = ns). Summed stress score of wall motion in responders improved from 23 to 21 (P = .027) whereas in non-responders no change was observed from 27 to 26) (P = ns).In IDC patients, global as well as regional improvement after initiation of beta-blocker treatment is accompanied by an improvement in regional perfusion parameters. On the other hand in IDC patients with further left ventricular function deterioration after initiation of beta-blocker therapy this is accompanied by a decrease in perfusion reserve.

Myocardial infarction (MI)-induced remodeling is associated with disturbed myocardial perfusion through vascular changes, such as reduced capillary density and endothelial dysfunction. Heart rate reduction (HRR) initiated immediately after MI stimulates angiogenesis and attenuates left ventricular dysfunction. We aimed to investigate the effects of long-term HRR on cardiac angiogenesis and endothelial function in a rat model of post-MI heart failure. Rats received early or late ivabradine or metoprolol for 12 or 9 weeks, respectively, and compared with untreated MI and sham animals 12 weeks after MI. Heart rate was measured in the conscious rat. MI resulted in an increased heart weight to body weight ratio, a decline in capillary density and a marked reduction in acetylcholine-induced relaxation. Early and late HRR by either ivabradine or metoprolol significantly increased capillary to myocyte ratio. Moreover, this ratio was significantly correlated to heart rate (r = -0.324 and P = 0.036). Neither early nor late chronic HRR prevented endothelial dysfunction, except a moderate improvement in late MI ivabradine group. In MI rats, HRR either by ivabradine or metoprolol treatment increases cardiac angiogenesis. Late HRR strategy was comparable to early HRR, suggesting that the beneficial effects are independent of the time of onset of therapy after MI.

Two women, aged 27, presented with different symptoms shortly after giving birth to their first child. Peripartum cardiomyopathy (PPCM) was diagnosed. PPCM is a rare form of cardiac failure occurring late in pregnancy or in the postpartum period. Many women experience dyspnoea, fatigue, and pedal oedema in the last month of pregnancy or postpartum, symptoms which are identical to early congestive heart failure. Therefore, the diagnosis of PPCM requires vigilance. A high mortality rate mid overall poor clinical outcome has been reported in a high percentage of these patients. Subsequent pregnancies remain controversial. (Neth Heart J 2008;16:415-8.)

AIMS: To investigate long-term outcome and to determine predictors of development of heart failure (HF) in patients with atrioventricular (AV) node ablation and permanent right ventricular pacing because of symptomatic refractory atrial fibrillation (AF).BACKGROUND: Atrioventricular node ablation and subsequent permanent pacing is a well-established therapy for patients with AF. Long-term right ventricular pacing may induce HF.METHODS AND RESULTS: In 121 (45 with previous HF) patients with drug refractory AF, AV node ablation and implantation of a pacemaker was performed. At baseline and after a mean follow-up of 4.3 +/- 3.3 years, New York Heart Association (NYHA) functional class for HF and left ventricular (LV) and atrial diameters were assessed. During and at the end of follow-up, hospitalizations for HF, mortality, and quality of life were assessed using the SF-36 and an AVN-specific questionnaire. No significant changes in NYHA functional class (87 vs. 77% in NYHA I/II at baseline vs. end of follow-up) and LV end diastolic diameter (51 +/- 7 vs. 52 +/- 8 mm) were observed. Left ventricular end systolic diameter decreased (from 37 +/- 9 to 34 +/- 7 mm, P = 0.03) and fractional shortening improved (from 28 +/- 10 to 34 +/- 9, P = 0.02) in all patients and in patients with previous HF, but not in patients without previous HF. Hospitalizations for HF occurred in 24 patients (20%), predominantly those with previous HF. All-cause mortality occurred in 31 (26%) patients. At the end of follow-up, quality of life was comparable with the control group.CONCLUSION: Long-term outcome of AV node ablation and permanent pacing is good. Atrioventricular node ablation remains a treatment option for AF.

Cell-based cardiac repair has the ambitious aim to replace the malfunctioning cardiac muscle developed after myocardial infarction, with new contractile cardiomyocytes and vessels. Different stem cell populations have been intensively studied in the last decade as a potential source of new cardiomyocytes to ameliorate the injured myocardium, compensate for the loss of ventricular mass and contractility and eventually restore cardiac function. An array of cell types has been explored in this respect, including skeletal muscle, bone marrow derived stem cells, embryonic stem cells (ESC) and more recently cardiac progenitor cells. The best-studied cell types are mouse and human ESC cells, which have undisputedly been demonstrated to differentiate into cardiomyocyte and vascular lineages and have been of great help to understand the differentiation process of pluripotent cells. However, due to their immunogenicity, risk of tumor development and the ethical challenge arising from their embryonic origin, they do not provide a suitable cell source for a regenerative therapy approach. A better option, overcoming ethical and allogenicity problems, seems to be provided by bone marrow derived cells and by the recently identified cardiac precursors. This report will overview current knowledge on these different cell types and their application in cardiac regeneration and address issues like implementation of delivery methods, including tissue engineering approaches that need to be developed alongside.

Background: Primary percutaneous coronary intervention (PCI) is effective in opening the infarct-related artery in patients with myocardial infarction with ST-segment elevation. However, the embolization of atherothrombotic debris induces microvascular obstruction and diminishes myocardial reperfusion. Methods: We performed a randomized trial assessing whether manual aspiration was superior to conventional treatment during primary PCI. A total of 1071 patients were randomly assigned to the thrombus-aspiration group or the conventional-PCI group before undergoing coronary angiography. Aspiration was considered to be successful if there was histopathological evidence of atherothrombotic material. We assessed angiographic and electrocardiographic signs of myocardial reperfusion, as well as clinical outcome. The primary end point was a myocardial blush grade of 0 or 1 (defined as absent or minimal myocardial reperfusion, respectively). Results: A myocardial blush grade of 0 or 1 occurred in 17.1% of the patients in the thrombus-aspiration group and in 26.3% of those in the conventional-PCI group (P Conclusions: Thrombus aspiration is applicable in a large majority of patients with myocardial infarction with ST-segment elevation, and it results in better reperfusion and clinical outcomes than conventional PCI, irrespective of clinical and angiographic characteristics at baseline. (Current Controlled Trials number, ISRCTN16716833.).

Randomized controlled trials (RCTs) are the golden standard for the assessment of drug efficacy. Little is known about the add-on value of observational studies in heart failure (HF). We aimed to assess the contribution of observational studies to actual knowledge regarding the effectiveness of angiotensin-converting enzyme inhibitors (ACEI), and beta-blockers (BB) in HF.Observational studies that assessed the effectiveness of ACEI and BB in HF were identified by searching Medline, Embase, Cochrane Database (1990-2005) and the bibliographies of published articles. Cohort, case-control and time-series analysis studies were considered for inclusion. Studies with A total of 23 cohort studies met the inclusion criteria. Studies of ACEI and BB showed a decrease in mortality with drug use in elderly patients with a broad range of ejection fraction (EF), and in those with depressed EF. Additionally, they showed a decrease in mortality in patients with renal insufficiency. The effect of ACEI and BB in HF with preserved EF was not clear, although last evidence suggests a potential benefit. Low-dose ACEI and BB may have beneficial effects. Target doses of ACEI seemed superior to low doses, but there was no clear dose-response relationship.Observational studies in HF validate the effectiveness of ACEI and BB in populations underrepresented or excluded from RCTs. Observational studies of drug effectiveness provide relevant additional information for clinical practice.

Aims Randomized controlled trials (RCTs) are the golden standard for the assessment of drug efficacy. Little is known about the add-on value of observational studies in heart failure (HF). We aimed to assess the contribution of observational studies to actual knowledge regarding the effectiveness of angiotensin-converting enzyme inhibitors (ACEI), and β-blockers (BB) in HF. Methods Observational studies that assessed the effectiveness of ACEI and BB in HF were identified by searching Medline, Embase, Cochrane Database (1990–2005) and the bibliographies of published articles. Cohort, case–control and time-series analysis studies were considered for inclusion. Studies with

Nebivolol is a third generation beta-blocker. It is highly selective for the beta 1-adrenoceptor, and has additional nitric oxide-mediated vasodilating and antioxidant properties, along with a favourable metabolic profile. Nebivolol is well tolerated by patients with hypertension and heart failure. Although several smaller studies were conducted with nebivolol in hypertensive patients, no large randomised clinical trials have been performed to prove efficacy on hard clinical end points. In patients with heart failure, a large mortality/morbidity trial was conducted, and nebivolol was shown to reduce the composite end point of mortality and hospitalisations. Nebivolol is registered, in Europe, for mild-to-moderate, uncomplicated hypertension and mild-to-moderate heart failure; and outside Europe, for hypertension. This review describes experimental and clinical data regarding this selective P-blocker with vasodilating and antioxidant effects.

Purpose To assess the impact of beta-blocker therapy on quality of life (QoL) in chronic heart failure (CHF) patients receiving optimal standard medication.Methods Randomised controlled trials (RCT) assessing QoL with a generic or disease specific instrument were identified by searching Medline, Embase, Pascual, Cochrane Controlled Trial database, and the bibliographies of the published articles. Studies published between 1985 and 2002 were included, regardless of language of publication. Cochrane Review Manager 4.2 software was used to analyse the data and standardised mean difference (SMD) was calculated to assess the effect on QoL.Results A total of 9 trials involving 1954 patients fit into the inclusion criteria for the analysis. QoL improved more in the beta-blocker group compared to the control arm, but the SMD did not reach statistical significance (SMD, 0.07; 95%CI [-0.16, 0.021; p=0.13). Subgroup analysis, per type of beta-blocker and various treatment follow-up showed similar results.Conclusions In this meta-analysis there is evidence that beta-blocker therapy, on top of standard medication, does not impair QoL. Clinicians may add beta-blockers to standard therapy without concerns of impairing QoL in patients with CHF. Copyright (c) 2006 John Wiley & Sons, Ltd.

Heart failure is a significant clinical issue. It is the cause of enormous healthcare costs worldwide and results in significant morbidity and mortality. Cardiac regenerative therapy has progressed considerably from clinical and preclinical studies delivering simple suspensions of cells, macromolecule, and small molecules to more advanced delivery methods utilizing biomaterial scaffolds as depots for localized targeted delivery to the damaged and ischemic myocardium. Here, regenerative strategies for cardiac tissue engineering with a focus on advanced delivery strategies and the use of multimodal therapeutic strategies are reviewed.

Objectives: To investigate the long-term impact of multivessel coronary artery disease (MVD) on cause-specific mortality in patients with ST elevation myocardial infarction (STEMI) treated with reperfusion therapy. Methods and results: Patients with STEMI (n = 395) treated with primary angioplasty or thrombolysis in the setting of a randomised clinical trial were enrolled in the study. Follow up was 8 (2) years. For patients who died all available records were reviewed to assess the specific cause of death. MVD was present in 57% of patients. Patients with MVD were older and more of them had diabetes and previous myocardial infarction. Compared with the non-MVD group, residual left ventricular ejection fraction was lower (45.9% v 49.6%, p = 0.001) and total mortality was higher in patients with MVD (32% v 19%, p = 0.002). After adjustment for potential confounders this association was not significant (hazard ratio 1.4, 95% confidence interval (CI) 0.9 to 2.2). When the specific cause of death was considered, sudden death was comparable between patients with and without MVD (10% v 8%, p = 0.49) but death caused by heart failure was significantly higher in patients with MVD (hazard ratio 7.4, 95% CI 1.7 to 32.2). Conclusion: Patients with STEMI and MVD have a higher long-term mortality than do patients with non-MVD. MVD is not an independent predictor of long-term total mortality or sudden death. However, MVD is a very strong and independent predictor of long-term death caused by heart failure.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting young as well as elderly patients and presenting a major therapeutic challenge for clinical cardiologists. Recent research has elucidated the progressive nature of AF, including the structural and electrical remodelling that may become manifest if normal sinus rhythm is not restored, and the serious morbidities associated with tong-term disease. The controversy over the merits of ventricular rate control vs. the restoration and maintenance of normal sinus rhythm in the treatment of AF has been explored in a number of large-scale, randomized clinical trials. The results of these trials suggest that whereas the two strategies may be equivalent for some patient populations, with both approaches requiring accompanying anticoagulation therapy, the restoration and maintenance of sinus rhythm provide important haemodynamic as well as subjective benefits not afforded by rate control. Although early intervention to limit the progression of this arrhythmia is hindered by the limitations of existing anti-arrhythmic therapies, it is nevertheless a critical goal.

Patients with increased cholesterol levels are at increased risk to experience cardiovascular events and to die from vascular disease. Statins have been proven to effectively reduce cholesterol levels and subsequently reduce cardiovascular events in patients with coronary artery disease or at increased risk to develop coronary artery disease. However, in patients with chronic heart failure (CHF), not high, but low levels of cholesterol are related to increased mortality. This phenomenon of reverse epidemiology is not unique to CHF, but also exists in other critical diseases and in the elderly in general as well. An important rationale has been provided by the endotoxin hypothesis, which suggests that cholesterol has an important scavenger function regarding harmful endotoxins. Indeed, these lines of evidence predict a harmful effect of statin treatment in patients with CHF. However, statins not only lower cholesterol, but also have been reported to exhibit a plethora of pleiotropic effects, including reduction of inflammation and improvement of endothelial function. In order to reconcile these contradictory lines of evidence, it is necessary to examine the pharmacological mechanisms of effects of statin treatment. Understanding the pharmacology of statin intervention in CHF models and patients may facilitate the development of therapeutic strategies. In this review, we provide an overview of the known associations between serum cholesterol and CHIF in human subjects. In addition, we review the available lines of evidence in animal models and humans predicting both harmful and beneficial effects of statin treatment in CHF. We emphasize the importance of additional research specifically in CHF models and patients. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Aims: Besides stimulating hematopoiesis, erythropoietin (EPO) protects against experimental ischemic injury in the heart. The present study evaluated the safety and tolerability of EPO treatment in non-anemic patients with acute myocardial infarction (MI). Methods and Results: In this single-center, investigator-initiated, prospective study, patients with a first acute MI were randomized to one bolus of 300 μg darbepoetin alfa or no additional medication before primary coronary intervention. Twenty-two patients (mean age 59 ± 2 years) were included. In the darbepoetin group, serum EPO-levels increased to 130–270 times that of controls, within the first 24 h. After darbepoetin administration, only small and non-significant changes in hematocrit levels were observed, while endothelial progenitor cells (EPCs, CD34+/CD45−) were increased at 72 h (2.8 vs. 1.0 cells/μl in control group, p < 0.01). No adverse events were recorded during the 30-day follow-up. After 4 months, left ventricular ejection fraction was similar in the two groups (52 ± 3% in darbepoetin vs. 48 ± 5% in control group, p = NS). Conclusions: Intravenous single high-dose darbepoetin alfa in acute MI is both safe and well tolerated. Darbepoetin treatment after MI stimulates EPCs mobilization. The results of this first pilot study support a larger scale clinical trial to establish efficacy of EPO administration in patients after acute MI.

Background: In patients with acute myocardial infarction, estimation of infarct size by cumulative lactate dehydrogenase release at 72 h (LDHQ72) is a simple and widely used method. Our objective was to study the value of estimating infarct size, by the cumulative release of LDH over 72, 60, 48 and 36 h in predicting left ventricular ejection fraction (LVef) and cardiac death at 1 year. Methods: In the Zwolle Infarction Study infarct size estimated as LDHQ was calculated in 1224 patients treated with primary percutaneous coronary intervention for acute myocardial infarction between December 1993 and June 2001. Patients were categorized as having small (LDHQ7272 800-2500 U/L) or large (LDHQ72>2500 U/L) myocardial infarction. Results: LDHQ72 was closely correlated with LDHQ60, LDHQ48 and LDHQ36 ( r = 0.998, 0.993 and 0.987, respectively, P ef (51% vs 45% vs 35%, P Conclusion: Infarct size classification based on LDHQ36 is an objective and widely available method for early risk stratification in patients treated with primary angioplasty for acute ST-segment elevation myocardial infarction.