Both ageing and hypertension are known risk factors for atrial fibrillation (AF) although the pathophysiological contribution or interaction of the individual factors remains poorly understood. Here we aim to delineate the arrhythmogenic atrial substrate in mature spontaneously hypertensive rats (SHR).SHR were studied at 12 and 15 months of age (n = 8 per group) together with equal numbers of age-matched normotensive Wistar-Kyoto control rats (WKY). Electrophysiologic study was performed on superfused isolated right and left atrial preparations using a custom built high-density multiple-electrode array to determine effective refractory periods (ERP), atrial conduction and atrial arrhythmia inducibility. Tissue specimens were harvested for structural analysis.Compared to WKY controls, the SHR demonstrated: Higher systolic blood pressure (p<0.0001), bi-atrial enlargement (p<0.05), bi-ventricular hypertrophy (p<0.05), lower atrial ERP (p = 0.008), increased atrial conduction heterogeneity (p = 0.001) and increased atrial interstitial fibrosis (p = 0.006) & CD68-positive macrophages infiltration (p<0.0001). These changes resulted in higher atrial arrhythmia inducibility (p = 0.01) and longer induced AF episodes (p = 0.02) in 15-month old SHR. Ageing contributed to incremental bi-atrial hypertrophy (p<0.01) and atrial conduction heterogeneity (p<0.01) without affecting atrial ERP, fibrosis and arrhythmia inducibility. The limited effect of ageing on the atrial substrate may be secondary to the reduction in CD68-positive macrophages.Significant atrial electrical and structural remodeling is evident in the ageing spontaneously hypertensive rat atria. Concomitant hypertension appears to play a greater pathophysiological role than ageing despite their compounding effect on the atrial substrate. Inflammation is pathophysiologically linked to the pro-fibrotic changes in the hypertensive atria. Both ageing and hypertension are known risk factors for atrial fibrillation (AF). Epidemiological studies have established that the odds ratio for developing AF was 2.1–2.2 and 1.4–1.5 for each decade of advancing age and hypertension respectively. The spontaneously hypertensive rat (SHR) is most commonly used in high blood pressure research to represent established human hypertension, with the Wistar Kyoto rat (WKY) as the normotensive control. This study was approved by the Animal Ethics Committee of the University of Adelaide, Adelaide, Australia . All animal experimentations conformed to the ‘Guide for the Care and Use of Laboratory Animals’ as adopted by National Institutes of Health, USA and all efforts were made to minimize suffering. A total of 32 male rats were included in this study: 16 were SHR and 16 were normotensive WKY control rats at 12 and 15 months of age (n = 8 per time point). The SHR  develops hypertension from 2–3 months of age which peaks from 6 months of age onwards with increasing compensatory concentric cardiac hypertrophy, before the onset of heart failure at the age of 15–18 months. ad libitum access to food and water and were housed in temperature-controlled rooms with 12 h light/dark cycle. For experimentations, they were first anesthetized with intra-peritoneal injection of ketamine (60 mg/kg) and medetomidine (0.5 mg/kg). Systolic blood pressure was then measured non-invasively using an inflatable tail-cuff and pressure transducer in conjunction with a PowerLab system . At least three measurements were performed and the average taken. Transthoracic echocardiography  was used to determine left ventricular wall thickness and systolic fractional shortening from M-mode measurements at the level of the papillary muscles with atria dimensions measured from the apical 4-chamber view. 2PO4, 1.2 MgSO4, 11 glucose and 10 HEPES-NaOH). Both right and left atria were then carefully dissected from the heart for immediate electrophysiological studies.All animals were given 2. The superfusate was circulated in a closed loop using a peristaltic pump  and its temperature regulated at 37.5°C with a heater. A lightweight mesh was placed over the tissue to ensure constant tissue contact with the underlying electrodes. The MEA was connected to a computerized recording system  with a sampling rate of 4 kHz and filtering from 10–500 Hz. For consistency, the atrial tissues were placed over the MEA in the same cranial-caudal and medial-lateral orientation with the epicardial surface in contact with the electrodes.Detailed information about the MEA system setup  has been described previously. Atrial effective refractory period (ERP) was measured at twice diastolic threshold from two sites in each atrium – RA free wall (RAFW), RA appendage (RAA), LA free wall (LAFW) and LA appendage (LAA). This was performed with eight basic (S1) stimuli at 400, 300, 200 and 100 ms followed by a premature (S2) stimulus in 5 ms decrement. Refractoriness was defined as the longest S1–S2 interval not resulting in a propagated response. A total of three ERP measurements were taken from each site at each cycle length and the total averaged. The coefficient of ERP variation (standard deviation/mean×100%) was determined to assess ERP heterogeneity.Conduction was assessed during stable S1 pacing at 400, 300, 200 and 100 ms from 2 pre-specified opposing corners of the MEA. Activation maps were created using semi-automated custom-made plaque analysis software . Each annotation was manually verified with the local activation time annotated to the peak of the largest amplitude deflection on bipolar electrograms. Conduction velocity was calculated from local vectors within each triangle of electrodes to derive a mean conduction velocity for each activation map. Conduction heterogeneity was assessed using an established phase mapping method during S1 pacing. This was assessed with rapid decremental pacing at the atrial appendage, starting from 100 ms cycle length, which was decreased in 5 ms intervals every 2 seconds until either atrial tachycardia/fibrillation (AT/AF) was initiated or there was loss of 1∶1 capture. This protocol of induction was implemented 10 times in total for determining inducibility and duration of induced arrhythmic episodes. AT/AF was defined as rapid regular/irregular atrial activation lasting more than 6 beats. A normalized voltage algorithm was implemented to visualize the wavefront propagation sequence during atrial arrhythmia  stain. Measurement of mean myocyte cross-sectional area was performed as previously described. P<0.05.All continuous variables are reported as mean ± SD and assessed for normality using the Shapiro-Wilk test. To improve presentation clarity, mean ± standard error of the mean was utilized in Detailed animal characteristics are shown in Significant bi-atrial hypertrophy was evident in the SHR as assessed by echocardiography and pathological examinations . These aAtrial ERP was significantly lower in the SHR as compared to the WKY controls at both time points (p = 0.008). However, in both SHR and WKY, ERP was not significantly different between the 12 and 15 month atria (p = 0.3) and ERP was unaltered by pacing cycle length in both groups (p = 0.8). To illustrate the above, ERP data from the LAFW are presented in Indeed, neither hypertension nor ageing had any significant effect on atrial conduction velocity  Bi-atrial enlargement and bi-ventricular hypertrophy; ii) Abbreviation of atrial refractoriness; iii) Increase in atrial conduction heterogeneity & iv) Increase in atrial myocyte dimension, interstitial fibrosis and CD68-positive macrophages infiltration. Together, these changes resulted in higher atrial arrhythmia inducibility and longer induced AT/AF episodes. In the presence of persistent hypertension and maximal left ventricular hypertrophy, ageing contributed to incremental bi-atrial enlargement, atrial myocyte hypertrophy and atrial conduction heterogeneity without affecting atrial refractoriness. Surprisingly, atrial arrhythmia susceptibility/sustainability and fibrosis were not higher due to ageing in these SHR despite the additional atrial enlargement and conduction changes. Perhaps, the atrial remodeling attributable to ageing was ameliorated by a significant reduction in CD68-positive macrophages. Here, hypertension appears to play a greater pathophysiological role than ageing in the remodeling of the mature SHR atria.It is now recognized that co-existing risk factors contribute to both the development and progressive nature of AF. On the structural level, both ageing and hypertension were associated with increased atrial fibrosis and myocyte hypertrophy that could account for the electrical changes of slowed atrial conduction, increased conduction heterogeneity and electrogram fractionation.The universal morphological finding of increased atrial fibrosis is likely to represent a final common pathway of structural remodeling that contributes to the maintenance of AF. Indeed, several pathophysiological signaling pathways are implicated in different structural heart diseases leading to the common manifestations of hypertrophy and fibrosis. Furthermore, active inflammation and immune response in human fibrillating atria have been reported with recruitment of CD68-positive macrophages found across the atrial endocardium. Hypertension accounts for more AF than any other risk factors due to its high prevalence in the population. As the prevalence of hypertension also increases with age, its arrhythmic burden is likely to be higher in the elderly. This study unravels the relative greater contribution of high blood pressure than ageing to the abnormal arrhythmogenic substrate in the hypertensive atria with established left ventricular hypertrophy. Our findings raise the importance of strict blood pressure management in the elderly, especially those with concomitant AF. This study also presents evidence regarding the important pathophysiological role of inflammatory macrophages in hypertensive atrial remodeling. Novel agents targeting these macrophages derived inflammatory pathways may provide alternate substrate specific upstream therapies in the future.The SHR is the most widely studied experimental model of hypertension. However, it remains uncertain whether we can directly extrapolate our findings to the wide range of human hypertensive syndromes. To facilitate high-density contact mapping of the atria, electrophysiological evaluations were performed ex-vivo in the superfused atria with 2,3-butanedione monoxime added to suppress motion artifacts. Although 2,3-butanedione monoxime has been reported to affect a number of cardiac ion channels, intracellular calcium levels and action potential duration, the dosage used in this study was significantly lower (order of 10×) than those used in the previous reports. We did not verify that the degree of oxygenation and substrate delivery were sufficient to meet the metabolic demands of the atrial tissues. Placement of a lightweight mesh over the atrial tissue on the MEA may induce mechanical stretch and affect atrial electrophysiology. However, at no time did we observe any degradation of signals with our MEA setup, with good tissue viability and high quality of electrogram recordings maintained well after completion of electrophysiological assessment. Significant atrial electrical and structural remodeling was seen with hypertension and ageing in the mature spontaneously hypertensive rat atria. In this study, hypertension appears to play a greater pathophysiological role than ageing. Inflammation is likely to be mechanistically important in the pro-fibrotic cascade of the hypertensive atria.Methods S1Supplement Methods.(DOC)Click here for additional data file.Movie S1This normalized voltage movie demonstrates a stable counter-clockwise wavefront propagation sequence consistent with a macro-reentrant type atrial tachycardia in the left atrium of a 12 month old spontaneously hypertensive rat. Here, the signal scale ranged from red to purple, representing normalized voltage from 0 to 1.(WMV)Click here for additional data file.Movie S2This normalized voltage movie shows irregularly irregular atrial wavefront propagations consistent with atrial fibrillation following delivery of a premature atrial stimulus in the left atrium of a 15 month old spontaneously hypertensive rat. Similarly, the signal scale ranged from red to purple, representing normalized voltage from 0 to 1.(WMV)Click here for additional data file.


Statistical quantification and classification of heart disease, using clinical indices such as ejection fraction (EF) or left-ventricular mass (LVM), are used routinely in clinical practice for both diagnosis and prognosis. However, 3D CMR of the left ventricle (LV) provides a wealth of shape features which can maximise the classification power and accuracy of such indices. To exploit these, we propose a framework whereby shape parameters of a 3D LV finite element atlas are used to optimally classify patients according to linear statistical decompositions Fig. .Multi-Ethnic Study of Atherosclerosis (MESA) cohort (1) and 300 patients with myocardial infarction from the Defibrillators To Reduce Risk By Magnetic Resonance Imaging Evaluation (DETERMINE) cohort (2) made available through the Cardiac Atlas Project (3). Bias due to scan protocol differences between cohorts was corrected (4). Shape classifiers were constructed to optimally detect which cohort each case belonged. A comparison between principal component analysis (PCA) and information preserving component analysis (IPCA) (5) was performed, using shapes at end-diastole (ED), end-systole (ES) and the difference in shape between ED and ES (ED-ES) which included information on regional wall motion. Traditional clinical classifiers of EF, end-diastolic/end-systolic volume (EDV/ESV) and LVM were also included for comparison. Ten-fold cross-validation experiments were performed in which 90% of the cases were used for training and 10% for validation, repeated 10 times with different training/validation cases.Finite-element shape models of the LV were customised to 600 cardiac MRI volumes with previously standardised and validated software . The dataset comprised 300 community-based participants without a history of cardiovascular disease, aged 45-84 from 4 ethnic groups from the Classification results showed that this framework was able to determine clinically relevant modes and that IPCA achieved the lowest error rates using the ED-ES shape difference, with a single classifier number. This classifier can also be used to quantify severity of disease (degree of match with each group). Ten-fold cross-validation experiments corroborated the robustness of this approach which averaged 100% specificity and 99% sensitivity for IPCA versus 83% and 93% respectively when compared to ejection fraction  and St. Jude Medical provided grant support for the DETERMINE trial. MESA was supported by contracts N01-HC-95159 through N01-HC-95169 from the NHLBI and by grants UL1-RR-024156 and UL1-RR-025005 from NCRR.


Atrial remodeling has emerged as the structural basis for the maintenance and recurrence of atrial fibrillation. Lactate signaling cascade was recently linked to some cardiovascular disorders for its regulatory functions to myocardial structural remodeling. It was hypothesized that lactate signaling cascade was involved in the maintenance and recurrence of atrial fibrillation by regulating atrial structural remodeling.Biopsies of right atrial appendage and clinical data were collected from sex- and age-matched 30 persistent atrial fibrillation, 30 paroxysmal atrial fibrillation, 30 sinus rhythm patients undergoing isolated mitral valve surgery and 10 healthy heart donors.Atrial fibrillation groups had higher atrial lactate expression and this upregulated expression was positively correlated with regulatory indicators of atrial structural remodeling as reflected by severe oxidative stress injury and mitochondrial control of apoptosis.The present findings suggest a potential role for lactate signaling cascade in the maintenance and recurrence of atrial fibrillation and possibly represent new targets for therapeutic intervention in this disorder. Atrial fibrillation (AF) is the most common clinically encountered arrhythmia associated with substantial cardiovascular morbidity and mortality . It is pThe fundamental mechanism underlying AF is primarily characterized by electrical remodeling, but limited success rates and uncertain long-term outcomes of current therapies based on this hypothesis, indicate that apart from electrical remodeling other factors are also involved in development of AF . In the In conventional wisdom, lactate, the end product of glycolysis, is formed as the result of oxygen insufficiency and utilized under fully aerobic conditions in contracting cardiac muscle. However, rapid progress in ongoing research has shown discordant results with the prevailing view. It is now known that lactate is produced continuously under fully aerobic condition and functions as a cell signaling molecule regulation cellular redox state . Under pTherefore, we hypothesized that the lactate signaling cascade was involved in development and perpetuation of AF by regulating atrial structural remodeling. To test this hypothesis, in the present study we measured lactate signaling cascade in right atrial appendage (RAA) tissues of AF and sinus rhythm (SR) patients matched with normal control (NC), and the positive results may be useful in designing targets for future upstream therapy.We have built a biobank for AF research in the First Affiliated Hospital of Nanjing Medical University since November 2007 ,14. The In the present study, we included the patients undergoing isolated mitral valve surgery and excluded some of them as follows: 1) patients who exceeded 65 years old or had a history of cancer; 2) patients with concomitant coronary artery disease; 3) patients with aortic or valvular calcification; 4) patients who suffered bacterial endocarditis or had detected rheumatic activity; 5) patients with complicated diabetes or renal dysfunction (serum creatinine>136 μmol/L). Finally, we recruited 30 patients with preoperative paroxysmal atrial fibrillation (PaAF) and 30 sex- and age-matched patients with persistent atrial fibrillation (PeAF) and SR. NC were 10 sex- and age-matched healthy heart donors. They were trauma victims and were free of cardiovascular pathology and documented AF.Before surgery, each patient received comprehensive transthoracic echocardiographic examination . As for the recommendation of the American Society of Echocardiography, the left ventricle dimension was evaluated using left ventricular end-diastolic and end-systolic diameters. Left ventricular ejection fraction was assessed by means of M-mode echocardiography (Teichholtz method) and atrial dimension was measured in the parasternal long axis view at endsystole. Pulmonary artery systolic pressure was derived from the regurgitant jet of tricuspid regurgitation using systolic transtricuspid pressure gradient calculated by the modified Bernoulli equation  and the addition of 10 mm Hg for right atrial pressure as previously performed. All measurements were performed by 2 observers.RAA tissue of each patient was obtained from the cannulation site before starting extracorporeal circulation. Sampling site was the same because of surgical maneuver. RAA specimens were obtained from donor hearts before perfusion.Fresh RAA tissue was immediately washed with prechilled isolation buffer containing 220 mM mannitol, 70 mM sucrose, and 5 mM MOPS, pH 7.4. The RAA tissue was then minced and homogenized by a motor-driven Teflon pestle in the isolation buffer. The homogenate was centrifuged at 500 g for 10 min at 4°C, and supernatant was collected by passing it through cheesecloth. The filtrate was centrifuged at 5,000 g for 10 min at 4°C. The pellet was washed again with isolation buffer and gently resuspended in respiration buffer . Protein concentration of the mitochondria preparation was determined by the Lowry method.+). The formed NADH was measured at 340 nm. Results were expressed as μmol/g wet tissue. Atrial lipid peroxidation products were estimated by determination of the thiobarbituric acid reactive substances (TBARS) [Atrial lactate expression was determined according to the method  that dep (TBARS)  that werFrozen RAA or cardiac mitochondria were used for protein isolation as described previously . Brieflyχ2 test was utilized for categorical variables. The statistical analysis was performed with the GBSTAT statistical analysis package .For the comparison among groups, one-way ANOVA test  or Mann–Whitney test  and Kruskal-Wallis test  was used for continuous variables, and The characteristics of the SR, PaAF, PeAF and NC groups included in the analysis are summarized in Table P=0.61)  . Expressions of cytochrome c .Western blot analysis Figure  promptedc Figure B, cleavec Figure C and clec Figure C were foTo our knowledge, this is the first study to provide evidence that lactate signaling cascade may play a role in maintenance and recurrence of AF. An increasing gradient of protein expression of lactate as well as MCT1 were identified in NC, SR and AF groups. Furthermore, the redox level and mitochondrial apoptosis proteins were also increased consistent with lactate expression in RAAs. Therefore, the present data support that the lactate signaling cascade might be one of the regulatory systems in the atrial structural remodeling of AF Figure As described previously, intracellular lactate shuttle hypothesis posits that in normal physiological circumstances intracellular lactate is produced as the result of glycolysis and glycogenolysis in the cytosol and balanced by oxidation in mitochondria. The presence of MCT1 in myocardial mitochondrial membrane allows mitochondrial lactate influx and oxidation. However, during pathological conditions such as hypoxia or ischemia the myocardial energy demands increases, glucose uptake and glycogenolysis raise many times which causes lactate concentration elevation. The corresponding increased expression of MCT1 would likely help the cell to attenuate intracellular acidification . In expeFortunately, two noteworthy observations preliminary unveil the veil. First the L6 cells incubated with exogenous lactate rapidly activated ROS production, upregulated the total mitochondrial mass and increased mitochondrial electron transport in vitro, indicating that lactate signaling affects ROS production and mitochondrial biological activities . Second,in vivo and in vitro [To illustrate lactate signaling in the cardiac myocyte, Kubasiak et al.  reportedin vitro . In hearFirst in our hospital-based study, the sample size was moderate, and therefore further studies with larger sample size are warranted to confirm the findings. Second, since the majority of our patients suffered from rheumatic mitral valve disorders, local inflammatory response may influence myocardial metabolism and atrial remodeling. Accordingly, to attenuate this effect, patients with detected rheumatic activity were excluded in the present study. Finally, Due to the nature of our study, whether lactate signaling cascade changes represent a cause-effect relationship or solely an association remains uncertain. However, activation of the lactate signaling cascade may not only be a marker but also a mediator in the development and perpetuation of AF, at least partly, by promoting atrial remodeling. Future cell and animal studies should address this issue.The present study revealed that atrial lactate expression increased in AF atrial myocytes, and was associated with the presence of oxidative stress damage and cardiomyocytes apoptosis, suggesting that the cascade may contribute to the development and progression of AF by regulating atrial remodeling. Thus, the current data indicates a potential role for known mediators of lactate signaling cascade in the pathogenesis of AF and possibly represents new targets for therapeutic intervention in AF.AF: Atrial fibrillation; PeAF: Persistent AF; PaAF: Paroxysmal AF; SR: Sinus rhythm; NC: Normal controls; ROS: Reactive oxygen species; RAA: Right atrial appendage; TBARS: Thiobarbituric acid reactive substances; MCT: Monocarboxylate transporterWe declare that we have no competing interests.JX, XHX and XWW participated in the design of the study and coordination, YFS, JWQ, YHW and SJZ participated in the samples and data collection, LJS and LX performed the statistical analysis, YJC helped to draft and modified the manuscript. All authors read and approved the final manuscript.


Clinical quantitative T1 and T2 mapping sequences are available, but it is unclear which, if either, is more accurate for determining myocardium at risk.To validate and determine the accuracy for using in vivo T1 mapping or T2 mapping for determining myocardium at risk, compared to blood flow quantification at coronary occlusion by microspheres.Dogs (n=12) underwent coronary occlusion (2 hours), during which microspheres were injected into the left atrium, followed by reperfusion (4 hours). The entire left ventricle was imaged at 1.5T (Siemens) in contiguous short-axis slices with a Modified Look-Locker Inversion-recovery sequence for T1 mapping , and a T2-prepared SSFP sequence for T2 mapping . Myocardium at risk was defined as regions in the left ventricle which had a T1 or T2 value greater than 2SD from remote. In four dogs, hearts were excised and blood flow (ml/min/g) was determined by microsphere analysis in 16 sectors per short-axis slice for all short-axis slices in the left ventricle. Myocardium at risk was defined as regions in the left ventricle with a blood flow at occlusion less than 2SD from remote.Global myocardium at risk, expressed as percent of left ventricular mass (%LVM), showed similar results for T1 mapping compared to T2 mapping . On a slice-by-slice basis , myocardium at risk was also similar for T1 and T2 mapping , T1 mapping corresponded to microsphere analysis , and T2 mapping corresponded to microsphere analysis . Figure When it comes to determining myocardium at risk after coronary ischemia and reperfusion, clinical non-contrast T1 mapping and T2 mapping sequences yield similar results, and both correspond excellently to microspheres. It appears that the relaxation properties T1 and T2 both change in a way which is consistent with the myocardial edema which occurs following myocardial ischemia/reperfusion.


Congenital heart disease is one of the major diagnoses in pediatric heart transplantation recipients of all age groups. Assessment of pulmonary vascular resistance in these patients prior to transplantation is crucial to determine their candidacy, however, it is frequently inaccurate because of their abnormal anatomy and physiology. This problem places them at significant risk for pulmonary hypertension and right ventricular failure post transplantation. The pathophysiology of pulmonary vascular disease in children with congenital heart disease depends on their pulmonary blood flow patterns, systemic ventricle function, as well as semilunar valves and atrioventricular valves structure and function. In our review we analyze the pathophysiology of pulmonary vascular disease in children with congenital heart disease and end-stage heart failure, and outline the state of the art pre-transplantation medical and surgical management to achieve reverse remodeling of the pulmonary vasculature by using pulmonary vasodilators and mechanical circulatory support.  Heart transplantation (HT) is increasingly considered a treatment option for patients with congenital heart disease (CHD) and end-stage heart failure. According to the registry of the International Society of Heart and Lung Transplantation, 63% of infant heart recipients, and 25% of heart recipients aged 11 to 17 years between January 1996 and June 2009, carry the underlying diagnosis of CHD [Congenital diagnosis remains a highly significant risk factor for mortality one and five years after HT . Accurat2, respectively) and concluded that “the increase in TPG and PVR to pathologic levels post HT reflects a fixed element of PVR that was unmasked with the introduction of normal pulmonary blood flow”. In patients with CHD, given the high post HT mortality risk, accurate assessment of PVR has increased importance, but paradoxically, these patients are often harder to assess. Anomalies within the pulmonary vasculature or dual supplies of pulmonary blood flow may make accurate calculations of resistance impossible. The sluggish pulmonary and hepatic blood flow in the Fontan circuit increases the risk for microemboli and arteriovenous malformations that may change the distribution of blood flow to the right and left lung. The assumption that elevated PVR may contribute to late Fontan failure even in patients with “normal” pre-HT PVR was studied by Mitchell and colleagues . This gr2 or if the TPG is greater than 15 mmHg. However, these recommendations do not take into account possible reversibility of elevated PVR. In fact, partial or complete reversibility of elevated PVR and TPG were observed acutely in response to short acting systemic and pulmonary vasodilators such as nitroprusside [1 [2 or if the TPG exceeds 15 mmHg (see discussion below: Hemodynamic unloading and regression of fixed pulmonary vascular resistance).The risk of post HT right ventricular failure and mortality in children with heart disease and elevated PVR is well established and underlines the need for pre-transplantation assessment of TPG and PVR. The same experience in adults led to recommendations that HT should not be performed if the PVR index exceeds 6 Wood units • mprusside , prostagsside [1 , and inhsside [1 , 10, andsside [1 -13, endosside [1 , and inosside [1 . Based o(1)As blood flows through a vessel it exerts a physical force on the vessel wall. This force generates stress that can be resolved into two principal vectors.  The stre2 predominates throughout much of the major systemic arterial vasculature. Recirculating flow occurs mainly around branch points and distal to areas of stenosis. The interaction between the hemodynamic forces generated by this flow and the systemic vascular endothelium may cause local formation of atherosclerotic lesions. It is important to note that the flow profiles within recirculation zones should not be confused with turbulent flow, since turbulence implies random movement of elements in the flow field. Turbulent flow accounts for a very small fraction of the total systemic flow. The absolute shear stress varies throughout the cardiac cycle because of its pulsatile nature. In regions where stable flow is unidirectional with no recirculation, the time-averaged fluctuations in shear stress are positive (forward flow). Such laminar flow is known as mean positive shear stress. Temporal shear-stress gradients are defined as the increase or decrease of shear stress over a small period of time at the same location. Spatial shear-stress gradients are defined as the difference of shear stress between two close points of an endothelial cell at the same point in time. Mean positive shear stress greater than 6 dyne/cmThe morphology of endothelial cells within regions of recirculating flow is significantly different from cells located within regions of mean positive shear stress , 18. CelBased on studies characterizing the force-transduction pathways -41. Whit(2)Studies in animals and humans performed in the current era support the causal relationship between pathological pulmonary blood flow and the development of pulmonary hypertension -45. The 1a, and enhanced release of endothelin-1. A mediator production profile that favors vasoconstriction. In animals, both increased , and decIn patients with congestive heart failure (CHF), persistent elevation of left-ventricular end-diastolic pressure causes passive pulmonary venous congestion and reactive pulmonary vasoconstriction. At this preliminary stage, PVR is readily reversible with pulmonary vasodilators. However, persistent pulmonary venous congestion causes remodeling of the pulmonary arterial wall due to abnormalities of the elastic fibers, intimal fibrosis and medial hypertrophy. Pulmonary hypertension secondary to structural remodeling is referred as fixed because it is resistant to pharmacological treatments. Delgado and colleagues  studied 1). A similar study performed by the same group at the Children’s Medical Center, Boston (July 1976 to January 1981) [1). Patients whose preoperative PVR was markedly elevated underwent biopsy first. If their pulmonary Heath-Edwards grade was IV to VI they were excluded from definitive repair. For the other patients, morphometric findings and Heath-Edwards grading were correlated with hemodynamic data from a cardiac catheterization performed immediately after surgery and about 1 year after surgery. Normal mean pulmonary pressure was taken as 18 mmHg or less and normal PVR index as less than 3.5 Wood units • m2. The Heath-Edwards grading system was predictive of pulmonary hypertension in the early but not late post-operative period. The study findings suggested, at least for patients undergoing an operation in the first 2 years of life, that even severe intimal change (Heath-Edwards grade III) is not prognostic of persistent elevation in PVR if growth and development of the pulmonary arteries has been relatively normal (morphometric grade A or B (mild)). Patients who underwent surgical correction in the first 8 months of life had normal pulmonary hemodynamics 1 year after repair despite marked structural abnormalities at the time of repair. Some of the patients operated on at ≥9 months of age that had pulmonary structural abnormalities as severe as in those operated on earlier had persistent elevation of PVR. Possible mechanisms are less complete regression of the abnormal findings, limited potential for growth of new normal vessels, or both. In patients with left to right shunt pulmonary vascular muscularization is accelerated, possibly because of mechanical or humoral growth stimulation generated by supra-physiological shear stress (see discussion of this term below) [In an older era, Rabinovitch and colleagues  performery 1981)  includedry 1981)  (Table 1m below) . One posm below) -56 .2 with vasodilator therapy. Studies in adults revealed that mortality after HT is increased if pharmacologic interventions are not able to reduce PVR below 2.5-3.5 Wood units • m2 [Pulmonary hypertension is a risk factor for early and late mortality after heart transplantation. Gajarski and colleagues  studied its • m2 , 59 . A Heterotopic (“piggy back”) HT that allows preservation of the entire native heart. The latter provides assistance to the vulnerable transplanted right ventricle, however, the failing recipient left ventricle places the recipient at risk for lethal arrhythmias, systemic emboli, and compression of the left lung , 61.Heart-lung transplantation. This procedure eliminates the diseased pulmonary vasculature, however, donors for heart-lung transplantation are rare, and the procedure has inherent long-term sequelae mainly related to its pulmonary component.Right ventricle-sparing heart transplant was attempted in a canine model , 63. TheTransplantation using hearts from donors with idiopathic pulmonary hypertension for recipients with high PVR (domino procedure). This is a viable but rare option in transplant centers where patients undergo heart and lung transplantation for idiopathic pulmonary hypertension . A recent laboratory study performed by O’Blenes and colleagues , tested 2 unresponsive to pulmonary vasodilator therapy. PVR index decreased to 1.4 and 4.6 Wood units • m2 after 33 and 41 days of support, respectively. Both patients underwent orthotopic HT. Their PVR index remained normal without pulmonary vasodilator therapy within 3 months after transplantation.Following that experiment, hemodynamic unloading of patients with fixed pulmonary hypertension with pulsatile and nonpulsatile ventricular assist devices led to reduction of PVR and allowed listing for orthotopic HT after a relatively short period of support (3-6 months), Furthermore, survival of these patients after transplantation was comparable with that of patients without prior pulmonary hypertension -77. BaseA child with end-stage HF adequately treated with oral anti CHF medications who presents with acute decompensated HF (ADHF) is admitted to the cardiac intensive care unit (CICU) for close non-invasive and invasive hemodynamic monitoring. The initial treatment line for these patients is inotropic support. A recent review of the pharmaceutical management of decompensated heart failure syndrome in children discusses in detail the indications, mechanism of actions, and dosages of the various available inotropes . At St. Elevated but reactive PVR in the context of elevated LA pressure. First line of treatment is inotropic support combined with IV diuretics. The second treatment line is intubation and positive ventilation. The latter is a potent afterload reducing method by way of decreasing the left ventricular (LV) transmural pressure and hence wall tension. Intubation of a child with ADHF may cause acute hemodynamic collapse and cardiac arrest because of acute reduction of sympathetic tone with the preintubation induction. The only indication to proceed is evidence of end-organ dysfunction and anaerobic metabolism. The third line of treatment, if systemic perfusion remains inadequate is mechanical circulatory support. Treatment with pulmonary vasodilators in this subset of patients prior to initiation of MCS may be risky since it may worsen pulmonary edema. The decompression of the LV by a VAD in these patients is usually sufficient to decrease PVR, again with no need to treat with pulmonary vasodilators.Fixed PVR in the context of LA hypertension. Treatment of these patients is determined by their hemodynamic status and systemic perfusion. Treatment is targeted at optimization of CO. The combination of pulmonary hypertension and LV failure usually results in inadequate systemic perfusion and shock because of ventricular interdependence and underlying LV systolic and diastolic dysfunction. These patients usually require aggressive cardiopulmonary support comprised of positive pressure ventilation, inotropic support, sedation and neuromuscular blockade. It is our opinion that pulmonary vasodilators in this subset of patients are not beneficial. Reverse remodeling of the pulmonary vasculature requires lowering the LVEDP. Achieving that with inotropic support and mechanical ventilation is questionable and may not be sustainable. Other considerations are the debilitation and muscle degeneration that develops during prolonged mechanical ventilation and prolonged use of neuromuscular blockade. Based on our experience reverse remodeling of the pulmonary vasculature using mechanical circulatory support can be achieved in children with CHD, and therefore, in this particular group of patients, we recommend early VAD implantation.Children with single ventricle physiology may develop ADHF following each one of the palliation stages. The initial management of these patients is similar in principal to the management of children with two-ventricle physiology with ADHF, and includes inotropic support and IV diuretics. Mechanical ventilation in children with ADHF following the Glenn and Fontan procedures may be problematic since it may increase their PVR, however, this consideration is offset by the need to minimize work of breathing and oxygen consumption. Their TPG and PVR are assessed in the cardiac catheterization laboratory following a period of stabilization. While severe, fixed elevation of pulmonary vascular resistance that would preclude heart transplantation are unlikely in patients with cavopulmonary connections, nonpulsatile pulmonary flow can be associated with mild to moderate elevations of pulmonary vascular resistance that can result in primary right heart graft failure after transplant.  Inhaled Experience with MCS in these patients other than ECMO is very limited. The literature reveals only sporadic case reports describing long-term MCS in the context of single-ventricle physiology -86. WithPatients with CHD associated with unequal distribution of pulmonary blood flow may develop pulmonary vascular remodeling in one lung whereas the second lung may have normal pulmonary vasculature or only minimal structural changes leading to PVR elevation amenable to medical treatment. Unequal pulmonary blood flow distribution can be found in patients with Tetralogy of Fallot and pulmonary atresia with major aortopulmonary collaterals. Another possible cause for pulmonary blood flow maldistribution is partial pulmonary venous obstruction involving pulmonary venous egress of one lung. Heart transplantation has been successfully performed in such patients . Pre-traIn patients with CHD and end-stage heart failure, pulmonary remodeling caused by abnormal pulmonary blood flow profiles may result in severe pulmonary hypertension refractory to pulmonary vasodilators, also known as fixed pulmonary hypertension. This entity is considered a contraindication to orthotopic heart transplantation . This enUntil recently, the treatment of patients with heart failure and fixed PVR was limited almost exclusively to combined heart-lung transplantation. However, over the course of the last decade, the concept of reverse remodeling of the pulmonary vasculature with hemodynamic unloading of the heart has been confirmed both in adults and children supported with ventricular assist devices. This option opens new treatment options for these patients. The definition of “fixed” pulmonary hypertension refractory to pulmonary vasodilator treatment that would preclude heart transplant in the current era of pediatric VAD availability is evolving as these new technologies are applied to congenital heart disease patients.


Sepsis has high incidence and mortality rates around the world. The role of cardiac depression in myocardial dysfunction during sepsis remains to be elucidated. This review attempts to summarize our understanding of the anatomical, histopathological, and pathophysiological mechanisms behind cardiac dysfunction. Biomarkers to detect cardiac depression have been used to recognize developing problems, but the actual impact of these tools remains unclear.  Sepsis and sepsis-induced mortality are major health concerns worldwide –3. SeptiMyocardial dysfunction can determine whether a patient survives. In survivors, ventricular compliance is increased with a higher end-diastolic volume that helps maintain an adequate stroke volume. Nonsurvivors, in contrast, are progressively unable to maintain the same stroke volume because of reduced diastolic compliance . ReversiIt was previously postulated that decreased circulating blood volume was responsible for the reduced cardiac output observed in septic shock. More recent studies demonstrate that this assumption is particularly true before fluid resuscitation occurs, when there may be an imbalance between continent (vessels) and inside it. After volemic restoration, however, when cardiac output does not match oxygen demand and there is no recruited preload, a level of myocardial depression may still occur. Recent studies have shown that patients with septic shock who were adequately resuscitated typically displayed a high cardiac output and also displayed myocardial depression in the form of a low systemic resistance hemodynamic circulatory condition. It is estimated that only 10 to 20% of patients who have myocardial depression need to receive inotropic drugs .The pathophysiology of cardiac depression is complex and involves a multitude of factors . This reMany anatomopathologic alterations have been described in fatal cases of septic shock. In 1948, Moon described degenerative myocardial changes in 21 patients who developed shock due to trauma . In a neEndotoxins mediate cardiovascular changes that mimic sepsis in both research animals  and huma An inflammatory immune response begins with the recognition of microorganisms and is mediated by pattern recognition receptors, such as the Toll-like receptor family (TLRs), which bind to highly conserved molecules on the pathogen called pathogen-associated molecular proteins (PAMPs). TLRs that recognize components of the bacterial cell wall are expressed on the cell membrane, while TLRs that recognize nucleic acids are located within the host cell. TLR1 recognizes Gram-positive bacteria, TLR2 recognizes the peptidoglycan of Gram-positive bacteria, and TLR4 binds the lipopolysaccharide of Gram-negative bacilli , 17.α)), which may result in cardiac impairment. Both microbial and endogenous proinflammatory mediators, such as bacterial endotoxin (lipopolysaccharide (LPS)), IL-1, and TNF-α, may directly depress myocardial contraction i, as compared to the constitutive NOS isoforms [ NO is synthesized upon the cleavage of L-arginine to L-citrulline by three distinct isoforms of NO synthase (NOS) within the myocardium: neuronal NO synthase (NOS1), inducible NOS (NOS2), and endothelial NOS (NOS3) . NOS1 anisoforms , and it isoforms . This mu2+ levels and myofilament sensitivity to Ca2+ [β-adrenergic receptor (β-AR) pathway. In particular, in vivo and whole heart experiments demonstrated that the knockout of NOS1 leads to a reduced contractile response to β-AR stimulation [NOS3 is present in endothelial cells, platelets, the brain, and the myocardium and is dependent on calcium. In the myocardium, NOS3 expression appears to be graded, such that NOS3 expression in left ventricular epicardial myocytes is significantly increased compared to left ventricular endocardial myocytes. Myocardial NOS3 may have an important protective role against sepsis-induced myocardial dysfunction. Experiments have shown that mice with cardiomyocyte-specific NOS3 overexpression are protected from myocardial dysfunction and death associated with endotoxemia. Increased myocardial NO levels attenuate endotoxin-induced reactive oxygen species production and increase total sarcoplasmic reticulum Ca to Ca2+ . In a re to Ca2+ . NOS1 ismulation .β-agonists was significantly reduced in LPS-treated cells relative to controls, and this reduction was abolished by the addition of the NOS inhibitor L-NMMA. Additionally, LPS exposure increased both nitrite production in myocytes and cGMP formation in fibroblasts, suggesting a possible cGMP-mediated mechanism for NO-induced negative inotropy [NOS2 can be found in macrophages, neutrophils, Kupffer cells, and hepatocytes, and it does not depend on calcium. While low doses of NO may increase LV function, excessive NO delivery from inflammatory cells (or cytokine-stimulated cardiomyocytes themselves) may result in profound cellular disturbances that lead to heart failure . Echocarinotropy . Recent inotropy .Endothelin 1 affects myocardial contractile properties and the progression of myocardial hypertrophy. Elevated concentrations of ET-1 in both the plasma and myocardium have been observed during sepsis and endotoxemia. However, the role of elevated ET-1 during sepsis is not completely understood. During endotoxemia, the inhibition of ET-1 biosynthesis leads to the downregulation of p38Y mitogen-activated protein kinase (p38-MAPK) phosphorylation and the expression of NO synthase II . Sharma 2−) generation, and it is activated by endotoxins in both neutrophils and cardiomyocytes [Reactive oxygen species (ROS) production is important for normal cellular function and survival. Oxidative stress results when ROS production and antioxidant protection mechanisms are unbalanced. Endotoxins can induce superoxide production via xanthine oxidase, NADH/NADPH oxidases, and mitochondria. It remains unclear if the self-amplifying cycle of ROS generation and mitochondrial damage occurs with mitochondrial dysfunction leading to oxidative stress and more mitochondrial impairment as the primary event, or if oxidative stress initiates mitochondrial dysfunction and further ROS release . In cardmyocytes . Overpromyocytes .Oxidative stress-mediated mitochondrial damage, therefore, appears to be fundamental to the pathophysiology of organ failure in sepsis, suggesting a therapeutic role for antioxidants. Mitochondrial damage is mainly the result of an inhibition of electron flow through Complexes I, III, and/or IV. Administration of a superoxide scavenger compound prevented the mitochondrial abnormalities and improved cardiac contractile function in an animal model of endotoxemia. Targeting antioxidants to mitochondria may offer a novel therapy in the future, but clearly further studies are needed .β-AR on the myocardium in a murine model of sepsis, and this decrease was associated with a disruption of myocardial signal transduction after β-AR stimulation that includes decreased levels of stimulatory G-proteins and increased expression of inhibitory G-proteins [If. They observed that LPS-induced If impairment reduced the responsiveness of the model cell to fluctuations of autonomic input, showing a direct impact of LPS on the cardiac pacemaker current If. This impact may contribute to the clinically observed reduction in heart rate variability in septic patients [β-ARs due to an excess of catecholamines and to endotoxin action on the effects of the cardiac pacemaker current If on ionic channels. During sepsis, a reduction in heart rate variability is a measure of autonomic dysregulation that reflects a loss of the balance between the sympathetic and vagal tone. Not only is the reduction in heart rate variability long lasting in patients with MODS, but also baroreflex sensitivity and chemoreflex sensitivity are impaired. These dysfunctions correlate with an unfavorable prognosis . Howeverproteins , 51. Thipatients . The myoSeveral studies have explored calcium involvement in the myocardial depression associated with sepsis. Calcium has a crucial and important role in myocardial contraction. All contractile pathways involving calcium can be connected to myocardial dysfunction. Several studies demonstrated that calcium has reduced peak currents during endotoxemia , 54. ImpP < 0.0001) [r2 = 0.74, P < 0.05) and prognosticated survival [P < 0.05), and patients with low ejection fractions had a higher mortality  [P = 0.0001), a greater risk of development of severe sepsis (P = 0.0001) and septic shock (P = 0.0001), and a higher rate of the triple composite outcome . The sensitivity was 63% (95% CI = 58% to 67%), the specificity was 69% (95% CI = 65% to 73%), the negative predictive value (NPV) was 63% (95% CI = 58% to 67%), and the positive predictive value (PPV) was 69% (95% CI = 65% to 74%). In multivariate analysis, after adjusting for age, gender, heart rate, white blood cell count, and creatinine, an elevated BNP was associated with increased odds of having a composite outcome. Outcome was similar in patients who did not have severe sepsis or septic shock upon arrival. BNP levels can be useful in prognosis but have some limitations [Biomarkers such as cardiac troponin T and I have also been studied in sepsis. Elevated cardiac troponin T and I levels correlate with the presence of left ventricular systolic dysfunction . Experim 0.0001) . The pot 0.0001) , 63. BNP 0.0001) . In a sm = 3.03) . In a re95% CI = % to 73%,Bouhemad et al. performed a prospective echocardiographic study to assess changes of left ventricular dimensions over time in patients with septic shock, and they associated those changes with troponin levels. They identified two groups of troponin I- (cTnI-) positive septic patients whose clinical and echocardiographic features were markedly different. Among patients with increased cTnI levels, patients could be separated according to echocardiographic left systolic ventricular dysfunction or isolated impairment of left ventricular relaxation. The concept of preload recruitment applies exclusively to patients with systolic left ventricular impairment, where ventricular enlargement may represent an adaptive mechanism to maintain cardiac output. Those patients presenting with ventricular relaxation impairment despite showing no ventricular dilation or a drop in ejection fraction exhibited the worst prognosis .2) optimization and lactate clearance. Keeping arterial pressure stable is very important for reestablishing organ perfusion pressure, which helps maintain blood flow to tissues. Norepinephrine is the vasopressor of choice when a patient is nonresponsive to fluids.The best treatment for myocardial dysfunction is the proper management of sepsis. The early collection of hemocultures in conjunction with adequate antibiotic care is the gold standard. Moreover, aggressive fluid replacement to remedy hypovolemia, guided by the examination of fluid responsiveness parameters, appears to be a rational strategy. This approach aims to provide adequate perfusion, as evaluated by central venous saturation  or dobutamine (5 μg−1·kg−1·min−1). Mean arterial pressure was sustained at approximately 70–80 mmHg with norepinephrine and volume therapy, which was guided by a Swan-Ganz catheter. Systemic or regional hemodynamic variables were evaluated. Although dobutamine did not alter any of the studied parameters, levosimendan had beneficial effects on both cardiovascular performance and regional perfusion. Indeed, the use of levosimendan was associated with a reduction in LV end-diastolic volume and a significant increase in the stroke index, the cardiac index, the oxygen delivery index, the oxygen consumption index, and the left ventricular stroke work index. Levosimendan also resulted in increased gastric mucosal flow, creatinine clearance, and urinary output and decreased lactate concentrations by lowering Gap PCO2 and improving lactate clearance and SvO2 [As cited above, only 10 to 20% of patients who have myocardial depression will need to receive inotropic drugs to obtain adequate tissue perfusion. Most patients will benefit from administration fluid infusion. However, when inotropes are indicated to optimize flow and cardiac output and improve hemodynamics, dobutamine is the first choice. Patients may have a poor response to erfusion –69. Onlyand SvO2 . UnfortuMany questions concerning myocardial dysfunction in sepsis remain, spanning topics from pathomechanisms to treatment. In reality, only support treatment is available for septic patients, and no specific drugs can reverse this dysfunction. In the future, with new approaches in sepsis treatment and a better understanding of the mechanisms of disease, myocardial dysfunction will be improved.


Patients with end stage dilated cardiomyopathy exhibit extensive remodeling of the left ventricle, annular dilation, and significant mitral and tricuspid regurgitation. These changes increase perioperative morbidity and mortality, and emphasize patient candidacy for heart transplantation. We previously published that Reductive Annuloplasty of Double  Orifices could be successfully applied in selective patients. However, it was unclear if implantation of the artificial mitral valve with preservation of native mitral valve could be used as a method in such cases.There were 16 patients  with ischemic dilated cardiomyopathy, mean ejection fraction below 30% (26.6±3.1%), and mean left ventricle end-diastolic internal diameter greater than 7.0cm (7.3±0.3 cm) with coaptation depth of the mitral valve (tenting area) significantly lower than 1.1cm. In addition to myocardial revascularization mechanical or biological artificial valve were implanted in 12 and 4 patients respectively. Modified De Vega tricuspid annuloplasty was performed in all patients.There was no postoperative 30-day mortality. Survival rate after 5 years was 93.75%.Reverse remodeling of the left ventricle by CABG surgery followed with implantation of the artificial mitral valve and tricuspid suture annuloplasty could be successfully applied in selective patients with ischemic dilative cardiomyopathy. Our method should not be recognized as a valve repair, but ventricular repair procedure also.


Atrial fibrillation (AF) is the most common form of arrhythmia in the world. As the population ages, it is estimated that the prevalence of AF will increase by 2.5 fold in the next 50 years.DM is one of the most common concomitant diseases in patients with AF.6In the observational cohort study of DM registry, the incidence of AF in diabetic patients was much higher than in controls (9.1% vs 6.6%) over a mean follow-up period of of 7.2 years. After adjustment for other risk factors, DM was associated with a 26% increased risk of AF among women , but not a statistically significant factor among men.10The link between DM and AF in epidemiology needs to be confirmed in large, prospective, long term study, although there were evidences showing the underlying biological interlink. Studies have indicated that inflammation might play a role in the generation, maintenance, and perpetuation of AF, although the mechanism of AF is still elusive. In atrial biopsies of patients with lone AF, there were increased CRP and IL-6and marked inflammatory infiltrates. Glucose and insulin disturbance can directly affect the myocardium in atrium and ventricle, leading to AF. Left ventricular (LV) hypertrophy has been associated with DM and abnormal glucose tolerance in several epidemiology studies. LV hypertrophy is a significant risk factor for AF. Analysis of the Framingham study subjects showed that LV mass increased with the worsening of glucose tolerance and the trend was more striking in women than in man. There were also close relationship between insulin resistance and LV mass, as well as LV wall thickness, in women both with normal and abnormal glucose tolerance.Several observations suggest that the automatic nerve system plays an important role in both the initiation and/ or the maintenance of AF in humans. In most patients with organic heart diseases, the paroxysmal AF episodes appear more sympathetically dependent. In the animal model of DM, the occurrence of AF was enhanced by adrenergic activation in diabetic heart, in which the sympathetic innervations was evident.In conclusion, the association between AF and DM has been proved both in epidemiology and experimental studies. The causal links need to be verified in large cohort study. A recent report from NIH stated that AF prevention has received less attention than treatment and there were great knowledge gaps in the understanding of risk factors of AF.


Assessment of regional ventricular deformation is more sensitive than ejection fraction (EF) for detecting myocardial dysfunction. We sought to compare a local sine-wave modelling (SinMod) method with the more established harmonic phase analysis (HARP) technique, for assessment of Lagrangian left ventricular (LV) peak systolic circumferential strain (εcc) from tagged cardiovascular magnetic resonance images, in patients with cardiomyopathies and healthy volunteers. The variability and rapidity of each technique, and the effect of contrast, were also assessed.Sixty participants  with a wide range of LV ejection fraction (14-78%) underwent spatial modulation of magnetization tagging of a mid-ventricular short-axis slice at 1.5 Tesla. Global and segmental peak transmural εcc were measured using HARP and SinMod. Repeated measurements were performed on 15 randomly selected scans (25%) in order to assess observer variability. Tagged images were acquired pre- and post-contrast in 10 additional patients in order to assess the effect of contrast.There was a high level of agreement between HARP and SinMod for global εcc . Dr Schmitt was supported by Greater Manchester Comprehensive Local Research Network funding. Dr McCann and Dr Steadman received support from the NIHR Leicester Cardiovascular Biomedical Research Unit and additionally, Dr Steadman was funded by the British Heart Foundation (PG/07/068/2334).


Necrosis after myocardial infarction may cause aneurysm in the left ventricle. Disorders of contractility in the left ventricle due to aneurysm can result with congestive heart failure, ventricular arrhythmia and thromboemboli. This is a retrospective analysis of our clinical experience in the restoration of left ventricular aneurysm via modified linear closure during off pump coronary artery bypass grafting (OPCABG) surgery.Ninety five patients who had post infarction, unruptured, true left ventricular aneurysm were operated between August 2006 and June 2013 during OPCABG. None of them had thrombus in their left ventricular cavity. Age of the patients were 63,14 ± 8,46 (38-82 year) meanly. Seventy two of them were male (75.8 %). Ejection fraction was 32,58% ± 6,98% preoperatively. Fifty three patients had totally occluded left anterior descending artery. Dyspnea (47.7%), angina (82.9%) and ventricular arrhythmia (11.3%) were the major symptoms. Six patients had posterior and 89 patients had anterior left ventricular aneurysm.Number of coronary artery bypasses were 2,21±1,1. LIMA, RIMA, radial artery and saphenous vein grafts were used. Mean operation time was 127,92±32,52 minutes. Average time of intubation was 5,6±4,5 hours, intensive care unit stay was 26,1±15,1 hours, hospital stay was 5,3±2,2 days. Supraventricular arrhythmia was seen in 20 patients, cardioversion was performed in 5. Positive inotrope agents were required for 11, ICD implantation for 5, IABP for 3 and ECMO for 1 patient. Three patients (3.1 %) were dead in hospital.The technique of anterior and posterior aneurysm repair via modified linear closure concomitant with OPCABG can be performed with low operative morbidity and mortality rates.


The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated with a wide array of mechanisms subsumed under the term “inflammation”. Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-α led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective. Congestive heart failure (CHF) is a leading cause for both hospitalization and death in the western world. Its prevalence is rather increasing with the broad implementation of standardized evidence-based treatment algorithms for heart failure. The heart failure syndrome is characterized by impaired systolic and/or diastolic function and various clinical signs such as fatigue, dyspnea, fluid retention, and cachexia. Besides symptomatic treatment to relieve these symptoms several classes of drugs improve the prognosis of patients with chronic heart failure. These agents target the so-called neurohumoral activation process that comes along with the evolution of the heart failure syndrome irrespective of the underlying pathophysiology. Inhibition of the activity of the renin–angiotensin–aldosterone system and β-adrenergic signaling are well-established treatment principles which are incorporated in current guidelines . HoweverAn inflammatory activation in CHF patients has long been recognized. Indeed, immune mechanisms modulate interstitial fibrosis, cardiomyocyte apoptosis, and hypertrophy, all of which are central processes leading to maladaptive remodeling in response to a variety of stimuli Fig. . EspeciaFirst, systemic cytokines came into focus, which have been monitored in several clinical trials , 112. ThMeanwhile, basic science and translational clinical research gathered a lot of mechanistic information on new players in the field of inflammation which constitute very promising future targets for therapy. Therefore, a recent scientific statement from the European Society of Cardiology defined key questions and requirements for future studies in the enormously expanding field .The current review will provide the reader with an elected overview of experimental and clinical evidence for immune activation in chronic heart failure, summarize key clinical trials addressing the immune system, and provide an outlook for several new promising clinical targets.Different etiologies like coronary artery disease, hypertension, infection, etc., lead to heart failure. Therefore, one of the key questions in the field is whether activation of immunity in humans and animal models of heart failure is independent of the etiology or if there are disease specific mechanisms. As it turns out, both are the case.Different heart failure models indicate a role of innate immunity independent of heart failure etiology. Innate immunity is activated in the myocardium early by recognition of rather unspecific stimuli, summarized as danger-associated molecular patterns . This foIt is likely that inflammation is also initiated in human myocardium by innate recognition of pathogen-associated molecular pattern even well before the heart failure becomes symptomatic/diagnosed. However, clinical data to corroborate findings made in animal studies are widely limited to the demonstration of increased circulating levels of soluble mediators, mainly cytokines , in a vaFor heart failure with reduced ejection fraction due to different clinical etiologies there is good evidence from both experimental and clinical studies that pro-inflammatory cytokines are locally expressed in myocardium. For example, TNF-α has been mechanistically related to more or less all etiologies of systolic heart failure. Besides its direct effect on myocardial contractile function , 155, TNNevertheless, there are also distinct differences in the activation of the immune system in different heart failure etiologies:Heart failure due to large myocardial infarction is the most prevalent cause of systolic heart failure, so the majority of small animal studies for heart failure were conducted in the permanent myocardial infarction model. Besides early infiltration of leukocytes and local expression of cytokines and chemokines, there is ongoing inflammation that extends to the remote myocardium and is a part of the underlying pathophysiology of left ventricular remodeling. A detailed review of all the processes involved in myocardial remodeling is beyond the scope of the present article and was summarized recently . InflammMost animal studies are performed in relatively acute settings with follow-up of no longer than 8 weeks. Especially experiments with genetically altered mice often do not really allow distinguishing the effect on initial myocardial injury and wound healing, when the most pronounced inflammatory activation takes place, from chronic remodeling of the myocardium. Therefore, therapeutic approaches based on such animal experiments rather reflect the clinical situation weeks to months after a myocardial infarction when mechanisms, such as infarct expansion are still operative and do not easily allow transfer of the findings to the situation of chronic, non-ischemic, systolic heart failure.In contrast to the broad evidence from small animal studies, due to the limited availability of myocardial specimens clinical evidence for immune activation in chronic ischemic heart failure mainly comes from analysis of cytokines and cytokine receptors in peripheral blood  which fiThe threshold of >14 leukocytes/mm² is widely accepted for the definition of myocardial inflammation . EndomyoIt is further unclear whether, in analogy to mouse models of auto-immune myocarditis induced by vaccination against myocardial proteins, auto-immune myocarditis develops in patients without previous infection of the myocardium. Data from the TIMIC trial  demonstr+ T-cells, especially modulate collagen deposition in myocardium.Chronic pressure overload also leads to the expression of chemokines, cytokines, and infiltration of monocytes in the myocardium. Most evidence comes from animal models of transverse aortic constriction. There is a well-described pathophysiological link between inflammation and fibrosis , 83, wheAn expression of pro-inflammatory cytokines was also described in myocardium from patients with aortic stenosis . Here, tInflammation in heart failure with preserved ejection fraction without overt hypertrophy has been less well characterized. In patients with coronary artery disease and diabetes, a small study found an association between pro-inflammatory serum cytokines and echocardiographic evidence of diastolic dysfunction .In sum, clinical evidence for the implication of inflammation in the development of myocardial hypertrophy and diastolic dysfunction is sparse, although experimental studies suggest a role especially for lymphocytes and macrophages.More and more evidence is accumulating that obesity is associated with a systemic inflammatory response that is characterized by endothelial cell dysfunction, oxidative stress, and the activation of leukocytes . The infThe amount of epicardial fat was often correlated with the severity of hypertrophy and cardiac dysfunction as evidenced mainly by non-invasive imaging with its inherent limitations in obese humans. Especially the adipocytokine adiponectin, which is decreased in patients with obesity-linked diseases, prevents left ventricular hypertrophy. Studies in adiponectin deficient mice revealed increased afterload-induced hypertrophy due to impaired activation of the activated protein kinase AMP . HoweverThe best studied pro-inflammatory cytokine in the scenario of heart failure is TNF-α , 102. ClBesides its immediate effects on the contractile performance of the myocardium, there is also good experimental evidence for a causal pathophysiological role of TNF-α for the progression of myocardial remodeling leading to chronic heart failure. Relevant mechanism demonstrated in experimental studies are induction of cardiomyocyte hypertrophy , inductiBased on these extensive animal data indicating a causal link between TNF-α and cardiac dysfunction in both the acute and chronic setting, clinical trials were launched which tested compounds initially developed for binding of TNF-α in rheumatic diseases. The compound etanercept consists of two human TNF-α receptor fragments linked to the Fc portion of immunoglobulin G. In a phase I study, etanercept single administration was well tolerated and improved ejection fraction in chronic heart failure patients . EtanercInfliximab is a chimeric antibody binding soluble and membrane-bound TNF-α and prevents it from binding to its receptors. In a smaller phase II trial (ATTACH), NYHA III–IV patients treated with lower doses of infliximab demonstrated an increase in ejection fraction, but there was an increased risk of hospitalization and death in a high dose group .Besides dosing and timing issues, two main points have been worked out as possible explanations for the disillusioning results . First, The disappointing results of the anti-TNF-α studies in CHF patients dampened the enthusiasm in the field and supported a common belief that the redundancy of the immune system precludes success of specific cytokine-targeting strategies. Thus, although other pro-inflammatory cytokines were demonstrated to be involved in cardiac injury and significantly correlated with clinical status and prognosis of patients with chronic heart failure , especiaOne of the first randomized trials on immuno-modulation was conducted years before the event of the anti-TNF-α trials. Glucosteroids were tested in a number of small studies before the advent of current reperfusion therapy. A number of rather small studies produced controversial results when patients were treated in the setting of an acute myocardial infarction to limit infarct size and improve wound healing . Later oThalidomide was initially believed to act as an anti-TNF-α agent. In a small pilot uncontrolled trial, thalidomide rather increased plasma levels of TNF-α in patients with chronic heart failure, but improved left ventricular function . ThalidoStatins are well known for their “pleiotropic” effects besides cholesterol lowering. Immuno-modulatory and anti-inflammatory effects have been described which in part, inter alia, relate to attenuation of T-cell activation by repression of MHC-II expression . RosuvasPentoxifylline is a phosphodiesterase inhibitor which is approved for the treatment of peripheral vascular disease. The initial rationale for using pentoxifylline was due to its ability to inhibit TNF-α transcription. Yet, not all studies could link improvements in clinical outcome to a concordant effect on TNF-α modulation .In several clinical trials, pentoxifylline therapy was reported to reduce circulating levels of C-reactive protein, FASL, and TNF-α in heart failure patients. In those small heart failure trials, pentoxifylline also improved ejection fraction and functional outcome , 124. HoOxidative stress is believed to play a causative role in the evolution of the heart failure syndrome mainly on the basis of experimental studies. On the cellular level, reactive oxygen species can activate multiple signaling pathways, including MAP kinases and nuclear factor-κB . This inAnother small double-blinded controlled randomized trial aimed to determine whether vitamin E supplementation of patients with advanced heart failure (NYHA III/IV) would modify levels of oxidative stress and improve functional status and prognosis. However, supplementation with vitamin E did not result in any significant improvements .Despite the theoretical potential of adding anti-oxidants to standard heart failure medication, which might have been underestimated on the basis of these rather small trials, it has to be mentioned that standard heart failure medication already includes drugs with anti-oxidant properties, especially ACE inhibitors and angiotensin receptor blockers .On the other hand, the addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure improved survival among black patients with advanced heart failure in the AHeFT trial , 136. ThAutologous blood exposed ex vivo to heat and oxidative stress induces anti-inflammatory effects in animal models . The preConsiderable epidemiological data found an association of omega-3 polyunsaturated fatty acid (ω-3 PUFA) intake, mainly from fish oils, and cardiovascular endpoints (reviewed in ). ReductDietary PUFA supplementation was studied by the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Heart Failure (GISSI-HF) study, a large-scale clinical trial in a chronic heart failure cohort. This trial showed a moderate, albeit significant benefit of ω-3 PUFA in addition to standard heart failure medication . The mecBased on these trials the clinical relevance of PUFAs in chronic heart failure patients is still not clear. Thus, PUFA supplementation received a class IIb, level of evidence B recommendation in the most current European heart failure guideline .There is a considerable proportion of patients with chronic heart failure, especially DCM, which have auto-antibodies . The higSeveral related studies have demonstrated that immuno-adsorption induces improvement of left ventricular function in patients with DCM , 126. ItA wide array of potential immuno-modulating effects has been attributed to intravenous immunoglobulins which demonstrated therapeutic efficacy in a variety of diseases with unrelated pathophysiology. However, clinical study results for treating heart failure are ambiguous. A small randomized trial in patients with symptomatic heart failure demonstrated a change in the balance between inflammatory and anti-inflammatory cytokines by immunoglobulin treatment. This effect was significantly correlated with an improvement in LVEF . AnotherThe underlying biological mechanism for the potential beneficial effects of immunoglobulins in DCM remains to be determined. A comprehensive overview of potential mechanism was recently provided by Gelfand . NeutralGiven the efficacy of immunoglobulins in attenuating virus replication in myocardium, it might thus be the case that the high prevalence of latent virus infection in the myocardium of DCM patients contributes to the positive effects of immunoglobulins in heterogeneous populations of DCM patients included in the above-mentioned trials.The field of therapeutic stem cell therapy has made great advance in the last years due to a number of clinical studies which are underway or just have been completed . Most anMost clinical trials were designed to improve repair/regeneration of the injured heart in the setting of myocardial infarction, while few studies yet addressed chronic heart failure patients.The TOPCARE-CHD trial tested intracoronary treatment with either bone marrow cells or peripheral progenitor cells in a crossover design in patients with chronic ischemic heart failure. Transplantation of bone marrow cells was associated with moderate but significant improvement in the left ventricular ejection fraction after 3 months  and evenAnother group reported similar promising results of intramyocardial delivery of bone marrow cells in chronic myocardial infarction and advanced chronic heart failure patients .It was speculated that progenitor cell therapy might be more promising in non-ischemic heart failure patients, as the functional capacity of endogenous progenitor cells is more severely impaired in patients with ischemic cardiomyopathy than in DCM patients . In the + stem cells in patients with DCM were reported. During the follow-up period, cell therapy was associated with a moderate but significant improvement in cardiac function (mean increase of EF 5.7 %), coming along with an improved exercise capacity and even decreased mortality [Recently, 5-year follow-up data of a well-designed, albeit not placebo-controlled and not double-blinded, randomized study investigating the long-term effects of intracoronary administration of G-CSF-mobilized CD34ortality . InteresHowever, none of the trials in chronic heart failure patients deeply assessed parameters of immune activation. Therefore, the contribution of putative immuno-modulatory effects of transferred cell preparations cannot be determined yet.There is a great variety of potential therapeutic targets in the field of pro-inflammatory signaling in heart failure. Perhaps, most experimental evidence has accumulated in experimental models of post-myocardial infarction heart failure concerning toll-like receptor and intracellular NFκB signaling .Besides numerous signaling molecules like cytokines, chemokines, and their related receptors which have meanwhile been identified and targeted in animal studies two novel targets should be highlighted here.Complement is activated during acute and chronic cardiac injury in different animal models. Michael Carroll’s group demonstrated complement activation by ischemia/reperfusion in different organs by a single IgM clone that recognizes a neo-epitope on hypoxic cells , 159. ThGlycoprotein-130 (gp130) is the common receptor of IL-6, which is elevated in patients with chronic heart failure . CardiomMBL and IgMs are independent trigger mechanisms for initiating the complement cascade. Both pathways converge on the activation of complement component C3 into cleaved C3a. Mice deficient for either C3 or the membrane receptor for C3a (C3aR) is protected against chronic left ventricular remodeling after myocardial infarction (own unpublished results).Accordingly, a prospective study in a chronic heart failure cohort comprising 182 patients demonstrated that complement activation is strongly linked to the outcome in chronic heart failure. Especially, high levels of activated C3, C3a, predicted cardiovascular events such as hospitalization and mortality . HoweverTherefore, there is a considerable experimental evidence that at least after ischemic myocardial injury, there is an ongoing complement activity in myocardium. Interventions inhibiting complement activation, especially the central component C3/C3a may represent a novel target for prevention and treatment of chronic heart failure after large myocardial infarction.+ regulatory T-cells came especially into focus.Most immuno-mechanisms studied in chronic heart failure till date address innate immunity, whereas adaptive immune mechanisms have gained much less interest so far. Recently, CD4+ T-cells comprise a subset of thymus-derived T-cells which are characterized by intracellular expression of the transcription factor Foxp3 [+CD25+CD127lowCD3+ T-cells. Regulatory T-cells are well known for preventing autoreactive immune responses which are associated with chronic myocardial diseases, such as auto-antibody formation [Regulatory CD4or Foxp3 . By meanormation . As disc+ T-cells might mediate part of the clinical effect of immuno-modulating therapeutic principles, which was already tested in clinical studies: intravenous immunoglobulins beneficially modulate several unrelated auto-immune diseases. As discussed above, clinical trials indicate that they might also have beneficial effect in inflammatory cardiomyopathies. It was speculated that sustained peripheral expansion of antigen-specific CD4+CD25+Foxp3+ regulatory T-cells might contribute to their therapeutic effect [Regulatory CD4c effect .+CD25+CD127low), and a decrease of activated T cells (CD4+CD69+ and CD8+CD69+ cells and CD28+ T cells) [Besides possible effects by neutralizing autoreactive antibodies, a recent study indicated that immuno-adsorption also modifies T cell-mediated immune reactions. Immuno-adsorption in patients with DCM was associated with a significant increase of regulatory T cells (CD4T cells) . The freT cells) .+CD25+ Foxp3+CD127low cells were found in peripheral blood of patients with chronic heart failure [+CD25+Foxp3+ T-cells in heart draining lymph nodes [+CD25+ T-cells was further reported to attenuate myocardial remodeling after experimental myocardial infarction in mice [+CD25+ cells ameliorates cardiac hypertrophy and fibrosis in response to angiotensin II [Furthermore, reduced numbers and impaired suppressive function of CD4 failure . There aph nodes . Our dat in mice , 132. Anensin II . Of noteTherefore, therapeutic expansion and activation of regulatory T-cells might tackle several immunological mechanisms contributing to the heart failure syndrome: mitigation of the expression of pro-inflammatory cytokines, suppression of auto-antibody production, and modification of recruitment, and differentiation of monocytic heart infiltrating cells contributing to both tissue repair and remodeling (own unpublished data).Besides transfer of autologous, ex vivo enriched regulatory T-cells, therapeutic expansion/activation in vivo might be more promising , 114. Mureg production by promoting acetylation of the Foxp3 transcription factor, which is a key regulator of Treg differentiation [Histone deacetylases (HDACs) catalyze the removal of acetyl groups from a variety of proteins. HDACs have been studied mainly in the context of chromatin, where they contribute to epigenetic regulation of gene expression by deacetylating nucleosomal histones. HDAC inhibitors stimulate Tntiation . On the ntiation . The mecMost completed trials on immuno-modulatory treatments were rather small including less than 100 patients/group. Data from randomized, placebo-controlled studies including more than 1,000 patients exist for TNF-α antagonists , 96. TheWhy did so many clinical trials, which were all launched on the basis of promising experimental data, show no additional benefit to current standard heart failure therapy?+Foxp3+ T-cells which have the ability to dampen pathological inflammation and auto-immune by a variety of mechanisms [As one hypothetical explanation, it must be mentioned here that standard drugs addressing neuro-humoral activation, which are obligatory co-medication in current heart failure trials also might have relevant effects on inflammatory activation. Especially ACE inhibitors have immuno-modulatory properties, as components of the renin–angiotensin–aldosterone system are expressed on leukocytes. Especially, the angiotensin–aldosterone system in T-cells came recently into the focus. T-cells contain an endogenous renin–angiotensin system that modulates pro-inflammatory T-cell function . Blockinchanisms . Accordichanisms . It remaOne might ask whether there is still a justifiable rationale for conduction of future clinical trials targeting inflammation as adjunct to our current pharmacological heart failure therapy. In our opinion, there is good experimental evidence that inflammation causally contributes to myocardial dysfunction and, thus, still constitutes a reasonable and promising therapeutic target, but some questions have to be carefully addressed before designing a clinical trial.First, which patients are best candidates for immuno-modulating treatment modalities? The hope to find a therapeutic principle that fits in all clinical scenarios of heart failure seems to be more and more unrealistic. It might be more promising in the future to individually characterize the immunologic status of a patient to decide whether he might benefit from the targeted immuno-modulation at the present time. Especially in patients with idiopathic DCM, this will have to include endomyocardial biopsies to gain more insights to define the present status of intramyocardial inflammatory activity and, especially, to exclude ongoing viral activity. Infectious  cardiomyopathy might become accessible to a completely different treatment in the future. Immuno-adsorption in patients with auto-antibodies, which have been evaluated for their cardio-specificity and toxicity, exemplifies such a first individualized approach . ComplemMonitoring of systemic, i.e., serum parameters of inflammation, especially cytokines, does likely not reflect myocardial inflammation, but is rather a marker of the overall clinical status. Therefore, one cannot conclude from the currently available serum parameters, which are often the only available biomaterial to monitor immunity in clinical studies, on the local effect on myocardial inflammation. Thus, at the moment, the real biological effect of immuno-modulating therapies, putatively beneficially influencing myocardial inflammation, cannot readily become assessed in clinical studies.As a different approach, as opposed to CHF patients, the wound healing phase after an acute myocardial infarction, which is the most important cause for heart failure in the Western word, might constitute another attractive phase for preventive immuno-modulation . ExperimSecond, how can we better identify immuno-modulating treatment principles tested in animal models to be suited for further translational clinical evaluation? Here, pre-clinical testing of therapeutic modalities warrants more attention. Several treatment modalities went into clinical trials, mainly on the basis of promising effects in rodent models, indicating that immuno-modulation, as evidenced e.g., by cytokine expression profiling or genetic lack/gain of function studies, might be causative. Here, we have to pay more attention on the transferability of immunological phenomena from small animal models to man. This does not only relate to the estimation of the putative therapeutic impact, but also to potential side effects. In addition, before going into man for phase I/II trials, large-animal studies have to be advocated. However, even a very good understanding of the biological mechanism of an immuno-modulating therapeutic tested in different species does not prevent from unexpected effects in man which can, at best lead to lack of efficacy, but also to deleterious side effects .Also essential, but widely underestimated, factors like age , co-mediTherefore, we pledge for even greater effort spent on translational cardio-immunological research which goes beyond phenomenological description of beneficial effects on myocardial function and remodeling and its association with parameters of inflammation. Given the inherent limitation to monitor the systemic and, especially local immunological processes within the myocardium in patients, a deep understanding of the biological effects of a therapeutic principle in different experimental models is vital before starting clinical studies.In addition, in this context, as many therapeutically principles have only been tested in the chronic myocardial infarction heart failure mouse model, other models of chronic heart failure, especially models of genetic and inflammatory cardiomyopathies, should receive more interest in the future.Summing up the current evidence from both experimental and clinical studies discussed here, we would like to conclude that inflammation is a promising therapeutic target in the setting of CHF. Current state of evidence from clinical trials indicates that unspecific immuno-modulation, e.g., by steroids or immuno-adsorption, holds some promise especially in the “orphan” field of idiopathic/inflammatory, non-viral DCM (see Table


Fibroids are the most common benign tumors of the uterus during female reproductive age. Uterine artery embolization (UAE) using embolic particles  to occlude the uterine arteries, have been reported as a relatively safe, effective, and durable nonsurgical alternative to hysterectomy in diminishing fibroid-related symptoms. To block the arterial blood supply to the fibroid completely, UAE is typically performed in both uterine arteries by an experienced interventional radiologist. Reduction in menorrhagia has been reported as 80-93 percent and the mean decrease in fibroid size varies from 50-78% in the literature. In our center improvement in menstrual bleeding after 6 months was 80.3%, and uterine fibroids underwent shrinkage of 63.7±33.7% after12 months. Complication rate including amenorrhea ranges from 1% - 7% in the literature. UAE may be followed by menopause in 1% of cases. Nevertheless, it is usually encountered in women in their late 40s. It seems that the future of UAE depends on optimal selection of patients according to volume-shrinkage prediction and fertility outcome. Although pregnancy is possible after embolization, however neither fertility preservation nor improvement can be guaranteed following UAE. Indeed, Women who desire to become pregnant should be cautioned about potential complications during pregnancy. The aim of this review is to discuss about the efficacy, safety, technique, and choice of embolic agent. Also we present the effects of this technique on fertility and pregnancy outcome and also methods for dose reduction during this procedure. Uterine artery embolization (UAE) has been accepted as a safe and effective alternative treatment for symptomatic fibroids firstly reported by Ravina in 1995 . FibroidThe preprocedural assessment should include a cooperative relationship between the gynecologist and interventional radiologist. This cooperation should be followed for post procedure care and long-term follow up . The decIt seems that a large number of patients with symptomatic fibroids are potentially suitable for UAE. Also in women who have asymptomatic fibroids, UAE usually is not suitable method and other treatments should be considered. In most women who have uterine fibroids, heavy menstrual bleeding is indicated for UAE. Those who have not responded to other therapies are potential candidates for UAE. Repeat surgery due to adhesion formation is technically complicated for those previously performed myomectomy.Preoperative MRI can be useful for assessment artery supply that may impact treatment planning. A myoma which has high signal intensity on T1-weighted images and shows no enhancement after Gd injection is unlikely to improve after UAE .UAE is contraindicated in patients with renal failure unless the patient is undergoing dialysis, severe prior anaphylactic reactions, and also pregnancy. Patients who have pelvic infection are contraindicated due to risks of septic uterus . Other tSubsequent to symptom evaluation, diagnosis of fibroids is usually made via Gynecologist by palpation of enlarge uterus. As history and physical examination have limitations and some conditions such as adenexal masses, adenomyosis, polyps, and cancers may mimic the fibroid related symptoms; fibroids must be confirmed with imaging. Imaging has an essential role in the evaluation, treatment and management of those women who underwent UAE. A number of imaging modalities such as ultrasonography and MRI are used for this purpose, and each method potentially has advantages and disadvantages. Ultrasound is the first technique for the evaluation of fibroids, and the preferred ultrasonography method is transabdominal. A linear probe with low to medium frequency (3.5-5 MHz) is suitable for this purpose.Transvaging ultrasonography may be useful for better depiction of endometrium, and in such cases 5-7 MHz transvaginal probes provide better spatial resolution . Using cUAE is typically performed from a right femoral artery puncture using 4 or 5-Fr Cobra catheter . AortogrIn circumstances that anastomoses encounter between the uterine and ovarian arteries, we position the catheter tip distal to the anastomosis and we use gelfoam particles to occlude the anastomosis temporarily and there after UAE will perform.We make our gelfoam particles from sponge sheets . We cut the sheet into small fragments with scissors.Finally, post embolization angiography should perform for the evaluation of redistribution.There is no consensus about the choice of embolic agent. Small particles are reported to cause more shrinkage in fibroids but associated with higher damage to myometrium and also cervical or ovarian ischemia -18.The technical aim of UAE is to release the embolic material into uterine arteries without permanent damage to uterine or other organs . In one In another study they found complete devascularization in more than 80 % of patients after contrast enhanced MRI .The most common immediate complication of UAE is pain, as a result of fibroid ischemia and myometrium ischemia. For this reason the patient undergoing UAE should be prepare for pelvic pain and also the symptoms of post embolization syndrome.The pain usually peaks during two to six hours after the procedure and may be accompanied by nausea. Uterine cramping is relatively mild with proper management for the patients. Pain may be severe and usually controlled by nonsteroid anti-inflammatory drugs . In patiAll fluoroscopic procedures are accompanied by radiation exposure, thus reduction of the exposure dose to the ovaries is very important in UAE due to the patient’s age and the presence of ovaries in this location. The ovaries are very sensitive organs to radiation due to the direct path of the beam during embolization. Estimated ovarian dose after UAE is 30–100 times more than the trunk CT (0.1–1.9 cGy) and 12–30 times less than the dose after radiotherapy for pelvis’s Hodgkin disease  . The levNot only the experience of the interventionalist but also factors like collimation, number of projections and DSA image acquisition mode can cause radiation dose reduction , 27. FlaThe leiomyomas are the most prevalent neoplasms during the fertility aged women that mostly develop in uterus  but can Redecha et al.  reportedWalker et al.  reportedMara et al.  conducteGoldberg et al in 2002 reviewed all pregnancy reports to date in addition of their two additional cases  . They shFirouznia et al.  in theirGoldberg compared 53 pregnancies after UAE and 139 after laparoscopic myomectomy. They reported a higher rate of preterm delivery and malpresentation after UAE but the risk of postpartum hemorrhage and spontaneous abortion were statistically similar . AccordiSome important point in this relation could be considered. First, it has been proposed the pregnancy complications are more probable in older women , 47. ThiSome future advances seem to be enthusiastic in the field of UAE. First, introduction of new imaging techniques for better delineation of fibroids will be useful as these techniques could further classify the patients in to more homogeneous subgroups that make the possibility of more precise prognosis determination or even better treatment plans. For example, Fallahi et al.  in theirAnother field of interest in the UAE could be application of the other embolization agents such as glues instead of PVA particles. The assessment of the efficacy of these agents in comparison to the PVA would be of interest.In addition, the assessment of long term follow up of patients treated with UAE and especially assessment of long term developmental profile of fetuses after UAE seems interesting.UAE for fibroids is an effective and safe therapeutic modality for symptomatic fibroids especially for those patients who like to preserve their uterus.This procedure needs no general anesthesia, no surgical incision, and no blood loss or transfusion. Recovery and time to return to normal activities is shorter than hysterectomy and open myomectomy.Management of fibroids needs multidisciplinary approach with gynecologist and interventional radiologist according to the symptoms, the desire to preserve fertility and uterus. Other options for the treatment of fibroids should be evaluated in terms of efficacy, safety, and effect on the future fertility.