Potential mechanisms are explored including diffuse ventricular fibrosis, focal myocardial scarring, and impaired myocardial perfusion and perfusion reserve. The complex relationship between AF, systemic inflammation, as well as endothelial/microvascular dysfunction and the effects of AF on ventricular calcium handling and oxidative stress are also addressed. Finally, consideration is given to the clinical implications of these observations and concepts, with particular reference to rate vs. rhythm control.Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is associated with significant morbidity, mostly secondary to heart failure and stroke, and an estimated two-fold increase in premature death. Efforts to increase our understanding of AF and its complications have focused on unravelling the mechanisms of electrical and structural remodelling of the atrial myocardium. Yet, it is increasingly recognized that AF is more than an atrial disease, being associated with systemic inflammation, endothelial dysfunction, and adverse effects on the structure and function of the left ventricular myocardium that may be prognostically important. Here, we review the molecular and  Efforts to increase our pathophysiological understanding of AF have focused on unravelling the mechanisms responsible for these progressive atrial abnormalities.6 However, it is now increasingly recognized that AF can also adversely affect ventricular function.7 While some patients develop overt left ventricular (LV) dysfunction and heart failure, others present with subclinical alterations in ventricular structure and function, which may only be revealed by detailed investigation.9The discovery that AF triggers are located in the pulmonary veins in the majority of cases led to the development of pulmonary vein isolation via catheter ablation,11 One such potential mechanism is impaired myocardial perfusion and perfusion reserve due to microvascular coronary dysfunction in the presence of AF.12 This could underlie the clinical observation of ischaemic chest pain, ST depression, and troponin release in patients with AF and no obstructive epicardial coronary artery disease.14Ventricular remodelling may be contributed to by the adverse haemodynamic effect of loss of coordinated atrial contraction and/or tachycardia-mediated cardiomyopathy from a persistently elevated ventricular rate. The possibility of additional mechanisms is suggested by the observation that some patients with AF and a controlled ventricular rate develop abnormalities in ventricular function, which are reversible following restoration of sinus rhythm (SR).17 A deeper understanding of the relationships between inflammation, endothelial function, and ventricular function in AF and the reversibility or otherwise of these alterations following restoration of SR may lead to more rational therapeutic strategies and ultimately to improved outcomes for patients.In addition to the LV abnormalities described, AF is also associated with systemic inflammation and impaired endothelial function.Figure 1) with a focus on AF-associated changes in ventricular structure, perfusion, and overall function. The relationship between AF and systemic inflammation and endothelial dysfunction is also briefly addressed. Finally, we discuss the implications of these findings for preclinical and basic research and provide a current clinical perspective.Here, we review the systemic correlates of AF  in heart failure trials,26 although it remains controversial whether this effect is truly independent.22AF is associated with impaired ventricular function, with a spectrum of severity ranging from congestive heart failure to subtle subclinical alterations in LV performance. Causation is much more challenging to ascertain, particularly when the index presentation is with both AF and LV dysfunction. The possibilities are that AF may promote ventricular impairment by raising the ventricular rate , or by other mechanisms such as endothelial dysfunction and impaired myocardial perfusion. Alternatively, a pre-existing ventricular cardiomyopathy may lead to AF, via mechanical stretch and structural remodelling of the atria and altered myocardial intracellular calcium handling.27 Instead, a substantial increase in the heterogeneity of conduction during atrial pacing is noted due to extensive atrial interstitial fibrosis, a finding not seen following short-term rapid atrial pacing.27 In clinical practice, a significant improvement in ventricular function following reduction in AF burden by cardioversion or ablation is perhaps the best identifier of a causal role of AF in the associated LV dysfunction, demonstrating that ventricular impairment is a reversible secondary effect. This notwithstanding, there are often multiple interacting causative factors in human AF and current classification schemes are unable to capture the inherent complexity and heterogeneity. This complicates the study of human AF, and underlines the importance of translating findings from animal models, each of which partially reproduces the pathophysiological spectrum of clinical AF.28Studies in a canine heart failure model have demonstrated that AF induced by a primary impairment in LV function is not associated with characteristic atrial electrical abnormalities such as the reduced atrial refractory period seen in AF induced by rapid atrial pacing with a controlled ventricular response.3.in vitro experiments on such preparations may not be fully reflective of in vivo conditions, these investigations have provided relevant insights into the changes in ion channel expression and function that accompany human AF.29The systematic evaluation of ventricular molecular and cellular abnormalities in AF is limited by poor access to human tissue samples. Atrial cardiomyocytes or trabeculae can be isolated from samples of the right atrial appendage excised at the time of cardiac surgery and cardiopulmonary bypass. Although the results of 30 Even when undertaken, biopsy carries the risk of sampling error, and patchy abnormalities may remain undetected.31 The limited human data in the literature largely represent small case series of ventricular biopsy32 or studies of tissue from explanted hearts following cardiac transplant.20 Interpretation of these data is made more difficult by the lack of matched tissue from healthy control subjects.The situation is even more challenging for investigations of the ventricular myocardium, as ventricular biopsy is rarely clinically indicated and is difficult to justify purely for research purposes due to the risk of complications.4.4.132 Importantly, all patients had structurally normal hearts without atrial or ventricular dilatation and a normal LV ejection fraction. Three of 14 had evidence of focal myocarditis (eosinophilic or lymphocytic) and initiation of corticosteroid therapy in addition to antiarrhythmic medications induced recovery of SR in all of this group. A further three patients had evidence of a diffuse cardiomyopathic process, whereas the remaining eight patients had a non-specific diffuse fibrotic change with or without evidence of cardiomyocyte necrosis. However, such changes may not be specific to AF as a separate study documented similar histological findings in the majority of patients with other forms of supraventricular tachycardia.33Although human data reporting ventricular changes in the presence of AF are sparse, one series that investigated 14 young patients with apparent ‘lone’ AF refractory to initial medical therapy demonstrated abnormal histology in all cases.T1 mapping,34 usually requiring administration of a gadolinium-based contrast agent. Several methods have been described: some rely on T1 measurement following contrast administration alone, while others combine these data with native (i.e. pre-contrast) T1 measurement and haematocrit to define myocardial volume of distribution or myocardial extracellular volume fraction (ECV).36 Contrast diffuses freely in the extracellular space and a low post-contrast T1 value reflects an elevated ECV, which is usually indicative of diffuse fibrosis. This method has been validated against histological assessment of fibrosis in right ventricular endomyocardial biopsy specimens taken from subjects who had undergone orthotopic heart transplantation.19 A study on post-contrast T1 mapping in subjects with paroxysmal (n = 40) and persistent AF (n = 27) as well as healthy controls (n = 23) demonstrated significantly lower post-contrast T1 values in both sets of AF patients compared with age- and sex-matched controls.37 Additionally, patients with persistent AF had lower post-contrast T1 values than the paroxysmal AF group. In keeping with established data showing that diffuse myocardial fibrosis increases with age, there was a negative correlation between increasing age and post-contrast T1 value in the healthy controls. In a multivariate model, only age, AF class, and LV ejection fraction were independent correlates of post-contrast ventricular T1 values. These data suggest that increasing AF burden is associated with progressive diffuse LV fibrosis, and may play a role in adverse cardiac remodelling.More data are available from non-invasive studies using MRI techniques, which have aimed to identify ventricular fibrosis in AF. Diffuse fibrosis cannot be visualized by the widely used method of late gadolinium enhancement (LGE) cardiac MRI, which relies on the presence of areas of normal myocardium to identify discrete areas of focal fibrosis, scarring, or infarction. However, diffuse fibrosis can be detected by the recently developed methods of 38 Heart failure and ventricular fibrosis have been reported in a similar dog model, despite the use of oral digoxin and metoprolol with the aim of achieving ventricular rate control.39 However, the degree of ventricular fibrosis was less marked than the observed atrial fibrosis , and the ventricular rates of up to 180 bpm reported in this study may have contributed to a tachycardia-mediated cardiomyopathy; no corresponding increase in ventricular fibrosis was detected by the same investigators in a pig model.39Data from animal studies suggest that the development of LV fibrosis is related to an elevated ventricular rate in the presence of AF. Induction of AF by rapid atrial pacing in dogs in the presence of atrioventricular (AV) node ablation and a paced ventricular rate of 80 bpm was sufficient to induce atrial but not ventricular fibrosis, whereas dogs without AV node ablation and a more rapid ventricular rate did develop significant ventricular fibrosis.40 Focal atrial tachycardia provides a good model for the study of human atrial arrhythmia as long-term ‘cure’, and maintenance of SR is feasible following ablation. The subgroup with LV cardiomyopathy at baseline had lower post-contrast T1 values on CMR imaging at a mean of 5 years following ablation, indicating a greater burden of diffuse ventricular fibrosis that was irreversible despite restoration of normal SR and improvement in LV ejection fraction. Interestingly, there was no significant difference in mean heart rate on 24-h ECG monitoring prior to ablation between the patients with and without cardiomyopathy. While this may reflect the lack of statistical power to detect a true difference, it is also possible that the maximum ventricular rate tolerated before the development of ventricular fibrosis and impaired LV function varies between individuals.Findings consistent with the paradigm of tachycardia-induced ventricular fibrosis have also been described in patients who had undergone previous ablation for incessant focal atrial tachycardia.41 Thus, ventricular tissue appears inherently less susceptible to the development of fibrosis than atrial tissue, though prolonged exposure to an elevated ventricular rate can nevertheless still result in ventricular fibrosis. In summary, although it is currently not possible to definitively determine causality, there is strong circumstantial evidence that AF can induce diffuse ventricular fibrosis.42Atrial and ventricular fibrosis in response to AF may be regulated by different mechanisms. The study of cultured rat atrial and ventricular fibroblasts shows that NADPH oxidase 4 (NOX-4) is more highly expressed in the atria than the ventricles, and this mediates the enhanced collagen and fibronectin production of atrial fibroblasts compared with ventricular fibroblasts in response to TGF-β.43 Intriguingly, the presence of LGE was a powerful predictor of mortality with each 1% increase in LGE associated with a 15% increased risk of death. The patterns of LGE seen in this study included an ischaemic pattern, which probably reflects silent myocardial infarction, and a non-ischaemic pattern, which may relate to inclusion of patients with heart failure and/or reduced ejection fraction or may reflect the presence of an AF-related ventricular cardiomyopathy in some of the studied cohort. The presence of focal ventricular fibrosis in patients with AF is not well described, and further studies are needed to identify whether these findings are more prevalent in this population than in a matched cohort of patients in SR.Furthermore, a recent study emphasized the prevalence and prognostic significance of focal myocardial scar, as detected by LGE. LV LGE was present in 13% of patients with AF and without known prior myocardial infarction undergoing a routine cardiac MRI study prior to pulmonary vein isolation.44 and also strongly predicts recurrence of AF following catheter ablation in hypertensive patients.45 If AF caused diffuse LV fibrosis and adverse remodelling, targeting an aggressive rhythm control strategy to the subgroup of patients in whom AF is the primary pathology (rather than a consequence of another disease state) could clearly be important. The hypothesis that this strategy would improve clinical outcomes would need to be examined in an appropriately powered clinical trial.There are also data defining the prognostic value of diffuse LV fibrosis in AF. ECV expansion (mainly due to diffuse fibrosis) is associated with increased mortality and heart failure in broadly unselected patients undergoing clinical cardiac MRI independently of age, ejection fraction, and previous infarct size,4.214 implying the presence of either microvascular coronary dysfunction or arrhythmia-induced coronary artery spasm. In a pig pacing model of AF, 6 h of rapid atrial pacing (600 bpm) are sufficient to elicit a substantial reduction in coronary flow reserve (CFR) in the absence of any significant change in fractional flow reserve (FFR).46 CFR is influenced by abnormal flow in the epicardial coronary arteries as well as the microcirculation, whereas FFR is specific to epicardial disease; hence, these data support the hypothesis that AF can rapidly adversely affect microvascular coronary function. The investigators report that this reduction in CFR was abolished by pretreatment with dronedarone (but not amiodarone), and suggest that this may reflect an attenuating effect of dronedarone on oxidative stress and consequent microvascular flow abnormalities.46 However, as ventricular rates were not reported, it is not possible to identify the extent to which tachycardia (and reduced diastole duration) may have contributed to the reduction in CFR.Patients with AF and without obstructive epicardial coronary artery disease may still demonstrate clinical evidence of ischaemia, such as chest pain, ST depression, or troponin release, often at the onset of arrhythmia,12 Myocardial blood flow at rest was markedly reduced in the AF group compared with age- and risk-matched controls as was adenosine-induced hyperaemic flow . Minimal coronary vascular resistance at rest and under hyperaemia was also significantly increased in AF patients compared with controls. Finally, in the subgroup of patients that maintained SR following cardioversion, myocardial blood flow at rest normalized and hyperaemic flow and coronary vascular resistance were significantly improved from baseline. These human findings are in accordance with the animal data, and suggest that the presence of AF induces abnormalities in microvascular coronary function that are at least partially reversible with restoration of SR. However, the subgroup that maintained SR following cardioversion was small (10 patients), and confirmation of these findings in a larger cohort is awaited.Myocardial perfusion and perfusion reserve have been evaluated using PET and radioactively labelled water in patients with persistent AF after exclusion of epicardial coronary artery disease.47 A coronary Doppler catheter was placed and measurements taken in SR, during AF induced by bursts of atrial pacing, and during regular atrial tachycardia with a rate of pacing equal to the overall ventricular rate observed during AF. The relative contribution of the irregularity of ventricular contraction in AF was also assessed by the inclusion of a second group of patients with complete AV block and dual-chamber pacemakers in situ; in this group, the ventricle was paced regularly at 115 bpm before and after induction of AF. Acute induction of AF led to an increase in coronary flow, which was lower than that seen in the presence of rapid atrial pacing and was associated with a reduction in CFR and vascular resistance. In contrast, only a small effect on coronary flow and an increase in CFR were seen in the group with pacemakers in situ. The increase in coronary flow following induction of AF is likely to be explained by the elevated ventricular rate following acute induction of AF, as patients in this study were not receiving rate control medications. However, this absolute rise in coronary flow appears insufficient relative to the increase in ventricular rate and a consequent increase in myocardial metabolic demand. A study in pigs demonstrated a similar finding of ‘supply-demand ischaemia’ in the atria following acute induction of AF,48 evidenced by an increase in atrial lactate production despite compensatory rises in both atrial coronary conductance and oxygen extraction.In a separate study, the effect of AF on coronary flow, flow reserve, and vascular resistance was assessed invasively in patients in SR with no ventricular or valvular dysfunction, and no significant epicardial coronary artery disease.48 Indeed, chronic ventricular ischaemia could underlie the impaired ventricular function commonly seen in AF.Atrial supply-demand ischaemia has also been proposed as a potential trigger for atrial structural remodelling and has a molecular phenotype that resembles changes seen in hibernating ventricular myocardium.4.347 leaving the possibility that irregular ventricular contraction might cause coronary vasoconstriction, possibly by increasing the release of vasoactive peptides such as angiotensin II or endothelin. Studies in a pig model of rapid atrial pacing have suggested that the angiotensin receptor blocker, irbesartan, abolishes the impairment of microvascular flow otherwise seen with rapid atrial pacing , as well as preventing ventricular oxidative stress.49 The link between AF and impaired vascular function is not limited to the coronary circulation, and there are numerous reports confirming an association between AF and systemic endothelial dysfunction. Non-invasive assessment of endothelial function is most readily undertaken using flow-mediated dilatation (FMD), which assesses nitric oxide production in response to shear stress and by measurement of plasma levels of markers of endothelial damage or dysfunction, such as the von Willebrand factor and circulating endothelial cells. Endothelium-dependent FMD is abnormal in patients with AF,15 and a causative role for AF in endothelial dysfunction is suggested by the finding that cardioversion52 and successful catheter ablation of AF16 are associated with significant improvements in endothelial function.The irregular pulse interval that is typical of AF seems to play a role in the impaired coronary flow observed in these patients, even when the overall ventricular rate is well controlled. Irregular pulse intervals can adversely affect blood pressure, but there was no correlation between blood pressure and coronary flow in the invasive study discussed,53 This group was compared with patients who underwent regular atrial pacing at 150 bpm, a control group of patients with paroxysmal AF who were not paced and remained in SR, and a further control group of patients with no history of AF undergoing ablation of left-sided accessory pathways who were also not paced and in SR. The study showed that even at the very short time point of 15 min, rapid atrial rates  were associated with increased local platelet activation and thrombin generation. Furthermore, AF  additionally led to local and systemic endothelial dysfunction (as assessed by levels of asymmetric dimethylarginine) and inflammation (as assessed by levels of soluble CD40L). These data suggest that even a short duration of AF may cause inflammation and endothelial dysfunction. Further studies are needed to investigate whether this may be an important mechanism underlying impaired myocardial perfusion and perfusion reserve and the thromboembolic risk of asymptomatic short-lasting episodes of AF.54Inflammation represents a potential link between AF, impaired endothelial function, and a reduction in myocardial perfusion and perfusion reserve. A recent study investigated the acute effects of AF induced by burst atrial pacing immediately prior to catheter ablation in patients with a history of paroxysmal AF but in SR at the time of the procedure.4.456 More recently, data from animal and human studies have suggested that, even in the absence of persistently elevated ventricular rates, AF can be associated with adverse atrial and ventricular remodelling and impairment of LV systolic and diastolic function.39 The relationship between AF and LV dysfunction is complex and potentially bi-directional, leading to a vicious electromechanical cycle.7 Causality in individual cases cannot be determined at a single time point, but a number of studies have undertaken serial evaluation around an intervention aimed at maintaining SR, and these have provided an important insight into causal relationships in the studied cohorts.It is well recognized that AF and other supraventricular tachycardias with an uncontrolled ventricular rate can cause a transient and reversible ventricular dysfunction that is termed ‘tachycardia-induced cardiomyopathy’.n = 26) compared with those randomized to medical rate control (n = 24).10 A similar improvement was seen in peak oxygen consumption and was mirrored by reductions in plasma B-type natriuretic peptide concentrations and NYHA class. Importantly, all patients were assessed for adequate rate control at baseline by ambulatory monitoring and exercise testing, thereby demonstrating that even rate-controlled AF has deleterious effects on LV function. The improvement in LV ejection fraction shown in this study is in keeping with the results of other  studies of patients with AF undergoing catheter ablation .A recent randomized study of patients with persistent AF, symptomatic heart failure, and LV ejection fraction <50% demonstrated a significant improvement in LV ejection fraction by 1 month (and persisting at 6 months) in those randomized to catheter ablation .58 The findings in the latter group may reflect the relatively low AF burden and the poor sensitivity of ejection fraction for detecting subtle changes in LV systolic function. Support for the latter possibility comes from a study by Tops et al.59 who utilized speckle-tracking to investigate LV strain in selected patients undergoing ablation for AF. Longitudinal and circumferential LV strain and strain rate were impaired at baseline compared with healthy controls. Intriguingly, maintenance of SR at follow-up was associated with improvement in these parameters, whereas recurrence of AF was associated with further deterioration. These data support the presence of subtle LV dysfunction in patients with AF and maintained LV ejection fraction; its reversibility following AF ablation strongly implies that AF is playing a causal role.A subsequent study which used cardiac MRI to evaluate LV function before and after ablation for short-lasting paroxysmal AF confirmed impaired LV systolic function at baseline and improvement in LV ejection fraction following ablation in all but patients with a normal ejection fraction at baseline  loss of atrial systole and AV synchrony, (ii) elevated overall ventricular rate, (iii) irregularity in the pulse interval, (iv) valvular regurgitation, and (v) neurohormonal effects. The role of some of these mechanisms has been directly assessed in human studies. In particular, in an invasive study involving ventricular pacing in patients with AF undergoing AV node ablation, AF and all forms of pacing were associated with reduced cardiac output compared with SR, emphasizing the importance of AV synchrony.61 While heart rate is slowed immediately and atrial contractility recovers by 1 week and remains unchanged thereafter, recovery of LV systolic function takes 1 month. Improvements in exercise tolerance and peak oxygen consumption mirrored the time course of recovery in LV function. These data suggest that the impairment in LV function seen in persistent AF may be due to a transient ventricular cardiomyopathy or stunning, due in part to an elevated ventricular rate but perhaps also to the irregular pulse interval.A separate study showed that, in patients with persistent AF and impaired LV function, improvement of atrial and ventricular function after successful cardioversion each follows a different time course.5.The molecular and cellular effects of AF on the ventricular myocardium are challenging to the study in humans due to limited clinical indications for ventricular biopsy and few other means of accessing ventricular tissue. In comparison, it is relatively straightforward to assess atrial tissue that is frequently excised in common cardiothoracic operations such as on-pump coronary artery bypass grafting. As a result, there are few studies which have explored this area in humans, although several findings have been obtained in animal models of AF.5.165 Less is known regarding the potential importance of ventricular oxidative stress in AF. Limited data are available from a study by Cai et al.,66 conducted in a pig model of rapid atrial pacing. The protein level of endothelial nitric oxide synthase was significantly decreased in LV tissue from animals with pacing-induced AF compared with controls, although this difference was less pronounced than in the left atrium. Importantly, this finding could not be attributed to an elevated ventricular rate as both groups of animals underwent AV node ablation and the ventricles were paced at 100 bpm in both the AF and control groups. A separate study, also conducted in a pig model of rapid atrial pacing, further demonstrated a significant increase in ventricular NADPH oxidase 2 (NOX2) expression, a finding that was prevented by treatment with irbesartan.49 Ventricular concentrations of F2-isoprostanes and LOX-1 protein, both markers of oxidative stress, were also elevated by rapid atrial pacing. These observations suggest that rapid atrial pacing induces oxidative stress in LV tissue by an angiotensin-mediated mechanism. Previous work demonstrated that plasma levels of angiotensin II are elevated within 6 h of rapid atrial pacing. Angiotensin II appears to be an important mediator of oxidative stress in AF67 by acting via the AT1 receptor to activate mitogen-activated protein kinases and stimulate proliferation of fibroblasts, cellular hypertrophy, and apoptosis as well as inducing calcium release and PKC activation, which in turn promotes activation of NOX2 and NOX1 NADPH-oxidases.68 A further study in the same model also reported a reduction in LV oxidative stress in the presence of dronedarone.46 In contrast to Cai et al., these studies cannot discriminate between the effect of AF and that of rapid ventricular rates induced by rapid atrial pacing with a competent AV node.Oxidative stress refers to the chronic disturbance of redox circuits and redox-responsive signal transduction pathways, and atrial oxidative stress is known to play an important pathophysiological role in the induction and maintenance of AF.5.269 Briefly, calcium handling abnormalities may be induced by oxidative stress70 and can promote AF via (i) induction of delayed afterdepolarizations and triggered events, (ii) enhanced Ca2+/calmodulin kinase type 2 activity and associated hyperphosphorylation and increased open probability of the type 2 ryanodine receptor, and (iii) up-regulation of the Na+/Ca2+ exchanger, increasing the size of the inward current for a given amount of aberrant Ca2+ release.71Calcium handling abnormalities in the atrial myocardium have been implicated in the initiation and maintenance of AF, and have been recently reviewed.n = 6 in SR and n = 6 in AF) who underwent cardiac transplantation as well as neonatal rat ventricular cardiomyocytes subjected to regular or irregular electrical stimulation ex vivo, to simulate SR and AF, respectively .20 To exclude effects of rate, all cardiomyocytes paced regularly or irregularly were stimulated the same number of times in total over a 24- h period. The mRNA and protein levels of sarcoplasmic reticulum ATPase 2a pump (SERCA), an important determinant of intracellular calcium levels, were significantly lower in the ventricular myocardium of the heart failure patients with AF compared with those in SR. This finding was recapitulated in paced rat ventricular cardiomyocytes, suggesting that irregularity of ventricular contraction influences SERCA expression beyond any effect of heart failure or ventricular rate. Additionally, in both models, AF was associated with a significant decrease in the phosphorylation of phospholamban (PLB), a key regulator of SERCA. Confirmation that these changes affect intracellular calcium handling was obtained from calcium imaging of rat cardiomyocytes, which demonstrated significantly reduced calcium transient amplitude and increased time-to-peak calcium transient amplitude in cardiomyocytes exposed to irregular pacing, compared with unpaced and regularly paced groups. Surprisingly, the rate of decay of the intracellular calcium transient was not significantly different between the groups.In contrast, very sparse data are available on calcium handling in ventricular myocardium in AF. Some insights are provided by a small study which examined human LV myocardial tissue obtained from end-stage heart failure patients with or without AF  failed to demonstrate any significant improvement in cardiovascular outcomes from a rhythm control strategy over a rate-control strategy. So, is there no rationale for trying to achieve SR in any patient with AF? There are several reasons that this may not be an appropriate conclusion to draw from these data.Human studies indicate that control of rhythm with cardioversion or ablation can, at least in selected groups of patients, restore LV function. Of particular importance for the clinician is determining whether this translates into long-term prognostic benefit. Experience over the last decade has not been encouraging: several large randomized clinical trials . The corollary of this is that a rhythm control strategy is less likely to successfully maintain SR the longer AF has been established or in disease states where primary atrial structural remodelling is the main substrate for AF (i.e. in the presence of heart failure).First, younger and more symptomatic patients are underrepresented in these trials. This population is more likely to have lone AF and to be at an earlier stage in the natural history of AF, and thus more likely to respond successfully to a rhythm control strategy. It is well established from animal models that the presence of AF induces progressive electrical and structural remodelling that augments AF stability , a large randomized trial of 3000 patients that is currently recruiting, will inform whether catheter ablation offers prognostic benefit beyond conventional medical strategy.8.AF is a common disease with significant clinical heterogeneity. Mechanistic and translational studies are providing important insights into its aetiology, and suggest that AF has important adverse effects on LV structure and function, in addition to a complex relationship with systemic inflammation and endothelial function. It is hoped that an improved understanding of the mechanisms underlying these observations will provide a platform for the development of much-needed advances in the therapeutic armamentarium against AF.Conflict of interest: none declared.The authors acknowledge support from the BHF Centre of Research Excellence, Oxford (RE/08/004).


Many patients with electrical dyssynchrony who undergo cardiac resynchronization therapy (CRT) do not obtain substantial benefit. Assessing mechanical dyssynchrony may improve patient selection. Results from studies using echocardiographic imaging to measure dyssynchrony have ultimately proved disappointing. We sought to evaluate cardiac motion in patients with heart failure and electrical dyssynchrony using cardiovascular magnetic resonance (CMR). We developed a framework for comparing measures of myocardial mechanics and evaluated how well they predicted response to CRT.CMR was performed at 1.5 Tesla prior to CRT. Steady-state free precession (SSFP) cine images and complementary modulation of magnetization (CSPAMM) tagged cine images were acquired. Images were processed using a novel framework to extract regional ventricular volume-change, thickening and deformation fields (strain). A systolic dyssynchrony index (SDI) for all parameters within a 16-segment model of the ventricle was computed with high SDI denoting more dyssynchrony. Once identified, the optimal measure was applied to a second patient population to determine its utility as a predictor of CRT response compared to current accepted predictors .Forty-four patients were recruited in the first phase  with mean QRSd 154 ± 24 ms. Twenty-one out of 44 (48%) patients showed reverse remodelling (RR) with a decrease in end systolic volume (ESV) ≥ 15% at 6 months. Volume-change SDI was the strongest predictor of RR . SDI derived from myocardial strain was least predictive. Volume-change SDI was applied as a predictor of RR to a second population of 50 patients  with mean QRSd 146 ± 21 ms. When compared to QRSd, LBBB morphology and scar burden, volume-change SDI was the only statistically significant predictor of RR in this group.A systolic dyssynchrony index derived from volume-change is a highly reproducible measurement that can be derived from routinely acquired SSFP cine images and predicts RR following CRT whilst an SDI of regional strain does not. Cardiac resynchronization therapy (CRT) is established as an effective treatment in selected heart failure patients with evidence of dyssynchrony, improving both morbidity and mortality . DespiteCardiovascular magnetic resonance (CMR) provides superior image quality and complete LV coverage,  as well The study had two phases:Phase 1 – Comprehensive evaluation of CMR based measures of mechanical dyssynchrony to determine the optimal predictor(s) of CRT response.Phase 2 – Application of the optimal predictor(s) identified in phase 1 to a second cohort of patients and comparison with accepted predictors of CRT response  ,16]..16].Forty-four patients fulfilling standard criteria for CRT  were prospectively recruited from a dedicated pre-assessment clinic for patients being considered for CRT in our institution. The local ethics committee (Westminster) approved the study and informed consent was obtained from each patient. Patients completed a quality-of-life questionnaire (QOL) and six-minute walk as well as standard 2D echocardiogram to assess LV volumes pre- and six-months post CRT. Echocardiographic measures of dyssynchrony were also measured. To assess dyssynchrony the inter-ventricular mechanical delay (IVMD) was calculated as the difference between the LV and right ventricular (RV) pre-ejection periods measured from QRS onset to the onset of pulmonary and aortic flows respectively . To measEchocardiograms were acquired on a GE vivid 7 scanner . Analysis was performed using EchoPac version 6.0.1 . Ejection fractions (EF) and LV volumes were measured using the 2D biplane Simpson’s method.42 software .Patients were scanned using 1.5 T MR-scanner  with a 32-element cardiac coil. The CMR framework described below was also performed on 10 healthy volunteers to assess the reproducibility of the measured variables. Cardiac synchronization was performed with vector electrocardiography. After localization and a coil sensitivity reference scan, an interactive real-time scan was performed to determine cardiac geometry in the short axis (SA), 4-chamber (4CH), 3-chamber (3CH) and 2-chamber (2CH) orientations. A multiple slice cine steady state free precession (SSFP) scan was performed in a stack of SA slices covering the LV and in the 4CH, 3CH and 2CH orientations . In addition, a SA and long-axis stack of breath hold complementary modulation of magnetization (CSPAMM) cine images or 3D CSPAMM  images  was determined using TomTec 4D LV-Analysis software . The software performs semi-automatic segmentation and propagation of the LV endocardial border from the SA stack and three long axis SSFP cine images  Manual slice-by-slice segmentation of the endocardial and epicardial borders of the LV in the stack of SA and three long-axis SSFP images in the first end diastolic (ED) cardiac phase.(2) Spatial re-positioning of the SA and long-axis SSFP and CSPAMM slices, to correct for any misalignment due to the different breath-hold positions by mutual rigid registration of the segmented SSFP endocardial and epicardial borders and CSPAMM slices.(3) Identification of the mitral valve plane from the insertion point of the valve leaflets in the first ED cardiac phase of the three long-axis images.(4) Deformation of a 3D atlas based model of the LV to the manually delineated endocardial and epicardial segmentations and mitral valve plane .(5) Deformable registration of the subsequent SSFP and CSPAMM phase of the cine images to the first ED phase and the extraction of deformation fields within the myocardium of the 3D heart model for myocardial motion and strain computation. Stronger weighting was given to the registration information from SSFP images for calculation of the deformation of the endocardial and epicaridal borders and from the registration information from CSPAMM images for the deformation within the body of the myocardium  The propagated endocardial and epicardial borders were checked against the SSFP images to ensure accuracy of the borders and the mitral valve plane throughout the cardiac cycle.(7) The myocardial wall thickening values were computed from the surface distance between the endocardial and epicardial surfaces for each of the 16 segments of the left ventricular myocardium.v for voxel x, from the ED phase to phase p, the myocardial motion was: (8) Myocardial strain was computed from the deformation field of the myocardium as follows. Having the deformation fields Strain was then calculated from the motion in the radial, circumferential and longitudinal directions for each voxel and all the values within each of the 16 segments of the myocardium were averaged to calculate overall strain as well as strain in each of the three directions.The SDI was calculated for regional cavity volume change, maximum muscle thickness and peak strain. The SDI was defined as the standard deviation (SD) of the regional times to peak volume change, maximum muscle thickness or peak strain. The SDI was expressed as a percentage of the cardiac cycle to allow for heart rate variation.Patients underwent CRT implant with the LV lead positioned in a lateral or posterolateral position wherever possible. Where venous anatomy restricted lead positioning to a non-lateral/posterolateral position, the choice of LV lead position was at the preference of the operator. Right ventricular and right atrial leads were implanted as per operator preference. The lead position relative to scar was determined using a modified clock-face method . BrieflyPatients were deemed to have reverse remodeled (RR) if there was a ≥ 15% reduction in LV end-systolic volume (ESV) as measured using the modified Simpson’s biplane method on 2D echo images . Th. Th26]. Forty-four patients were recruited to the first phase of the study , and 50 patients for the second phase . The clinical characteristics of patients studied in phase 1 and phase 2 are shown in Table Pre-implant LVESV and LVEF were 175 ± 67 ml and 25 ± 9% respectively. These improved over the follow-up period to 155 ± 68 ml (P = 0.03) and 31.8 ± 10.2% (P < 0.001). RR was seen in 21 out of 44 patients (48%). Thirty-six (82%) patients had a reduction of at least one NYHA class at 6 months, 38 (86%) had a ≥ 20% reduction in quality of life score. Twenty-eight patients (64%) increased their 6-minute walk distance by 10% or more. Using the pre-determined definition of a clinical responder, 36 (82%) were deemed clinical responders to CRT.Table LGE imaging for scar was possible in 43 patients. Twenty-four patients had scar and the mean scar burden in this group was 21.4 ± 7.9% of myocardium. The cut-off for predicting lack of reverse remodeling was 14.7% with a sensitivity of 91% and specificity of only 50%. This level of scar or greater was a predictor of attenuated RR response . Four patients were identified as having their LV lead position in a position of scar. Of these, none demonstrated RR at 6 months.The four echocardiographic measures of dyssynchrony were evaluated as predictors of RR. A forest plot comparing the echocardiographic measures and CMR-derived measures is shown in Figure Twenty patients and 10 volunteers were selected for intra and inter-observer variability for volume SDI. In healthy controls the intra-observer average difference was 0.06 ± 0.4% and coefficient of variation (COV) was 2.0 ± 1.1% and the inter-observer average difference was 0.40 ± 1.2% and COV was 3.1 ± 2.6%. In CRT patients, the intra-observer average difference was 0.20 ± 0.5% and the COV was 2.8 ± 0.9%. The inter-observer average difference was 0.70 ± 1.0% and the COV 3.6 ± 3.0%.The mean accuracy score for the endocardial and epicardial segmentation propagation was 3.89 ± 0.89% (a score of 5 indicating perfect tracking and a score of 1 inaccurate tracking).RR was seen in 35 (70%) of patients and clinical response  was seen in 42 (84)%. The differences in clinical characteristics between RR responders and non-responders are shown in Table The purpose of our study was to use comprehensive CMR assessment to deliver better insights into the complexities of cardiac mechanical dyssynchrony in heart failure whilst exploring the relationship to CRT response. Different measures of mechanical dyssynchrony were assessed using the same 16 regional segment framework of the LV so as to understand and compare the effectiveness of each measure in predicting chronic RR to CRT.The main findings were:1) An SDI of ≥ 9.75% derived from volume change was sensitive, specific and superior to other mechanical dyssynchrony measures for predicting chronic reverse remodeling. In multivariate analysis it was the only significant independent predictor of RR post-CRT.2) An SDI derived from peak strain  was poor at predicting RR.Increasing the response rate to CRT has been the focus of many studies and the results to date have been conflicting. QRS duration remains the most widely utilised marker of dyssynchrony and it has the advantage of being relatively easy to measure and highly reproducible. Historic guidelines advocated the use of QRSd >120 ms as a cut-off for CRT but the importance of more prolonged QRSd (≥150 ms) and QRS morphology (LBBB) in predicting response has been reflected in the most recent iterations of international guidelines for CRT implant . In our Many studies have focused on the use of echocardiographic measures to predict response. The failure to deliver robust, reproducible measures is well documented  and thisA striking finding was the failure of strain measures to predict response. Although surprising, considering the focus of previous studies on measures of myocardial strain ,14], th, th14], The main limitations of the study are the relatively small sample size and the follow-up duration of only 6 months. The fact that CMR cannot be used for follow up studies with most current CRT devices is worth considering as the use of change in ESV measured using echo as an end-point also has some limitations. It is important to acknowledge the history of echocardiographic measures of dyssynchrony which appeared promising in single-centre studies but which were then found to be less robust and reproducible when investigated in a multi-centre study  The dataVolume-change SDI is easily derived from the most commonly run cine sequences and strongly predicted response in patients receiving CRT whilst measures of dyssynchrony based on regional strain did not. At a time when increasing numbers of heart failure patients are undergoing evaluation with CMR (given its excellent resolution and tissue characterisation) the addition of this novel predictor of CRT response may be of potential value.The literature is replete with studies designed to identify better (mainly echocardiographic) predictors of CRT response. The role of mechanical dyssynchrony as a discriminator for patient selection has been strongly challenged and most contemporary CRT guidelines focus on the importance of the electrical substrate, with the strongest recommendations reserved for those with the widest QRS and LBBB. The superior imaging afforded by CMR has not been comprehensively evaluated till now and in 2 independent cohorts of patients meeting conventional CRT criteria we have shown that CMR-derived volume change SDI is a superior predictor of RR than both QRS duration and LBBB morphology. We acknowledge the importance of learning lessons from studies evaluating dyssynchrony measures derived from echocardiography and the findings of this study need to be further assessed in a larger, multi-centre setting. If our findings are confirmed then we would contend that patients meeting criteria for CRT implant should receive conventional CRT if their volume change SDI is >9.75% and that the group with SDI <9.75% should be evaluated more closely. Alternative means of delivering CRT, including multi-site and LV endocardial pacing, may provide superior options in this group (many of whom have an ischaemic aetiology and have areas of scar) .CRT: Cardiac resynchronization therapyLV: Left ventricleRR: Reverse remodellingCMR: Cardiovascular magnetic resonanceLBBB: Left bundle branch blockEF: Ejection fractionQOL: Quality of lifeSA: Short axisSSFP: Steady state free precessionCSPAMM: Complementary modulation of magnetizationED: End diastolicSDI: Systolic dyssynchrony indexESV: End systolic volumeEDV: End diastolic volumeNYHA: New York Heart AssociationROC: Receiver operating characteristicPR: Prevalence responseDr Manav Sohal, receives research funding from St. Jude Medical.Dr Matthew Ginks, receives research funding from St. Jude Medical.Dr Anoop Shetty, receives research funding from St. Jude Medical.Dr C Aldo Rinaldi, is a Consultant to St. Jude Medical and receives investigator led grant funding from St Jude Medical and Medtronic Inc.Professor Reza Razavi, receives investigator led grant funding from Philips Healthcare.MS, SGD, CAR, GCW and RR conceived and designed the study. MS and SDG performed the data analyses and MS drafted the manuscript. XZ, WS, SK, SN, NS, SO and DR designed the image processing framework. MG, AS and ES were responsible for clinical data collection. All authors read and approved the final manuscript.


Obesity is associated with increased risk of death that may be related to underlying structural and functional changes in the heart. Cardiac MR (CMR) can provide detailed structural and functional information about the heart and vasculature that may improve our understanding of obesity related cardiac morbidity and mortality.A cohort of 77 obese patients referred for stress CMR for evaluation of dyspnea prior to weight-loss surgery (WLS) were identified from our research registry. All patients underwent standard vasodilator stress perfusion protocol with late gadolinium enhancement (LGE) imaging on a 1.5T MR system. We collected demographic and CMR data including ventricular volumes, global and regional functional indices, and results of stress and LGE imaging. Comparison of CMR was made to previously derived and universally accepted normative data. The goal will be to assess these parameters 1 year post WLS and analyze the structural, functional and microvascular changes.Please see table Multiple cardiovascular abnormalities are noted in severely obese patients including LV and RV dilation and microvascular ischemia that may contribute to the increased cardiovascular morbidity and mortality observed in this population.Empire Clinical Research Investigator Program (ECRIP).


Patients with rheumatoid arthritis (RA) experience an excess risk of congestive heart failure (CHF), chronic inflammation plays a pivotal role in this increased risk. Despite the growing body of research on cardiovascular (CV) disease in RA, the key pathways underlying the development of abnormalities in myocardial structure and function associated with CHF remain obscure. Cardiac magnetic resonance imaging (CMR) has been used to identify early functional and structural changes in the left ventricle (LV) before development of clinically overt CHF. We evaluated LV function and structure using a CMR in RA patients (pts) without cardiac symptoms, and determined the impact of non-biologic DMARDs and biologic DMARDs.Consecutive RA pts and healthy control were enrolled. RA pts received biologic DMARDs (bDMARDs) or non-biologic DMARDs (nbDMARDs). All subjects underwent evaluation of LV function and structure using non-contrast CMR. LV function was based on LV ejection fraction (EF), end-systolic volume (ESV), end-diastolic volume (EDV), stroke volume (SV), and cardiac output (CO). LV hypertrophy was measured by absolute LV mass (LVM) and LV mass index (LVMI) determined by LVM/body surface area. Subjects were classified into four categories based on LVMI and LVM/EDV of control subjects, with the mean + 2 SD of each measure defined as elevated LVMI and LVM/EDV.p=0.002). Compared to the control group, the nbDMARDs group showed significantly higher LVMI and lower EF . There were no significant differences in LVMI and EF between the control and the bDMARDs groups. LV structure was classified as (1) concentric remodeling (LVMI<66.9 and LVM/EDV>1.02 (2) concentric hypertrophy (LVMI>66.9 and LVM/EDV>1.02 (3) eccentric hypertrophy (LVMI>66.9 and LVM/EDV <1.02 and (4) normal geometry . Mass/EDV tended to be associated with SDAI (p=0.07). Adjustment for ESR did not modify the association of SDAI with EF and LVMI .We compared 90 female RA pts  with a matched 20-patient control group . 46 RA pts received nbDMARDs  and 44 RA pts received bDMARDs [ plus MTX]. The Simplified Disease Activity Index (SDAI) was significantly higher in the nbDMARDs group than in the bDMARDs group (Biologics treatment may reduce progression of subclinical LV dysfunction and normalize LV structure in association with the reduction in disease activity. It can be presumed that active RA may be an important contributor to the development of myocardial abnormalities.None.


Based on observations from cardiovascular magnetic resonance (CMR) imaging, it is not clear whether chronic myocardial infarction (MI) is associated with abnormal perfusion at rest. Our aim was to investigate this question using semi-quantitative analysis of resting myocardial perfusion to compare areas of infarct and remote myocardium in patients with known coronary anatomy.We identified 19 patients who underwent regadenoson stress CMR , had MI confirmed by late gadolinium enhancement (LGE), and underwent invasive coronary angiography within 6 months of CMR. Stress perfusion images were obtained during first pass of Gadolinium contrast agent one minute after regadenoson (0.4mg IV bolus) injection, and followed by reversal with aminophylline (75-125 mg), rest perfusion and late gadolinium enhancement (LGE) imaging 10-15 minutes later. Resting time-intensity curves were generated for a region of interest (ROI) in the area of MI, remote myocardium, and blood pool (Medis). Myocardial curves were used to obtain maximal up-slopes and normalized by the blood pool. Up-slopes were compared between the infarcted and remote myocardial ROIs.There was no significant difference between the slopes in the infarcted and remote myocardium (0.31 ± 0.17 vs 0.32 ± 0.18 1/s) irrespective of presence of significant stenosis (>70%), or in ROIs supplied by arteries with or without significant stenosis (0.31 ± 0.18 vs 0.32 ± 0.17 1/s) irrespective of presence of scar.Resting myocardial perfusion on CMR images does not reflect either the presence of chronic MI or underlying coronary patency. Accordingly, normal resting perfusion should not be used to rule out either significant stenosis or the presence of an underlying MI.N/A.


Critical Care, 0.5 M sodium lactate infusion for 24 hours was reported to increase cardiac output in patients with acute heart failure. This effect was associated with a concomitant metabolic alkalosis and a negative water balance. Growing data strongly support the role of lactate as a preferential oxidizable substrate to supply energy metabolism leading to improved organ function  in ischemic conditions. Due to its sodium/chloride imbalance, this solution prevents hyperchloremic acidosis and limits fluid overload despite the obligatory high sodium load. Sodium lactate solution therefore shows many advantages and appears a very promising means for resuscitation of critically ill patients. Further studies are needed to establish the most appropriate dose and indications for sodium lactate infusion in order to prevent the occurrence of severe hypernatremia and metabolic alkalosis.In a recent issue of  Critical Care, Nalos and colleagues evaluated the effect of 0.5 M sodium lactate (SL) solution on cardiac function in patients presenting acute heart failure [In a recent issue of  failure . The keyFirst, hyperlactatemia is a good marker of poor outcome in critically ill patients. Tissue hypoxia is responsible for an increased lactate production resulting from glycolysis ,3. PropoEvidence is now accumulating that lactate is a preferred substrate readily oxidizable in energy crisis conditions -6. In phThe second point raised by Nalos and colleagues is the induction of metabolic alkalosis by SL infusion , which rThird, the infusion of a large amount of sodium in patients with acute heart failure represents a clear danger as sodium restriction is the classic treatment for this condition. Surprisingly, the authors showed that the 24-hour and 48-hour water balances were strongly negative in patients receiving SL compared with the control group. This finding is in agreement with previous studies performed in cardiac surgery and traumatic brain-injured patients ,11. The In conclusion, the study by Nalos and colleagues provides additional arguments to strongly consider SL as a valuable means for resuscitation. Thanks to its high lactate and low chloride concentrations, SL offers substantial clinical improvement in organ functions, especially for the heart and brain.SL: sodium lactate.The authors declare that they have no competing interests.


Myocardial scarring can be assessed by cardiac magnetic resonance imaging with late gadolinium enhancement and by endomyocardial biopsy. However, accuracy of late gadolinium enhancement for predicting microscopic myocardial scarring in biopsied specimens remains unknown in hypertrophic cardiomyopathy. We investigated whether late gadolinium enhancement in the whole heart reflects microscopic myocardial scarring in the small biopsied specimens in hypertrophic cardiomyopathy.Twenty-one consecutive patients with hypertrophic cardiomyopathy who were examined both by cardiac magnetic resonance imaging and by endomyocardial biopsy were retrospectively studied. The right interventricular septum was the target site for endomyocardial biopsy in all patients. Late gadolinium enhancement in the ventricular septum had an excellent sensitivity (100%) with a low specificity (40%) for predicting microscopic myocardial scarring in biopsied specimens. The sensitivity of late gadolinium enhancement in the whole heart remained 100% with a specificity of 27% for predicting microscopic myocardial scarring in biopsied specimens. Quantitative assessments of fibrosis revealed that the extent of late gadolinium enhancement in the whole heart was the only independent variable related to the microscopic collagen fraction in biopsied specimens .Although there was a compromise in the specificity, the sensitivity of late gadolinium enhancement was excellent for prediction of microscopic myocardial scarring in hypertrophic cardiomyopathy. Moreover, the severity of late gadolinium enhancement was independently associated with the quantitative collagen fraction in biopsied specimens in hypertrophic cardiomyopathy. These findings indicate that late gadolinium enhancement can reflect both the presence and the extent of microscopic myocardial scarring in the small biopsied specimens in hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy (HCM) is a primary cardiac disorder characterized by myocardial hypertrophy in the absence of other loading conditions, such as aortic stenosis or hypertension Myocardial scarring is defined as increased collagen with evidence of cardiomyocyte loss Twenty-three consecutive HCM patients who were examined both by LGE-CMR and by endomyocardial biopsy at Kanazawa University Hospital were retrospectively studied. HCM was diagnosed by the presence of a non-dilated and hypertrophied left ventricle on two-dimensional echocardiography  in the absence of another disease that could account for the hypertrophy A standard 12-lead ECG  was recorded in the supine position during quiet respiration. Pathological Q waves were defined as follows; Q wave >1/3 of the ensuing R wave in depth and/or >40 msec in duration in at least 2 contiguous leads except aVR Standard M-mode and two-dimensional echocardiographic studies were performed to identify and quantify morphological features of the left ventricle in accordance with the guideline of the American Society of Echocardiography Selection of patients for endomyocardial biopsy was clinically determined according to a scientific statement regarding the role of endomyocardial biopsy in the management of cardiovascular disease CMR imaging was performed with a 1.5 Tesla scanner (GE). Delayed-enhancement images for detection of fibrosis were obtained 10 minutes after intravenous administration of gadolinium–DTPA (0.2 mmol/kg) Values are expressed as the mean ± standard deviation. Correlation was assessed by linear regression analysis and the Pearson correlation coefficient. Unadjusted and multivariate-adjusted linear regression analyses were used to assess the associations between the clinical parameters and the microscopic collagen fraction. First, each parameter was univariately analyzed in the regression model using the percentage area of microscopic fibrosis as the dependent variable (unadjusted model). Then, significant variables in the unadjusted analysis were subjected to the multivariate analysis together with age and gender (Multivariate model). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were defined as previously reported Baseline characteristics of the 21 patients with HCM are summarized in Qualitative assessments of myocardial fibrosis in biopsy specimens revealed that interstitial fibrosis without myocardial scarring was present in 11 (52%) of the 21 patients, and interstitial fibrosis with myocardial scarring was present in 6 (29%) of them . The meaWe first investigated whether LGE in the ventricular septum predicted microscopic myocardial scarring in small biopsied specimens in the 21 HCM patients. For predicting microscopic myocardial scarring, LGE showed an excellent sensitivity (100%); all of the 6 patients who had microscopic myocardial scarring showed LGE in the ventricular septum. In contrast, 6 (40%) of the 15 patients who did not have microscopic myocardial scarring were negative for LGE in the ventricular septum. Thus, the sensitivity, specificity, PPV, NPV and accuracy of LGE in the ventricular septum for predicting microscopic myocardial scarring were 100%, 40%, 40%, 100% and 57%, respectively . We thenLGE in the ventricular septum showed poor diagnostic accuracy for predicting microscopic interstitial fibrosis in the 21 HCM patients; the sensitivity, specificity, PPV, NPV and accuracy were 76%, 50%, 87%, 33% and 29%, respectively . AdditioThe study population included 5 patients with end-stage HCM . Even whSince the results showed an excellent sensitivity of LGE in the whole heart for predicting microscopic myocardial scarring in biopsied specimens, we then asked whether or not the extent of LGE in the whole heart predicted the microscopic collagen fraction. Unadjusted regression analyses demonstrated a correlation between the LGE fraction in the whole heart and the microscopic collagen fraction in biopsied specimens  , Table 6We next examined whether the LGE fraction correlated with the microscopic collagen fraction even when the 5 end-stage HCM patients were excluded from analyses. In the remaining 16 HCM patients with preserved left ventricular ejection fraction, a correlation between the LGE fraction in the whole heart and the microscopic collagen fraction in biopsied specimens was observed  .These data demonstrate that the sensitivity of LGE was excellent for prediction of microscopic myocardial scarring in HCM although there was a compromise with specificity. Furthermore, the extent of LGE independently correlated with the severity of microscopic collagen fraction in biopsied specimens in HCM patients.There is excellent agreement between the location of myocardial scarring determined postmortem and the antemortem LGE location on CMR in HCM Although recent data showed that the LGE fraction at the myectomy site accurately reflected the histopathological fibrosis fraction in large myectomy specimens from HCM patients One limitation of this study was the small sample size. Another limitation is a selection bias regarding the severity of the disease because this study population was enrolled in a tertiary referral center. Specifically, a high prevalence (24%) of end-stage HCM patients in the studied population might have affected the results. Although correlations between LGE and microscopic fibrosis were observed even when these end-stage HCM patients where excluded from the analyses , Table 5Although there was a compromise in specificity, LGE showed an excellent sensitivity for predicting microscopic myocardial scarring in small biopsied specimens. Moreover, the quantitative LGE fraction in the whole heart correlated with the severity of microscopic collagen fraction in biopsied specimens in HCM. These findings suggest that qualitative and quantitative assessments of noninvasive LGE-CMR may be used to predict both the presence and the severity of microscopic myocardial scarring in HCM.


The left pulmonary artery (LPA) contributes more than the right (RPA) to total pulmonary regurgitation (PR) in patients after tetralogy of Fallot (TOF) repair, but the mechanism of this difference is not well understood. This study aimed to analyze the interplay between heart and lung size, mediastinal geometry, and differential PR.Forty-eight Cardiovascular Magnetic Resonance (CMR) studies in patients after TOF repair were analyzed. In addition to the routine blood flow and ventricular volume quantification cardiac angle between the thoracic anterior-posterior line and the interventricular septum, right and left lung areas as well as right and left hemithorax areas were measured on an axial image. Statistical analysis was performed to compare flow parameters between RPA and LPA and to assess correlation among right ventricular volume, pulmonary blood flow parameters and lung area.2 vs 2.86 ± 0.89 L/min/m2; p = 0.02), smaller net forward flow , and greater regurgitant fraction (RF)  than the RPA. There was no difference in regurgitant flow volume between RPA and LPA (p = 0.29). Indexed right ventricular end-diastolic volume (RVEDVi) correlated with LPA RF , but not with RPA RF (p = 0.09). Larger RVEDVi correlated with a more leftward cardiac axis  and with smaller left lung area . LPA RF, but not RPA RF, correlated inversely with left lung area . The follow-up CMRs in 20 patients showed a correlation of the rate of RV enlargement with the rates of LPA RF worsening , and of increasing left lung compression .There was no difference between LPA and RPA diameters. The LPA showed significantly less total forward flow (2.49 ± 0.87 L/min/mAn enlarged and levorotated heart is associated with left lung compression and impaired flow into the left lung. Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease. Early postoperative outcomes after closure of the ventricular septal defect and reconstruction of the right ventricular outflow tract are excellent in the majority of patients . HoweverCardiovascular Magnetic Resonance (CMR) is the gold standard for the quantification of PR and RV volume –12. UsinBased on these previous reports and our clinical observations, we hypothesized that compression of the left lung, as a result of cardiomegaly and rotation of the heart into the left chest, leads to greater LPA flow reversal. The objective of this study was to assess the relationship between heart size, mediastinal geometry and differential pulmonary regurgitation.We retrospectively analyzed the CMR studies performed in patients after TOF repair at our institution between June 2007 and November 2009. Patients with a RV to pulmonary artery conduit, status post stent implantation in the main pulmonary artery (MPA) or branch pulmonary arteries, more than mild discrete branch pulmonary artery narrowing defined by gradient >20 mmHg estimated via Doppler echocardiography, less than mild MPA regurgitation, defined as a regurgitant fraction (RF) <10 %, were excluded. Likewise, those with dextrocardia, congenital absence of the pulmonary valve, or a previous pulmonary valve replacement were excluded. The first CMR during the study period was included. For those patients who had undergone more than one CMR up until March 2016, the latest CMR study before pulmonary valve replacement was included as follow-up to delineate the change in geometric, volumetric, and flow parameters relative to the others. Clinical data including age at CMR, age at surgery, surgical procedure, were retrospectively collected from the patients’ medical records. This study was approved by the institutional research ethics board, and consent was waived.All patients underwent clinical CMR examinations at 1.5 T . The protocol consisted of scout imaging of the entire thorax in the axial plane using standard ECG gated steady state free precession (SSFP) imaging. A stack of SSFP short axis cine loops for ventricular volumetry and phase-contrast flow velocity mapping in the proximal RPA and LPA were obtained. Parameters of SSFP imaging were as follows: Flip angle 70°, parallel imaging with an acceleration factor of 2. Temporal resolution was adjusted to allow for 20 true reconstructed phases per cardiac cycle. For both SSFP and phase contrast imaging the in-plane spatial resolution was 1.5 mm × 1.5 mm and slice thickness 5 mm, minimal repetition and echo times. Other parameters of phase-contrast imaging were as follows: Flip angle 30°, 25 true phases per cardiac cycle.Ventricular volumetry and phase contrast flow analysis were performed in the routine clinical fashion, using commercially available software . Flow quantifications included forward flow volume; regurgitant flow volume; net flow volume (forward flow volume – regurgitant flow volume) and RF .2).All geometric measurements were made by a single reader (CD) on a ‘Centricity Enterprise’  picture archiving and communication system (PACS) viewing station using the preset window settings. On the axial plane scout image Fig.  with theT-test. Correlations were assessed using Pearson’s correlation analysis. In order to evaluate the association of a change in one parameter with the change in another parameter over time, the rate of change rate (Δ) was calculated as follows: Δ = (data at follow up – data at baseline) ÷ data at Baseline ÷ . The method described by Bland and Altman was used to assess interobserver variability [P-values of less than 0.05 were considered significant. Statistical analysis was performed using R software, version 3.2.2.Continuous variables are expressed as mean ± SD if normally distributed and otherwise as median and range. Categorical variables are given as counts and percentages of total. CMR parameters between left and right were compared using the Student’s iability . P-valuen = 23), insufficient data (n = 22), intravascular stents (n = 22), less than mild PR (n = 10), absent pulmonary valve syndrome (n = 8), status post pulmonary valve replacement (n = 3), significant pulmonary artery stenosis (n = 4), and dextrocardia (n = 1). Forty-eight studies were included in the analysis. Patient characteristics and the CMR results are summarized in Table 2). Mean RV ejection function was 48 ± 10 %. There were no patients with accidental significant pulmonary parenchymal issues, including lung hypoplasia, atelectasis, emphysema, or pleural effusion.One hundred seventy eight CMR studies were performed in 141 patients during a 29-month period. The first diagnostic study per patient was included. Patients were excluded because of RV-to-pulmonary artery conduit . Regurgigtant fraction was greater in the LPA than the RPA . There was no difference in regurgitant flow volume between the RPA and the LPA (p = 0.29). Right pulmonary artery CSA correlated with forward flow volume  and with regurgitant flow volume . Left pulmonary artery CSA correlated with regurgitant volume , but not with forward flow (p = 0.45).The flow data in the branch pulmonary arteries are summarized in Table R = 0.48, p < 0.001), and a trend towards a correlation with RPA RF was present  and there was a trend towards a correlation with LPA regurgitant volume .RVEDVi correlated with LPA RF , i.e. a larger RV was associated with an increased rotation of the heart to the left, and inversely with left lung area ratio . RVEDVi correlated with indexed left ventricular end-diastolic volume .RVEDVi correlated with α angle  and α angle   There was no correlation between left lung ratio and LPA forward flow (p = 0.09) or LPA regurgitant volume (p = 0.9). RPA flow parameters were independent of left lung ratio.Left lung ratio correlated inversely with LPA RF  and Δ left lung ratio . Δ RVEDVi correlated inversely with Δ left lung ratio . Δ LPA RF correlated with Δ RVEDVi , whereas it did not correlate with Δ left lung ratio nor Δ α angle. Δ RVEDVi did not correlate with Δ RPA RF.Out of 48 patients with a baseline CMR, 20 patients (40 %) had follow up CMRs at a mean interval of 4.4 ± 2.1 years without interim pulmonary valve or branch pulmonary artery interventions. There was no significant difference in RVEDVi, LPA RF, RPA RF, α angle and left lung ratio between baseline and follow-up. The change (Δ) of α angle correlated with Δ RVEDVi right ventricular enlargement and rotation of the heart lead to compression of the left lungandIn the present study, a smaller left lung area was associated with a greater RF in the LPA. Like any flow, pulmonary regurgitation is determined by a blood pressure gradient, in this case between the pulmonary artery and the RV during diastole. The majority of young patients after successful TOF repair can be assumed to have low RV diastolic pressures. Therefore, in the absence of pulmonary stenosis (which was an exclusion criterion in the present study), the primary determinant of diastolic flow reversal is the peripheral pressure in the lungs or, in the absence of shunts, the PVR . Indeed,If PVR is indeed elevated in patients after TOF repair, why should the left lung be more affected than the right lung? Vosar et al. , who als2), implying that there might be a threshold beyond which RV enlargement more significantly and directly impacts left lung volume. The mechanism of lung compression from enlarged hearts is well recognized in heart failure patients, in whom restrictive pulmonary physiology and reduced alveolar volume have been demonstrated [Progressive enlargement of the right ventricle is typical in patients after TOF repair as a result of PR, tricuspid regurgitation, and RV dysfunction , 8, 24. nstrated , 26. TheSeveral limitations of this study warrant mention: Firstly, a larger cohort size than the present one may have unveiled additional associations. Secondly, cross-sectional lung area in a single-plane axial image was used as a surrogate for lung volume because lung segmentation was not feasible from the available images. Thirdly, pulmonary vascular resistance was not calculated, as invasive pulmonary artery pressure measurements were not widely available for this cohort. However, in the absence of branch pulmonary artery obstruction, LPA and RPA pressures are (nearly) identical and differences in PVR between the right and left lung will be solely the result of differences in blood flow which we captured. Therefore, no additional insight would have been gained from PVR measurements in this setting.Based on the findings from the current and other studies the following scenario is plausible Fig. : Volume CMR, cardiovascular magnetic resonance; LPA, left pulmonary artery; MPA, main pulmonary artery; PR, pulmonary regurgitation; PVR, pulmonary vascular resistance; RF, regurgitant fraction; RPA, right pulmonary artery; RV, right ventricle; RVEDVi, indexed right ventricular end-diastolic volume; RVOT, right ventricular outflow tract; SSFP, steady state free precession; TOF, Tetralogy of Fallot.


Data relating high-sensitive troponin T (hs-cTnT) to long-term myocardial function and damage in patients after STEMI are lacking. We evaluated the use of serial and peak concentrations of hs-cTnT versus creatine kinase (CK), lactate dehydrogenase (LDH) and high sensitive C-reactive protein (hs-CRP) for prediction of myocardial function as well as infarct scar assessed by cardiac magnetic resonance imaging (CMR) one year after first ST-segment elevation myocardial infarction (STEMI).®). Other biomarkers were assessed using commercially available assays.Sixty-six patients receiving primary percutaneous coronary intervention (p-PCI) for first STEMI were enrolled in this single-centre, observational study. All participants underwent cine and contrast-enhanced CMR within the first week and 12 months after the index event. Serial biomarkers were determined on admission, 6 h, 12 h, 24 h, and 12 months following p-PCI. Hs-cTnT concentrations were measured by a fourth generation high-sensitive immunoassay   and infarct size (IS) . Peak CK , peak LDH , and peak hs-CRP  were also significantly related with CMR parameters . In receiver-operator characteristic analysis, peak hs-cTnT (AUC = 0.82 (0.71 - 0.92) and 0.89 (0.81 - 0.97), respectively) and peak LDH (AUC = 0.83 (0.74 - 0.93) and 0.91 (0.84 - 0.99), respectively) displayed the best performance for prediction of reduced LVEF  and large infarct size at follow-up . The combination of biomarkers did not significantly improve the predictive power of hs-cTnT alone (p > 0.05).In patients with first STEMI, peak concentrations of hs-cTnT are closely correlated to long-term myocardial function and infarct size. Maximum concentrations of CK, LDH, and hs-CRP were also correlated with 12-months LVEF and infarct size, but did not add any significant prognostic value compared to hs-cTnT alone.Austrian Society of Cardiology.


However, the current approach requires multiple breath-holds and can take nearly 10-15 minutes to complete. Faster acquisitions could potentially improve patient comfort and cost-effectiveness of CMR exams. the objecttive of this study is to develop and test a free-breathing, three-dimensional, cardiac MR approach which can yield fast, accurate, T2-prepared, three-dimensional gradient-echo acquisitions with different echo times  with near perfect navigator efficiency on a clinical 3T system. The proposed approach was tested and validated in ex-vivo porcine hearts, healthy volunteers and canines with reperfused acute myocardial infarction (rAMI). On the basis of the navigator signals, images were corrected for respiratory motion and were fit to a mono-exponential function to derive T2 maps of the whole left-ventricular myocardium.We developed an ECG-triggered, free-breathing, T2 values of the proposed approach (3D FB MoCo) were not different from standard 2D approaches : 48.7±0.9 ms (3D FB MoCo) vs. 48.2±0.6 ms (2D spin echo) and 47.5±0.8 ms (2D T2-prepared bSSFP (T2-prep bSSFP)). In healthy volunteers, compared to 3D FB MoCo and 2D BH, myocardial T2 maps, 3D FB Non-MoCo T2 myocardial maps showed longer T2 values (p<0.05), larger coefficient-of-variations (COV) in T2 (p<0.05), and lower image quality (p<0.05). Conversely, the mean and COV in myocardial T2 and image quality of 2D BH and 3D FB MoCo T2 were not different . In canines with rAMI, edema volumes measured from 2D BH and 3D FB MoCo T2 maps were closely correlated (both R2 = 0.97 and p<0.05). In Bland-Altman analysis, mean T2 of edematous and remote zones and edema volumes were within the limits of agreement (bias in T2 = 0.4 ms and edema volume = 0.9%).Ex-vivo myocardial T2 mapping approach at 3T enabled whole-heart acquisitions within 5 minutes with an accuracy in T2 not different from that of the state-of-the-art breath-held T2 mapping approach.The proposed free-breathing, three-dimensional TThis work was supported in part by National Heart, Lung, and Blood Institute HL091989 (R.D.).The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, And Blood Institute or the National Institutes of Health.


Patients who undergo right ventricular (RV) outflow augmentation inevitably develop RV remodeling due to pulmonary insufficiency-related volume overload (VOL). However, the reversibility of this remodeling is not fully understood. The goal of this study was to establish an animal model of VOL and unloading to characterize the functional and pathological characteristics and reversibility of RV remodeling.n = 8).VOL-RV was successfully induced by establishing direct RV-pulmonary artery (PA) bypass for 12 weeks in beagle canines. There were no procedure-related mortalities (n = 4 each). In addition, the bypass division also reversed the pathological changes seen in VOL-RV.The RV developed typical functional features of VOL-related remodeling, such as a significant increase in end-diastolic/systolic volume and end-systolic pressure and a significant reduction in ejection fraction at 12 weeks, as assessed by three-dimensional echocardiography and cardiac catheterization. The RV developed typical pathological signs of remodeling, microstructural disorganization of cardiomyocytes, and/or structural/functional deterioration of the mitochondria. Volume unloading by division of the RV-PA bypass reversed the increase in the end-systolic/diastolic volume over 4 weeks when compared with a sham operation (VOL-RV that yielded typical functional and pathological features of RV remodeling was reproducibly achieved by direct RV-PA bypass in canines. The RV remodeling due to VOL was functionally and pathologically reversed by volume unloading via the bypass division. Surgical augmentation of congenitally stenotic outflow of the right ventricle (RV) yields favorable clinical outcomes. However, most patients undergoing this procedure ultimately develop volume overload (VOL) of the RV due to pulmonary valve insufficiency . ProlongLeft ventricle (LV) VOL secondary to aortic valve insufficiency induces LV remodeling, in which cardiac fibroblasts are activated to modulate the extracellular matrix  and in wPulmonary valve replacement may also reverse the RV remodeling associated with pulmonary valve insufficiency . HoweverAnimal studies were performed with the approval of the institutional ethics committee. All protocols conformed to the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals .n = 8) were anesthetized with intravenous administration of propofol (2–4 mg/kg/h) after a intramuscular injection of xylazine (5 mg/kg) and followed by intubation and inhalation anesthesia with 1.5–2.5 % sevoflurane delivered through a volume-controlled respirator  with room air.A canine model of RV-pulmonary artery (PA) conduit bypass model was established to create RV volume overload without mechanical circulatory support Fig. a, b. UndA left thoracotomy was performed at the fourth intercostal space, and the main PA was carefully exposed. We modified the RV-PA technique using a 10-mm ring-enforced vascular graft consistent with the pulmonary trunk (PT) diameter . A pursen = 4) or sham operation  followed by intravenous infusion of potassium chloride (10 mmoL), and their hearts were promptly excised Fig. .Fig. 2StTransthoracic echocardiography was performed under inhalational anesthesia (1.5 % sevoflurane) to acquire short-axis and four-chamber views with the Intelligent Echocardiography System 33 . Real-time three-dimensional echocardiography was then performed using an X3-1 Matrix-Array probe  to visualize the RV from the four-chamber view. The three-dimensional RV images were then reconstructed  to calculate end-diastolic/systolic volumes (EDV/ESV) and ejection fraction (EF) . These cp/dt max/min . Subsequently, end-systolic/end-diastolic pressure–volume relationships (ESPVR/EDPVR) were measured by occluding the inferior vena cava [A conductance catheter  was placed in the RV apex through the main PA with animals under general anesthesia. A Millar 5 Fr pressure-tip catheter  was also placed in the RV cavity through the anterior wall. Pressure–volume loops and intracardiac electrocardiograms were monitored to measure end-systolic/diastolic pressure (ESP/EDP), heart rate (HR), and dena cava . Functio® . The RV free-wall and interventricular septum was promptly separated from the excised hearts and was blotted dry and weighed.Venous blood was collected every 4 weeks, and the plasma was promptly stored at −80 °C. N-terminal pro-brain natriuretic peptide (NT-pro BNP) level in the plasma was assessed by CardiopetThe excised RV free-wall tissue was fixed with 10 % formalin and embedded in paraffin, and cut into 5-μm-thick sections. Sections were stained with H&E to measure short-axis length of the RV cardiomyocytes in the ≥100 fields per slide, including endocardial, epicardial and mid layers, by ImageJ software. Sections were also stained with picro-sirius red. The percentage of red-stained area, corresponding to fibrotic area, was assessed using a computer-based method . The red4 at 4 °C for 3 h and dehydrated by dipping into a graded series of ethanol for 10 min each. Samples were then incubated in propylene oxide for 30 min, followed by incubation in a mixture of propylene oxide and epoxy resin for 1 h. They were subsequently embedded in a gelatin capsule with epoxy resin at 60 °C for 2 days. Ultrathin sections were stained with uranyl acetate and lead citrate .Tissue samples were fixed in 30 M 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer containing 2 % glutaraldehyde at 4 °C and were post-fixed in 2 % OsOSeven-micrometer-thick cryosections from the RV tissues were incubated with 0.1 mol/l Tris–HCl (pH 7.4), 10 mg/ml sodium succinate, 1 mg/ml Nitroblue tetrazolium and 25 μg/ml phenazine methosulfate at 37 °C for 30 min. Slides were rinsed in water and dehydrated with acetone for assessment under microscopy .RNA was extracted from the RV using the RNeasy Kit (Qiagen) and then was reverse-transcribed using Omniscript reverse transcriptase (Qiagen). Real-time PCR was performed for succinate dehydrogenase (SDH), cytochrome (Cyt)-C, mitochondrially encoded Nicotinamide adenine dinucleotide (NADH) dehydrogenase (mtND)1 and mitochondrially encoded Adenosine Triphosphate (ATP) synthase 6 (mtATP6) using the 7500 Fast real-time PCR system (Applied Biosystems). The quantities of the respective messenger RNAs (mRNAs) were normalized using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a control . p < 0.05 was considered to represent statistical significance.Data are expressed as the mean ± SEM. NT-pro BNP and echocardiographic data were analyzed by two-way repeated analysis of variance (ANOVA) for differences across the entire time course, and one-way ANOVA with the Turkey–Kramer post hoc test was used to verify the significance for specific comparison at each time point. Other data were assessed by the unpaired There were no procedure-related mortalities or morbidities for this operation. Doppler echocardiography detected blood flow through the bypass conduit in both the systolic and diastolic phases with competent pulmonary valve in all canines after the RV-PA bypass was established.Three-dimensional echocardiography showed a progressive increase in EDV and ESV and a progressive reduction of EF over 12 weeks Fig. a–c. Plasp < 0.05, Fig. p < 0.05, Fig. Size of the RV cardiomyocytes, assessed by H&E, was significantly greater in VOL-RV hearts when compared with normal hearts  group than in the overloading (O) group or relative to baseline values taken prior to bypass division (p = 0.24) but was significantly lower than that in the O group . Quantity of collagen in the RV interstitium was significantly less in the O–U group than in the O group .A large number of patients who undergo repair of RV outflow obstruction develop progressive RV failure due to pulmonary valve insufficiency-induced VOL . Howeverp/dt max, dp/dt min or Tau over the 12-week study period. These findings are consistent with those reported by Agger et al. [p/dt max or min, which represents systolic/diastolic function, was impaired in this model, possibly because these parameters are modulated by both contractile function and preloading conditions [In this study, we used three-dimensional echocardiography to assess RV volume and function, which correlated well with that by cardiac magnetic resonance in clinical practice . In the r et al.  who indur et al.  induced nditions . RVESP snditions .Plasma NT-pro BNP level is a sensitive indicator of RV function after TOF correction . In the The relationship between cardiac performance and histological/biochemical parameters in the VOL-RV has not been investigated, but reversibility of aortic insufficiency-induced LV failure correlates with recovery in the activity of mitochondrial enzymes, such as ATPase or SDH . InteresA volume-unloading intervention, such as pulmonary valve replacement, can functionally reverse RV remodeling in clinical practice, but the mechanisms underlying this process remain poorly understood. In this study, a volume-unloading intervention elicited recovery of systolic RV function over 4 weeks. Such immediate recovery of RV contractility after the unloading intervention may result from improvement in energy supply and improvement in the demand ratio associated with recovery of mitochondria. This functional recovery was associated with reverse pathological remodeling, including reversal of cardiomyocyte hypertrophy, interstitial fibrosis, and/or mitochondrial dysfunction. In addition, plasma NT-pro BNP levels decreased following volume unloading. These findings suggest that an optimally timed volume-unloading intervention might fully reverse VOL-induced RV remodeling.This study was limited by the use of an animal model and the small number of cases  in each VOL-RV induced by direct RV-PA bypass in canines reproducibly yielded typical functional and pathological features of RV remodeling, including hypertrophy of the RV cardiomyocytes, interstitial fibrosis and structural and functional deterioration of the mitochondria. The RV remodeling due to VOL was functionally and pathologically reversed by volume unloading via division of the bypass.


Precise assessment of left ventricular (LV) contractility during veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is crucial. However, changes in loading conditions may mask changes in LV function when assessed with load-dependent indices like LV ejection fraction (LVEF). Indeed, these indices do not reflect intrinsic LV contractility but are the result of interaction between preload, contractile function and afterload .The aim of this study was to show that precise assessment of LV function with a load-independent index is feasible during VA-ECMO.We used end-systolic elastance (Emax), which is the load-independent reference parameter corresponding to the maximum elastance of the left ventricle, to determine LV intrinsic contractility . We combEmax increased from 0.51 to 1.09 mmHg/mL, LVEF decreased from 17 to 14%, SV decreased from 27 to 20 mL and Ea increased from 2.63 to 4.45 mmHg/mL.While LVEF and SV decreased because of increased afterload, LV function assessed with Emax revealed an improvement in LV contractility. Emax is more reliable than LVEF to assess LV function when the loading conditions are changing. This load-independent parameter may be determined simply by using changes in VA-ECMO flow.Leon Fredericq Foundation of the University of Liège, Belgium