Post-implantation therapies to optimize cardiac resynchronization therapy (CRT) focus on adjustments of the atrio-ventricular (AV) delay and ventricular-to-ventricular (VV) interval. However, there is little consensus on how to achieve best resynchronization with these parameters. The aim of this study was to examine a novel combination of doppler echocardiography (DE) and three-dimensional echocardiography (3DE) for individualized optimization of device based AV delays and VV intervals compared to empiric programming.25 recipients of CRT  were included in this study. Ejection fraction (EF), the primary outcome parameter, and left ventricular (LV) dimensions were evaluated by 3DE before CRT (baseline), after AV delay optimization while pacing the ventricles simultaneously  and after individualized VV interval optimization. For AV delay optimization aortic velocity time integral (AoVTI) was examined in eight different AV delays, and the AV delay with the highest AoVTI was programmed. For individualized VV interval optimization 3DE full-volume datasets of the left ventricle were obtained and analyzed to derive a systolic dyssynchrony index (SDI), calculated from the dispersion of time to minimal regional volume for all 16 LV segments. Consecutively, SDI was evaluated in six different VV intervals (including LV or right ventricular preactivation), and the VV interval with the lowest SDI was programmed .EF increased from baseline 23±7% to 30±8 (p<0.001) after AV delay optimization and to 32±8% (p<0.05) after individualized optimization with an associated decrease of end-systolic volume from a baseline of 138±60 ml to 115±42 ml (p<0.001). Moreover, individualized optimization significantly reduced SDI from a baseline of 14.3±5.5% to 6.1±2.6% (p<0.001).Compared with empiric programming of biventricular pacemakers, individualized echocardiographic optimization with the integration of 3-dimensional indices into the optimization protocol acutely improved LV systolic function and decreased ESV and can be used to select the optimal AV delay and VV interval in CRT. Despite progress in the treatment of heart failure the five year mortality still remains over 50% Several studies showed that increased scar burden, especially in the postero-lateral LV segments, the preferred region of the LV lead positioning, may lead to suboptimal clinical outcome In the clinical setting programming of CRT systems is frequently done empirically In small studies it has been shown that optimized programming of the AV delay leads to improved hemodynamics, as well as to improved symptomatic response and LV systolic function in the short and the longer term There are scarce studies that evaluated the effect of a combined approach of AV delay and VV interval optimization The AV delay may be optimized with Doppler echocardiography by evaluating the aortic velocity time integral (AoVTI), which serves as a surrogate for LV stroke volume In the present study we therefore evaluated the feasibility of three-dimensional echocardiography (3DE) to optimize the inter-ventricular interval of biventricular pacemakers.All patients included in this study gave written informed consent prior to entry into the study. The study complies with the principles of the Declaration of Helsinki and was approved by the institutional ethics committee of Deutsches Herzzentrum München, Technical University of Munich, the only institution, where participants were recruited and this study was conducted .In this study we prospectively included patients who underwent CRT implantation according to 2006 guidelines Routine baseline 2D and 3D echocardiography (Philips iE33) were performed in all patients according to institutional guidelines. 3D echocardiography was performed using the X3-1 matrix transducer. Apical views were optimized to allow complete visualization of the left ventricle in the 4- and 2-chamber views. During breath-hold a complete 3D volume was acquired during 7 to 8 cardiac cycles. Angle and depth were minimized to ensure optimal temporal resolution while still acquiring the entire LV volume. The volume data were sent to a workstation for off-line processing and analysis , using the 3DQ-Advanced plugin. The software allows semi-automated delineation of end-systolic and end-diastolic endocardial borders . ThroughEchocardiographic guided optimization of the CRT device was performed the day after implantation. First, AV delays were analyzed from 80 to 200 ms, with steps of 20 ms. Aortic flow was recorded as a velocity-time integral (AoVTI) using continuous-wave Doppler at the level of the aortic valve, according to the consensus statement of the American Society of Echocardiography All continuous variables are expressed as mean ± standard deviation. Presence of a normal distribution was evaluated by Kolmogorov-Smirnov test, means were compared by paired t-test. Where a non-parametric distribution was assumed, Wilcoxon test was performed. Categorical variables were tested by the chi-square test. To assess intra- and inter-observer variabilities, intra-class correlations (ICC) were calculated, and the variability is expressed as the absolute difference between 2 measurements divided by the average of the 2 measurements. Resulting p-values<0.05 were considered statistically significant.A total of 25 patients were included in the study. The mean age was 67 years with 56% males . 56% hadFor AV delay optimization aortic velocity time integral (AoVTI) was examined in eight different AV delays, and the AV delay with the highest AoVTI was programmed. Aortic flow increased from baseline 24±7 cm to 27±9 cm after AV delay optimization (p<0.05). The optimal mean sensed AV delay programmed was 108 ms [80–140 ms] and the optimal paced AV delay programmed was 133 ms [120–140 ms]. The SDI improved significantly from 14.3±5.5% to 9.0±4.6%, as well as the EF, which rose from a baseline value of 23±7% to 30±8% after AV delay optimization .After AV delay optimization, the VV intervals were analyzed by evaluating the 3D full volume datasets. For each VV interval a separate 3D dataset was analyzed. The VV interval with the lowest corresponding SDI was used for programming the device.We observed a further decrease in SDI values from 9.0±4.6% to 6.1±2.6% . In mostOnly 28% of patients achieved the lowest possible SDI with the standard setting of simultaneous activation of left and right ventricle. 86% of patients with ischemic cardiomyopathy needed pre-activation versus only 55% of patients with dilated cardiomyopathy p<0.05, .The intra- and inter-observer agreement was generally very good.Intra-observer variability in measured SDI was 14±8%. Intra-observer variability in ejection fraction, end-diastolic volume, and end-systolic volume was 3±2%, 2±2%, and 3±3%, respectively. Intra-class correlation coefficients were 0.974 for SDI, 0.997 for EF, 0.998 for EDV and 0.998 for ESV.Inter-observer variability in measured SDI was 17±14%. Inter-observer variability in ejection fraction, end-diastolic volume, and end-systolic volume was 8±6%, 3±4%, and 4±3%, respectively. Intra-class correlation coefficients were 0.948 for SDI, 0.981 for EF, 0.997 for EDV and 0.996 for ESV.In the present study we tested a new protocol of combined AV delay and VV interval optimization of CRT-systems including standard Doppler-echocardiography for AV delay, and 3D echocardiography for VV interval optimization. This elaborate protocol led to a significant improvement of LV function immediately after implantation of a CRT device compared to empiric device programming. The examined cohort existed of typical candidates for cardiac resynchronization therapy. All were highly symptomatic and on recommended optimal pharmacological therapy. Moreover, all patients showed QRS prolongation of more than 120 ms, and had a mean ejection fraction of 23%.After the first step of optimization (AV delay optimization) the ejection fraction rose from 23% to 30% and could be increased even further by VV interval optimization (32%). End-systolic volume was reduced significantly already after AV delay optimization, with a moderate further reduction after VV interval optimization. The SDI, as a marker of interventricular dyssynchrony, fell sharply after each optimization step, whereas the aortic VTI, a surrogate marker of stroke volume, was only affected by AV delay optimization. In most patients the VV interval had to be programmed differently from the standard setting (i.e. simultaneous activation of left and right ventricle), only 28% of patients achieved the lowest possible SDI with the standard setting of simultaneous activation of left and right ventricle.These results strongly support an individualized optimization of CRT-systems, specifically tailored to the patients. CRT is used in patients with several etiologies of severely symptomatic heart failure This is the first study to use 3DE for VV interval optimization. The only modest further improvement of LV-EF after VV interval optimization in addition to AV optimization was lower than anticipated. Nevertheless, the pronounced decrease of the systolic dyssynchrony index (SDI) with each optimization step was striking and may lead to further improvement of LV-EF in the long-term. It is also known from a small study by Valzania et al. The positive acute results are especially encouraging as LV resynchronization acutely after the implantation of biventricular pacemakers predicts response to CRT in the long-term Furthermore, AV delay optimization can maximize the benefits of cardiac resynchronization therapy. If programmed poorly, it may curtail beneficial effects of VV interval optimization and of CRT in general. Optimized AV synchrony is achieved by an AV delay that provides the best left atrial contribution to LV filling resulting in maximum stroke volume. Several echocardiographic methods have been used for AV delay optimization VV interval optimization has been attempted with several techniques with varying success The SDI seems to be a promising parameter for VV interval optimization, as it may help to overcome the problems arising from LV-lead latency and from slowed conduction due to increased scar burden in patients with ischemic cardiomyopathy Although this optimization technique is more sophisticated and thus slightly more time consuming as compared to traditional echocardiographic optimization protocols due to offline analysis, it can be easily integrated into the usual workflow of post-operative CRT treatment in a patient with a hospital stay of 3 to 4 days. Images can be obtained postoperatively, AV delay programmed immediately and VV interval programmed after offline analysis before discharge from the hospital.Several limitations apply to our study. This was a small study to evaluate a new concept of optimized resynchronization therapy. There was no control group in this study. Moreover no assumptions regarding the long-term benefit can be made. This has to be addressed in an adequately powered, prospective trial. The resolution of most 3D ultrasound scanners is still reduced compared to standard 2D technology. Especially, temporal resolution is still a major issue, leading to high variability of the measurements. This could hamper the analysis of small-scale variations of ventricular dyssynchrony and could thus influence the parameter setting with respect to the VV synchronization. Future technical improvements of 3D scanners might improve temporal as well as spatial resolution and lead to more reliable results.In the present study we could demonstrate, that an individualized echocardiographic optimization with the integration of 3-dimensional indices into the optimization protocol significantly improves LV function in CRT compared to empiric VV interval programming. This novel individualized echocardiographic optimization protocol can be used to select the optimal AV delay and VV interval in CRT.


Current data challenge the concept that pulmonary arterial hypertension (PAH) is purely a disorder of impaired vasomotor tone. Instead, we recognise today that the phenotype of PAH represents the complex and disordered regulation of expression of key signalling molecules and abnormal molecular trafficking. Discovery of mutations of the ubiquitous receptors of the transforming growth factor beta (TGF-β) superfamily in many patients with PAH has been instrumental in unravelling the pathobiology of this otherwise fatal disorder. Much still needs to be learnt before we are able to substantially alter the natural history of PAH. Until such time, therapies that fundamentally attempt to restore vasomotor tone continue to be developed and tested.Current clinical research in the therapeutic arena is focused on defining the best permutation of the three major groups of drugs – prostacyclin analogues, phosphodiesterase type-five inhibitors and the endothelin receptor antagonists. However, if we are to make any significant impact on the otherwise dismal outcome of PAH, we have to recognise that even more important than the challenge of new therapies, is the challenge in diagnosing the condition early in the course of its relentless progression to right heart failure and eventual death. Since the first recorded description of pulmonary arterial hypertension by Romberg in 1891,54 count or viral load, and does not appear to be responsive to highly active anti-retroviral therapy. Secondly, as in many countries elsewhere, an advocacy group is sorely required here to promote all aspects of the diagnosis and therapy of PAH and importantly, to lobby funders not to shirk their responsibility toward the management of this small but desperate group of patients.An increased awareness of PH in South Africa is particularly important for several reasons, all of which have served as an impetus for the formation of the Pulmonary Hypertension Interest Group. Firstly, there is reason to believe that PH in general is a prevalent condition in this country. Apart from the frequent contribution of valvular heart disease, cardiomyopathy and congenital heart disease, missed at the time of birth and during infancy, to the overall burden of PH, preliminary data from elsewhere suggest that retroviral infection may now be the leading cause. The incidence of PAH in cohorts of patients with HIV is estimated at about 0.5%.PAH is a disease of the pre-capillary pulmonary arterial bed, including the medium-sized pulmonary arteries and pulmonary arterioles characterised by vascular obliteration. Current knowledge implicates unchecked proliferation of smooth muscle cells and dysregulated control of endothelial cells with apoptosis and dysfunction in some areas and profuse proliferation in others.Plexiform arteriopathy 5While pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis share some features in common with other causes of PAH, they are pathologically distinct and have been included in a separate category termed 1′ by the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines.3The complexity of receptor activation, signalling molecules and downstream pathways with cross-talk at different levels between these makes it unfortunately difficult to pinpoint a precise mechanism for PAH 7TGF-β receptors together with their ligands (proteins that bind to the receptor) control diverse processes involved in vascular remodelling, including among others, cell proliferation and apoptosis, cellular differentiation, and collagen and extracellular matrix turnover. These are all processes that are fundamentally involved in PAH but the precise link between the genotype and the expression of the pulmonary hypertensive phenotype remain elusive.According to the current hypothesis, a loss-of-function mutation in the BMPR2 receptor results in an imbalance in the equilibrium between the opposing effects of TGF-β and BMP signalling, which in the smooth muscle cell (SMC) favours a pro-proliferative and anti-apoptotic response but in the case of the endothelial cell (EC), has an anti-proliferative and pro-apoptotic effect 8Although PAH is optimally defined on pathology, this is rarely possible except post-mortem. From a haemodynamic perspective, pulmonary vascular resistance is the best measure of the resistance of the pulmonary circulation to flow but this in general requires invasive cardiac catheterisation, which is inappropriate as a screening test. Therefore an estimate of pulmonary artery pressure forms the starting point for diagnosis of PH.The time-honoured clinical methods, including a left parasternal heave, palpable P2, pulmonary ejection click and narrow A2-P2 split are important, as are the ECG showing P-pulmonale, right-axis deviation and a tall R in V1 and chest X-ray with characteristic dilatation of the proximal pulmonary arteries and attenuation of distal third of the vasculature. However, echo-Doppler is an easily available, inexpensive and non-invasive way of obtaining a comprehensive assessment of pulmonary haemodynamics and is recommended as the initial investigation of choice in most guidelines.3Apart from measuring pulmonary artery systolic and diastolic pressure from the tricuspid and pulmonary regurgitant jets, respectively, echocardiography allows exclusion of left heart pathology and congenital shunts as possible aetiologies. Additionally, right ventricular size and function, which have important prognostic value, may be derived using a variety of indices. The echocardiographic definition of PH is a pulmonary artery systolic pressure greater than 40 mmHg.Once suspected, a series of investigations should be undertaken The classification of PH has undergone a series of modifications since the original description endorsed by the WHO in 1973, with the latest proposal published from a symposium held in Dana Point, California.Despite advances in non-invasive imaging, including echocardiography, CT and MRI, invasive left and right heart catheterisation is imperative to confirm pulmonary hypertension, rule out passive (category 2) aetiologies and intra-cardiac shunts, assess for acute vaso-reactivity and for prognostication purposes. Pulmonary angiography is not routinely necessary but may be useful to exclude thrombo-embolic disease, vasculitis and peripheral pulmonary artery stenosis.The haemodynamic definition of PAH is a mean pulmonary artery pressure greater than 25 mmHg at rest or 30 mmHg with exercise, with a pulmonary capillary wedge pressure or left ventricular end-diastolic pressure less than 15 mmHg and a pulmonary vascular resistance greater than 3 ru. When there are marked respiratory variations in wedge pressure, values should be measured at end-expiration.Oxygen and inhaled nitric oxide (10–30 ppm) are the most useful agents for acute vaso-reactivity testing in the catheterisation laboratory. Inhaled nitric oxide has the advantage that it acts selectively on the pulmonary circulation, since it is rapidly inactivated by haemoglobin on entry into the blood stream and it does not cause ventilation–perfusion mismatch because it is only distributed to lung segments that are normally ventilated.Only 5 to 10% of patients subjected to vaso-reactivity testing are classified as responders, variously defined as an absolute reduction in mean pressure greater than 10 mmHg to a mean value less than 40 mmHg, or a greater-than 20% reduction in mean pressure and pulmonary vascular resistance.9General measures for patients with PAH include limitation of physical effort, vaccination against influenza and home oxygen for hypoxic individuals. Although not supported by rigorous evidence, prophylactic warfarin anticoagulation, diuretics for those with systemic venous congestion and digitalis for right ventricular dysfunction may be appropriate. Women of child-bearing age should be strongly discouraged from falling pregnant since maternal mortality is in excess of 50%, and should utilise appropriate techniques for contraception.Patients identified as acute responders on vaso-reactivity testing benefit from high-dose dihydropyridine calcium antagonists but should be monitored closely since about one-half may relapse in the long term. Empirical use of calcium antagonists without vaso-reactivity testing, a practice that is not infrequent, should be strongly discouraged.Current therapy specifically targeted at PAH comprises the prostanoids, endothelin antagonists and phosphodiesterase type-5 inhibitors. The prostanoids may be administered intravenously , subcutaneously (trepostinil), by inhalation (iloprost) or orally (beraprost). Endothelin antagonists may cause non-specific blockade of both the type A and B receptor (bosentan) or selective inhibition of the type A receptor (sitexantan and ambrisentan). The phosphodiesterase type-5 inhibitors  increase nitric oxide availability by inhibiting the breakdown of the second messenger, cyclic guanosine monophosphate. For a more detailed account of these drugs the reader is referred to a recent review,Based on published evidence, all class 4 patients should receive intravenous epoprostenol, since this is the only therapy that has demonstrated a survival benefit in patients with PAH.Patients refractory to medical therapy and with advanced symptoms may be considered for balloon atrial septostomy or lung transplantation. The rationale of creating a right-to-left shunt percutaneously is based on the fact that patients with Eisenmengers syndrome have a much better survival than other groups of PAH, perhaps because of the possibility of unloading the right ventricle and increasing systemic blood flow, even though this may be at the expense of desaturated blood.The still-dismal outcome of patients with PAH has stimulated intense and exciting avenues of research into new therapies that would hopefully reverse the pulmonary hypertensive phenotype. As we delve deeper into the pathobiology of PAH, we increasingly realise the complexity of pathways involved in vascular remodelling. While many new approaches have shown promise at the bench side and in the monocrotaline-induced rat model of PAH, these remain to be tested in the clinical arena.Inhibition of TGF-β receptors with antibodies or losartan, statins which increase BMPR2 gene promoter function, inhibition of tyrosine kinase, which is an important mediator of cellular proliferation and migration, with drugs such as imatinib, and alteration of intracellular signalling via the SMAD pathway are but a few examples of potential therapeutic targets. Since right ventricular function may be an even more robust predictor of outcomes than the actual level of pulmonary pressure, more detailed study of right ventricular remodelling and the molecular determinants of hypertrophy and failure of this chamber are also crucial.In the not-too-distant future, we may be able to provide our patients with PAH with a cure. Until such time, however, it behoves us as clinicians to always consider the possibility of PAH, institute a diligent workup to make a precise diagnosis and assessment of severity and reversibility, and do all we can to make available potential therapies to this desperate group of patients.


To compare the efficacy of two quantitative methods for discrimination between benign and malignant focal liver lesions (FLLs): apparent diffusion coefficient (ADC) values and T2 relaxation times.b = 50, 400, 800) and dual-echo T2TSE . ADC values and T2 relaxation times of FLLs were calculated. Sensitivity, specificity and accuracy of both techniques in diagnosing malignancy were assessed.Seventy-three patients with 215 confirmed FLLs  underwent 1.5-T MRI with respiratory-triggered single-shot SE DWI (−3 mm2/s) was significantly lower (P < 0.05) than that of benign lesions (1.86 × 10−3 mm2/s ); however, with the use of the optimal cut-off value of 1.25 × 10−3 mm2/s, 20 false positive (FP) and 20 false negative (FN) diagnoses of malignancy were noted, generating 79 % sensitivity, 82.6 % specificity and 80.9 % accuracy. The mean T2 relaxation time of malignant tumours (64.4 ms) was significantly lower (P < 0.05) than that of benign lesions (476.1 ms). At the threshold of 107 ms 22 FP and 1 FN diagnoses were noted; the sensitivity was 99 %, specificity 80.9 % and accuracy 89.3 %.The mean ADC value of malignant tumours (1.07 × 10Quantitative analysis of T2 relaxation times yielded significantly higher sensitivity and accuracy in diagnosing malignant liver tumour than ADC values.Diffusion-weighted magnetic resonance imaging is increasingly used for liver lesions.• But ADC values demonstrated only moderate accuracy for differentiation of liver lesions.• T2 relaxation times yielded higher accuracy in diagnosing malignant liver tumours.• Both ADC and T2 values overlapped between focal nodular hyperplasia and malignant lesions.• Nevertheless T2 liver mapping could be valuable for evaluating focal liver lesions.•  During the past decade magnetic resonance imaging (MRI) has emerged as the leading modality for the detection, characterisation and preoperative assessment of focal liver lesions (FLLs) –7. AdvanResearchers recently investigated the efficacy of DW imaging based on quantitative analysis of apparent diffusion coefficient (ADC) values of liver lesions to differentiate between benign and malignant lesions –21. The Before the implementation of DW MR liver imaging, another quantitative method based on calculation of T2 relaxation times of FLLs was used for the characterisation of liver tumours by several investigators –33. AnalTo our knowledge, there are no published studies comparing ADC values obtained with DW MR imaging and T2 relaxation times for the differentiation of liver lesions. Thus, the purpose of this study was to compare the accuracy of two quantitative techniques for the characterisation of focal liver lesions: evaluation of ADC values based on the SE EPI sequence and assessment of T2 relaxation times derived from the double-echo TSE sequence.From May 2008 to January 2010, 125 patients underwent MR imaging of the liver at our institution. The MRI studies were conducted according to our routine liver protocol, which included respiratory-triggered diffusion-weighted single-shot echo-planar imaging (DW-SS-EPI) and dual-echo turbo spin-echo sequence. Fifty-two patients were excluded from our analysis due to (1) lack of sufficient data to confirm the nature of the lesions, (2) no focal liver lesion detected on MR imaging or (3) small size of FLLs detected on MR imaging (maximum diameter less than 5 mm). Thus, the study group comprised 73 patients  with a mean age of 54.2 years (age range 18–84 years). Six patients had liver cirrhosis. In one patient with hepatocellular carcinoma there was no evidence of hepatic cirrhosis. One patient underwent right hemihepatectomy for treatment of liver metastases before MR imaging; another underwent hepatic segmentectomy due to HCC before MR. Three patients had previously been treated with chemotherapy, although not within the year before MR.Hepatic lesions were solitary in 19 patients and multiple in 54 patients. In 24 patients only malignant liver lesions were detected, in 7 patients both malignant and benign lesions were diagnosed and the remaining 42 patients had only benign lesions, although 8 of them had more than one type of benign lesion. In patients with multiple lesions, a maximum of 5 lesions per patient were selected for analysis .n = 20), neuroendocrine carcinoma (n = 20), pancreatic adenocarcinoma (n = 16), gallbladder carcinoma (n = 5), lung cancer (n = 3) and sarcoma (n = 1).A total of 215 hepatic lesions were evaluated  comprising 47 haemangiomas, 42 cysts, 13 FNHs, 12 abscesses, 1 biliary cystadenoma, 65 metastases, 19 hepatocellular carcinomas (HCCs), 13 haemangioendotheliomas, 2 peripheral cholangiocarcinomas (CCAs) and 1 biliary cystadenocarcinoma. The primary sites of metastatic lesions included colorectal carcinoma (In 36 of 73 patients (49 %) the reference standard for the diagnosis was histopathologic proof obtained intra-operatively in 12 patients  and from biopsy in 24 patients . In the remaining 37 patients no histological proof was obtained and the final diagnosis was based on results of previous imaging studies and the follow-up with a minimum of 6 months’ observation period , laboratory tests and clinical data.Magnetic resonance imaging was performed on a 1.5-T system , using a phased-array multicoil system (12 elements).Analysed breath-hold dual-echo T2-weighted TSE images and DW-SS-EPI were part of our routine liver imaging protocol, which consisted of the respiratory-triggered T2-weighted TSE sequence with fat saturation, the breath-hold in- and out-of-phase spoiled gradient dual-echo sequence, and a dynamic contrast-enhanced 3D gradient-echo volumetric interpolated breath-hold examination (VIBE) sequence, performed during arterial, portal venous, equilibrium and delayed phases and in hepato-biliary phase (after injection of gadobenate dimeglumine).b values of 50, 400 and 800 s/mm2.Diffusion-weighted images were acquired using the SE single-shot echo-planar sequence in the axial plane with respiratory triggering. Integrated parallel imaging technique (iPAT) with generalised autocalibrating partially parallel acquisition (GRAPPA) and an acceleration factor of 2 was applied. The other parameters were as follows: repetition time (TR) 1,700 ms, TE 90 ms, flip angle 90°, EPI factor 120, slice thickness 6 mm, 120 × 192 matrix, 2 acquisitions, field of view 344 mm, bandwidth 1,736 Hz/pixel, spectral fat suppression. Diffusion gradients were applied in three orthogonal directions separately with three increasing The breath-hold dual-echo TSE sequence was performed in the axial plane with repetition time (TR) 1,800 ms, first effective TE (TEeff) 84 ms, second TEeff 228 ms, flip angle 150°, turbo factor 29, slice thickness 6 mm, 207 × 256 matrix, 1 acquisition, acceleration factor of 2, field of view 340 mm, bandwidth 260 Hz/pixel.ADC measurements were performed on a commercial workstation  by drawing regions of interest (ROIs) on DWI images, which provided the best delineation of analysed liver lesions. The ROI included the largest possible part of the lesion, avoiding partial volume effects, areas of necrosis, blood vessels and artefacts. Then the ROI was copied and pasted from the DWI image to the corresponding ADC map and the measurement on ADC map was recorded. The ADC was measured twice for each lesion and the two measurements were averaged.S = S0 exp(−b ADC), where S is the signal intensity after application of the diffusion gradient and S0 is the signal intensity at b = 0 s/mm2. Three b values  were applied for ADC calculation.ADC values were calculated by mono-exponential regression with following formula: On dual-echo T2-weighted TSE images signal intensities (SI) of all analysed lesions were measured, separately for each echo time . Two measurements of SI of each lesion were performed and the mean values were used for calculation of the T2 relaxation time. If the lesion consisted of solid and liquid parts, measurements (ROIs) were confined to its solid component, just as in ADC measurements.K exp−(TE/T2), where K is a machine-dependent constant [Assuming that TR is much greater than T1, the standard equation for SE signal intensity may be simplified to SI = constant . Therefoconstant .T2 relaxation times of liver lesions were calculated according to the following formula:The statistical analysis was performed using Statistica software (version 10.0).U test was applied to assess statistically significant differences between the mean ADC values and between mean T2 relaxation times of benign and malignant focal liver lesions. This test was also used to assess statistically significant differences between lesions’ sizes in selected groups.The Mann–Whitney 2 test was used to compare sensitivities, specificities, accuracies, positive predictive values (PPV) and negative predictive values (NPV) of both quantitative techniques implemented for differentiation of FLLs. A P value of less than 0.05 was considered significant.The χA receiver operating characteristic (ROC) curve analysis was implemented to define ADC and T2 cut-off values for the optimal differentiation of benign and malignant liver lesions.The accuracy of each MR technique (ADC versus T2 relaxation times) was determined by calculating the area under the ROC curve (AUC). The differences between ROC curves were tested for significance.Mean ADC values and mean T2 relaxation times of analysed benign and malignant hepatic lesions are shown in Table −3 mm2/s, ranging from 0.74 × 10−3 to 2.2 × 10−3 mm2/s, whereas the mean ADC value of benign FLLs was 1.86 × 10−3 mm2/s, ranging from 0.67 × 10−3 to 3.22 × 10−3 mm2/s . The calculated area under the ROC curve for diagnosing malignant lesion was 0.874 , with a sensitivity of 79 % and a specificity of 82.6 %, using a cut-off ADC value of 1.25 × 10−3 mm2/s.The mean ADC value of malignant FLLs was 1.07 × 10P < 0.001; Fig. P < 0.001) than the area under the ROC curve for ADC values  vs. 476.06 ms  and the difference was statistically significant  at optimal threshold values are summarised in Table P < 0.001), accuracy (P = 0.015) and NPV (P < 0.001) for diagnosing a malignant lesion than the use of ADC values, whereas the differences in specificity (P = 0.64) and PPV (P = 0.59) were not statistically significant.Analysis of T2 relaxation times yielded significantly higher sensitivity , colorectal carcinoma (n = 3) and sarcoma (n = 1).With the use of ADC values 20 false positive diagnoses of malignant lesions  and 21 false negative cases  were noted Figs. , 5 and 6P < 0.05) than the mean size of all studied haemangiomas (19.8 mm). Four out of 8 misclassified haemangiomas were smaller or equal to 8 mm, whereas the remaining lesions ranged from 13 to 21 mm  and only one false negative case (biliary cystadenocarcinoma). No metastatic lesion or HCC was misclassified with the use of this technique. In total, quantitative analysis of T2 relaxation times led to 23 hepatic lesion misclassifications, including all examined FNHs. The mean size of 8 haemangiomas falsely diagnosed as malignant (12.3 mm) was significantly smaller P < 0.0 than theSeveral groups of researchers have published promising results regarding the implementation of DW MR imaging for the detection , 34–40 a−3 to 1.63 × 10−3 mm2/s have been proposed for the optimal differentiation of benign and malignant lesions [−3 mm2/s). There are several possible reasons explaining this difference, including the use of different hardware, absence of standardization of image acquisition , various methods for ADC calculation and different patient populations.Given the limitations of visual assessment, quantitative analysis based on ADC values of FLLs has been proposed for the discrimination of benign from malignant lesions , 18–21.  lesions –14. In tb values  and the method for ADC calculation  have important implications for the calculated ADC values. For instance, application of a two-point mono-exponential regression with low b values (including b = 0 s/mm2) results in the overestimation of ADC  owing to the incorporated effect of perfusion [b values  is lower and probably more reliable [b values than in the majority of prior studies and omitted the lowest b value of 0, leading to some decrease of the perfusion effect. Such a choice of parameters resulted in lower mean ADC values being obtained for liver lesions and a lower ADC cut-off for differentiation of FLLs.The choice of erfusion , 41, 42.reliable , 42. TheThe patient population also has important implications for the performance of ADC quantification in FLL characterisation. The best results were obtained by investigators who studied patients with no or a small number of solid benign tumours  and abscesses, which often have ADC values in the range of those of malignant lesions , 13. GouIn the current study we attempted to compare the performance of DW MRI with T2-weighted TSE imaging for the discrimination between benign and malignant lesions. Previously such comparisons were performed, but only by applying qualitative, visual assessment of FLLs on T2-weighted images , 15. As In the past T2 quantifications were successfully applied by several groups using different techniques of image acquisition, including conventional SE, moderately T2-weighted TSE, heavily T2-weighted TSE and T2 EPI sequences with a varied number of echoes utilized for T2 calculations –33. GoldIn our comparative study of two quantitative techniques, the sensitivity for the diagnosis of malignant lesions was significantly higher with the use of T2 values (99 %) than with ADC values (79 %). Implementation of T2 times led to only a single false negative diagnosis of malignancy (cystadenocarcinoma), whereas ADC quantification resulted in 21 such cases . Slightly more numerous false positive diagnoses of malignant lesions were noted with analysis of T2 relaxation times than with ADC values (22 vs. 20) leading to better specificity of ADC quantification (82.6 % vs. 80.9 %). Moreover, 13 FNHs , which accounted for most of the 23 misclassified hepatic lesions by T2 quantifications, had typical appearance on contrast-enhanced images. Therefore, the combined evaluation of all obtained MR images would lead to the correct diagnosis in these cases.Beside FNHs, the majority of remaining false positive cases of malignancy for T2 calculations were 8 haemangiomas Fig. . Their mb values ; therefore, calculated ACD values are approximate. The inclusion of more b values would probably lead to more accurate ADC calculation, however at the expense of prolonged examination time. Secondly, mono-exponential regression using three b values  was implemented for ADC calculations. The ADC value depends not only on diffusion but also incorporates the effect of perfusion and signal attenuation is bi-exponential with DW imaging. We cannot exclude that application of a bi-exponential model using more b values for ADC calculation would result in obtaining more reliable ADC values. Thirdly, we implemented only two echoes in the T2-weighted TSE sequence. Inclusion of more echoes would probably lead to more accurate estimation of T2 relaxation times of FLLs, but at the expense of extended imaging time. Fourthly, the composition of our study population did not fully represent the typical spectrum of liver lesions, including 13 haemangioendotheliomas and lacking adenomas. Finally, histopathological proof was not available in 37 of 73 patients (51 %), although it was obtained in all patients with malignant lesions.Several limitations of this study should be mentioned. Firstly, we applied only three The results of our study confirm that the DWI technique with ADC quantification has potential in the differentiation of FLLs. However, in this first published comparison of two quantitative techniques  for characterisation of FLLs, T2 values yielded significantly higher sensitivity for diagnosing malignant lesions than ADC values. It is at variance with the results of previous publications comparing DW MRI with T2-weighted TSE imaging, although in these studies only qualitative assessment of T2-weighted images was employed , 15.Compared with assessment of ADC values on ADC maps, generated automatically on a commercial workstation, analysis of T2 times of FLLs was not that simple and required separate, manual drawing of ROIs on images acquired with different TEs and then transferring all data to a PC to obtain T2 values using a commercial calculation sheet . In our opinion, inclusion of multiple-echo T2-weighted TSE sequences in MR protocols dedicated for liver imaging, along with automatically generated T2 maps on commercial MR consoles (similarly to ADC maps or T2 mapping used for assessment of articular cartilage), should be considered by MR vendors. We presume that it would provide important quantitative data, helpful in the differentiation of FLLs.Despite the usefulness of T2 and ADC quantification for the differentiation of FLLs, some pitfalls of these techniques must be kept in mind. There is substantial overlap between highly cellular, solid benign lesions, such as FNH, HCA and malignant tumours  on both DW and T2-weighted TSE images. Moreover, some abscesses, due to cellular debris and exudates, may also display restricted diffusion. Therefore, DW and T2-weighted images should be used as complementary methods for the characterisation of FLLs, in conjunction with clinical context and pre- and post-contrast T1-weighted scans, including dynamic and hepatobiliary phase images. In our material the most important advantage of T2 quantification over ADC values was the more confident characterisation of metastatic lesions, abscesses and haemangioendotheliomas.In conclusion, comparison of the two quantitative methods used for the characterisation of FLLs demonstrated significantly higher sensitivity and accuracy of T2 relaxation times than ADC values  for diagnosing hepatic malignancy. Inclusion of multiple-echo T2-weighted TSE sequences in MRI liver protocols together with T2 mapping of the liver on MR consoles may be an additional valuable tool facilitating the discrimination of malignant and benign hepatic lesions.


Desmin-related myopathy (DRM) is known to cause different types of cardiomyopathy. Late gadolinium enhancement cardiovascular magnetic resonance (CMR) has been shown to identify fibrosis in ischemic and non-ischemic cardiomyopathies. We present a rare case of desmin-related hypertrophic cardiomyopathy, CMR revealed fibrosis in the lateral wall of the left ventricle. CMR is superior to conventional echocardiography for the detection of myocardial fibrosis in desmin-related cardiomyopathy, which may be useful to detect early cardiac involvement and predict the patient prognosis. Desmin is a primary element of the intermediate filament network in skeletal, cardiac and smooth muscle cells. Desmin-related myopathy (DRM) is an autosomally inherited skeletal and cardiac muscular myopathy mainly caused by mutations in the desmin gene . DRM is A 16 year old female presented to our cardiac department with progressive exertional dyspnea, palpitation, and skeletal muscle weakness for about two years. Two years ago she was diagnosed with hypertrophic cardiomyopathy by echocardiography. Her laboratory data showed creatine kinase (CK) 996 HU/L, brain natriuretic peptide(BNP) 2634 Hpg/ml. The electrocardiogram showed atrial fibrillation. At the referring hospital, skeletal muscle biopsies and mutation screening of the desmin gene had been performed according to the neurological workup of pathology.Tranthoracic echocardiography showed symmetrical myocardial hypertrophy of interventricular septum and the wall of left ventricle. The wall motion was normal. Left ventricular ejection fraction (LVEF) was 66%, left ventricular (LV) diastolic (DD) and systolic (SD) diameter was 40 and 26 mm, respectively. The left atrium (LA) was dilated with diameter of 56 mm.CMR was performed with a 1.5T Magnetom Sonata . Fast-gradient-echo steady-state free precession cine demonstrated symmetrical wall thicken of interventricular septum and the lateral wall of left ventricle Figure . The lefThe histopathological study of skeletal muscle was in line with the pathological pictures of desminopathy. Modified Gomori staining (MGT) showed multiple dark blue materials depositing in muscle fibers Figure , which wDesmin is the main intermediate filament protein expressed in skeletal, cardiac, and smooth muscle . It inteThe clinical manifestationsis of desminopathies are quite broad including progressive skeletal myopathy, typically presents with lower and later with upper limb muscle weakness, sometimes slowly spreading to involve truncal, neck flexor, facial and respiratory muscles ,6. DiffeDesmin-related cardiomyopathy is usually diagnosed with echocardiography through characteristically functional and morphological changes. Cardiomyopathy has been reported in up to 50% of desmin gene mutation carriers, with DCM and RCM being the most prevalent form, but HCM has seldom been reported. In recent years, CMR has evolved as the non-invasive reference standard for accurate and highly reproducible determination of cardiac function and morphology. But the study of desmin-related cardiomyopathy with CMR is really rare. Only one study systematically used CMR imaging to evaluate myocardial involvement in desminopathies. It revealed subtle focal hypertrophic myocardial changes in two desmin-related cardiomyopathy patients which were missed by echocardiography . The reaAnother important finding of CMR is the detection of fibrotic intramyocardial lesions by LGE imaging. It is the only direct and noninvasive imaging technique which can find myocardial fibrosis in cardiomyopathy. The finding of myocardial fibrosis is especially noteworthy since some desmin-related cardiomyopathies with myocardial fibrosis were not associated with global or focal systolic wall motion abnormalities and therefore might be missed by wall motion studies. The extent of myocardial fibrosis has been related to patient prognosis, including worsening of LV function and adverse outcome .In conclusion, CMR was able to detect myocardial fibrosis in desmin-related hypertrophic cardiomyopathy. CMR may prove useful to detect early cardiac involvement and predict the patient prognosis of desminopathies.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.YH: Literature research, manuscript preparation and editing. ZZ: Revising the manuscript. DH: Carried out the molecular genetic and pathological studies. QD: Picture editing. TJ: Case collection.All authors read and approved the final manuscript.YH: MD, Deptartment of Radiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China


Most heart failure research and quality improvement efforts are targeted at treatment and secondary prevention of patients with manifest heart failure. This is distinct from coronary disease where primary prevention has been a focus for over three decades. Given the current importance and the projected worsening of heart failure epidemiology, a more focused effort on prevention is urgently needed.  It is estimated that over 5.5 million subjects in the United States have heart failure and more than 650,000 are diagnosed for the first time each year . PatientHeart failure prevalence is rising and this trend will worsen. This is attributed to the increasing elderly population and the increasing prevalence of cardiovascular risk factors like diabetes and obesity. The aging of the 78 million baby boomers will result in 1 in 5 Americans to be over the age of 65 years by 2050. Heart failure incidence and prevalence are the highest amongst the elderly, and 80% of patients hospitalized with heart failure are over 65 years old. Thus the increasing age of the population is expected to significantly worsen the current heart failure epidemic. 2 [Risk factors for heart failure range from lifestyle factors to comorbidities, medications, laboratory, and imaging characteristics to novel biomarkers and genomic markers . Heart f2 , and mye2  have beeα2C adrenergic receptors (α2C del322–325) or β1 adrenergic receptors (β1 Arg389) are associated with heart failure. Homozygous blacks for α2C del322-325 have a 5-fold higher risk. If this polymorphism is associated with homozygosity for β1 Arg389, the risk increases by 10-fold.Several chemotherapeutic agents, for example, doxorubicin, cyclophosphamide, trastuzumab, and 5-fluorouracil are associated with heart failure. Cyclooxygenase-2 inhibitors may increase risk of myocardial infarction. Thiazolidinediones have been associated with edema and precipitation of heart failure . Several Population attributable riskrepresents the proportional reduction in disease risk that would be achieved by eliminating the risk factor from the population, assuming a causal relationship. In a recent report , coronarAlthough many heart failure risk factors have been described, determining their role in predicting a future event is still challenging. Despite strong etiologic association with a disease, a risk factor may be limited in its prognostic role . AlthougMost studies on heart failure risk factors have studied individual risk factors. Recently, Health ABC Heart Failure Risk Model was developed using the data from 2935 individuals participating in the health ABC study. Independent predictors of heart failure included age, history of coronary heart disease and smoking, systolic blood pressure and heart rate, serum glucose, creatinine, and albumin levels, and electrocardiographic left ventricular hypertrophy; the model has good discrimination and calibration. A simple point score was created to predict incident heart failure risk into 4 risk groups corresponding to <5%, 5% to 10%, 10% to 20%, and >20% 5-year risk was developed. The investigators externally validated the model in the cardiovascular health study; the model retained adequate predictive capabilities [2O, circulation time ≥25 seconds, hepato-jugular reflux, or pulmonary edema or visceral congestion or cardiomegaly at autopsy. Minor criteria included bilateral ankle edema, nocturnal cough, dyspnea on ordinary exertion, hepatomegaly, pleural effusion, reduced vital capacity by one third from maximum, and heart rate ≥120 beats/minute. Investigators from the Cardiovascular health study developed alternative criteria that included medication use and imaging modalities [Several unique issues make heart failure risk assessment challenging. First, heart failure is a clinical diagnosis and this leads to diversity in opinions and diagnostic uncertainty in a proportion of cases. The most common clinical criteria used to diagnose heart failure is the Framingham criteria that requires the presence of at least two major, or one major and two minor criteria . Major cdalities . When bodalities . Similardalities . Part of this discordance is related to diagnosing heart failure with preserved ejection fraction. Many of the symptoms  and signs  are nonspecific and can be seen in other conditions for example obesity or chronic lung disease. The European Society of Cardiology developed a consensus statement for diagnosing this condition using biomarker and imaging-based detailed protocols . SimilarCurrently, incident heart failure risk modulation is primarily targeted towards risk factor management individually. For coronary artery disease, patient treatment plan is targeted based on the individualized risk profile related to the various combinations of risk factors, for example, blood pressure goals or low-density lipoprotein level. On the contrary, no such paradigm for heart failure risk modulation currently exists. Many heart failure risk factors cannot be intervened upon, for example, age and gender. Other risk factors like proinflammatory states may be targets for intervention in the future. This section describes interventions, which directly or indirectly reduce the risk for incident heart failure that is currently known. Several studies have reported reduced risk for heart failure with healthy lifestyle. Healthy weight, avoiding smoking, engaging in exercise, and a healthy diet have been shown to reduce heart failure risk factors including coronary disease , 43, dia2) is clearly associated with an increased risk for heart failure [2) [Body mass index is associated with heart failure in a positive and linear  fashion  failure , 47, thelure [2) , 48. Abdlure [2) , even inlure [2) . Severallure [2) , 52 incllure [2) , (c) actlure [2) , (d) prolure [2) , (e) prelure [2) , and (f)lure [2) . The prilure [2) . Myocardlure [2) . The rollure [2) . Aerobic Activity. Moderate-intensity aerobic physical activity for a minimum of 30 min on five days each week or vigorous-intensity aerobic activity for a minimum of 20 min on three days each week. Muscle-Strengthening Activity. It is recommended that 8–10 exercises should be performed on two or more nonconsecutive days each week using the major muscle groups. To maximize strength development, a resistance (weight) should be used that allows 8–12 repetitions of each exercise resulting in volitional fatigue. Activity Dose. Vigorous-intensity activities may have greater benefit than moderate-intensity physical activity. Physical inactivity is an important risk factor for cardiovascular diseases including heart failure . RegularWalking have been reported as beneficial regarding primary prevention , this shExcessive alcohol consumption is associated with alcoholic cardiomyopathy , 68. IntIn the Dietary Approaches to Stop Hypertension (DASH) diet, individuals are encouraged to consume more (i) fruits and vegetables, (ii) grains and grain products, (iii) lean meats, fish, poultry, (iv) low fat or nonfat dairy foods, and (v) nuts, seeds, and legumes, and reduce the consumption of red meat, fat, and sugar while maintaining a low sodium intake. Initially, this was promoted for hypertension; however, recent evidence supports reduction of heart failure risk with an observed 37% lower rate in women who adhere to the DASH diet . The DASFish consumption exerts beneficial effects on heart failure risk with about a 20% lower risk associated with an intake of 1 to 2 times per week and about a 30% lower risk with intake ≥3 times per week, compared with intake less than 1 time per month. Estimated intake of marine n-3 fatty acids was associated with 37% lower heart failure risk in the highest quintile of intake compared with the lowest. Short-term trials of fish oil supplementation of 3–5 grams per day may reduce risk whereas dietary doses of about 0.5 grams per day may result in more modest effects that over long term may reduce heart failure risk. It has been reported that broiled or baked fish consumption is inversely associated with systolic blood pressure, C-reactive protein levels, and carotid intimal medial thickness, whereas fried fish intake is positively associated with them, indicating that the type of cooking could impact the effects .Historically, human ancestors consumed less than 0.25 grams of salt per day . The recSmoking is a strong predictor of heart failure in both men and women, with 45% and 88% increased risk . The delMedications. Several medications are available for tobacco dependence. Seven first-line medications reliably increase long-term smoking abstinence rates including bupropion SR, nicotine gum or inhaler or lozenge or nasal spray or patch, and varenicline. Counseling and Psychosocial Support. Individual, group, telephone practical counseling, and social support are effective, and their effectiveness increases with treatment intensity. Combination. The combination of counseling and medication, however, is more effective than either alone, therefore, clinicians should encourage all individuals making a quit attempt to use both counseling and medication. All smokers should be counseled to quit. Patients should be referred to formal cessation programs, and pharmacological therapy should be offered to increase the success rate. Current recommended strategies include the following:In the studies of left ventricular dysfunction trials, the risk for heart failure hospitalizations and myocardial infarctions was reduced after quitting . Women'sHypertension is an antecedent condition in the majority of individuals developing heart failure . By age The progression from hypertension to structural ventricular changes and systolic and diastolic ventricular dysfunction is well established. Increases in cardiac afterload, left ventricular mass, and wall stress accompanied by impairment of diastolic filling properties occur in the chronic setting –107. TheThe placebo-controlled trials and the meta-analysis arising from them demonstrate the benefit of antihypertensive therapy in reducing the incidence of cardiovascular diseases . Fewer sDiuretics. Secondary outcomes of the antihypertensive and lipid-lowering treatment to prevent heart attack trial reported a higher rate of incident heart failure with amlodipine (relative risk of 1.35) and a nonsignificantly increase with lisinopril (relative risk of 1.09) compared with chlorthalidone [halidone . On the halidone  reportedRenin-Angiotensin System Modulators. Meta-analysis of double-blind trials that measured the effects of antihypertensive drugs on left ventricular mass [lar mass  shows thlar mass –119. A rlar mass . Beta-Blockers. Although beta-blockers are effective in lowering blood pressure, these medications are less effective in preventing hypertension complications including coronary artery disease, cardiovascular, and all-cause mortality [ortality , 122, orortality . Howeverortality . Calcium Channel Blockers. There are limited experimental data on the effects of calcium antagonists on left ventricular mass or incident heart failure. A recent meta-analysis suggested that treatment of hypertension with calcium channel blockers is less effective for reducing heart failure for the same reduction of blood pressure [pressure . In patients with hypertension, systolic and diastolic blood pressure targets are <140/90 mm Hg except for patients with diabetes or renal disease where the goal is <130/80 mm Hg. Since most patients with hypertension, especially those over age 50, will reach the diastolic blood pressure goal once systolic blood pressure is at goal, the primary focus should therefore be on systolic blood pressure. Recent trials have demonstrated that effective blood pressure control can be achieved in most patients, but the majority will require two or more medications in combination . Data frDiabetes mellitus is an independent risk factor for heart failure in all age groups , 25. TheSeveral mechanisms proposed for the development of “the following diabetic cardiomyopathy” include : (a) micInsulin. Randomized controlled trials indicate that insulin use in ACC-AHA stage. A heart failure does not appear to increase the risk for heart failure [ failure , whetherSulfonylureas. Sulfonylurea therapy does not increase the risk of heart failure compared with other oral antidiabetic agents [c agents . Metformin. The risk of new onset heart failure among patients treated with metformin compared with patients treated with other oral antidiabetic medications was reported in ADOPT and the findings were similar as for sulfonylureas [nylureas .Thiazolidinediones. Although treatment with thiazolidinediones increased myocardial glucose uptake, and myocardial glucose uptake seems to be positively correlated with left ventricular function [function , the rosfunction .Other Agents. There are limited data regarding other antidiabetic therapies for incident heart failure, except for the α-glucosidase inhibitor acarbose [acarbose . Althougacarbose . In the United Kingdom prospective diabetes study (UKPDS) 33, no significant reduction in the development of macrovascular disease or heart failure was demonstrated with intensive blood glucose control . Because hypertension further increases the risk of cardiovascular disease and heart failure in patients with diabetes, aggressive blood pressure management is essential to prevent long-term complications in this population. In UKPDS 38, tight blood pressure control reduced the risk for heart failure by 56% . The sevMedications like ACEI, ARB, and beta-blockers benefit patients with diabetes and prevent complications of diabetes including heart failure. The heart outcomes prevention evaluation (HOPE) trial , and theRecently, a randomized trial evaluated the effects of the Cu(II)-selective chelator trientine on left ventricular hypertrophy in diabetes mellitus and showed a 10% decrease in left ventricular mass index after 12 months . This deCoronary heart disease predisposes an increased risk for developing heart failure in both men and women , with reAcute myocardial infarction leads to a cascade of adaptive mechanisms that promote left ventricular remodeling . VentricIschemia caused by abnormalities in coronary arteries can produce increases in the concentration of neurohormones, for example, norepinephrine, epinephrine, endothelin, and dopamine, that results in myocardial apoptosis, fibrosis, and susceptibility to ventricular arrhythmias . Thus, iPrevention of coronary heart disease and ischemic events is a key point to maintaining functional myocyte reserve; however, in patients with established coronary heart disease, an aggressive management can reduce development of heart failure. A number of cardioprotective medications and procedures can prevent development of symptomatic heart failure in coronary heart disease. The combination of medications along with therapeutic lifestyle changes should be applied aggressively in all patients to reduce the risk of heart failure.Mechanical  or pharmacological revascularization of the infarct-related artery and reduces the size of the acute infarct and prevents subsequent heart failure , 151 if Angiotensin-converting enzyme inhibitors have favorable properties in reducing left ventricular stress and progression of left ventricle enlargement. In the third Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI) trial, early lisinopril therapy in acute infarction reduced mortality and left ventricular dysfunction despite therapy with aspirin, thrombolytics, and beta-adrenergic blocking agents. Similar findings were demonstrated in the survival of myocardial infarction long-term evaluation trial with zofenopril . The HeaAngiotensin-receptor blockers are at least equally effective as angiotensin-converting enzyme inhibitors in reducing mortality in patients with myocardial infarction complicated by left ventricular dysfunction or heart failure , 146. HoBeta-blockers have been proven to be beneficial after acute myocardial infarction for over 20 years. Notably, long-term beta-blocker use is recommended for secondary prevention in patients at the highest risk, for example, those with low ejection fraction or heart failure . The revSpironolactone combined with angiotensin-converting enzyme inhibitors ameliorated left ventricle remodeling after acute myocardial infarction . AldosteAspirin in patients with established vascular disease has been demonstrated to reduce risk for cardiovascular events and heart failure  and is rStatins are of proven benefit in patients with coronary heart disease ; howeverConsidering the worsening epidemiologic trends and increase in the heart failure prevalence in the society, escalating costs, and continued poor quality of life and outcomes for these patients, the importance of heart failure prevention cannot be overemphasized. This will require efforts in all levels of the prevention spectrum ranging from advocacy efforts to research. Population-level efforts at risk factor prevention and adoption of healthy lifestyle habits are essential to promote overall cardiovascular health and reduce heart failure risk specifically. Towards this direction, the American Heart Association has taken a bold step in defining their 2020 goals that include not only achieving further reductions in mortality due to cardiovascular disease and stroke but also improving the health of the population based on a comprehensive specifically designed metric that includes multiple healthy lifestyle parameters. Lastly, whether treatment goals of heart failure risk factors should be individualized based on any given individuals cumulative risk profile needs further study.


To investigate whether respiratory variation of inferior vena cava diameter (cIVC) predict fluid responsiveness in spontaneously breathing patients with acute circulatory failure (ACF).Forty patients with ACF and spontaneous breathing were included. Response to fluid challenge was defined as a 15% increase of subaortic velocity time index (VTI) measured by transthoracic echocardiography. Inferior vena cava diameters were recorded by a subcostal view using M Mode. The cIVC was calculated as follows: (Dmax - Dmin/Dmax) × 100 and then receiver operating characteristic (ROC) curves were generated for cIVC, baseline VTI, E wave velocity, E/A and E/Ea ratios.n = 24), haemorrhage (n = 11), and dehydration (n = 5). The area under the ROC curve for cIVC was 0.77 (95% CI: 0.60-0.88). The best cutoff value was 40% . The AUC of the ROC curves for baseline E wave velocity, VTI, E/A ratio, E/Ea ratio were 0.83 (95% CI: 0.68-0.93), 0.78 (95% CI: 0.61-0.88), 0.76 (95% CI: 0.59-0.89), 0.58 (95% CI: 0.41-0.75), respectively. The differences between AUC the ROC curves for cIVC and baseline E wave velocity, baseline VTI, baseline E/A ratio, and baseline E/Ea ratio were not statistically different .Among 40 included patients, 20 (50%) were responders (R). The causes of ACF were sepsis  are usually associated with fluid responsiveness while low values (< 40%) do not exclude fluid responsiveness. Assessment of fluid responsiveness remains a daily therapeutic challenge in spontaneously breathing critically ill patients with acute circulatory failure (ACF) . In mechUse of respiratory IVC diameter variation (cIVC) is very popular because it is very easy to record, and needs a short learning curve, even for non-cardiologist residents or physicians . cIVC haTherefore, the present study was aimed at assessing the usefulness of cIVC recorded by transthoracic echocardiography (TTE) to predict fluid responsiveness in spontaneously breathing critically ill patients with acute circulatory failure.This observational study was approved by our local institutional review board . It was stated that informed consent was not necessary; nevertheless, the patients or their relatives were orally informed, in accordance with French legislation.The study was conducted in a 16-bed ICU of a university hospital within a 24-month period (April 2009 to April 2011). Forty patients with ACF were prospectively included within the study period. ACF was defined as mean arterial pressure (MAP) < 65 mmHg, urine output < 0.5 mL/Kg/h, tachycardia, mottled skin and/or biological signs of hypoperfusion . We excluded patients in whom fluid challenge would be deleterious: those with clinical evidence of pulmonary edema, echocardiographic evidence of right ventricular (RV) failure (right telediastolic ventricle area to left telediastolic ventricle area ratio > 1)  or echocFor each patient, the following data were recorded: diagnosis, age (years), weight (Kg), height (cm), Acute Physiology and Chronic Health Evaluation (APACHE)-II score at admission, MAP (mmHg), heart rate  and CVP (mmHg) when available.Echocardiographic measurements were performed by four trained (level 3 ) operatoIVC was observed by a subcostal long axis view. In order to differentiate the aorta and IVC, the junction between the IVC and the right atrium was systematically assessed. A pulse wave Doppler of the IVC was also recorded in order to verify the presence of a typical venous flow spectrum. A time-motion record of the IVC diameter was generated by M-mode imaging at 2 to 3 cm from the right atrium ,30. MaxicIVC = (Dmax-Dmin)/Dmax.cIVC was expressed as a percentage. In addition, to be sure that the formula:2)(Dmax - Dmin/((Dmax + Dmin)/2 = cIVCcould not be more informative, we also built its respective receiver operator characteristic (ROC) curves.The VTI was recorded by pulse waved Doppler on a five-chamber apical view . For eacIn parallel, the left ventricular filling pressures were assessed using the mitral inflow coupled to tissue Doppler imaging. The transmitral diastolic inflow, or E/A velocity ratio (velocity of the E wave/velocity of the A wave in cm/s) was recorded by pulse Doppler in the apical four-chamber view at the distal extremity of the mitral leaflets ,33. In tRight ventriclular dilatation was defined as a right to left telediastolic ventriclular area ratio > 1 (RV/LV area ratio) . Left ve0), HR, MAP, E, A, and Ea velocities, E/A ratio, E/Ea ratio, and subaortic VTI were recorded. Then a fluid challenge was performed with 500 mL of a 6% 130/0.4 hydroxyethylstarch solution  infused over 15 minutes. After this fluid challenge (at T15), HR, MAP, E, A, and Ea velocities, E/A ratio, E/Ea ratio, and subaortic VTI were recorded. Fluid responsiveness was defined as an increase in the subaortic VTI ≥ 15% after the fluid challenge. This served to split the patients into responders (R) and non-responders (NR) [After ruling out the exclusion criteria, a first echocardiography was performed in all spontaneously breathing patients with ACF. At this time (Ters (NR) ,36. Of nth and 95th percentiles. For the comparisons between R and NR, Mann-Whitney, Chi square and Fisher exact tests were performed when appropriate. ROC curves were constructed to evaluate the ability of cIVC to predict fluid responsiveness. When the AUC was greater than 0.5, the best cutoff value was defined by the closest value to the Youden index [P-values were two-tailed and a P-value < 0.05 was considered significant. We assumed that cIVC would be clinically relevant if the 95% confidence interval (CI) of its area under the curve (AUC) was > 0.75, corresponding to an AUC of a good clinical tool as reported by Ray et al. [Data are expressed as medians with the 5en index . ROC curen index . Statisty et al. . For thiy et al. .Among 40 spontaneously breathing patients with ACF included in this analysis, 20 (50%) responded to the fluid challenge. Regarding demographics and disease severity, no difference was observed between R and NR Table . The cauP = 0.08 compared to 0.5) . For E wave velocity, the best cutoff value was 0.7 , and the positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio was 84%, 83%, 6.67, and 0.37, respectively. For E wave velocity, Youden's index was 0.64 and accuracy 0.88.Individual values of cIVC according to the fluid responsiveness are shown in Figure ) Figure . The besP = 0.46, 0.99, 1.00, and 0.26, respectively).The AUC for the VTI, E/A ratio, and E/Ea ratio was 0.78 , 0.76 , and 0.58  respectively. There was no difference between the AUC of the ROC curve for cIVC and E wave velocity, VTI, E/A ratio or E/Ea ratio , the AUC of ROC curve for cIVC2 was 0.77 . The best cutoff value was 25%. The AUC of the ROC curve for baseline E wave velocity, VTI, E/A ratio, and E/Ea ratio were 0.83 , 0.78 , 0.76 , and 0.58 , respectively. There were no statistical differences between the AUC for cIVC2 and E wave velocity, VTI, E/A ratio, and E/Ea ratio .When using the formula (Dmax - Dmin/((Dmax + Dmin)/2) , the present study shows that cIVC cannot reliably (inferior limit of CI < 0.75) predict fluid responsiveness in spontaneously breathing patients with ACF. More precisely, a cIVC value below 40% cannot exclude fluid responsiveness while patients with cIVC above 40% are more likely to respond to fluid challenge. The 40% cutoff value is in agreement with recent studies .The first explanation for these imperfect results is that, as previously suggested, cIVC is a dynamic preload index. In contrast with findings reported in mechanically ventilated septic patients, dynamic parameters have been shown to be ineffective to predict fluid responsiveness in spontaneous breathing patients ,7. SpontBecause previous studies have reported a good correlation between cIVC and blood volume removal during hemodialysis ,24 or duet al. [P = 0.03) or at the level of the left renal vein  [et al. [The conditions of measurement of cIVC could be discussed. In the present study, the IVC diameter was measured by M mode at 2 or 3 cm from the right atrium, as described in previous studies ,18,22. Het al.  recently= 0.002) . This fi [et al.  recently2) could better analyse the variability of IVC ventilatory variations. After testing the two formulas, we did not observe any difference between the two indices. Then, the type of formula is not a major determinant of IVC respiratory variation analysis.The choice of the formula for cIVC could also be debated. As described in the method section, we used the cIVC formula (Dmax - Dmin/Dmax). One could argue that the cIVC formula used by an other group  (cIVC2) P = 0.0005). Even if it was not the primary objective of this study, this suggests that E wave velocity < 70 cm/s  could help to identify responders A spontaneously breathing patients.Mitral Doppler inflow patterns allow indirect assessment of left ventricular filling pressure . In partThe present study has some limitations. First, the physicians were not blinded. Second, the patients were not consecutive. Indeed, to be included, the study required the presence of an eligible patient and the presence of a physician certified in cardiac echography. As most patients admitted to our ICU were mechanically ventilated, 2 years were needed to complete the present study. Third, the PLR test could be used in order to avoid unnecessary fluid infusion. Performing a PLR test with echocardiography to assess fluid responsiveness is validated in spontaneous breathing patients . In the In summary, cIVC moderately predicted fluid responsiveness in spontaneously breathing patients with ACF. In patients with a low cIVC value (< 40%), fluid responsiveness cannot be excluded, while patients with cIVC above 40% are more likely to respond to fluid challenge. Then, despite its simplicity of use, cIVC should be used with caution in spontaneously breathing patients with ACF. Additionally, our results also suggest that low values of E wave velocity (< 0.7 m/s) could be used to identify responders to fluid challenge.In spontaneously breathing patients with ACF, despite its apparent simplicity, cIVC should be interpreted with caution. A high cIVC value (> 40%) is usually associated with fluid responsiveness while low values (< 40%) do not exclude fluid responsiveness.• As demonstrated in controlled mechanical ventilation, large respiratory variations (> 40%) of inferior vena cava diameter are usually associated with a positive response to fluid challenge in spontaneous breathing patients.• In contrast to what was demonstrated in controlled mechanical ventilation, low variations (< 40%) of IVC diameter cannot rule out a need for fluid therapy in spontaneously breathing patients with acute circulatory failure.• In such situations, a low value of E wave velocity (< 0.7 m/S) is usually associated with positive response to fluid challenge.ACF: acute circulatory failure; APACHE: Acute Physiology and Chronic Health Evaluation; AUC: area under curve; CI: confidence interval; cIVC: respiratory variation of inferior vena cava diameter, collapsibility of inferior vena cava diameter; CVP: central venous pressure; HR: heart rate; ICU: intensive care unit; LV: left ventricle; LVEDP: left ventricle end diastolic pressure; MAP: mean arterial pressure; NR: non-responders; PLR: passive leg raising; R: responders; ROC: receiver operating characteristic; RV: right ventricle; TTE: transthoracic echocardiography; VTI: velocity time index.The authors declare that they have no competing interests.LM conceived the study, wrote the manuscript and performed some echocardiography exams. JYL was the director of this research project and participated in the writing of this manuscript. XB, MT and GL performed some echocardiography exams. NM was responsible for the statistical analysis. BR, HQ and ML significantly helped to draft the manuscript. LZ checked the English language. All authors read and approved the final manuscript.