Studies have shown that left ventricular mass, diagnosed by echocardiography, correlated poorly with blood pressure, even when the 24-hour ambulatory blood pressure monitoring was taken into account in the analysis. This may be partly because there are other determinants of left ventricular mass such as age, gender, neurohormonal factors and heredity.Knowledge of the correlates of left ventricular mass could help design individual and population strategies to prevent or reverse left ventricular hypertrophy. To the best of our knowledge, there is a paucity of such studies in native Africans. Hence the purpose of this study was to define the correlates of left ventricular mass in hypertensive Nigerians.p < 0.05.The study was a retrospective analysis of prospectively collected data in 285 hypertensive subjects. Echocardiographic left ventricular mass was determined using the standard formula. Stepwise multiple regression analysis was used to determine the independent predictors of left ventricular mass with a probability value to enter and remove of r2 of 0.945, thus explaining about 95% of left ventricular mass variability.There were 153 men (53.7%) and 132 women (46.3%) in the study. The mean age of all subjects was 58.2 ± 13.7 years. There was no significant gender difference in most of the echocardiographic parameters. In a stepwise multiple regression analysis, left ventricular wall tension, left ventricular wall stress, left atrial size, diastolic blood pressure, alcohol consumption and a family history of hypertension were the independent predictors of left ventricular mass in this population. The optimum multivariate linear regression main effects had an adjusted model, Mechanical or haemodynamic factors possibly interacting with genetic and social factors are the likely determinants of left ventricular mass in hypertensive Nigerians. Therefore modulation of some of these factors pharmacologically or non-pharmacologically will be of benefit in the management of this patient population. Left ventricular hypertrophy (LVH) has been shown to be a significant risk factor for adverse outcomes both in patients with hypertension and in the general population.4Studies have shown that, among other things, increased left ventricular mass (LVM) is associated with a significant excess of cardiovascular morbidity and mortality.4LVH defined by ECG has been shown to be an independent risk factor for cardiovascular events.12Regression of LVH has also been shown to be possible using either antihypertensive drugs  or non-pharmacological lifestyle modifications. Therefore an understanding of the factors promoting increased LVM in hypertensive Nigerians may permit the development of strategies aimed primarily at preventing LVH or promoting regression more effectively. Moreover, to the best of our knowledge, no work of this nature has been carried out in this environment.The objectives of the present study were to assess the nonhaemodynamic and haemodynamic correlates of LVM among hypertensive Nigerians seen at the University College Hospital (UCH), Ibadan, Nigeria.The study was carried out at the Medical Outpatient Unit of the University College Hospital, Nigeria. It was a retrospective analysis of prospectively collected data. Eligible patients were men and women aged 18 years and older with established hypertension, who were attending the hypertension clinic at the hospital. Diagnosis of hypertension was based on systolic blood pressure of ≥ 140 mmHg and diastolic blood pressure of ≥ 90 mmHg or those on antihypertensive therapy.13Subjects with a previous history or symptoms of ischaemic heart disease, echocardiographic evidence of regional wall motion abnormalities, or established congestive heart failure were excluded from the study. Other exclusion criteria included patients with hypertrophic cardiomyopathy, left bundle branch block and those with incomplete echocardiography reports. Ethical approval was obtained from the institution’s ethical review board.The estimated minimum sample size was 255 hypertensive subjects. The calculation of the minimum sample size was based on the prevalence of echocardiographic LVH in hypertensive subjects at the UCH, Ibadan, which was between 16.5 and 25.8% depending on the cut-off value used in defining LVH.Baseline clinical and demographic characteristics were obtained from the subjects’ case notes. These included date of birth (age), gender, history of diabetes, history of smoking, duration of their hypertension, and family history of hypertension. Also obtained were the blood pressure, pulse rate, body weight and height at the time of echocardiography. Body mass index (BMI) was calculated using the formula:2) = weightheight²BMI (kg/mBody surface area (BSA) was calculated using the formula of Dubois:152) = 0.0001 × 71.84 × [weight (kg)]0.425 × [height (cm)]0.725BSA  and a 3.5-MHz linear array transducer. This was performed on each subject in the left lateral decubitus position. All measurements were made according to the American Society of Echocardiography leading edge-to-leading edge criteria.16LV measurement was obtained at end-diastole and end-systole. The LV measurements recorded included interventricular septal thickness at end-diastole (IVSTd), posterior wall thickness at end-diastole (PWTd), and the LV internal dimensions at end-systole (LVIDs) and end-diastole (LVIDd). Other parameters obtained were left atrial diameter, aortic root diameter, indices of LV diastolic function .Two experienced cardiologists performed the echocardiography. In our laboratory, the intra-observer concordance correlation coefficient ranged from 0.76 to 0.98 while that of the inter-observer concordance ranged from 0.82 to 0.96.17r = 0.90) to necropsy LV weight and which has good inter-study reproducibility.18Left ventricular mass was calculated using the formula that has been shown to yield values closely related (LVM (ASE) = 0.8 [1.04 (IVSTd + LVIDd + PWTd) 3 + 0.6 g2.7 in both men and women.Relative wall thickness was calculated as twice the posterior wall thickness/LV internal dimension in diastole. Relative wall thickness of 0.43 or greater was considered abnormal.et al.21Left ventricular volumes were estimated using the formula of Teichholz LV end-diastolic volume (EDV) (ml) = 7[LV internal in diastole (LVIDd) + 2.4] × LVIDdLV end-systolic volume (ESV) (ml) = 7[LV internal in systole (LVIDs) + 2.4] × LVIDsStroke volume (SV) (ml) = EDV – ESVCardiac output (CO) (ml) = SV × heart rate (HR)Mean arterial blood pressure (MAP) (mmHg) was calculated as: diastolic BP + 1/3 pulse pressureMAP ×80COTotal peripheral resistance was assessed as: Pulse pressure (mmHg) was estimated as: SBP – DBP100 ×(LViDd -LVIDs)LViDdFractional shortening (%) = 100 ×(EDV-ESVEDVEjection fraction (%) = The ratio of pulse pressure to stroke volume was used as an indirect estimate of global arterial stiffness.232) was calculated as: 0.86 ×(0.0334 ×SBP ×LViDd)PWTd ×1 +PWTd-2 LVIDdLV peak wall stress  = t-test was used for comparison of continuous variables between men and women.SPSS version 11.0  was used for statistical analysis. Continuous variables were expressed as mean ± SD and categorical variables as percentages. We assessed differences in categorical variables by Chi-square analysis while the unpaired To determine the independent predictors of LV mass, multiple regression models were created. Univariate regression was first performed for each continuous and categorical variable. Thereafter variables having a significant correlation with LVM were entered in stepwise multiple regression models.p ≤ 0.05.In the final model, variables that exhibited a high degree of collinearity were added or deleted iteratively. This was to achieve a model with consistency and conciseness. The probability value to enter and remove was set at Of the 285 subjects enrolled, there were 153 men (53.7%) and 132 women (46.3%); overall mean age was 58.2 ± 13 years. Of these, 146 patients were presenting for the first time at the hypertension clinic (51.2%).About 70.2% of the subjects were on thiazide diuretics and 56% were on calcium channel blockers. Angiotensin receptor blockers and beta-blockers were prescribed for 44.6 and 13.7% of the subjects, respectively. More than 60% of the subjects were receiving two or more classes of drugs.p = 0.0006) while the women were heavier than the men  and those with normal LV mass, significant differences were found in their clinical, biochemical and echocardiographic characteristics. Hypertensive subjects with left ventricular hypertrophy were found to be older, heavier and had higher baseline systolic, diastolic and mean arterial blood pressures. Their resting heart rate was also significantly higher. They had higher serum sodium, lower serum potassium (0.015), higher serum creatinine and higher uric acid levels. This group also had higher fasting blood glucose and lipid profiles . Accordingly they also had lower mean HDL cholesterol levels.Comparison of their echocardiographic variables revealed that subjects with increased LV mass (LVH) had larger aortic root diameters, left atrial diameters and LV wall thickness. LV internal dimensions (both in systole and diastole), LV enddiastolic and end-systolic volumes, stroke volume and cardiac output were also higher in the group with LVH.On the other hand, subjects with increased LVM had lower indices of LV systolic function , relative wall thickness, total peripheral resistance and pulse pressure–stroke volume ratio. These were all statistically significant. There was no difference in the indices of LV diastolic function .r = 0.123), alcohol consumption (r = 0.209), cigarette smoking (r = 0.190), presence of diabetes mellitus (r = 0.187), body weight (r = 187) and height (r = 0.195). LV mass was also positively related with body surface area (r = 0.228), systolic BP (r = 0.200) diastolic BP (r = 0.235) and mean arterial BP (r = 0. 239). Serum creatinine (r = 0.225), serum uric acid (r = 0.362), aortic root diameter (r = 0.238), left atrial diameter (r = 0.514), LV end-diastolic volume (r = 0.727) and LV end-systolic volume (r = 0.989) were all positively and directly related to LV mass.As shown in r = –0.380), ejection fraction (r = –0.415), total peripheral resistance (r = –0.329) and pulse pressure/stroke volume ratio (r = –0.284), which showed a negative relationship with LV mass. LVM was not significantly related to indices of LV diastolic function. However the relationship with A-velocity and deceleration time was negativeAll the haemodynamic parameters also showed a relationship with LV mass. The relationship was mostly positive except for fractional shortening .This study did not find age as an independent determinant of LVM as previously reported.There was little gender difference in the echocardiographic parameters. Gender also correlated weakly with LV mass. Two possible reasons are that (1) the influence of gender on LV mass could have been accounted for by other factors such as height, weight and body surface area; (2) the choice of a non-gender-specific partition value for the definition of LVH in this study could have obliterated any gender difference. Some workers have reported gender as a determinant of LV mass.41et al.Aortic root diameter did not enter our model as a predictor of LVM. The study by Chan et al.31Although total peripheral resistance showed a strong relationship with LVM in the univariate analysis, it was not an independent predictor of LVM. This corroborates some studies that showed that vascular resistance is not a good index of haemodynamic loading.The first limitation of the study was the fact that it was retrospective and cross-sectional. It can only claim association but not causality. Secondly, clinic or casual blood pressure was measured in the subjects. Many studies have shown that ambulatory blood pressure is more closely associated with LV mass than clinic blood pressure.Thirdly, other variables such as insulin resistance, blood viscosity, and carotid intima–media thickness that have been documented as determinants of LV mass were not assessed in this study. Fourthly, this study did not correlate ECG findings with ECHO findings. The authors will explore this in future research.et al.31 They tested the reliability of M-mode parameters by comparing them with those obtained with the two-dimensional echocardiographic truncated ellipsoid formula, which were devoid of M-mode-derived parameters in 1 238 subjects. They noted a lower overall model variance (0.59 vs 0.74) but with the same top predictors of LV mass contributing to 98% of the total variance.Lastly, there may be concern about the independence of the haemodynamic parameters, which were derived from some M-mode measurements also used in the calculation of LV mass. This concern has been addressed in the recent report by Chan This study found that the most important determinants of LV mass were LV wall tension, left atrial size, LV wall stress, diastolic BP, a family history of hypertension, and alcohol consumption. These factors appeared to explain about 95% of the variability in LV mass in hypertensive Nigerians seen at the University College Hospital, Ibadan. Mechanical or haemodynamic factors, possibly interacting with genetic and social factors are the likely determinants of LV mass in Nigerian hypertensive men and women. Therefore modulation of these factors pharmacologically or non-pharmacologically will be of benefit in the management and control of hypertension in this population.The implications of this study are that measures that effectively modulate wall stress and wall tension as well as blood pressure control, for example antihypertensive therapy, can cause early regression of LVH. Early screening of relatives of hypertensive subjects may provide an effective blood pressure-control programme. Non-pharmacological treatment such as avoidance of excessive alcohol consumption may be an effective tool in a blood pressure-control programme.However, based on the recent findings by the LIFE study,


Subclinical primary left ventricular (LV) dysfunction is a complication of systemic sclerosis (SSc) related to progressive diffuse myocardial fibrosis. Myocardial T1-mapping has recently been proposed as a cardiac magnetic resonance (CMR) method to quantify interstitial fibrosis early in the disease course whereas late-gadolinium enhancement (LGE) imaging remains normal.We aimed to evaluate whether myocardial T1-mapping could detect subclinical abnormalities in SSc patients with normal standard parameters of LV function and normal LGE imaging.We prospectively studied 37 patients (52±12 years) presenting with SSc with no history of heart disease, no pulmonary hypertension at rest, a normal LV assessed by conventional echocardiography , and no LGE. SSc patients were compared to16 matched controls healthy volunteers (47±7 years old). T1 quantification was performed using a Modified Look-Locker Inversion-recovery (MOLLI) sequence at 1.5T (Siemens) on a LV short axis before, 5min and 15 min after 0.2 mmol/Kg gadolinium injection. Imaging protocol included also standard Cine-SSFP imaging, and LGE imaging. LV diastolic function  was further assessed using echocardiography.A non significant shorter mean T1 time  was observed in SSc patients compared to controls both at 5  and 15  minutes after gadolinium injection. Echocardiography displayed a LV diastolic dysfunction in 47% of SSc patients and in 25% of controls (p=0.04). The SSc patients with a LV diastolic dysfunction had a shorter 15 minutes post-contrast T1 time (ms) than those with a normal diastolic function .Post-contrast T1-mapping identifies changes in LV myocardial T1 times in patients with SSc, normal LVEF and impaired LV diastolic function. These abnormalities may reflect the impact of diffuse interstitial myocardial fibrosis in SSc that could be early detected in the future.


The aim of the study was to compare the diagnostic accuracy of point-of-care cardiac ultrasonography performed by a novice examiner against results from a specialist in cardiology with expert skills in echocardiography, with regard to the assessment of six clinically relevant cardiac conditions in a population of ward patients from the Department of Cardiology or the Department of Cardiothoracic Surgery.Cardiac ultrasonography was performed by a novice examiner at the bedside and images were interpreted in a point-of-care context with dichotomous outcomes (yes/no). Six outcome categories were defined: 1) pericardial effusion (≥10 mm), 2) left ventricular dilatation (≥62 mm), 3) right ventricular dilatation (≥42 mm or ≥ left ventricular diameter), 4) left ventricular hypertrophy (≥13 mm), 5) left ventricular failure (EF ≤ 40%), 6) aortic stenosis (maximum flow velocity ≥3 m/s). The examiner was blinded to the patients’ medical history and results from previous echocardiographic examinations. Results from the interpreted point-of-care ultrasonography examination were compared with echocardiographic diagnosis made by a specialist in cardiology.A total of 102 medical and surgical patients were included. Assessments were made in six categories totalling 612 assessments. There was agreement between the novice examiner and the specialist in 95.6% of the cases; overall sensitivity was 0.91 and specificity was 0.97. Positive predictive value was 0.92 and negative predictive value was 0.97. Kappa statistics showed good agreement between observers (κ=0.88).This study showed that a novice examiner was able to detect common and significant heart pathology in six different categories with good accuracy using POC ultrasonography. Severe heart disease is a serious entity worsening outcome in the emergency department ,2, durinTraditionally, physicians have relied on medical history, physical examination, electrocardiography and chest radiographs to screen for cardiovascular pathology. However, the diagnostic performance of these techniques has been questioned -9.Full evaluation by an expert in cardiology including a diagnostic transthoracic echocardiography (TTE) offers a comprehensive assessment of the most severe heart diseases . HoweverTo address problems associated with limited availability of a full TTE, several point-of-care (POC) ultrasonography protocols have emerged -13. POC The development of POC protocols was facilitated by advances in technology, providing high quality equipment with great portability , and forIf POC cardiac ultrasonography is to be used among novice examiners and non-cardiologists, knowledge about sensitivity and specificity is required. Furthermore, the novice user is required to be able to recognise normal images, be able to provide reproducible ultrasonography standard views, be able to recognize pathology and to relate the findings to the clinical context. Another key element of POC ultrasonography is to be able to detect cardiac pathology with a high degree of reliability.The purposes of this study was to compare the diagnostic accuracy of point-of-care cardiac ultrasonography performed by a novice examiner against results from a specialist in cardiology with expert skills in echocardiography with regard to the assessment of six clinically relevant cardiac conditions in a population of ward patients from the Department of Cardiology or the Department of Cardiothoracic Surgery.The study was performed in accordance with the Helsinki Declaration and informed consent was obtained from all patients. The study was reviewed by the The Central Denmark Region Committees on Health Research Ethics and due to the design of the study it was exempt from further ethical approval.Patients undergoing a standard echocardiographic examination at the Department of Cardiology were eligible for inclusion. The selection process was performed by an independent nurse and physician affiliated with the study. During data collection, patients were always screened and included consecutively in order to avoid selection bias. All eligible patients were assessed on all study days. In addition to Table Prior to study initiation the novice examiner had the following experience:• One year of training in internal medicine and two years of training in anaesthesiology, this includes emergency medicine and intensive care medicine in Denmark.• A one day predominantly hands on workshop covering basic imaging techniques and FATE views as well as teaching using a scenario based approach.• In addition to the basic FATE course, a short introduction to continuous wave Doppler pressure estimation and the 5-chamber view was given.• Approximately 50 POC cardiac ultrasonography examinations including 10 with supervision from an expert (level 3).These prerequisites are similar to level 1 competence agreed by experts published in a variety of statement papers and is the minimum requirements for performing unsupervised POC cardiac ultrasonography ,20.A Vivid S6  ultrasound system equipped with a M4S phased array transducer (1.5 – 4.5 MHz) with second harmonic imaging was used for data acquisition.All patients underwent POC cardiac ultrasonography at the bedside. No guidance or supervision was provided for the novice examiner during image acquisition or interpretation throughout the study period.POC ultrasonography included the following views: Subcostal 4-chamber, apical 4-chamber, apical 5-chamber including continuous wave Doppler of the left ventricular outflow tract, parasternal long- and short-axis. Raw data were digitally stored in cineloop format defined by the R-wave in the corresponding electrocardiogram for off-line analyses. The examination was initially performed with patients placed in the supine position, and if the condition of the patient allowed, image acquisition was also performed in the left lateral position.All examinations were interpreted by the novice examiner who had performed the image acquisition, and the novice examiner was blinded to results from previous echocardiography examinations. The interpretations and estimates were done as post-examination analyses using EchoPac software . Images were interpreted and categorised according to dichotomous outcomes in the following six categories Table :• Pericardial effusion (≥10 mm). The severity was measured as simple two-dimensional calliper assessments of the largest echo-free zone between the pericardial layers in any cardiac view.• Left ventricular dilatation (≥62 mm). The left ventricle diameter was measured at the end of diastole in the parasternal long axis view or the apical 4-chamber view, at the tip of the mitral leaflets, at the interface between blood and inner ventricular wall.• Right ventricular dilatation (≥42 mm or ≥ left ventricular diameter). The right ventricle diameter was measured at the end of diastole in the apical 4-chamber view, at the tip of the tricuspid leaflets, at the interface between blood and inner ventricular wall.• Left ventricular hypertrophy (≥13 mm). The left ventricular wall thickness was measured at the end of diastole in the parasternal long axis view or the parasternal short axis view, at the base of the ventricle on the interventricular septum.• Left ventricular failure (EF ≤ 40%). Left ventricular ejection fraction was measured by estimating the left ventricular volume during systole and diastole using the method of discs in the apical 4-chamber view. In the case of suboptimal image quality eyeballing was used.• Aortic stenosis (maximum flow velocity ≥3 m/s). In the case of aortic stenosis, the severity was measured using a combination of two-dimensional observations from the parasternal long axis view and the apical 5-chamber view and spectral Doppler analyses of the blood flow through the aortic valve.The cut-off values of outcome variables are primarily selected based on current recommendations from the European and American societies of echocardiography ,22. AlsoIn order to establish gold standard results for all examinations a second interpretation was made by a specialist in cardiology with expert skills in echocardiography. This expert examiner reviewed all the images obtained by the novice examiner and categorised all patients according to the dichotomous outcomes in the pre-defined criteria. In the case of sub-optimal image quality or doubt about the outcomes, the expert also had full access to images and interpretations obtained from the original clinical echocardiogram done by another cardiologist. The expert was blinded to results made by the novice examiner.Diagnostic performance was estimated with sensitivity and specificity. Predictive values were calculated and kappa statistics were applied. Comparison of results between the novice examiner and the specialist was estimated by McNemar’s test. Tests and calculations were performed using Stata 11.0 software .A total of 102 medical and surgical patients were included. The mean age of patients was 63.2 ±16.4 years and 31% were females. Information on discharge diagnosis is shown in Table Overall, 102 assessments were made in six categories totalling 612 assessments. Pericardial effusion was present in 15 patients, left ventricular dilatation was present in 22 patients, right ventricular dilatation was present in 19 patients, left ventricular hypertrophy was present in 27 patients, left ventricular failure was present in 38 patients and aortic stenosis was present in 33 patients. A detailed description of pathological findings is shown in Table There was agreement between the novice examiner and the specialist in 95.6% of the cases. The overall sensitivity was 0.91 and specificity was 0.97. Positive predictive value was 0.92 and negative predictive value was 0.97. Kappa statistics showed good agreement between observers (κ=0.88). McNemar’s test showed no difference between the novice examiner and the specialist (P = 1.00). Detailed results from each category are shown in Table In this study the results showed very good agreement between a novice examiner performing POC cardiac ultrasonography and reference values when dealing exclusively with dichotomous outcomes.The reason for choosing dichotomous outcomes instead of continuous variables relates to the fundamental ideas of POC ultrasonography and also the clinical reality in which POC ultrasonography is used. In the context of anaesthesiology, critical care or emergency medicine it is sufficient to identify the presence of normal or reduced EF. In these settings it is not clinically relevant to sub-categorize EF in intervals of e.g. 5-10%, since this discrimination will have no immediate implications for the clinical management of the patient. Similarly, it is often not clinically relevant to discriminate between small differences in left ventricular end-diastolic diameters, but it is important to know if the left ventricle is severely dilated or not ,24.Results in most pathology categories showed very good agreement, although some categories performed better than others. Sensitivity with regard to RV diameter and myocardial thickness was 0.84 and 0.85, respectively, whereas sensitivities in the remaining categories were all above 0.9. The reason for suboptimal diagnostic performance when assessing the RV can be explained by the complex geometry of the ventricle and incomplete visualization by 2-dimensional ultrasonography. Suboptimal diagnostic performance when measuring myocardial thickness can be attributed to the fact that many of the cases were borderline hypertrophic. This has a major impact on the results due to the dichotomous categorization. The same phenomenon of borderline measurements on the wrong side of the cut-off accounts for almost every false positive and false negative result. Each of the false results was reviewed and almost every one proved to be borderline cases. Unfortunately, we do not have data on the continuous variables assessed by the expert, and hence it is not possible to provide further details on these borderline cases. However, the reason for most of the borderline cases can be attributed to the fact that significant pathology in one category (e.g. left ventricular failure) and insignificant pathology  in another category were allowed into the study, introducing difficult estimations close to the cut-off values. In contrast, patients with only mild pathology in only one category were not allowed into the study reducing the number of borderline cases.An aortic stenosis often represents a clinical challenge in the context of anaesthesiology, critical care or emergency medicine. In this study we found a very high sensitivity and specificity probably because of a relatively low number of borderline cases. However, the detection and quantification of an aortic stenosis can be challenging especially with concomitant left ventricular failure. Thus, to further increase the diagnostic accuracy when assessing aortic valves it should be recommended to supplement the Doppler recordings with simple 2D imaging of the valve.POC ultrasonography is already common in many clinical settings and it is predicted that the modality can decrease medical errors and provide efficient real-time diagnoses .In the cardiopulmonary area there is increasing evidence that novice examiners can learn focused POC ultrasonography protocols and implement them in a variety of medical contexts . An obviThe equipment used in the current study was a high-end cart-based system with the purpose of optimal conditions for the novice examiner. However, bedside POC ultrasonography in the future will probably be performed on pocket sized systems and studies investigating novice examiners using these relatively new machines have already been published showing diagnostic accuracy superior to a normal clinical examination ,27.Considering the present and also other recent studies, it seems reasonable to allow novice examiners to perform and interpret POC ultrasonography. However, it should always be remembered that the ultrasonographic findings can never stand alone. Whether or not an ultrasonographic finding represents hemodynamically significant pathology or not requires a full clinical evaluation and possibly further testing or imaging.During the design phase of the current study the number of novice examiners performing POC cardiac ultrasonography was thoroughly considered. The statistically and methodological optimal setting would probably have been to include 10–20 novice examiners from the same department and have them evaluate all the patients. This would contribute information on variability in skill among examiners. However, several patients included were suffering from severe heart disease and some of them even dying, so it was not ethically feasible to subject the patients to ultrasonography by 10-20 different novice examiners.The fact that one novice examiner evaluated all the patients may raise the question as to whether this person was truly a novice at the end of the study. However, experts agree that level 1 or novice skills in POC cardiac ultrasonography requires between 150–300 studies ,20. ThisThe novice examiner performing all the examinations in the current study was motivated to acquire skills in POC ultrasonography and therefore questions about selection bias can be raised. However, the novice examiner did have any special skills or prerequisites not obtainable by other physicians and, in general, young physicians are usually highly inclined to POC ultrasonography.Pleural scanning is usually part of the FATE protocol. However, we did not include assessment of the pleural cavity is this study, as no reference assessments were available from the reference echocardiographic images. In addition, simple colour Doppler assessment of valvular regurgitations was not part of the POC protocol used in the present study, since most examiners are non-cardiologist with limited experience. However, as skills increase this could be a relevant addition in future studies since this modality is now available even in pocket sized devices.The medical and surgical patients included were screened according to the criteria listed in Table The pre-defined outcome categories used in this study were chosen because they represent clinically important situations. However, assessment of these six categories does not represent a total hemodynamic evaluation. This would require a full specialist echocardiography and sometimes even invasive measures.Nevertheless, the cut-off values chosen for this study were needed to operate with dichotomous outcomes which seem relevant in the context of anaesthesiology, critical care or emergency medicine where POC ultrasonography is predominant.It is a well-known fact that even when experts perform full standard TTE considerable intra- and inter-observer variation has to be taken into account. In addition, the expert responsible for gold standard assessment in this study did not perform the examinations himself. These two facts may have contributed to additional variation in the results. In addition, full standard TTE is sometimes hampered by poor image quality requiring transesophageal examination. Only two patients were excluded due to poor image quality in this study plausibly representative of everyday clinical practice.This study showed that a novice examiner was able to detect common and significant heart pathology in six different categories with good accuracy using POC ultrasonography. Interpretation of the results has limitations and further studies must be conducted in order to assess whether limited systematic education leads to sufficient skills and whether implementation of the modality leads to an improved patient outcome.TTE: Transthoracic echocardiography; POC: Point-of-care; FATE: Focus assessed transthoracic echocardiography.The authors declare that they have no competing interest.CF, PJ, NA, and ES participated in the design of the study. CF and PJ carried out the data acquisition. CF and NA performed the data analysis and CF performed the statistical analysis. CF and ES drafted the manuscript. All authors read, revised and approved the final manuscript.


Cardiovascular CT is considered the diagnostic standard for establishing the presence of a functional and dynamic imaging system. It is difficult, however, to estimate the ventricular motion and volumes that are processed using hundreds and thousands of CT images, in a few moments.The main concept and design of our work are two fold — the development of effective semi-automatic tools for measuring the sequential left ventricular volumes from the hundreds or thousands of cardiac trans-axial images, and providing a simple interface with an interactive diagnostic tool for the volumetry of left ventricle and valuable cardiac 4D visualisation.We converted ten and more sequential volume data sets of the heart acquired from retrospective ECG-gating helical scan into 3D images by volume rendering. These sequential 3D images could be displayed as a movie (4D cardiac image) file. Furthermore, we developed a method for semi-automatic calculation of ejection fraction (EF) and cardiac cycle (%)-volume (ml) curve for estimation of the motion and the volume of the left ventricle. This method involved the use an interactive selection tool in the region of interest (ROI). All 3D processing methods, such as, cutting objects, segmentation, and image fusion were based on mask processing data. We now describe the software developed for cardiac 4D imaging and the estimation of ventricular volume. Multislice computed tomography (MSCT) offers good cardiac image quality using ECG synchronised technique, producing no motion artefacts -5. The hAs the development of computer hardware and software has been incredibly fast and inexpensive, a system of real-time visualisation and image analysis should provide the user with good quality image and movie display. First, we developed effective semi-automatic tools for measuring the sequential left ventricular volumes from the hundreds or thousands of cardiac trans-axial images. We adopted this technique and made several improvements to overcome the problem of automatic calculation of the left ventricular volumes for different motion phases acquired from the retrospective ECG-gating helical scan. Second, we extended this technique to display 3- and 4D images of the heart with real-time volume rendering on the personal computer (PC).By this, we reduced the time and the effort taken for cardiac function analysis and 4D display. We introduced a design-integrated system for cardiac data acquisition and various tools for cardiac function analysis.Retrospective gating is needed for helical scanning, and ECG gating has been used for years in magnetic resonance imaging (MRI). It consists of contiguous data acquisition with parallel registration of the patient’s ECG . SubsequThe advantages of ECG gating over ECG triggering is that the data acquisition is independent of the patient’s heart rate, and it is possible to visualise the imaged region during different times in the cardiac cycle. This permits functional evaluation. The disadvantage is the prolonged data post processing procedure and the associated higher radiation dose.We installed 4D cardiac analysis software on a standard PC with Pentium 4 3.00 GHz CPU, and 2.00 GB RAM on Microsoft Windows XP and Intel Core Duo, 2.00 GHz CPU and 2.00 GB RAM on Mac OS X. The processing and the image rendering tools of the software are based on the open-source libraries with OsiriX . CuscreeECG leads were placed on both wrists and the left forearm of the patients to avoid artefacts. Following a scout view for positioning, the contrast-enhanced CT data were acquired during a single breath-hold. Patients inhaled 3.0 l/min of oxygen prior to the acquisition, while the scan parameters were established. Fifty seconds after intravehicular injection of the contrast medium , the scan was started with the ECG-gating technique. The exact start and end points of the helical scanning synchronised ECG record were monitored on the multislice CT console. The parameters used were 0.5 sec per rotation, and the value for 2-mm-detector row collimation of the helical pitch (length of table translation divided by X-ray beam width) was 0.2:1. The time of breath hold was about 75 rotations through 12 cm during 37.5 sec. The X-ray tube voltage and current were 140 kV and 160 mA, respectively. The volume data sets for phases of cardiac motion were prepared as 10 sets reconstructed for every 1mm interval using 50% overlap reconstruction from raw-helical CT data. For each patient, 10 sets of volume data were created by using both half-scan and segment reconstruction based on the retrospective ECG-gating helical scanning [After loading the 10 sets of volumes for all cardiac trans-axial slices, the user can easily change the order of the series to make sequential 4D cardiac image.To reduce time and effort, the parameters of volume rendering  were automatically synchronised with just one volume operation. The remaining nine sets of series were processed in sync with a series of interest. The EF, a parameter of global ventricular function, is calculated from the volumes at end diastolic EDV and end systolic ESV as: This is the single most powerful prognostic indicator, and its value correlates with the risk of morbidity and mortality in different types and stages of heart disease. The presence of an abnormality in the regional wall motion suggests ischemic heart disease, the location of the hypokinesis correlates loosely with the coronary artery that is affected, and the size of the functional defect suggests the amount of myocardium that is ischemic or infracted. In our software, semi-automatic EF calculation was applied with simple segmentation and volume calculation using voxel counting to avoid the error of segmentation at the level of tricuspid valve.The procedure to calculate the semi-automated EF is as follows:Selection of the arbitrary ROI around the left ventricular cavity on trans-axial images in end-diastolic phase. . Copying the ROIs of the end-diastolic phase to all other phases. Left ventricular cavities with all phases covered by left ventricular cavity at end-diastolic phase. Estimation of threshold Hounsfield Unit (HU) value for segmentation of left ventricular cavity using histogram analysis applied Mode method ,11. The Automatic drawing of the cardiac cycle (%) – volume (ml) curve and EF calculation.The resulting 3D image set consists of 109 slices per temporal frame and 10 temporal 3D frames per cardiac cycle. The results of the segmentation of LV volume and cardiac cycle (%) – volume (ml) curve are displayed in One of the most effective techniques for cardiosurgery is temporal 3D display of prosthetic valve after prosthetic valve replacement (The DICOM-supported software for 4D cardiac imaging and function analysis with online connection to multislice CT apparatus is useful to comprehend the left ventricular motion and volumes.


Diabetic cardiomyopathy contributes to increased cardiovascular mortality in diabetes mellitus (DM) patients and is characterized by a progressive alteration of left ventricular (LV) function. At a preclinical stage, a decrease in systolic myocardial strain has been suggested in echocardiographic studies.MRI techniques remain the gold standard for quantification of myocardial deformation but only a single study suggested systolic abnormalities in type 2 DM patients with evidence of diastolic dysfunction.MR-tagging is the most common technique for strain calculation using CMR but is intrinsically limited in measuring transmural variations. Cine-Displacement ENcoding Imaging with Stimulated Echoes(DENSE) has been recently proposed as an alternative that benefits from an increased spatial resolution.To evaluate whether cine-DENSE and MR-tagging confirm the existence of a sub-clinical myocardial dysfunction in a population of type 2 DM patients with no sign or history of heart disease and normal conventional echo and MRI parameters.c) was calculated from cine-DENSE and MR-tagging acquisitions on 16 LV segments. Average maximal systolic strain in each slice and a whole heart mean value(εcmean) for each patient were calculated. Post-processing of cine-DENSE acquisitions included adaptive phase-unwrapping and spatial filtering. CSPAMM images were processed using InTag post-processing toolbox  implemented in OsiriX software  with motion estimation based on the Sine Wave Modeling approach.37 patients with type 2 DM  and 21 age-matched controls  underwent a CMR study on a 1.5T scanner. Subjects were excluded if standard echocardiography showed significant abnormality. After a standard CMR study for conventional LV function assessment, two-dimensional cine-DENSE pulse sequence with short-echo train echo-planar imaging readout and cine-tagging with complementary spatial modulation of magnetization(CSPAMM) were acquired in short axis views at the same basal, mid and apical levels. LV volumes and ejection fraction were measured on cine-MRI images. Regional circumferential maximal systolic strain(εc at basal, mid and apical LV level and in εcmean in the DM group as compared to controls. MR-tagging confirmed a decrease in εc at the 3 LV levels and in εcmean in DM patients as compared with controls.Standard cine-MRI LV function parameters were normal and comparable between groups table . WhereasCine-DENSE and MR-tagging confirm subclinical myocardial dysfunction in asymptomatic patients with Type II DM.


Deterioration of left ventricular (LV) function after myocardial infarction (MI) is a major cause of heart failure. Myocardial perfusion performance may play an important role in deterioration or improvement in LV function after MI. The aim of this study was to evaluate the myocardial perfusion reserve (MPR) and stress perfusion in deteriorating and non-deteriorating LV segments in patients after MI by PET and MRI, respectively.13N-ammonia perfusion 24 months after MI. Segments were divided into four groups according to deterioration or improvement in wall thickening.Regional wall thickening of 352 segments in 22 patients was assessed at 4 and 24 months after MI by cardiac MRI. PET was performed to evaluate MPR and adenosine stress p < 0.001). Furthermore, dysfunctional segments that improved had a significantly higher mean stress perfusion PET value than dysfunctional segments that remained dysfunctional (p < 0.001).Normal functional segments at 4 months after MI that remained stable had a significantly higher mean MPR and mean stress perfusion PET value than deteriorated segments (This study demonstrated the additional value of myocardial perfusion assessment in relation to the functional integrity of the injured myocardium. Segmental functional LV improvement after MI was associated with better regional myocardial perfusion characteristics. Furthermore, the amount of wall thickening reduction was associated with regional myocardial perfusion abnormalities in patients after MI. During recent decades, substantial improvements in the treatment strategies in patients with myocardial infarction (MI) have been achieved. Although this has greatly reduced the rate of early mortality, MI-induced heart failure remains a major cause of MI-associated morbidity and late mortality . After MMyocardial perfusion performance depends on the condition of large  and small (resistance) vessels. Deficient myocardial perfusion is considered to play a key role in pathophysiological processes involved in MI-induced heart failure . Inadequ13N-ammonia perfusion, and changes in regional myocardial WT after MI as assessed with MRI.PET-based myocardial perfusion imaging is used for absolute quantification of myocardial perfusion (millilitres per minute per gram) at the global and regional levels . Due to Patients with MI admitted to the University Medical Center Groningen (UMCG) were retrospectively included in this study. They all underwent percutaneous coronary intervention (PCI). Before starting the PCI procedure patients were treated with aspirin, heparin and clopidogrel. After PCI patients received a beta-blocker, aspirin, lipid-lowering therapy, and a renin-angiotensin-aldosterone system inhibitor combined with clopidogrel. Patients participated in the HEBE trial  and undeAt 4 and 24 months after infarction cardiac MRI was performed to assess left ventricular (LV) function. A 1.5-T MRI scanner with a four-element phased array cardiac receiver coil was used. Images were analysed using a dedicated software package . Endocardial and epicardial borders in end-diastolic and end-systolic images were outlined manually on short-axis slices, covering the entire LV from base to apex including the papillary muscles to the volume. For regional analysis the LV was divided into 16 different segments. Segmental end-diastolic wall thickness (EDWT) and end-systolic wall thickness (ESWT) were determined in millimetres. WT was calculated in each segment by subtracting EDWT from ESWT. At each time-point a cut-off value of 3 mm was applied to consider segments as functional versus dysfunctional . All seg13N-ammonia PET scan and an adenosine-induced stress 13N-ammonia PET scan 24 months after MI. Patients refrained from caffeinated beverages from 12 h prior to scanning. Imaging was performed with the patient supine on an ECAT HR+ PET camera . A transmission scan for further attenuation correction was acquired for 5 min using an external ring source filled with 68Ge/68Ga. Accidental coincidence and dead time were automatically corrected. Myocardial perfusion imaging at rest was started 2 min after injection of 400 MBq of 13N-ammonia and was continued for 15 min. The same protocol was used 6 min after intravenous injection of 0.14 mg/kg per minute adenosine to acquire stress myocardial perfusion images. A parametric polar map was generated from the PET data. These data were corrected for partial volume effects and activity spillover from the blood pool. Regional (stress and rest) myocardial blood flow was calculated using a 17-segment model, but reformatted in a 16 segment model corresponding to the obtained MRI data. Segmental MPR was calculated by dividing the adenosine stress 13N-ammonia PET result by the rate pressure product normalized rest 13N-ammonia for each segment.The patients underwent a rest t-test was used to assess differences in WT between baseline and follow-up MRI. The significance level was set at 0.05.The results are expressed as means ± SD. The Kolmogorov-Smirnov test was used to assess whether the MPR and WT values were distributed normally. Due to a non-normal distribution of WT values in the sample, the Kruskal-Wallis test was used to compare the MPR and stress perfusion PET values between different groups of WT. A paired Student’s We evaluated 352 segments in 22 patients. There were no revascularization procedures between the first and second time-points. Descriptive data on cardiovascular risk factors, LV ejection fraction (LVEF), MPR, wall thickness and WT at both time-points are shown in Table p < 0.01), 11.4 ± 3.5 mm (p < 0.01) and 4.0 ± 2.5 mm (p < 0.01), respectively.The first MRI scan was performed 4 months after MI. In all 352 segments the mean values of EDWT, ESWT and WT were 7.0 ± 1.8, 10.4 ± 2.9, and 3.5 ± 2.1 mm, respectively. The second MRI scan was performed 24 months after MI to follow-up the patients’ myocardial function. The mean values of EDWT, ESWT and WT in the second scan were 7.3 ± 2.2 mm  than the group with remaining normal functional segments. Groups 3 and 4  showed higher mean MPR and stress perfusion PET values in the functionally improved segments at 24 months  than the group with remaining dysfunctional segments (Table The mean MPR values were 1.7 ± 0.6, 1.2 ± 0.5, 1.5 ± 0.6, and 1.3 ± 0.5 in groups 1–4, respectively. Overall, the mean MPR in the 352 segments was 1.5 ± 0.6 (Table In the present study we evaluated the relationship between changes in regional myocardial WT between 4 and 24 months after MI and PET myocardial perfusion. The main finding of this study was the association between segmental LV function deterioration and a lower stress perfusion as well as perfusion reserve.Congestive heart failure is the leading cause of MI-associated mortality and mortality . The infThe prognostic role of regional and global MPR in patients with hypertrophic cardiomyopathy , 15, idiUsing serial MRI measurements after MI functional segmental LV changes can be identified. At present the clinical importance of such changes remains to be determined. PET perfusion imaging may be of additional clinical assistance. It would be worth evaluating the usefulness of prospective PET perfusion assessment in the prediction of LV deterioration/heart failure in later stages. If such an approach was proved to be of value, it could be used for guiding personalized therapy in patients with heart disease.A limitation of this study was the relatively low number of included patients, but the number of analysed LV segments was large. Also data on long-term outcomes were not available in this study, but need to be collected in future studies. These data are of importance for determining if stress perfusion and MPR PET are still linked over the long term with LV the contractility pattern after MI.In conclusion, the combination of PET and MRI is a powerful tool for evaluating the relationship between myocardial perfusion and contractility changes after MI at a regional level. The observation that functional deterioration is accompanied by reduced stress perfusion as well as perfusion reserve further emphasizes the relationship between sufficient oxygen supply and cardiac remodelling after MI. Future research should establish whether prognostic evaluation of perfusion reserve could identify patients at risk of developing heart failure.


Cardiogenic shock continues to be a life-threatening condition carrying a high mortality and morbidity, where the prognosis remains poor despite intensive modern treatment modalities. In recent years, mainly technical improvements have led to a more widespread use of short- and long-term mechanical circulatory support, such as veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and left ventricular assist devices (LVADs). Currently, LVADs are indispensable as ‘bridge’ to cardiac recovery, heart transplantation (HTX), and/or as destination therapy Importantly, both LVADs and HTX put a vast burden on financial resources, besides significant short- and long-term risks of morbidity and mortality. These considerations underscore the importance of optimal timing and appropriate patient selection for LVAD therapy, avoiding as much as possible an unfortunate and costly clinical path. In this report, we present a series of three cases with acute refractory cardiogenic shock  successfully treated by ECMO and early optimal medical therapy preventing a certain path towards LVAD and/or HTX, for which they were initially referred. This conservative approach in INTERMACS profile one patients warrants very early introduction of adequate medical heart failure therapy under the umbrella of a combination of short-term mechanical circulatory and inotropic support by phosphodiesterase inhibitors. Therefore, this novel combined medical-mechanical approach could have important clinical implications for this extremely challenging patient category, as it may avoid an unnecessary and costly clinical path towards LVAD and/or heart transplantation. Cardiogenic shock continues to be a highly dangerous condition carrying considerable risk of mortality and morbidity despite all currently available treatment modalities. In clinical practice, urgent resuscitation by short-term mechanical support is often the only remaining therapeutic option to prevent a certain death . Among tHere, we present an alternative therapeutic strategy, exemplified by a series of three cases presenting with acute, severe and refractory cardiogenic shock and successfully treated by early veno-arterial ECMO Table . The latA 28-year-old male without any cardiovascular history but known alcohol and drug (amphetamine) abuse, was admitted to our Intensive Cardiac Care Unit with acute, severe and refractory cardiogenic shock Table . LaboratA 25-year-old female with no history of cardiovascular disease was admitted with severe cardiogenic shock and decompensated heart failure after a week of fever, myalgia, nausea and vomiting Table . Blood rA 50-year-old male with no relevant medical history presented to a referring hospital with severe left-sided heart failure with signs of dilated cardiomyopathy on echocardiography Table . He compHere, we present a series of cases with acute, severe and refractory cardiogenic shock, successfully treated with ‘short-term’ ECMO support and optimised medical therapy preventing a certain path towards LVAD and/or heart transplantation. Importantly, this more conservative approach in INTERMACS profile 1 incorporates early introduction of heart failure therapy, already during ECMO, using phosphodiesterase inhibition as an ‘umbrella’ to allow early initiation of oral heart failure therapy including beta blockers and angiotensin enzyme inhibitors.momentum for these patients to survive the first critical phase (crash to certain death) and afterwards continue in the upward line of clinical recovery, thereby preventing the path towards LVAD or HTX.We hypothesised that the very early initiation of medical-mechanical support and introduction of heart failure medication (under the umbrella of enoximone) provides the Cardiogenic shock remains a highly dangerous condition with a high risk of mortality and morbidity despite extensive current medical and mechanical support –3. With In this case series, we discuss an alternative approach in selected patients with severe cardiogenic shock to use a VA-ECMO as bridge-to-recovery, enhanced by introducing very early heart failure medication, including ACE inhibitors and beta blockers using enoximone and ECMO. Our approach of using VA-ECMO for a prolonged period of time under the umbrella of enoximone therapy is new and could be a way to prevent the bridge-to-destination or bridge-to-transplantation paths. The current approach has worked for several of our patients with great success, as presented in our case series. However, patient numbers (and experience) in this category will remain small and dependent largely on clinical experience. We believe that –in our centre- this approach was partly feasible due to the unique cooperation of cardiac intensive care specialists as well as heart failure specialists in a combined intensive care unit and cardiac care unit.The proposed period of bridging with VA-ECMO and very early introduction of heart failure therapy (including beta blockers) under the umbrella of enoximone, can give the needed time to evaluate the clinical course of the patient’s illness and select the appropriate patients to either await clinical recovery or proceed to LVAD. After stabilisation, enoximone provided the necessary back-up to introduce B1-selective beta blockers as these agents are independent of beta-receptor signalling and beta receptors in contrast to dobutamine , 8. The In all three patients, cardiogenic shock and multi-organ failure persisted despite conventional support which was the reason to expand treatment with VA-ECMO rapidly as an option for short-term (temporary) mechanical support. The choice for VA-ECMO depends on experience and device availability in the centre. VA-ECMO can be inserted – percutaneously – rapidly and buy time. It is essential to take this decision as early as possible on the first day, before multi-organ failure has advanced to such a degree that VA-ECMO is also doomed to fail. Realistically, some patients will cope (as presented in the current cases), but others will not and still need LVAD or heart transplantation despite all efforts . VA-ECMOconservative approach in INTERMACS profile 1 patients by combining short-term mechanical circulatory support with early introduction of medical heart failure therapy under the umbrella of phosphodiesterase inhibitors, which could be a successful way to treat refractory cardiogenic shock patients. This novel approach may have clinical implications as it shows that the clinical path towards LVAD and/or heart transplantation can be diverted in some, which makes the discussion on applicable patients for LVADs even more challenging and efforts to reduce unnecessary LVAD implantation even more warranted.In conclusion, we advocate an initial


Increased left atrial (LA) size measured at left ventricular (LV) end systole is associated with cardiovascular morbidity and mortality in population based studies. LA function can be divided into 3 components: LA filling during LV systole, a passive emptying phase during early diastole and active atrial systole during LV late diastole. We sought to assess the relationships of LA volume and emptying function to invasive LV end diastolic pressure (LVEDP).Forty one patients underwent cardiac MRI (CMR) within 5 hours of clinically indicated left heart catheterization. Sixteen healthy volunteers served as CMR controls. LV and LA volumes and ejection (EF) were assessed from cine images. Using the biplane formula, LA volume was calculated at LV end-systole (LAVmax), LV end-diastole (LAVmin) and at the end of LV early filling before LA systole. LA function was divided into global emptying function (LAEF), passive LAEF and active LAEF expressed as fractional volume change. LVEDP was measured invasively during diagnostic catheterization. The association of LA indices with LVEDP was assessed using Receiver Operating Characteristics.Mean age was 59 years in patients and 53 years in control (NS). As compared to controls, patients had larger LVEDV  and lower LVEF . Mean LVEDP was 14±8 mmHg in patients. Of the LA volume indices LAVmin was significantly more closely associated with LVEDP elevation (>12 mmHg)  than LAVmax  (p=0.048 for LAVmin vs. LAVmax). LAVmin ≥ 23 ml/m2 was associated with LVEDP elevation with 86% sensitivity and 63% specificity. Of the LAEF indices global LAEF had the closest association with LVEDP elevation , followed by active LAEF  and passive LAEF . Global LAEF ≤ 35% was associated with LVEDP elevation with 71% sensitivity and 89% specificity while active LAEF ≤16% was associated with LVEDP elevation with 43% sensitivity and 93% specificity.LAV measured at LV end diastole had a stronger association with LVEDP than LAV measured at LV end systole. Global and active LAEF were significantly reduced with increasing LVEDP.None.


Myocardial infarction causes irreversible loss of cardiomyocytes and may lead to loss of ventricular function, morbidity and mortality. Infarct size is a major prognostic factor and reduction of infarct size has therefore been an important objective of strategies to improve outcomes. In experimental studies, glucagon-like peptide 1 and exenatide, a long acting glucagon-like peptide 1 receptor agonist, a novel drug introduced for the treatment of type 2 diabetes, reduced infarct size after myocardial infarction by activating pro-survival pathways and by increasing metabolic efficiency.The EXAMI trial is a multi-center, prospective, randomized, placebo controlled trial, designed to evaluate clinical outcome of exenatide infusion on top of standard treatment, in patients with an acute myocardial infarction, successfully treated with primary percutaneous coronary intervention. A total of 108 patients will be randomized to exenatide (5 μg bolus in 30 minutes followed by continuous infusion of 20 μg/24 h for 72 h) or placebo treatment. The primary end point of the study is myocardial infarct size (measured using magnetic resonance imaging with delayed enhancement at 4 months) as a percentage of the area at risk (measured using T2 weighted images at 3-7 days).If the current study demonstrates cardioprotective effects, exenatide may constitute a novel therapeutic option to reduce infarct size and preserve cardiac function in adjunction to reperfusion therapy in patients with acute myocardial infarction.NCT01254123ClinicalTrials.gov:  Myocardial infarction (MI) causes loss of cardiomyocytes and may lead to loss of ventricular function, morbidity and mortality. The impairment of left ventricular function may lead to heart failure and death and has a major impact on the quality of life of the patient. Infarct size is a major prognostic factor after MI,2. ReducIt was previously demonstrated that early reperfusion of the infarct related coronary artery, usually by primary percutaneous intervention (PCI) limits myocardial necrosis and improves clinical outcome in patients with acute MI. DespiteMultiple strategies have been investigated to reduce reperfusion injury. One of them is glucose-insulin-potassium (GIK) infusion that has been postulated to possess cytoprotective potential and has been investigated in several clinical trials for cardioprotection in patients with MI. Its efficacy is controversial, with some studies reporting a reduction in mortality in patients with acute MI-8, whereThe promising clinical results obtained with GLP-1 and with exenatide in the experimental setting constituted the rationale for the initiation of the EXAMI trial. This randomized placebo controlled multi center study will assess the cardioprotective effects of intravenous exenatide infusion on top of standard treatment in patients with ST elevation myocardial infarction undergoing primary PCI.http://www.clinicaltrials.gov; unique identifier NCT01254123). The trial is conducted in two Dutch hospitals: the VU University Medical Center in Amsterdam, and the University Medical Center Utrecht. The study was approved by the institutional ethical committee on human research and will be carried out in compliance with the Helsinki Declaration. To be eligible for participation in the trial, patients have to fit the inclusion and exclusion criteria listed in Table The EXAMI trial is a multi-center, prospective, randomized, placebo controlled clinical trial, designed to evaluate the safety and clinical efficacy of exenatide on top of standard treatment, in patients with an acute MI, successfully treated with PCI  and if possible primary PCI will be performed. Patients can be excluded during CAG or primary PCI based on the criteria listed in table Byetta injection pens  containing 1, 2 ml exenatide  will be obtained. Three doses (15 μg) will be diluted in 49 ml saline and 1 ml Human Serum Albumin  to obtain an exenatide concentration of 0.30 μg/ml. Infusion will start immediately after informed consent, just prior to PCI. During the first 30 minutes it will be infused intravenously at 33.33 ml/h (5 μg bolus in 30 minutes), followed by intravenous infusion at 2.78 ml/h (20 μg/24 h) for 72 hours. New solutions will be made every 8 hours. Based on experiences with healthy subjects, this is the maximum well-tolerated intravenous dose.Nausea is a side effect of exenatide as it slows gastric emptying. It occurs in 40-50% of the patients, but is usually mild, and severe nausea is reported in 3.5% of the patients. Nausea During hospital admission and follow up visits blood analysis will be performed. An overview of blood analysis during the study is listed in table Patients who are hyperglycemic at presentation will be treated with intravenous actrapid as long as necessary to maintain blood glucose levels between 4 and 8 mmol/L. Actrapid will be started at a dose of 1 unit/hour and the dose will be adjusted according to blood glucose levels that will be checked every three hours.Mild to moderate hypoglycemia is expected in approximately 5% of the patients, severe hypoglycemia is not expected.Three to 7 days and 4 months after primary PCI a cardiac MRI with delayed contrast enhancement (DCE) will be performed to assess left ventricular function and infarction size. The first MRI is performed to visualize myocardial edema, i.e. the area at risk. The second MRI is preformed to measure myocardial fibrosis, i.e. infarct area. Doing so, infarct size can be measured as a percentage of the area at risk. Patients are studied on a clinical 1, 5 Tesla scanner with a cardiac phased array receiver surface coil placed on the thorax.ECG-gated cine MR images are obtained during repeated breath-holds in the 3 standard long axis views . Additional short axis slices are acquired covering the entire left ventricle to examine regional and global left ventricular function. T2-weighted imaging will be acquired in long and short axis views and will be used to estimate the area at risk-23. DuriAll images are stored on a database where it will be forwarded for later blinded analysis. The MRI data are analyzed using a software package . On the short axis cine slices, the endocardial and epicardial borders are outlined manually in end-diastolic and end-systolic images, excluding trabeculae and papillary muscles. Assessment of global left ventricular function is obtained by calculating left ventricular volumes, mass, and ejection fraction using the summation of slice method multiplied by slice distance. For analysis of segmental myocardial function, each short axis slice is divided in 12 equiangular segments, starting at the posterior septal insertion of the right ventricle. Segmental wall thickening is expressed in absolute values  and relative values . Areas of hyperenhancement are outlined, including central dark zones of microvascular obstruction, allowing the calculation of total infarct size by summation of all slice volumes of hyperenhancement.Two to 7 days and 4 months after primary PCI, transthoracic echocardiography will be performed to measure global and regional cardiac function, using the iE33 ultrasound system  equipped with a S5-2 phased array (1 to 5 MHz broadband) transducer . A systematic imaging protocol will be performed, consisting of parasternal long-axis, short-axis and 4-, 2-, and 3-chamber apical views, closely following current guidelines. Global function of the left ventricle will be assessed with biplane Simpson's method. Global right ventricular function will be measured with the functional parameter tricuspid annular plane systolic excursion (TAPSE). Mitral, tricuspid, pulmonary and aortic valve will be assessed with color Doppler, measuring filling times, E- and A-top of the mitral valve and valvular function. In addition, the diastolic left ventricular function will be assessed with coded tissue Doppler imaging measuring peak tissue velocity during early diastole (E') at the basal left ventricular septum and lateral wall. Finally, using the same ultrasound system equipped with a X3-1 matrix-array transducer  a complete real-time 3-dimensional echo dataset will be obtained for blinded off-line analysis of global and regional left ventricular function.All patients visit our outpatient clinic at 6 weeks and at 4 months after primary PCI. The visits consist of clinical evaluation, blood analysis, and 12-lead electrocardiogram. Major cardiovascular events  will be documented. Furthermore, cardiac arrhythmias, heart failure, repeat coronary angiography, stroke, and hospital admission) are documented. At 4 months a second MRI and echocardiography will be performed to assess cardiac function and infarct size.The primary endpoint of the study is myocardial infarct size as a percentage of the area at risk (i.e. the perfusion territory of the infarct related coronary artery) as measured by MRI. The area at risk is measured 3-7 days after primary PCI and myocardial infarct size is measured 4 months after primary PCI. All secondary endpoints are indicated in table Myocardial infarct size as a percentage of the area at risk will be the primary endpoint of the study. With a power of 0.9 and an alpha error of 0.05, and with an anticipated 15% reduction in myocardial infarct size in the treatment arm considered clinically relevant, 48 patients per treatment arm have to be enrolled. To allow for dropout of 10% (based on previous experience), a total of 108 patients will be enrolled.The study results will be evaluated based on intention to treat analysis. Depending on the distribution of continuous outcomes, independent samples t-test or Mann-Whitney U test will be used as appropriate. Binary end points will be compared using Fisher exact probability test. For survival and clinical events, Kaplan Meijer curves will be displayed and comparison of the curves will be done using log rank testing based on a proportional hazards model.The EXAMI study, as outlined above, is a randomized clinical trial to investigate the cardioprotective properties of exenatide in patients with acute MI undergoing primary PCI, by means of measuring final infarct size compared to area at risk as measured with MRI. If reduction in infarct size is accomplished, exenatide may constitute a valuable therapeutic auxiliary for reperfusion therapy in patients with acute MI.Currently including patientsThe authors declare that they have no competing interests.MS made contributions to conception and design and of the trial, data acquisition and has been involved in drafting the manuscript. LT contributed to conception and design of the trial and drafted the manuscript. FB, RD and WC contributed to data acquisition and critically revised the manuscript for important intellectual content. AB contributed to trial design, designed the MRI protocols and critically revised the manuscript for important intellectual content. OK contributed to trial design, designed the echocardiography protocols and critically revised the manuscript for important intellectual content. MD, AH, HN, AR, NR, PD and YA contributed to conception and design, and critically revised the manuscript for important intellectual content. All authors have given final approval of the version of the manuscript to be published.


ABCC6 gene, is a rare multiorgan disease characterized by the mineralization and fragmentation of elastic fibers in connective tissue. Cardiac complications reportedly associated with PXE are mainly based on case reports.Pseudoxanthoma elasticum (PXE), caused by mutations in the −/−Abcc6) and wild-type controls (WT) were analyzed.A cohort of 67 PXE patients was prospectively assessed. Patients underwent physical examination, electrocardiogram, transthoracic echocardiography, cardiac magnetic resonance imaging (CMR), treadmill testing, and perfusion myocardial scintigraphy (SPECT). Additionally, the hearts of a PXE mouse models  dimension and function values were within the normal range. LV hypertrophy was found in 7 (10.4%) patients, though the hypertrophy etiology was unknown for 3 of those patients. Echocardiography revealed frequent but insignificant mitral and tricuspid valvulopathies. Mitral valve prolapse was present in 3 patients (4.5%). Two patients exhibited significant aortic stenosis (3.0%). While none of the functional and histological parameters diverged significantly between the −/−Abcc6 mice suggests that old PXE patients might be prone to developing late cardiopathy.Despite sporadic cases, PXE does not appear to be associated with frequent cardiac complications. However, the development of cardiac hypertrophy in the 24-month-old  ABCC6 gene encoding an ATP-binding cassette transporter Abcc6 knockout mouse model (−/−Abcc6) has confirmed ABCC6 critical role in the pathogenesis of PXE Pseudoxanthoma elasticum  is an autosomal recessive disorder characterized by the mineralization and fragmentation of elastic fibers, in the skin, retina, and vascular walls In most cases, the diagnosis of PXE is based on the combination of cutaneous and ophthalmologic findings. The main dermatological features include yellowish papules and loss of skin elasticity on the main flexural areas. Eye lesions consist of angioid streaks, which often lead to retinal hemorrhages and the loss of central vision. PXE has been associated with an increased risk of several cardiovascular complications, including hypertension, intermittent limb claudication, diastolic myocardial dysfunction, restrictive cardiomyopathy, mitral valve prolapse or stenosis, coronary artery disease, stroke, and sudden death −/−Abcc6 mice.Here we report the results of comprehensive cardiac investigations of a cohort of PXE patients that we compared to the cardiac findings obtained with In total, 67 adult PXE patients were prospectively included in our referral center . All patients provided informed written consent, and the study was approved by our local Ethics Committee at the University Hospital of Angers (France). The study was registered at ClinicalTrials.gov (Identifier: NCT01446380).PXE diagnosis was based on the combination of established criteria: clinically suggestive skin changes, angioid streaks, and histological demonstration of fragmented and calcified elastic fibers on skin biopsy i.e., systolic/diastolic blood pressure >140/90 mmHg or use of antihypertensive medication), diabetes (fasting glucose ≥1.25 g/L or use of glucose-lowering medication), and hyperlipemia .Body height and weight measurements, medical history, physical examinations, and blood pressure measurements were routinely performed. Blood samples were collected after overnight fasting for glycemia measurement and lipid profiling. Cardiovascular risk factors were recorded for all patients: smoking habits, hypertension  imaging performed on 42 patients (63%), treadmill tests on 40(60%), and perfusion myocardial scintigraphy on 28(42%).Complete standard data from 2-dimensional echocardiography and Doppler studies was collected with a commercially-available system . LV end-diastolic and end-systolic diameters and LV mass were calculated by M-mode on a parasternal long-axis view according to American Society of Echocardiography (ASE) guidelines CMR was performed using a 1.5T scanner  with an 8-element phased-array cardiac receiver coil. Localization was carried out using breath-hold real-time and steady-state free precession images of true anatomical axes of the heart. LV function was determined with cine imaging using a segmented steady-state free precession pulse sequence in multiple short-axis views, covering the entire LV. Late gadolinium-enhancement (LGE) was performed 7–10 minutes after administering a gadolinium-based contrast agent (cumulative dose of 0.2 mmol/kg of body weight) with a 2-dimensional segmented inversion recovery gradient-echo pulse sequence. The inversion time was individually adapted to null normal myocardium.Commercially-available software  was used for the analysis. Endocardial and epicardial borders were manually outlined on all end-diastolic and end-systolic short-axis cine slices. LV end-systolic and end-diastolic volumes, EF, and LV myocardial mass were then calculated in a standard manner. Myocardial fibrosis was defined by the presence of late gadolinium enhancement, which was evaluated under visual analysis, during which the window setting could be freely adjusted to the personal preference of the observers.PXE patients underwent a computer-assisted treadmill-exercise test according to the Bruce protocol. Cuff blood pressure measurements and standard 12-lead surface electrocardiograms were obtained in the standing position at baseline and at 3-minute intervals until the end of the recovery phase. Electrocardiograms were digitally stored and analyzed by an experienced observer. Exercise stress tests were symptom-limited or -terminated according to electrocardiographic criteria . An ischemic response was defined as a horizontal or down-sloping ST-segment depression of >1 mm.Patients received an intravenous dose of technetium 99mTc-MIBI (3.7 MBq/kg) immediately after the exercise test. For the study under resting conditions, which was performed 4 hours after exercise stress test imaging, thrice the dose (11 MB/kg) was administered 30 minutes prior to image acquisition. Images were acquired using a 2-detector Ventri™ scintillation camera . Images were reconstructed, and short-axis, horizontal long-axis, and vertical long-axis sections were obtained and displayed at a processing and review station, featuring a comprehensive set of cardiac applications. Technetium uptake was analyzed using a 17-segment myocardial model.−/−Abcc6 mice was previously described −/−Abcc6 mice backcrossed more than 10 times into a C57BL/6J background and their wild-type (WT) littermates of the same background were used in the study.All animal procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals, published by the US National Institutes of Health , and approved by the Animal Care and Use Committees of the University of Angers and the University of Hawaii. The generation of Mice aged 12 and 24 months were lightly anesthetized using ketamin (60 mg/kg i.p.). Echocardiography was performed using a commercially-available ultrasound system  equipped with a 13-MHz linear-array probe (IL13). All images were digitally stored on hard disk for offline analysis. Anterior wall (AW) and posterior wall (PW) thickness, LV cavity diameters, and LV shortening fraction (LVSF) were obtained from M-mode tracings recorded from the parasternal short-axis view at the level of the papillary muscles with two-dimensional image guidance −/−Abcc6 and WT mice were harvested and weighed to establish heart weight over body weight  ratios. Hearts were excised, fixed with formalin, and embedded in paraffin. Several sections of each heart (4–5 mm thick) were prepared, stained with picrosirius red for collagen deposition, and then visualized using light microscopy. For cardiomyocyte cross-sectional area measurements, the sections were stained with FITC-conjugated wheat germ agglutinin (WGA) from Invitrogen  to visualize membranes of cardiomyocytes and counterstained with DAPI. The periphery of cardiomyocyte was measured using the NIH ImageJ software (http://rsb.info.nih.gov/ij/). The dimension of 100 cardiomyocytes was determined for both −/−Abcc6 and WT mice groups.Hearts from 6-, 12- and 24-month-old t-tests. p values <0.05 were considered as statistically significant.Continuous variables were presented as mean ± standard deviation (SD) in PXE patients and standard error of the mean (SEM) in mice. Categorical variables were provided as counts or absolute frequencies. Statistical analyses were performed using SPPS 15 . In Study 2, between-group differences were assessed using Student The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.All patients exhibited sinus rhythm at the time of the examination. Q-waves were found in only one patient, who had a history of RCA angioplasty. A first degree atrio-ventricular block was present in one patient, a complete left-branch block was found in another, a complete right-branch block was identified in three patients, negative T waves was observed in one patient with LV hypertrophy related to severe aortic stenosis, and early repolarization syndrome was seen in two patients.As shown in Exercise treadmill tests were performed on 40 PXE patients, combined with SPECT for 27 of them. A further patient underwent dipyridamole SPECT because of severe intermittent lower limb claudication. The peak heart rate reached during exercise testing exceeded 85% of the theoretical maximal heart rate in most patients . In two patients, peak heart rate was 65% and 72% of the theoretical maximal heart rate on account of beta-blocker intake. For one of these two patients, dipyridamole perfusion was added to the exercise test at the time of scintigraphy. Lower limb claudication has also restricted exercise tests for three of our patients. Exercise treadmill tests were all negative. In one patient, SPECT combined with the exercise treadmill test revealed perfusion abnormality in one of the 17 myocardial segments. No further investigation was performed on this patient, who was otherwise asymptomatic with normal echocardiography. Finally, dipyridamole SPECT showed abnormalities in two anterior wall segments in one diabetic patient, though his coronary angiogram was normal.CMR-derived and echographic parameters of myocardial function are presented in Echocardiography revealed only hemodynamically-insignificant mitral and tricuspid valvulopathies . IncreasTwenty 12 month-old mice and ten 24 month-old mice underwent echocardiography. A single 24 month-old WT mouse was excluded from echocardiographic analysis because of poor image quality.−/−Abcc6 and WT mice groups: 482±31 beats/min in −/− vs.Abcc6 531±77 beats/min in WT, and 565±33 beats/min in −/− vsAbcc6. 525±23 beats/min in WT, 12-month and 24-month old mice, respectively. None of the echocardiography parameters in mice 12-month- and 24-month-aged were significantly different between the −/−Abcc6 and WT mice groups ; and WGA staining revealed a clear increase in the size of cardiomyocytes  in a subset of trained conscious mice. Systolic blood pressure was measured daily 6 consecutive days. The results showed no significantly different between −/−Abcc6 and WT mice: 115±10 mmHg in −/−Abcc6 mice group vs. 118±11 mmHg in WT mice group.In order to clarify whether the cardiac hypertrophy observed in ABCC6 gene's responsibility for the disease and compared our results with one of the animal models currently available.The exact susceptibility of PXE patients to cardiac complications has never been firmly established et alSevere CAD has been commonly reported in PXE cases Large PXE patient cohorts are rare, and to the best of our knowledge, prospective assessment of myocardial ischemia has never been reported. In this study, treadmill tests were normal in the 40 patients we tested. Furthermore, SPECT revealed only a minor perfusion defect in one patient out of 27, and a moderate perfusion defect in another, whom had an otherwise normal coronary angiogram. The prevalence of CAD in our cohort was at 6.0%, including the patient with a minor perfusion defect on SPECT, which is within the same range as the estimated prevalence for the European population (7.3%) between the age of 40 and 70 (mean = 52) ENPP1 gene in the majority of cases, but it was recently demonstrated that ABCC6 mutations accounted for a significant subset of GACI patients Whether these cases of CAD are directly linked to ABCC6 deficiency is unclear but deserves further thorough investigation. Clinical findings from generalized arterial calcification of infancy (GACI [MIM 208000]), another rare autosomal-recessive disorder characterized by calcification of the internal elastic lamina, myointimal proliferation of coronary arteries, and resultant myocardial ischemia and death in young children, may support this hypothesis. Indeed GACI is associated with biallelic mutations in the ABCC6 gene mutation (p.Arg1141X) are at an increased risk for CAD Interestingly, it has been suggested that Caucasian carriers of the most frequent et al. found mitral valve prolapse in 70% of 14 PXE patients in 1982 et al. reported only one case (2%) of mitral valve prolapse in a cohort of 42 patients Fibrous thickening of the endocardium and mitral valves leading to restrictive cardiomyopathy et al., we frequently detected mitral valve and tricuspid valve insufficiencies in our cohort , all of which were graded as “mild” et al. showed that mitral and triscupid regurgitations detectable by color Doppler echocardiography were highly prevalent in the general population at more than 80% Of note, similar to the data reported by Vanakker et al. analyzed the systolic and diastolic functions of 19 PXE patients Autopsies of PXE cases revealed direct involvement of the myocardium with endocardial lesions, characterized by degenerated elastic fibers with calcification in the subendocardium −/−Abcc6 mice recapitulate many of human PXE aspects, including the late onset ectopic mineralization, which becomes evident around 5–6 weeks of age −/−Abcc6 strain we used in this study −/−Abcc6 mice and their controls. These results are in line with the echocardiography and CMR findings in the PXE patient cohort.−/−Abcc6 mice. −/−Abcc6 mice have normal reproductive age and life expectancy While a LV hypertrophy of unknown etiology was found in 4.5% of our PXE patients, heart weight and cardiomyocyte size were significantly increased in the 24-month-old et al. have recently noted an increased infarct size in −/−Abcc6 mice after cardiac ischemia-reperfusion Finally, Mungrue Abcc6-deficient mice  even though a previous histology analysis has not found cardiac calcification in 10- to 12-week-old −/−Abcc6 mice In this study, we did not search for cardiac calcifications. Indeed, dystrophic cardiac calcification following a cardiac injury is a prominent feature in −/−Abcc6 mice does suggest that the old PXE patients could develop late cardiopathy.The main findings of this prospective cohort of 67 PXE patients were: 1) the low prevalence of myocardial ischemia, 2) the low prevalence of severe cardiac valve anomalies, 3) the mostly normal systolic and diastolic LV function, and 4) the lack of myocardial fibrosis. Despite sporadic counter-examples, PXE does not appear to be associated with frequent cardiac complications. However, the development of cardiac hypertrophy in the 24-month-old


Vasodilatory shock frequently occurs after cardiac surgery, particularly after cardiac assist device implantation. This complication is often associated with high mortality, especially if refractory to conventional vasoconstrictor treatment. Methylene blue, a guanylate cyclase inhibitor, has been successfully used in the management of vasodilatory shock associated with cardiopulmonary bypass. We present four successive cases after implantation of cardiac assist devices suffering from norepinephrine and vasopressin refractory severe vasodilatory shock. In all patients, administration of a single dose of methylene blue (2 mg/kg body weight) resulted in an immediate and persistent decrease in vasoconstrictor dosages and serum lactate concentrations. Despite of this benefit, all patients deceased during hospital stay, however, this was not related to the methylene blue treatment. Methylene blue seems to be a promising therapeutical option in patients with otherwise resistant vasodilatory shock after cardiac assist device implantation. However, controlled clinical trials are necessary to substantiate safety and efficacy. Vasodilatory shock is a frequent complication in the postoperative period in patients undergoing cardiac surgery which increases morbidity and mortality. It is characterized by peripheral vasodilatation, severe hypotension and by a poor response to therapy with vasoconstrictors. One important pathophysiological facet of this disease is an increased synthesis of nitric oxide , 2. The All patients received a single dose infusion of methylene blue (2 mg/kg body weight intravenously) over 30 minutes.A 49-year-old male patient  suffered from decompensated dilative cardiomyopathy. As he did not respond to conventional treatment  a Jarvik 2000 left ventricular assist device  was implanted. Postoperatively, the patient developed right heart failure, necessitating the implantation of an additional temporary right ventricular assist device . Severe postoperative bleeding required rethoracotomy and mass transfusion. Despite no further bleeding and faultless function of both cardiac assist devices, the patient developed a severe vasoplegic shock, requiring very high dosages of norepinephrine (4.0 mg/h) and vasopressin (6.0 I.U./h). After administration of a single dose methylene blue both norepinephrine and vasopressin dosages rapidly decreased and serum lactate concentrations normalized . On the A 46-year-old male patient  with a history of myocardial infarction and limited cardiac function (LVEF 20%) underwent resection of a massive left ventricular anterior wall aneurysm combined with mitral valve annuloplasty. Despite adequate filling pressures, use of multiple inotropic agents including levosimendan and insertion of an intraaortic balloon pump, cardiogenic shock occured postoperatively. He was transferred to the operating room for venoarterial extracorporal membrane oxygenation  rescue therapy. Since weaning from ECMO remained unsuccessful for four days, a permanent left ventricular assist device (Jarvik 2000) was inserted. Postoperatively, the patient suffered from right heart failure resistant to inhalation of iloprost and milrinone, so that venoarterial ECMO had to be re-implanted. Despite good function of both cardiac assist devices the patient suffered from severe vasodilatory shock resistant to high dosages of norepinephrine (3.0 mg/h) and vasopressin (8.0 I.U./h). Administration of methylene blue resulted in a reduction of norepinephrine and vasopressin to acceptable dosages within four hours . HoweverIn a 32-year-old male patient  with decompensated dilative cardiomyopathy a biventricular assist device  was implanted, as a bridge to transplant. Postoperatively, severe septic shock caused by pneumonia occurred and was treated empirically with meropenem, moxifloxacin, and linezolid. Despite adequate filling pressures, 7.0 mg/h of norepinephrine and 7.0 I.U./h of vasopressin were necessary to stabilize circulatory conditions. Methylene blue was applicated and vasoconstrictor dosages could be reduced within hours . On the A 70-year-old male patient  with pre-existing coronary heart disease underwent coronary angiography with instable angina pectoris. A significant stenosis of the right coronary artery was detected. The attempt to insert the wire into the right coronary artery resulted in a complete dissection of the vessel. Emergency coronary artery bypass operation with a saphenous vein graft was performed immediately, but revascularisation was technically impossible. Accordingly, the patient developed right heart failure and received venoarterial ECMO. Postoperatively, norepinephrine (1.6 mg/h) and vasopressin (8.0 I.U. /h) resistant vasodilatory shock occurred. After a single dose of methylene blue vasoconstrictor dosages decreased within hours . DespiteThe present case series shows that intravenous single dose administration of methylene blue in patients with vasodilatory shock after cardiac assist device implantation resulted in improved hemodynamics. An immediate and persistent decrease of vasopressor (norepinephrine and vasopressin) dosages was observed in all patients. Moreover, the lower lactate levels after infusion suggest that methylene blue increased the vascular tone without compromising global tissue perfusion .One underlying mechanism of vasodilatory shock involves increased nitric oxide production. The release of nitric oxide leads to activation of the enzyme guanylate cyclase, which increases the synthesis of cGMP, a mediator of vascular smooth muscle relaxation . MethyleAt the time point of methylene blue administration all patients were severely ill with multiple organ failure and high Apache II scores ranging between 32 and 40 with a predicted mortality between 76% and 91% [We conclude that methylene blue, through its effect on the nitric oxide pathway, is a promising option in the treatment of patients with vasodilatory shock after cardiac assist device implantation. However, a controlled clinical trial is needed to evaluate the benefit and best time point of application of methylene blue in severely ill patients before routine use can be recommended.