Placental growth factor [PlGF) is a cardiovascular (CV) risk marker, which is related to left ventricle hypertrophy (LVH) in animal models. Currently there are no data available regarding the possible relationship of PlGF and the development of LVH or diastolic dysfunction in patients with chronic kidney disease (CKD) and the relationship of PlGF to other CV risk factors in CKD patients. The aim of our study was to determine the possible association of PlGF and several other CV risk markers to echocardiographic parameters in CKD population.We prospectively examined selected laboratory  and echocardiographic parameters in 62 patients with CKD 2–4. Mean follow-up was 36 ±10 months. Laboratory and echocardiographic data were collected 2–3 times, at the shortest interval of 12 months apart. Multivariate regression analysis was used to detect independent correlations of variables.2.7) was found in 29% patients with CKD 2–4, left ventricular (LV) diastolic dysfunction was detected in 74.1% patients . After 36 ± 10 months increased LVMI was found in 37.1% patients with CKD 2–4, LV diastolic dysfunction was detected in 75.8% patients . Following independent correlations were found: LVMI was related to PlGF, cholesterol, BNP, systolic blood pressure and serum creatinine. EN-RAGE correlated positively with left atrial diameter and inversely with E/A ratio. During the follow-up we found a significant increase in LVMI and left atrial diameter, whereas a significant decrease in LVEF was noted.Increased left ventricular mass index (LVMI, g/mAccording to our data, PlGF is independently related to increased LV mass in CKD, whereas EN-RAGE is more likely related to diastolic dysfunction in this population. Cardiovascular risk in patients with chronic kidney disease is increased in early stages of renal insufficiency and rises with its progression. Traditional as well as specific CKD-related risk factors lead to vascular calcification, left ventricular hypertrophy (LVH) and myocardial fibrosis -3. In CKA number of pathways possibly responsible for the high CV risk in CKD are currently being studied. These mechanisms include hypertension, hyperactivity of the renin-angiotensin-aldosterone system, anaemia, sodium and volume retention, endothelial dysfunction, mineral and vitamin D disorders, micro-inflammation and oxidative stress . These pOne of the above mentioned biomarkers - Placental growth factor (PlGF) - is a 149 aminoacid heterodimer, expressed in human placenta, heart, thyroid gland, lung and skeletal muscle. PlGF is a member of the pro-proliferative vascular endothelial growth factor family and a pro-atherogenic cytokine which stimulates angiogenesis in ischemic tissues. It is up-regulated in atherosclerotic lesions, stimulates vascular smooth muscle growth and up-regulates production of tumour necrosis factor (TNF). PIGF is a biomarker of vascular inflammation and CV risk . In animNo data exist so far, about the possible relationship of PlGF and the development of LVH or diastolic dysfunction in CKD patients and the possible relationship of PlGF and other CV risk markers. Little is known about echocardiographic changes in patients with earlier CKD stages. Therefore, we aimed to study the possible association of PlGF and several other pro-atherogenic molecules or CV risk markers with echocardiographic parameters in CKD 2–4 patients.2.Between December 2004 and May 2009, 76 subjects with mild to moderate renal insufficiency (CKD 2–4) were consecutively recruited in the Outpatient unit of the Department of Nephrology . These subjects were followed during a mean period of 36 ± 10 months. We prospectively examined selected laboratory and echocardiographic characteristics of these subjects. Data were collected 2–3 times, at the shortest interval of 12 months apart. During the follow up period 8 patients died and 6 withdrew the informed consent. Final data analysis was performed only in 62 patients who completed the whole follow up period. Estimated glomerular filtration rate (eGFR) was calculated by MDRD formula. CKD was defined as a reduction in eGFR below 1 ml/s/1.73 mClinical and demographic characteristics of the group are presented in Table History of CV disease was taken from medical records of each patient, comprising coronary heart disease, peripheral arterial obstructive disease and/or cerebrovascular disease. History of CV disease was noted in 31 patients (50%). No patient had symptoms of severe heart failure (NYHA III. or IV.) or hemodynamically significant valvular defect.Fasting venous blood samples from each patient were collected. All samples were centrifuged for 10 min at 1.450 g (4°C). Sera were stored at −80°C until analysis.http://www.rndsystems.com), EN-RAGE . Routine biochemical parameters were assessed by standard laboratory methods.FGF23  was measured with ELISA kit according to the manufacturer protocol . PAPP-A was assessed immunochemically with the TRACE (Time Resolved Amplified Cryptate Emission) technology based on non-radiating energy transfer . MMP-2 and PlGF were measured with ELISA, Standard kits Quantikine, RD systems, Minneapolis, MN, USA. Biointact parathyroid hormone levels were analysed with ECLIA method . Brain natriuretic peptide (BNP) and troponin I (cTnI) were measured by chemiluminiscence methods . sRAGE and EN-RAGE were measured using standard ELISA kits according to the manufacturers’ protocols: sRAGE 3) + 0.6 [2.7, thus obtaining left ventricular mass index (LVMI). LV hypertrophy was defined as LV mass index >46.7 g/m2.7 in women or 49.2 g/m2.7 in men. Relative wall thickness, calculated as 2-times posterior wall thickness divided by LV internal diastolic dimension, was used to characterise LV geometry into following categories: normal , concentric remodeling , concentric hypertrophy (− increased LVMI and RWT > 0.42), and eccentric hypertrophy (− increased LVMI and RWT ≤ 0.42). LV volumes, comprising end-diastolic (LVEDV) and end-systolic volume (LVESV) were estimated using modified Simpson method, and used to calculate LV ejection fraction. Doppler characteristics of LV filling and diastolic function were assessed by using transmitral flow pattern along with pulmonary venous inflow parameters. In most patients we recorded mitral annular velocities. According to the current recommendations the filling was categorized as normal, impaired relaxation, pseudonormal and restrictive [2). In patients with mild diastolic dysfunction, the mitral E/A ratio is < 0.8, deceleration time of inflow of the E wave, (DT) is > 200 ms. In patients with moderate diastolic dysfunction (grade II), the mitral E/A ratio is 0.8 to 1.5  and decreases by ≥ 50% during the Valsalva maneuver. With severe diastolic dysfunction (grade III), restrictive LV filling occurs with an E/A ratio ≥ 2, DT < 160 ms [Complete two-dimensional M-mode and Doppler studies were performed via standard approaches, using Vivid 7 . M-mode examination was performed according to American Society of Echocardiography guidelines  LV mass 3) + 0.6 . The valtrictive ,15. Left< 160 ms ,15.The study was approved by the Ethical Committee of General University Hospital in Prague, reference number: 50/08. A written informed consent was obtained from all participants.The results of biochemical parameters are expressed as mean ± SD, in case of non-normal data distribution as medians and interquartile ranges. Comparisons were conducted with paired sample t tests for normally distributed continuous variables and Wilcoxon test for non-normal distributions. Variables with non-normal distributions were ln- transformed where appropriate. Association among analyzed parameters was assessed by Pearson’s correlation coefficient. Subsequently, linear regression analysis for determinants of echocardiographic parameters influential variables was performed. All variables significantly associated with echocardiographic characteristics were included in the multiple regression stepwise analyses . Qualitative variables, such as tobacco smoking, history of CV disease, use of ACE inhibitors, were analysed using the Kruskal-Wallis test. Chi-Squared Test for Trend was used to compare baseline and final echocardiographic findings in the subject group (Table Baseline echocardiographic parameters of the study group (Table).1. oup Table.Increased LV mass was noted in 29% patients. We identified 56.5% subjects with normal LV geometry, 12.9% subjects with concentric remodelling, 9.7% subjects with concentric hypertrophy and 21% subjects with eccentric hypertrophy. Normal LV diastolic function was found in 25.8% patients, impaired LV relaxation in 43.5% patients and pseudonormal pattern in 30.6% patients. No one met the criteria of restrictive pattern of LV diastolic filling.Echocardiographic parameters of the study group after 36 ± 10 months (Table2).2. Increased LV mass was noted in 37.1% patients. We identified 43.5% subjects with normal LV geometry, 21% subjects with concentric remodelling, 9.7% subjects with concentric hypertrophy and 25.6% subjects with eccentric hypertrophy. Normal LV diastolic function was found in 24.2% patients, impaired LV relaxation in 43.5% patients and pseudonormal pattern in 32.3% patients. No one met the criteria of restrictive pattern of LV diastolic filling.Independent correlations of echocardiographic parameters, laboratory markers and blood pressure .3. LV mass index was positively related to PlGF, BNP, systolic BP and serum creatinine. BNP positively correlated also with left atrial diameter. EN-RAGE was positively related to left atrial diameter and inversely to E/A. PTH inversely correlated with LVEF. No independent correlations were found between echocardiographic parameters and haemoglobin, PAPP-A, FGF23 or vitamin D levels. PlGF was not related to blood pressure.Impact of renal function on laboratory and echocardiographic parameters and their changes during the follow-up period (multiple regression) .4. eGFR was positively related to E/A ratio and inversely related to LVMI and left atrial diameter. During the follow-up, with the decline of eGFR, we noted a significant increase in LVMI, left atrial diameter, EN-RAGE, FGF23 and BNP, whereas a decrease was observed in LVEF, serum albumin, vitamin D and haemoglobin. No significant changes in blood pressure were noted.Laboratory parameters in patients with history of CV disease.5. History of CV disease was noted in 50% of patients. These patients had higher LVMI (p < 0.02), serum creatinine (p < 0.01), triacyglycerols (p < 0.05), FGF23 (p < 0.02) and PAPP-A (p < 0.05), whereas they had lower 25OHvitamin D (p < 0.05) and serum albumin levels (p < 0.01), compared to those free of such history. Relation of PlGF to CV disease history was of borderline significance (p = 0.05).To sum up the results: During the follow-up period  we noted an increased LVMI in 29%, resp. 37.1% of patients, abnormal LV geometry in 43.5%, resp. 56.5% and abnormal LV diastolic function in 74.1%, resp. 75.8 of subjects. However, these trends were not significant. LVMI correlated with PlGF, BNP, systolic BP and eGFR. LV diastolic function was related to EN-RAGE and eGFR. During the follow-up, with declining eGFR we noted an increase in LVMI, left atrial diameter, EN-RAGE, FGF23 and BNP, whereas a decrease was observed in LVEF, serum albumin, vitamin D and haemoglobin.In the group of patients with mild to moderate CKD, we noted a high prevalence of LV remodelling and increased LV mass with rising frequency in more severe CKD. We detected increased LVMI in 14% patients with CKD 2, in 21% with CKD 3 and in 48% patients in CKD 4 stages  contributes to inflammation and atherosclerosis  and an eDuring the follow-up period we noted a rising percentage of subjects with increased LVMI, abnormal LV geometry, decreased LVEF and LV diastolic dysfunction Table , but thiCurrently, the regression of LVH may be achieved mainly by antihypertensive and anemia treatment ,40. Of nOur data describe for the first time an independent and significant relationship of PlGF to increased LV mass in mild to moderate CKD. EN-RAGE seems more likely related to diastolic dysfunction in this population. We report serial echocardiographic changes in CKD 2–4, such as increased LV mass index and diastolic dysfunction progressing with time along with the declining renal function. Further investigation is needed to demonstrate which strategy is most efficient in preserving the cardiac structure and function.atrial - A) ventricular filling velocity; ECLIA: Electrochemiluminescence immunoassay; eGFR: Estimated glomerular filtration rate; ELISA: Enzyme-Linked ImmunoSorbent Assay; EN-RAGE: Extracellular newly identified RAGE-binding protein; FGF-23: Fibroblast growth factor 23; IgA: Immunoglobuline A; IVSd: Interventricular Septal Thickness at Diastole; LAD: Left atrial diameter; LV: Left ventricle; LVEDD: Left ventricular end-diastolic diameter; LVEDV: Left ventricular end-diastolic volume; LVEF: Left ventricular ejection fraction; LVESV: Left ventricular end-systolic volume; LVH: Left ventrikle hypertrophy; LVMI: Left ventricular mass index; MDRD: Modification of. Diet in Renal Disease; MMPs: Matrixmetalloproteinases; ms: millisecond; NF-kB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NYHA: New York Heart Association; PAPP-A: Pregnancy associated protein; PlGF: Placental growth factor; PRIMO: study Paricalcitol Capsules Benefits in Renal Failure Induced Cardiac Morbidity in Subjects With Chronic Kidney Disease Stage 3/4; PTH: Parathyroid hormone; PWTd: Diastolic posterior wall thickness; RAGE: Receptor for Advanced glycation Endproducts; ROC: Receiver operating characteristic; RWT: Relative wall thickness; SWTd: Diastolic septal wall thickness; TAG: Triacylglycerols; TNF: Tumour necrosis factor.ACE: Angiotensin-converting-enzyme; AGEs: Advanced glycation Endproducts; ANCA: Anti neutrophile cytoplasma antibodies; ARBs: Angiotensin II receptor; BNP: B-type natriuretic peptide; BSA: Body Surfaře Area; CKD: Chronic kidney disease; cTnI: Cardiac Troponin I; CV: Cardiovascular; DT: Decelaration Time; DTE-MI: Decelaration Time on Mitral Valve; E/A ratio: Ratio between early (E) and late (All the authors declare that they have no competing interests.MP participated in sample collection, clinical data collection, laboratory processing and preparation of manuscript. MK is the main consultant, took part in laboratory processing, interpretation of the data and preparation of manuscript. MH was inestimable in sample collection and clinical data collection. VD, EN, AB and DA are experienced cardiologists who effected echocardiographic measurements, interpretation of the data and manuscript preparation. BM was responsible for statistical analysis. HB participated in biochemical analysis of study samples. TZ, AL and VT provided expert opinion, took important part in data interpretation and manuscript preparation. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/14/142/prepub


There is no consensus regarding the need of surgical correction of mild-to-moderate ischemic mitral regurgitation (IMR) during surgical revascularization procedure. Left alone it could either improve or progress to a more severe degree and deteriorate patient’s condition, remodeling processes and quality of life.To evaluate the changes in structure and function of the left cardiac chambers and mitral valve apparatus after isolated surgical revascularization we perform follow-up on 69 patients subjected to CABG in the setting of mild-to-moderate IMR. Mean follow-up was 22 (6 to 52) months. Left atrial and ventricular dimensions and volumes were evaluated preoperatively and at the follow-up.At follow-up 56 % of all survivors showed improvement in IMR grade, 32 % presented with the unchanged valve function and in only 12 % IMR grade was more severe than preoperative. Preoperative effective ejection fraction increased from 26 ± 8% to 32 ± 14% (p = 0.002) at the follow-up. Left ventricular end-systolic volume index (LVESVI) decreased from 35 ± 16 ml/m2 to 30 ± 14 ml/m2 (p = 0.001). Significant left ventricular reverse remodeling (≥ 15% reduction of LVESVI) was observed in 45 % of all survivors. In 21 % of all survivors significant left atrial reverse remodeling was present although mean left atrial volume index did not change significantly.Isolated surgical revascularization improves the valve function in ischemic mitral regurgitation. It also triggers significant left ventricular reverse remodeling in half of the patients. It remains unclear how the persisting or advancing remodeling process seen in the other half changes the prognosis of these individuals.


We investigated longitudinal right ventricular (RV) function assessed using speckle-tracking strain echocardiography in patient with myocardial infarction (MI), and identified the contributing factors for RV dysfunction.We retrospectively studied 71 patients with old MI (the OMI group) and 45 normal subjects (the Control group) who underwent a transthoracic echocardiography. Global and free wall RV peak systolic strains (PSSs) in the longitudinal direction were measured by using speckle-tracking strain echocardiography. Left ventricular (LV) PSSs were measured in the longitudinal, radial and circumferential directions. Cardiac hemodynamics including peak systolic pulmonary artery pressure was also assessed non-invasively. Plasma brain natriuretic peptide (BNP) levels were measured in all patients.In the OMI group, 73% of the patients had a normal estimated peak systolic pulmonary artery pressure of less than 35 mmHg. Global and free wall RV PSS were impaired in the OMI group compared with the Control group, and these RV systolic indices were significantly associated with heart rate, logarithmic transformed plasma BNP, greater than 1 year after onset of MI, Doppler-derived estimated pulmonary vascular resistance, LV systolic indices, LV mass index, infarcted segments within a territory of the left circumflex artery and residual total occlusion in the culprit right coronary artery. Multivariable linear regression analysis indicated that reduced longitudinal LV PSS in the 4-chamber view and BNP levels ≥500 pg/ml were independently associated with reduced global and free wall RV PSS. Moreover, when patients were divided into 3 groups according to plasma BNP levels , only patients with BNP ≥500 pg/ml had a strong correlation between RV PSS and longitudinal LV PSS in the 4-chamber view .Longitudinal RV systolic strain depends significantly on longitudinal LV systolic strain especially in patients with high plasma BNP levels, but not on estimated peak systolic pulmonary artery pressure. These results indicate that process of RV myocardial dysfunction following MI may be governed by neurohormonal activation which causing ventricular remodeling rather than increased RV afterload. Myocardial infarction (MI) is associated with compensatory mechanisms involving both the left and right ventricles, and, even if the right ventricle is initially spared, right ventricular (RV) structure and function can still be altered later on . ImportaWe retrospectively reviewed the consecutive echocardiographic data between July 2005 and January 2009, and selected 71 patients with OMI (the OMI group: 67 ± 11 years) who underwent complete echocardiography including optimal RV-focused apical four-chamber images using Vivid 7 among various echocardiography ultrasound systems in our echo laboratory at Mie University Hospital, which were available for off-line analysis . All patients had experienced MI for over 1month and were diagnosed with reference to their personal history, physical examinations, laboratory tests, electrocardiography, echocardiography, coronary angiography, and cardiac magnetic resonance imaging. Patients were excluded from the study if they had suboptimal images, atrial fibrillation, significant primary valvular heart disease, prosthetic valves, or a pacer wire in the right ventricle. To minimize the influence of confounding factors in the evaluation of RV function after MI in the LV myocardium, patients with a coexisting RV infarction were excluded in the present study. Patients who had been diagnosed with non-ischemic dilated cardiomyopathy before the onset of MI were also excluded in the present study. The diagnosis of RV infarction was defined by ST segment elevation >0.1 mV in lead V4R in the 12-lead electrocardiography examination. Non-existence of obvious RV infarction was confirmed by using cardiac MRI and coronary angiography in patients with silent OMI who did not undergo 12-lead electrocardiography examination at the onset of MI. We also studied 45 age-matched and gender-matched normal subjects (the Control group: 66 ± 11 years) who had no history of cardiopulmonary disease, and who had normal electrocardiographic results and normal echocardiographic results. The protocol was approved for use by the Human Studies Subcommittee of Mie University’s Graduate School of Medicine.Arm-cuff blood pressure measurements were performed at the beginning of the echocardiographic study for all subjects . InterveSpeckle-tracking analysis was used to generate regional and global myocardial strain in both the left and right ventricles Figure . LongituAfter echocardiography assessments, patients were followed for 4.7 ± 2.3 years (median 5.3 years). The study end-point was heart failure hospitalization or cardiovascular death. The causes of death were determined by the attending doctors blinded to the group assignment.P values < 0.05 were considered statistically significant. Analyses were performed using SPSS for Windows, version 19 .The mean of each continuous variable was presented along with the standard deviation. Categorical variables were presented as percent frequencies. Between-group comparisons were assessed using analysis of variance for continuous variables and the Fisher exact test for categorical data. Bonferroni’s correction was applied for multiple comparisons. Associations between RV PSS and independent variables were examined through Pearson’s correlation coefficient and linear regression. Multivariate linear regression analyses were performed to examine the independent correlates between RV PSS and clinical, echocardiographic and laboratory parameters. The β-coefficients were standardized regression coefficients. Logarithmic transformation was performed to achieve approximate normal distribution for BNP. Intra-observer variability was determined by having one observer repeat the measurement of global RV PSS and free wall RV PSS d observer measure these variables in the same datasets. Intra- and inter-observer variability values were calculated as the absolute difference between the corresponding two measurements as a percentage of the mean. There were a total of 99 culprit territory vessels. Forty-six patients (65%) had one infarcted segment within a territory of the left anterior descending artery (n = 29), the left circumflex artery (n = 8), or the right coronary artery (n = 9), and 25 patients (35%) had more than one infarcted segments. The time interval from the first onset of MI was <1 year in 28% of patients, ≥1 year (range 1–35 years) in 39% of patients, and was unknown in 32% of patients mainly because of silent MI. Successful primary revascularization early in the course of AMI was achieved only in 27 patients and 27% of the all culprit coronary lesions responsible for MI, mainly due to high prevalence of patients with silent ischemia with multivessel disease. There were 26 vessels with residual total occlusion in the culprit lesion responsible for MI. Table Table Speckle tracking was possible in 100% of the 3480 attempted segments from the 116 echocardiographic studies with technically adequate images. Table Successful primary revascularization was not statistically associated with global or free wall RV PSS. We assessed the potential impact of infarcted site and residual total occlusion in the culprit lesion responsible for MI on RV function. When patients were divided into two groups according to median value of the global RV PSS: -19.1%, patients with reduced global RV PSS (−13 ± 4%) had a higher prevalence of residual total occlusion in the culprit right coronary artery than those with preserved global RV PSS (−23 ± 3%) Table . There wSince the time interval between the acute MI onset and the echocardiographic evaluation varied individually in the present study, we investigated the potential influence of the chronicity of MI on RV function. Patients <1 year after onset of MI had much more impaired global and free wall RV PSS than those ≥1 year after onset of MI among the 3 groups  although age, gender, log-transformed plasma BNP, and longitudinal LV PSS in the 4-chamber view were similar.Tables Kaplan–Meier event-free survival curves for the composite endpoint of heart failure hospitalization and cardiovascular death were constructed, and statistical differences between patients with preserved and reduced indices of RV function were assessed by the Log-rank test. During the follow-up periods, there were 6 events (17%) in patients with preserved global RV PSS above the median value, and 19 events (54%) in those with reduced global RV PSS. As shown in Figure Inter-observer and intra-observer variability were 5.7 ± 4.4 and 3.6 ± 3.8% for global RV PSS and 5.4 ± 3.6 and 3.8 ± 3.7% for free wall RV PSS.The major findings of our study include the following: 1) longitudinal RV strain was reduced in patients with OMI in the absence of RV infarction, and 2) RV strain depends highly on longitudinal LV strain especially in patients with high plasma BNP levels. Although LV dysfunction is considered a major mechanism underlying the development of heart failure, several studies have shown the pivotal importance of RV function. Recently, several experimental and clinical studies have demonstrated that longitudinal function mainly reflects global RV systolic function ,15,16 anThe mechanisms leading to RV dysfunction following MI in the LV myocardium are not completely clear , but it Infarction or ischemia of the RV and/or the septum are common in patients with MI and can also contribute to abnormal RV systolic function. Residual total occlusion in the right coronary artery was one of the independent contributors of reduced global RV PSS in the present study, indicating that residual ischemia in the right coronary artery may affect RV function. Contraction of the interventricular septum contributes to RV ejection  and effiOther potential mechanisms underlying RV free wall dysfunction include neurohumoral activation or inflammation . We founRV function provides strong prognostic information in patients with MI ,28. AntoLimitations of this study include the small sample size and retrospective nature of data collection. For example, although no significant relationships between RV an LV longitudinal functions both in patients with BNP <100 pg/ml and patient with 100 <BNP <500 pg/ml were observed, these results can be due to type 2 error. Furthermore, there was a heterogeneous distribution of RV function in our study population. Invasive pressure measurements were not used in this study. Therefore, peak systolic pulmonary artery pressure and PVR estimated by using Doppler echocardiography were recruited as markers of the severity of RV pressure overload. However, Doppler-derived estimations of these hemodynamic indices are widely recognized to work well with simultaneous catheter-derived measurements and are widely used clinically. Quantitative assessment of myocardial infarction size was not involved in the present study. Although we assessed the potential impact of residual total occlusion in the culprit lesion responsible for MI on RV function, the presence and severity of stress-induced myocardial ischemia was not evaluated in our study. Finally, three dimensional myocardial tracking in both the left and right ventricle would be warranted for the precise understanding of the pathophysiological mechanism responsible for RV functional impairments after MI.Speckle-tracking echocardiography effectively quantified and characterized the RV systolic function and its association with the LV myocardial impairment in patients with OMI. Our data showed that longitudinal RV systolic strain depends highly on longitudinal LV systolic strain, especially in patients having high plasma BNP levels. These results may indicate that longitudinal RV dysfunction following MI does not owe fully to excessive afterload but also due to neurohormonal activation which causing ventricular remodeling response to altered LV wall stress. Application of speckle-tracking echocardiography to conventional measurements of ventricular function could provide a more thorough and quantitative pathophysiological characterization of functional RV adaptation following MI.RV: Right ventricular; MI: Myocardial infarction; PSS: Peak systolic strain; LV: Left ventricular; BNP: Brain natriuretic peptide; E/A: Ratio of peak early to late diastolic transmitral flow velocity; DT: Deceleration time; Ea: Peak early diastolic mitral annular velocity; E/Ea: Ratio of peak early diastolic transmitral flow velocity to Ea; EDA: End-diastolic area; ESA: End-systolic area; FAC: Fractional area change; TAPSE: Tricuspid annular plane systolic excursion; MPI: Myocardial performance index; PA: Pulmonary artery; PVR: Pulmonary vascular resistance; NYHA: New York heart association; HF: Heart failure.The authors declare that they have no competing interests.KK; Acquisition of data, analysis and interpretation of data, drafting of the manuscript, KD; Corresponding author, protocol design, drafting of the manuscript, critical revision of the manuscript for important intellectual content. MT, YS, KW, and ES: Acquisition and analysis of data, NK, SN, HN, and TY: Interpretation of data, KO and MN: Critical revision of the manuscript for important intellectual content, study supervision, TN and MI: Final approval of the manuscript submitted. All authors read and approved the final manuscript.Movie 1. Left ventricular (LV) longitudinal strain image in the apical four-chamber view from the same normal subject shown in the Figure Click here for fileMovie 2. Right ventricular (RV) longitudinal strain image in the apical four-chamber view from the same normal subject shown in the Figure Click here for fileMovie 3. Left ventricular (LV) longitudinal strain image in the apical four-chamber view from the same patient with old myocardial infarction shown in the Figure Click here for fileMovie 4. Right ventricular (RV) longitudinal strain image in the apical four-chamber view from the same normal subject shown in the Figure Click here for fileMovie 5. Left ventricular (LV) longitudinal strain image in the apical four-chamber view from the same patient with old myocardial infarction shown in the Figure Click here for fileMovie 6. Right ventricular (RV) longitudinal strain image in the apical four-chamber view from the same patient with old myocardial infarction shown in the Figure Click here for file


Some patients may have normal wall motion after myocardial infarction. The aim of this study was to determine the prevalence and prognosis of patients with myocardial scar in the absence of abnormal wall motion. We studied patients with suspected or known coronary artery disease (CAD) who were referred for cardiovascular magnetic resonance (CMR) for the assessment of global and regional cardiac function and late gadolinium enhancement (LGE) and had normal left ventricular wall motion. Prognostic value was determined by the occurrence of hard endpoints  and major adverse cardiac events (MACE) which also included hospitalization due to unstable angina or heart failure or life threatening ventricular arrhythmia.A total 1148 patients (70.3%) were studied. LGE was detected in 104 patients (9.1%). Prevalence of LGE increased in patients with increased left ventricular mass. Average follow-up time was 955 ± 542 days. LGE was the strongest predictor for hard endpoints and MACE.LGE was detected in 9.1% of patients with suspected or known CAD and normal wall motion. LGE was the strongest predictor of significant cardiac events. Assessment of structural heart disease or ventricular function has been recommended for patients presenting with signs or symptoms of heart disease such as dyspnea on exertion, heart failure , chest pCardiovascular magnetic resonance (CMR) is considered the gold standard for the assessment of global ventricular function ,10 and aThe objectives of this study were 1) to determine prevalence of myocardial scar in patients with known or suspected CAD in the absence of abnormal wall motion and 2) to determine the prognostic value of myocardial scar in patients with known or suspected CAD in the absence of abnormal wall motion.We studied patients who were referred for CMR from January 2002 to December 2007. Patients were referred for CMR due to clinical symptoms suspected to be related to CAD. Patients were included in this study if 1) known or suspected CAD who was referred for CMR for the evaluation of myocardial function and LGE 2) age more than 30 years and 3) normal left ventricular wall motion from CMR. Types of symptoms are shown in Table This study was approved by the Ethics committee of Siriraj Hospital. All patients provided written informed consent.All patients underwent CMR which included functional study and assessment of LGE using a 1.5 Tesla Gyroscan NT Philips scanner . After scout images, functional study was performed with a steady-state free-precession technique in horizontal long axis view, 2-chamber view, 4-chamber view and multiple slice short axis view. LGE was performed in 3-D fashion 7-10 minute after the injection of gadolinium 0.2 mmol/kg. Multiple short-axis slices at the same level as the functional study, 2-chamber and 4-chamber view were acquired for LGE.Parameters for functional images were as follows: repetition time/echo time/number of excitations = 3.7/1.8/2, 390 × 312 mm field of view, 256 × 240 matrix, 1.52 × 1.21 reconstruction pixel, 8 mm slice thickness, 70 degree flip angle. Typical temporal resolution was 25-30 ms. The LGE images were acquired with the use of 3 D segmented-gradient-echo inversion-recovery sequence with echo time 1.25, repetition time 4.1, 15 degree flip angle, 303 × 384 mm field of view, 240 × 256 matrix, in-plane resolution 1.26 × 1.5 mm, slice thickness 8 mm and 1.5 Sensitivity encoding factor. The whole study for each patient took approximately 40 minutes. Patients had ECG performed on the same day before undergoing CMR. Myocardial infarction by ECG was defined by the standard criteria .The analysis was performed on the ViewForum workstation . Functional CMR data were analyzed for volume, mass and ejection fraction of the left ventricle. The software made an automatic detection of the endocardial and epicardial border of the left ventricle during diastole and endocardial detection for images during systole. Manual adjustment was performed by an experienced technician. The software then made calculations for left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular mass (LVMASS), and LVEF. Calculation of indices of LVEDV (LVEDVI), LVESV (LVESVI) and LVMASS (LVMASSI) was performed to adjust for body surface area. Intra- and interobserver variability presented as percentages of the mean of 2 repeated measurements averaged ± standard deviations were 3 ± 4% and 4 ± 4% for LVEDV, 4 ± 5% and 6 ± 6% for LVESV and 3 ± 4% and 5 ± 5% for LVMASS.LGE was analyzed by visual estimation for the presence or absence of LGE and quantification of LGE. LGE was graded segmental extent of LGE as follows: 0 = no scar, 1 = 1-25%, 2 = 26-50%, 3 = 51-75%, and 4 = 76-100% of LGE areas in comparison to segmental myocardial areas. Analysis of myocardial segments was based on 17-segment models  with therd reader. Regional wall motion was analyzed by the use of the 17-segment model proposed by the American Heart Association [Analysis of wall motion was performed by visual assessment. Wall motion and LGE was assessed by 2 readers independently of the history. Disagreement was solved by a 3ociation . Wall moociation -8. Visuaociation . For thePrimary outcomes include both hard cardiac events and major adverse cardiac events (MACE). Cardiac death and myocardial infarction were considered as hard cardiac events. MACE includes hard cardiac events and hospitalization due to unstable angina, heart failure or life-threatening ventricular arrhythmia. Assessment of cardiac events was performed by the review of medical records and telephone interview followed by document confirmation.Data were described as mean ± standard deviation (SD) for continuous data and count (percentages) for categorical data. Independent-samples T-test was used for the comparison of continuous data. Comparisons of categorical data were made by the Chi-square test or Fisher exact test wherever appropriate. Cox-regression analysis was used for the assessment of predictors for clinical outcomes and was described as hazard ratio and 95% confidence interval (CI). Kaplan-Meier analysis with log-rank test was used for survival analysis with comparison of survival data between groups. A p-value of ≤ 0.05 was considered significant.We excluded 248 patients with a history of revascularization, 252 patients with a history of myocardial infarction, 18 patients who were unable to complete CMR examination, 8 patients with inadequate image quality, 4 patients with pacemakers, 5 patients with unstable clinical conditions, 14 patients unobtainable clinical follow-up data, 10 patients with mid-wall or patchy scar likely to be non-ischemia cardiomyopathy scar, 3 patients with scar at the insertion site of right ventricular free-wall likely to be related to hypertrophic cardiomyopathy, 2 patients with subepicardial scar likely to be related to myocarditis, and 1 patient with diffuse LGE likely to be related to amyloidosis. After the exclusion, total of 1148 patients with normal left ventricular wall motion were included in this study. Average age was 64.6 ± 11.3 years. LGE was detected in 104 patients (9.1%). Table nd, 3rd and highest quartile respectively  had LGE without abnormal wall motion. Among patients without LGE, coronary angiogram was performed in 145 patients (13.9%) which demonstrated single vessel disease in 39, 2-vessel disease in 30, 3-vessel disease in 30, and no significant CAD in 46 patients.Coronary angiography data after CMR of those who had LGE was explored to confirm the underlying CAD in this group. Among 104 patients with LGE, 48 46.2%) underwent coronary angiography, 12 had single vessel disease, 15 had 2-vessel disease, 20 had 3-vessel disease, and only 1 patient had no significant CAD. Among those who underwent coronary angiography, 24 were in the highest quartile of LVMASS index, 13 in the 3% underweDuring an average follow-up time of 955 ± 542 days, 18 patients (1.6%) had hard cardiac events and 54 (4.7%) had MACE. The frequency of cardiac events is shown in Table Additional analysis was performed for the assessment of the prognostic importance of the extent of LGE. By using the median size of LGE of 6.25% of myocardium, we graded the extent of LGE into 3 groups: no LGE, LGE ≤ median and LGE > median. Hazard ratios and 95%CI for hard cardiac events and MACE for patients with LGE ≤ median were 2.14 (0.28-16.53), p = 0.467 and 3.36 (1.32-8.55), p = 0.011 compared to those without LGE. Multivariable analysis showed that patients with LGE ≤ median had no significant increase in risk of hard events but had a significant increase in risk of MACE  compared to those without LGE. For patients with LGE > median, hazard ratios for hard events and MACE were 8.59 (3.23-24.37), p < 0.001 and 4.69 (2.28-9.67), p < 0.001 compared to those without LGE. Multivariable analysis showed that patients with LGE > median had a significant increase in risk of hard events  and MACE  compared to those without LGE.The results of our study showed that in patients with known or suspected CAD and normal wall motion, 9.1% had LGE. Patients with LGE had an increased risk of cardiovascular events compared to those without. In fact, LGE is the strongest predictor of cardiac events.Echocardiography is an investigation for the evaluation of evidence of structural heart disease in patients with sign or symptoms of heart disease -3. CMR, We showed that, among patients with normal wall motion, the prevalence of LGE increased in patients with high LVMASS index with the prevalence up to 19% in the highest quartile of LVMASS index. This finding is consistent with a previous report  which shCompared to earlier report  on the pThe results of this study on the prevalence of LGE and its prognostic value can be applied to patients who were referred for CMR with normal left ventricular wall motion without known cause of LGE. This is the reason that we excluded patients with history of myocardial infarction and other known causes of LGE including those with history of revascularization which may have a significant number of procedure-related LGE which was detected by CMR in up to 64% .There are some limitations of this study. Firstly, although we exclude hypertrophic cardiomyopathy and many conditions that might cause LGE, we did not exclude left ventricular hypertrophy or aortic stenosis which has been shown to have an association with LGE . HoweverThis is the first study that demonstrated the prognostic importance of LGE in patients with normal wall motion. The prognostic value of LGE in this patient population was even more confirmed by the quantitative analysis of LGE. Therefore, clinicians cannot assume that patients without wall motion abnormality have no evidence of structural heart disease and have a good prognosis. Although myocardial infarction by ECG was also an independent predictor for hard endpoints, LGE was the strongest predictor of hard endpoints and MACE.ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; CAD: coronary artery disease; CI: confidence interval; CMR: cardiovascular magnetic resonance; HR: hazard ratio; LGE: late gadolinium enhancement; LVEDV: left ventricular end-diastolic volume; LVEDVI: left ventricular end-diastolic volume index; LVEF: left ventricular ejection fraction; LVMASS: left ventricular mass; LVMASSI: left ventricular mass index; LVESV: left ventricular end-systolic volume; LVESVI: left ventricular end-systolic volume index; MACE: major adverse cardiac event; MI: myocardial infarction, SD: standard deviationThe authors declare that they have no competing interests.RK study design, data interpretation, writing manuscript, PS data acquisition and interpretation, revise manuscript, TB data interpretation, revise manuscript, SU data analysis and interpretation, revise manuscript. All authors approved the final version of the manuscript.


Infective endocarditis is a relatively rare complication of hypertrophic cardiomyopathy. Infective endocarditisin hypertrophic cardiomyopathy is almost always seen in patients with outflow obstruction and is more common in thosewith both outflow obstruction and atrial dilatation. We present a case of culture negative mitral valve endocarditis in apreviously asymptomatic woman with hypertrophic cardiomyopathy who died in the course of the disease. Antibiotic prophylaxis is no longer recommended in patients with hypertrophic cardiomyopathy (HCM) in current guidelines unless otherwise indicated. We present a case of endocarditis in a patient with hypertrophic cardiomyopathy with significant outflow obstruction, and intend to discuss the use of antibiotic prophylaxis in such patients.A 37-year-old woman was admitted due to a week-long history of malaise, myalgia, sweating and high fever. On admission, she had a body temperature of 39°C, a heart rate of 100 beats/ min and a blood pressure of 110/80 mmHg. The auscultation revealed a systolic murmur suggestive of mitral regurgitation. A 12-lead electrocardiogram showed a sinus tachycardia of 100 beats /min, signs of left ventricular hypertrophy and abnormal lateral repolarization. The chest X-ray showed a normal cardiothoracic index. Laboratory investigation revealed leukocytosis (13.700 /mm3) and raised inflammatory markers.1) and supplementary video 1).  and supplementary video 2) was started after blood samples were drawn for cultures. On the second day of hospitalization, she was entubated as she developed severe dyspnea and hypotension. The bedside TTE revealed moderate to severe mitral regurgitation. The patient died of cardiac arrest subsequently before the planned surgery could be carried out. The patient’s blood cultures were later found to be negative. Transthoracic echocardiography (TTE) demonstrated minimally pericardial effusion, septal hypertrophy  with systolic anterior motion of the mitral valve, left atrial enlargement (47 mm), mild to moderate mitral regurgitation and a suspected image of vegetation on the anterior mitral leafletInfective endocarditis (IE), although not very common, has been reported in HCM patients in the literature. The data relating the prevalence of IE are limited, and the most comprehensive study of prevalence and incidence was done by Spirito and colleagues . They foSome significant changes have been made relating the antibiotic prophylaxis in recent guidelines , 5. The


Atherosclerotic renal artery stenosis (ARAS) is common in cardiovascular diseases and associated with hypertension, renal dysfunction and/or heart failure. There is a paucity of data about the prevalence and the role of ARAS in the pathophysiology of combined chronic heart failure (CHF) and chronic kidney disease (CKD). We investigated the prevalence in patients with combined CHF/CKD and its association with renal function, cardiac dysfunction and the presence and extent of myocardial fibrosis.The EPOCARES study  investigates the role of erythropoietin in anaemic patients with combined CHF/CKD. Eligible subjects underwent combined cardiac magnetic resonance imaging (cMRI), including late gadolinium enhancement, with magnetic resonance angiography of the renal arteries (MRA).MR study was performed in 37 patients  43.3 ± 11.2%), of which 21 (56.8%) had ARAS (defined as stenosis >50%). Of these 21 subjects, 8 (21.6%) had more severe ARAS >70% and 8 (21.6%) had a bilateral ARAS >50% . There were no differences in age, NT-proBNP levels and medication profile between patients with ARAS versus those without. Renal function declined with the severity of ARAS (p = 0.03), although this was not significantly different between patients with ARAS versus those without. Diabetes mellitus was more prevalent in patients without ARAS (56.3%) against those with ARAS (23.8%) (p = 0.04). The presence and extent of late gadolinium enhancement, depicting myocardial fibrosis, did not differ (p = 0.80), nor did end diastolic volume (p = 0.60), left ventricular mass index (p = 0.11) or LVEF (p = 0.15). Neither was there a difference in the presence of an ischemic pattern of late enhancement in patients with ARAS versus those without.ARAS is prevalent in combined CHF/CKD and its severity is associated with a decline in renal function. However, its presence does not correlate with a worse LVEF, a higher left ventricular mass or with the presence and extent of myocardial fibrosis. Further research is required for the role of ARAS in the pathophysiology of combined chronic heart and renal failure. The combination of chronic heart failure (CHF) and chronic kidney disease (CKD) is prevalent and associated with a high cardiovascular mortality and morbidity -3. Both In CHF, in several observational studies, patients with ARAS had prolonged hospital admissions and a higher mortality rate -10. ThisWe hypothesized that ARAS is prevalent in patients with combined CKD and CHF and that its presence is associated with a worse renal function, more severe cardiac dysfunction and the presence and extent of myocardial fibrosis. Therefore we assessed, in anaemic patients with combined heart and renal failure: 1. The prevalence of ARAS and 2. The association of ARAS with renal and cardiac dysfunction and the presence of myocardial fibrosis. We used cardiac magnetic resonance imaging (cMRI) for this purpose, as the quantitative values for cardiac volumes, left ventricular mass and function are more accurate than with echocardiography. In addition, intravenous gadolinium contrast material can be used both for magnetic resonance angiography (MRA) of the aorta and the renal arteries, as well as for late gadolinium enhanced (LGE) assessment of myocardial fibrosis, thereby providing information about the underlying aetiology of the cardiac dysfunction.This study is a sub study of the EPOCARES study . The study design has been published elsewhere . In shorCardiovascular Magnetic Resonance Imaging and magnetic resonance angiography (MRA) of the renal arteries were performed on a 1.5 Tesla Philips Intera . Both the heart and the renal arteries were assessed in a 45-minute protocol. The patient was placed in the supine position with a five-channel phased array coil for the cardiac analysis and a circularly polarized spine coil in longitudinal direction over the area of the kidneys below the cardiac coil for MRA of the renal arteries.ECG-triggered breath hold multiphase steady-state free procession (SSFP) images were acquired in the four-chamber, short-axis, and two- chamber view scans of the left ventricle. The short axis plane covered both ventricles from apex to base using 8-mm slices without interslice gap with the following scan parameters: TR/TE 4.0/2.0 ms, flip angle 50, FOV 350–400, matrix 256x256, voxel size 1.6x1.6x8.0 mm.Gadolinium-based contrast  was administered intravenously to first obtain MRA of the renal arteries at the time of injection (first pass) and 15 minutes later delayed enhancement scans of the heart. For MRA of the renal arteries a standard breath hold 3D T1 contrast-enhanced MRA technique was used. Scan parameters: TR/TE 3.7/1.33 ms, flipangle 25, FOV 430x430x75, voxel size 0.8x0.8x1.5 mm.For the delayed enhancement of the heart, breath hold inversion recovery T1 pulse images were acquired in four-chamber, short axis and left two-chamber view. Scan parameters: TR/TE 4.4/1.3 ms, flipangle 15, FOV 410x410x80, matrix 300x169, voxel size 1.4x1.4x5.0 mm. There were no complications related to the MRI procedures, and all patients tolerated the procedure well.The SSFP cine short axis scans were used to acquire measurements of the left ventricle end diastolic volume (EDV), end systolic volume (ESV), ejection fraction (EF) and wall mass . Endocardial and epicardial contours were traced manually on the stack of contiguous short-axis cine-images at end-diastole. This technique has been validated, with high accuracy and reproducibility . A trainAssessment of segmental wall motion and late gadolinium enhancement (LGE) was performed by two independent investigators, blinded for clinical data (BV and YA). The left ventricle was divided in 17 segments according to standardized nomenclature . Late enThe number of renal arteries as well as patency and presence or absence of stenosis was assessed by two independent investigators, blinded for clinical and cMRI data (JV and LM). Stenosis was graded as: no stenosis, <50% stenosis, 50-70% stenosis, 70-99% stenosis, occlusion 100% or previous stent placement. The presence of a renal artery stenosis was defined as having a stenosis >50% or previous renal revascularization, conform criteria from the Stenting in Renal dysfunction caused by atherosclerotic Renal Artery Stenosis .χ2 test, Mann–Whitney U test or the Kruskal-Wallis one-way ANOVA when appropriate. Differences were considered significant when P < 0.05. For statistical analyses the Statistical Package for Social Sciences  version 18 was used.Data are presented as medians with inter-quartile ranges (IQR) for non-normally distributed variables and means ± standard deviation (SD) for normally distributed continuous variables. Differences between groups were compared with the The original study population of the EPOCARES study comprised of 62 patients. Five patients withdrew their informed consent and one patient was excluded due to a suspected malignancy (diagnosed on routine X-ray at baseline). Of the 56 patients that eventually participated in the study, 37 patients underwent a cMRI/MRA. Nineteen patients did not undergo cMRI/MRA due to presence of cardiac implantable electronic devices n = 15), orthopnoea (n = 2), claustrophobia (n = 1) or a GFR < 30 ml/min (n = 1). These data are obtained after run in treatment with optimal medical therapy for CHF and oral iron supplementation, but before treatment with EPO. Clinical characteristics of these 37 patients are shown in Table 5, orthopOf the 37 patients that underwent cMRI/MRA, 21 patients (56.8%) had a renal artery stenosis defined as >50% stenosis. A more severe stenosis, defined as >70%, was present in 8 (21.6%) patients. A bilateral ARAS (>50%) was present in 7 (18.9%) patients. All stenosis were of atherosclerotic origin. One patient (2.7%) was previously treated bilaterally by angioplasty with stent placement. Baseline demographic, clinical and laboratory characteristics of the patients, divided up by the presence or absence of ARAS, defined as >50% stenosis, are provided in Table Data regarding cMRI are shown in Table Our study shows a high prevalence (56.8%) of atherosclerotic renal artery stenosis (ARAS) in patients with combined heart and renal failure, defined as having a stenosis >50%. When taken a stricter cut-point (> 70% stenosis) the prevalence of ARAS was still as high as 21.8% in this population. The presence of ARAS was not associated with the extent in abnormalities in left ventricular function or myocardial fibrosis based on cardiac MRI findings with late gadolinium enhancement (LGE), when compared to patients with combined CHF/CKD without ARAS. Neither did we observe a difference in the presence of an ischemic pattern of LGE. Furthermore; we found a weak association between eGFR and the severity of ARAS and observed a negative association between diabetes mellitus and ARAS. This could indicate that our small cohort may consist of two different groups of cardiorenal patients: non-diabetic patients in which ARAS is highly prevalent and diabetic patients with a much lower ARAS prevalence.ARAS is very common in patients with manifestations of non-renal atherosclerosis, particularly in patients with peripheral arterial and aortic disease. A recent literature review found a pooled prevalence of 25.3% in patients with peripheral arterial disease and 33.1% in patients with aortic aneurysm . Only fenot affect renal function [According to the present American Heart Association guidelines for the management of patients with peripheral arterial disease, the indication for percutaneous renal revascularization with stent placement (PTA) of ARAS is limited to “flash pulmonary oedema, recurrent episodes of unexplained congestive heart failure or unstable angina” . There ifunction ,19,24. Ofunction . The resNonetheless, diagnosing ARAS can be important for more reasons than to find patients suitable for PTA. One could interpret the presence of ARAS as a marker of “atherosclerotic burden” associated with a high risk of cardiovascular events, which would warrant more aggressive medical therapy . Indeed,In addition to determining the prevalence of ARAS in patients with both CHF and CKD, we determined whether there is an association between left ventricular structure and function and the presence of ARAS. Although one could hypothesize that ARAS would be associated more often, and to a greater extent, with cardiac abnormalities, such as left ventricular hypertrophy, we found no differences in left ventricular mass index, left ventricular volumes and LVEF in patients with and without ARAS. We also hypothesized that the existence of ARAS represents an “atherosclerotic burden”, representing one of the mechanisms of combined CHF/CKD. However, we found no difference in the presence of ischemic aetiology of CHF. Moreover, we could not demonstrate a difference in the presence, the location and the extent of fibrosis, as depicted by LGE. The study by Wright et al. showed more diastolic dysfunction and left ventricular hypertrophy in patients with ARAS when compared with a matched control group with similar renal dysfunction . In contCoincidentally we found a negative association between diabetes and ARAS; the patients with combined CHF/CKD without ARAS were markedly more likely to have diabetes mellitus than those patients with ARAS Figure . Some stA point of debate is the definition of ARAS, since no uniform definition exists. Previously, most studies defined ARAS as >50% stenosis ,24,30-32Some limitations of this study need to be acknowledged. The small study population, due to the complexity of the study design, consists of a selected group of stable ambulant patients, almost all using RAS inhibitors which, in addition to the exclusion of uncontrolled hypertension and patients with flash pulmonary oedema, may have led to underestimation of the prevalence of ARAS in CRS. However, despite this small study population, we believe that these data are valuable and robust, due to a paucity of data in the present literature about this subject and the reliable assessment with cardiac MRI. Furthermore, the data are baseline data from a randomized intervention study, which precludes spontaneous follow-up.In conclusion, ARAS is prevalent in patients with combined CHF and CKD and its presence does not correlate with worse left ventricular function, left ventricular volumes, mass, nor myocardial fibrosis as assessed by MRI. However, the severity of ARAS is weakly associated with renal dysfunction and ARAS is remarkably negatively associated with diabetes mellitus in this cohort. Further research is needed to investigate its role in the pathophysiology of combined chronic heart failure and chronic kidney disease and subsequent therapeutic consequences.CKD: Chronic kidney disease; CHF: Chronic heart failure; ARAS: Atherosclerotic renal artery stenosis; cMRI/MRA: Combined cardiac magnetic resonance imaging with magnetic resonance angiography of renal arteries; NT-proBNP: N-terminal pro brain natriuretic peptide; LGE: Late gadolinium enhancement; LVEF: Left ventricular ejection fraction.The authors declare that they have no  competing interests.CG, BB and KvP initiated this study. ME helped in the study design, wrote the manuscript, together with CG and BB, participated in the recruitment of patients and collection of data, together with KvP, did the statistical analyses with HH and analysed the imaging data. MJ, BK and YA analysed the cardiac data. JV and LM interpreted the MRA of the renal arteries. PD contributed to the study design and the discussion. All authors read and approved the final version of the manuscript.This investigator-initiated study was supported by the Netherlands Heart Foundation (grant number 2005B192) and by an unrestricted grant from Roche Pharmaceuticals, the Netherlands. A Heart and Stroke Foundation of Canada New Investigator award supports Branko Braam. This is an investigator-initiated study and no changes to the study protocol were made upon request of Roche, neither did Roche have insight in the data.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2261/12/76/prepub


The aim of this study was to investigate associations between different parameters of diastolic function assessed from cine CMR, biomarkers of cardiac injury and left ventricular function and strain in patients with STEMI.Presence of diastolic dysfunction in patients with history of myocardial infarction represents a marker of adverse outcomes. However, its role in acute ST-elevation myocardial infarction (STEMI) is not fully elucidated. Cardiovascular magnetic resonance (CMR) allows quantitative measurement of volumetric changes that occur during diastole and form basis for calculation of different parameters of diastolic function. The relationships between these parameters, LV systolic function and strain, and markers of cardiac injury in STEMI are unknown.80 - proportion of diastole required to recover 80% stroke volume). Longitudinal, radial and circumferential strain were assessed from standard echocardiographic views using 2D speckle-tracking software . All patients had serial troponin values (at least three) measured.Thirty patients with acute STEMI undergoing primary PCI were prospectively enrolled and underwent CMR imaging and 2D echocardiography within 48 hours of admission. CMR images were planimetered  in all slice positions across all temporal phases to calculate diastolic parameters: E/A ratio, peak filling rate , time to peak filling rate (TPFR), and diastolic volume recovery . LV ejection fraction as well as global LV longitudinal strain correlated with nPFR  but the association with DVR80 was not significant . Patients in the lowest time to reperfusion tertile had significantly higher nPFR compared to patients in the highest tertile (3.32+0.84 s-1 vs 2.27+0.52 s-1). Figure Median troponin value was 34ng/mL IQR 15.8-101.8) and median time from symptom onset to reperfusion was 194 minutes (IQR 158-277). Normalized PFR and DVR5.8-101.8In acute STEMI patients diastolic function parameters by cine CMR imaging predict the extent of cardiac injury and are associated with the time to reperfusion. The role of these new measures of myocardial function in prognosis post STEMI remains to be investigated.


To evaluate the inter-study, inter-reader and intra-reader reproducibility of cardiac cine and scar imaging in rats using a clinical 3.0 Tesla magnetic resonance (MR) system.Thirty-three adult rats (Sprague–Dawley) were imaged 24 hours after surgical occlusion of the left anterior descending coronary artery using a 3.0 Tesla clinical MR scanner  equipped with a dedicated 70 mm solenoid receive-only coil. Left-ventricular (LV) volumes, mass, ejection fraction and amount of myocardial scar tissue were measured. Intra-and inter-observer reproducibility was assessed in all animals. In addition, repeat MR exams were performed in 6 randomly chosen rats within 24 hours to assess inter-study reproducibility.The MR imaging protocol was successfully completed in 32 (97%) animals. Bland-Altman analysis demonstrated high intra-reader reproducibility (mean bias%: LV end-diastolic volume (LVEDV), -1.7%; LV end-systolic volume (LVESV), -2.2%; LV ejection fraction (LVEF), 1.0%; LV mass, -2.7%; and scar mass, -1.2%) and high inter-reader reproducibility . In addition, a high inter-study reproducibility was found .Cardiac MR imaging of rats yielded highly reproducible measurements of cardiac volumes/function and myocardial infarct size on a clinical 3.0 Tesla MR scanner system. Consequently, more widely available high field clinical MR scanners can be employed for small animal imaging of the heart e.g. when aiming at serial assessments during therapeutic intervention studies. The accurate and reproducible assessment of cardiac function by measurement of leftventricular (LV) volumes, ejection fraction, and the amount of myocardial scar tissue is fundamental for evaluating heart diseases in cardiovascular research. A great advantage of cardiac magnetic resonance (CMR) imaging is the inherently high soft tissue contrast, and the possibility to image cardiac and vascular anatomy in a three-dimensional manner. The accuracy of CMR imaging for the evaluation of LV volumes, mass and scar amount has been validated in several human and small animal studies -6. HowevThe study was approved by the Charité Institutional Review Board. Thirty-three adult Sprague–Dawley rats (7–16 weeks old) with a mean weight of 355.5 ± 91.8 g (range 269–589 g) were included in our study protocol. For surgical intervention, the animals were anesthetized with 0.3 ml Domitor® (1 mg/1 mL) + 0.8 ml Dormicum® (5 mg/1 mL)/kg BW. After thoracotomy, the left anterior descending coronary artery (LAD) was occluded on the level of the first diagonal branch by placing a snare ligature around the artery and a small portion of the surrounding myocardium. All animals underwent CMR imaging within 24 hours after surgery.CMR imaging was performed using a clinical 3.0 Tesla MR system  equipped with a Quasar Dual gradient system  using a dedicated 70 mm solenoid receive-only coil placed perpendicular to B0 providing a high signal-to-noise ratio . Anaesthesia was induced and maintained during the CMR examination with 3% isoflurane administered by a nasal cone. The animals were placed in a specially-designed cradle with four neonatal ECG electrodes (3 M™ Red Dot™ 2269 T) being attached to the paws in order to record an electrocardiogram for triggering of image data acquisition . Following cine imaging, a bolus of gadolinium-DTPA  was administered via a catheter placed in a tail vein. After a 15 minute waiting period, full left-ventricular coverage, three-dimensional late enhancement (LE) imaging was performed in identical short axis geometry using an inversion prepared segmented gradient-echo-sequence . The delay of the inversion prepulse was determined from an inversion prepared cine scan (Look-Locker sequence) and individually adjusted to optimally suppress signal from normal myocardium. All acquisitions were performed during free breathing with respiratory motion being partially compensated for by employing signal averaging .For cine imaging a segmented gradient echo sequence was applied .Endocardial borders were traced manually at end-diastole and end-systole Figure  with endEndo-and epicardial borders were manually traced on LE images. The amount of scar was quantified by manual segmentation with the signal intensity threshold set to >2 standard deviations above the mean signal intensity of a remote myocardial region Figure . The volThe intra-reader and inter-reader reproducibility of LV volumes and mass were evaluated in all animals. To assess intra-reader reproducibility, left-ventricular contours were redrawn by the original observer  one month after the initial analysis. In order to assess inter-reader reproducibility an additional observer  carried out a separate analysis. For the assessment of inter-study reproducibility, 6 randomly chosen animals were scanned twice within 24 hours and evaluated by the first observer being blinded to the animal data.Statistical analyses were performed using SPSS, version 17.0, software . Values are reported as means ± standard deviations. The mean bias between the reads and their limits of agreement were determined according to the method described by Bland and Altman  and by cImage data acquisition was successfully completed in 32 out of 33 animals (97%) and in all 6 animals 100%) undergoing repeat CMR examinations. Heart rate ranged from 270 to 310 beats per minute (bpm), one CMR examination suffered from ECG-related triggering problems and could not be finalized. All 32 completed CMR examinations were of diagnostic image quality and constituted the final study population for analysis  sequence type since the latter resulted in poor image quality mainly due to flow-/bloodpool-related artifacts with impairment of endocardial visibility . However, small animal CMR imaging at 3.0 Tesla proved to be feasible with a success rate of >97%. Recently, Saleh et al.  proved tAccurate depiction of myocardial infarct size in animal models of cardiac diseases is crucial; hence, late enhancement imaging was incorporated in the current study protocol. Recently, Voelkl et al.  showed tEven though clinical MR scanners are more abundant than dedicated animal MR scanners, they may not always be available for animal studies and/or local rules may prevent their use. Image quality of small animal imaging on clinical scanners is generally restricted by limited shim capabilities which may be addressed by introducing high-order shimming. In addition, for small objects like rats and mice, the noise not only arises from physiological and thermal object noise but is rather dominated by noise from the electronic pathways; hence, a fully digital broadband system with analog to digital signal conversion in the radiofrequency coil may prove beneficial. Taking advantage of such technical improvements may allow for example to use steady-state free precession imaging sequences.The present study showed that a conventional clinical 3.0 Tesla MR scanner environment can be adapted to achieve high quality functional and morphological cardiac MR imaging of rats in vivo. Measurements of LV functional parameters and scar amount were highly reproducible. Consequently, the performance of therapeutic interventions aiming at the improvement of contractile function and the reduction of myocardial scar amount (e.g. stem cell therapy) may be studied in small animal models using widely available clinical CMR scanners.The authors declare that they have no competing interests.RM, CJ, IP, BS and KG conceived of the study, participated in its design and coordination and performed the statistical analysis. RM, CJ, RG and IP carried out the imaging studies and drafted the manuscript. RM and TH carried out image analysis. TH and TD carried out animal preparation and experimental setup. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2342/13/44/prepubComparison of cine and late enhancement imaging. Cine and late enhancement imaging revealed akinetic wall motion and corresponding myocardial scar tissue resulting from myocardial infarction (same animal as in Figure Click here for file


Traditional magnetic resonance (MR) imaging can identify abnormal changes in ipsilateral thalamus in patients with unilateral middle cerebral artery (MCA) infarcts. However, it is difficult to demonstrate these early changes quantitatively. Diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy (MRS) are potentially sensitive and quantitative methods of detection in examining changes of tissue microstructure and metabolism. In this study, We used both DTI and MRS to examine possible secondary damage of thalamus in patients with corona radiata infarction.Twelve patients with unilateral corona radiata infarction underwent MR imaging including DTI and MRS at one week (W1), four weeks (W4), and twelve weeks (W12) after onset of stroke. Twelve age-matched controls were imaged. Mean diffusivity (MD), fractional anisotropy (FA), N-acetylaspartate (NAA), choline(Cho), and creatine(Cr) were measured in thalami.P< 0.05). NAA was significantly decreased at W4 compared to W1, and at W12 compared to W4  in the ipsilateral thalamus. There was no significant change in FA, Cho, or Cr in the ipsilateral thalamus from W1 to W12. Spearman's rank correlation analysis revealed a significant negative correlation between MD and the peak area of NAA, Cho, and Cr at W1, W4, and W12 and a significant positive correlation of FA with NAA at W1.T1-weighted fluid attenuation inversion recovery (FLAIR), T2-weighted, and T2-FLAIR imaging showed an infarct at unilateral corona radiate but no other lesion in each patient brain. In patients, MD was significantly increased at W12, compared to W1 and W4 (all These findings indicate that DTI and MRS can detect the early changes indicating secondary damage in the ipsilateral thalamus after unilateral corona radiata infarction. MRS may reveal the progressive course of damage in the ipsilateral thalamus over time. Secondary damage in the ipsilateral thalamus separate from the primary infarcted area has been demonstrated by a number of studies -9. In raDiffusion tensor imaging (DTI) is able to characterize brain tissue structure by measurement of water diffusion, and it can detect changes not identified by traditional MR imaging. It is expressed as two indices, mean diffusivity (MD) and fractional anisotropy (FA). MD is a parameter of magnitude of average molecular motion considered in all directions. FA is a quantitative measure of the degree of anisotropy, which is characterized by the random motion of water preferentially restricted to movement in one direction ,11. StudProton magnetic resonance spectroscopy (MRS) allows for non-invasive imaging of metabolic changes within the brain. Evidence of neuronal or axonal loss and damage can be obtained from measurement of N-acetylaspartate (NAA), which is considered a marker for neuronal and axonal integrity, viability, activity, and function -18. SeveThe corona radiata is the core of the hemispheric white matter, and its infarction may compromise the integrity of the corticospinal tract and thalamic radiations, causing sensation, movement, and cognitive dysfunction -22. HervThe research protocol was approved by the medical ethical committee of the First Affiliated Hospital, Sun Yat-Sen University for clinical research, and informed consent was signed from all participants. We selected 12 consecutive patients  between October 2008 and December 2009 in Department of Neurology and Stroke Center, the First Affiliated Hospital, Sun Yat-Sen University, within 7 days of a focal infarct in the unilateral corona radiata, without any other signal abnormalities on T1-weighted fluid attenuation inversion recovery (FLAIR) and T2-weighted images. Mean age was 62.7 ± 6.5. Patients with unstable vital signs or a history of central nervous system disorders were excluded. Demographic characteristics and vascular risk factors were recorded in each patient. All patients were investigated with DTI and MRS at 1 week , 4 weeks , and 12 weeks  following a pre-defined protocol. Infarct volume was estimated from the T2-weighted FLAIR images at W12. Controls were 12 healthy age-matched volunteers recruited over the same period examined once by DTI and MRS.b factor of 1,000 s/mm2 and diffusion-sensitive gradients were applied along 15 gradient directions. In addition, a reference image without diffusion weighting (b = 0 s/mm2 ) was acquired. 15 repeats were acquired and averaged to improve signal to noise ratio. The scanning baseline was parallel to the antero-posterior commissural (ACPC) line. Axial slices covering the whole brain were obtained using a fast spin echo T2  serving as a matrix for the spectroscopic measurement and serving to position a spectroscopic volume of interest (VOI). Positioning of VOI was adjusted to the individual anatomy on T2 images covering the left and right thalamus  equipped with gradient hardware allowing up to 23 mT/m. T1-FLAIR was obtained within the first week. Fast spin echo T2-weighted imaging, T2-FLAIR, DTI, and proton MRS imaging were performed at W1, W4, and W12. Typical acquisition parameters of conventional MR imaging were: T1-FLAIR , T2-FLAIR . DTI was obtained with an echo planar imaging sequence . DTI was acquired with a An experienced radiographer carried out image post-processing without knowing the purpose of the study. The DTI data were transferred to a workstation and spatially filtered using a median 3 × 3 filter. Acquiring the DTI data with the dual-echo EPI sequence and ramp sampling considerably reduced, but did not eliminate, the geometric distortions. We corrected the residual distortions by registering the diffusion weighted imaging with the reference image using the two-dimensional module of the automated image registration package (eight-parameter with perspective) . With thThe post-processing and quantification steps were automatically done using ADW4.2 Software. Spectral post-processing was comprised of line broadening, zero-filling, reducing the residual water resonance, linear baseline correction, and peak integration. Data were obtained from three adjacent voxels in the thalami on each side Figure . Each spt test. DTI parameters  and metabolite levels  obtained at W1, W4, and W12 were analyzed using the Tukey test for multiple testing. To reduce inter-patient and inter-exam variability, asymmetry indices  of MD, FA values, and peak areas of NAA, Cho, Cr obtained in patients, were calculated according to methods described by Hervé et al. [P < 0.05.MD, FA values, and proton metabolite levels obtained at W1, W4, and W12 in patients were first compared with those of controls with a two-tailed Student's Twelve patients  and 12 controls  were recruited in the study. All patients and controls were right handed. Each patient had one or more vascular risk factors (Table 3 (15615 ± 4740 mm3) on T2 images at W12. No definite abnormal signal was observed in the brains of control patients, nor in thalami on T1-FLAIR, T2-weighted and T2-FLAIR images throughout the duration of the study.Thirty-six examinations in patients and 12 examinations in controls were performed. Within the first week from stroke onset, T2-weighted and T2-FLAIR images showed focal hyperintensity confined to the unilateral corona radiata in each patient , FA , NAA , Cho  and Cr  the data obtained in the right thalamus were selected to compare absolute values in patients and controls.In controls, in the absence of any significant difference between the left and right thalami for MD . There was a significant time effect on MD calculated in the ipsilateral, but not in the contralateral thalamus. A significant increase of MD in the ipsilateral thalamus was found between W1 and W12 and between W4 and W12 (P = 0.012 and P = 0.003 respectively). However, no obvious MD value changes were found in contralateral thalami . There was a significant time effect on MRS metabolites measured on the ipsilateral side. NAA in ipsilateral thalami were significantly decreased between W1 and W4, between W1 and W12, and between W4 and W12 , however, no obvious NAA changes were found in the contralateral thalami . There was no significant changes in the asymmetry indices for peak areas of Cho or Cr from W1 to W12  between DTI parameters  with the corresponding MRS parameters  in patients showed a significant negative correlation of MD with NAA, Cho, and Cr at W1 , W4 , and W12 , and a significant positive correlation of FA with NAA at W1 . There was no significant correlation between FA and NAA at W4 and W12, between FA and Cho at W1, W4, and W12.Spearman's correlation  patients. A negative correlation between NAA and ADC was found in ppMS patients and controls ,27. In oUsing DTI and MRS, we found significantly increased MD at W12, and decreased NAA at W4 and W12 in the ipsilateral thalamus in patients with acute unilateral infarction of the corona radiata, indicating notable secondary damage in the ispilateral thalamus in the early stages after stroke. DTI and MRS can detect early secondary damage in the ipsilateral thalamus, and MRS may reveal the dynamic process of damage in the ipsilateral thalamus. The pathologic basis behind the secondary damage in ipsilateral thalamus may be mainly a result of neuronal and/or axonal degeneration, loss, and dysfunction. Moreover, neuronal and/or axonal structural loss was consistent with the neuronal and/or axonal dysfunction.The authors declare that they have no competing interests.CL participated in the design of the study, collected the data and wrote the primary manuscript, XL carried out image postprocessing, SL conducted the MR images analysis, AX assisted with the data collection, YZ assisted with the statistical analysis, SX assisted with the data collection, PZ participated in the design of the study, JZ designed the study, interpreted the results and critically revised the manuscript, all authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/11/49/prepub


Several beneficial effects have been demonstrated for secretogranin II (SgII) in non-cardiac tissue. As cardiac production of chromogranin A and B, two related proteins, is increased in heart failure (HF), we hypothesized that SgII could play a role in cardiovascular pathophysiology.in vitro. Processing of SgII to shorter peptides was enhanced in the failing myocardium due to increased levels of the proteases PC1/3 and PC2 and circulating SgII levels were increased in mice with HF. Examining a pathophysiological role of SgII in the initial phase of post-infarction HF, the SgII fragment secretoneurin reduced myocardial ischemia-reperfusion injury and cardiomyocyte apoptosis by 30% and rapidly increased cardiomyocyte Erk1/2 and Stat3 phosphorylation. SgII levels were also higher in patients with stable, chronic HF compared to age- and gender-matched control subjects: median 0.16 (Q1–3 0.14–0.18) vs. 0.12 (0.10–0.14) nmol/L, p<0.001.SgII production was characterized in a post-myocardial infarction heart failure (HF) mouse model, functional properties explored in experimental models, and circulating levels measured in mice and patients with stable HF of moderate severity. SgII mRNA levels were 10.5 fold upregulated in the left ventricle (LV) of animals with myocardial infarction and HF . SgII protein levels were also increased in the LV, but not in other organs investigated. SgII was produced in several cell types in the myocardium and cardiomyocyte synthesis of SgII was potently induced by transforming growth factor-β and norepinephrine stimulation We demonstrate increased myocardial SgII production and processing in the LV in animals with myocardial infarction and HF, which could be beneficial as the SgII fragment secretoneurin protects from ischemia-reperfusion injury and cardiomyocyte apoptosis. Circulating SgII levels are also increased in patients with chronic, stable HF and may represent a new cardiac biomarker. Heart failure (HF) is associated with changes in systemic and pulmonary hemodynamics, complex neurohumoral activation, as well as local molecular alterations in the myocardium 154–186) and a number of interesting pathophysiological effects have been reported in other organs than the heart The protein secretogranin II (SgII) is a 587 amino acid long protein from the chromogranin-secretogranin (granin) protein family To study SgII production in the left ventricle (LV) in HF, we first compared SgII mRNA levels in non-infarcted LV tissue of HF animals to levels in sham animals. HF animals exhibited increased lung weights and increased LV and right ventricular mass, reflecting pulmonary congestion and compensatory myocardial hypertrophy . By echoLV SgII mRNA levels were markedly upregulated in HF animals compared to sham animals  and the infarcted region of the LV  in HF animals as measured by radioimmunoassay (RIA) . As prevThe complex processing of SgII  [3], , and no hospitalization for HF during the last three months prior to study commencement, were compared to 20 control subjects with no history or current symptoms of chronic disease. The control subjects had a normal physical examination, did not use medication regularly, and were hospital employees or recruited from outside of the hospital.t-test except circulating biomarker values in patients that were compared by the Mann-Whitney U-test due to a severe right-skewed distribution (p<0.001). Serial data were compared by Two-Way ANOVA, and categorical data by the chi-square test or Fisher’s exact test as appropriate. Correlations were calculated by Spearman rank correlation. P-values <0.05 were considered significant for all analyses. Statistical analyses were performed with SPSS for Windows version 16.0  except receiver operating analysis which was performed with MedCalc for Windows, version 9.5.1.0  by the method of Hanley and McNeil Continuous data are presented as mean (± SEM) or median (quartile [Q] 1–3) and categorical values as counts (percentage). Continuous variables were compared by Student’s Details regarding methods can be found in the Supporting Figure S1Hearts from male adult rats were rapidly excised and mounted on a Langendorff system. After 40 min of stabilization, hearts were subjected to 30 min of global ischemia, and then reperfused for 120 min. In the experimental group (secretoneurin group), 0.66 µg/mL secretoneurin (SN) was added to the perfusate 20 min prior to ischemia, and also used throughout the reperfusion period.(TIF)Click here for additional data file.Table S1Correlations between mRNA levels of granins and BNP in the left ventricle of heart failure and sham-operated mice.(DOC)Click here for additional data file.Table S2Correlations between circulating levels of granin proteins and BNP in patients with heart failure and healthy control subjects.(DOC)Click here for additional data file.Supporting Information S1Enhanced albumin levels in pulmonary tissue of HF animals were identified by mass spectrometry peptide mass fingerprinting. Coomassie stained protein bands were cut out from SDS-polyacrylamide gels and identified by mass spectrometry peptide mass fingerprinting. A, Representative Commassie stained gel from pulmonary tissue with arrow indicating extracted band for mass spectrometry peptide mass fingerprinting. B, Results for the mass spectrometry peptide mass fingerprinting identifying albumin for all 8 samples after searching the NCBI database. Significant hits for sample 1.1 are given below and they all represent slightly different variants of albumin. The same proteins were reported for the other 7 samples. All the main signals in the spectra are assigned to albumin.(DOC)Click here for additional data file.Supporting Information S2Supplemental methods.(DOC)Click here for additional data file.


Assessment of the haemodynamically unstable patient is a core part of ICU management and relies predominantly on a combination of clinical skill and measurement of physiological variables. Echocardiography in the ICU has become increasingly popular as a tool for assessment of cardiac output, fluid status and ventricular function. Traditionally transoesophageal echo (TOE) has been favoured due to the belief that it gave superior images . TransthData were collected prospectively in all patients undergoing echocardiography in a teaching hospital ICU from January 2008 to January 2011. The main focus of our investigation was to ascertain the clinical questions to be answered and the outcome of echo on management.A total of 238 echoes were performed on 216 patients with an average age of 59.75 years . The most commonly asked questions were on filling status and contractility (40%) and left ventricular function (33%). Ninety percent of clinical questions asked were answered fully (74%) or partially (16%) by echo. Sixty-one percent of echoes resulted in a change of management (5% of which were to continue with increased confidence). TTE performed by operators with basic training resulted in a 54% change in management. Changes included more filling (39%) and changes in inotropes or diuretics.Echocardiography in the ICU patient relies on numerous factors including skill and equipment availability and patient windows . Our res