The aim of this article is to present an optimized acquisition and analysis protocol for the echocardiographic evaluation of left ventricle (LV) remodeling in a mouse model of myocardial infarction (MI).13 female DBA/2J mice underwent permanent occlusion of the left anterior descending (LAD) coronary artery leading to MI. Mice echocardiography was performed using a Vevo 770  before infarction, and 7, 14, 30, 60, 90 and 120 days after LAD ligation. LV systolic function was evaluated using different parameters, including the fractional area change (FAC%) computed in four high-temporal resolution B-mode short axis images taken at different ventricular levels, and in one parasternal long axis. Pulsed wave and tissue Doppler modes were used to evaluate the diastolic function and Tei Index for global cardiac function. The echocardiographic measurements of infarct size were validated histologically using collagen deposition labeled by Sirius red staining. All data was analyzed using Shapiro-Wilk and Student's t-tests.2 = 0.90; p<0.05). Moreover, the measured Tei Index values confirmed significant post-infarction impairment of the global cardiac function .Our results reveal LV dilation resulting in marked remodeling an severe systolic dysfunction, starting seven days after MI . A strong statistically significant negative correlation exists between the infarct size and long-axis FAC% (r = −0.946; RIn summary, we have performed a complete characterization of LV post-infarction remodeling in a DBA/2J mouse model of MI, using parameters adapted to the particular characteristics of the model In the future, this well characterized model will be used in both investigative and pharmacological studies that require accurate quantitative monitoring of cardiac recovery after myocardial infarction. Cardiovascular disease, and more specifically myocardial infarction (MI), is the first cause of morbidity and mortality in the world Quantitative bi-dimensional transthoracic echocardiography is routinely used to characterize the LV remodeling associated with ischemic cardiomyopathies in vivo micro-imaging system, which has been used in this study. Ultrasound imaging provides a fast and inexpensive alternative to magnetic resonance imaging Several murine models of myocardial infarction exist, based on permanent occlusion of the left anterior descending coronary artery (LAD). These models have been used to elucidate mechanisms of myocardial remodeling and provide new insights into the physiology and treatment of cardiovascular disease The most common parameters used to evaluate the systolic function of the LV are the fractional shortening (FS%), ejection fraction (EF%) and cardiac output (CO) Using the above method, the LV function can also be measured as the percentage of change in left ventricular cross-sectional area between diastole and systole , which has been found to correlate well with EF% both in normal and abnormal subjects Cardiologists, beyond the standard systolic dysfunction, are starting to analyze post-infarction diastolic dysfunction, which precedes the depression of systolic function in patients of all ages suffering from both permanent and temporary ischemic cardiomyopathies. The standard approach to diagnose diastolic dysfunction uses a pulsed-wave Doppler scan of transmitral flow, although a variety of other measurements can be used Finally, since the isolated analysis of systolic and diastolic mechanisms may not be reflective of overall cardiac dysfunction, the Tei index has been recently introduced. The Tei Index is a simple, reproducible, quantitative estimate of global dysfunction, independent from heart rate and blood pressure levels, characterized by low inter-observer and intra-observer variability The aim of the present article is to present an optimized echocardiographic quantification of LV remodeling in a mouse model of myocardial infarction. All the above-described parameters have been included and compared in our evaluation, and those that have morphological significance, correlated with histological measurements.The rest of the article is organized as follows. In Section 2, we briefly summarize our mice model of MI by LAD ligation, the image acquisition protocols and parameters used to evaluate cardiac function. The results are presented in Section 3. A final discussion (Section 4) and conclusions (Section 5) end the article.Pelacho et al.Seventeen 8-week-old female DBA/2J mice  underwent coronary artery ligation as described in All experiments were performed in accordance with the principles of laboratory animal care formulated by the National Society for Medical Research and the guide for the care and use of laboratory animals of the Institute of Laboratory Animal Resources . All animal procedures were approved by the University of Navarra Institutional Committee on Care and Use of Laboratory Animals.Echocardiography was performed using a Vevo 770 ultrasound system  equipped with a real time micro-visualization scan head probe (RMV-707B) working at a frame rate ranging between 110 and 120 frames per sec (fps). The nosepiece-transducer used has a central frequency of 30 MHz, a focal length of 12.7 mm and 55 µm of nominal spatial resolution. The Vevo 770 is equipped with ECG-gated kilohertz visualization software (EKV™), which synthesizes high temporal resolution B-Mode images by combining several ECG-synchronized heart cycles. The EKV image reconstruction software produces B-mode sequences at up to 1000 frames per second.Mice were anesthetized with isoflurane , at a concentration of 4% (induction) and 1.5% (maintenance) in 100% Oxygen. Each animal was placed on a heating table in a supine position with the extremities tied to the table through four electrocardiography leads. The chest was shaved using a chemical hair remover . Warmed ultrasound gel  was applied to the thorax surface to optimize the visibility of the cardiac chambers. The heart rate (HR) of the animals was recorded immediately before the echocardiographic study.Echoes were acquired at baseline (before LAD ligation), and 7, 14, 30, 60 and 90 days after LAD ligation. LV remodeling was quantified according to the guidelines and standards of American Society of Echocardiology, the guide to micro-echocardiography study using the Vevo770 First we quantified the LV structural analysis. To that end the LV diameters at basal (Dbvi), middle (Dmvi) and apical level (Davi), the end-diastolic (Aread) and end-systolic (Areas) areas were measured on a two-dimensional (B-mode) parasternal long-axis view.The functional analysis of the heart was next evaluated, starting with the LV systolic function that was measured several ways:The ejection (EF% tei) and shortening (FS%) fractions were calculated from the LV diameters  measured on an M-mode examination of the LV. To obtain the classical LV M-mode tracing, the M-mode cursor was vertically positioned at a transthoracic parasternal short axis view –visualizing both papillary muscles-.n), namely:The normalized mean velocity of circumferential fiber shortening (VcFc) was calculated as the ratio between the shortening fraction and the heart rate (HR) corrected ejection time , from a long axis view and four short axis views at different levels of the LVThe fractional area change (FAC%), was measured asFirst, we calculated the FAC% using one parasternal short-axis view at mid-ventricular level (FAC% short). Given the poor definition of the endocardial border on the short-axis view, especially at mid-ventricular and apical levels, caused by the apical location of the infarction in our model, we also calculated the FAC% in one EKV-mode parasternal long-axis view (FAC% long). Both short and long-axis views were acquired using gain settings that optimized the visualization of the endocardial and epicardial walls.The peak velocity of the septal basal level  and the posterior wall (S′ post) were measured using Tissue Doppler from a four chamber and short axis view, respectively.The cardiac output (CO), was measured from the left ventricular output tract length (LVOT) and HR measured on a long axis view, and the area under the curve of a Doppler measured on the aortic valve.The LV diastolic function was evaluated using pulsed-wave Doppler sensing of the transmitral inflow obtained from LV apical two or four chamber views. From the pulsed-wave Doppler graph, we measured the peak E wave velocity (early filling wave), peak A wave velocity , E/A ratio, deceleration time (MVDT), ejection time from opening to closure of the aortic valve (ET ms) and LV isovolumetric relaxation (IVRT) and contraction (IVCT) times. During the scan, the ultrasound beam was kept as parallel as possible to the blood flow. Representative Doppler curves obtained from one of the animals in all time points are included as The Tei Index –an indicator of global cardiac function- was calculated from the pulsed-wave Doppler graph:Finally, an estimate of both systolic and diastolic function was also obtained using tissue Doppler imaging on the LV septal basal portion of the mitral annulus, and on the LV posterior wall, taken from a parasternal short-axis view at the level of the papillary muscle. From the tissue Doppler imaging graph, we calculated the negative E′ wave , negative A′ wave , and the ratio E/E′  Representative tissue Doppler curves obtained from one of the animals in all time points are included as All measurements were performed offline using dedicated Vevo770 quantification software (Vevo 770 v. 3.0.0).Mice were anesthetized, injected with 100 µl saline containing 0.1 mM cadmium chloride (Sigma), and perfusion-fixed for 10 min with 4% paraformaldehyde under physiological pressure. The hearts were excised, fixed overnight in 4% paraformaldehyde at 4°C, and cut in three 3.0 mm blocks  using a mouse heart slicer matrix .All data are expressed as mean ± standard deviation. The Shapiro-Wilk test was used to verify that the data followed a normal distribution, which justified or not the use of a parametric test. A Student's The average study was 15 minutes long. Four mice from the experimental group were excluded from the study: Three of them died during surgery and one more 7 days after myocardial infarction. The results of the structural and functional measurements performed on the control –sham- group are included in These data indicate that the ventricular dilation extends progressively from the apical origin of the infarction towards healthy myocardial areas, resulting in marked changes of both size and shape. This is clearly visualized in The systolic measurements taken on short axis views at the level of the papillary muscles -The EF% calculated using the Simpson's rule -Finally, We used the pulsed wave Doppler of the mitral filling to measure diastolic dysfunction. We observed no significant increase of the ratio E/A -The Tei Index, used as an indicator of global cardiac function, -The tissue Doppler analysis reveals significant deterioration of the diastolic function at the septal basal velocity –2 = 0.90; p<0.05). However, the correlation with FAC% calculated in a short-axis view was lower , due to the difficulty of obtaining good short-axis views in this specific model.At the end point of the experiment −90 days post-infarction-, the percentage of infarcted tissue was measured as described in the material and methods section. The evaluation of cardiac function in mice has been hampered until this date by technical issues, such us the fast mouse heart rate, the difficulty to obtain clear echocardiographic views of the heart, and the translational motion present during image acquisition This study has been carried out in the context of a broader effort aimed at characterizing the long-term effects of stem cell based therapies in post-infarction cardiac remodeling. We will use induced pluripotent stem (IPS) cells derived from DBA/2J cardiomyocytes, which will be injected in the infarcted myocardial areas. To avoid unwanted immunological response, the cells will be injected in infarcted hearts of DBA/2J mice. Previous studies on mouse models of MI were done mostly on C57BL mouse background We have done a complete characterization of our myocardial infarction model by measuring the untreated progression of the LV systolic, LV diastolic and global cardiac function post MI. Other groups have done similar studies using the same equipment Our analysis of the evolution of FAC% with time shows that systolic dysfunction –visible as early as 7 days after MI- is directly related to the progressive dilation of the LV internal diameter and with the increase of the end-systolic and end-diastolic areas. However, changes in the diastolic function were not so evident, and were only detected using the IVRT. Contrarily, we found no significant changes of DT and the ratio E/A, while E′ measured at the posterior wall reflected significant changes only 14 days post-infarction. This is consistent with the findings of recent studies that claim that the isolated analysis of systolic or diastolic function may not be reflective of overall cardiac function et al.The measurement of the infarcted area in tissue sections is the common ex-vivo approach to determine the infarct size in animal models In summary, we have performed a complete characterization of LV remodeling in a mouse model of MI, establishing a valuable control for future pharmacological, cellular or tissue engineering studies of post-infarction cardiac remodeling, such as those reported by us and others Figure S1Pulsed-wave Doppler analysis. Sample Doppler pulsed-wave recordings of the transmitral inflow obtained from LV apical two or four chamber views. The recordings were obtained from the same animal before infarction (top) and 7, 14, 30, 60 and 90 days (bottom) after infarction.(TIF)Click here for additional data file.Figure S2Tissue Doppler analysis. Sample tissue Doppler recordings of the LV septal basal portion of the mitral annulus, taken from a parasternal short-axis view at the level of the papillary muscle. The recordings were obtained from the same animal before infarction (top) and 7, 14, 30, 60 and 90 days (bottom) after infarction.(TIF)Click here for additional data file.Figure S3Tissue processing. A) Rodent heart slicer (Zivic Instruments). The heart is located into the slicer hole and two blades (Stanley) inserted (3 mm separated of each other). Once the blades are partially inserted, they are aligned with another one and simultaneously pressed down until the end. B) Heart blocks. The blades are raised out and the three heart blocks  removed.(TIF)Click here for additional data file.Table S1HR: heart rate. EF% tei: ejection fraction using Teichholz. EF% simp: ejection fraction using Simpson's rule. FS% tei: shortening fraction using Teichholz. FAC% short: fractional area change measured on a short axis view. FAC% long: fractional area change measured on a long axis view. VcFc: normalized mean velocity of circumferential fiber shortening. LVID d: LV internal diameter (diastole). LVID s: LV internal diameter (systole). CO: cardiac output. LV vol d: LV volume (diastole). LV vol s: LV volume (systole)  (DOCX)Click here for additional data file.Video S1Parasternal short axis sample EKV video recording at baseline.(AVI)Click here for additional data file.Video S2Parasternal short axis sample EKV video recording 7 days post-infarction.(AVI)Click here for additional data file.Video S3Parasternal short axis sample EKV video recording 30 days post-infarction.(AVI)Click here for additional data file.Video S4Parasternal short axis sample EKV video recording 90 days post-infarction.(AVI)Click here for additional data file.Video S5Parasternal long axis sample EKV video recording at baseline.(AVI)Click here for additional data file.Video S6Parasternal long axis sample EKV video recording 7 days post-infarction.(AVI)Click here for additional data file.Video S7Parasternal long axis sample EKV video recording 30 days post-infarction.(AVI)Click here for additional data file.Video S8Parasternal long axis sample EKV video recording 90 days post-infarction.(AVI)Click here for additional data file.


This study is the first to use quantitative perfusion CMR to evaluate regional differences in myocardial blood flow (MBF) in patients with left bundle branch block (LBBB).LBBB is often associated with underlying CAD but its presence can limit the diagnostic accuracy of non-invasive imaging tests. In particular, there is a high incidence of false-positive results with exercise SPECT due to apparent septal perfusion defects. The use of vasodilator stress has reduced but not eliminated this problem. Several hypotheses have been postulated to explain the cause of such perfusion defects, and these include early activation of the septum, leading to shortened diastole and reduced blood flow; partial volume effects caused by impaired septal thickening; and increased septal intra-myocardial pressure during diastole, resulting in reduced flow reserve. A number of small studies using PET or early quantitative SPECT techniques have evaluated regional differences in MBF in patients with LBBB, but the results have been conflicting and have shown either no regional differences or a relative but not absolute reduction in septal perfusion. This study re-evaluates the unresolved question of septal perfusion in LBBB using quantitative perfusion CMR.9 patients with LBBB and no significant CAD underwent adenosine stress/rest perfusion CMR at 1.5T and X-ray coronary angiography. Absence of CAD was defined as luminal stenosis <40% on quantitative coronary angiography in all major vessels. Mid-ventricular perfusion data were segmented into 3 regions for each patient: septal, adjacent (anterior-inferior) and lateral. MBF and myocardial perfusion reserve (MPR) were then determined for the septal and lateral regions by Fermi function deconvolution.Resting MBF was similar in both septal and lateral regions in all patients  .


The hallmark lesion of arrhythmogenic right ventricular cardiomyopathy (ARVC/D) is the RV myocardial loss with replacement by fibrofatty tissue. Emerging tools offer the possibility to directly visualize fibrofatty ventricular scar. electroanatomic voltage mapping (EVM) by CARTO system has been demonstrated to identify low-voltage myocardial areas  invasively, whereas contrast-enhanced cardiac magnetic resonance CE-CMR has the potential to detect regions of delayed contrast-enhancement (“DCE scar”) non-invasively.The aim of the present study was to compare EVM and CE-CMR for imaging scar lesion in ARVC/D patients.23 consecutive patients  with a clinical diagnosis of ARVC/D who additionally underwent both RV EVM and CE-CMR. Analysis of RV free wall regions for scar location included the RV outflow tract (RVOT), the antero-lateral region, the infero-basal region and the apex.RV EVM was abnormal in 21/23 (91%) patients, with a total of 45 EAS: 17 (38%) in the infero-basal region, 12 (26.6%) in the antero-lateral region, 8 (17.7%) in the RV outflow tract (RVOT) and 8 (17.7%) in the apex. RV DCE was found in 9/23 (39%) patients with a total of 23 RV DCE scars: 4 (17.4%) in the infero-basal region, 9 (39.1%) in the antero-lateral region, 4 (17.4%) in the RVOT and 6 (26.1%) in the apex. Comparative analysis showed a mismatch in 24 RV scar areas, with 22 EAS not confirmed by the DCE , and 2 DCE scars (both in the RVOT) undetected by the EVM. In 9/12 (75%) patients with abnormal RV EVM/normal RV DCE, ≥ 1 DCE were identified in the left ventricular (LV) free wall or interventricular septum, which affected the subepicardial/midmural layers. Overall, ventricular DCE was detected by CE-CMR in 78% of ARVC/D patients.EVM and CE-CMR allow identification of RV scar lesions in the majority of ARVC/D patients, although a mismatch between the two techniques was found with fewer RV scars identified by CE-CMR. The high prevalence of LV DCE in ARVC/D patients with abnormal RV-EVM/normal RV-DCE confirms the frequent biventricular involvement and points out the diagnostic relevance of LV scar detection by CE-CMR.


The aim of this study was to investigate the modified Ross criteria score and the diagnostic cut-off level for plasmatic amino-terminal pro-brain natriuretic peptide (NT-proBNP) in the diagnosis of pediatric heart failure, by analyzing the receiver operating characteristic (ROC) curve. The plasma NT-proBNP level was measured in 80 children diagnosed with heart failure according to the modified Ross criteria, 80 children with non-cardiogenic dyspnea and 80 healthy children. The NT-proBNP levels were then compared using an F-test. The cut-off score for heart failure in the modified Ross criteria and the diagnostic cut-off level for plasmatic NT-proBNP in pediatric heart failure were determined by ROC curve analysis. The results demonstrated that the NT-proBNP level was markedly increased in 76 of the 80 children with heart failure, and the correlation with the modified Ross criteria was 95%. Based on ROC curve analysis, the diagnosis of pediatric heart failure was most accurate when the modified Ross criteria score was ≥4 and the plasmatic NT-proBNP level was ≥598 ng/l. The NT-proBNP level was normal (0–300 ng/l) in the children with non-cardiogenic dyspnea and the healthy children. Significant differences were observed in the comparison of the three groups (P<0.01). In conclusion, a NT-proBNP level of ≥598 ng/l, combined with a modified Ross criteria score ≥4, is highly diagnostic of heart failure in children. Heart failure is one of the most serious diseases in children, and is characterized by a progressive left ventricular pump dysfunction, leading to cardiac dilatation, thinned walls and poor contractility . FollowiThe diagnostic measures of pediatric heart failure include the Ross criteria , modifieA total of 240 children were involved in this study. These included 80 children with heart failure, who were admitted to the Women and Children’s Health Care Hospital of Shunde  from March 2010 to January 2012, 80 children with non-cardiogenic dyspnea and 80 healthy children. The diagnosis of pediatric heart failure was made based on the modified Ross criteria ,7. AmongPrior to and following treatment, 2 ml whole blood was obtained from each child and stored in a fluid tube containing EDTA. Following this, 0.75 ml blood was aliquoted to a tube containing NT-proBNP quantitative buffer, and was mixed thoroughly. The NT-proBNP level was assayed within 5 min by the Canadian RAMP heart failure diagnostic instrument method. The testing materials were provided by the Response Biomedical Corp. . The normal adult range of NT-proBNP is 0–300 ng/l, and a value of ≥450 ng/l is suggestive of heart failure. At present, there are no clear standards and there is no normal range for children.high NT-ProBNP/Nheart failure) × 100. The data were analyzed using the F-test, and statistical analyses were performed using SPSS version 13.0 statistical software . P< 0.05 was considered to indicate a statistically significant difference.A receiver operating characteristic (ROC) curve was created, and the cut-off score for heart failure, based on the modified Ross criteria, and the diagnostic cut-off level for plasma NT-proBNP in pediatric heart failure were determined by analyzing the specificity and sensitivity of the diagnosis. The number of children with an elevated NT-ProBNP level in the heart failure group was compared with the number diagnosed with heart failure according to the modified Ross criteria. A coincidence rate was obtained by using the following formula: (NThe ROC area under the curve (AUC) of heart failure in the modified Ross criteria was 0.958  . A diagnThe ROC AUC of plasma NT-proBNP level in pediatric heart failure was 0.979 , moderate (27 cases) and severe heart failure (12 cases), which were diagnosed according to the modified Ross criteria, were 1,184.31 , 3,353.57  and 16,883.22 , respectively. There was no overlap in the 95% CIs .The F-test revealed that there were significant differences in the NT-proBNP levels among the mild, moderate and severe heart failure groups  . The plaThe F-test revealed that the NT-ProBNP levels in the group with heart failure, the group with non-cardiogenic dyspnea and the group of healthy children were significantly different  . The NT-The results of the study indicate that the NT-ProBNP level is a sensitive and reliable biomarker for the diagnosis of heart failure, and is highly correlated with the modified Ross criteria. Analysis of the ROC curve revealed that a score of ≥4 in the modified Ross criteria was notably more effective than a score of ≥3 for the diagnosis of pediatric heart failure. Furthermore, the accuracy of the diagnosis greatly improved when the plasma NT-proBNP level was set at ≥598 ng/l. Based on these data, we designed combined diagnostic criteria for heart failure  and suggThe importance of the NT-proBNP level in the diagnosis and evaluation of heart failure has been widely accepted –11. BNP et al (et al (The commonly utilized criteria of heart failure include the international Ross criteria, the modified Ross criteria and the NYU PHFI score. All of these, with the exception of the NYU PHFI score, are based on clinical signs and symptoms. In 1987, based on the classification of heart failure for adults, designed by the New York Heart Association, Ross proposed a novel pediatric classification for babies aged <6 months . This wal (et al . AlthougAside from the score parameters in the modified Ross criteria, the NYU PHFI score  also incThe combined diagnostic criteria for heart failure proposed in the present study were based on the modified Ross criteria, and introduced an objective diagnostic parameter, the NT-proBNP level. The results of this study demonstrated that the diagnosis of pediatric heart failure according to the modified Ross criteria and the NT-proBNP level was 95% accurate. It was observed that ∼93% of children with mild and 100% of children with severe heart failure were included in the 95% CI. In addition, there was no overlap in the 95% CIs of mild, moderate and severe heart failure, and the NT-proBNP level was observed to increase with increasing modified Ross criteria scores. Therefore, the modified Ross criteria and the NT-proBNP level were included in the combined diagnostic criteria for heart failure, in order to achieve a greater accuracy of diagnosis. Moreover, the measurement of the NT-proBNP level is easy, fast, accurate and inexpensive.


LVAD = Left Ventricular Assist Device; LV = Left Ventricle; LA = Left Atrium; AO = Aorta A 41-year-old male Indian patient was admitted to our hospital due to refractory congestive heart failure. The patient received a left ventricular assist device (LVAD) as destination therapy. The images show the preoperative, intraoperative, and postoperative echocardiography findings Figures .Figure


Left ventricular noncompaction (LVNC) is a genetically heterogenous form of cardiomyopathy which may remain undiagnosed till adulthood due to the late presentation of typical symptoms such as dyspnea, congestion, ventricular arrhythmias and thromboembolism. Symptomatic bradycardia secondary to persistent sinus node dysfunction is very rare. Coexistent cardiac defects are common in children however in adults the disease is usually in isolated form. Here, we present a case of twenty-three year-old female LVNC patient with patent ductus arteriosus, bicuspid aortic valve and persistent sinus node dysfunction who presented with dizziness as the first manifestation of the disease. Left ventricular noncompaction (LVNC) is a myocardial disorder characterized by excessive trabeculations and deep recesses that communicate with the ventricular cavity. Concomitant heart defects, mostly ventricular septal defects are encountered in these patients and are accepted as a result of ventricular maldevelopment during embryologic life. The major manifestations of the disease are heart failure, thromboembolism and ventricular arrhythmias whereas symptomatic bradycardia is very rare. ,2. Here,A 23-year-old female patient admitted to our emergency department with a complaint of dizziness which started within 12 hours. On physical examination her skin was pale and diaphoretic, her pulse was regular but bradycardic with a rate of 40 beats/min. Her arterial blood pressure was measured 110/70 mmHg. On auscultation, a continuous murmur which was loudest at the left upper chest was determined. The remainder of the physical examination was normal. Her medical and family history was unremarkable. A 12-lead electrocardiogram revealed QRS complexes of 100 msec width with regular R-R intervals without any preceding p waves . In laboLeft ventricular noncompaction is accepted as a genetically heterogenous form of cardiomyopathy and was initially defined in pediatric population with congenital syndromes . Heart fArrhythmias are common in LVNC and sudden cardiac death is the major cause of mortality which is reported to be 4% per year in isolated LVNC cases [In addition, pre-excitation syndromes, atrioventricular and interventricular conduction disturbances may be encountered in LVNC patients ,6. SteffIn adult population, LVNC is mostly in isolated form. Zavelata et al. reported coexistence of other heart defects with a proportion of 26% in 23 adult LVNC cases including 2 cases of PDA and a case of bicuspid aortic valve . In addiTo date, intracardiac cardioverter defibrillator (ICD) implantation is the most promising therapy in LVNC patients with ventricular arrhythmias. Guidelines recommend ICD implantation in ventricular noncompaction cases who are survivors of sudden cardiac death; who have spontaneous sustained ventricular tachycardia whether hemodynamically unstable or stable; who have a left ventricular ejection fraction less than or equal to 35%. In our case, as a sustained ventricular arrhythmia was not detected and left ventricular systolic function was mildly depressed, we implanted a dual pacemaker without cardioverter properties. During the follow-up ventricular arrhythmias were not detected and the patient was asymptomatic.In conclusion, our case shows that persistent sinus node dysfunction may be the first symptom in LVNC cases. Considering LVNC as a congenital heart disease, accompanying heart defects including PDA and bicuspid aortic valve should be investigated in every patient with different imaging modalities when necessary.


Dilated cardiomyopathy (DCM) occurring due to an unknown etiology or genetic predisposition is termed as idiopathic dilated cardiomyopathy (iDCM), although iDCM may also result from viral exposure. However, the incidence of myocardial inflammation and its relation to left ventricular (LV) function in iDCM remains unknown.Cardiovascular magnetic resonance (CMR) imaging allows for the visualization of myocardial inflammation using early Gadolinium enhancement (EGE). We applied EGE imaging in the setting of clinically suspected iDCM to determine both the incidence and relation of myocardial inflammation to LV function.26 patients  were referred to us for the assessment of iDCM following a clinical suspicion of iDCM, based upon the following criteria: ejection fraction below 45%; invasive exclusion of significant coronary artery disease using a cutoff of 50% stenosis; stable clinical course for at least 3-months prior to the CMR study; exclusion of myocarditis within the past 12 months; as well as exclusion of comorbidities which may otherwise account for patient presentation including valvular heart disease.Standard CMR imaging procedures for the assessment of LV function and EGE were utilized. EGE images were acquired before and early after (over 4 minutes) Gd-DTPA 0.1ml/kgBW contrast injection using T1-weighted images.LV function was assessed by manually tracing endo- and epicardial contours. Myocardial signal intensity was normalized to skeletal muscle, generating a ratio that had to be greater than or equal to 4 to be considered positive for EGE.Eighteen patients (69%) presented with EGE and a significantly increased EGE ratio . The ratio of EGE correlated with LVEDVI  and LVESVI , LVSVI , and LVEF . Patients with elevated EGE had significantly dilated left ventricles and globally reduced ventricular function: LVEDVI  and LVESVI  were increased, while LVSVI  and LVEF  were reduced (Figure Using CMR-based EGE as a surrogate marker of myocardial inflammation, we provide first evidence for a high incidence of inflammation in patients with clinically suspected iDCM. The extent of myocardial enhancement was directly related to reduced ventricular function. CMR-based assessment of myocardial inflammation may be utilized as a biomarker for patient prognosis and guide medical therapy to target those patients in whom there is active myocardial inflammation.


Dexmedetomidine is known to provide sympatholysis and also to have direct atrioventricular and sinoatrial node inhibitory effects. In rare instances, orthotopic lung transplantation has been associated with disruption of autonomic innervation of the heart. The combination of this autonomic disruption and dexmedetomidine may be associated with severe bradycardia and/or asystole. Since orthotopic lung transplant patients with parasympathetic denervation will not respond with increased heart rate to anticholinergic therapy, bradyarrhythmias must be recognized and promptly treated with direct acting beta agonists to avoid asystolic cardiac events.Dexmedetomidine is an  Bradycardia and asystole in the cardiothoracic intensive care unit (CTICU) setting can be due to a broad range of etiologies. Certain patients may be more predisposed to bradyarrhythmias and/or asystole due to a combination of factors such as the surgical procedure, medications being administered, and preexisting patient comorbidities. We report a case of severe bradycardia leading to asystole after a bilateral orthotopic lung transplantation (OLT) in a patient receiving dexmedetomidine sedation. We consider the possibility that cardiac sympathetic denervation secondary to the OLT in conjunction with atrial-ventricular node conduction delay caused by the dexmedetomidine may have led to the asystolic event.A 55-year-old woman with sarcoidosis was admitted to the CTICU after receiving a bilateral OLT involving significant tracheal dissection. On postoperative day 1, sedation was weaned, and she was communicating appropriately while intubated and desired to have an epidural catheter placed for pain control prior to extubation. Timing of the epidural for patients on anticoagulation was in accordance with the American Society of Regional Anesthesia and Pain Medicine guidelines [2 of 95% and was consistent with her vitals prior to initiating the dexmedetomidine infusion. After obtaining the sitting position, her sinus rhythm deteriorated to bradycardia of 30 beats per minute, and she subsequently became hypotensive. She became agitated, ceased following commands, and became unresponsive. The dexmedetomidine infusion was immediately stopped, and one milligram of intravenous atropine was administered for the bradycardia with no effect. The bradycardia continued to decline and deteriorated to an asystolic event confirmed by arterial pressure monitoring, and cardiopulmonary resuscitation (CPR) was initiated. After 3–5 minutes of CPR, an additional 1-milligram bolus of intravenous atropine was administered along with a 1-milligram bolus of intravenous epinephrine, resulting in a heart rate of 130 beats per minute and a systolic blood pressure of 220 mmHg, which rapidly decreased to 130 mmHg. Her hemodynamic profile remained stable, and the epidural placement was aborted. Transesophageal echocardiogram (TEE) failed to show any signs of a pulmonary embolus.With her assistance and the endotracheal tube remaining in place, she was placed in a sitting position for epidural placement, and 50 micrograms of intravenous fentanyl was given for additional analgesia. Hemodynamic and respiratory stability was maintained with a sinus rhythm of 95 beats per minute, blood pressure of 130/63 mmHg, and SpODifferential diagnosis for the asystolic arrest included myocardial infarction, pulmonary embolism (PE), relative hypovolemia, a vasovagal event, the Bezold-Jarisch reflex, cardiac sarcoidosis, and direct atrial-ventricular conduction inhibition by dexmedetomidine. Our patient had increased troponin levels; however, these were difficult to interpret due to the CPR efforts and the previous day's lung transplantation operation. Her electrocardiogram remained in sinus rhythm after the resuscitation with no ST abnormalities, and her TEE was unchanged from her baseline, arguing against a saddle embolus or myocardial infarction as the cause of the arrest. While patients with systemic inflammatory diseases are at risk for developing a deep venous thrombosis, this patient was on prophylactic subcutaneous heparin. Cardiac sarcoidosis was also considered; however, this was less likely given that during the preoperative evaluation she denied any previous history of arrhythmias or knowledge of cardiac sarcoidosis. In terms of relative hypovolemia, our patient's fluid balance was negative; however, she was maintaining adequate perfusion pressures with sufficient urine output. Additionally, her ICU bed had previously been positioned in the semirecumbent position with no hemodynamic instability. Unfortunately, she never regained consciousness following the arrest. Computed tomography (CT) of her head and electroencephalogram (EEG) did not demonstrate pathology explaining her comatose state, and she did not meet the criteria for brain death. She remained unresponsive and expired almost a month later from massive gastrointestinal bleeding. On postmortem autopsy, several small pulmonary infarcts consistent with pulmonary emboli were noted. However, the significance and timing of these infarcts could not be established with certainty.α2-adrenergic receptors. These receptors are further categorized into three main subtypes which exist in the periphery (αA2), brain, and spinal cord  [α2 receptors in the locus ceruleus producing a sedative state similar to physiologic sleep. Lastly, dexmedetomidine is especially beneficial for postsurgical patients in that it preserves the respiratory drive, provides sympatholysis and decreases the inflammatory response [Dexmedetomidine, a D-enantiomer of medetomidine, is a highly selective agonist of G-protein-coupled B, α2C) . DexmedeB, α2C) , decreasB, α2C) , decreasB, α2C) , 6. Partresponse .The most common side effects during dexmedetomidine infusion are hypotension and bradycardia . Accordiα and β receptors are still present on the heart. The decentralized heart will continue to respond to directly acting catecholamine agents, such as epinephrine, isoproterenol, and dobutamine [It is known that during heart transplantation, both sympathetic and parasympathetic denervation occur leading to an increase in basal heart rate as the heart rate and electrical activity of the transplanted heart become entirely dependent on the intrinsic electrical system of the heart rather than relying on the neurological input from the recipient. The milieu of the denervated heart is complicated by the fact that while separation of sympathetic and parasympathetic occurs centrally, there is evidence that postganglionic fibers remain functional in these patients . In othebutamine . HoweverHowever, there is less knowledge of cardiac decentralization following lung transplantation. The operative dissection, especially that surrounding the trachea, likely leads to interruption of sympathetic and parasympathetic pathways to the heart . This waWhile atrial arrhythmias following lung transplantation can occur during the immediate postoperative period, bradycardia is less defined in the literature. Atrial arrhythmias following lung transplantation are commonly due to inflammation or edema at the pulmonary vein left atrial anastomoses . The arrPrevious case reports have emerged citing dexmedetomidine as a contributing source of bradycardia followed by asystole in various settings –16. In t Clinicians must be aware of the possibility of cardiac chronotropic alterations following OLT, similar to that following heart transplantation. Acknowledging the valuable and beneficiary role that dexmedetomidine plays in the management of OLT patients, we would suggest that heightened vigilance and prompt recognition of dysrhythmias when using dexmedetomidine in these patients may prevent a life-threatening event.


Cardiac resynchronization therapy is proven efficacious in patients with heart failure (HF). Presence of biventricular HF is associated with a worse prognosis than having only left ventricular (LV) HF and pacing might deteriorate heart function. The aim of the study was to assess a possible significance of right ventricular (RV) pre-implant systolic function to predict response to CRT.We studied 22 HF-patients aged 72 ± 11 years, QRS-duration 155 ± 20 ms and with an LV ejection fraction (EF) of 26 ± 6% before and four weeks after receiving a CRT-device.There were no changes in LV diameters or end systolic volume (ESV) during the study. However, end diastolic volume (EDV) decreased from 226 ± 71 to 211 ± 64 ml (p = 0.02) and systolic maximal velocities (SMV) increased from 2.2 ± 0.4 to 2.6 ± 0.9 cm/s (p = 0.04). Pre-implant RV-SMV (6.2 ± 2.6 cm/s) predicted postoperative increase in LV contractility, p = 0.032.Pre-implant decreased RV systolic function might be an important way to predict a poor response to CRT implicating that other treatments should be considered. Furthermore we found that 3D- echocardiography and Tissue Doppler Imaging were feasible to detect short-term changes in LV function. Chronic heart failure (CHF) is a frequent cause of in-hospital health care with a high cost. These patients have a poor quality of life (QoL) and a high readmission rate despite drugs such as RAAS- and beta-blockers, diuretics and aldosterone-antagonists which all have positive prognostic effects -5.Cardiac Resynchronization Therapy (CRT) is established as an effective therapy to reduce mortality and morbidity in patients with systolic heart failure (HF) and prolonged QRS in functional class (NYHA) III-IV despite optimal medical treatment -10.Dyssynchrony was pointed out as a baseline predictor of a beneficial effect of CRT in an analysis of the PROSPECT trial ,12. The We assessed whether pre-implant systolic RV function could predict short-term response to CRT and if 3D- and TDI-echocardiography could be used to detect early changes in LV dimensions and function.We enrolled 22 consecutive HF patients fulfilling standard criteria for CRT. All patients had a reduced systolic left ventricular (LV) function with an ejection fraction (EF) below 35%, QRS - duration > 120 ms and NYHA class III-IV despite optimal medical treatment  echocardiography was acquired in three apical views using the Vivid 7 or 5 (the later for 3-D echocardiography only) systems , with a 2.5 MHz probe. Three consecutive beats were registered and mean values were used for further analysis. Analyses were made off-line . The 16 segments LV-model of the American Society of Echocardiography was used for orientation [Trans thoracic 3D Echo was performed using a 2.5 MHz transducer mounted in a handheld rotation device. The cardiac images were recorded from the apex during end-expiratory apnoea within one breath hold, whereby the need for respiratory triggering was abolished as previously described . End dia®, Medtronic) implanted transvenously as described previously [All patients received a CRT device . Multivariable regression was performed by the best subset technique of Statistica. The ability of the right ventricular function variables to explain change in left ventricular function was the main analysis. The robustness of the variables to predict this change was also tested by using variable importance (VIP) in a Projection to Latent Structures (PLS)-regression analysis. We regarded p < 0·05 (two-sided) as significant.Continuous variables with a normal distribution were analyzed by paired Students t-test and given as mean ± SD. Other variables were analyzed by nonparametric tests and data are given as medians and range. All analyses were performed by StatisticaBaseline characteristics of the patients are presented in table ). The increase in LV-SMV could by 41% (adjusted R2 in best subset multiple regression) be explained by pre-implant RV-SMV and RV-TT. These two variables were also shown to be the most important predictor variables in a PLS regression. Inclusion of pre-implant LV-SM and LV-TT in the multivariable regression did not improve the explanation of the change in LV-SM  and SMV increased from 2.2 ± 0.4 to 2.6 ± 0.9 cm/s (p = 0.04SM Table . The sigWe found that pre-implant RV systolic function as assessed by TDI could predict short-term response to CRT. The results are plausible from a mechanistic point of view but should of course be reproduced in a larger cohort of patients and with a longer follow-up.The clinical implication of a role of pre-implant systolic RV function in the response to CRT should of course be that other treatments than CRT should be considered in patients with severe RV HF.Our findings are supported by others using other methods and longer follow-up to study the importance of pre-implant RV systolic function ,19. ScutA suggested echocardiographic cut-off value of response to CRT is an decrease by approximately 10% in the end diastolic and end systolic volume ,21. HoweOne explanation to the suggested importance of pre-implant systolic RV function might be a preload increase caused either by an acute deterioration in RV systolic function or by a miss match improvement where the LV function improves more than the RV function resulting in non-responding to CRT.Furthermore, in the revised ESC guidelines on device therapy in HF it is pointed out that conventional pacing might increase symptoms and deteriorate LV function and therefore biventricular pacing is recommended regardless of QRS prolongation in patients with LV dysfunction and signs of HF .In conclusion our findings implicate that pre-implant RV systolic function might be an important predictor of the poor response to CRT in some patients with biventricular heart failure and other treatments should be considered in these patients. Furthermore 3D- echocardiography and TDI seem feasible to detect changes in LV function during short-term follow-up.No conflicts of interest.ME was responsible for planning and writing. MR and PH performed echocardiographic and statistical analyses and helped writing manuscript. All authors read and approved the final manuscript.


Background. Heart development is a complex process, and abnormal development may result in congenital heart disease (CHD). Currently, studies on animal models mainly focus on cardiac morphology and the availability of hemodynamic data, especially of the right heart half, is limited. Here we aimed to assess the morphological and hemodynamic parameters of normal developing mouse embryos/fetuses by using a high-frequency ultrasound system. Methods. A timed breeding program was initiated with a WT mouse line (Swiss/129Sv background). All recordings were performed transabdominally, in isoflurane sedated pregnant mice, in hearts of sequential developmental stages: 12.5, 14.5, and 17.5 days after conception (n = 105). Results. Along development the heart rate increased significantly from 125 ± 9.5 to 219 ± 8.3 beats per minute. Reliable flow measurements could be performed across the developing mitral and tricuspid valves and outflow tract. M-mode measurements could be obtained of all cardiac compartments. An overall increase of cardiac systolic and diastolic function with embryonic/fetal development was observed. Conclusion. High-frequency echocardiography is a promising and useful imaging modality for structural and hemodynamic analysis of embryonic/fetal mouse hearts. Heart development is a complex process during which the heart will form from a single myocardial heart tube to a fully septated four-chambered heart with functional atrioventricular (AV) and ventriculoarterial valves and a separated outflow tract. The primary heart tube is derived from the splanchnic mesoderm in the embryonic plate and initially consists mainly of a left ventricle (LV) and AV canal. During further development, significant contributions to the heart tube will continue to be made from the mesenchyme situated behind the heart, the so-called second heart field (SHF). The cells of the SHF will form the right ventricle (RV) and outflow tract at the arterial pole of the heart as well as myocardial and vascular structures at the venous pole of the heart .in vivo imaging are limited. Furthermore, functional parameters and their course at subsequent stages of normal mouse heart development have only been described in a few studies [Abnormal heart development results in congenital heart disease (CHD), the most common birth defect with an estimated incidence of six per 1000 live born children . In the  studies –7. SpeciIn clinical practice ultrasound is the most frequently used minimally invasive imaging modality at pre- and postnatal stages of heart development. Clinical ultrasound machines have also been used for imaging of embryonic mouse hearts; however, ultrasound frequencies 8–15 MHz) are not sufficient for a detailed morphological and hemodynamic analysis. Recently developed high-frequency ultrasound systems (30–50 MHz) are able to offer sufficient spatial-temporal resolution for detailed and reliable imaging of embryonic mouse hearts. Thus far, there are only limited studies describing the hemodynamic and morphological changes at subsequent stages of heart development using such ultrasound systems , 6, 8.–15 MHz aHemodynamics play an important role in normal heart development by the activation of shear-stress dependent signaling pathways. During development genes like Klf-2  and periIn the current study we aim to provide an overview of hemodynamic and morphological changes during embryonic and fetal stages of normal mouse heart development using a high-frequency ultrasound system. Knowledge of these functional parameters is highly relevant for the interpretation of results obtained in genetically mutated mouse models. We expect that knowledge of how echocardiographic parameters shift over development will eventually contribute to the early detection of CHD during human pregnancy.n = 11) were subjected to high-frequency ultrasound recordings at 3 subsequent stages of embryonic/fetal development, being 12.5, 14.5, and 17.5 dpc. At 12.5 dpc, the pregnant mother mouse was anaesthetized using isoflurane , the most commonly used anesthetic in mouse experiments [Animal experiments were approved by the local animal welfare committee (DEC number 10177) of the Leiden University Medical Center. A timed breeding program was initiated with a WT (Swiss/129Sv background) mouse line. The day after breeding was considered to be 0.5 days after conception (dpc). All pregnant mice . The ultrasound recordings were performed with a high-frequency ultrasound system  with an axial resolution of 55 rinciple . Betweenn = 105). In individual embryos/fetuses, the left and right side were established to identify the position of the heart including the individual cardiac compartments and structures. At 12.5 dpc these compartments included the left atrium (LA), right atrium (RA), LV, RV, the common AV canal (cAVC) encompassing the future mitral valve (MV) and tricuspid valve (TV) orifices, common outflow tract (cOFT), developing interventricular septum (IVS), and the interventricular foramen, that is, the continuity between the LV and RV before completion of ventricular septation. At later stages (14.5 and 17.5 dpc) the MV and TV orifices, aorta (Ao), and pulmonary trunk (PT) were identified.All ultrasound recordings were performed by NDH and EEC. During the ultrasound recordings the two laterally located uterus horns were scanned for the presence and position of the embryos/fetuses  and developing MV and TV orifices  were performed to assess the peak-E (early/passive ventricular filling by ventricular relaxation in early diastole) and peak-A wave velocities ; hence the E/A ratios were calculated. The recordings across the MV orifice cAVC and developing were also used to evaluate the embryonic heart rate (HR) in beats per minute (BPM), cardiac cycle length , diastolic ventricular filling time , ejection time , isovolumetric contraction time , and isovolumetric relaxation time  of the LV , also known as Tei index, evaluates the combined LV systolic and diastolic function was calculated using the following formula: (IVRT + IVCT)/ET [The methods that were used for pulsed-wave Doppler flow recordings are summarized in f the LV . The myon = 15) and Ao and PT at 14.5 dpc (n = 18 and n = 12) and 17.5 dpc  and the diameters of the cOFT (n = 2) and Ao  were evaluated from B-mode echoloops in order to calculate the mean stroke volume (SV) per developmental stage according to the following formula: mean SV = mean TVI × (mean diameter of Ao or cOFT/2)2 × π. Hence, the mean cardiac output (CO) was calculated (mean CO = mean SV × mean HR) for the three developmental stages.Pulsed-wave Doppler recordings were also performed in the cOFT at 12.5 dpc  and RV  and IVS diameter . Cardiac fractional shortening (FS%) for the LV and RV was calculated using the formula: (VIDdiastole − VIDsystole)/VIDdiastole × 100%. Due to the size of the hearts at 12.5 dpc, the resolution often limited the possibility to discriminate the epicardial, myocardial, and endocardial layer of the ventricular free wall. Therefore, at this stage the distances from the epicardial layer to the IVS in end-systole and end-diastole were used to calculate the FS%.For morphological assessment M-mode measurements in short- or long-axis views of the ventricles were performed, to evaluate the end-systolic and end-diastolic ventricular inner diameter of the LV . Flow parameters were calculated by the average of pulsed-wave Doppler complexes of three consecutive beats; similar methods were applied for M-mode recordings and diameter calculations on B-mode echoloops.Although a complete hemodynamic and morphological assessment for each heart was aimed for  .P < 0.05 (2-tailed) was considered to be significant; all values are given as mean ± SEM. All boxplots indicate the upper and lower quartile of the median, which is indicated by the horizontal bar. The whiskers indicate max/min range of the values.All statistics were performed with the statistical package for the social sciences 15.0  and GraphPad Prism . A http://dx.doi.org/10.1155/2014/531324).Reliable imaging of hearts as small as 2 mm was feasible in all stages examined. Representative examples are shown in online Movie 1  ventricular septation has been initiated but is not completed resulting in a primitive interventricular foramen that directly connects the lumen of LV and RV. M-mode recordings at these stages show a mean systolic IVS diameter of 0.20 ± 0.045 mm. At early fetal stages of 14.5 dpc the heart has increased in size  and ventAt late fetal stages (17.5 dpc) the size of the RV and LV and IVS (0.39 ± 0.009 mm) has increased significantly . Mature P < 0.0001) from 125 ± 9.5 up to 219 ± 8.3 BPM. Ventricular inflow patterns across the developing MV and TV annulus were studied by pulsed-wave Doppler imaging.During embryonic and fetal development the HR increases significantly (P < 0.0001) whereas that of the TV also showed an increasing trend, albeit not significant . The peak-E wave also increased significantly for both LV  and RV  and showed a relatively greater increase than the peak-A wave during development. As a result, the E/A ratio, a measure for the ventricular diastolic function, showed a significant increase for both LV  and RV   did not differ significantly at the three stages assessed . LV and  Figures .P = 0.037) decrease between 12.5 (0.15 ± 0.011) and 14.5 dpc (0.12 ± 0.004) and remained stable at later fetal stages 17.5 dpc (0.12 ± 0.003)  demonstrated a significant (± 0.003) , indicat≈30 and 40%. Furthermore, except for 17.5 dpc  no significant differences were observed between the FS% of the LV and RV  and 14.5 dpc (0.43 ± 0.010) but significantly decreased at 17.5 dpc   after closure of the IVS at 14.5 dpc. At late fetal stages (17.5 dpc) the MPI did not change significantly .A combined assessment of LV systolic and diastolic function was performed by calculating the MPI. At embryonic preseptated stages (12.5 dpc), the MPI was 0.64 ± 0.012 and decreased to 0.49 ± 0.017 (P = 0.010) and PT  along fetal life.The pulsed-wave Doppler recordings performed in the cOFT demonstrated a peak flow of 0.27 ± 0.021 m/s at preseptated stages. As from 14.5 dpc two individual ventricular outflow tracts could be discriminated; especially the high echodensity of the blood at these stages enabled to discriminate the flow in the Ao (0.34 ± 0.013 m/s) and PT (0.33 ± 0.021 m/s) that are closely related to each other. As can be observed in Heart development is a complex process, which has been extensively studied in both WT and genetically mutated mouse models . It is oIn the current study we aimed to provide an overview of hemodynamic parameters and changes that occur at subsequent stages of heart development, using a high-frequency ultrasound system.Compared to other reports in mouse using similar ultrasound techniques we did not only focus on development of the future LV but also on that of the RV. Key findings of our study are (1) a reliable assessment of LV and RV in- and outflow patterns can be performed from 12.5 dpc to term; (2) a significant improvement occurs in the diastolic and systolic function of both LV and RV; (3) over the developmental period of 12.5 dpc to 17.5 dpc, the ratio between RV and LV size, as well as the FS% of both ventricles, did not change significantly.Knowledge regarding the functional parameters of the RV is important since the RV is commonly affected in CHD. During development, the RV including the TV annulus develops subsequent to the LV by addition of SHF derived cells to the developing heart . Many geAt early embryonic stages endocardial cushion tissue is positioned in the primitive AVC and OFT, which later on will contribute to formation of the TV and MV and Ao and PT semilunar valves. Some clinical studies argued that AV valve regurgitation is a common phenomenon during the first trimester of pregnancy . Our stuRegarding growth of the heart we demonstrated that there was a 31% increase of LVID, 34% of RIVD, and 35% of IVS diameter from 12.5 up to 17.5 dpc. We showed a trend towards a smaller RVID as compared to the LVID at all stages, which was not mentioned in other studies.Improvement of ventricular systolic and diastolic function occurs throughout the length of embryonic and fetal development. With respect to the diastolic function we demonstrated a significant increase of E/A ratio across the developing MV and TV orifices, which was related to an increase of the peak-E wave, that is, the fraction of diastolic ventricular filling that is defined by ventricular relaxation. These data are in accordance with the study of Zhou and colleagues, who demonstrated that the E/A ratio is increasing during development, which seems to continue up to approximately 3 weeks after birth . Around ≈30–40%) for both ventricles throughout development. We did find a significant difference favoring the LV FS% as compared to the RV FS% at 17.5 dpc. Interestingly, the same phenomenon of FS% difference between LV and RV has been reported in a study of human fetal hearts between 14 and 40 weeks of pregnancy. However, as in mouse, differences between human LV and RV FS% is subtle, [With respect to systolic ventricular function, the FS% remained stable ( subtle,  and whet subtle, , 29. WitThe MPI or Tei index  is a meaWe demonstrated the course of several morphologic and hemodynamic parameters along embryonic and fetal life. Our data show that a reliable assessment can be made not only of the left, but also of right ventricular function during embryonic/fetal stages. We demonstrate an overall improvement of cardiac diastolic and systolic function of both LV and RV along heart development. The implementation of high-frequency ultrasound in embryonic/fetal mouse heart development is a promising and useful tool. The data presented in this study might be useful as reference values in future studies in genetic mutated mouse models of CHD.Representative B-mode movies of 4-chambers view at 12.5, 14.5 and 17.5 dpc. The LA, LV, RA and RV can be discriminated.Click here for additional data file.


LV intraventricular dyssynchrony is commonly assessed by systolic dyssynchrony index (SDI), which is defined by the dispersion of time of minimum regional cavity volume. Several studies have reported conflicting results on cardiac resynchronization therapy (CRT) responses based on SDI values. In this study, we aim to characterise SDI distributions in asymptomatic patients and to analyse how particular regions affect the global SDI measurement in different patient groups.We randomly selected 292 asymptomatic patients  from the MESA cohort [The distributions of regional EF in asymptomatic patients in Fig. Late regional contraction in septal base has a significant effect on the SDI values. Since SDI is measured by the dispersion of time, this effect was dominant. The delayed, as well as the increased variability, time-to-peak regional EF in these segments both seem to contribute to SDI variability. This study shows that eliminating septal base segments significantly decreased SDI values and narrowed their variation. Further validation is still needed to investigate whether this elimination protocol will better predict CRT responses.1) The Cardiac Atlas Project, NIH - National Heart, Lung and Blood Institute (R01HL087773), and 2) Faculty Research Development Fund (FDRF), The University of Auckland.


Cardiac contractility modulation (CCM) is a new treatment being developed for heart failure (HF) involving application of electrical current during the absolute refractory period. We have previously shown that CCM increases ventricular force through β1-adrenoceptor activation in the whole heart, a potential pro-arrhythmic mechanism. This study aimed to investigate the effect of CCM on ventricular fibrillation susceptibility.n = 25). The effects of CCM  on the left ventricular basal and apical monophasic action potential duration (MAPD) were assessed during constant pacing (200 bpm). Ventricular fibrillation threshold (VFT) was defined as the minimum current required to induce sustained VF with rapid pacing (30 × 30 ms). Protocols were repeated during perfusion of the β1-adrenoceptor antagonist metoprolol (1.8 μM). In separate hearts, the dynamic and spatial electrophysiological effects of CCM were assessed using optical mapping with di-4-ANEPPS.Experiments were conducted in isolated New Zealand white rabbit hearts  with increased MAPD dispersion  (n = 8). Optical mapping revealed greater spread of CCM induced MAPD shortening during basal vs. apical stimulation. CCM effects were abolished by metoprolol and exogenous acetylcholine. No evidence for direct electrotonic modulation of APD was found, with APD adaptation occurring secondary to adrenergic stimulation.CCM significantly shortened MAPD close to the stimulation site . VFT was reduced during CCM  and was correlated (rCCM decreases VFT in a manner associated with increased MAPD dispersion in the crystalloid perfused normal rabbit heart. We have previously shown that sympathetic nerve stimulation increases the susceptibility of the heart to ventricular fibrillation (VF) The aims of this study were to investigate: 1) the role of pre and post-ganglionic signalling in CCM, 2) any role for ACh in modulating the acute ventricular response to CCM and 3) the effects of CCM on ventricular electrophysiology and arrhythmia susceptibility.22.1n = 22), using the non-innervated and innervated heart preparations. All procedures were undertaken in accordance with ethical guidelines set out by the UK Animals (Scientific Procedures) Act 1986 and conformed to the Guide for the Care and Use of Laboratory Animals Published by the US National Institutes of Health .Experiments were conducted on Adult male New Zealand White rabbit hearts  of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.2.2Adult male New Zealand White rabbit hearts were isolated as previously described 2.3The innervated Langendorff perfused isolated heart preparation was utilised as previously described 2.4+ 138.0, K+ 4.0, Ca2 + 1.8, Mg+ 1.0, HCO3− 24.0, H2PO4− 0.4, Cl− 121.0, glucose 11.0 and acetate 20.0. The solution was continuously bubbled with 95% O2–5% CO2 to maintain a constant pH of 7.4. Temperature was maintained at 37 °C. A 3 F polypropylene catheter  was inserted at the left ventricular (LV) apex for drainage of Thebesian venous effluent.Hearts were perfused with Tyrode solution of the following composition (mM): Na2.5Intra-ventricular LV pressure (LVP) was measured with a fluid-filled latex balloon connected to a pressure transducer  inserted into the LV via the left atrium. LV end diastolic pressure was maintained between 0 and 5 mm Hg. Aortic perfusion pressure (PP) was monitored with a second pressure transducer connected in series to the aortic cannula.2.6MAP-TIP recording catheters , with a tip diameter of 1.5 mm electrode spacing of 4 mm, were used to record action potentials from the epicardial surface of the LV using a DC-coupled high input impedance differential amplifier . MAPs were recorded from the LV epicardium at apical and/or basal sites depending on the experimental protocol.Pacing electrode locations are illustrated on 2.7Square wave electrical pulses were generated using a Neurolog modular system  with signals delivered using a constant current stimulator . CCM stimuli were triggered using the pacing stimulus as previously described 2.7.12.7.1.1innervated Langendorff heart in the absence and presence of the nicotinic ACh channel antagonist hexamethonium (0.5 mM) The effects of CCM on ventricular and electrophysiological performance were assessed in the 2.7.1.2the non-innervated Langendorff heart preparation in the absence (Control) and presence of;A.The muscarinic ACh receptor antagonist atropine (0.1 mM) B.Exogenous ACh (1 μM) The effects of CCM on ventricular and electrophysiological performance were assessed in 2–3 stimulations were conducted at baseline and during perfusion. The order of perfusion was randomised from heart to heart to reduce any bias. CCM was applied in basal regions of the LV.2.7.1.32.7.1.3.1non-innervated Langendorff heart. VFT was obtained by RV endocardial, LV endocardial or LV epicardia pacing using a train of 30-stimuli  spanning the refractory period following a 20-beat S1 drive train  and determined by progressively increasing the pacing current (0.5 mA steps), with 2-second rest period before the next pacing train if no VF was induced (see The susceptibility of the heart to VF was studied by measuring the ventricular fibrillation threshold (VFT) in the uced see . VFT was2.7.1.3.2The effective refractory period (ERP) was estimated using an extra-stimulus protocol consisting of a 20-beat drive train (S1) at a constant CL (300 ms) followed by an extra-stimulus (S2) at progressively shorter CLs . ERP was measured in RV endocardial, LV endocardial and LV epicardial regions during basal and apical CCM. ERP was defined as the longest S1-S2 interval that failed to capture. Pacing stimuli were applied at twice the diastolic threshold current, with a pulse width of 2 ms.2.7.1.3.3non-innervated hearts). These data were obtained during the period of constant pacing (CL = 300 ms), prior to the assessment of VFT, as described above, at baseline and during CCM delivery in basal and apical regions.Ventricular MAPD dispersion was measured as the difference between in MAPD the two sites using contact electrodes . Optical action potentials (AP) were recorded following a bolus injection of di-4 ANEPPS . Hearts were illuminated episcopically with an LED light source (535 nm). Emitted light was filtered through a 630 nm long-pass filter and collected using a Hamamatsu 16 × 16 element photodiode array . Hearts were mechanically uncoupled with blebbistatin (5 μM). Optical studies were conducted in the non-innervated rabbit heart.2.7.1.4.1Experiments were performed to assess the dynamics to APD change during CCM. Optical APs were recorded continuously at stable baseline (300 ms CL) and during applications of biphasic CCM signals  to the LV free wall. The effects of CCM on APD was assessed at regions within 2 mm of the stimulating electrode and in APs with a clear deflection associated with CCM stimulation.2.7.1.4.2CCM  was applied in basal and apical regions during constant pacing (CL = 300 ms). The degree of spread of APD shortening during CCM was assessed from the site of CCM signal delivery (Base → Apex or Apex → Base). Studies were conducted in the non-innervated rabbit heart.2.890) averaged over 20-cardiac cycles recorded during steady state before and immediately on cessation of CCM stimulation due to signal interference from the current used during CCM. Optical APD90 was assessed before and during the steady state response to CCM signal delivery as there was no signal interference from the current used during CCM on the recorded APs. Both MAPD90 and optical APD90 calculations were performed using custom written analysis software .Functional parameters and MAPs were recorded with a PowerLab 8 s system and digitised at 2 kHz using Chart and Scope software (ADInstruments Ltd). Optical AP signals were digitised at 2 kHz and recorded on a custom designed computer system  using QRecord software . LV contractile performance was assessed from an average of 20 cardiac cycles during baseline and subsequently during the steady state CCM response. Contact MAPD was measured at 90% repolarisation  or MAPD90 shortening (∆-27 ± 9 [Atropine] vs. ∆-28 ± 7 [Control] ms) associated with CCM (n = 5), indicating no role for endogenous ACh release in the acute ventricular effects of CCM.Perfusion of atropine had no effect on the increase in LVP (∆3.9 ± 0.7 [Atropine] vs. ∆4.2 ± 0.6 [Control] mm Hg), dP/dt3.2.290  but not apical regions (far from) Diii. Sim3.3.390 and max-min dispersion are presented in 90 was similar between basal and apical regions during RV and LV endocardial pacing but longer in basal, vs. apical, regions during LV epicardial pacing  and LV endocardial (5Eii), but not LV epicardial (5Eiii), pacing. It is apparent that the reduction in VFT with basal CCM, during LV epicardial pacing, may be the product of increased MAPD90 dispersion and shortening of ERP at the site of CCM stimulation. Analysis of LV epicardial pacing, when basal CCM data are removed from the dataset, reveals a trend of correlation between VFT and max-min MAPD90 dispersion (Mean data on the effect of CCM on MAPDl pacing B. CCM cant sites B resultiites (90 C (n = 8)ites  and apical CCM . Max-min MAPD90 dispersion during CCM stimulation with metoprolol was similar to baseline values  .Perfusion of metoprolol abolished the shortening of MAPD3.43.4.190  not present in contact electrode recordings (133 ± 6 [Apex] vs. 131 ± 6 [Base]) and attributable to the adverse electrophysiological effects of blebbistatin.Optical action potentials (n = 4) recorded at baseline under un-stimulated conditions were significantly longer than those recorded with contact electrodes  in both basal  and apical  regions. Optical recordings were associated with a significant apico-basal dispersion of APD3.4.290. Rather, APD shortened over a period of seconds with a maximal response at 30 s. Responses recovered to baseline 2–3 min after cessation of stimulation (data not shown).Raw and mean data demonstrating time dependent adaptation of ventricular APD during LV free wall CCM are presented in 3.4.3Raw and mean data demonstrating the effect of CCM on optically recorded APs are illustrated in 4To the best of our knowledge, this is the first study to demonstrate that CCM  increases susceptibility to ventricular fibrillation, an effect that is dependent on β1-adrenoceptor activation and is associated with an increase in ventricular APD dispersion. In addition, we have shown that the ventricular effects of CCM are abolished during the perfusion of exogenous ACh but unaffected during muscarinic receptor antagonism and ganglionic blockade, suggesting that local intracardiac/spinal reflex pathways are not involved. These data support the notion that the acute effects of CCM are mediated through local release of NE from post-ganglionic sympathetic nerves.4.1Intracardiac and intrathoracic ganglia have been shown to be involved in the beat-to-beat control of ventricular performance independently from the central nervous system 4.2We confirm our previous finding that CCM increases ventricular contractility and shortens MAPD through β1-adrenoceptor activation following NE release It is well known that the vagus nerve antagonises the action of the sympathetic nervous system. Binding of NE to the β−adrenoceptors increases the activity of soluble adenylyl cyclase, catalysing the formation of cAMP, which activates protein kinase A to phosphorylate several protein targets increasing contractile force. ACh binds to muscarinic receptors reducing the release of NE from sympathetic nerves and inhibits the formation of cAMP within cardiac myocytes 4.3CCM was initially proposed as a technique to increase cardiac contractility through direct modulation of calcium entry during the action potential . However, our data demonstrate that application of CCM signals to the ventricle stimulates the release of NE from sympathetic nerves Initial experiments describing an electrotonic modulation of action potential duration by CCM were performed in the isolated rabbit papillary muscle and utilised unipolar field stimulation. These studies demonstrate that cathodic and anodic electrical stimulation have opposing influences on force and APD, presumably due to an accumulation of electrical charge at the stimulating electrode and resultant modulation of membrane potential and L-type calcium current. However, the electrotonic hypothesis predicts that opposing effects would be exerted at the anodal and cathode electrodes and that the net change in contractility during bipolar CCM could be zero . Furthermore, CCM is applied in a biphasic manner and should exert equal depolarising and hyperpolarising influences at each electrode. The electrotonic hypothesis does not provide adequate explanation for the effects of CCM in whole heart and the lack of any immediate contractile effects in whole heart studies provides support for the hormone hypothesis 4.4Ks) We have previously shown that the CCM induced APD shortening was partially mediated by activation of the slow delayed rectifying potassium current , applied to the LV epicardial surface of the normal rabbit heart, promote localised action potential shortening and give rise of non-uniformities of APD across the ventricular surface. We demonstrate that CCM increases apico-basal APD dispersion in a manner correlated with a downward shift in VFT and dependent upon b1-adrenoceptor stimulation (being abolished by metoprolol). Furthermore, ERP is substantially shortened at the site of CCM stimulation and appears to contribute to the pro-arrhythmic phenotype, causing a greater reduction in VFT when compared to the effects of MAPD4.5.1Our data demonstrate that CCM increases the susceptibility of the crystalloid perfused rabbit heart to experimentally induced VF, however it is recognised that the present study utilises healthy non-disease animal hearts and as such we are cautious of offering direct correlations with clinical application of CCM therapy in human heart failure. Further study in animal models of heart failure, failing human tissue and prospective clinical studies would be necessary to confirm our results. It is clear that CCM signals of ± 20 mA and 20 ms applied to the rabbit heart may not be directly comparable to the application of similar or smaller amplitude signals in the larger canine or human heart and these values were selected from our previous experience and not as a comparison to clinical CCM. Nevertheless, the observed effects on action potential dispersion, regional repolarisation and VFT may be of scientific and clinical interest.Anecdotal evidence from clinical studies of CCM suggests that there is no increase in the number of serious adverse arrhythmic events with CCM. However these trials are relatively small in size, short in duration and do not provide any record on the occurrence of arrhythmic events i.e. number of premature ventricular beats, non-sustained VT events, other than those presenting in clinic i.e. sustained VT and VF Whilst exercise regimes and CCM are both adrenergic in nature, it should be noted that clinical studies of CCM have been carried out in patients on β-blockers. Although the degree of β-blockade cannot be accurately assessed in each patient, there is the possibility that the level of β-blockade present could counteract at least in part the adverse effects of CCM on arrhythmogenesis. Complete β-adrenoceptor blockade is unlikely to be achieved clinically due to the association with significant side effects with potentially high doses. Rather the goal of β-blockade therapy in heart failure is to reduce sympathetic over-activation. CCM has been shown to be effective  in patients receiving β-blockade drugs 4.6As with our previous study, CCM increased LV pressure development and contractility but had little effect on ventricular relaxation. This finding is in accordance with other reports 4.7The susceptibility of the heart to VF was studied by measuring the VFT, which is a quantifiable and reproducible measure reflecting electrical stability 4.84.8.1We use epicardial LV sites for CCM delivery to ascertain the effects and mechanisms underlying CCM. Importantly, this method is in accordance with previous mechanistic studies in both the canine and ferret . Clinically, the site of CCM delivery chosen is the RV septum Histological studies suggest that there exists a transmural dispersion of nerve distribution through the hearts, with less sympathetic innervation but more parasympathetic innervation of the ventricular endocardium Although the spacing between our electrodes is proportionally similar to that used in larger species (e.g. dogs and humans) we cannot exclude that a 20 mA stimulus might stimulate a greater proportion of the smaller rabbit heart in relation to larger hearts. Despite this, the degree of inotropic enhancement is similar to that reported in other studies 4.8.2During optical mapping we use the electromechanical uncoupler blebbistatin to prevent cardiac movement during imaging. We have recently reported that blebbistatin has a direct effect on ventricular electrophysiological parameters prolonging APD and increasing resistance to VF induction 5To our knowledge, this study represents the first direct investigation of the effects of CCM on ventricular arrhythmia vulnerability. Our data show that CCM  increases the vulnerability to ventricular fibrillation through a β1-adrenoceptor dependent mechanism and is associated with APD shortening and an increase in APD dispersion . In conjunction with our previous study, we conclude that the acute effects of CCM are mediated via NE release from efferent postganglionic sympathetic nerves as the response to CCM can be abolished by exogenous ACh perfusion.None.


Estimation of left ventricular end-diastolic pressure (LVEDP) among patients with mitral valve disease may help to explain their symptoms. However, conventional Doppler measurements have limitations in predicting LVEDP in this group of patients. The aim of this study was to construct a Doppler-derived LVEDP prediction model based on the combined analysis of transmitral and pulmonary venous flow velocity curves.Thirty-three patients with moderate to severe mitral stenosis (MS) who had indications for left heart catheterisation enrolled. Two-dimensional, M-mode, colour Doppler and tissue Doppler imaging indices, such as annular early diastolic velocity (Ea), isovolumic relaxation time (IVRT), pulmonary vein systolic and diastolic flow velocities, velocity propagation, left atrium area (LAA), interval between the onset of mitral E and annular Ea (TE–Ea), and Tei index were obtained. LVEDP was measured in all patients during left cardiac catheterisation. Linear correlation and multiple linear regressions were used for analysis.p = 0.05, R2 = 0.11). However, in multivariate regression, LAA, Tei index and Ea remained in the model to predict LVEDP . For prediction of LVEDP ≥ 15 mmHg, the best model consisted of LAA, IVRT and Ea, and had a sensitivity of 85% and specificity of 85%.The mean of LVEDP was 9.9 ± 5.3 mmHg. In univariate analysis, the only significant relationship was noted with LAA (Our results provided evidence that, in patients with moderate to severe MS, LVEDP can be estimated by combining Doppler echocardiographic variables of mitral flow. However, more studies are required to confirm these results. Mitral stenosis (MS) is prevalent in developing countries. By improving healthcare systems, it could be expected that the incidence of new cases would decrease and therefore the mean age of mitral stenosis patients would increase. This increase in age of MS patients is accompanied by the occurrence of other diseases, such as coronary artery disease, hypertension, diabetes mellitus and chronic obstructive pulmonary disease.In a number of patients with MS, the question arises of the impact of mitral valve disease (MVD) on the presenting symptom. For example, in patients presenting with dyspnea, with both significant MS and hypertension, increased left ventricular (LV) filling pressure due to hypertension could influence assessment of the severity of MS. In these patients, severity of MS could be underestimated because the increased diastolic pressure reduces the mitral valve gradient, and the increased LV stiffness shortens pressure half-time (PHT).Similarly, patients with both pulmonary disease and MS may have dyspnoea because of pulmonary rather than cardiac cause. It is therefore advantageous to assess LV filling pressure in these cases in an attempt to prove or refute a cardiac cause for dyspnoea.Using Doppler measurements to estimate LV filling pressures is desirable. However, conventional Doppler measurements have limitations in the prediction of left ventricular end-diastolic pressure (LVEDP) in this group of patients. For example, in patients with MS, the left atrium (LA) is enlarged to compensate for the increase in LA pressure. Similarly, mitral inflow peak early diastolic velocity (E) is highly dependent on LA pressureHowever, other Doppler and tissue Doppler echocardiographic indices and time intervals, such as peak early diastolic velocity of mitral annulus (Ea), E/Ea ratio, mitral inflow propagation velocity (VP), E/VP, pulmonary vein velocities, Tei index and the ratio of isovolumic relaxation time (IVRT) to interval between the onset of mitral E and annular Ea (TE–Ea), which have shown promising values in the prediction of LV filling pressure in a variety of diseases,The aim of this study was to analyse the components of mitral and pulmonary waves in patients with mitral stenosis and to construct a Doppler-derived LVEDP prediction model based on the combined analysis of transmitral and pulmonary venous flow velocity curves.2, who were undergoing heart catheterisation, had no more than moderate mitral or aortic regurgitation, and the absence of aortic or tricuspid stenosis. To include these 33 patients, we screened 36 patients. Three were excluded; two had moderate to severe MR and one had moderate to severe AR.The study population comprised 33 consecutive patients with a mean age of 37 ± 9 years, and 23 were women. Inclusion criteria were patients with moderate to severe MS, defined by planimetry as mitral valve area (MVA) of less than 1.5 cmThe reasons for undergoing heart catheterisation in patients with MS in our hospital are diagnostic coronary angiography before mitral valve surgery or performing percutaneous transvenous mitral commissurotemy. All patients were evaluated in the left lateral decubitus position by conventional  and tissue Doppler echocardiography examinations, a maximum of three hours before cardiac catheterisation, by an experienced echocardiologist.The institutional review board of Imam Khomeini Hospital, which is a tertiary hospital, approved the study protocol. All participants gave written informed consent. This investigation was in accordance with the Declaration of Helsinki.All Doppler values represent the average of three and 10 beats in sinus and atrial fibrillation (AF) rhythm, respectively. Two-dimensional measurements were performed according to the recommendations of the American Society of Echocardiography.Mitral inflow propagation velocity was measured as the maximum slope of the first aliasing velocity during early filling from the mitral valve plane to 4 cm distal to the LV cavity in the apical four-chamber view using colour M-mode Doppler. Pulmonary vein systolic flow velocity (PVs) and diastolic flow velocity (PVd) were measured from the apical four-chamber view by placing a sample volume in the right upper pulmonary vein using Doppler echocardiography Isovolumic contraction time (IVCT), isovolumic relaxation time and ejection time (ET) were assessed by simultaneously measuring the flow into the LV outflow tract and mitral inflow using Doppler echocardiography The pulsed-wave tissue Doppler imaging (TDI) was performed by activating the tissue Doppler function in the same echocardiographic machine. Mitral annulus velocities  were measured using a pulsedwave TDI technique by placing a 1–2-mm sample volume at the level of the septal and lateral annulus. Early diastolic and late diastolic (Aa) velocities of the mitral annulus were determined from the septal and lateral aspects, and the average was calculated.In addition, ratios such as E/Ea, E/Vp, IVRT/Tei, and PVs/PVs + PVd were calculated. The time intervals between the peak of the R wave and the onset of the mitral E velocity, as well as the time interval between the peak of the R wave and the onset of Ea at the lateral mitral annulus were also measured Haemodynamic measurements were done by placing a 6-F fluid-filled catheter in the LV from the right femoral approach under fluoroscopic guidance. The fluid-filled pressure was balanced and calibrated with the external pressure transducer positioned at the mid-axillary level. All recordings were performed before the injection of contrast agent. LV end-diastolic pressure was measured at the nadir of the atrial contraction wave before the onset of rapid LV systolic pressure rise or at the peak of the R wave in a simultaneous ECG if the atrial contraction wave did not exist.In MS patients undergoing percutaneous commissurotomy, the mean left atrial pressure (LAP) was also recorded. Haemodynamic data were collected at end-expiration by an investigator unaware of the echocardiographic measurements and represented the average of five and 10 cycles in sinus and AF rhythm, respectively.We described continuous variables as mean ± standard deviation (SD) and categorical data are expressed as frequencies and percentages. Two variables  had > 15% missing data and were omitted from further analysis. Missing values in other variables were imputed using a multiple imputation technique. The first set of imputations was used for further analyses.p-value threshold of 0.3. We then applied a backward selection procedure to develop the final prediction model using linear regression. Model performance was quantified with regard to discrimination [area under the receiver operating curve (AUC)]. The AUC ranges from 0.5 to 1.0 for sensible models. Statistical analyses were done with SPSS for Windows , and R for Windows (Version 2.11.1).Due to the small sample size, we chose to perform a univariate pre-selection of clinically relevant predictors with a 2). The mean MVA was 0.89 ± 0.19 cm2. Less than moderate AI and MR were seen in 60 and 66.7% of patients, respectively. Recording of PV flow was feasible in 30 out of 33 patients (90%). Echocardiographic and haemodynamic characteristics of the patient population are reported in Table 1.All patients had moderate to severe MS, and 20 (58.8%) had severe MS . However, in multivariate regression, LAA, Tei index and Ea remained in the model to predict LVEDP . This model The mean LVEDP for the 33 patients was 9.9 ± 5.3 mmHg and ranged from 3–25 mmHg. The results of the univariate analyses are presented in We then dichotomised the LVEDP as below 15 and above 15 mmHg. In our series of patients, six had LVEDP ≥ 15 mmHg and the remaining 27 had values below 15 mmHg. The best model for predicting this variable consisted of LAA, IVRT and Ea. The results of univariate and multivariate logistic regression for predicting dichotomised LVEDP (< 15 vs ≥ 15 mmHg) are presented in p < 0.001).For prediction of a mean LVEDP ≥ 15 mmHg and with the use of ROC curves, the model had a sensitivity of 85% and a specificity of 85% p = 0.005, r2 = 0.22), E/VP , LAA  and PVs/PVs + PVd . In multivariate analysis E/Ea, LAA and PVs/PVs + PVd remained in the model to predict LAP . The results of the univariate and multivariate analyses are presented in Table 4.The LAP for the 29 patients was 21.6 ± 8.9 mmHg and ranged from 8 to 50 mmHg. In univariate analysis, significant relationships were noted between E/Ea  by using mitral inflow in patients with MR,In our study, in patients with MS (with and without AF), there were no associations between mitral inflow velocities  and LVEDP or mean LAP. This finding was expected, given the confounding effects of LV relaxation, LV stiffness, LAP and MVA on these measurements.r = –0.71, p < 0.05) and mitral valve area . Peak velocity and the velocity–time integral in systole also significantly correlated with mean LAP .18Previous studies have shown that there is a correlation between pulmonary vein parameters and LAP in patients with mitral stenosis. In one study, among the variables of PV flow, the systolic fraction  correlated significantly with mean LAP  than in patients with preserved LVEF (≥ 50%).16IVRT has been used for decades in the clinical evaluation of patients with MS, being shorter in patients with more severe MS. LV relaxation also influences IVRT.Although some previous studies showed strong relationships between the time interval TE–Ea and LV relaxation,Previous studies have established the value of left atrial size for the prediction of heart failure with both depressedThere were several limitations to this study. First, there were few patients with MS and LV systolic dysfunction or a depressed EF. Also older patients and those with other cardiovascular diseases  were absent in our study. There were only six patients with AF in this study. Therefore, we were limited in extrapolating conclusions to these particular subgroups.Second, in order to obtain meaningful results, a strict and time-consuming methodology must be used, which may limit the everyday application of this method in a busy clinical practice. Therefore the results of our study could be applied in equivocal cases where conventional echocardiography is not matched with the patient’s symptoms.Despite these limitations, our results provide evidence that, in patients with mitral stenosis, LV filling pressure can be estimated by combining Doppler echocardiographic variables of mitral flow. However, more studies are required to confirm these results. Doppler echocardiography, a simple, readily available, non-invasive tool, may in future reduce the need for right heart catheterisation in patients with mitral stenosis and unexplained symptoms.


Obesity is an epidemic affecting over 1 in 3 adults in the United States. Patients who are obese have increased cardiovascular mortality compared to those with normal weight, partly due to direct effects on the heart. However, the effect of obesity on advanced measures of cardiac function such as strain, torsion and synchrony are poorly understood.Ten 12-week-old male C57BL/6 mice were randomized to one of two diets: 1) a high-fat ‘western' diet with 60% of calories from fat or 2) a low-fat diet with 10% of calories from fat. After 5 months on the diet, the mice were imaged on a 7T ClinScan MRI  using a cine DENSE protocol and a 4-element phased array cardiac coil. Three short-axis slices  and two long-axis slices (4-chamber and 2-chamber) were acquired with 15-20 frames per cardiac cycle. These data were then used to quantify left ventricular strain, torsion and measures of synchrony using semi-automated post-processing software written in MATLAB .Left ventricular sub-epicardial strain was significantly lower in the obese mice with a 40% reduction in circumferential strain (p<0.001), a 19% reduction in longitudinal strain (p=0.03), and a 53% reduction in radial strain (p=0.06). By contrast, left ventricular sub-endocardial strain was modestly reduced in the obese mice in the circumferential direction by 12% (p=0.01), and not significantly different in the radial (p=0.63) or longitudinal (p=0.44) directions. Peak left ventricular torsion was reduced by 34% in the obese mice (p=0.06). Finally, the radial uniformity of strain index showed a reduction in the synchrony of contraction in the left ventricle (p=0.01) with a time delay in the septal to free wall direction.Diet-induced obesity leads to a reduction in cardiac contractility in mouse models as evidenced by reductions in left ventricular strains and torsion. Reductions in cardiac strain are mostly limited to the sub-epicardial layer of the left ventricle, with relative preservation of function in the sub-endocardium. Diet-induced obesity also leads to reduced synchrony of contraction in the left ventricle of the heart.This work was supported by an NIH pilot project from a COBRE grant (5P20RR021954-05 and 8P20GM103527-05), the University of Kentucky Cardiovascular Research Center, and contributions made by local businesses and individuals through a partnership between Kentucky Children's Hospital and Children's Miracle network.


We sought to characterize the features of sickle cell cardiomyopathy and to identify causative mechanisms using comprehensive cardiac magnetic resonance, echocardiography, and arterial tonometry. We found that sickle cell cardiomyopathy is characterized by 4-chamber dilation, myocardial fibrosis, abnormal myocardial perfusion reserve, diastolic dysfunction, and only rarely myocardial iron overload. Left ventricular dilation and myocardial fibrosis are associated with increased blood transfusion requirements; where as, diastolic dysfunction is due to increased aortic stiffness.Cardiovascular disease is an important cause of morbidity and mortality in adults with sickle cell disease (SCD). We sought to characterize the features of SCD cardiomyopathy and to identify causative mechanisms.Stable adults with SCD (n=38) and matched controls (n=13) were prospectively recruited to undergo 1) multiparametric cardiovascular magnetic resonance (CMR) , and myocardial and hepatic multi-echo time (TE) single breath-hold T2* imaging), 2) echocardiography (TTE), and 3) applanation tonometry . Chamber size and function were measured from CMR using method of disks. Myocardial perfusion reserve index (MPRi) was calculated from time intensity curves generated from first pass perfusion images as the stress to rest ratio of mid-ventricular myocardium upslope . LGE was considered present if the signal intensity (SI) was >5 standard deviations above normal remote myocardium and if seen in 2 consecutive slices or 2 imaging planes. Myocardial and hepatic T2* times were calculated using the formula ΔTE/ ln(SI TE2/SI TE1). Presence of diastolic dysfunction (DD) was determined using American Society of Echocardiography criteria. Aortic augmentation index was determined using standard tonometry methods.Compared to controls, patients with SCD had severe dilation of the left ventricle (124±27 vs 79±12 ml/m2), right ventricle (127±28 vs 83±14 ml/m2), left atrium (65±16 vs 41±9 ml/m2), and right atrium (78±17 vs 56±17 ml/m2), p<0.001 for all. SCD patients had a 21% lower MPRi than controls . Twenty-five percent (8/32) of SCD patients (but no controls) had LGE (see figure). One SCD patient had evidence of myocardial iron overload. DD was more commonly present (26% (9/35) vs 8% (1/13)) and filling pressures (E/e’) were higher in SCD patients . Aortic augmentation index was higher  in SCD patients. LV dilation and the presence of LGE were inversely correlated to hepatic T2* times (i.e. hepatic iron overload due to frequent blood transfusions), p<0.05 for both; whereas, DD and increased filling pressures correlated with aortic stiffness (augmentation index), p<0.05.SCD cardiomyopathy is characterized by 4-chamber dilation, myocardial fibrosis, abnormal MPRi, DD, and rarely myocardial iron overload. Left ventricular dilation and myocardial fibrosis are associated with increased blood transfusion requirements; whereas, DD is due to increased aortic stiffness.Study funded through departmental funds.