The study was designed to evaluate whether the preserved coronary flow reserve (CFR) 72 hours after reperfused acute myocardial infarction (AMI) is associated with less microvascular dysfunction and is predictive of left ventricular (LV) functional recovery and the final infarct size at follow-up.2 analysis, continuous variables were analysed with the independent Student's t test. In order to analyse correlation between CFR and the parameters of LV function and perfusion, the Pearson correlation analysis was conducted. The linear regression analysis was used to assess the relationship between CFR and myocardial contractility as well as the final infarct size.In our study, CFR was assessed by transthoracic Doppler echocardiography (TDE) in 44 patients after the successful percutaneous coronary intervention during the acute AMI phase. CFR was correlated with contractile reserve assessed by low-dose dobutamine echocardiography and with the total perfusion defect measured by single-photon emission computed tomography 72 hours after reperfusion and at 5 months follow-up. The ROC analysis was performed to determine test sensitivity and specificity based on CFR. Categorical data were compared by an χWe estimated the CFR cut-off value of 1.75 as providing the maximal accuracy to distinguish between patients with preserved and impaired CFR during the acute AMI phase . Wall motion score index was better in the subgroup with preserved CFR as compared to the subgroup with reduced CFR: 1.74 (0.29) vs. 1.89 (0.17) (p < 0.001) during the acute phase and 1.47 (0.30) vs. 1.81 (0.20) (p < 0.001) at follow-up, respectively. LV ejection fraction was 47.78% (8.99) in preserved CFR group vs. 40.79% (7.25) in impaired CFR group (p = 0.007) 72 hours after reperfusion and 49.78% (8.70) vs. 40.36% (7.90) (p = 0.001) after 5 months at follow-up, respectively. The final infarct size was smaller in patients with preserved as compared to patients with reduced CFR: 5.26% (6.14) vs. 23.28% (12.19) (p < 0.001) at follow-up.The early measurement of CFR by TDE can be of high value for the assessment of successful reperfusion in AMI and can be used to predict LV functional recovery, myocardial viability and the final infarct size. Early and successful percutaneous coronary intervention (PCI) is the most effective and preferred reperfusion strategy for treating ST-elevation AMI (STEMI), reducing the infarct size and improving the clinical outcomes. The achievement of an adequate tissue level  perfusion is the goal of reperfusion therapy. Nevertheless, myocardial damage is not terminated immediately, even in successful primary PCI with Thrombolysis In Myocardial Infarction (TIMI) flow grade 3 in the infarct-related artery (IRA) . Paradox1. Injury of anatomical and functional integrity of microcirculation, causing the no-reflow phenomenon - inadequate myocardial perfusion of a given coronary segment without angiographic evidence of mechanical vessel obstruction -12.2. Myocardial stunning, which refers to transient dysfunction of myocardium contractility. It results from alterations in contractile proteins due to oxidant stress and/or disturbed cellular calcium homeostasis -17.3. Extension of the infarct zone.4. Reperfusion arrhythmias (life threatening arrhythmias).There are several explanations for the impairment of myocardial microcirculation: the plugging of distal segments of the coronary artery tree by microemboli of thrombotic or atherosclerotic debris; endothelial dysfunction which includes increased expression of adhesion molecules, selectins and release of vasoactive substances, resulting in vasoconstriction; increased activation of platelets, neutrophils, the complement system and inflammation; intensified generation of oxygen-free radicals, increased membrane permeability and swelling of endothelial cells and myocites, apoptosis and necrosis of cardiomyocites -22. All The early evaluation of myocardial reperfusion by transthoracic Doppler echocardiography and single-photon emission computed tomography (SPECT) in AMI provides important clues for predicting patient's prognosis -32. The The measurement of CFR by TDE has recently entered the stress echo laboratory -45. CFR The aim of our study was to evaluate the association of coronary flow reserve assessed 72 hours after reperfused AMI with myocardial reperfusion and to estimate CFR predictive value for LV functional recovery, myocardial viability and the final infarct size at follow-up.The sample of the study was sellected by purposive sampling: all the enrolled patients were treated in the Intensive Care Unit (ICU) of the Department of Cardiovascular Medicine, Vilnius University Hospital Santariskiu Klinikos from February 2008 till September 2010 and fulfilled the inclusion criteria. Totaly 44 patients  were studied. All the patients were with the first anterior STEMI without prior angina pectoris. Inclusion criteria were typical anginal chest pain lasting ≥ 30 min, ST-segment elevation of > 0.2 mV in at least two contiguous electrocardiographic leads, ≥ 3-fold increase in serum creatine kinase (CK) or Troponin I level, angiographically documented single vessel disease with the occluded left anterior descending coronary artery (LAD), with TIMI flow grade 0 - 1 before PCI and TIMI flow grade 3 after PCI. Exclusion criteria were pregnancy, lactation, unstable condition, more than one coronary artery disease, residual LAD stenosis after intervention > 20%, previous myocardial infarction and/or coronary revascularisation, second or third degree atrioventricular block, severe valve disease, systolic blood pressure < 90 mm Hg, bronchial asthma or chronic obstructive pulmonary disease.All the patients underwent revascularization of the LAD by PCI and stent placement using standard technique within 12 hours after the onset of chest pain. Contrast flow through the IRA was graded by the means of the TIMI flow classification. Collateral flow was graded according to the Rentrop classification . 31 patiVivid S5 System .Immediately after PCI, two-dimensional echocardiography (2D Echo) was performed in all the patients in the ICU. LV ejection fraction (LVEF), end-diastolic volume (EDV), end-systolic volume (ESV) were computed by the Simpson biplane method and wall motion score index (WMSI) was calculated using the standard 16-segment LV model . ImagingThe 12-lead electrocardiograms (ECGs) were obtained at the admission, in an hour, 6 hours and 12 hours after the reperfusion. Blood sampling for serum markers of myonecrosis  was routinely taken at the admission, 6 hours, 12 hours and 24 hours after the admission to estimate the peak concentration of these markers.All the patients underwent 3D Echo, dobutamine stress echocardiography (DSE), CFR, SPECT evaluation 72 hours after the reperfusion. First of all, we performed 3D Echo. Shortly, the myocardial contractility was examined by low-dose dobutamine echocardiography (LDDE). On the same day, several hours after LDDE, adenosine intravenous infusion was administered at a rate 140 μg/kg/min for six minutes for CFR evaluation and for gated-SPECT stress imaging. Spectral Doppler signals of the coronary flow in the distal portion of the LAD were recorded 60 s after the onset of the infusion for CFR off-line analysis. Afterwards, the infusion of adenosine was continued for myocardial perfusion stress imaging. Myocardial perfusion rest images were obtained one day later. The patients were offered chocolate milk to drink before acquisition in order to diminish bowel artefacts. Examinations were performed in the fasting state. Beta-blockers and nitrates were discontinued for 48 hours. No side effects occurred during these procedures. The same examinations were repeated for all the patients at 5 month follow-up.All the patients gave written informed consent. Study conformed to the principles outlined in the Declaration of Helsinki. Approval of the Lithuanian Bioethics Committee was granted .Page Writer Trim III . The ST-segment elevation (60 ms from the point J) was measured in the single lead  with maximal elevation. The normalization of ST-segment elevation during 1 hour after PCI comparing with the initial ECG was calculated according to the formula:An ECG was recorded using the The ST-segment resolution ≥ 70% was defined as complete resolution, 30-70% - partial resolution and < 30% - no resolution of the ST-segment.Vivid 7 Dimension Ultrasound System  equipped with a V3 matrix-array transducer. The digital real-time 3D echocardiographic LV data sets were analyzed off-line using Tom Tec's 4D LV Function software by semi-automatic detection of LV contours. LVEF, EDV, ESV were computed.Real-time 3D Echo harmonic imaging was performed using the Vivid 7 Dimension ultrasound system  with second harmonic technology. For colour Doppler (3 MHz) flow mapping, the velocity range was set at 12 to 20 cm/s. Coronary flow velocity was measured with pulsed wave Doppler at 2.8 MHz (sample volume 2.0 mm) using colour Doppler (CD) as a guide. The angle correction was performed if the angle between the flow and the Doppler beam exceeded 20 degrees and was maintained during rest and stress studies. The spectral trace of the coronary flow was characteristically biphasic with a dominating diastolic component.The assessment of CFR by TDE was performed using the The patients were examined in the left position. We recorded the flow in the most distal part of the LAD. A short axis view of the LV and the anterior groove was interrogated with CD. When diastolic CD blood flow was detected, the transducer was slowly rotated clockwise to obtain the best long axis view of the LAD.First of all, we recorded baseline spectral Doppler signals in the distal portion of the LAD. Then, spectral Doppler signals were recorded during hyperaemic conditions (60 s after the onset of the infusion of adenosine). Stop frames and clips were digitally recorded for off-line analysis. Recordings were done during a brief period of holding breath. The images were interpreted by 2 experienced physicians. Measurements were averaged over three consecutive heart beats. The peak diastolic flow velocity was measured at baseline and at peak hyperaemic conditions. CFR was defined as the ratio of hyperaemic to basal peak diastolic coronary flow velocity . 2D Echo and 12-lead ECG monitoring were performed with low-dose dobutamine infusion. The standard dobutamine stress protocol consisted of continuous intravenous infusion of dobutamine in 3 minutes increments, starting with 5 μg/kg/min and increasing to 10 μg/kg/min. Echo images  were semiquantitatively assessed by 2 experienced physicians using a 16-segment LV model, a wall motion four-grade scale model in resting condition, each stage thereafter and during the recovery phase. We estimated WMSI. In the non-viability response (without contractile reserve), a segment with resting dysfunction remained fixed during stress. If the improvement of wall motion was present in at least four contiguous dysfunctional segments by ≥ 1 grade or WMSI decrease ≥ 0.25 during low-dose dobutamine infusion, they indicated the presence of the stunned myocardium with preserved contractile function which is the predictor of segmental functional recovery at the follow-up period [DSE studies were performed with p period . When DSINFINIA GP 3 . 99 m Technetium (Tc) tetrofosmin (750 MBq) was injected intravenously at the third minute of the infusion of adenosine. Supine electrocardiographically gated-SPECT images were acquired after 45 minutes. Rest images were obtained one day later using the same radioactivity of 99 m Tc tetrofosmin with acquisition starting 60 minutes after the injection. The gated and non-gated data were separately reconstructed on a workstation for off-line analysis. No scatter or attenuation correction was applied. The images were interpreted by 2 experienced physicians. We performed both visual semiquantitative analysis, which accounts for a variety of artefactual patterns that can be recognized only by visual inspection, and automatic quantitative computer-generated analysis.Gated-SPECT studies were performed using a two-day stress/rest protocol with a dual-detector gamma camera  fully automated quantitative analysis of myocardial perfusion was carried out from "bull's eye" (polar map) images: combined extension and severity of the perfusion defect in one variable - the total perfusion defect in% (TPD%) - was defined at stress and at rest imaging. We referred that TPD < 5% to be normal, between 5 and 9% was termed mild, 10-15% - moderate, and > 15% - severe. We assessed the success of myocardial reperfusion as the TPD  by repeated SPECT at follow-up after 5 months.An investigator evaluated visually all images by intensity of myocardial colour-coded scintillation, which depends on the uptake of the radiotracer. The entire LV myocardium was divided into 20 segments. Each segment was scored using a five-point system: the score 0 was used for normal perfusion, i.e. the uptake of the radiotracer was not disturbed; 1 - perfusion was slightly reduced (slight reduction of the uptake); 2 - moderate reduction of the uptake; 3 - severe reduction of the uptake; 4 - no perfusion. Using special software package QPS The statistical analysis was performed with the use of the SPSS software package for Windows 17.0. Data were expressed as mean ± standard deviation (SD) or number (%) of patients. The Receiver Operating Characteristic (ROC) curve analysis was performed to determine test sensitivity and specificity based on CFR. The test performance was estimated by calculating the area under the curve (AUC). The optimal cut-off value of CFR was defined as that providing the maximal accuracy to distinguish between the patients with preserved and impaired CFR during the acute MI phase.2 (chi square) analysis, continuous variables were analysed with the independent Student's t test. In order to compare WMSI changes separately in the subgroups of patients with preserved and impaired CFR 72 hours after the reperfusion, at LDDE and at follow-up Echo, paired samples t test was conducted. A value of p < 0.05 was considered to be significant.Categorical data were compared by an χIn order to analyse correlation between CFR and contractile reserve at LDDE, LVEF, TPD at rest and at stress in the infarct area 72 hours after reperfusion and at 5 months follow-up, the Pearson correlation analysis was conducted.The linear regression analysis was used to assess the relationship between CFR evaluated 72 hours after PCI and preserved myocardial contractility (viability) as well as the final infarct size.The ROC analysis was performed to estimate test sensitivity and specificity based on a wide range of cut-off points of CFR for the detection of myocardial viability, spontaneous LV functional recovery and a moderate final infarct size. For the evaluation of LV segmental functional recovery, the decrease of WMSI ≥ 0.25 at LDDE during the acute MI phase and at 5 months follow-up echocardiography (as compared to the acute phase echocardiography) was described as a marker of myocardial viability and spontaneous functional recovery. The TPD ≤ 15% was defined as a moderate final infarct size after reperfused MI at follow-up. We estimated the optimal CFR cut-off value of 1.75 as providing the maximal accuracy to distinguish between patients with preserved CFR (N = 19) and impaired CFR (N = 25) during the acute MI phase . The AUC was 0.88 ± 0.1 (p < 0.001) Figure .According to the estimated CFR cut-off value all the patients were divided into two subgroups. Clinical history, risk factors, anti-ischaemic therapy before AMI and angiographic characteristics in both subgroups did not differ significantly, with the exception of timing to reperfusion and ECG ST-segment complete resolution in patients with preserved and impaired CFR Table .The majority of patients with preserved CFR (94.8%) received PCI during 6 hours after the onset of chest pain as compared to 56% of patients with impaired CFR. On the contrary, only 5.2% of patients with preserved CFR received PCI after 6 hours from the onset of chest pain as compared to 44% of patients with impaired CFR (p = 0.011). Thus, the timing of reperfusion is very important for the maintenance of the intact microvasculature of the myocardium during AMI. We also revealed statistical difference of ECG ST-segment complete resolution results between the two subgroups: more than 47% of patients with preserved CFR had complete ST-segment regression during 1 hour after PCI as compared to 16.7% of patients with impaired CFR (p = 0.033).According to these results we can state that an incomplete ST-segment resolution correlates with impaired structural and functional integrity of microcirculation and suboptimal myocardial reperfusion.In order to analyse the correlation between CFR assessed 72 hours after reperfusion and the parameters of LV function and perfusion during the acute MI phase and at 5 months follow-up the Pearson correlation coefficient was calculated Table .A moderate direct correlation between CFR and preserved contractile reserve was observed during the acute MI phase  and at follow-up , also with spontaneous segmental  and global LV  functional recovery at the follow-up. CFR was inversely correlated with the TPD which was an indicator of anatomical and functional microvascular integrity and no-reflow extent in the infarct area after reperfusion at rest  and at stress imaging . Also CFR was inversely correlated with the final infarct size assessed as the TPD at follow-up . Most significant correlations were observed between early assessed CFR and the TPD at rest  and at stress imaging  after 5 months, also with contractile reserve during the acute MI phase  and at follow-up . There was no statistically significant correlation between CFR and WMSI at rest, LVEF and ESV during the acute MI phase, while correlation between CFR and these parameters was observed after 5 months .According to these data from our study, CFR measured non-invasively 72 hours after reperfused AMI is an indicator of microvascular integrity and function (the extent of no-reflow), segmental and global LV functional recovery, myocardial viability and the final infarct size.In order to compare the parameters of LV function and perfusion during the acute MI phase and at the follow-up period in preserved and impaired CFR groups, we performed the independent Student's t test analysis Table .Patients with preserved CFR had a statistically significant smaller TPD than patients with impaired CFR: the TPD was 12.58% (1.22) vs. 30.16% (11.32) (p < 0.001) at rest and 19.68% (12.77) vs. 37.76% (11.59) (p < 0.001) at stress myocardial perfusion imaging during the acute MI phase; the final infarct size was 5.26% (6.14) vs. 23.28% (12.19) (p < 0.001) at rest and 8.74% (9.44) vs. 28.12% (9.72) (p < 0.001) at stress imaging after 5 months, respectively.Global LV systolic function (LVEF as assessed by 3D Echo) was significantly better in patients with preserved than in patients with impaired CFR: 47.78% (8.99) vs. 40.79% (7.25) (p = 0.007) during the acute MI phase and 49.78% (8.70) vs. 40.36% (7.90) (p = 0.001) at follow-up.Wall motion and contractility did not improve significantly in patients with impaired CFR with WMSI changing from 1.89 (0.17) 72 hours after PCI to 1.80 (0.21) at LDDE (p = 0.138) and to 1.81 (0.20) at follow-up Echo (p = 0.159). In the group with preserved CFR, WMSI changed significantly from 1.74 (0.29) 72 hours after PCI to 1.48 (0.27) at LDDE (p = 0.009) and to 1.47 (0.30) at the follow-up period (p = 0.008).Thus, the viable myocardium, spontaneous regional and global LV functional recovery, the smaller no-reflow zone and the final infarct size were more common in patients with preserved CFR than in patients with impaired CFR.The computed linear univariate regression showed an inverse correlation between CFR assessed 72 hours after AMI and the final infarct size , e.g. if a patient's CFR was the same as our study cut-off value of 1.75, the final infarct size was 13.92%. Linear regression also showed statistically significant relation between CFR and preserved contractility , e.g. if the patient's CFR was the same as our study cut-off value of 1.75, the difference between WMSI at rest and WMSI at LDDE was 0.2954.Finally, we analysed the strength of the relationship between early assessed CFR, the final infarct size and myocardial viability Table . The senAccording to these data we concluded that preserved CFR during the acute MI phase can predict the preserved myocardial contractility and viability  and the smaller final infarct size at the follow-up period.The no-reflow phenomenon was first explored by Ito et al.  in patiePrevious studies highlighted the importance of non-invasive analysis of CFR in predicting LV functional recovery after coronary reperfusion in AMI ,63,65-67Due to the progression of microvascular damage and reactive hyperaemia after reperfusion in AMI, timing of CFR assessment is very important. Lepper et al.  found a The optimal cut-off value of 1.75 to predict myocardial viability, spontaneous LV functional recovery and a moderate final infarct size was proven as that providing the maximal accuracy to distinguish the patients with preserved and impaired CFR. As we predicted, there were differences comparing patients with preserved and impaired CFR according to the time interval from the onset of chest pain to reperfusion. These data was confirmed in other experimental and clinical studies ,29, suggElectrocardiographic analysis of ST-segment resolution is one of the simplest and most widely used criterion to assess the effectiveness of restoration of antegrade coronary flow in the IRA and predicts not complicated post-infarction course . HoweverOur study has been limited by a relatively small number of patients. However, the two study subgroups were quite homogeneous, so the results should be widely applicable. CFR assessment by TDE is a simple, non-invasive technique to obtain the diastolic flow and its velocity in the LAD with the success rate of 90-96%. However, the success rate to obtain the diastolic flow in the right coronary artery is 34-50% and in the circumflex coronary artery - 60-80%, thus restricting its application. Besides, we used dobutamine-induced contractility and wall motion recovery during the acute MI phase and at the follow-up period as indicators of myocardial viability. This approach has been based on semiquantitative analysis, therefore has some limitations when compared with positron emission tomography or magnetic resonance imaging with contrast .The early, non-invasive measurement of CFR by TDE provides insight into the pathophysiological changes of microcirculatory integrity and function after reperfused AMI. We revealed that CFR measurement can be of high value for the assessment of successful reperfusion in AMI. The preserved CFR with the cut-off value of 1.75 during the acute MI phase can predict the LV functional recovery, myocardial viability and a moderate final infarct size (TPD ≤ 15%) at follow-up with high sensitivity and specificity . Besides, the combination of the myocardial perfusion test by CFR and SPECT studies as well as the analysis of LV wall motion abnormalities by LDDE represent the evaluation of the flow-function relationship. Concordant contractility and myocardial perfusion results enhance the diagnostic accuracy in the prediction of LV functional recovery after reperfused AMI. Furthermore, the CFR study adds quantitative information to the qualitative assessment of wall motion analysis.Thus, early assessment of CFR by TDE provides important prognostic information in patients with recent myocardial infarction and should be integrated in the routine evaluation of these patients.ACE: angiotensin converting enzyme; AMI: acute myocardial infarction; AUC: area under the curve; CD: colour Doppler; CFR: coronary flow reserve; CK: creatine kinase; DSE: dobutamine stress echocardiography; ECG: electrocardiography; EDV: end-diastolic volume; ESV: end-systolic volume; IR: ischaemic-reperfusion injury; IRA: infarct-related artery; LAD: left anterior descending coronary artery; LDDE: low-dose dobutamine echocardiography; LV: left ventricular; LVEF: left ventricular ejection fraction; MBq: megabecquerel; MI: myocardial infarction; PCI: percutaneous coronary intervention; ROC: Receiver Operating Characteristic curve; SD: standard deviation; SPECT: single-photon emission computed tomography; STEMI: ST-elevation acute myocardial infarction; Tc: Technetium; TDE: transthoracic Doppler echocardiography; TIMI: Thrombolysis In Myocardial Infarction; TPD: total perfusion defect; WMSI: wall motion score index; 2D: two-dimensional echocardiography; 3D: three-dimensional echocardiography.The authors declare that they have no competing interests.ES and DZ have been involved in data acquisition, analysis and interpretation, drafted the manuscript. LR and JC participated in drafting the manuscript and revising it. AR and SA were involved in the design of the study. AL conceived of the study, and participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.


The method was successfully tested in five healthy and four infarcted mice (C57BL/6J) at heart rates of 495.1 ± 45.8 beats/min. Signal-intensity-time profiles showed a percentage myocardial signal increase of 141.3 ± 38.9% in normal mice, compared with 44.7 ± 32.4% in infarcted segments. Mean myocardial blood flow by Fermi function for constrained deconvolution in control mice was 7.3 ± 1.5 mL/g/min, comparable to published literature, with no significant differences between three myocardial segments. In infarcted segments, myocardial blood flow was significantly reduced to 1.2 ± 0.8 mL/g/min (P < 0.01). This is the first report of first-pass myocardial perfusion MR in a mouse model on a clinical 3-T MR scanner and using a k-t undersampling method. Data were acquired on a 3-T scanner, using an approach similar to clinical acquisition protocols, thus facilitating translation of imaging findings between rodent and human studies. Magn Reson Med, 2010. © 2010 Wiley-Liss, Inc.First-pass contrast-enhanced myocardial perfusion MRI in rodents has so far not been possible due to the temporal and spatial resolution requirements. We developed a new first-pass perfusion MR method for rodent imaging on a clinical 3.0-T scanner  that employed 10-fold  Genetically modified mice are increasingly used to study the pathophysiology of cardiovascular disease –4. One oIn humans, the preferred method for myocardial perfusion assessment is dynamic first-pass contrast-enhanced acquisition. The method has been well validated in clinical models . Howeverk-space and time domain undersampling [k-t sensitivity encoding (k-t SENSE)] have been developed, achieving acceleration of data acquisition by up to a factor of 8 in clinical studies ] permit even higher acceleration factors, with fewer training profiles and improved temporal fidelity , preparation pulse delay 100 msec, acquisition window 43 msec). To improve temporal fidelity of the data at the high undersampling factors used, the k-t PCA method was used for image reconstruction . The pulse sequence was based on a method previously used for human application  and adaptruction .Nine 10- to 12-week-old homozygous C57BL/6J male mice were acquired from Charles Rivers Laboratories  or were bred within the Animal Unit of the Rayne Institute at King's College London. The housing and care of the animals and all the procedures used in these studies were performed in accordance with the guidelines and regulations of the United Kingdom Home Office. Five animals served as healthy controls, and in four animals permanent myocardial infarction was induced 3 days prior to imaging. For the induction of myocardial infarctions, mice were anesthetized by isoflurane inhalation and ventilated by tracheal intubation. Following left-side lateral thoracotomy, an 8-0 nylon suture was carefully placed around the left anterior descending coronary artery and was tied by the edge of the left atrium.After the completion of the imaging study, 300 μL of Evans Blue (2% w/v) was injected into the tail vein to delineate the area at risk and the animals were sacrificed. Hearts were excised, mounted in agarose, and sliced into 1.5mm sections from apex to base. Slices were fixed overnight in 10% formaldehyde and were then digitally imaged, using a high-resolution optical scanner. Areas stained negative for Evans Blue were defined as not perfused and thus to be perfusion territory of the ligated coronary artery. Locations were identified as septal, anterolateral, and inferolateral, as described for perfusion MRI. Areas stained positive for Evans Blue were considered remote zones.Mice were anesthetized and maintained under inhalational anesthesia via nose cone (1.4% isoflurane/oxygen). Rectal temperature was monitored continuously and a warm air flow  was adapted to maintain temperature at 37°C. For reliable electrocardiogram (ECG) synchronization and artifact-free high-resolution imaging, a dedicated small-animal ECG device, 1025-MR (SA Instruments), and dedicated microscopy receive coils  were used . Two ECG2, matrix 300 × 300, slice thickness 2mm, pulse repetition time/echo time 20/5.8 msec, flip angle 20°, number of slices nine. Subsequently, pseudo two- and four-chamber gradient echo cine scans were acquired with prospective ECG-triggered spoiled gradient echo sequences. Imaging parameters were field of view 70 × 70mm, matrix 224, slice thickness 1.5mm, pulse repetition time/echo time 14/5.3 msec, flip angle 30°, two lines/RR interval, temporal resolution 18 msec. High-resolution (0.2 × 0.2 × 1mm3) short-axis, two- and four- chamber (biplane) views were then planned on those views. Imaging parameters were field of view 35 × 35mm2, matrix 160, slice thickness 1mm, pulse repetition time/echo time 11/5.3 msec, flip angle 20°, one line/RR interval, temporal resolution 11 msec, number of signal averages two. These images allowed for planning of the true short-axis views of the left ventricle. Perfusion imaging was performed in midventricular short-axis orientation, using the pulse sequence described above.All data were acquired during free breathing of the animal. For localization of the heart, a low-resolution gradient echo scout scan was acquired in the coronal and transverse orientations, using the following parameters: field of view 300 × 300mmA catheter was placed in the tail vein of the mouse and 0.1 mmol/kg bodyweight Gadolinium Gadopentetate Dimeglumine (Gd-DTPA)  was injected after the perfusion scan was started. To ensure a reproducible bolus injection, the contrast agent, as well as 25 μL of saline, was preloaded into small-bore tetrafluoroethylene tubing and injected manually over 3 sec.Semiquantitative analysis was performed using dedicated image analysis software . Endocardial and epicardial contours were drawn on images with best blood to myocardium contrast and copied to all other dynamic images. The position of individual contours was then manually corrected to account for respiratory motion. The myocardium was divided into three sectors of equal circumferential extent along the myocardial centerline, starting from a reference point placed at the anterior septal insertion of the right ventricle .To obtain the arterial input function, a region of interest was drawn inside the left ventricular (LV) blood pool. Signal intensity (SI)/time curves were generated for the LV blood pool, for the myocardium as a whole, and for the three myocardial sectors. The maximal upslope of the profiles was generated using five-point fitting. SI profiles were then generated for each sector and the region of interest in the LV blood pool. Enhancement ratio of signal increase and normalized SI upslope ratios between the blood pool and myocardium were calculated as (enhancement ratio = (SI max – SI baseline)/SI baseline) and .In addition to this semiquantitative upslope-based analysis, absolute MBF was computed from the LV blood pool and myocardial tissue SI vs. time curves, using Fermi constrained deconvolution ,17. The P < 0.05 and high significance was considered for P < 0.01.Continuous data were expressed as mean ± standard deviation. For comparing groups (>2), the analysis of variance test was used, and for comparing pairs of a group, Tukey's test was used. Statistical significance was considered for Myocardial infarcts were successfully induced in the four operated mice. In the midventricular slice that was investigated by perfusion imaging, all infarcts were localized in the anterolateral myocardial segment. All areas stained negative for Evans Blue matched with the MR perfusion defect.P > 0.05).First-pass myocardial perfusion imaging was successfully performed in all five control and the four infarcted mice. All mice tolerated the scanning without any complications. The observed heart rate was within the expected physiological range, with no significant hemodynamic effect from the anesthetic observed. There was no significant difference in heart rate between the two groups .SI/phase profiles derived from control and left anterior descending infarcted mice –5 showedP < 0.01) . Estimated MBF differed significantly between normal and infarct segments  and high temporal resolution (43 msec) imaging with accurate depiction of signal enhancements in the blood pools and in the myocardium was possible. Relative to previous k-t SENSE protocols for human application  and k-t SENSE reconstructions. Moreover, respiratory excursions of the anesthetized animals were shallow and relatively regular, which may have helped to minimize artifacts.The first-pass contrast-enhanced myocardial perfusion imaging protocol used in this study was based on highly accelerated data acquisition with the lication , a higheprofiles . In the In this study, signal-time intensity profiles did not show signs of temporal low-pass filtering, and the calculated MBFs were comparable to that of published literature from arterial spin labeling and microsphere data –10,19. IData in this study were acquired on a clinical 3-T CMR scanner, using an approach that closely resembles clinical acquisition protocols and thus facilitating clinical translation of imaging findings. Increasingly, rodent imaging is performed on clinical CMR systems  because Cardiovascular MR has been shown to hold potential for a comprehensive workup of cardiac function in rodents. Global and regional cardiac function can be quantified accurately with cine and tagging MR methods ,21. PresContrast delivery in this study was manual but can in principle be automated to improve reproducibility. The optimal contrast dose and injection speed need to be optimized to account for physiological differences between rodents and humans. The current implementation only allows for the acquisition of one slice at each RR interval. More slices could potentially be acquired if acquisitions were shared between multiple RR intervals at the expense of lower temporal resolution or with further refinements of the acquisition protocol. Finally, the ability to acquire first-pass myocardial perfusion MR data during vasodilator stress needs to be tested and validated.We present a novel approach for first-pass myocardial perfusion MRI in rodents that provides MBF values within the expected range in normal and left anterior descending infarcted mice. The method is fast and may permit data acquisition under pharmacological stress. With the increasing range of mouse models in cardiovascular disease, this method could provide a useful tool to systematically investigate the role of ischemia in atherosclerosis, diabetes, hypertension, or heart failure.


We analyzed the association between renal and cardiovascular parameters in fetuses with isolated severe urinary tract malformations.2-microglobulin, and hemoglobin were determined from fetal blood samples.39 fetuses at a mean gestational age of 23.6 weeks with nephropathies or urinary tract malformations and markedly impaired or absent renal function were prospectively examined. Fetal echocardiography was performed, and thicknesses of the interventricular septum, and left and right ventricular wall were measured. Blood flow velocity waveforms of the umbilical artery, middle cerebral artery, and ductus venosus were obtained by color Doppler ultrasound. Concentrations of circulating n-terminal pro-B-type natriuretic peptide (nt-proBNP), cystatin C, ß2-microglobulin concentrations were elevated as follows (mean ± SD) 1.85±0.391 mg/L and 8.44±2.423 mg/L, respectively . No correlation was detected between cardiovascular parameters and urinary tract morphology and function. Despite increased levels of nt-proBNP cardiovascular function was preserved, with normal fetal Doppler indices in 90.2% of cases.Malformations included 21 cases of obstructive uropathy, 10 fetuses with bilateral nephropathy, and 8 cases of bilateral renal agenesis. Marked biventricular myocardial hypertrophy was present in all cases. The ratio between measured and gestational age-adjusted normal values was 2.01 (interventricular septum), 1.85, and 1.78 . Compared to controls, levels of circulating nt-proBNP were significantly increased (median (IQR) 5035 ng/L (5936 ng/L) vs. 1874 ng/L (1092 ng/L); p<0.001). Cystatin C and ßUrinary tract malformations resulting in severe renal impairment are associated with biventricular myocardial hypertrophy and elevated concentrations of circulating nt-proBNP during fetal life. Cardiovascular findings do not correlate with kidney function or morphology. In children and adults chronic kidney disease (CKD) is associated with an increased rate of cardiovascular complications In adult and pediatric cardiology n-terminal pro-B-type natriuretic peptide (nt-proBNP), the inactive cleavage product of brain natriuretic peptide (BNP) is an established marker of cardiovascular dysfunction 2-microglobulin, and hemoglobin was analyzed in umbilical vein samples of affected fetuses. Additionally, echocardiography and color Doppler examination of the fetal cardiovascular system was performed, and myocardial wall dimensions and cardiothoracic area were measured.The aim of our study was to analyze the association between renal and cardiovascular parameters in fetuses with severely reduced or absent renal function secondary to isolated urinary tract malformations. For that, nt-proBNP, cystatin C, ßOur hypothesis was that renal and cardiac function is interrelated during gestation, and that changes in cardiovascular function are present in fetuses with impaired or absent renal function.Patients referred to our center between January 2007 and October 2011 with a diagnosis of bilateral nephropathy or urinary tract malformation who underwent fetocide or fetal blood sampling (FBS) were eligible. Fetocide was performed as part of termination of advanced pregnancy in accordance with national legislation. Indications for FBS included rapid karyotyping due to late referral or kidney function analysis. We excluded fetuses with any of the following conditions: unilateral nephropathy, unilateral urinary tract malformation, associated structural malformations, aneuploidy, moderate or severe anemia The study was approved by the university of Bonn ethics committee. All participating pregnant women gave their written consent.2, applying only the fetal use adapted ultrasound machine settings. A detailed ultrasound of the fetal anatomy, echocardiography with measurement of myocardial wall dimensions, and color Doppler examination of the fetal and uterine vessels was performed. Thicknesses of the interventricular septum (IVS) and the right (RVW) and left (RVW) ventricular wall were determined in B-mode; a standard lateral four-chamber-view was obtained, and measurements were taken at the tip of the atrioventricular valve leaflets during diastole. Doppler recordings of blood flow velocities in the middle cerebral artery (MCA) and umbilical artery (UA) were obtained at an insonation angle between 0° and maximally 10° to flow and <30° for ductus venosus (DV) and uterine arteries (utA), using standard positioning of the sample volume; angle correction was not performed. The high-pass-filter was set at 60 Hz. At least five consecutive uniform Doppler velocity waveforms with the highest velocities and a narrow band of frequencies were recorded, and one cycle was analyzed. Indices were calculated accordingly; abnormal values were defined as UA pulsatility index >90th percentile for GA or absent or reversed end-diastolic flow; DV pulsatility index for veins >90th percentile for GA or absent or negative a-wave; utA resistance index >90th percentile for GA or bilateral notching; peak systolic velocity of the middle cerebral artery (PSV-MCA) >1.28 times the median for GA. All examinations were performed prior to invasive intervention.High-resolution ultrasound equipment  was used in all cases with 5 to 9 and 2 to 6, 7, and 8 MHz respectively, convex transducers. The spatial peak temporal average power output was kept at <100 W/cmSpecimens were collected as part of the FBS procedure  or fetocide . The umbilical cord was punctured under ultrasound control near its placental insertion site. One mL of fetal venous blood was withdrawn either before injecting the cardioplegic solution or before proceeding with the FBS.2-microglobulin were analyzed by nephelometry, all on a Dimension Vista 1500 . Hemoglobin was analyzed on a Sysmex XE-2100 . Inter- and intra-assay coefficients of variation were 3.5% and 2.3% for nt-proBNP, 2.6% and 2.4% for cystatin C, 3.2% and 3.1% for ß2-microglobulin, and 0.41% and 0.38% for hemoglobin. All samples were processed within two hours after retrieval.NT-proBNP was measured by chemiluminescence immunoassay, cystatin C and ßVesico-amniotic shunting was performed under ultrasound control. Using Seldinger technique a Harrison fetal bladder stent 5.0 Fr/1.3-3.5 cm  was inserted under local anesthesia. Correct position was verified by ultrasound and indirectly by prompt reduction in bladder volume.(2.84–8.55/GA)To adjust for the effect of gestational age hemoglobin values were transformed into multiples of the median (MoM). Expected hemoglobin values were calculated with the following formula: e2); RVW-GA = −0.1473+(0.02045 * GA)−(0.0002 * GA2); LVW-GA = −0.136+(0.01967 * GA)−(0.00019 * GA2) Gestational age-adjusted normal values and standard deviations were calculated for the interventricular septum (IVS-GA) and the right and left ventricular wall (RVW-GA and LVW-GA) using the following formulas: IVS-GA = −0.1321+(0.01927 * GA)−, 30 fetuses were male (76.9%). A normal karyotype was present in all examined cases .41 analyses were performed in 39 fetuses. In two fetuses with obstructive uropathy measurements were taken twice (before and after shunting) with two weeks interval. Cystatin C and hemoglobin values could not be determined in three cases, ßMalformations were classified in three categories:Obstructive uropathy, n = 21 (53.9%): lower  urinary tract obstruction with or without development of urinoma or urinous ascites.Bilateral nephropathy, n = 10 (25.6%): autosomal recessive polycystic kidney disease; bilateral multicystic dysplastic kidneys; unilateral multicystic dysplastic kidney with contralateral renal agenesis or dysplasia.Bilateral renal agenesis, n = 8 (20.5%).Severe oligohydramnios (amniotic fluid index ≤2 cm) or anhydramnios was present in all cases. Pulmonary hypoplasia, defined as cardiothoracic area ratio (CTAR) >0.3 could be demonstrated in 36 fetuses (87.8%); CTAR was normal in 3 (7.3%), and measurement was not available for 2 cases (4.9%).Myocardial wall dimensions were markedly altered, see 2-microglobulin and GA-adapted hemoglobin concentrations are listed in 2-microglobulin were found to be increased. Additionally, cystatin C and ß2-microglobulin concentrations were significantly higher in bilateral renal agenesis compared to obstructive uropathies .Compared to controls, nt-proBNP concentrations were significantly increased in the study group (median (IQR) 5035 ng/L (5936 ng/L) vs. 1874 ng/L (1092 ng/L), p<0.001), see 2-microglobulin concentrations were closely correlated .No correlation was present between nt-proBNP and markers of kidney function or hemoglobin, whereas cystatin C and ßA significant inverse correlation between MoM Hb and GA  was detected, see In cases with obstructive uropathy, 14 samples were taken before and nine after vesico-amniotic shunting. There was no difference in any of the variables except for hemoglobin, which was significantly higher after shunting (MoM Hb before versus after shunting: p = 0.010).In our group of fetuses with severely impaired or absent renal function secondary to isolated nephropathies and urinary tract malformations biventricular myocardial hypertrophy with preserved myocardial function was present. Nt-proBNP concentrations were significantly elevated in the study group compared to controls; no difference was present between the various malformation categories.During human development, natriuretic peptides (NPs) are involved in cardiac morphogenesis. By mid-gestation the cardiac natriuretic system (ANP and BNP) is assumed to be functional. Fetal and maternal compartments are separated and placental transfer of NPs does not occur Limited data are available on the association of myocardial hypertrophy and structural or functional abnormalities of the urinary tract during fetal life. In a series of 50 cases with cardiomyopathy 10% were associated with renal abnormalities The role of nt-proBNP as marker of cardiovascular dysfunction in CKD has been a matter of debate In contrast, the increase in circulating nt-proBNP observed in our study group was not associated with major changes in the fetal cardiovascular function. Therefore, our results do not support a role of nt-proBNP as marker of cardiovascular impairment in nephropathies or urinary tract malformations during fetal life.Various factors may contribute to the increase in nt-proBNP concentration in fetuses with nephropathies and urinary tract malformations.Firstly, alterations in the vascular bed of the urinary tract may cause increased afterload.Renal blood flow in the fetus amounts to 3% of the combined cardiac output and is characterized by high vascular resistance. Vascular resistance within the often grossly enlarged kidneys of severe nephropathy has not been measured. In fetuses with lower urinary tract obstruction increased downstream impedance in the common iliac arteries has been demonstrated and was interpreted to be caused by compression of the distended bladder Secondly, impaired or absent kidney function may result in volume load. In fetal lambs, intra- and extracellular volume is reduced after second-trimester nephrectomy Thirdly, even minor degrees of anemia are able to induce a rise in nt-proBNP The number of cases is small, thereby limiting the significance of our findings. Nevertheless, the study represents the largest such cohort in the literature to date. Bökenkamp et al. 2001 Nephropathies and urinary tract malformations are associated with biventricular myocardial hypertrophy and elevated levels of circulating nt-proBNP during fetal life. The cardiovascular findings do not correlate with kidney function or morphology, but may be caused by changes in prorenin concentrations and increased afterload.Dataset S1(SAV)Click here for additional data file.


Cardiotoxic chemotherapy including anthracyclines remains a standard of care in paediatric cancers. Recent data suggest that heart failure secondary to chemotherapy is, to some degree, reversible, but requires early detection and prompt intervention. Since a substantial proportion of paediatric patients still develop heart failure, this work aims to develop a follow-up protocol based on cMRI to evaluate the patient’s cardiovascular function and haemodynamics, as well as myocardial iron overload, perfusion and viability.2) were prospectively identified as candidates for cardiotoxic chemotherapy. All patients underwent a cMRI to evaluate 1) systolic and diastolic function on steady-state free precession cine and tagged imaging, 2) myocardial perfusion and viability after Gadolinium injections, 3) mitral and aortic flows through velocity-encoded sequences, and 4) myocardial and liver iron content based on T2* MRI.From October 2009 to September 2010, 38 children ; mean BSA of 0,98m2). No significant liver or cardiac iron overload was detected . Evaluation of the inter-observer and intra-observer variability was performed for all variables studied and confirmed that the coefficients of determination were very strong , as previously reported by others.The study protocol was completed in all patients within the first month of diagnosis, under general anaesthesia for the 14 youngest patients. The mean MRI acquisition time 40+/-9min. Systolic biventricular volumes, mass and function as well as left ventricular (LV) diastolic function were normal in all patients, with a mean LV EF of 62,2+/-8% and RV EF of 49,5+/-7,2%. Although a perfusion defect was not retrieved in any of these pre-chemotherapy assessments, mild LV myocardial scaring  was frequently identified by gadolinium-enhanced imaging. Aortic and mitral flux showed normal LV stroke volumes (mean of 3,78L/min/mOur preliminary study shows that a detailed cardiovascular evaluation of young patients undergoing chemotherapy is achievable in a reasonable time in the early phase following diagnosis. We believe that the low intra and inter-observer variability of cMRI makes it suitable for a complete mid- and/or long-term follow-up of cardiovascular function. This should allow to evaluate the true harmful effects of cardiotoxic medications used against paediatric cancers and to confirm the potential role of cMRI as a first-line approach to subclinical heart failure in children.


The purpose of this paper is to describe imaging techniques and findings of T2-weighted magnetic resonance imaging (MRI) of edema in myocardial diseases. T2-weighted cardiac MRI is acquired by combining acceleration techniques with motion and signal suppression techniques. The MRI findings should be interpreted based on coronary artery supply, intramural distribution, and comparison with delayed-enhancement MRI. In acute myocardial diseases, such as acute myocardial infarction and myocarditis, the edema is larger than myocardial scarring, whereas the edema can be smaller than the scarring in some types of nonischemic cardiomyopathy, including hypertrophic cardiomyopathy. T2-weighted MRI of edema identifies myocardial edema associated with ischemia, inflammation, vasculitis, or intervention in the myocardium and provides information complementary to delayed-enhancement MRI. Delayed-enhancement magnetic resonance imaging (MRI) is valuable for the diagnosis and assessment of the severity of both ischemic and nonischemic myocardial diseases –8. HowevT2-weighted cardiac MRI of edema is acquired by combining acceleration techniques with motion suppression and prepulse techniques. These MRI techniques freeze the cardiac and respiratory motion effectively with giving high contrast between the blood, fat, normal myocardium, and myocardial edema. Turbo spin-echo imaging with multiple refocusing pulses has replaced spin-echo imaging in T2-weighted cardiac MRI because the scan time is reduced by a factor of 10–12 . A paralAn ECG-gating technique is usually used for cardiac MRI. This technique allows for data acquisition at the end diastole when the myocardium is static. A breath-hold technique suppresses respiratory artifacts. Alternative methods to the breath-holding technique are navigator-gating and respiratory-gating techniques . The black-blood prepulse technique, consisting of two inversion-recovery pulses combined with ECG-gating, is applied to T2-weighted cardiac MRI . By usinMyocardial edema is quantified with T2-weighted MRI with T2-prepared or multiecho acquisition . ZagroseImage interpretation of T2-weighted cardiac MRI is based on comparison with coronary artery supply, intramural distribution  and morphology  of the edema, and comparison with delayed-enhancement MRI.The location of the myocardial edema should be compared with the coronary artery supply. Myocardial edema or ischemia associated with acute myocardial infarction distribute to the coronary artery supply and often show transmural involvement . The myoAt the acute stage of ischemic or inflammatory cardiomyopathy, myocardial edema is larger than myocardial scarring seen in delayed-enhancement MRI, because the edema may surround inflammatory or dying tissues , 11. WheThe intraventricular flow close to the hypokinetic myocardium is not nullified sufficiently . ArrhythMyocardial edema distributes to the coronary artery supply in acute myocardial infarction , 11. T2-In acute myocarditis, myocardial edema is usually observed in the lateral wall  11, 19], 1911, 1 In eosinophilic myocarditis, myocardial edema appears patchy or diffuse . Churg-S18FDG-PET (Patchy myocardial edema is occasionally observed in cardiac sarcoidosis . The myo8FDG-PET . Scarred8FDG-PET . Patchy mesocardial edema is often observed in hypertrophic cardiomyopathy . The myo Takotsubo cardiomyopathy is a reversible cardiomyopathy that occurs following a stressful event. This disease affects postmenopausal women, and the clinical and ECG findings are similar to those of myocardial infarction. However, takotsubo cardiomyopathy does not show myocardial scarring on delayed-enhancement MRI . T2-weigT2-weighted MRI is useful for the detection of myocardial edema after ablation therapy for ventricular arrhythmia associated with some cardiomyopathies. These patients tend to receive repeated ablations for arrhythmogenic myocardial scarring. T2-weighted MRI distinguishes the recently ablated region with edema from the myocardial scarring or previously ablated region .T2-weighted cardiac MRI of edema is acquired in combination with acceleration, motion suppression, and other techniques. T2-weighted cardiac MRI visualizes myocardial edema that corresponds to ischemia, active inflammation, vasculitis, or recently performed intervention in the myocardium and provides information complementary to delayed-enhancement MRI.


Although total left ventricular (LV) stroke volume (SV) is equal in healthy subjects and heart failure patients with mild LV remodeling, the SV’s transventricular flow paths to ejection and diastolic energetics are different. These flow-specific markers of inefficiency of the failing heart are detectable prior to clinical decompensation, and might be predictors of progressive adverse cardiac remodeling.Heart failure is a common disorder with a dismal prognosis. Cardiac remodeling is a key component of heart failure that progresses from adaptive to maladaptive as the disease worsens, and is associated with increased risks of symptoms and mortality. In earlier stages of heart failure with adaptive remodeling, patients may remain clinically compensated and the failing heart’s left ventricular (LV) stroke volume (SV) remains the same as in the normal heart. Recently, time-varying and complex three-dimensional flow patterns and energetics within the normal LV have been demonstrated. Based on such 4D flow-specific measures, we hypothesized that while the SV of normal and failing LVs may be equal, the SV’s diastolic kinetic energy (KE) and transventricular routes to ejection are different in the two states.In ten patients with dilated cardiomyopathy (DCM)  and ten healthy subjects , 4D phase-contrast CMR velocity data and morphological data were acquired at 1.5T (Philips Achieva). A previously validated method was used for the analysis: The LV endocardium was segmented from the morphological images at end-diastole (ED) and end-systole. Pathlines were emitted from the ED blood volume and traced forward and backward in time until end-systole, allowing separation of the Total SV into two flow components . While the Total SV was equal in the two groups , the Direct SV represented a significantly smaller part of the Total SV in DCM compared to healthy  (figure Although total LV stroke volume is equal in healthy subjects and in clinically compensated heart failure patients with mild LV remodeling, the diastolic routes through the LV and pre-systolic energetics of the SV are significantly different in the two states. Inefficient flow may augment the chronic stress on the failing heart’s reserve, promoting progressive maladaptive cardiac remodeling.The Swedish Research Council


Myocardial oedema, myocardial salvage and myocardial salvage index, have been described as markers of prognosis and surrogate markers for clinical trials. The time-course of oedema following revascularised MI has been described in the first 6 months following PPCI but there is wide disagreement on the time to complete resolution. We therefore aimed to determine the time-course of post infarct myocardial oedema using serial T2-weighted CMR imaging for the first year following MI.16 patients with acute ST-elevation MI who underwent primary PCI with stent implantation within 12 hours of symptom onset were recruited. Patients were scanned on days 1, 3, 10, 20, 96 and 384 days following their PPCI with a 1.5T Philips Achieva . Images were obtained as continuous short-axis stacks covering the left ventricle with a slice thickness of 8mm and gap of 2mm. Myocardial oedema was assessed at all time points using T2-weighted triple inversion turbo spin echo STIR imaging . Image analysis was performed using dedicated software, CMR42 . Scar and oedema volumes were calculated by manually drawing endocardial and epicardial contours followed by semi-automated selection of normal remote myocardium per slice. The oedema was described as >2SD in signal intensity from remote normal myocardium. Values are expressed as a percentage of the LV mass (%LVM).Patient age was 55.6 ± 8.7 years . Myocardial oedema was identified in all patients on days 1, 3, 10 and 20 post MI and on day 96 it was present in all but two of the 16 patients. On day 384 the oedema had resolved in 15 of the 16 patients, with one patient still demonstrating myocardial oedema in the same coronary territory (this patient had recently had a further NSTEMI prior to this last scan). A repeated measures 1-way Anova showed a significant difference between the means (p=<0.0001). A Bonferroni's Multiple Comparison Test was performed, showing no significant difference between days [1 and 3], [1 and 10] and [10 and 20]. All other comparisons were significant (p=<0.001). A post-test for linear trend showed a downward slope of -3.24 (p=<0.0001).Myocardial oedema post successfully revascularised ST-elevation MI peaks at day 3, persists at 96 days and shows complete resolution at 1 year. There is no significant change between days 10-20 which may provide the most appropriate time period to assess myocardial oedema.This study was funded by an unrestricted grant from Barts and The London Charity.


Diastolic heart failure is a common clinical entity that is indistinguishable from systolic heart failure without direct evaluation of left ventricular function. Diastolic heart failure is a clinical diagnosis in patients with signs and symptoms of heart failure but with preserved left ventricular function and normal ejection fraction, and is often seen in patients with a long-standing history of hypertension or infiltrative cardiac diseases. In contrast, diastolic dysfunction represents a mechanical malfunction of the relaxation of the left ventricular chamber that is primarily diagnosed by two-dimensional transthoracic echocardiography and usually does not present clinically as heart failure. The abnormal relaxation is usually separated in different degrees, based on the severity of reduction in passive compliance and active myocardial relaxation. The question whether diastolic dysfunction ultimately will lead to diastolic heart failure is critically reviewed, based on data from the literature. Treatment recommendations for diastolic heart failure are primarily targeted at risk reduction and symptom relief. Currently, few data only are reported on diastolic dysfunction and its progression to systolic heart failure. Even though often interchangeably used in the clinical setting, there is a distinction between diastolic dysfunction and diastolic heart failure. A PubMed literature search revealed a total of 1 478 articles using the search terms diastolic heart failure and review. In contrast, only a few randomised controlled trials are available on diastolic heart failure alone. Controversy remains regarding the optimal therapy in patients with either diastolic dysfunction or diastolic heart failure.In daily routine, heart failure is often separated into systolic and diastolic failure based on preservation of left ventricular ejection fraction.2Heart failure in general and diastolic heart failure in particular causes a significant financial burden and increasing consumption of healthcare resources, especially among the elderly population (i.e. for patients 65 years of age or older).Diastolic dysfunction is a mechanical abnormality brought upon by a breakdown in the passive (compliance) and active  intrinsic properties of the ventricle during diastole. Myocardial hypertrophy (e.g. left ventricular hypertrophy secondary to hypertension) and myocardial ischaemia have been shown to impair the energy-dependant process of myocardial relaxation. The increased afterload in patient with aortic stenosis or hypertension can also inhibit myocardial relaxation by reducing the ability of the left ventricle to contract to small end-systolic volume, and hence limit the ensuing elastic recoil’s ability to enhance myocardial relaxation. Also, diastolic dysfunction can be secondary to pathological states that adversely affect the passive compliance during diastole, such as increases in myocardial wall thickness observed in concentric hypertrophy as a result of longstanding hypertension, or in myocardial fibrosis in patients with infiltrative pathology.5Diastolic function can be evaluated non-invasively using two-dimensional transthoracic echocardiography. The evaluation of left ventricular diastolic function should be an essential part of any echocardiography examination.A complete left ventricular diastolic assessment should include assessment of the IVRT, peak E velocity, peak A velocity, E/A ratio, deceleration time (DT), and A duration, which are obtained from the transmitral inflow velocities 7Based on the echocardiographic parameters, diastolic dysfunction has been divided into three different grades of severity of ventricular compliance, relaxation rate and filling pressures.Mitral annular velocity by tissue Doppler imaging also has been used to assess diastolic function. This is referred to as E. The Em /E¢ (annular) ratio has been found to correlate well with increased pulmonary capillary wedge pressure (PCWP). The E/E¢ ratio is normally less than 8. The E¢ is shown to be low, in restrictive stage less than 8. A ratio of greater than 15 indicates elevated PCWP 9Although rarely performed for evaluation of diastolic dysfunction alone, the most accurate invasive diagnostic technique is cardiac catheterisation with direct measurements of left ventricular end-diastolic pressure.In its simplest form, left ventricular diastolic dysfunction is defined as impairment in the capacity of the left ventricle to accept blood without a compensatory increase in left atrial pressure.12The underlying connection in the possible aetiologies of left ventricular diastolic dysfunction is their ability to hinder one or both of the intrinsic diastolic properties of compliance or relaxation. Pathological states such as fibrosis and concentric hypertrophy can reduce compliance of the myocardium by increasing passive ventricular stiffness, thereby affecting the passive property of compliance in diastole. Ischaemia and disease processes leading to increased afterload affect diastole by impairment of the active rate of relaxation.The prevalence as well as overall significance of diastolic heart failure has become distinctly apparent. Diastolic heart failure was originally reported in 1937 when Fishberg referred to it as ‘hypodiastolic failure’, a form of cardiac insufficiency secondary to inadequate filling of the left ventricle during diastole.Recognising the difficulty of non-invasive assessment of the LV diastolic function, in 2000, Vasan and Levy proposed a classification scheme for diagnosis of diastolic heart failure in the hope of reducing the difficulty of diagnosis of this rather prevalent pathology.More recently, Zile and colleagues have published several prospective studies, concluding that the diagnosis of diastolic heart failure does not require objective recording of left ventricular diastolic dysfunction but only documentation of preserved systolic function. In two separate studies utilising both Doppler echocardiography and cardiac catheterisation, the authors observed a statistically significant percentage of patients with clinical diagnosis of heart failure and normal ejection fraction (EF > 45%) to be suffering from abnormalities in active relaxation or passive compliance.19The degree of involvement that left ventricular diastolic dysfunction plays in preserved ejection fraction heart failure is debatable and has been the major argument made by those that believe diastolic heart failure is the correct diagnosis for patients with heart failure and normal ejection fraction, given that these patients do not suffer from significant valvular, pericardial or pulmonary disease. Left ventricular diastolic dysfunction has also been found to be present in patients with heart failure and reduced ejection fraction, a form of heart failure that was originally believed to be mainly secondary to a systolic dysfunction pathophysiology.20In 1972 Gaasch and colleagues performed some of the first studies to evaluate the possible effects of left ventricular diastolic dysfunction. The authors described that left ventricular diastolic dysfunction has a negative impact on systolic function through its limitation of the Frank-Starling mechanism.Exercise tolerance in patients with left ventricular diastolic dysfunction who are asymptomatic at rest may be compromised secondary to the inability to enhance diastolic filling by the degree necessary to increase the cardiac output during exercise without causing an abnormal elevation in left atrial pressure. Diastolic dysfunction has been found to be aggravated by exercise, especially with an increase in blood pressure. Recent studies have observed the development of left ventricular diastolic dysfunction in the presence of hypertension prior to the development of ventricular hypertrophy.et al. performed a cross-sectional survey of 2 042 randomly selected residents over the age of 45 years in Olmsted County, Minnesota.The magnitude of asymptomatic left ventricular diastolic dysfunction in the general population is still unclear. In an attempt to determine the prevalence of pre-clinical diastolic dysfunction, Redfield A prospective trial in 206 patients with the clinical diagnosis of heart failure (New York Heart Association Grade II or higher) reported that, based on echocardiographic parameters, 91% of 102 patients with an EF greater than 50% had some degree of diastolic dysfunction, and 92% of 71 patients with an EF of less than 40% suffered from left ventricular diastolic dysfunction.In patients with heart failure with preserved EF, left ventricular diastolic dysfunction was accompanied by left ventricular hypertrophy, while in patients with heart failure and reduced EF, left ventricular diastolic dysfunction was associated with left ventricular dilation and marked systolic dysfunction. The overall prognosis and mortality appears to be significantly influenced by the degree of left ventricular diastolic dysfunction in heart failure patients, regardless of ejection fraction.26et al. compared 75 patients with heart failure and normal ejection fraction with 75 patients without cardiovascular disease.The American College of Cardiology and the American Heart Association (ACC/AHA) Task Force has previously stated that a definitive diagnosis can be made in heart failure patients with preserved EF if there is a decreased rate of ventricular relaxation with elevated LV filling pressure, clarifying the need for coexistence of normal contractility (LV systolic function) and LV volume.After analysing both echocardiographic parameters and data derived from cardiac catheterisation, it appeared that left ventricular systolic function, contractility and performance was intact in patients with presumed diastolic heart failure .29p = 0.014), but there was no significant difference with regard to cardiovascular mortality. As an important finding on the side, a significant 40% reduction was seen in the development of new diabetes mellitus in the candesartan group compared with the placebo group . This has gained even more interest in view of recently published data on diabetes as an independent predictor of cardiovascular morbidity and mortality in heart failure patients, regardless of their EF,The frequently quoted CHARM-preserved trial was one of two large trials, studying a total of 3 023 patients with heart failure with preserved EF of more than 40%, treated with the angiotensin receptor blocker candesartan.The I-PRESERVE trial, published in 2008, studied 4 128 heart failure patients 60 years of age and older with an EF of at least 45% who were randomly assigned to receive 300 mg of the angiotensin receptor antagonist irbesartan or placebo. Primary event rates as assessed as a composite of death from any cause or hospitalisation for a cardiovascular cause in the irbesartan and placebo groups were 100.4 and 105.4 per 1 000 patient-years, respectively,Similar to left ventricular diastolic dysfunction, there have been multiple aetiologies associated with impairment in mechanical compliance as well as relaxation parameters that lead to right ventricular diastolic dysfunction. Over the years, right ventricular diastolic dysfunction has been observed in a variety of settings, including obesity, cystic fibrosis, chronic aortic stenosis, arterial hypertension and Chagas disease.38Normal hepatic venous flow is defined as a ratio of systolic to diastolic velocities greater than one with the atrial wave reversal less than half the maximum systolic wave velocity.Moderate or severe right ventricular diastolic dysfunction can be assumed to be present if a reduced or inverted systolic waveform, respectively, is present on the Doppler hepatic vein flow signal. Studies on pulmonary hypertension patients have led to the speculation that right ventricular diastolic dysfunction may be an independent factor contributing to right heart failure and death in patients with pulmonary hypertension.40et al. showed that in patients with pulmonary hypertension, the increase in right ventricular afterload resulted in ventricular hypertrophy and right ventricular diastolic dysfunction.Gan et al. published the first study that systematically assessed right ventricular diastolic dysfunction in 1996; comparing 114 patients with symptomatic heart failure (EF < 50%) with 31 patients with pulmonary hypertension (pulmonary systolic artery pressure > 40 mmHg) as well as 40 healthy subjects.Right ventricular diastolic dysfunction in the setting of heart failure was first reported by Riggs in 1993.In their analysis of 105 patients with systolic heart failure, Yu and Sanderson demonstrated right ventricular diastolic dysfunction to be present in 21% of patients as assessed by echocardiography.et al. reported that the distension of one ventricle during diastole can affect the compliance of the neighbouring ventricle.47The French physician Bernheim was one of the first to report the concept of ventricular interdependence in 1910, noting that right ventricular performance can be compromised through compression of the right ventricle by a dilated or hypertrophied left ventricle.The term diastolic ventricular interaction refers to the concept that compliance of one ventricle is influenced through a shared septum by the changes in volume, pressure, and/or compliance of the other ventricle.Right ventricular diastolic dysfunction has been observed in pathological conditions that result in elevated left ventricular pressure, such as systemic hypertension, aortic stenosis and hypertrophic cardiomyopathy.et al. published the possible rate of progression from asymptomatic diastolic dysfunction to clinical heart failure.In 2001, Aurigemma Despite arguments regarding exercise limitations and left ventricular diastolic dysfunction representing a possible early marker of myocardial damage, the rate of progression from diastolic dysfunction to diastolic heart failure remains uncertain. Currently there are no large clinical trials assessing the possible progression from asymptomatic right ventricular diastolic dysfunction to clinical right ventricular failure.The difficulties in the diagnosis of diastolic heart failure have been partly responsible for the limited number of larger randomised, controlled trials to guide treatment. In 1998, the European study group published one of the first widely analysed guidelines for diagnosis of diastolic heart failure, stating the need for evidence of heart failure with normal systolic function (LVEF ≥ 0.50) as well as evidence of abnormal filling, diastolic distensibility, LV relaxation or diastolic stiffness.532) and (3) evidence of left ventricular diastolic dysfunction.The European Society of Cardiology recently published their latest guidelines for diagnosis of diastolic heart failure in 2007; providing specific guidelines on how to diagnose and exclude heart failure with normal ejection fraction.The diagnostic strategy provided in this set of guidelines allows for non-invasive methods of assessing for left ventricular diastolic dysfunction through tissue Doppler parameters  and routine blood test biomarkers (brain natriuretic peptide > 200 pg/ml) to play a role in situations when invasive haemodynamic measurements (LV end-diastolic pressure > 16 mmHg or mean pulmonary capillary wedge pressure > 12 mmHg) are not available.Current treatment of diastolic heart failure has been aimed at controlling blood pressure and tachycardia, using diuretics to control pulmonary congestion and peripheral oedema, and alleviation of myocardial ischaemia. The ACC/AHA also recommend using beta-adrenergic blocking agents, angiotensin receptor blockers, angiotensin converting enzyme inhibitors, calcium antagonists in those patients with controlled blood pressure, and digitalis in order to control heart failure symptoms. In the latest update of the ACC/AHA practice guidelines for the diagnosis and management of chronic heart failure in the adult, which comprises a document of 63 pages, the treatment of diastolic heart failure is summarised in less than one page.55et al. described the combined use of beta-blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers and spironolactone as potential disease-modifying therapy.Chinnaiyan Currently, only a few large randomised clinical trials have assessed the possible benefit of pharmacotherapy at different stages of non-invasively diagnosed diastolic dysfunction, such as the CHARM Preserved trial and I-PRESERVE (see above).et al. studied 20 patients with mild diastolic dysfunction, diagnosed by Doppler echocardiography, with a marked hypertensive response to exercise.Some small trials have been carried out in an attempt to evaluate possible benefits of pharmacotherapy for patients with left ventricular diastolic dysfunction and decreased exercise tolerance. Warner et al. demonstrated that angiotensin II receptor blockers, calcium channel blockers and diuretics all have the ability to blunt an increase in SBP during exercise in patients with asymptomatic left ventricular diastolic dysfunction, but only angiotensin II receptor blocker therapy increased exercise duration and improved quality of life, as assessed by questionnaires.60Similar studies confirmed the benefits of angiotensin II receptor blockers on exercise tolerance by comparing its effects with calcium channel blockers (verapamil) or diuretics (hydrochlorothiazide). In two separate trials, Little Further research is needed to improve current knowledge of diastolic dysfunction and diastolic heart failure as well as its progression over time. The management of diastolic heart failure is currently aimed at symptomatic management and control of physiological factors known to affect ventricular relaxation, and control of risk factors and co-morbidities (such as hypertension and diabetes mellitus). A timeline for initiation of treatment for diastolic dysfunction has yet to be defined. It is anticipated but not proven whether early initiation of pharmacotherapy once diastolic dysfunction has been diagnosed even in the absence of symptoms will prevent or delay the onset of symptomatic heart failure.


Disturbances in calcium handling play a central role in the disturbed contractile function in myocardial failure. Measurements of twitch tension in isolated left-ventricular strips from explanted cardiomyopathic hearts compared with non-failing hearts show flat or biphasic FFR, while it is up-sloping in normal hearts. Starting in 2003 we introduced the FFR measurement in the stress echo lab using the end-systolic pressure (ESP)/End-systolic volume index (ESVi) ratio (the Suga index) at increasing heart rates. We studied a total of 2,031 patients reported in peer-reviewed journals: 483 during exercise, 34 with pacing, 850 with dobutamine and 664 during dipyridamole stress echo. We demonstrated the feasibility of FFR in the stress echo lab, the clinical usefulness of FFR for diagnosing latent contractile dysfunction in apparently normal hearts, and residual contractile reserve in dilated idiopathic and ischemic cardiomyopathy. In 400 patients with left ventricular dysfunction (ejection fraction 30 ± 9%) with negative stress echocardiography results, event-free survival was higher (p < 0.001) in patients with ΔESPVR  ≥ 0.4 mmHg/mL/m2. The prognostic stratification of patients was better with FFR, beyond the standard LV ejection fraction evaluation, also in the particular settings of severe mitral regurgitation or diabetics without stress-induced ischemia. In the particular setting of selection of heart transplant donors, the stress echo FFR was able to correctly select 34 marginal donor hearts efficiently transplanted in emergency recipients. Starting in 2007, we introduced an operator-independent cutaneous sensor to monitor the FFR: the force is quantified as the sensed pre-ejection myocardial vibration amplitude. We demonstrated that the sensor-derived force changes at increasing heart rates are highly related with both max dP/dt in animal models, and with the stress echo FFR in 220 humans, opening a new window for pervasive cardiac heart failure monitoring in telemedicine systems.Up-regulation of Ca The assessment of left ventricular contractility  is an old dream for the cardiologist, but until recently it has also been a methodological nightmare. The pressure-volume relationship is a conceptually immaculate way to assess contractility and is extensively used in the experimental setting for animal studies, but only rarely in the clinical arena, and then only for research purposes in complex, technically demanding studies requiring invasive cardiac catheterization and maneuvers in the cath lab, with the attending risks of invasivity, contrast injection and radiation exposure. In the last 10 years, left ventricular contractility was brought into the noninvasive stress imaging lab, and particularly in the stress echo lab, where with minimal extra-computing time and virtually no extra-imaging time, left ventricular contractility can be measured at baseline and during stress with simple raw measurements of end-systolic pressure (by tonometry or cuff sphygmomanometer) and end-systolic volume . In this way, left ventricular contractility no longer “cuts the airy way” of pathophysiology but has entered the real world of clinical cardiology. This review will discuss the pathophysiological basis, experimental evidence, and clinical data supporting a more extensive use of contractile reserve in key diagnostic domains such as identification of coronary artery stenosis, myocardial viability and initial occult cardiomyopathy.2+ ions in the myocardial cytosol. Ca2+ ions enter through the calcium channel that opens in response to the wave of depolarization that travels along the sarcolemma. These Ca2+ ions “trigger” the release of more calcium from the sarcoplasmic reticulum (SR) and thereby initiate a contraction-relaxation cycle to the LV end-systolic volume indexed for body surface area. The ESPVR is determined at rest and at peak stress. The ΔESPVR  is calculated as the variation between rest and peak stress ESPVR. The rest ESPVR, the peak stress ESPVR and the ΔESPVR are built offline[The evaluation of LV contractility is potentially amenable to non-invasive assessment in the cardiac imaging lab, since cuff systolic pressure is a proxy of end-systolic pressure (in absence of aortic stenosis) and end-systolic volumes can be evaluated by radionuclide ventriculography or – wit offline-8,11. Th offline,13 , was the best predictor of future primary cardiovascular events   was also effective in stratifying the risk in the subgroups with progressively more severe baseline dysfunction  at increasing heart rates. We studied a total of 2,031 reported patients in peer-reviewed journals: 483 with exercise stress, 34 with pacing stress, 850 with dobutamine stress echo, 664 with dipyridamole stress echo,15-27. TIn patients with normal baseline left ventricular function and negative stress echo by standard wall motion criteria, the evaluation of contractile reserve provided additional diagnostic information. Lack of contractile reserve can identify minor forms of anatomically significant coronary artery disease (CAD) that are unable to give the absolute subendocardial underperfusion necessary to induce true regional ischemia and wall motion abnormalities. In patients with negative stress and significant (≥ 50%) obstructive CAD, the contractile reserve is attenuated in proportion to the severity of stenosis. A negatGalderisi et al. assessedIn an another paper by Jellis et al., in subcLimitations of this noninvasive study include that peak cuff systolic pressure was used as a surrogate marker of end-systolic pressure. However, there is a close relationship between these two variables, and any sampling error is duplicated between rest and stress values, thereby not affecting the overall ratio. CalciumIn recent years, the FFR has been transferred from the experimental lab to the clinical arena, and in particular within the clinical arena from the cardiac catheterization to the stress echo lab, with an obvious step-up in interest and applicability. Ideally, the non-invasive, imaging-independent, objective assessment of FFR would greatly further enhance its practical appeal Figure . A new cPatients with abnormal rest LVEF and negative stress echocardiography by conventional regional wall motion criteria may still experience an adverse outcome in the long-term follow-up, which can be identified by ΔESPVR, providing a prognostic stratification in addition to that given by regional wall motion abnormalities and LVEF. Despite exercise, pharmacological and pacing are different ischemic stressors in terms of cardiac, systemic and coronary hemodynamics, the same contractile reserve cut-off value of ΔESPVR stratifies patients equally well for non-ischemic events at follow-up. In this task, the contractility information complements clinical, coronary flow reserve (CFR), and therapeutic information, allowing stratification of the different “shades of white” of a negative response, with very benign prognosis in subjects with normal resting function, preserved resting LV function, normal (> 2.0) CFR on LAD, and normal test studied off-therapy, with hard events rate < 1% per year. At the other end of the spectrum are subjects with subclinical tests, undergoing therapy with impaired resting LV function, blunted contractile reserve, reduced CFR and hard-event rate > 3% Table . ContracBSA: Body surface area; CABG: Coronary artery by-pass grafting; CAD: Coronary artery disease; CFR: Coronary flow reserve; CHF: Chronic heart failure; CRT: Cardiac resynchronization therapy; DC: Dilated ischemic cardiomyopathy; DCM: Idiopathic dilated cardiomyopathy; DIP: Dipyridamole; DOB: Dobutamine; ΔESPVR (or simpler PVR pressure-volume relation): The difference between peak stress and rest ESPVR; EF: Ejection fraction; ESP: End-systolic pressure; ESPVR: End-systolic pressure-volume-ratio; EX: Exercise; FFR: Force-frequency relation; ICD: Implantable cardioverter defibrillator; LV: Left ventricle; LVESP: Left ventricular end-systolic pressure; MR: Mitral regurgitation; PM: Pace-maker; PVR: Pressure-volume relation; TX: Heart transplant; PCI: Percutaneous coronary intervention; 2-DE: Two-dimensional echo.The authors declare that they have no competing interests.TB conceived this review, performed the data analysis, and drafted the manuscript; MZ and TL are chief and coworker of the Scientific Visualization Unit Group; QC, LC, EA, LP, were responsible for data collection and revised the manuscript; SS performed the statistical analysis; EP contributed to the preparation of review design, data discussion, and critical revision of the manuscript. All authors read and approved the final manuscript.TB, Scientific Coordinator of the CCM project n. 48 “Aged Donor Heart Rescue by Stress Echo – ADONHERS” Institute of Clinical Physiology, National Research Council, Pisa, Italy. MZ, Director, Scientific Visualization Unit, Institute of Clinical Physiology, National Research Council, Pisa, Italy. QC, Division of Cardiology, Fatebenefratelli Hospital, Benevento, Italy. EA, Division of Noninvasive Cardiology, Cardiothoracic Department, San Raffaele Hospital, IRCCS, Milano, Italy. SS, PhD, Institute of Clinical Physiology, National Research Council, Pisa, Italy. TL, Scientific Visualization Unit, Institute of Clinical Physiology, National Research Council, Pisa, Italy. LP, Institute of Clinical Physiology, National Research Council, Pisa, Italy. EP, Acting Director Institute of Clinical Physiology, National Research Council, Pisa, Italy.Dilated Cardiomyopathy: A molecular view. Dilated Cardiomyopathy is a common heart disease that causes heart myofibers to pulse in a weakened way, which becomes particularly dangerous under stress, when heartbeat is accelerated. .Click here for fileDilated Cardiomyopathy: The sarcomere At each cycle of heartbeat, the heart cell contracts (shortens) at systole and relaxes at diastole. Under stress, both the speed and the intensity of the movement are increased. In the DCM heart, both the structure and the activity are impaired: the mitochondrion is enlarged, due to the excess ATP request, and the fibers are not as compact and aligned as in the healthy fiber. The relaxation phase is never complete, resulting in the typical ECG track. Under stress the situation is worsened: the heart fibers, unable to completely de-contract, try to compensate by even stronger contraction, in a forward loop that worsens with time, and can lead to heart failure. .Click here for fileDilated Cardiomyopathy: Ca2+ induced Ca2+ release (zoom to synaptic junction). The signal to initiate contraction is a brief depolarization of the membrane, which triggers a very rapid release of calcium from the sarcolemma. This is followed by more sustained release of Ca2+ from the ryanodine receptor on the T Tubules. In this way, the signal rapidly diffuses throughout the contractile fiber. When more blood is needed in the organism, the frequency of signal is increased, and more Ca2+ is released. However, all Ca2+ is removed from the fiber before the onset of next beat. The DCM heart is impaired in the re-uptake of Ca2+, resulting in a small amount of Calcium constantly present in the fiber. When more CA2+ is released because of higher demand, the problem of re-uptake worsens. .Click here for fileDilated Cardiomyopathy: Actin-myosin contraction. Contraction is the result a sliding of actin and myosin fibers, due to the activity of the myosin cycle: this cycle is active in the presence of Calcium, which mediates transmission of signal to both the actin and myosin fibers, via other accessory proteins. The activity requires energy, in the form of ATP (not shown). When Calcium has been removed, the myosin heads detach from the actin fibers and the muscle can relax. In the DCM heart calcium re-uptake is incomplete: this leads to a constant contraction which, on one hand requires more energy (hence the enlarged mitochondria) and on the other impedes full extension of the heart fibers during relaxation, thus limiting the amount of incoming blood. The problem is even worse under stress conditions. Note that due to the excess work and the lack of total relaxation, the actin and myosin fibers of the dilated heart are not regularly aligned and the overall structure of the myofiber is slightly disorganized. .Click here for fileDilated Cardiomyopathy: Calcium re-uptake. Clearing of intracellular Calcium is carried out by the Sarcoplasmic Reticulum Calcium Pump (known as SERCA), a very efficient protein capable of concentrating Calcium at a rate of two ions for one ATP. One of the molecular defects of the dilated heart is the reduced efficiency of this pump: this is physiologically counterbalanced by a higher expression (and more intense activation) of the Na+/Ca2+ exchanger of the plasma membrane. The problem is especially felt under stress: in this condition, with faster cycles, even more Calcium is released, aggravating the burden of re-uptake on the defective SERCA, not well-complemented by the activity of the plasma membrane exchanger. Since this pump is also inefficient, the final result is that blood circulation is not sustained to the required level. .Click here for fileForce-frequency curve with stress echo in a normal subject. Upper panel: On the left, systolic blood pressure by cuff sphygmomanometer ; left ventricular end-systolic volumes calculated with biplane Simpson method ; heart rate increase during stress ; in the lowest row, the force-frequency curve built off-line with the values recorded at baseline (second column), and at different steps  up to peak stress (sixth column). An increased heart rate is accompanied by an increased systolic pressure with smaller end-systolic volumes .Click here for fileForce-frequency curve with stress echo in a subject with dilated cardiomyopathy and depressed baseline left ventricular function (EF% = 30%). On the left: systolic blood pressure by cuff sphygmomanometer ; left ventricular end-systolic volumes calculated with biplane Simpson method ; heart rate increase during stress ; in the lowest row, the force-frequency relation built off-line with the values recorded at baseline (second column), and at different steps  up to peak stress (sixth column). An increased heart rate at peak exercise is accompanied by no changes in end-systolic volumes .Click here for file


Fat suppressed T2-weighted black blood turbo spin echo (BBTSE) imaging can detect myocardial edema developed after acute myocardial infarction (MI) and characterize the extent of myocardium at risk in comparison to late gadolinium enhancement (LGE) imaging.We hypothesized that T2-extent at baseline and changes during follow-up are associated with dynamic changes of infarct heterogeneity during the convalescence phase of infarct healing. We further explored the strength of association in quantifying T2-based myocardial edema, using a semi-automated method and manual tracing.Fifty-one patients (40 men) underwent 3T cardiac MRI both at 18±10 days and 7.7±1.1 months after an acute MI, including: 3 short-axis slices of T2-weighted fat-suppressed BBTSE, LV function assessment by SSFP and LGE imaging. Area of hyperintensity on T2 images was assessed by a semi-automated method using a threshold of mean signal intensity in the remote ROI ± 2 SD and by manual tracing. In further analyses, correlations of T2 extent, expressed as the percentage of total myocardium, and other MRI results were assessed by Spearman correlation.P<0.0001). Table 1Correlations between the T2 extent, LV parameters, infarct heterogeneity and their respective changes are displayed in the table. At baseline, hyperintense T2 myocardium was demonstrated in 50 patients (98%) and represented 20.5±14.0% of total myocardium. Baseline T2 size was inversely correlated with LVEF and was directly correlated with total MI size. Hyperintense T2 areas persisted in 12 patients (24%) at follow-up. Manual-tracing was correlated well with the semi-automated method (Spearman’s rho 0.84; T2 extent early after an MI is a predictor of shrinkage of infarct size and regression of the PIZ.While the clinical significance of persistent hyperintense T2 areas after initial infarct healing remains unknown, resolution of infarct edema by T2 imaging appears to be associated with a reduction of the periinfarct zone of LGE. Edema measurement by manual drawing was consistent with the 2SD threshold method and is a reliable quantitative method.


Accurate measurement of neonatal cardiac function remains a key goal to improve understanding of circulatory pathophysiology in prematurity. Cardiac MRI has been shown to be viable in this population, but robust validation is crucial.Our aim was to assess the accuracy of cardiac functional measures derived from MRI ventricular stack segmentation against phase contrast measures in term and preterm neonates.http://segment.heiberg.se) with manual correction of segmentation where necessary. Correction for long axis motion was performed using the mean of three measures of atrio-ventricular valve descent from a 4 chamber view. Right ventricular stacks were segmented for endocardial contours on 20 infants  using the same technique. Cardiac output (CO) was measured by semi-automatic segmentation  of phase contrast(PC) images of the left ventricular outflow tract. The two techniques were compared using a Bland Altman plot. Infants with known patent ductus arteriosus were excluded.Cardiac MRI scans were performed on a 3T Philips Achieva scanner  in 40 infants . Left ventricular stacks were segmented for epicardial and endocardial contours at end systole and end diastole using Segment software  of 16.6%. Bland Altman analysis of right ventricular output by stack and left ventricular output by PC showed a mean bias of 39.7 ml/min, with limits of agreement of -36.9 to 116.5 ml/min corresponding to a repeatability index (RI) of 17.3%. For comparison Bland Altman of neonatal heart rate during by stack and PC imaging showed a mean bias of -2.12 beats/min, with limits of agreement of -19.21 to 14.96 beats/min, corresponding to a repeatability index (RI) of 11.92%.Given the wide variability of heart rates and potential for motion in preterm neonatal scanning, our findings suggest stack segmentation at our improved resolution can give relatively accurate measures of preterm cardiac function.Dr Finnemore is a British Heart Foundation Clinical Training Fellow