Late H/M ratios were calculated and evaluated using a linear mixed model with the mean late H/M ratio at 4 h p.i. as a reference. A difference in late H/M ratios of more than 0.10 between the different acquisition times in comparison with the late H/M ratio at 4 h p.i. was considered as clinically relevant.Forty-nine patients with HF  referred for cardiac Statistically significant mean differences were observed between the late H/M ratios at 1, 2 and 3 h p.i. compared with the late H/M ratio at 4 h p.i. . However, the mean differences did not exceed the cut-off value of 0.10. On an individual patient level, compared to the late H/M ratio at 4 h p.i., the late H/M ratios at 1, 2 and 3 h p.i. differed more than 0.10 in 24 (50 %), 9 (19 %) and 2 (4 %) patients, respectively.123I-MIBG between 2 and 4 h p.i. does not lead to a clinically significant change in the late H/M ratio. An earlier acquisition time seems to be justified and may warrant a more time-efficient cardiac 123I-MIBG imaging protocol.Variation in acquisition time of  Figure p < 0.001) as well as in the non-ischaemic HF group . In the non-ischaemic HF group only the mean late H/M ratio at 1 h p.i. exceeded the predefined clinically relevant 0.10 difference with the late H/M ratio 4 h p.i.The H/M ratios of the early scan and the late scan performed at 1, 3 and 4 h p.i. were significantly higher in the non-ischaemic HF group in comparison with the ischaemic HF group (p <0.001). There was no statistically significant difference between the washout rates in the ischaemic HF and the non-ischaemic HF subgroups.The mean washout rate between the early scan and the late scans at 1, 2, 3 and 4 h p.i. increased from 11 ± 12 % to 21 ± 16 %, 29 ± 17 % and 34 ± 17 %. The mean washout rates between the early scan and the late scans at 1, 2 and 3 h p.i. differed all statistically significantly from the washout rate between the early and 4-h p.i. scan  as well as on uptake-2  activity. The clearance half-time of neuronal 123I-MIBG uptake (via uptake-1) was 112 min, in contrast to the much lower clearance half-time of extraneuronal 123I-MIBG uptake (uptake-2) of 22 min. Finally, Sisson et al. demonstrated that 123I-MIBG patterns in the heart were consistent with the concept that 123I-MIBG resides mostly in adrenergic neurons, mainly via the uptake-1 mechanism [123I-MIBG in the myocardial vesicles at the nerve terminals, while accumulation in extraneuronal compartments is relatively low.The late H/M ratio is the most frequently used parameter to semi-quantitatively analyse the cardiac 23I-MIBG . This re23I-MIBG –17. Firs23I-MIBG . This sto et al. . This grechanism , 17. Thi123I-MIBG of approximately 1.3 versus 1.44 [123I-MIBG using a cadmium zinc telluride camera. The mean H/M values ± SD, at 125 min, extrapolated to 176 and 240 min, were 4.33 ± 1.23 %, 3.95 ± 1.46 % and 3.63 ± 1.64 %, respectively. In addition, Okuda et al. demonstrated in 96 patients that the mean count density in the cardiac ROI and the mediastinum ROI at 3 h were highly correlated with the mean count density in the cardiac ROI and the mediastinum ROI at 4 h  as well as the fact that there was only a small mean difference of 0.02 between the late H/M ratios at 3 and 4 h p.i.  [123I-MIBG from the neuronal compartments can probably explain the small differences between late H/M ratios in the latter and the present study [In the present study only small differences (≤0.10) were observed between the late H/M ratios at 1, 2 and 3 h p.i. compared with the commonly used late H/M ratio at 4 h p.i. Subgroup analysis between patients with ischaemic and non-ischaemic HF showed similar results. At the patient level, a high percentage of patients (50 %) exceeded a difference of 0.10 between the late H/M ratio at 1 h p.i. compared to the late H/M ratio at 4 h p.i. In contrast, between the late H/M ratio at 2 h p.i. and the late H/M ratio at 4 h p.i. the percentage of patients who exceeded a difference of 0.10 was much lower 19 %). In comparison with the late H/M ratios at 3 and 4 h p.i. only 4 % of the patients had a difference of more than 0.10. These results are in line with a previous investigation by Kline et al., who demonstrated a small difference in late heart to lung ratio in four healthy subjects between 1 and 2 h after administration of 74 MBq  %. In cont study , 18.123I-MIBG and the acquisition time of the late scan for the determination of the late H/M ratio, especially in patients with HF.The present results show that, at a group as well as at an individual patient level, the change in the late H/M ratios between 2 and 4 h p.i. is limited and probably not clinically relevant. Since the late H/M ratio has been proven to provide important information in predicting prognosis in HF patients [123I-MIBG and the “late” scan the washout rate will change. Previous studies have shown that the instant myocardial uptake of 123I-MIBG uptake normalized for blood pool activity is close to zero after 3 h [r = 0.606, p < 0.0001) [p < 0.001) [n = 8) at 4 h p.i. and 123I-MIBG retention appeared to be lower and showed greater disparity in the washout rate. In the present study, myocardial 123I-MIBG washout increased over time from 11 ± 12 % at 1 h p.i. to 34 ± 17 % at 4 h p.i. The mean washout rates between the early scan and the late scans at 1, 2 and 3 h p.i. differed all statistically significantly from the washout rate between the early and 4-h p.i. scan .With a shorter interval between the injection of fter 3 h . Evaluat 0.0001) . Moreove< 0.001) . Additio123I decay and mediastinal background, the myocardial washout rate can still be influenced by 123I-MIBG washout in surrounding lung and liver tissues [It should be addressed that although myocardial washout rates were corrected for  tissues . Moreove123I-MIBG between 2 and 4 h p.i. does not lead to a clinically significant change in the late H/M ratio. With the knowledge that the late H/M ratio is the best validated and most used prognostic parameter for cardiac sympathetic innervation in patients with HF, an earlier acquisition time seems to be justified and may warrant a more time-efficient cardiac 123I-MIBG imaging protocol.Variation in acquisition time of


Diabetic cardiomyopathy is a well-recognised entity, with multifactorial aetiology. We and others have previously shown impaired myocardial energetics (decreased PCr/ATP using cardiac 31P Magnetic Resonance Spectroscopy-MRS) in patients with type II diabetes mellitus (T2DM) at rest. Furthermore, diabetic patients are known to have impaired myocardial perfusion reserve even in the absence of epicardial coronary artery disease likely due to microvascular dysfunction. However, it is unknown whether this hypoperfusion is translated to further energetic derangement at stress.27 patients  with T2DM and 24 healthy volunteers of similar age and BMI  were studied. Patients were on oral antidiabetic therapies only, with mean HBA1c 7.4±1.3% and no history of diabetic complications. Obstructive coronary artery disease (defined as> 50% lumen diameter reduction) was excluded in all patients by CT coronary angiography. Cardiac 31P-MRS (3T) was performed at rest and during 8 minutes of leg exercise lying prone, with 2.5 kg weights attached to both legs. First-pass perfusion images  were also acquired at stress  and rest at mid ventricular short axis. myocardial perfusion reserve index (MPRI) were measured from perfusion images.2, p=0.168). Increases in rate pressure product with exercise  and adenosine stress  were similar. There was no change in PCr/ATP during exercise in healthy volunteers . Resting PCr/ATP was reduced in patients  compared to controls, and during exercise, there was a further reduction in PCr/ATP . As expected, myocardial perfusion reserve was significantly reduced in diabetic patients . Furthermore, there was a significant correlation between MPRI and exercise energetics , but not rest energetics.Left ventricular ejection fraction (LVEF) and mass index (LVMI) were similar in patients with T2DM and healthy volunteers (LVEF 70±1 vs 71±0.9%, p=0.494; LVMI 56.7±1.8 vs 52.6±2.4g/mDuring exercise, the pre-existing energetic deficit in diabetic cardiomyopathy is further exacerbated. While myocardial energetics at rest is not related to coronary microvascular dysfunction and is primarily a result of metabolic dysfunction, during exercise, microvascular dysfunction exacerbates the energetic deficit.The National Institute for Health Research Oxford Biomedical Research Council and Sir Henry Dale Fellowship from the Welcome Trust and the Royal Society [Grant Number 098436/Z/12/Z] supported this work.


Sequences with ultra-short echo time (UTE) are popular for their ability to measure tissue components with short T2*. For cardiac applications, UTE MRI was recently employed to detect fibrosis after myocardial infarction  and diffMice were measured at 9.4T. A self-gated UTE sequence was implemented as shown in Figure Figure 6X undersampled UTE Cine acquisition of the mouse heart was achieved with high image quality and without significantly compromising the determination of cardiac functional parameters. Whole heart coverage can be obtained in less than 8 min.This research is funded by the Imaging Science & Technology group Eindhoven.


Cardiac Pacing and Cardiac Resynchronization Therapy , CRT has currently a Class I indication in patients with 1) chronic heart failure , 2) a left bundle branch block (LBBB) on the ECG with a QRS width >120 ms (preferably >150 ms), and 3) a left ventricular ejection fraction < 35 % [Cardiac resynchronisation therapy (CRT) emerged more than a decade ago as a useful form of device therapy for heart failure associated with abnormal ventricular conduction indicated by a wide QRS complex , 2. AccoCRT consists of biventricular pacing with or without an internal cardioverter defibrillator (ICD): in combination with an ICD, CRT is called CRT-D (efibrillator); without an ICD, the treatment is called CRT-P (acing). According to Daubert et al. , the preOwing to the potential incremental survival benefit of CRT-D over CRT-P, the prevailing opinion among the members of this Task Force is in favour of a superiority of CRT-D in terms of total mortality and sudden death. However, no strict recommendations can be made, and the Task Force prefers to merely offer guidance regarding the selection of patients for CRT-D or CRT-P, based on overall clinical condition, device-related complications and cost.In the choice between CRT-D and CRT-P, the 2013 ESC guidelines - endorsed by our national society, the NVVC- clearly state: Speaking of device-related complications and costs, these are crucial issues to be considered as there are still 20–30 % non-responders to CRT despite following the appropriate guideline indication –7. ThereRecently, Vernooij et al.  from MaaIn summary, sharper indications for CRT, and the permanent consideration of choosing CRT-P or CRT-D, would be cost-saving and might provide health benefits. This is in line with the recent findings by Looi et al.  who showLastly, there remains an urgent need for randomised clinical trials in CRT subgroups such as in patients with right bundle branch block, NYHA Class I, atrial fibrillation, and in patients with specific conditions . When these studies have been completed, then we might speak of true CRT optimisation to better serve patients with chronic heart failure.


Percutaneous pulmonary balloon valvuloplasty (PBV) remains the treatment of choice for pulmonary stenosis (PS). This procedure is effective, safe and gives excellent results. Pulmonary artery (PA) dissection is a rare complication of PBV. This report is a case of an asymptomatic 17-year-old male with a history of PBV due to severe PS dating back to fifteen years ago. During recent echocardiography, an intimal flap was detected in the main PA and entry site was clearly seen by contrast study. Balloon diameter should be at least 10% to 20% longer than the pulmonic valve annulus.3 In contrast to the aortic value, pulmonic valve is elastic and often requires oversize to achieve adequate results.3 Maximum measure of balloon inflation should be a factor of 1.2 to 1.4 of the approximate size of the pulmonary annulus.3 The goal of the procedure is a final peak to peak valvular gradients less than 30 mmHg by cardiac catheterization.4 Echocardiography shows the results and recognizes rare complications of PBV such as PA dissection; but the use of nonstandard views may be necessary since diagnosis of PA dissection is difficult and it is classically recognized during postmortem examination.5Almost all pulmonary valve stenisis (PS) have congenital source and its acquired form is extremely rare.6PA dissection is an extremely rare and fatal disease. PA dissection has most commonly been described in patients with structural heart disease such as congenital disorders or rheumatismal involvement; and in those with pulmonary thrombosis and chronic obstructive pulmonary disease. Catheter-induced PA dissection has been reported as extreme rare cause.This report is a case of a 17-year-old male with a history of PBV dating back to fifteen years ago. The patient had severe PS with a peak pressure gradient of 126 mmHg. PBV was carried out on the patient with multipurpose A2 balloon number 15. After the procedure, peak pressure gradient decreased to 37 mmHg. Annular size of pulmonic valve was 12 mm and standard echocardiographic evaluation showed mild residual valvular PS with mild pulmonary valve regurgitation.The patient was asymptomatic and serial follow up echocardiography showed no other complications. At the recent presentation, fifteen years after valvuloplasty, the patient was still asymptomatic and had a systolic murmur on the upper left sternal border. The transthoracic echocardiography showed mild RV enlargement with normal function, mild to moderate residual PS , moderate PI, mild TR and RVSP~50 mmHg. An intimal detachment was seen in lateral side of PA trunk from ST junction to PA bifurcation (PA annular=2.4 cm); although this complication was revealed in off axis views and then in RVOT view. The entry site was seen clearly by contrast study -3.The study plan for managing such asymptomatic patient with only “mild RV dilatation, normal RV function and moderate pulmonary regurgitation” was conservative with periodic echocardiographic follow-up. PA dissection could be clearly distinguished by TTE without any ambiguity on the diagnosis. Considering the proposed treatment plan in conjunction with patient’s financial restrictions, TEE or other extra modalities (multi-detector computed tomography or magnetic resonance imaging) were not carried out.7 In majority of patients, the use of oversized balloons at least 10% to 20% larger than the pulmonic valve annulus is recommended.3Since the first introduction of pulmonary balloon valvuloplasty (PBV) by Kanetal in 1982, PBV has become the treatment of choice for pulmonary valvular stenosis in newborns and children.8 Such complications includes death (0.2%), cardiac perforation (0.1%) and tricuspid insufficiency (0.2%).8 Except for transient arrhythmias, no serious complications were encountered among the reported series with any early or late death.8 Furthermore, PA dissection is a rare complication of balloon valvuloplasty. It is often associated with structural heart disease  as well as chest trauma.9 In 2005, Khattar et al. examined 63 patients with pulmonary artery dissection who were reported over the past two centuries. It was found that only 8 (13%) cases were diagnosed while alive and only 7 (11%) were diagnosed as having idiopathic or unspecified dissection.6 Echocardiography could be an excellent modality for evaluating the results and recognizing the complication of balloon valvuloplasty.Major complications of PBV are rare as previously reported in infants and children.However using nonstandard views may be necessary, especially in patients with poor-views.In the patient of this report, the intimal detachment was seen in off axis views and outflow view, but in parasternal short axis view it was seen with difficulty. This is the most probable reason for not describing the complication in the previous echocardiography reports. Clearly, experience of echocardiographer as well as equipment quality is critical for a better visual station of the pulmonary artery.10 It is worth mentioning that these presentations have been frequently reported on the base of pulmonary artery hypertension or aneurysm. Catheter-induced PA dissection is extremely rare and consequently optimal management of it remains ambiguous. With respect to asymptomatic of the current patient without PA dilation or pulmonary artery hypertension, conservative medical therapy with close follow up was the preferred option. Interestingly, the patient was consistently asymptomatic two years after recognition of the problem without noticeable change of the main PA diameter.The optimal management of pulmonary artery dissection is surgery, since PA dissection is frequently presented as cardiogenic shock or sudden death.11Qingbao Li et al. reported a child with severe PS whom pulmonary balloon valvoplasty (PBV) was performed. Follow up transthoracic echocardiography after one month of the procedure revealed dilated PA with obvious flap inside the main PA. The patient was nominated for surgery despite the fact that the patient was asymptomatic as they found more dilation of the main PA than prior to the valvoplasty.It is believed that the natural course of PA dissection is not known due to the paucity of cases in the literature.Conservative treatment with follow up echocardiography for stable pulmonary balloon valvoplasty is recommended. Surgery would be proposed for patients who show further dilation of the PA or occurrence of related symptoms.


To evaluate transthoracic minimally invasive device closure of atrial septal defects by performing transthoracic echocardiography to measure changes in cardiac hemodynamics and loading conditions.Between January 2012 and December 2012, we performed transthoracic minimally invasive device closure of atrial septal defects in 95 patients with secundum atrial septal defects (ASD), and performed transthoracic echocardiography to measure blood flow velocities at the tricuspid valve orifice and at the pulmonary valve orifice, sizes of the left and right atria and ventricles, right ventricular fractional area change, right ventricular Tei index, three-dimensional right ventricular ejection fraction, tricuspid annular plane systolic excursion and left ventricular ejection fractions before the procedure and 1 week, 3 months, and 1 year post-procedure.P<0.05). In 3 months and 1 year’s follow-up, the inner diameter of the middle portion of the pulmonary artery, and diameters of the right atrium and right ventricle decreased significantly post-procedure (P<0.05). The diameters of the left atrium and left ventricle increased after the procedure (P<0.05). One week after the procedure, the right ventricular fractional area change, three-dimensional right ventricular ejection fraction, right ventricular Tei index and tricuspid annular plane systolic excursion had significantly reduced compared with the preoperative data (P<0.05). While these four parameters were still decreased at the 3 months and at 1 year’s follow-up, but the differences were not statistically significant compared with the 1 week’s postoperative data (P>0.05). One week post-procedure, left ventricular ejection fraction had not changed significantly, but at 3 months and at 1 year post-procedure, left ejection fraction had increased significantly compared with the preoperative data (P<0.05).Varying degrees of improvement were observed post-procedure at later time points. The maximum blood flow velocity at the pulmonary valve orifice, mean flow velocity, velocity-time integral, and A peak and E peak blood flow velocity at the tricuspid valve orifice decreased significantly post-procedure (Echocardiographic evaluation has demonstrated that cardiac hemodynamics and loading conditions improved significantly after transthoracic minimally invasive device closure of atrial septal defects. Atrial septal defect (ASD) is a common congenital heart disease, the treatment of which includes intracardiac repair under direct vision with extracorporeal circulation, or percutaneous closure.  In recenThe present study was approved by the ethics committee of our university, and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from the patients or parents of the patients.Ninety-five patients who underwent transthoracic minimally invasive device closure of atrial septal defect in our hospital between January 2012 and December 2012 were selected for the current study. There were 42 males and 53 females, with a mean age of 18.2±16.6 years , and a mean body weight of 28.5±15.1 kg . These patients chose intraoperative device closure for treatment of their atrial septal defects. The indications for our procedure were the same as those used for surgical or percutaneous closure, which included a hemodynamically significant left-to-right shunt, significant chamber enlargement, mild-to-moderate or severe pulmonary hypertension despite medical therapy, a history of infective endocarditis, or any combination of the above indications. Those with other coexisting cardiac anomalies were excluded from our study.  An–7 An5–7](1) The short axial view of the great vessels was used to measure the maximum systolic blood flow velocity at the pulmonary artery orifice, the mean blood flow velocity, the velocity-time integral, and the inner diameter of the middle portion of the pulmonary artery. (2) Apical four-chamber view was used to measure the diastolic E peak and A peak blood flow velocities at the tricuspid valve orifice. The end-diastolic length and width of the right ventricle, the end-systolic and end-diastolic lengths of the left ventricle, and the end-systolic lengths and widths of the right atrium and the left atrium were also measured. (3) The short axial view of the left ventricle was used to measure the end-systolic and end-diastolic anteroposterior diameters and widths of the left ventricle at the level of the chordae tendineae. (4) The parasternal long axis view of the left ventricle was used to measure the end-diastolic anteroposterior diameter of the middle portion of the right ventricle. (5) The left ventricular ejection fractions were calculated.RVFAC was defined using the formula (end-diastolic area—end-systolic area)/end-diastolic area×100%. Using thAll RT-3DE images were processed offline using a dedicated analysis software package . After manual selection of the central reference points of the tricuspid and mitral valve annuli and of the LV apex, the software visualized the RV cavity by the coronal, sagittal, and frontal cut planes automatically obtained from the 3D data set both at end-systole and at end-diastole. After manual tracing of the endocardial borders, on each of the 3 cut planes at both end-diastole and end-systole, the software automatically detects the RV surfaces throughout the cardiac cycle. Manual correction to adjust the endocardial contours in each frame prior to quantification was performed when needed. RV volumes were computed throughout the cardiac cycle, from which RV end-diastolic volume (RVEDV) and RV end-systolic volume (RVESV) were obtained as maximums and minimums, respectively. RV ejection fraction (RVEF) were then measured as the difference and as the percentage change of the volumes, respectively. The RV Tei index is defined as (A—B)/B, where A is time interval between the end and onset of tricuspid annular diastolic velocity and B is the duration of tricuspid annular systolic velocity (or RV ejection time). And The RV Tei index were determined from the average of 3 measurements. ,11TAPSE was recorded from the apical four-chamber view. The M-mode cursor was placed at the junction of the RV free wall and the tricuspid valve in such a way that the tricuspid annulus moved along the M-mode line and the maximal longitudinal shortening and relaxation of the RV free wall was recorded. The amplitude of the excursion of tricuspid annulus from the base toward the apex in systole was defined as TAPSE. The indicators outlined above were measured with transthoracic echocardiography before the procedure, and 1 week, 3 months, and 1 year after the procedure for all patients.P value of <0.05 was defined as statistically significant.Continuous data were presented as mean± standard deviation and range. Differences time periods of datas were compared with the analysis of variance with repeated measurement data, comparing the two using Tukey HSD test. A All patients underwent successful closure of an ASD. The mean diameter of the defect was 18.9±11.8 mm  and the size of the occluder was 21.3±13.6 mm . No significant residual shunt or device dislodgement occurred, nor did any other major complication occur during the follow-up period. The Qp/Qs ratio was significantly improved in most patients.max, Vmean, and VTI at the pulmonary valve orifice decreased significantly after the procedure (P<0.05). In addition, E peak and A peak blood flow velocity at the tricuspid valve orifice were reduced significantly after the procedure (P<0.05).P>0.05). At 3 months and at 1 year after ASD closure, the end-systolic length and width of the right atrium, end-diastolic anteroposterior diameter, length and width of the right ventricle, and the inner diameter of the middle portion of the pulmonary artery were significantly reduced compared with the preoperative data (P<0.05).One week after the procedure, the right ventricular fractional area change, three-dimensional right ventricular ejection fraction, right ventricular Tei index and tricuspid annular plane systolic excursio had significantly reduced compared with the preoperative data (P<0.05). While these four parameters were still decreased at the 3 months and at 1 year’s follow-up, but the differences were not statistically significant compared with the 1 week’s postoperative data (P>0.05).P>0.05); the end-systolic width of the left ventricle were increased significantly compared with the preoperative data (P<0.05). At 3 months and at 1 year after the procedure, the end-systolic length and width of the left atrium and the end-systolic and end-diastolic anteroposterior diameters, and the width and length of the left ventricle had increased significantly (P<0.05). In 3 months and 1 year’s follow-up, the left ventricular ejection fraction had increased significantly compared with the preoperative data (P<0.05).Patients with ASD are usually asymptomatic and thus, most patients with this condition could wait to undergo elective intracardiac repair under direct vision with extracorporeal circulation, or undergo percutaneous closure. In recent years, many surgeons have tried to repair ASDs using transthoracic minimally invasive device closure, and have achieved satisfactory clinical outcomes. –4,13,14 In our previous reports, we demonstrated that transthoracic echocardiography can play an important role in the surgical procedure. Some investigators have reported that transesophageal echocardiography and real-time three-dimensional ultrasound are more accurate than transthoracic echocardiography;  however,Because a right-to-left shunt occurs in patients with ASD, volume loading of the right heart is increased, which leads to increased blood flow velocity at the tricuspid valve orifice and the pulmonary valve orifice, and an enlarged right atrium and right ventricle, finally resulting in high-volume loading and a hyperkinetic circulatory state. Ağaç et al. reported that closure of ASD using Amplatzer devices led to a decrease in the right heart chamber size, tissue Doppler-derived tricuspid annular velocities, and tricuspid annular plane systolic excursion in the early period.  Other reIn the current study, we observed that after ASD closure, the real-time right-to-left shunt disappeared, the diastolic blood flow velocity at the tricuspid valve orifice and the systolic blood flow velocity at the pulmonary valve orifice decreased, and hemodynamic abnormalities were corrected. One week after the procedure, the systolic blood flow velocity of the pulmonary artery and the diastolic blood flow velocity in the tricuspid valve were significantly reduced. The end-systolic length and width of the right atrium, the length and width of the right ventricle had decreased, these observations suggest the right ventricular volume load reducing gradually after the procedure. At 3 months and at 1 year after the procedure, various measures of the right heart system were reduced significantly in most patients compared with the preoperative data. All of these changes showed that the high-volume loading state of the right heart was reduced significantly.Evaluating right ventricular (RV) function with 2-dimensional echocardiography is a troublesome endeavor. ,32 RV-FARigatelli and his colleagues assessed passive and active emptying of the LA, LA conduit function, and LA ejection fraction before and 6 months after the procedure, and then yearly. They found that relatively small occluder devices are probably effective enough to promote left atrial functional remodeling.  In the cThe current study has a few shortcomings. First, the sample size is relatively small and the follow-up period is short. Therefore, studies with larger sample size and long-term follow-up should be carried out to verify our results. Because of financial limitations, our study includes relatively few indicators; later studies should include more qualitative and quantitative indicators. Second, we used relatively large occluders for only a few cases with relatively large ASDs. Although we have reported that the indications for transthoracic minimally invasive device ASD closure are broader than those for percutaneous ASD closure, and even that a 44-mm occluder can be used for some cases, we are not sure whether large occluders affect the intracardiac structures. Further large-sample follow-up studies should be performed to address this question. Third, the results of the current study are based on transthoracic minimally invasive device ASD closure. We do not know whether percutaneous ASD closure can achieve similar clinical outcomes, and would require further investigation to compare these procedures. Fourth, our study group included both adults and children. In further studies, we should evaluate pediatric and adult patients separately, especially when measuring changes in the size of the chambers of the heart.In conclusion, transthoracic minimally invasive device ASD closure is safe and effective, as we have demonstrated in our previous studies.–4 Postop


Type 2 diabetes mellitus is an independent risk factor for the development of heart failure. To better understand the mechanism by which this occurs, we investigated cardiac structure, function, and perfusion in patients with and without diabetes.P = 0.01) and in diabetics than prediabetics . LV torsion angle was higher in diabetics than non-diabetics , and MPR was lower in diabetics than non-diabetics . There was significant correlation between MPR and early diastolic strain rate  and LV torsion . In multivariable linear regression analysis, non-diabetics waist–hip ratio, but not body mass index, had a significant association with RWM .Sixty-five patients with no stenosis >30% on invasive coronary angiography were categorized into diabetes (19) and non-diabetes (46) which was further categorized into prediabetes (30) and controls (16) according to the American Diabetes Association guidelines. Each patient underwent comprehensive cardiovascular magnetic resonance assessment. Left-ventricular (LV) mass, relative wall mass (RWM), Lagrangian circumferential strain, LV torsion, and myocardial perfusion reserve (MPR) were calculated. LV mass was higher in diabetics than non-diabetics (112.8 ± 39.7 vs. 91.5 ± 21.3 g, Patients with diabetes have increased LV mass, LV torsion, and decreased MPR. There is a significant association between decreased MPR and increased LV torsion suggesting a possible mechanistic link between microvascular disease and cardiac dysfunction in diabetes. Once established, heart failure in patients with diabetes is associated with worse clinical outcomes, independent of CAD.6 Observational studies have demonstrated that patients with systolic heart failure and diabetes have a mortality that is almost doubled compared with their normoglycaemic counterparts.8Cardiovascular disease is a major cause of morbidity and mortality in patients with diabetes mellitus.10 Observational research has shown that diabetes is associated with an increase in left-ventricular (LV) mass11 and impaired diastolic function.12 Over time, these structural and functional changes lead to impaired systolic function and the clinical syndrome of heart failure.13Several mechanisms have been proposed for the association between diabetes and heart failure including endothelial dysfunction, abnormal calcium handling, myocardial fibrosis, and inappropriate activation of the renin–angiotensin–aldosterone system.Cardiovascular magnetic resonance (CMR) offers a unique opportunity to assess these changes in cardiac structure and function as well as changes in myocardial perfusion in a single examination.In this study, we undertook a comprehensive assessment of cardiac structure, function, and perfusion by CMR in patients with diabetes, prediabetes, and normal insulin sensitivity, in whom significant CAD was excluded by coronary angiography. We hypothesized that patients with diabetes have increased LV mass, abnormal strain patterns, and impaired myocardial perfusion and that patients with prediabetes would have similar, albeit less severe, changes.We prospectively screened 399 consecutive patients with non-obstructive  CAD on routine coronary angiography typically clinically indicated for the investigation of chest pain at our tertiary cardiology centre. Patients with a history of previous myocardial infarction, coronary revascularization or other significant heart disease, contraindications to CMR or adenosine, and known claustrophobia were excluded. Of the remaining patients, 72 agreed to participate in the study. The study was approved by the local Ethics Committee. All patients gave fully informed written consent.14 diabetes mellitus was defined as fasting glucose ≥7 mmol/L, HbA1c ≥6.5%, or a past history of diabetes. Duration of diabetes was reported by the patients. Those that did not meet this definition were defined as non-diabetes. Prediabetes was defined as fasting glucose 5.6–6.0 mmol/L or HbA1c 5.7–6.4%. Those that did not meet the definition of diabetes or prediabetes were defined as controls. Hypertension was defined as clinic SBP >140 mmHg (the level at which treatment is recommended in current ADA guidelines). Hypercholesterolaemia was defined as current use of HMG-CoA reductase inhibitors (statins) or low-density lipoprotein (LDL) >100 mg/dL (the level at which statins are recommended in ADA guidelines). All subjects had their height, weight, hip circumference, and waist circumference measured. The homeostatic model assessment of insulin resistance (HOMA-IR) was calculated using the following formula: serum fasting glucose (µU/mL) × serum fasting insulin (mg/dL)/405.15 In diabetic patients, this was only calculated for those not taking exogenous insulin. Waist–hip ratio (WHR), body mass index (BMI), and Mosteller body surface area (BSA) were calculated.Smoking history, clinic non-invasive blood pressure, lipid profile, and drug history were recorded. In line with current American Diabetes Association (ADA) guidelines,Urine was tested for albumin–creatinine ratio. Blood samples were obtained from participants after 8 h of fasting and tested for glucose, insulin, total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, serum urea and electrolytes, and glycosylated haemoglobin (HbA1c).16CMR was performed on a 1.5 T whole-body magnetic resonance scanner  using vectorcardiographic gating and a 5-element cardiac phased-array receiver coil. Data were acquired during breath holding at end expiration. From scout CMR images, the LV long and short axes were determined. Then, tagged CMR images were acquired at the apex, mid-ventricle, and base . Slices were positioned using the highly reproducible ‘3 of 5 technique’.17 For perfusion acquisition, a contrast dose of 0.05 mmol/kg gadopentetate dimeglumine  was administered at a rate of 5 mL/s followed by a 20 mL saline flush. Breath holding was carried out during the first pass of contrast agent. The same mid-myocardial section was imaged twice–once in mid-systole and end-diastole by choosing two appropriate trigger delays from the cine images. A stress perfusion scan was performed during maximal vasodilatation, stimulated by intravenous infusion of adenosine at a dose of 140 µg/min/kg for 4 min.Next, myocardial perfusion CMR was planned in the mid-LV short axis orientation with a saturation recovery fast gradient echo method accelerated by two-fold sensitivity encoding (SENSE), TR/TE/flip angle 2.7/1.0/15°, typical field of view 380 × 380 mm, image matrix 160 × 160, in plane spatial resolution 2.4 × 2.4 mm, slice thickness 10 mm, 60 dynamics, preparation pulse delay (to middle of k-space) 150 ms, and shot duration 130 ms.Then, a retrospectively triggered, balanced steady-state free precession (SSFP) short-axis cine stack covering the entire LV was acquired .After a 15 min delay from stress perfusion imaging, a rest perfusion scan was performed in identical locations and using the same approach as the stress acquisition followed by an additional top-up bolus of 0.1 mmol/kg Gd-DTPA.18 End-diastolic, end-systolic (ES) LV volumes, stroke volume (SV), ejection fraction (EF), and LV mass including papillary muscles were calculated. Relative wall mass (RWM) was calculated by dividing LV mass by LV end-diastolic volume (EDV).19 Left atrial volume was calculated from the SSFP 4- and 2-chamber cine at end-systole using the following formula:20Using dedicated image analysis software , the epicardial and endocardial borders were traced off line on the LV cine stack.Figure 1). The position of individual contours was then manually corrected to account for any respiratory motion. In order to obtain an arterial input function (AIF), another region of interest was drawn inside the LV blood pool. This method has previously been shown to be highly reproducible.21 Myocardial blood flow (MBF) was measured in the systolic phase where the myocardium is thicker and easier to contour and has previously been shown to be as accurate as diastolic MBF measurement.22 AIF was measured in the diastolic phase when there was the largest area of blood pool to contour. Signal intensity vs. time profiles were then generated for the mid-LV myocardial slice as a whole without dividing into segments and for the LV blood pool. Signal intensity vs. time data generated in MASS were analysed with MATLAB7 R2009b, . Fermi-constrained deconvolution was used to generate estimates of absolute MBF in mL/g/min.23 The myocardial perfusion reserve (MPR) was calculated by dividing hyperaemic (stress) by baseline (rest) MBF.Analysis was performed with the same dedicated software package. Endocardial and epicardial contours were outlined on one representative dynamic perfusion frame with the optimum blood-to-myocardial contrast, with papillary muscles excluded, and copied to all other dynamic frames . The software then tracked the contours throughout all phases of the cardiac cycle. Circumferential Lagrangian strain and strain rate were measured at the mid-ventricular level, which has previously been shown to be the most reproducible.16 Early diastolic strain rate was defined as peak rate in the first four phases after end-systole. LV twist was calculated by subtracting the basal rotation from the apical rotation. LV torsion was calculated by the following formula:24Analysis was performed for the entire myocardial slice from each acquisition with a dedicated tagging analysis software package using HARP analysis . Endocardial and epicardial contours were drawn by a semi-automated process for each slice, and a mid-myocardial contour was automatically calculated between the endocardial and epicardial contours (® Statistics 19.0. Continuous variables were expressed as means ± standard deviation (SD). Means of the diabetes and non-diabetes groups were compared using an unpaired two-tailed t-test with assumed equal variance. To compare the diabetes, prediabetes, and control groups, analysis of variance with post hoc Tukey correction was used. A P-value of <0.05 was considered statistically significant. Kolmogorov–Smirnov test was used to establish that MPR was not normally distributed. Correlations between MPR and strain measurements were assessed by Spearman’s test. Univariable analyses were performed to identify predictors of increased LV mass index (LVMI), RWM, and LV torsion and reduced MPR. Variables with a probability value of <0.1 in the univariable analysis were included in a stepwise multivariable analysis, based on a linear regression model. Error bars for mean values denote 95% confidence interval.Statistical analysis was performed using IBM SPSSOf the 72 recruited patients, three could not complete the scan because of claustrophobia. Two patients in the diabetes group had tagging data of poor quality that could not be interpreted. In two patients, one of the perfusion data sets was of insufficient quality for quantitative analysis (excessive through plane motion). These four patients were excluded from the final analysis. Of the 65 patients with completed scans, 19 were classed as diabetic and 46 non-diabetics (of whom 30 were defined as prediabetic). The mean duration of diabetes was 7.3 ± 9.0 years.Table 1. The proportion of males  was higher in the diabetics than non-diabetics. Serum creatinine  and WHR  were higher in diabetics than non-diabetics. There was no significant difference between diabetics and non-diabetics for age, BMI, hypertension, hypercholesterolaemia, albumin–creatinine ratio, or smoking history. HOMA-IR was significantly higher in diabetics (not taking exogenous insulin) than in non-diabetics , but there was no significant difference between prediabetics and controls.Patient characteristics of the study groups are shown in P = 0.03). There were no other differences in patient characteristics.When diabetics, prediabetics, and controls were compared, serum creatinine was higher in diabetics than controls , EDV (171.0 ± 43.0 vs. 151.1 ± 26.2 mL P = 0.03), and SV (95.9 ± 25.7 vs. 86.6 ± 12.2 mL P = 0.05) were higher in diabetics than non-diabetics. There were no significant differences in LVMI, RWM, LA area, or LA area indexed to BSA (Table 2).LV mass .On comparing diabetics, prediabetics, and controls, LV mass was higher in diabetics than prediabetics . LV twist  and shear torsion angle  were significantly higher in diabetics than non-diabetics. Early diastolic strain rate  was higher in diabetics than non-diabetics bordering on significance.There was no significant difference in EF, peak Lagrangian circumferential strain, or systolic strain rate between diabetics and non-diabetics (P = 0.04).Diabetics had LV twist that was significantly greater than prediabetics . However, MPR was significantly decreased  in diabetics compared with non-diabetics.There was no significant difference in MBF at stress or at rest between diabetics and non-diabetics (P = 0.05). There was no difference in MPR between prediabetics and controls.MPR was decreased in diabetics compared with prediabetics of borderline significance  and LV torsion .Calculation of Spearman’s correlation coefficient revealed a modest significant correlation between MPR and early diastolic strain rate (Table 3), only male sex was associated with increased LVMI . RWM had a significant association with WHR only . The only factor significantly associated with increased LV torsion shear angle was a history of diabetes . On univariable regression analysis, age, sex, and diabetes had a correlation with decreased MPR (P < 0.1) and were included in the multivariable analysis. In the multivariate analysis, diabetes  and age  had a significant association with decreased MPR.In the multivariable linear regression model of all patients (Table 4), only male sex was associated with increased LVMI . RWM had a significant association with WHR . None of the risk factors had a significant association with LV torsion. MPR only had a significant association with male sex .In the multivariable linear regression model of only non-diabetic patients . The findings of the present study corroborate these findings and also demonstrate that diabetic subjects have an increase in LV mass compared with subjects with prediabetes.Data from the large observational Multi-Ethnic Study of Atherosclerosis study19 and abnormal LV function.26 In our study, patients with prediabetics had LVMI and RWM similar to controls; however, in the multivariable linear regression analysis of all subjects and non-diabetics RWM (a marker of LV remodelling) had a significant correlation with WHR but not BMI or HOMA-IR. The role of visceral adipose tissue in cardiac remodelling and dysfunction is increasingly being recognized,27 and our finding of a correlation between WHR and LV remodelling independent of diabetes status or HOMA-IR adds further evidence to this hypothesis.Previous observational studies have demonstrated that insulin resistance and prediabetic states are associated with concentric LV remodelling28 Our results and our finding of a negative correlation between MPR and LV torsion suggest that this hypothesis is also applicable in Type 2 diabetes. It is plausible that abnormal myocardial perfusion in Type 2 diabetes contributes to the progressive changes in cardiac strain and function reported in this study and in previous studies.29 The hypothesis that impaired MPR leads to cardiac dysfunction raises the possibility of future therapeutic trials of pharmacological agents that increase coronary microvascular function to prevent heart failure. One recent study in which patients with diabetes were randomized to receive the selective phosphodiesterase inhibitor sildenafil or placebo30 reported that sildenafil reversed LV remodelling as well as decreasing LV torsion compared with placebo. The possible mechanistic link between microvascular disease and cardiac dysfunction does suggest a need for further trials into drugs that vasodilate the coronary microvasculature.Further, we have demonstrated that diabetics have increased LV twist and torsion despite unchanged circumferential strain. This finding has previously been reported in patients with Type 1 diabetes mellitus and was attributed to subendocardial myocardial dysfunction secondary to small vessel disease.12 and decreased MPR.31 In both of these studies, the diabetic patients had significantly higher blood pressure (BP) than the controls. It has previously been reported that hypertension leads to increased torsional shear angle, decreased circumferential strain,32 and decreased MPR.34 In our study, there was no significant difference in clinic BP between the study groups making the reported changes likely due to diabetic status of the patients.It has been reported in previous CMR-based research that diabetic patients when compared with controls have increased LV torsion35 where MPR was also reduced in diabetics but not prediabetics.36 Other CMR techniques such as T1 mapping38 or measuring aortic distensibility40 have been demonstrated to show changes in diabetes and may be more sensitive to detect subclinical cardiac changes in prediabetes.We had hypothesized that patients with prediabetes would also show abnormalities in LV structure, function, and perfusion. The techniques employed in this study did not demonstrate any abnormalities in prediabetes. Our findings have also confirmed MPR measurements by positron emission tomographyThe three patient groups had similar characteristics, but there were more men and higher creatinine in the diabetic group than non-diabetic group. We attempted to control for this retrospectively by indexing results to BSA where appropriate and by conducting a multivariable linear regression analysis. The correlations reported are modest which reflects the fact that multiple factors influence ventricular structure, function, and perfusion.Diabetics also had significantly higher use of angiotensin-converting-enzyme (ACE) inhibitors and statins than non-diabetic patients. This may have influenced our results, but any effects would be expected to improve the studied parameters in patients taking ACE inhibitors or statins.21 We have not reported the segmental analysis of CSPAMM or MPR because we are investigating a diffuse process that affects the whole myocardium. With regard to MPR, our aim was to optimize image acquisition and our study aims to examine ubiquitous changes in the myocardium rather than to detect coronary disease (which was excluded at patient inclusion). For this purpose, single slice coverage was considered sufficient.We have only carried out CSPAMM and MPR analysis at the mid-ventricular short axis level because this has previously been demonstrated to be the most reproducible level for analysis of both of these techniques.Patients were recruited at the time of coronary angiography, typically for investigation of chest pain. It is possible that these patients by nature of their symptoms are not representative of all diabetic or non-diabetic patients.Patients with diabetes, without CAD, have increased LV mass, LVMI, and LV torsion and decreased MPR when compared with non-diabetic patients. There is a significant association between decreased MPR and increased LV torsion suggesting a possible mechanistic link between microvascular disease and cardiac dysfunction in diabetes.Conflict of interest: None declared.Libyan Ministry of Higher Education & Scientific Research, Tripoli, Libya to A.M.L. and British Heart Foundation to S.P. (FS/10/62/28409). S.P. and J.P.G. received unrestricted educational grants from Philips Healthcare. Funding to pay the Open Access publication charges for this article was provided by The University of Leeds.


Adverse left ventricular (LV) remodeling after acute myocardial infarction is characterized by LV dilatation and development of a fibrotic scar, and is a critical factor for the prognosis of subsequent development of heart failure. Although myofiber organization is recognized as being important for preserving physiological cardiac function and structure, the anatomical features of injured myofibers during LV remodeling have not been fully defined. In a mouse model of ischemia–reperfusion (I/R) injury induced by left anterior descending coronary artery ligation, our previous histological assays demonstrated that broad fibrotic scarring extended from the initial infarct zone to the remote zone, and was clearly demarcated along midcircumferential myofibers. Additionally, no fibrosis was observed in longitudinal myofibers in the subendocardium and subepicardium. However, a histological analysis of tissue sections does not adequately indicate myofiber injury distribution throughout the entire heart. To address this, we investigated patterns of scar formation along myofibers using three‐dimensional (3D) images obtained from multiple tissue sections from mouse hearts subjected to I/R injury. The fibrotic scar area observed in the 3D images was consistent with the distribution of the midcircumferential myofibers. At the apex, the scar formation tracked along the myofibers in an incomplete C‐shaped ring that converged to a triangular shape toward the end. Our findings suggest that myocyte injury after transient coronary ligation extends along myofibers, rather than following the path of coronary arteries penetrating the myocardium. The injury pattern observed along myofibers after I/R injury could be used to predict prognoses for patients with myocardial infarction. In a mouse model of ischemia–reperfusion injury induced by left anterior descending coronary artery ligation, three‐dimensional images of myocardial scarring obtained from tissue sections (solid yellow area) indicate that the scar sequentially extends from the base to the apex in the midcardium. At the apex, the scar formation tracks along the myofibers in an incomplete C‐shaped ring that converges to a triangular shape toward the end. These findings suggest that myocyte injury after transient coronary ligation extends along myofibers, rather than following the path of coronary arteries penetrating the myocardium. Adverse left ventricular (LV) remodeling is a common occurrence following acute myocardial infarction (MI), and an important factor in determining the prognosis for subsequent development of heart failure  for 30 min in mice. We showed via histological assays that a broad fibrotic scar extended from the initial infarct zone to remote zones along midcircumferential myofibers, while no fibrosis was observed in longitudinal myofibers of the subendocardium and subepicardium  for visualization and measurement of cardiomyocyte (CM) size. We traced the outline of individual CMs that fell along a radial line between the papillary muscles, and measured their size with Image J . The scar area, which was not stained by antidystrophin, was omitted during the measurement of cell count and area. For 3D images, we sliced 224 sections from the heart and stained 137 sections with Masson's trichrome staining to show tissue fibrosis. Of those, 31 representative tissue sections were selected at equally spaced intervals from the base to the apex, from which 3D images were rendered.Hearts were excised, fixed overnight in 4% paraformaldehyde, dehydrated, and embedded in paraffin. Cross sections were cut at 5 To generate the 3D model, digital images of the sections were outlined to highlight fibrotic areas with the ventricular lumens and the epicardium in the background, and realigned for anatomic accuracy . The modified images were reconstructed using WinSURF v1.0  distribution in two‐dimensional images of the normal heart, we used an antidystrophin antibody to immunohistochemically stain and delineate the sarcolemmal membrane of CMs in horizontal tissue sections that were coplanar with the papillary muscles Fig. . As CM sIn our model of I/R injury, we ligated the LAD coronary artery of mouse hearts and released the suture after 30 min ischemia. Fluorescent microspheres were injected into the LV cavity during LAD ligation to indicate the perfused area. The area with a lack of fluorescent microspheres corresponded to the area perfused by the LAD, which experienced ischemia during LAD ligation. The darkened area perfused by the LAD delineated along transmural lines Fig. A. To seeWe measured the cross‐sectional area of CMs located along the transmural line in the LV free wall 1 week after the I/R operation Fig. . FibrotiTo assess the structure of myofiber injury, we generated a 3D view rendered from 31 sections that were selected at equidistant intervals from the base to the apex using WinSURF v1.0  hypertrophy is observed in the midcardium of hearts subjected to I/R injury by LAD ligation.The 3D image obtained from multiple tissue sections highlighted fibrotic scar distribution according to the myofiber architecture. As discussed in our previous report .This movie shows a 3D image of myocardial scarring rendered from multiple tissue sections from theheart following I/R injury. The solid yellow area indicates the fibrotic scar, and the semi-transparent red area indicates the surface of the epicardium or LV/RV lumen.Click here for additional data file.


A variety of CMR methods for detecting intramyocardial haemorrhage (IMH) has been proposed, including T2-weighted imaging (T2w), T2-mapping and T2* mapping. IMH detected by T2w imaging is associated with adverse LV remodelling and adverse outcome post acute myocardial infarction (MI). We compare the sensitivity, specificity, CNR and SNR of the three IMH imaging techniques.i-SNRIMH).Twenty patients underwent CMR at 3T  within 3 days following reperfused ST-elevation MI. Black blood, cine, T2w, T2-mapping, T2*-mapping and LGE imaging (0.1mmol/kg gadolinium DTPA) were performed in identical short axis locations using the ‘3 of 5' approach. Data were evaluated offline using commercial software . On the LGE images showing the largest infarct volume, infarct size was determined by using a semi-automated histogram-based thresholding method. This slice was evaluated for visual presence of IMH by the three methods. Signal intensity (SI) and respective standard deviation of SI (SD) were measured for the infarcted myocardium, remote myocardium and any IMH (if present). SNR was computed for each using the formula=0.655((SI)/(SD)). CNR was determined comparing contrast-to-noise of infarcted myocardium to IMH  had IMH on T2w-imaging. The mean (±standard deviation) SNR and CNR values are listed in Table 1 had IMHQuantitative and qualitative T2w-imaging assessment for IMH is superior to T2-mapping and T2*mapping.JPG and SP receive a research grant from Philips Healthcare. SP is funded by British Heart Foundation fellowship (FS/10/62/28409).


Acute myocardial infarction and congestive cardiac failure are characterized by high levels of cardiac sympathetic drive. In these conditions, sympathetic neurotransmitters such as neuropeptide Y (NPY) can be released in addition to noradrenaline, and plasma levels correlate with infarct size and mortality. Even in the presence of β-blockers, NPY is able to bind to its own receptors located on cholinergic ganglia and ventricular myocytes. In this symposium report, I review the evidence that NPY can inhibit acetylcholine release during vagus nerve stimulation and limit the subsequent bradycardia. I also present preliminary, as yet unpublished data, demonstrating that NPY may be pro-arrhythmic by directly influencing ventricular electrophysiology. Targeting NPY receptors pharmacologically may therefore be a useful therapeutic strategy both to reduce heart rate and to prevent arrhythmias in the setting of myocardial infarction and chronic heart failure. Such medications would be expected to act synergistically with β-blockers, angiotensin-converting enzyme inhibitors and implantable cardiac devices, such as defibrillators and vagus nerve stimulators. What is the topic of this review?This symposium report discusses the evidence for release of cardiac sympathetic cotransmitters in addition to noradrenaline.What advances does it highlight?It highlights the potential role of neuropeptide Y in reducing vagal neurotransmission and directly influencing ventricular myocyte excitability in the presence of β-receptor blockade.β-Blockers, introduced over 50 years ago, are the only anti-arrhythmic drug proven to improve mortality after myocardial infarction and in chronic congestive heart failure, where sympathetic drive to the heart is high ISIS-1, . We havein vivo as early as 1982  or the delayed rectifier potassium current  via an inhibitory G-protein-sensitive pathway  in the guinea-pig , but stimulates this current in the rat (Millar et al. 1 receptor pathway coupled to activation of phospholipase C (Heredia Mdel et al. The role of NPY in arrhythmogenesis may extend beyond sympathovagal cross-talk, because NPY receptors, particularly Y1-dependent mechanism. Combining a Y1 receptor antagonist with metoprolol also prevents the fall in VFT following high-frequency stellate stimulation. Optical mapping experiments in the isolated rat heart using a voltage-sensitive dye also show that NPY steepens the action potential duration restitution curve, demonstrating a direct pro-arrhythmic action on ventricular electrophysiology. Combining β-blockade with an antagonist of the NPY Y1 receptor may therefore be a useful strategy for preventing arrhythmias in conditions where cardiac sympathetic drive and NPY release are high.As part of the symposium presentation, I presented unpublished data suggesting that NPY may play an important role by acting directly on ventricular myocytes to increase susceptibility to ventricular fibrillation. Dr Manish Kalla and I have developed a Langendorff-perfused rat heart with intact innervation, enabling simultaneous or individual stimulation of each stellate ganglion. The susceptibility of the heart to VF can be evaluated after high-frequency burst pacing at increasing current amplitude following a pacing drive train so that VFT can be measured accurately independent of heart rate. Ventricular fibrillation is cardioverted with a bolus of high-concentration potassium chloride solution, and control experiments demonstrate that VFT remains constant over consecutive inductions. Whilst a maximal concentration of NA lowers the VFT, metoprolol can completely block its effect, demonstrating its efficacy as an antiarrhythmic β-blocker. However, metoprolol is unable to prevent the fall in VFT following prolonged high-frequency stimulation of either the right or the left stellate ganglion, despite the chronotropic effect being completely abolished. This suggests that an additional substance released from sympathetic nerve endings during these conditions may also be acting as a pro-arrhythmic signal. Consistent with this hypothesis, exogenous NPY also directly lowers VFT by a Yet al. et al. et al. Several studies published over 20 years ago demonstrate that plasma NPY levels are elevated following acute coronary syndromes and during left ventricular failure in humans where they correlate positively with the severity of heart failure and 1 year mortality (Hulting 2 receptor may facilitate vagal bradycardia and reduce resting heart rate, whilst Y1 receptor inhibition may prevent ventricular arrhythmias independent of heart rate (see Fig.Targeting NPY receptors pharmacologically may therefore be a useful therapeutic strategy after myocardial infarction. Targeting the Yhttp://ep.physoc.org/letters/submit/expphysiol;100/4/354Readers are invited to give their opinion on this article. To submit a comment, go to:


Spasticity is one of the most disabling and difficult-to-treat symptoms shown by patients with multiple sclerosis, who often show a suboptimal and unsatisfactory response to classic treatment and new available nonpharmacological alternatives. Due to the progressive nature of this condition, the early management should be essential to improve long-term outcomes.We performed a narrative literature review of the contribution of spasticity to the burden of multiple sclerosis and the potential role of classic disease-modifying drugs.Added to the underlying pathophysiology of spasticity, certain external factors and drugs such as interferon may exacerbate the existing condition, hence their awareness is crucial as part of an effective management of spasticity. Furthermore, the evidence for the effectiveness of glatiramer acetate in preventing spasticity in naïve patients and in those switching from interferon should not be ignored.This literature review proposes the examination of spasticity and the influence of classic disease-modifying agents on the level of existing condition among the variables to be considered when deciding on therapy for multiple sclerosis in clinical practice. Spasticity is one of the most prevalent symptoms in multiple sclerosis (MS)  are effective in RRMS and CIS patients. However, their impact on symptoms such as spasticity and fatigue are not usually considered in clinical practice despite being as important as relapses , interferon beta-1a 60 μg (15 patients), or placebo (20 patients). Contrary to what was reported in the mentioned studies, this study did not show a significant increase in spasticity in patients with PPMS treated with interferon beta-1a, though a trend can be noted toward increased spasticity in both treatment groups (33%) versus placebo (15%). In addition, a sustained increase in spasticity was less frequent in the interferon beta-1a 60 μg (13%) compared to interferon beta-1a 30 μg (60%) group.Also in PP forms, Leary and Thompson  conducteAn open-label 2-year follow-up study  and a cohort of naïve patients (n = 15). After 18 months of follow-up and compared to baseline, all patients who switched from interferon beta to GA showed a significant reduction in mean scores on the MAS for the right hemibody  and left hemibody , and also in scores of the PSFS  and Global Pain Scale (GPS) . In patients who started GA as the first disease-modifying drug, no change was seen in their degree of spasticity on any of the clinical scales used, probably because they had a baseline mean degree of spasticity that was very mild and lower than those treated with interferon beta. However, they did show a significant reduction in H-reflex latency in the left hemibody , and H/M ratio in the right hemibody , two objective electrophysiological indicators of improvement in spasticity, whose sensitivity, validity and reproducibility have been previously confirmed (Levin and Hui-Chan Glatiramer acetate (GA) has been shown to have a clear beneficial effect on spasticity in patients with RRMS previously treated with interferon beta. In treatment-naïve patients, its effect has been shown to be less pronounced, but without evidence of worsening of spasticity. Only two studies have been conducted to evaluate this effect, which is summarized below, and whose main data are given in Table The results of this first study with GA were supported by a subsequent multicenter study (the ESCALA study) in patients with RRMS and confirmed spasticity who switched to GA after interferon beta (Meca-Lallana et al. The results of a subanalysis of the ESCALA study (Meca-Lallana et al. The management of spasticity in multiple sclerosis is complex and, therefore, constitutes a challenge for neurologists. Besides being the symptom most affecting the QoL and functionality of the patients, it shows a limited response to traditional treatment and nonpharmacological alternatives.If the progression of spasticity that accompanies the natural course of the MS may cause a high level of immobility, then early intervention on its clinical course should be essential to improve prognosis and associated complications.As part of an effective spasticity management, the awareness or even the elimination of externally exacerbating factors is considered as crucial. In this sense, the evidence, although limited and well recognized, of worsening spasticity after interferon should be not ignored, nor the effectiveness GA shows in preventing spasticity. This review does not advocate for the use of a concrete drug, but encourages neurologists to consider both the evaluation of spasticity and how classic DMDs can influence the level of the existing condition when deciding on therapy for MS in clinical practice.


Tako-tsubo cardiomyopathy (TCM) is an acute cardiac syndrome with regional hypokinesia in the left ventricle (LV), often affecting the apex causing apical ballooning. TCM is frequent in patients with adrenergic overstimulation and is probably common in ICU patients . In a TCn = 12 in each group) were sedated with either pentobarbital, ketamine, isoflurane or no anesthetic before i.p. isoprenaline. One additional group received the K-ATP blocker glyburide before sedation with isoflurane. In the second setting, rats were anaesthetized with ketamine + midazolam, mechanically ventilated and the carotid artery was cannulated. Before i.p. isoprenaline, animals were randomized to either no isoflurane (0 MAC), isoflurane 0.5 MAC or isoflurane 1.0 MAC (n = 12 in each group). Arterial blood gas was obtained before isoprenaline and 60 minutes after isoprenaline. The heart rate (HR), systolic blood pressure (SBP) and body temperature (BT) were recorded continuously. After 90 minutes, echocardiography was performed. Extent of akinesia was expressed as the percentage of total LV endocardial length. End-diastolic and end-systolic LV volumes were measured, and stroke volume (SV) and cardiac output (CO) were calculated.Isoprenaline was intraperitoneal (i.p.) injected, which induces LV akinesia and apical ballooning within 90 minutes . We perfIn spontaneously breathing rats, the degree of akinesia was significantly lower with pentobarbital and isoflurane (± glyburide) but not with ketamine compared with controls. The degree of akinesia was lowest with isoflurane. In ventilated rats, the degree of apical akinesia (%) was significantly lower at 0.5 MAC (8.7 ± 7.3) and 1 MAC (5.7 ± 7.4) versus 0 MAC (17.7 ± 8.0). This was accompanied by a higher CO and SV. HR was lower at 1 MAC (6%) and SBP was lower at 0.5 MAC (106 ± 7) and 1 MAC (98 ± 7) versus 0 MAC (126 ± 8). BT and pH was lower in both isoflurane groups. In a multivariate model, isoflurane was the only variable that was independently associated with the degree of LV akinesia.Isoflurane prevents experimental TCM and preserves LV function, an effect not mediated via opening of K-ATP channels. The effect cannot be explained entirely by attenuation of myocardial stress. Isoflurane sedation in the ICU might be an interesting approach for patients suffering from hyperadrenergic conditions at risk of developing TCM.


The data were analysed with a suite of methods that focused on different aspects of the myocardium. In the slack heart, we observed a similar transmural gradient in helix angle of the primary eigenvector of up to 23.6°/mm in the left ventricle and 24.2°/mm in the right ventricle. In the contractured heart, the same transmural gradient remained largely linear, but was offset by up to +49.9° in the left ventricle. In the right ventricle, there was an increase in the transmural gradient to 31.2°/mm and an offset of up to +39.0°. The application of tractography based on each eigenvector enabled visualisation of streamlines that depict cardiomyocyte and sheetlet organisation over large distances. We observed multiple V- and N-shaped sheetlet arrangements throughout the myocardium, and insertion of sheetlets at the intersection of the left and right ventricle. This study integrates several complementary techniques to visualise and quantify the heart’s microstructure, projecting parameter representations across different length scales. This represents a step towards a more comprehensive characterisation of myocardial microstructure at the whole organ level.Myocardial microstructure and its macroscopic materialisation are fundamental to the function of the heart. Despite this importance, characterisation of cellular features at the organ level remains challenging, and a unifying description of the structure of the heart is still outstanding. Here, we optimised diffusion tensor imaging data to acquire high quality data in  These cells occupy the majority of the ventricular volume, and are organised in a highly structured three-dimensional (3D) pattern . The twoTraditional histo-anatomical characterisation methods, such as gross anatomical dissection or histology, have laid the foundation for our current understanding of cardiac structure . While t−5 m region, they do not yet resolve cellular features. Polarised light imaging also offers good coverage, but resolution is limited to the 10−5 m range, and fibre orientation estimates are sensitive to the elevation angle of the cells   and X-rahe cells . Scanninhe cells  and confhe cells , in cont−4 m, the technique is sensitive to the microscopic diffusion of water in the 10−6 m range, and its interactions with the cellular environment. This facilitates assessment of the 3D arrangement of cardiac fibres and sheetlets  are understood to correspond to the fibre long-axis, the fibre-normal/in-sheet and the sheetlet-normal directions respectively, of cells in myocardial laminae (Diffusion tensor imaging (DTI)  enables heetlets . In DTI, laminae , as vali laminae .v3 to the orientation of the ventricular sheetlets  and right ventricle (RV). Superquadric glyphs are used to aid voxel-wise display of tensors, transmural angle profiles are quantified regionally, and global tractography is employed to help visualise macroscopic distributions of fibres and sheetlet alignments. The study (i) uses multiple approaches to augment our understanding of myocardial structure in rabbit hearts, and (ii) investigates structural differences between the diastolic (slack) and systolic (contracture) states.Improvements in magnet and gradient system hardware, as well as data acquisition protocols, now allow one to acquire high quality DTI data at comparatively high isotropic resolution in the isolated fixed heart. Here, we combine a state-of-the-art preclinical MRI system with optimised 3D spin echo DTI acquisition to improve the signal-to-noise ratio, supporting an isotropic imaging resolution of 200 μm in 22.13 25, KCl 5.4, NaH2PO4 1.2, MgCl2 1, Glucose 5.5, CaCl2 1.8, pH to 7.4 with NaOH and oxygenated with 95% O2/5% CO2) containing heparin (5 IU/mL). The first heart was arrested using physiological saline with elevated potassium (20 mM KCl) to induce diastolic arrest, while the second heart was exposed to lithium-replacement of sodium to induce contracture   Act 1986 (UK). Hearts were isolated from two male New Zealand White rabbits after induction of terminal anaesthesia (pentobarbitone under Schedule 1 protocol). Isolated hearts were swiftly cannulated and perfused in constant pressure Langendorff mode for 5 min with normal physiological saline  . Hearts 2.22, acquisition time = 21:36 h. Based on these diffusion times and assuming unrestricted diffusion, the root mean squared displacement in tissue with apparent diffusivities ranging from 1.0–1.5 × 10−3 mm2/s would have ranged from 3.1 to 3.8 μm  with a shielded gradient system , and transmit/receive quadrature coil . Acquisition parameters were: repetition time = 250 m, echo time = 10 m, field-of-view = 43.2 × 28.8 × 28.8 mm, matrix size = 216 × 144 × 144, resolution = 200 × 200 × 200 μm, number of non-diffusion-weighted (DW) images = 3, number of DW directions = 12 , diffusio 3.8 μm . Sample o 3.8 μm .2.33D tensors were fitted to the DTI data using non-linear least squares. Manual segmentation of the LV and RV myocardium was performed based on reconstructed fractional anisotropy (FA) maps . The DTI1, λ2 and λ3, FA and transverse anisotropy λ2/λ3, were calculated , anterior-posterior (green) and lateral-septal (blue).Parametric maps, including the mean apparent diffusion coefficient (ADC), principal eigenvalues λlculated  and repoerformed , and 95%lipsoids . As illu Toolkit . The fiblgorithm  was usedlgorithm . The terIn order to mitigate variations arising from local tissue deformations, the helix angles (HA) and transverse angles (TA) were defined relative to a local coordinate system. Local radial unit vectors were computed using Laplace’s method in the LV and RV separately . Local cv1 in the long-axis and its deviation from the circumferential axis in the short-axis plane respectively. In order to assess sheetlet structures, we similarly define HA and TA based on v3. The HA of a given eigenvector is the angle subtended by the projection of the eigenvector onto the tangential plane and the short-axis plane. The TA is the angle subtended by the projection of the eigenvector onto the short-axis plane and the tangential plan. HA  and TA  maps were generated in the whole heart. A custom cyclic colour map was used to avoid discontinuities at transitions between −90° and +90°.Typically, HA and TA reflect the orientation of v1, v3) and TA  were reported in these ROIs in a basal, middle and apical slice. To do so, HA and TA, corresponding to each ROI, slice and heart, were averaged in polar coordinates within radial bins of 0.2 mm. HA and TA were then reported as a function of myocardial wall thickness. Wrap-around of HA and TA from −90° to +90° and vice versa, as occurring particularly in epicardial and endocardial regions, was avoided by expanding the dynamic angle range to −150° to +150°. The linearity of the profiles was characterised by the R2 obtained with a linear fit  and TA  were computed in the LV and RV across three adjacent mid-ventricular slices with a bin size of 2°. All processing was performed using in-house code .ROIs in the LV and RV myocardium were identified according to near fit . The tot31 was relatively homogeneous across the myocardium in the slack heart, whereas λ2 and λ3 were elevated in the subendo- and subepicardium, contributing to a locally higher mean ADC and lower fractional and transverse anisotropy. Data from the contractured heart were less heterogeneous than in the slack heart. Transverse anisotropy was higher is the contractured heart, but remained low within the papillary muscles. Summary data of these observations in the whole heart are presented in 1, λ2 and λ3 were lower in both the LV and RV of the contractured heart, by up to 8.8%.Diffusion parameter maps in a mid-ventricular slice in slack and contractured hearts are presented in v1/v2/v3) = 6.2°/14.8°/13.6° (slack) and 6.7°/12.8°/11.3° (contracture) averaged across the myocardium. Maps of 95% COU show that precision of v1,v2 and v3 are excellent throughout most of the myocardium, and poorer where there are major vessels and edges with residual partial volume. In addition, precision of v2 and v3 are also poorer in the papillary muscles, in myocardial regions containing greater extracellular space and in regions near the apex. We find that 99%/90%/91% (slack) and 99%/93%/94% (contracture) of voxels in the myocardium fall within a threshold of 95% COU (v1/v2/v3) < 30°.In terms of measurement precision, 95% COU  and TA  maps are presented in digitally resected hearts as v1 in the slack heart is relatively uniform and linear across the LV lateral, apical, septal and posterior walls, with gradients in a mid-myocardial slice ranging from 18.2°/mm to 23.6°/mm and linearity ranging from 0.94 to 0.99. In the contractured heart, HA v1 remains linear with R2 > 0.94, but there is a constant offset across the myocardium depending on region. For instance, there is a decrease of between 16.3° and 48.5° in the LV lateral endocardium depending on the height of the short-axis slice, and an increase of between 41.7° and 49.9° in the LV septal subendocardium. In the RV of the slack heart, a similar trend of increasingly right helical fibres is observed from the subepicardium to the subendocardium in the anterior, lateral and posterior walls at the middle and basal slices. The gradients in a mid-myocardial slice range from 19.2°/mm to 24.2°/mm depending on region, and are remarkably similar to those in the LV wall of the slack heart. In the RV of the contractured heart, the linear trend towards increasingly right helical fibres in the subendocardium continues with R2 > 0.94. However, there is a notable increase in the gradients, which ranges from 28.3°/mm to 31.2°/mm, and a rightward shift of between 25.2° and 34.2° at the midline of the anterior wall, and between 27.1° and 39.0° at the midline of the lateral wall. These descriptions are likewise reflected in the tracking and 3D angle mapping in HA  in a sizeable region of the LV and RV in the contractured heart relative to the slack heart.The distributions of TA 4ex vivo imaging protocol, with its extended acquisition time, afforded higher sensitivity to subtle changes in diffusivity than prior life-heart DTI in rat heart  = 3.7° ± 0.2°/14.7° ± 1.0°/14.4° ± 1.0° (ex vivo preparations continue to provide data with the highest quality and resolution due to the longer acquisition times and lack of sample motion. In addition, tensors were visualised using superquadric glyphs. While ellipsoids are a more direct representation of the diffusion tensor, superquadric shapes may provide a more intuitive representation of the known orthotropy of myocardial structure.The limitations of the study include a small sample size that precludes statistical analysis, and comparison of two ° ± 1.0° . This un° ± 1.0° , albeit 5Our data reconfirm the highly complex and ordered nature of cardiac architecture. Measuring, understanding and communicating the wealth of macro- and microstructural information is not trivial. To address this challenge, we have combined multiple complementary techniques to quantify and visualise measurements at different length scales. Superquadric glyphs facilitate voxel-wise interrogation of tensors, transmural profiles highlight changes across the myocardial wall, 3D maps describe global parametric distributions, histograms capture summary metrics, and localised and global tractography can potentially identify functionally important groups of fibres and sheetlets.Please see also related communications in this issue by


Echocardiography is pivotal in the diagnosis and management of the shocked patient. Important characteristics in the setting of shock are that it is non-invasive and can be rapidly applied.In the acute situation a basic study often yields immediate results allowing for the initiation of therapy, while a follow-up advanced study brings the advantage of further refining the diagnosis and providing an in-depth hemodynamic assessment. Competency in basic critical care echocardiography is now regarded as a mandatory part of critical care training with clear guidelines available. The majority of pathologies found in shocked patients are readily identified using basic level 2D and M-mode echocardiography. A more comprehensive diagnosis can be achieved with advanced levels of competency, for which practice guidelines are also now available. Hemodynamic evaluation and ongoing monitoring are possible with advanced levels of competency, which includes the use of colour Doppler, spectral Doppler, and tissue Doppler imaging and occasionally the use of more recent technological advances such as 3D or speckled tracking.The four core types of shock—cardiogenic, hypovolemic, obstructive, and vasoplegic—can readily be identified by echocardiography. Even within each of the main headings contained in the shock classification, a variety of pathologies may be the cause and echocardiography will differentiate which of these is responsible. Increasingly, as a result of more complex and elderly patients, the shock may be multifactorial, such as a combination of cardiogenic and septic shock or hypovolemia and ventricular outflow obstruction.The diagnostic benefit of echocardiography in the shocked patient is obvious. The increasing prevalence of critical care physicians experienced in advanced techniques means echocardiography often supplants the need for more invasive hemodynamic assessment and monitoring in shock. Whether the cause of shock is unknown, suspected, or established, echocardiography is utilized in its diagnosis and management and to monitor progress. It is recommended as the modality of first choice in consensus guidelines . No otheCompetency standards are well established for both basic and advanced critical care echocardiography and the scope of this review will cover both , 3 Tabl. Both trShock can be defined as a life‐threatening, generalized form of circulatory failure associated with inadequate oxygen delivery to the cells . The fouCardiogenic shock is the extreme end of the acute deteriorating heart failure spectrum. A global study involving 666 hospitals involving nearly 5000 patients admitted to hospital with acute heart failure found 36 % were first time episodes, 37 % were in pulmonary edema, and 12 % were in cardiogenic shock ) indicates a normal RAP of 3 mmHg, whereas an IVC diameter >21 mm that collapses <50 % with a sniff indicates a RAP of >15 mmHg [Guidelines recommend that in the spontaneously breathing patient an IVC diameter (D) <21 mm that collapses with a sniff /Dmin, with a threshold of 18 % discriminating between responders and non-responders with 90 % sensitivity and 90 % specificity [For practical purposes, in the acute setting for the spontaneously breathing patient in shock, the IVC diameter is measured within 0.5–3 cm from the caval–right atrial junction in the subcostal view and when the diameter is less than 10 mm the patient is likely to respond to fluid, but when greater than 20 mm that is unlikely. Collapse of >50 % between the diameters of 10–20 mm should result in a trial of fluid. In the patient on fully supported positive pressure ventilation, the distensibility index (dIVC) is a good guide to fluid responsiveness. The dIVC is calculated as the ratio of 2) of the chosen location. CO and SV are measured using pulsed‐wave Doppler with the sample volume placed at the level of the aortic annulus for left ventricular outflow (where SV = VTI × CSA and CO = SV × Heart rate). Care must be taken to properly align the Doppler beam to the flow and VTI is measured by tracing the modal velocity.The use of static measurements to assess fluid status is recognized to be inadequate in the majority of situations and dynamic techniques need to be applied. Administration of a bolus of intravenous fluid, passive leg raising, and positive pressure ventilation-induced variation in stroke volume (SV) and CO are commonly employed. As a guide, fluid responsiveness is determined if there is, on average, a >15 % increase in SV or CO. The underlying physiology is well covered elsewhere and the focus of this review is on the practical application of echocardiography in shocked patients. . EssentiApplication of a bolus of intravenous fluid has long been used to assess fluid responsiveness with clinical parameters, especially systemic blood pressure, used as an endpoint. Pulse pressure variation is used as blood pressure does not always reflect fluid responsiveness, particularly when other factors, such as impaired left ventricular contraction or marked vasoplegia, exist. With increasing awareness of the perils of excessive fluid administration, the practice of mini‐boluses of fluid is attractive. This is particularly the case in patients with impaired left ventricular function who are at greater risk of acute pulmonary edema. In a study on 39 low volume-ventilated critically ill patients, sub-aortic VTI was measured following an initial 100 ml of starch administered over 1 minute followed by another 400 ml over 14 minutes. A change in VTI of >10 % after the first 100 ml predicted fluid responsiveness with a sensitivity and specificity of 95 % and 78 %, respectively (area under curve (AUC) = 0.92) .During the inspiratory phase of positive pressure ventilation, right ventricular output is reduced because of a decrease in venous return (increased intrathoracic pressure) causing a subsequent decrease in left ventricular output after two to three beats if both ventricles are volume responsive. These approaches are limited to fully ventilated patients and studies were performed using tidal volumes of 8–10 ml/kg. As smaller tidal volumes are not proven to be diagnostically helpful, it may be necessary to temporarily increase these to 8 ml/kg. A SV variation >10 % is highly predictive of volume responsiveness . An incrOne factor to consider when using positive pressure ventilation to predict fluid responsiveness in mechanically ventilated patients is right ventricular function. Using TDI of the tricuspid annulus, Mahjoub and colleagues  found thPassive leg raising (PLR) has been demonstrated to be applicable in both spontaneously breathing and ventilated patients. Correct positioning of the patient is essential. CO is measured using pulsed‐wave Doppler. An increase in CO or SV of >12 % during PLR was highly predictive of fluid responsiveness with an AUC of 0.89 for the cardiac index and 0.9 for the SV. Sensitivity and specificity values were 63 and 89 % for CO, and 69 and 89 % for SV, respectively . Using eAssessing intravascular volume should be the first step in managing all types of shock. A basic approach using RACE generally identifies gross hypovolemia. Where uncertainty exists about intravascular fluid status, more advanced techniques utilizing Doppler and dynamic maneuvers should be employed.The common mechanism in patients with obstructive shock is resistance to blood flow through the cardiopulmonary circulation. Specific pathological diagnoses are acute pulmonary embolus, cardiac tamponade, and dynamic outflow obstruction; on occasion, it also occurs as a result of a type A dissection of the thoracic aorta or a tension pneumothorax. Constrictive pericarditis is a rare cause of obstructive shock.Classic right heart changes identified by echo are diagnostically and prognostically very helpful, indeed essential, in the shocked patient . DiagnosThe McConnell sign, where good apical but poor free wall contraction is seen, is considered an important sign by some . HoweverAs a guide, a PAcT of 70–90 ms indicates a pulmonary artery systolic pressure of >70 mmHg. The presence of mid‐systolic notch also indicates severe pulmonary hypertension Fig. .Fig. 4ExThe classic 2D sign of pulmonary hypertension resulting in a marked increase in right ventricular pressures is paradoxical septal motion, whereby a D‐shaped left ventricle is seen on the parasternal short axis view. The presence of mobile thrombo‐emboli in the right heart chambers, inferior vena cava, or pulmonary artery are occasionally seen and may push the clinician to early administration of thrombolytic therapy. Examination of the left ventricle is also informative in severe acute pulmonary embolus, with small chamber size and reduced cardiac output reflecting reduced left heart filling.When the intrapericardial pressure exceeds right heart filling pressure (diastole), impaired filling of the chambers results in tamponade. A pericardial effusion is usually readily identified by echo, although size is no guide to the presence of tamponade. Fluid in the pericardial space is generally easy to differentiate from a pericardial fat pad or a pleural effusion. The crucial echo findings in RACE establishing the presence of tamponade and the need for rapid drainage are either right atrial wall systolic collapse for longer than one-third of the cardiac cycle, right ventricular wall diastolic collapse, and a dilated IVC .Doppler interrogation across the valves by the advanced user can be used for added diagnostic support. Normal respiratory variation results in an increase of tricuspid flow during inspiration and decrease during expiration with reciprocal changes occurring with mitral valve flow. Increases in peak tricuspid velocity are usually <25 % and peak mitral velocity <15 %, whereas with tamponade the variation is much greater.Echo is the investigation of choice in suspected cardiac tamponade, with the diagnosis generally easy to make when aligned with clinical findings. It also assists with urgent pericardiocentesis.The true incidence of dynamic left ventricular outflow obstruction in critically ill patients is unknown. It requires advanced echo Doppler expertise and in the past has usually gone unrecognized. Left ventricular wall hypertrophy classically has alerted the clinician to the possibility of hypertrophic obstructive cardiomyopathy and searching for LVOT obstruction would be seen as standard practice.Dynamic LVOT obstruction can be present in the aged ambulatory population in the absence of wall hypertrophy . FactorsA variety of cardiac changes can be associated with septic shock, although a normal study also is not unusual Table . AbnormaA variety of patterns can occur in septic cardiomyopathy, including global left and/or right ventricular hypokinesis, left ventricular segmental wall motion defect patterns, and subtle changes only identified on sensitive examination, such as with speckle tracking using global longitudinal strain . ImportaAnaphylactic, neurogenic, hypo‐adrenalism, and other less common causes of shock will be assisted by the application of urgent echocardiography, sometimes in directing the clinician away from the heart as a cause of shock in the presence of a normal study.Echocardiography is perhaps the most single useful tool in the diagnosis and management of shock, particularly where the etiology is undifferentiated or multifactorial. Non‐invasive and rapid to initiate, it can be applied at the bedside anytime during the day or night. An initial basic or RACE study can lead to commencement of treatment, with a more advanced study subsequently providing incremental and vital additional information.


Pre-zygotic isolation is often maintained by species-specific signals and preferences. However, in species where signals are learnt, as in songbirds, learning errors can lead to costly hybridization. Song discrimination expressed during early developmental stages may ensure selective learning later in life but can be difficult to demonstrate before behavioural responses are obvious. Here, we use a novel method, measuring changes in metabolic rate, to detect song perception and discrimination in collared flycatcher embryos and nestlings. We found that nestlings as early as 7 days old respond to song with increased metabolic rate, and, by 9 days old, have increased metabolic rate when listening to conspecific when compared with heterospecific song. This early discrimination between songs probably leads to fewer heterospecific matings, and thus higher fitness of collared flycatchers living in sympatry with closely related species. The association between male signals and female preferences can break down if both traits are learned prior to sexual maturity, and there is a risk of learning or preferring a heterospecific signal . For exaThe age at which nestlings discriminate among songs may have important consequences for song learning, because perception of vocalizations can be influenced by early auditory experience , even duThe auditory brain regions underlying song discrimination differentiate even before hatching , suggestFicedula albicollis) are cavity-nesting passerines that co-occur with closely related pied flycatchers (F. hypoleuca) in central Europe and on the Baltic island of Öland [Collared flycatchers  since 2002. By monitoring nest boxes at regular intervals, we determined the precise laying date, hatching date, and thus age of all nestlings. Both parents were ringed and measured, females during incubation and males while feeding nestlings. Collared and pied flycatchers sometimes hybridize , but we To test whether collared flycatcher embryos and hatched nestlings had different metabolic responses to conspecific and heterospecific songs, we measured the change in respiration during the period prior to and during song playbacks, hereafter referred to as ‘metabolic response’. We used a respirometer, where embryos and nestlings were kept at a constant temperature, and air parameters were measured once per second, although we used the mean oxygen estimate over each period as our response . In 2015, we collected eggs 2 days prior to the expected hatching date, as well as 4-, 7-, 9- and 12-day-old nestlings. Eggs and nestlings were exposed to 5 min of silence followed by 5 min of song from collared flycatchers or from heterospecific birds, specifically pied flycatchers and great tits . We compWe used linear mixed effects models to test whether the metabolic response could be explained by the age of the nestling, the type of song played , or an interaction between nestling age and song type. Additionally, we included the nest identity as a random effect to control for a shared environment. The focal age response was always compared to the embryonic response, and metabolic responses to heterospecific songs were always compared to the metabolic response to conspecific song. We implemented all models in lme4 in R ,19 and u3.t55 = 4.03, p = 0.0002), 9-day-old  and 12-day-old  nestlings responded more than embryos in eggs did, while 4-day-old nestlings responded similarly to embryos .We measured 15 embryos and 45 nestlings  in 2015 . We found that nestlings have an increased metabolic rate response to sound  compared with a silence treatment as they age, where 7-day-old , limits our ability to compare different heterospecific song types specifically.We demonstrate that collared flycatcher nestlings had increased metabolic rates in response to song playbacks 7 days after hatching, more than 10 days before fledging. As we did not use a non-song playback as a control, we can only conclude that they can respond to sound at this age . More importantly, we found that as young as 9-day-old collared flycatcher nestlings had a higher metabolic response to collared flycatcher song than to either pied flycatcher or great tit song. While 12-day-old nestlings responded greatest to pied flycatcher song, the small sample size of pied flycatcher song playback (Our results suggest that collared flycatchers begin to respond to sounds as early as 7 days post-hatching, and are able to discriminate between conspecific and heterospecific songs as early as 9 days post-hatching. The regions in the brain involved in song processing, discrimination and learning differentiate and become interconnected at different time periods in development . For exaIn contrast to 9-day-old nestlings, 12-day-old collared flycatcher nestlings had a higher metabolic response to heterospecific songs than to collared flycatcher songs . This apWhen song discrimination arises before song learning, juveniles may be in less danger of misimprinting and ultimately producing or preferring heterospecific songs. In most songbirds, song imprinting and learning is thought to occur after juveniles fledge from the nest . The abiPasserine nestlings develop consistently exposed to a cacophony of sounds that they must ignore in order to learn their conspecific song adequately. By developing song discrimination well before song learning, as appears to be the case in collared flycatchers and other species , nestlin