The late hyperenhancement on MSCT was presented as incomplete nuclide filling on the 99mTc-MIBI imaging. The results suggested that a single MSCT examination in previous myocardial infarction without revascularization facilitates to provide some valuable information on the nature of the occluded lesion, myocardial perfusion and globe cardiac function, which would be helpful to design appropriate revascularization strategy in these subjects.Accurate assessment of coronary chronic total occlusion (CTO) lesion is essential to design an appropriate procedural strategy before revascularization. The present study aims to evaluate the significance of a single multislice computed tomography (MSCT) examination in patients with CTO lesion. We retrospectively analyzed the clinical data of 23 CTO lesions in twenty patients underwent computed tomography coronary angiography (CTCA) and SPECT. The CTCA was more powerful and sensitive to determine the CTO lesion length (100% v.s 47.8%) and to identify the length and location of calcification in occluded vessels compared with the coronary angiography (CAG). The LVEF measured by MSCT was comparable to that from the gated SPECT. Myocardial perfusion imaging showed that the location of the early defect region identified by MSCT was corresponded to the nuclide filling defect on the stressed  Chronic total occlusion (CTO) of a coronary artery was documented in nearly 15% patients undergoing coronary angiography (CAG), and represents of 10% lesions treated by percutaneous coronary intervention (PCI)et alRecently, noninvasive imaging techniques, including computed tomography coronary angiography (CTCA), magnetic resonance imaging and single-photon emission computed tomography (SPECT), on the assessment of coronary artery disease have been developed and well documented in many studiesThe research was approved by Shanghai Chest Hospital ethics committee. Written consent was given by the patients for their information to be stored in the hospital database and used for research.During Jan 2010 to Dec 2010, a total of 600 patients with coronary heart disease were diagnosed in the Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University. Patients with atrial fibrillation, renal insufficiency (serum creatinine >120 mmol/L), known allergy to iodine contrast media, unstable clinical conditions, and other routine contraindications for MSCT or SPECT were excluded. After exclusion, 20 patients with a total of 23 CTO lesions identified by invasive CAG and MSCT were entered in this retrospective study.MSCT imaging was performed using a 64-detector single-source CT scanner . Beta-blockade was used if the heart rate was >65 beats/min. Scanning parameters were as follows: tube voltage 80 to 100 kV, tube current 650–800 mA, depending on body mass index, slice thickness  = 0.6 mm, increment  = 0.3 mm. An 80 ml bolus of Ultravist 370 was injected intravenously at a rate of 4 ml/s, followed by 25 ml saline flush at same flow rate was used. To time the scan, automated detection of peak enhancement in the aortic root was used. All images were acquired during an inspiratory breath hold, while an electrocardiogram (ECG) was used simultaneously for retrospective analysis of the data. MSCT images were acquired at 45 seconds and 5 minutes after bolus injection, and raw data were stored for subsequent reconstruction. Source images were analyzed by software, at 60–75% of the RR interval with a retrospective multi-cycle ECG gating algorithm, slice thickness  = 3 mm, reconstruction increment  = 0.3 mm to assure image quality. Axial slices were reconstructed for assessment of necrotic myocardium, various myocardial signal intensities, left ventricular ejection fraction (LVEF) and coronary artery stenosis. Radiation dose was determined based on the dose-length product documented in the CT scan protocol, separately for the ‘test bolus’ acquisition and the coronary CTA acquisition. Effective dose was estimated based on the dose-length product, using a conversion factor of 0.014 for chest CT in adults.Images were analyzed by two experienced cardiovascular radiologists, using a dedicated workstation with multiplanar reconstruction images, and volume rendering (VR). The VR allowed reconstruction of three-dimensional (3D) images . For each slice, endocardial and epicardial contours of the left ventricle in both end-systolic and end-diastolic periods were drawn manually and independently by a radiologist, and global function parameters, including end-systolic volume, end-diastolic volume and LVEF were calculated. To assess myocardial viability, the signal intensity in a separate myocardial area was measured.201TICI was performed when stress was induced, as indicated by any of the following: heart rate 85% of the expected highest heart rate or ≥130 bpm; severe angina symptoms; serious arrhythmia; systolic blood pressure ≥28 KPa or blood pressure decreased by >3 KPa; ST segment decreased by ≥2 mm. Myocardium perfusion imaging was performed 10 minutes later, and nuclide myocardial perfusion was observed.Dobutamine was injected intravenously at a rate of 5 µg/kg/min initially, then increased by 5 µg/kg/min every 3 minutes to 20 µg/kg/min. Injection of 111–148 MBq (3–4 mCi) 201TICI resting perfusion imaging was performed 4 hours after the first examination, and 201TI distribution was observed. 201TI redistribution was defined as an ischemic myocardial region; no redistribution was defined as an infarcted region; and reverse redistribution was defined as a damaged region.Delayed 201TICI resting perfusion imaging. 99mTc-MIBI 1110 MBq (30 mCi) was injected after 5 minutes, followed by 99mTc-MIBI perfusion imaging 1 hour later. The region with residual nuclide filling defect was defined as necrotic myocardium.Nitroglycerin (0.5 mg) was given immediately after delayed All above SPECT data were collected at three examination time-points. Parameter settings were as follows: low energy high resolution parallel-hole collimators, 64×64 matrix, 1.00 zoom, peak energy 70–80 keV, window width 20%, and dual-detector with an angle of 60°. Original data were collected for reconstruction. Horizontal long-axis, vertical long-axis and short-axis images were acquired to define early perfusion defect (ED) regions and LVEF, and to compare qualitatively between MSCT-derived zones.After the above noninvasive imaging examination, a conventional CAG was performed in all 20 patients according to the standard technique. An experienced operator blinded to the MSCT data visually evaluated the coronary angiograms.Continuous variables were expressed as mean ± standard deviation. Agreement between MSCT- and SPECT-derived LVEF was assessed with the Pearson's correlation coefficient and by Bland-Altman analysis.25 Statistical analysis was performed with SPSS 13.0 software. For Bland-Altman analysis, MedCalc® software was used. Statistical significance was defined as two-sided P value <0.05.The study population consisted of seventeen men and three women, mean age was 66±10 years. Mean heart rate was 61±3 beats/min, duration of breath hold was 15s. Clinical characteristics of the study population are summarized in A total of twenty-three CTO lesions were assessed by CTCA and CAG in 20 patients, including eight CTOs in the left anterior descending coronary artery, seven in the left circumflex coronary artery and eight in the right coronary artery. The length of the occluded segment was determined by CTCA examination in all 23 CTOs. In contrast, only 11 CTOs was measured by CAG because of missing collateral angiography. In eleven patients with data acquired both by MSCT and CAG, the length of the CTOs showed no significant difference between two methods . However, CTCA had higher sensitivity in the rate of detection of calcification lesion compared with CAG . Also, the length of calcification lesion could be successfully measured by CTCA (10.1±5.5 mm), but not by CAG. It is noted that CTCA could detect the detailed location  of calcification in occlusive vessels, and facilitated to visualize the tract of the occluded segment by using 3D reconstruction .The assessment of global LV function has important diagnostic and prognostic values in patients with CAD, especially for CTO. The average LVEF (58%±11%) obtained by gated SPECT was comparable to that measured with MSCT (57%±15%). The measurement of LVEF by using MSCT and SPECT methods are highly correlated with a r Pearson coefficient value of 0.79 (P<0.01). Bland-Altman plot analysis indicated a good agreement between the two methods .Quantitative analysis from MSCT biphasic imaging in all CTO patients showed a statistically significant difference in attenuation values between the normal and the perfusion defect regions in early scanning images . Three patients had residual perfusion defect regions in late scanning images and the attenuation values were lower than those in the normal regions . Late hyperenhancement (LH) regions were detected in eight patients and had higher attenuation values compared with the normal regions .201TI-SPECT perfusion imaging. In patients with late hyperenhancement in MSCT, 99mTc-MIBI imaging showed incomplete nuclide filling. By contrast, the complete nuclide filling was shown on 99mTc-MIBI imaging in patients without late hyperenhancement on MSCT scan. In addition, Accurate assessment of CTO lesion is essential to design the strategy of revascularization before PCI procedure. Accumulating evidence demonstrated that combination of multiple coronary artery imaging techniques provides a comprehensive assessment on coronary artery lesionsMany studies have demonstrated that the success rates of PCI for CTO are influenced by marked lesion calcification at the stump, severe tortuosity of the proximal vessel, the orientation and long length of the occluded segment as well as the location of the vessel distal to the occlusionSerious calcification was shown to have strong association with the success rate of CTO recanalizationThe most common reasons for procedural failure of PCI for CTOs include the inability to cross the lesion into the true lumen of the distal vessel with a guidewire (>60%), intimal dissection with creation of a false lumen, contrast extravasation, failure to cross the lesion with a balloon, or failure to dilate adequately. In fact, the absence of morphological information of occluded artery including tortuosity or bending, exact occlusion length or vessel diameter, localization of soft or calcified plaque with traditional CAG, significantly increase the difficulty of CTO recanalization by PCIPrevious studies have shown that LVEF measured by MSCT had an excellent correlation with that by SPECT or transthoracic echocardiography201TI-SPECT perfusion imaging. The late hyperenhancement on MSCT examination was shown to be incomplete nuclide filling on 99mTc-MIBI imaging. The results suggested that during a single examination, MSCT can provide a comprehensive cardiac assessment of lesion morphological, myocardial perfusion and cardiac function, indicating the feasibility of MSCT in assessment of CTO lesion.In addition, with its high spatial and temporal resolution achievable, MSCT recently was used to assess cardiac function and myocardial perfusionFor patients with CTO, comprehensive cardiac assessment, including the occluded segment, cardiac function and the viable myocardium should be performed prior to decision-making. The present study confirmed the ability of MSCT to provide comprehensive cardiac information of CTO lesions. However, there are still some limitations. For example, because of exposure of patients to X-rays and potentially toxic contrast agents, MSCT perfusion imaging is presently unlikely to become a first-line test to assess myocardial viability in all patients. Until now, this modality has only been recommended for use in patients with definite CTO or previous myocardial infarction. Also, it is still difficult and time-consuming to analyze the myocardial perfusion images. With the development of dedicated software, the problem of the heavy workload could be diminished in the future.In conclusion, in this study, we have demonstrated that except for screening diagnostic purpose on coronary heart disease, a single MSCT examination in previous myocardial infarction without revascularization might provide some valuable information on the nature of CTO lesion, myocardial perfusion and globe cardiac function, which would be helpful for subsequently designing appropriate revascularization strategy in these subjects.


In recent weeks, two pioneering cardiac surgery teams, Dhital and colleagues in Australia  and LargAs would be expected, a handful of specialists from around the world enthusiastically recognize a realistic complement to “traditional” cardiac donation after brain death (DBD), whereas others may condemn this approach, considering the ethical, practical, and liability aspects as indomitable. Many remain uncertain, possibly because of the apparent paradox, or at least the uncertainty, surrounding transplantation of hearts obtained from donors after “cardiac death.” The Times recently titled “«dead» hearts successfully transplanted into living patients” , 3. WhenOne important aspect of these reports lies in the fact that this approach goes against the established dogma that irreversible lesions immediately follow the onset of myocardial ischemia. Indeed, the very first heart transplantations, including those performed by Barnard in 1967, were performed with DCD organs . DistincImportantly, all potential DCD grafts undergo unavoidable warm ischemia before cold preservation solutions can be instilled. Notably, the warm ischemic times reported by Dhital for three of their cases ranged between 22 and 28 min, in agreement with previous pediatric DCD heart transplantations  and multex vivo, portable perfusion apparatus primed with the donor’s own (deleukocyted) blood. In all cases, hearts resumed contractile activity and lactate metabolism was assessed for graft evaluation before the decision to proceed with transplantation was taken. Using a somewhat different approach, Large’s group in the UK returned the heart to a beating state in situ to enable functional graft evaluation prior to ex vivo perfusion. For DCD hearts, graft evaluation is especially critical since no surgeon would take the risk of transplanting a heart without assessing its suitability. Indeed, as compared to traditional procedures in which graft evaluation and the decision to transplant occur before donor circulatory arrest, heart perfusion in DCD, whether it be regional in situ or ex vivo perfusion, provides the opportunity for graft evaluation after donor circulatory arrest and in a contracting mode. Also, with continuous perfusion on a portable system, assessment can be prolonged, for example in case of ambiguous results, and the decision to transplant can be delayed.Now these recent reports of DCD heart transplantation are not simply arbitrary provocations, but rather the result of mature, albeit somewhat differing, strategies. Providing that the warm ischemic time was <30 min, Dhital and colleagues instilled hearts with cardioplegic solution before establishment on an All the same, precise, evidence-based protocols for every step of the DCD heart transplantation process remain to be established. Indeed, conventional methods used with DBD hearts may not yield optimal outcomes as DCD hearts have undergone a period of ischemia prior to procurement and may thus be less tolerant than DBD hearts to additional exposure to damaging conditions. For example, given that DCD hearts are already arrested at the time of procurement and that strategies effective in limiting ischemic heart damage may only be allowed at reperfusion (procurement) for ethical reasons, conventional cardioplegic solutions may not be optimal for DCD hearts. Indeed, Thatte and colleagues have proposed a new cardioplegic solution developed specifically to limit damage to DCD heart grafts . Along sex vivo perfusion, Colah and colleagues demonstrated that left ventricular hemodynamics may be of potential value for graft evaluation (Importantly, it may well be that evaluation reliability will be improved with the addition of other parameters in the future. We, and others, have shown that several relatively easily measurable parameters correlate very well with post-transplantation performance. For example, in pre-clinical aluation ; while oaluation , 15.ex vivo graft perfusion which may contribute to a better recovery, but also cardioprotective pharmacological and molecular strategies. It is true that varying ethical and legal limitations, such as the duration of the no-touch period, among countries are likely to influence the precise clinical strategies chosen (The DCD approach for cardiac transplantation should be contemplated in light of not only new technological advances, such as s chosen . StrategThe recent reports from Australia and the UK may one day be seen as critical events, marking fundamental changes in the way we view medicine. By transplanting hearts with potentially higher risks of post-operative dysfunction, both transplantation team and patient are asked to accept possibilities of higher post-operative morbidity and mortality, as well as reduced survival as compared to current standards. In other words, increasing the pool of donors with DCD may imply a “weakening” of reported transplantation results, although this “weakening” effect may already be ongoing, considering the increasing use of marginal donors , or the Obviously, many aspects must be thoroughly evaluated before DCD heart transplantation can become a routine procedure. Although these recent reports demonstrate the feasibility of this approach as a concrete and rapidly applicable possibility for helping more patients on the waiting list, it would be wrong to generalize without careful ethical, cultural, legal, and practical considerations. Nevertheless, there is an urgent need to find a solution for the rapidly growing number of patients who will never receive a DBD heart . We defThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Tuberous sclerosis complex (TSC) is an autosomal-dominant tumor suppressor gene syndrome that is characterized by the development of distinctive benign tumors and malformations in multiple organ systems . Cardiac rhabdomyomas are intracavitary or intramural tumors observed in 50–70 % of infants with TSC but only cause serious clinical problems in a very small fraction of these patients ; most individuals have no clinical symptoms and their tumors spontaneously regress. However, despite being clinically silent, these lesions can provoke arrhythmias and heart failure .We here report the clinical findings of an infant suffering from TSC complicated with dilated cardiomyopathy (DCM) after the regression of cardiac rhabdomyomas. Although his tumors improved spontaneously, tachycardia and irregular heart rate due to frequent premature ventricular and supraventricular contractions persisted from the newborn period and were refractory to several medications. His cardiomyopathy was suspected to have been induced by the tachycardia or arrhythmia. We found carvedilol therapy to be safe and highly effective in treating the cardiomyopathy. To our knowledge, this is the first case report of TSC with DCM after regression of cardiac tumors and its successful treatment.The patient’s clinical course suggests that careful life-long disease management is important, even in TSC patients without apparent symptoms. Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor gene syndrome that is characterized by the development of benign tumors and malformations in multiple organ systems . AlthougThe male patient was born spontaneously at term after an uneventful pregnancy despite the detection of cardiac tumors at 36 weeks by fetal echocardiography. After birth, he was diagnosed as having TSC based on the diagnostic criteria of white leaf-shaped hypomelanotic macules, a subependymal nodule, and a retinal hamartoma . MultiplAt 20 months of age, the patient’s cardiac function was preserved; echocardiography revealed a left ventricular end-diastolic diameter (LVDd) of 30.8 mm (Z-score: 0.5) and a left ventricular fractional shortening (LVFS) of 28 %.At 23 months of age, he was admitted to our hospital due to cardiac dysfunction. His body height and weight were 85 cm (+0.1 SD) and 11.5 kg (+0.1 SD), respectively. Blood pressure was 88/47 mmHg. Heartbeat was irregular at 134 bpm without extra heart sounds or murmurs. Neither hepatomegaly nor pretibial edema was observed. Laboratory data including blood cell counts, electrolytes, CRP, CK-MB, troponin T, glucose, ammonia, lactic and pyruvic acid, and thyroid function showed no abnormalities. However, brain natriuretic peptide (BNP) and human atrial natriuretic peptide levels were markedly increased at 619 pg/ml  and 654 pg/ml , respectively. There were no significant increases of viral antibody titers in his serum, including those for the Coxsackie virus, adenovirus, or echovirus. His cardiothoracic ratio was 64 % on a chest radiograph. Twelve-lead ECG revealed irregular tachycardia (139 bpm) and sporadic PSVC without ST abnormality or wide QRS duration Fig. . Severe Diuretics and angiotensin converting enzyme inhibitor were administered as anti-heart failure therapies. To control tachycardia and reduce afterload on the failing heart, we also commenced oral administration of carvedilol at 0.15 mg/day (0.01 mg/kg/day) that was gradually increased to 3.0 mg/day (0.3 mg/kg/day) 3 months later. Although frequent PSVC persisted, the boy’s mean HR gradually decreased and the incidence of PVC and its short run became markedly diminished Fig. . BNP graWe here report the clinical findings of an infant boy suffering from TSC complicated with DCM. Although his tumors regressed spontaneously, tachycardia and heart rate irregularity due to frequent PSVC and PVC persisted from the newborn period. After the commencement of carvedilol aimed to control heart rate and reduce afterload in the failing heart, BNP and LV systolic function improved within months and LV volume recovered slowly over several years.The most frequent cardiac involvement in TSC is multiple cardiac rhabdomyomas, which may spontaneously regress during the first few years. However, TSC is a known cause of heart failure because of myocardial depression and inflow or outflow obstruction by tumors –3. TSC iTSC-related cardiac rhabdomyomas can combine with several other kinds of arrhythmias –3. HowevAtrial ectopic tachycardia is the most common arrhythmia in pediatric arrhythmia-induced cardiomyopathy (AIC), for which beta-blockers are frequently used as the first-line therapy . Heart rThe relationship between arrhythmia and cardiomyopathy can be difficult to characterize because arrhythmias may exist for years before their recognition and the development of cardiomyopathy . CardiacAs a non-selective beta-blocker with additional vasodilating properties, carvedilol has been demonstrated to improve survival in adult patients with severe chronic heart failure . In a muTo our knowledge, this is the first reported case of an infant suffering from TSC complicated with DCM after the regression of cardiac rhabdomyomas whose cardiomyopathy was suspectedly induced by arrhythmia. We found that carvedilol therapy was safe and effective for treating the cardiomyopathy despite the patient’s very young age. TSC rhabdomyomas generally disappear spontaneously and have a good prognosis. However, the present case exhibited heart failure with severely reduced LV function during the course of illness, suggesting the importance of meticulous life-long follow-up, even in apparently asymptomatic patients with TSC.Written informed consent was obtained from the patient’s parents for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.


Introduction: To study effects of various sites of right ventricular pacing lead implantation on left ventricular function by 2-dimensional (2D) speckle tracking for radial strain and LV dyssynchrony.Methods: This was retrospective prospective study. Fifteen patients each with right ventricular (RV) apical  and non-apical  were programmed to obtain 100% ventricular pacing for evaluation by echo. Location and orientation of lead tip was noted and archived by fluoroscopy. Electrocardiography (ECG) was archived and 2D echo radial dyssynchrony was calculated.Results: The baseline data was similar between two groups. Intraventricular dyssynchrony was significantly more in apical location as compared to non-apical location . The left ventricular ejection fraction was decreased more in apical location than non apical location. Interventricular dyssynchrony was more in apical group but was not statistically significant. The QRS duration, QTc and lead thresholds were higher in apical group but not statistically significant.Conclusion: Pacing in non apical location (RV mid septum or low RVOT) is associated with less dyssynchrony by specific measures like 2D radial strain and correlates with better ventricular function in long term. The relationship between RV apical pacing and mechanical dyssynchrony has been studied in various trials.11 Though they provide good patho-physiologic insight, they are not sufficient to recommend an optimal RV pacing site mainly because of the variability in lead insertion site. We planned this study to answer some of these questions by identifying the lead position on fluoroscopy and then comparing electrocardiography (ECG) and dyssynchrony parameters with ventricular function on medium term follow up.Cardiac pacing is treatment of choice in the management of patients with bradyarrhythmias and drug refractory heart failure in the form of cardiac resynchronization therapy (CRT).2-dimensional (2D) strain based speckle tracking which evaluates circumferential strain (CS), longitudinal strain (LS), and radial strain (RS) by self tracking of myocardial segments allows better advantage in comparison to tissue Doppler imaging as it does not depend on Doppler angle and also monitors strains in two dimension rather than one dimension, thus increasing reproducibility and accuracy. Therefore, we used this technique in our study.This was a retrospective-prospective study, in which we retrospectively selected 30 patients with single chamber pacemaker (VVI) with RV apical  and RV non apical  pacing and who satisfied the inclusion criteria and prospectively followed them for 40 months and evaluated them for ventricular function and dyssynchrony parameters.Patients with normal pacemaker function, without any structural heart disease, who were more than 18 years, had ≥ 80% pacing at follow up (by pacemaker interrogation or in 2 ECGs taken at two different times) and who provided consent for the study were included in the study. Patients who refused consent, had coronary or structural heart disease, cardiomyopathies or any form of cardiac surgery were excluded from the study.The date of pacemaker implantation, indication for implantation, lead implant location, lead parameters and hardware used while implanting the pacemaker were noted from patients’ records. Fluoroscopy was performed after obtaining patients consent. The lead location and orientation of the lead tip were noted and archived by fluoroscopy  . A 12 leWhen 100% ventricular pacing was confirmed, echocardiography was performed with PHILIPS iE 33 . First, the position of the lead was confirmed and then 2D short axis images of the left ventricle at the mid papillary muscle level with breath held in expiration was obtained, following which four loops with frame rate of 50 to 80 per second was recorded. After this all the analysis was done offline using Q-lab software for PHILIPS iE 33 machine. During offline evaluation, first, the endocardium was traced manually at the end-systolic frame and divided into 6 segments and then strain curves for each segment was constructed. After this, the time to peak radial strain of each segment was measured. And then finally, the absolute time interval of peak strain between anteroseptum and posterior segment was calculated along with radial dyssynchrony . We alsot test and presented as mean ± SD. P<0.05 was considered as significant. Pearson correlation coefficient test was used to see correlation between various dyssynchrony indices.All statistical analysis was done using SPSS 14 software . Categorical data were analyzed using chi-square test. Continuous data were analyzed by student P=0.829); while the mean age of females was 61.1 ± 7.3 years vs. 63 ± 18.7 years respectively (P=0.796). Overall the mean age of apical and non apical pacing was 62.0 ±15.3 years vs. 61.9 ±17.1 years respectively (P=0.991).Thirty patients; 15 with RV apical  and 15 with RV non apical (mid septum and low RVOT) pacing having single chamber pacemaker with VVI pacing were studied. 7 patients (46.6%) were males and 8 (53.3%) were females  in each Five patients in apical group had pacing lead in RV apex position and 10 patients had in apical septal position; whereas in non apical group 7 patients had pacing lead in mid septum and 8 patients at low RVOT pacing . At baseP=0.575). There was no significant difference in lead impedance, lead threshold, and percentage change in lead impedance in both the groups at baseline and on follow up . QTc duration was 466.1 ± 22.9 ms and 463.5 ± 23 ms respectively (P=0.759). Mean QRS Axis was -69.46 degrees in apical group and +76.76 degrees in non apical group  than non apical location . But there was no significant difference among percent change in EF when both groups compared to each other . There was no significant difference between mean peak strain in the 2 groups  though it was less in non apical group. Interventricular dyssynchrony was also more in apical group but not statistically significant   .P=0.035) and non apical group  though it was significant only in apical group. It was positively correlated with SL delay in apical  and negatively in non-apical group  but it was not statistically significant  Lewicka-Nowak et al12 were able to show significant drop in ejection fraction. Similarly, the result of other short term studies15 could also be confounded by the same problem. In our study, the mean duration of follow up was 38.2 months in apical group and 32.6 months in non-apical group which may be a considerable long time to unmask the deleterious effect.There was no significant difference between 2 groups regarding baseline mean age, DM, hypertension, dyslipidemia, smoking. The duration of study has been a concern in pacemaker studies as short duration may not be able to mask the true deleterious effect. Tse et al16 study we too did not find any difference in the lead threshold, lead resistance and percentage change of both parameters in both groups, both in the beginning as well as on follow up. We in our study found the mean QRS, QTc duration and left ventricular ejection fraction was not statistically significant in RV apical and non apical group. However, a meta-analysis done by de Cock et al13 and another trial by Victor et al15 showed shorter or near normal QRS duration was associated with better LV contraction and less LV dysfunction in RVOT and septal pacing than in apical pacing. Though difficult to explain it may be due to shorter duration of our study and small sample size. The intraventricular dyssynchrony was significantly more in apical pacing group than in non apical pacing group; however, the peak strain, and also the interventricular dyssynchrony was not significant in the two group. Pearson correlation showed significant positive correlation between radial dyssynchrony and SPW delay in apical pacing group. Though non significant, SL delay was positively correlated with radial dyssynchrony in apical pacing and negatively correlated in non apical pacing group. Favorable haemodynamics and less dyssynchrony was seen in RVOT and septal location pacing in comparison to apical location pacing in most trials17,and a meta analysis13; however, some contradicts too.18 More physiologic activation pattern of LV activation may have lead to less LV dyssynchrony in these trials. One study from Korea19 showed despite increase in QRS duration after pacing; M-mode, Doppler and TDI failed to show any difference in dyssynchrony parameters. 2D speckle tracking method for the dyssynchrony was not used in this study. A study from Japan20 that used speckle tracking method was able to show right ventricular septal (RVS) pacing preserves global left ventricular longitudinal function in comparison with RV Apical (RVA) pacing. They noted that due to heterogeneous RV apical pacing there was deterioration on LV longitudinal contraction and therefore, RV septal pacing could be a better pacing alternative when LV dyssynchrony and longitudinal LV function was concerned. Similarly, in our study too we found less radial dyssynchrony in non-apical location which may result in favorable hemodynamics and preserved LV function on long term follow up. However due to small sample size the other correlation may not have been significant. As noted by others21 tissue Doppler imaging and derived strain and strain rate measurements lacks reproducibility which may limit their use in clinical studies. The lack of reproducibility may be because of the dependency on Doppler angle for their measurement. Other factors like regional myocardial velocities that causes tethering effects from other myocardial segments and translational motion of the entire heart may play role. Due to avoidance of these limiting factor 2D speckle tracking technique for strain measurement may provide better information.25As with Burri et alRight ventricular apical and high septal pacing to preserve left ventricular function (Protect Pace)"26 study showed no deterioration in LV functions when RV apical pacing was compared to septal pacing at two years. However, in a subgroup analysis27 of the same patient inefficient dyssynchronous contraction and decrease in apical strain was seen with RV apical pacing which may lead to global LV function deterioration. There are two other studies that are underway  and Right Ventricular Apical versus Septal Pacing [RASP]) that may throw light on this problem.28Though recently published "The sample size is small and also the duration may not have been enough to study some factors that may have affected the study. However, we plan to take this study as a pilot study and extend this study by recruiting more patients for a longer duration so that a robust conclusion could be reached.Pacing in the non apical location (RV mid septum or low RVOT) is associated with less dyssynchrony by specific measures like 2D radial strain and may correlate with better ventricular function in the long term. However, longer duration follow up and larger sample size is required to confirm this finding.The Study was approved by Institutional ethical committee.Authors declare no conflict of interest in this study.


Although myocardial function is clinically assessed with global measurements , recent research has shown that regional measurements, such as wall-thickening, strain, and torsion, could provide earlier sub-clinical markers to examine left ventricular (LV) dysfunction and myocardial diseases.Cardiovascular Magnetic Resonance myocardial feature tracking (CMR-FT) technique is used to post-process cine CMR images to provide a quantitative assessment of LV motion deformation parameters. It derives myocardial motion deformation from image features such as myocardium-blood cavity boundary and pixel intensities, and relies only on standard cine images to extract motion deformation. The main objective of this study is to compare two current feature tracking software packages in hypertensive patients.29 hypertensive subjects were prospectively recruited from a tertiary hypertension clinic and enrolled to undergo CMR examinations. All images were acquired using a 1.5T scanner , and a cardiac surface coil. LV function was assessed with cine acquisitions in the following planes: 2-chamber, 4-chamber and short-axis slices .LV deformation was analysed using: 2D Cardiac Performance Analysis, MR  and CVI42 . Endocardial and epicardial LV contours were drawn manually at the end diastolic phase in order to achieve best tracking results; the software packages then allow semi-automated analysis to provide quantitative measurement of global and regional deformation parameters.Results of circumferential, radial, and longitudinal strains are given in table From our results, there is a trend in circumferential strain in short-axis  where there is a significant difference in the values obtained by the two software packages, whereas radial and longitudinal strain values showed no clear trend. Therefore, there is a clear need for a gold standard validation to assess the accuracy of cardiac motion analysis software packages.This project is funded by a Saudi scholarship to the author.


Churg-Strauss syndrome (CSS) is a rare systemic necrotizing vasculitis characterized by asthma, hypereosinophilia, cardiac failure, renal damage and peripheral neuropathy. CSS typically develops in three clinical phases, beginning with asthma, followed by tissue eosinophilia and finally in a systemic small-vessel vasculitis. During the late phase, coronary vessels and myocardium are interested leading to a variety of clinical manifestations such as myocarditis, heart failure, pericarditis and coronary vasculitis. Heart involvement is found in over 50% of autopsied CSS patients with evidence of an extremely high mortality in those with cardiac disease left untreated. Cardiac MR has emerged as a promising technique not only for the early diagnosis of cardiac involvement in the setting of this insidious and complex condition, but also for a better risk stratification and tailoring of immunosuppressive therapy.We studied 11 CSS pts with CMR. Standard volumes and LGE-CMR scans were carried out on a 1.5-T scanner , with a dedicated cardiac protocol including right and left ventricular volumes, regional and global wall motion assessment, tissue characterization with T1 and T2-weighted sequences, T1 and T2 mapping and conventional late-enhancement (LGE). MOLLI T1 maps were acquired from 3 short axis slices, extracellular volume was derived from pre and post contrast MOLLI T1 mapping calibrated by blood hematocrit.Nine out of 11 pts showed the following cardiac involvement: pericarditis (3/11), STEMI (3/11), heart failure (3/11). We observed a case of severe cardiogenic shock requiring extracorporeal membrane oxygenation (ECMO). Intraventricular thrombus was detected in 3 out of 11 pts, 2 developed cardio-embolic stroke. Comparing pts with CSS with normal subjects indexed volumes tended to be higher  and LVEF resulted significantly lower , with no differences in cardiac mass and right ventricular function. LGE was detected in 9 out of 11 pts (82%), 2 with endocardial LGE, 3 intramyocardial LGE, 3 LGE of papillary muscles, 1 LGE with infiltrative pattern. Higher values of pre-contrast T1  were detected in CSS pts compared to the control group. Patients with EF < 60% had higher LV volumes compared to those with EF ≥ 60%  and higher ECV compared to healthy subjects .Patients with CSS have lower LVEF and higher pre-contrast T1 values. LGE was positive in the majority of patients, most often with an endocardial layer pattern. In above 25% of patients a left ventricular thrombus was detected by CMRI.None.


Reversible, depressed cardiac function is frequently encountered during septic shock and commonly called septic cardiomyopathy. Previous studies demonstrated reduced ejection fraction and left ventricular dilatation in both humans and animal models. However, the majority of the studies in humans excluded pre-existing cardiac disease and animal studies were performed on healthy specimen and/or without vasopressor support during sepsis. In order to more closely mimic the actual patients’ conditions on intensive care units and to assess the influence of both cardiac comorbidity and vasopressor support on septic cardiomyopathy, we evaluated the left ventricular function in a porcine model of resuscitated septic shock with pre-existing atherosclerosis.n = 8 animals; n = 5 pigs underwent sham procedure. Sepsis resuscitation included administration of fluids and noradrenaline. Left ventricular function was analysed via pressure-conductance catheters before, 12 and 24 h after the induction of sepsis.Hypercholesterolaemic, atherosclerotic pigs due to homozygous low-density lipoprotein receptor mutation and high-fat diet were anaesthetised and surgically instrumented. Faecal peritonitis was induced by inoculation of autologous faeces into the peritoneal cavity in τ decreased while dp/dtmax increased. Cardiac nitrotyrosine formation increased while expression of the endogenous hydrogen sulphide (H2S)-producing enzyme cystathionine γ-lyase (CSE) decreased.The main findings were impaired ventricular dilatation (no significant change in the left ventricular end-diastolic volume) and unchanged ejection fraction in septic pigs with pre-existing atherosclerosis. The relaxation time constant 2S release in the pathophysiology of septic cardiomyopathy.The data of the present study are in conflict with previously published data from healthy animal models, most likely as a result of ongoing resuscitation including noradrenaline treatment or intrinsic pathophysiologic processes of the pre-existing atherosclerosis. Moreover, increased nitrotyrosine formation and decreased expression of CSE suggest the implication of augmented oxidative/nitrosative stress and/or reduced bioavailability of nitric oxide as well as diminished endogenous HThe online version of this article (doi:10.1186/s40635-016-0089-y) contains supplementary material, which is available to authorized users. There is extensive evidence for reversible intrinsic cardiac dysfunction and myocardial depression in patients with sepsis or septic shock, a condition frequently called septic cardiomyopathy . These cThe study was approved by the University of Ulm Animal Care Committee and the Federal Authorities for Animal Research. The experiments were performed in adherence to the National Institute of Health Guidelines on the Use of Laboratory Animals and the European Union “Directive 2010/63/EU on the protection of animals used for scientific purposes”. The present study is a post hoc analysis of the data available from the vehicle-treated group of a previous study  and sham−1 azaperone. After establishment of an intravenous access via the ear vein, anaesthesia was induced with propofol (1–2 mg kg−1) and ketamine (1–2 mg kg−1). The pigs were endotracheally intubated, and their lungs were mechanically ventilated  of 35–45 mmHg, inspiratory/expiratory (I/E) ratio 1:1.5, fraction of inspiratory oxygen (FiO2) 35 %, positive end-expiratory pressure (PEEP) 10 cm H2O, peak airway pressure ≤40 mmHg). Anaesthesia was maintained with continuous intravenous infusion of pentobarbitone (8–12 mg kg−1 h−1). Buprenorphine was used for analgesia . Pancuronium (0.1 mg kg−1 h−1) ensured appropriate muscle relaxation. Ringer’s solution (10 ml kg−1 h−1) was infused for fluid homeostasis.Before the experiments, pigs were fasted for 12 h with free access to water. Intramuscular premedication consisted of 2.5 mg atropine and 5 mg kgBoth internal jugular veins were exposed. A heat exchange catheter was inserted in the left internal jugular vein to control and maintain body core temperature at 37.5–38.5 °C. A central venous catheter sheath was placed in the right internal jugular vein. The central venous catheter was subsequently used for infusion therapy and application of intravenous drugs including catecholamines. A balloon-tipped thermodilution pulmonary artery catheter was inserted via the sheath and used for the measurement of the central venous pressure (CVP), mean pulmonary arterial pressure (MPAP), pulmonary artery occlusion pressure (PAOP) and cardiac output (CO). An arterial catheter was inserted into the femoral artery to monitor the arterial blood pressure (MAP). Exposure of the left carotid artery was followed by the insertion of an arterial catheter sheath for the introduction of a pressure-conductance catheter allowing the analysis of LV function. A midline mini-laparotomy allowed the insertion of a catheter into the bladder to collect urine. Two tubes were placed through the abdominal wall into the peritoneal cavity for subsequent induction of peritonitis. During surgery, hydroxyethyl starch was infused as needed to maintain cardiac filling pressures.−1 autologous faeces was collected during premedication, dissolved in 500 ml 0.9 % saline and incubated at 38 °C for 12 h. Of the supernatant, 3 ml kg−1 was injected into the peritoneal cavity via the abdominal tubes. Eight animals received autologous faeces while five animals underwent sham surgery without inoculation of faeces. Animals were monitored for 24 h, and additional data sets were acquired 12 and 24 h after the induction of peritonitis. Ringer’s solution (10 ml kg−1 h−1) was continuously infused. For additional circulatory support, hydroxyethyl starch  was administered. If MAP remained below baseline values despite volume resuscitation, noradrenaline was used to stabilize MAP at pre-peritonitis values. However, infusion rates of noradrenaline were not further increased if the heart rate was higher than 170 beats per minute (bpm) in order to avoid tachycardia-induced myocardial ischemia. One animal in the sepsis group had a heart rate of 173 bpm after 24 h, and therefore, noradrenaline application was not further increased. Respirator settings were modified  during the experiments when the Horowitz index  to FiO2) dropped below 300 or 200 mmHg, respectively. FiO2 was incrementally increased to maintain an arterial haemoglobin O2 saturation of ≥90 %. At the end of the experiment, the pigs were euthanized under deep anaesthesia via injection of potassium chloride.After 4 h of surgery, the pigs were allowed to recover for 8 h before baseline data were collected. Subsequently, faecal peritonitis was induced. For this purpose, 1 g kg2, pCO2), glucose, lactate, base excess and LV function. For the assessment of LV function, a pressure-volume catheter  was placed via the arterial catheter sheath in the left carotid artery. Subsequently, the catheter was advanced towards the heart and into the left ventricle across the aortic valve under the control of the online arterial pressure signal. The catheter was connected to a Sigma 5 DF signal processor (CD Leycom). Prior to insertion, the catheter was put into 0.9 % saline at room temperature and calibrated according to the manufacturer’s protocol. The principle of the pressure-volume catheter has been described previously [parallel conductance and can be determined by the injection of a bolus of hypertonic (20 %) saline via the central venous catheter. The saline bolus is assumed to temporarily change the blood conductivity without affecting the parallel conductance. From this change in conductivity, parallel conductance can be obtained. Knowing the specific conductance of blood, the electrode spacing and the parallel conductance, the total volume of the ventricle can finally be calculated. Thus, the pressure-volume catheter allows continuous online recording of cardiac pressures and volumes. Further analysis of cardiac data from pressure volume loops was performed using Conduct NT software (CD Leycom).Immediately before, 12 and 24 h after induction of faecal peritonitis, data sets were collected. Measurements included haemodynamics , arterial and mixed venous blood gases (pOeviously . Briefly2S-producing enzyme cystathionine γ-lyase (CSE). Therefore, the specimen was fixed in formalin, embedded in paraffin, dewaxed in xylene and rehydrated with a graded series of ethanol. After incubation in citrate buffer and boiling for heat-induced antigen retrieval, samples were blocked with goat sera and subsequently incubated with primary anti-nitrotyrosine  or anti-CSE antibodies . Primary antibody detection was performed by alkaline phosphatase-conjugated secondary antibodies and visualized with a red chromogen  followed by counterstaining with haematoxylin. Slides were visualized using a Zeiss Axio Imager A1 microscope with a ×10 objective. Quantification for intensity was performed using the AxioVision 4.8 software . Results are presented as median densitometric sum red. Specimens of coronary arteries were stained with haematoxylin. Polyclonal anti-adipophilin antibody  was used for adipophilin staining.Heart specimens were immediately collected post-mortem and analysed for nitrotyrosine formation and expression of the endogenous Hp value less than 0.05 was considered statistically significant. GraphPad Prism 6 software was used for statistical evaluation and graphical display.All data are expressed as median (IQ range). Differences within each group were tested by using a Friedman analysis of variance on ranks and a subsequent Dunn’s test for multiple comparisons with Bonferroni correction. Inter-group differences were analysed by the Mann-Whitney rank sum test. A p < 0.05) despite aggressive supportive volume and vasopressor therapy. Consequently, heart rate (p < 0.005) and cardiac output (p < 0.005) were significantly increased at 12 and 24 h of sepsis when compared to pre-shock values. MPAP progressively increased both in septic and sham animals but was significantly higher in septic animals at the end of the experiment (p < 0.02). Systemic vascular resistance significantly decreased in septic animals compared to baseline (p < 0.003) and to control group (p < 0.005).Table 2 (p < 0.05) and the Horowitz index (p < 0.001) as well as progressive lactic acidosis.Table max values significantly increased after 12 and 24 h in septic pigs compared to baseline values. dp/dtmin, stroke volume, ejection fraction, left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV) did not reveal significant statistical differences between both groups and within groups compared to baseline. However, slightly lower LVEDV together with higher left ventricular end-diastolic pressure (LVEDP) after 24 h of sepsis indicate increased LV stiffness. The isovolumetric relaxation time constant τ significantly decreased in septic pigs compared to control pigs (p < 0.02) and to baseline values (p < 0.01).The cardiac function data are summarized in Table p < 0.002, Fig. 2S-producing enzyme CSE significantly decreased during sepsis  impaired LV dilatation (no significant change in LVEDV), (2) unchanged ejection fraction and 3) increased cardiac nitrotyrosine formation and reduced cardiac expression of CSE in septic animals with pre-existing atherosclerosis and ongoing vasopressor support. Parker et al. initially described a reversible reduction of LV systolic function measured as EF and a marked LV dilatation in patients with septic shock. Interestingly, these changes only occurred in survivors of sepsis while non-survivors showed no ventricular dilatation and presented with preserved EF. However, afterload assessed as systemic vascular resistance index was decreased in non-survivors, which might have resulted in sustained EF despite possible systolic impairment. LV dilatation was considered as adaptive response to maintain stroke volume despite cardiac dysfunction  increase and muri impairedmax was significantly elevated in septic animals after 24 h. The increase in dp/dtmax most likely reflects catecholamine treatment and the positive inotropic effects of noradrenaline [−1 min−1 (0.52–2.11) in septic versus 0.06 μg kg−1 min−1 (0.02–0.13) in sham pigs). As dp/dtmax is essentially heart rate dependent [max. In contrast to dp/dtmax, EF remained largely unchanged for 24 h in the septic swine. However, EF represents a load-dependent parameter of LV function [max and EF in combination with NA treatment may have obscured the detection of impaired LV systolic function. Of note, in a rat model of septic shock with severe myocardial dysfunction, noradrenaline administration 18 h after the induction of sepsis significantly improved cardiac performance associated with increased EF and dp/dtmax [In our study on hypercholesterolaemic pigs with pre-existing atherosclerosis, dp/dtrenaline  -producing enzyme. CSE and endogenous H2S have also been implicated in atherogenesis: Overexpression of CSE exerted anti-atherosclerotic effects [2S have been shown to be significantly reduced in patients with CAD [2S donor sodium hydrosulphide (NaHS) improved diastolic heart function by significantly reducing LVEDP and improving dp/dtmin in isolated rat hearts subjected to I/R [2S due to decreased expression of CSE in the atherosclerotic pigs in our study might also be responsible for impaired diastolic cardiac function besides increased nitrotyrosine formation.Additionally, sepsis significantly reduced cardiac expression of CSE, an endogenous hydrogen sulphide (H effects , whereas effects . Plasma with CAD . Moreovewith CAD , and CSEwith CAD . Adminisd to I/R  as well d to I/R . Thus, cd to I/R , reducedThe major limitation of our study represents the lack of healthy control pigs. As mentioned above, the present study is a post hoc analysis of the data available from the vehicle-treated group of a previous study  and shamn = 8 septic animals in our study might have led to the underestimation of possible dilatory effects in the atherosclerotic animals. However—considering the percentages of dilatation in the aforementioned studies—one would expect at least more than only one dilator described here. It is conceivable that pre-existing CAD does not completely prevent LV dilatation but rather reduce its incidence. Clearly, further studies with larger groups are needed to draw valid conclusions on the frequency of the occurrence of LV adaption. The duration of our study was only 24 h. We cannot exclude the possibility that LV dilatation might have occurred at later time points. In awake dogs with sepsis [In the initial report by Parker et al., only survivors of sepsis displayed the dilatational response of the left ventricle, whereas LVEDV of non-survivors remained largely unchanged. As the experiments of the present study were terminated 24 h after the induction of peritonitis, sepsis mortality could not be assessed. Therefore, we cannot exclude the possibility that the severity of our sepsis model might have impaired possible LV dilation in line with other human non-survivors data , 21. Howh sepsis , 53, LV h sepsis . Therefo2S to be involved in the impairment of LV distension in septic cardiomyopathy. As previous studies describing LV dilatation mainly used healthy animal models without vasopressor therapy or excluded cardiac comorbidities in humans, ongoing catecholamine therapy or intrinsic pathophysiologic processes of atherosclerosis are most likely responsible for the opposing results.We evaluated cardiac function during resuscitated septic shock in a porcine model of pre-existing atherosclerosis. Neither decreased ejection fraction nor adaptive LV dilatation could be detected. Increased formation of nitrotyrosine and reduced expression of CSE suggest augmented oxidative/nitrosative stress and/or reduced bioavailability of NO or H2, fraction of inspiratory oxygen; H2S, hydrogen sulphide; I/E, inspiratory/expiratory; ICU, intensive care unit; LV, left ventricular; LVEDP, left ventricular end-diastolic pressure; LVEDV, left ventricular end-diastolic volume; MAP, mean arterial pressure; MPAP, mean pulmonary arterial pressure; NO, nitric oxide; PAOP, pulmonary artery occlusion pressure; PEEP, positive end-expiratory pressureBPM, beats per minute; CAD, coronary artery disease; CO, cardiac output; CSE, cystathionine γ-lyase; CVP, central venous pressure; EF, ejection fraction; FBM, familial hypercholesterolemia Bretoncelles Meishan; FiO


Aortic Stenosis (AS) is characterized by pressure overload hypertrophy (LVH) with associated diastolic dysfunction. The presence of LVH, diastolic dysfunction and microvascular dysfunction appear to be important determinants of exercise capacity in AS. There are no medical therapies in AS of proven value. Ranolazine is licenced for the treatment of angina and inhibits late sodium channel activation. Ranolazine has been shown to improve diastolic dysfunction in isolated myocytes.In this prospective, open label study with blinded endpoint analysis, patients with asymptomatic moderate/severe AS and diastolic dysfunction or LVH were recruited. Patients, underwent trans-thoracic echocardiography, exercise testing and adenosine stress cardiac magnetic resonance imaging at baseline, 6 weeks after commencing Ranolazine (maximum dose 750mg BD) and again at 10 weeks (4 weeks after discontinuation). Tagged images were acquired at three short-axis slices on a 3T platform (Siemens Skyra). Myocardial perfusion reserve was calculated from stress and resting blood flow. The primary hypothesis was that Ranolazine would improve peak early diastolic strain rate (PEDSR) on tagged MRI.2, LV mass index 66.72±15.35 g/m2) completed the week-6 visit and 13 completed the final visit. Results are shown in table Fifteen patients . GPM is funded by an NIHR research fellowship and AS by the NIHR Leicester CVBRU.


Acute heart failure (AHF) is characterized by inadequate cardiac output (CO), congestive symptoms, poor peripheral perfusion and end-organ dysfunction. Treatment often includes a combination of diuretics, oxygen, positive pressure ventilation, inotropes and vasodilators or vasopressors. Lactate is a marker of illness severity but is also an important metabolic substrate for the myocardium at rest and during stress. We tested the effects of half-molar sodium lactate infusion on cardiac performance in AHF.We conducted a prospective, randomised, controlled, open-label, pilot clinical trial in 40 patients fulfilling two of the following three criteria for AHF: (1) left ventricular ejection fraction <40%, (2) acute pulmonary oedema or respiratory failure of predominantly cardiac origin requiring mechanical ventilation and (3) currently receiving vasopressor and/or inotropic support. Patients in the intervention group received a 3 ml/kg bolus of half-molar sodium lactate over the course of 15 minutes followed by 1 ml/kg/h continuous infusion for 24 hours. The control group received only a 3 ml/kg bolus of Hartmann’s solution without continuous infusion. The primary outcome was CO assessed by transthoracic echocardiography 24 hours after randomisation. Secondary outcomes included a measure of right ventricular systolic function (tricuspid annular plane systolic excursion (TAPSE)), acid-base balance, electrolyte and organ function parameters, along with length of stay and mortality.P < 0.01) and TAPSE from 14.7 ± 5.5 mm to 18.3 ± 7 mm (P = 0.02). Plasma sodium and pH increased , but potassium, chloride and phosphate levels decreased. There were no significant differences in the need for vasoactive therapy, respiratory support, renal or liver function tests, duration of ICU and hospital stay or 28- and 90-day mortality.The infusion of half-molar sodium lactate increased (mean ± SD) CO from 4.05 ± 1.37 L/min to 5.49 ± 1.9 L/min (Infusion of half-molar sodium lactate improved cardiac performance and led to metabolic alkalosis in AHF patients without any detrimental effects on organ function.NCT01981655. Registered 13 August 2013.Clinicaltrials.gov  Symptom illness . Standar illness . Vasodil illness . The pro illness -7. There illness .Blood lactate is regarded as a marker of illness severity, and increased plasma lactate levels are common in AHF and acute coronary syndromes -11. AlthHerein we report the results of our prospective, open-label, pilot, randomised, controlled clinical trial of half-molar sodium lactate infusion to improve cardiac function in critically ill patients with acute heart failure and reduced left ventricular ejection fraction (LVEF).The study was conducted between December 2009 and November 2012 in the Department of Intensive Care Medicine at Nepean Hospital, University of Sydney, Australia. The Sydney West Area Health Service Ethics Committee approved the study (HREC/09/NEPEAN/4) in accordance with the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained from the patients or their next of kin prior to enrolment. Adult patients over 18 years of age were prospectively screened and considered eligible if two of three criteria for AHF were met: (1) LVEF ≤40%; (2) acute pulmonary oedema or respiratory failure of predominantly cardiac origin requiring mechanical ventilation, including noninvasive ventilation; and (3) currently receiving inotropes and/or vasopressors. The exclusion criteria were pregnancy, hypernatremia >145 mmol/L, hypertrophic obstructive cardiomyopathy, uncorrected severe valvular heart disease, third-degree heart block, sustained ventricular tachycardia, cardiac tamponade, septic shock, acute respiratory distress syndrome, moribund patients, presence of major diseases with a poor prognosis , end-stage  renal failure, and likely to receive haemodialysis and/or filtration within 6 hours of enrolment) and acute liver failure  unrelated to warfarin use.Following study enrolment, patients were randomised to receive either half-molar sodium lactate , denominated the lactate group, or Hartmann’s solution , classified as the control group. Randomisation was carried out in blocks of variable size in sequentially numbered, opaque, sealed envelopes provided by an independent statistician. After baseline parameters were recorded and transthoracic echocardiography (TTE) was performed, patients were given an intravenous bolus of 3 ml/kg actual body weight (ABW) of the assigned fluid according to randomisation over the course of 15 minutes. A continuous infusion of half-molar sodium lactate at 1 ml/kg/h ABW for 24 hours was then infused in the lactate group. To prevent potentially harmful fluid overload, no additional study fluid was infused in the control group. The Scientific Committee of the local Ethics Committee mandated this aspect of the protocol. Both groups received standard therapy for AHF according to best practice, which included a combination of inotropes, vasopressors, vasodilators, diuretics, intraaortic balloon counterpulsation and mechanical ventilation as required. Patients had TTE performed 24 and 48 hours after enrolment, except for those who died or were discharged from the ICU. Arterial blood gas analysis was performed at baseline, after the initial study fluid bolus and together with other laboratory and vital sign parameters at 6, 12, 24 and 48 hours after enrolment. These laboratory examinations included fluid balance, electrolytes, full blood count and renal and liver function tests. All patients were followed up for up to 90 days.2 × Velocity time integral (VTI) of the blood flow signal in the LVOT. The LVOT diameter was obtained from the parasternal long axis, and the LVOT VTI was determined from the apical five-chamber view using pulsed wave Doppler (PWD). Tricuspid annular plane systolic excursion (TAPSE) in the apical four-chamber view was recorded to assess right ventricular systolic function. Early mitral inflow velocity (E) was measured by PWD at the tip of the mitral valve during diastole, and tissue Doppler imaging–derived early diastolic motion velocity (E′) and systolic motion of the mitral annulus  by tissue Doppler imaging (SmTDI) were obtained by placing the sample gate at the level of the mitral annulus of the interventricular septum and lateral wall in the apical four-chamber view. E′ and SmTDI from both locations were averaged as recommended previously [Qualified sonographers or clinicians performed TTE using ultrasound systems equipped with tissue Doppler . LVEF was estimated on the basis of apical two- and four-chamber views according to Simpson’s formula as recommended by the American Society of Echocardiography . CO was eviously . A qualiE/E′ ratio and TAPSE, overall fluid balance, blood pressure, acid-base status, electrolytes, renal and liver function tests, need for mechanical ventilation (including noninvasive), ICU and hospital lengths of stay and 28- and 90-day mortality.The primary study outcome was CO at 24 hours after study entry, which was measured by TTE as described above. Secondary outcome parameters included SmTDI, post hoc analyses were performed by using Student’s t-test. The significance level was set at 0.05 and adjusted for multiple comparisons by the Bonferroni correction method. To adjust for baseline imbalances and the unequal amount of intravenous fluid in the study groups, the ‘regression to the mean’ effects and analysis of covariance (ANCOVA) were carried out using a linear model containing primary outcome as the dependent variable, with treatment as a dummy variable with baseline CO and 24-hour fluid balance used as the covariates. Time to events data were analysed using Kaplan-Meier statistics with survival compared using a logrank test. This trial was a pilot study, so no formal sample size calculation was possible. An arbitrary number of 40 patients was chosen.Data are expressed as mean ± standard deviation (SD). Between-group and within-group differences due to treatment (lactate vs. control) were assessed by two-way repeated-measures analysis of variance and Fisher’s exact test for qualitative data . In cases where significant intra- or intergroup differences were present, pairwise From among the 194 screened patients, 41 were randomised  and remained higher than at baseline at 48 hours . The improvement in CO remained significant even after adjusting for the baseline imbalance by ANCOVA (Table P = 0.02) , it was reduced  in the control group, suggesting reduction in left atrial pressure  within 15 minutes of half-molar sodium lactate solution bolus. The pH, bicarbonate and BE continued to rise over the 24-hour period . Once the half-molar sodium lactate infusion ceased, pH, bicarbonate and BE declined, but they remained higher than either baseline or the control group at 48 hours. Plasma lactate remained elevated during the infusion; however, the mean lactate at 24 hours was similar to baseline and declined further, so that it was lower than in the control group at 48 hours (Table There were no significant changes in any of the acid-base parameters in the control group apart from significant increases in bicarbonate levels and base excess (BE) at 48 hours. In the lactate group, pH increased from 7.4 ± 0.06 to 7.45 ± 0.05, bicarbonate from 23.3 ± 3.3 to 25.9 ± 4.1 mmol/L, BE from -0.3 ± 4.1 to 2.7 ± 4.2 mmol/L and lactate from 2.4 ± 2.3 to 4.8 ± 2.0 mmol/L . We also noted a significant decrease in levels of potassium , chloride  and phosphate , despite clinically driven supplementation. There were no significant changes in electrolyte levels in the control group (Table There were significant changes in electrolyte levels in the lactate group. The sodium level increased from 136 ± 4 mmol/L at baseline to 146 ± 6 mmol/L at 24 hours (P = 0.011)  increased CO in critically ill patients with AHF. The effect was related to a significant increase in SV rather than HR. We also observed improvement in right ventricular systolic function as assessed by TAPSE. The infusion of half-molar sodium lactate was safe and well tolerated, but it had a marked effect on acid-base status and plasma electrolytes. The total amount of intravenous sodium lactate  was associated with modest metabolic alkalosis and hypernatraemia as well as mild hypochloraemia, hypokalaemia and hypophosphataemia.Under normal conditions, the main energy supply for the heart is the oxidation of fatty acids, whereas other nutrients such as glucose lactate and amino acids contribute to myocardial ATP generation in varying proportions. At rest, approximately 10% to 40% of energy is derived from pyruvate formed either by glycolysis or the conversion of lactate. Although fatty acids have higher yields of ATP per molecule, the ATP yield per oxygen molecule utilized is 5% to 10% better with lactate and glucose, respectively . During per se may lead to improved myocardial function [Although we do not provide direct evidence of lactate oxidation by the heart, the relatively low plasma lactate levels, together with an increase in SV and CO in the lactate group, suggest myocardial lactate metabolism. Previous studies have documented lactate oxidation in patients with cardiogenic shock while receiving a short-term sodium lactate infusion (2.5 mmol/kg for 15 minutes) . The efffunction . As the function ,27,29. Hfunction -32. NeveWe conducted a pilot, single-centre, open-label clinical trial. Despite the relatively small number of randomised patients, we demonstrate a significant effect of half-molar sodium lactate on cardiac function, a finding similar those reported by others ,26. We dThe findings of our present study regarding increased SV, CO and right ventricular systolic function in critically ill patients with AHF receiving half-molar sodium lactate challenge the dogma that exogenous lactate is detrimental to myocardial function in the critically ill and support the view that endogenous lactate may be an important substrate for myocardium during periods of physiological stress . We suggper se is detrimental to myocardial function.• Infusion of half-molar sodium lactate (13.5 mmol over 24 hours) improved cardiac performance, challenging the dogma that lactate • Our results support an important role of lactate in cardiac metabolism during periods of critical illness.• Half-molar sodium lactate can be thought of as an alternative inotrope in AHF patients with reduced LVEF who possess organ function sufficient for lactate metabolism.XML was a member of the Innogene International Scientific Board of Advisors. The other authors declare that they have no competing interests.MN conceived of and designed the study, collected and analysed the data and was involved with manuscript writing. XL conceived of and designed the study, was responsible for logistics and drafted the manuscript. SH was involved with the study design, data analysis and manuscript writing. LW and IT were involved with the study design, data collection and analysis and manuscript writing. RP collected and analysed data and was involved with writing the manuscript. IMS was involved in the study design, data collection and manuscript writing. ASM obtained financial support, collected and analysed the data and was involved with manuscript writing. All authors, except the late Prof Xavier Maurice Leverve, read and approved the final manuscript.


Cardiovascular impairments are frequent in Cushing's syndrome and the hypercortisolism can result in cardiac structural and functional changes that lead in rare cases to dilated cardiomyopathy (DCM). Such cardiac impairment may be reversible in response to a eucortisolaemic state.A 43-year-old man with a medical past of hypertension and history of smoking presented to the emergency department with global heart failure. Coronary angiography showed a significant stenosis of a marginal branch and cardiac MRI revealed a nonischemic DCM. The left ventricular ejection fraction (LVEF) was estimated as 28% to 30%. Clinicobiological features and pituitary imaging pointed toward Cushing's disease and administration of adrenolytic drugs (metyrapone and ketoconazole) was initiated. Despite the normalization of cortisol which had been achieved 2 months later, the patient presented an acute heart failure. A massive mitral regurgitation secondary to posterior papillary muscle rupture was diagnosed as a complication of the occlusion of the marginal branch. After 6 months of optimal pharmacological treatment for systolic heart failure, as well as treatment with inhibitors of steroidogenesis, there was no improvement of LVEF. The percutaneous mitral valve was therefore repaired and a defibrillator implanted. The severity of heart failure contraindicated pituitary surgery and the patient was instead treated by stereotaxic radiotherapy.This is the first case reporting a Cushing's syndrome DCM without improvement of LVEF despite normalization of serum cortisol levels. Hypercortisolism can also cause cardiac structural and functional changes5: hypertrophy, concentric remodeling, fibrosis, biventricular and left atrial systolic dysfunction, and diastolic dysfunction, leading in rare cases to dilated cardiomyopathy (DCM).Endogenous Cushing's syndrome may be caused by overproduction of adrenocorticotropic hormone (ACTH) (Cushing's disease in most cases) or by an independent high cortisol secretion from the adrenal cortex.We present here the case of a man with DCM related to Cushing's disease (CD).A 43-year-old man with a medical history of hypertension for 8 years and history of smoking, presented to the emergency department with dyspnea. He was under treatment with amlodipine at a dose of 5 mg/day. Physical examination, blood tests, and chest imaging revealed global heart failure. Coronary angiography revealed an isolated significant stenosis in the marginal branch of the circumflex artery. Transthoracic echography showed a globally dilated heart (left ventricular end-diastolic diameter: 64 mm), a mild left ventricular hypertrophy, and a global hypokinesia with a more prominent posterolateral wall hypokinesis . Left ventricular ejection fraction (LVEF) was calculated as 28% to 30%. No significant valvular heart disease, no sign of pulmonary hypertension, and no pericardial effusion were noted. Cardiac magnetic resonance imaging (MRI) also showed a DCM, with no sign of necrosis. The patient reported no excessive alcohol consumption and investigations for usual infective, autoimmune and infiltrative causes of cardiomyopathy were negative.The clinical picture suggested a Cushing's syndrome: easy bruising, reddish purple striae Fig. , proximaPituitary surgery had to be postponed due to the severe heart failure.7 2 adrenolytic drugs (metyrapone and ketoconazole) were initiated: UFC was normalized within 2 months  and, as described in such severe conditions,hs Table .Unfortunately, a new episode of acute heart failure occurred two months after initial presentation. Transthoracic cardiac echography showed mitral insufficiency related to rupture of the mitral valve pillar. Percutaneous transluminal angioplasty and stenting  was performed in the obtuse marginal artery. Another cardiac MRI then revealed an impaired lateral contractility  related this time to necrosis Fig. . InfectiIn spite of optimal treatment and normalization of cortisol levels, no improvement was found in the LVEF 6 months after discovery of the Cushing's disease Table .Thus a single-chamber defibrillator was implanted for primary prevention, and percutaneous mitral valve repair (Mitraclip) was performed to treat the mitral regurgitation.After 1 year, since LVEF remained at 30%, cardiac transplantation was discussed.In view of the patient's heart failure, anesthesia for transphenoidal surgery was considered too dangerous; therefore, stereotaxic radiotherapy was performed to treat the CD 14 months after initial presentation. While awaiting the therapeutic effects of the pituitary irradiation, tolerance and efficacy of the 2 adrenolytic agents proved acceptable.8 Some studies having examined the relationship between cardiac dysfunction and hypercortisolism, found that cardiac remodeling is independent of hypertension, and is probably due to a direct action of cortisol on myocardial tissue via glucocorticoid receptors.4Cardiovascular complications, including myocardial ischemia, left ventricular hypertrophy and cardiomegaly account in part for the higher mortality rate among patients with Cushing's syndrome.5 Repetition of imaging after treatment revealed that these systolic dysfunctions and structural changes are reversible upon correction of hypercortisolism. None of the patients in this study had DCM.A recent cardiac MRI study showed that patients with Cushing's syndrome have lower left ventricular, right ventricular, and left atrial ejection fractions and increased left ventricular mass.18  for adrenal adenomas, 25%  for pituitary adenomas, and 38% after bilateral adrenectomy in the subject for whom the cause was undetermined. In view of these observations, DCM related to hypercortisolism could be considered as “reversible.”Interestingly, all these cases showed an improvement in LVEF after several months of cortisol normalization . Cushing's syndrome was due to unilateral adrenal adenoma in 5 cases,Here we have reported the first case showing no improvement of DCM in a context of Cushing's syndrome. At presentation the cardiomyopathy could only be attributed to hypercortisolism . This combination of different causes of DCM  could explain the absence of improvement of LVEF in response to a eucortisolemic state.Another possible explanation can be a publication bias due to the selective reporting of cases in which DCM had been reversed.19 For recurrent or residual disease, therapeutic possibilities are second transphenoidal surgery, radiotherapy, medical adrenolytic therapy  or bilateral adrenalectomy in cases of uncontrolled cortisol levels.The standard treatment of CD is transphenoidal surgery with up to 65% remission rate for macroadenomas.6  and by ectopic ACTH syndrome or adrenal carcinoma.7Unfortunately for our patient, anesthesia for pituitary surgery was contraindicated due to very low LVEF. Combination of 2 adrenolytic agents  normalized cortisol levels and tolerance was good. The observed efficacy is consistent with results from 2 studies in which this combination provided rapid control of severe hypercortisolism elicited by ACTH-dependent Cushing's syndromeOur patient was treated by external pituitary radiation, the therapeutic effects of which will be delayed.In conclusion, we report here the case of a DCM as a presenting feature of CD, without improvement of LVEF after normalization of cortisol level (probably explained by subsequent associated ischemic lesions).


We performed comprehensive transmitral and pulmonary venous Doppler echocardiographic studies to devise a novel index of diastolic function. This is the first study to assess the utility of the acceleration rate (AR) of the E wave of mitral inflow as a primary diagnostic modality for assessing diastolic function.Study group consisted of 84 patients (53 + 11 years) with left ventricle (LV) diastolic dysfunction and 34 healthy people (35 ± 9 years) as control group, who were referred for clinically indicated two-dimensional transthoracic echocardiogram (TTE) during 2012 and 2013 to Imam Hospital. Normal controls were defined as patients without clinical evidence of cardiac disease and had normal TTE. LV diastolic function was determined according to standardized protocol of American Society of Echocardiography (ASE). As our new parameter, AR of E wave of mitral inflow was also measured in all patients. It was represented by the slope of the line between onset of E wave and peak of it. Correlation between AR of E wave and LV diastolic function grade was measured using the Spearman correlation coefficient. Receiver operating characteristic (ROC) curve was used to determine the sensitivity and specificity of AR of E wave in diagnosing LV diastolic dysfunction in randomly selected two-thirds of population then its derived cutoff was evaluated in rest of the population. The institutional review board of the hospital approved the study protocol. All participants gave written informed consent. This investigation was in accordance with the Declaration of Helsinki.2 in patients whereas the mean value for the normal controls was 701 ± 210 cm/s2. There was a strong and graded relation between AR of E wave of mitral inflow and LV diastolic function grade . ROC curve analysis revealed that AR of E wave of mitral inflow =750 cm/s2 predicted moderate or severe LV diastolic dysfunction with 89 % sensitivity and 89 % specificity . Application of this cutoff on test group showed 96 % sensitivity and 77 % specificity with AUC = 0.932 and P <0.0001.The mean value of AR was 1010 ± 420 cm/sAR of E wave of mitral inflow could be used for assessment of diastolic function, especially moderate or severe diastolic dysfunction. However, before its clinical application, external validation should be considered. Over the past two decades, the prevalence of heart failure due to diastolic dysfunction has been gradually rising. Despite the growing incidence of this disorder, no effective therapies exist to treat the disease, halt its progression or reduce the associated mortality . The assE- e’) between onset of mitral E and annular e,less than 2 (IVRT/TE-e’ <2), pulmonary artery systolic pressure ≥35 mm Hg (in the absence of pulmonary disease), and maximal LA volume ≥34 mL/m2 are all indicative of increased LV filling pressures. The presence of ≥2 abnormal measurements increases the confidence in the conclusions [The estimation of LV filling pressures in patients with normal ejection fractions (EF)s is more challenging than in patients with depressed EFs. In this patient group, the ratio of mitral peak velocity of early filling (E) to early diastolic mitral annular velocity (e’), the E/e’ ratio, should be calculated. An average ratio ≤8 identifies patients with normal LV filling pressures, whereas a ratio ≥13 indicates an increase in LV filling pressures. When the ratio is between 9 and 13, other measurements are essential. A pulmonary venous (PV) atrial reversal wave (Ar) duration longer than 30 ms of that of the transmitral A wave, a change in E/A ratio with the Valsalva maneuver of ≥0.5, ratio between isovolumetric relaxation time (IVRT) and the time delay  between 2012 January and 2013 May. The inclusion criterion was presence of LV diastolic dysfunction in TTE. Patients with unstable hemodynamic state, arrhythmia, valvular heart disease, congenital heart disease, constrictive pericarditis or permanent pacemaker implantation were excluded. Normal controls were defined as patients without clinical evidence of cardiac disease and had normal TTE. Clinical data were obtained through a comprehensive review of patient’s medical records.The institutional review board of Imam Khomeini Hospital which is a tertiary hospital approved the study protocol. All participants gave written informed consent. This investigation was in accordance with the Declaration of Helsinki.Complete M-mode, two-dimensional and Doppler echocardiogram was performed by two experienced cardiologists according to standardized protocol of American Society of Echocardiography , 8 usingE/A velocity ratio were measured. Pulmonary venous velocities were obtained from the same window with the sample volume placed 1 cm into the right upper pulmonary vein. The flow velocities were recorded, the ratio of systolic to diastolic flow (S/D ratio) was calculated and duration of atrial reversal flow was measured. Doppler tissue imaging was used to measure E'  and A' velocities by placing a 1–2 mm sample volume in the septal and lateral mitral annulus.Mitral inflow was assessed from the apical 4-chamber view with pulsed wave Doppler by placing a 1–2 mm sample volume between the tips of the mitral leaflets during diastole. From the mitral inflow profile, the E- and A-wave velocity, E-deceleration time (DT), A-wave duration, and E/A velocity ratio, E-DT, PV atrial reversal velocity and duration, PV S/D ratio, and mitral E/E'  ratio. Diastolic function is graded as normal, abnormal relaxation (Grade I), pseudonormal (Grade II), and restrictive (Grade III) as described previously. Pseudonormal (Grade II) is differentiated from normal by having (i) PV atrial reversal duration longer than mitral A duration by 30 ms; or (ii) peak PV atrial reversal velocity >35 cm/s; or (iii) mitral E/E' >12  or >15  [LV diastolic function was determined using standard echocardiographic parameters including annulus) .As our new parameter acceleration rate and time of E was also measured in all patients. Acceleration rate of E (cm/sec2) was represented by the slope of the line between an anchored point and a crosshair Fig. . This liSPSS release 21.0 statistical package was used for data analysis. All values were expressed as mean ± SD. Correlation between AR and AT of E wave and LV diastolic function grade was measured using the Spearman correlation coefficient. Multivariate Logistic Regression analysis was also done to adjust the age and gender effect. Receiver operating characteristic (ROC) curve was used to determine the sensitivity and specificity of AR of E wave in diagnosing LV diastolic dysfunction and elevated left ventricle diastolic pressure (LVDP). Study population randomly assigned into two groups with 2:1 ratio. ROC curve was performed in randomly selected two-thirds of population (derivation group), then the derived cutoff was evaluated in the rest of the population (Test group). Therefore, ROC curve analysis was performed two times. First, we recoded the “diastolic function” into a dichotic variable just based on presence or absence of any degree of diastolic dysfunction . Second, we recoded the “diastolic function” into another dichotic variable, this time based on presence or absence of elevated LVDP (moderate and severe diastolic dysfunction).The study population consisted of 84 adult patients (64 % men), mean age 53 ± 11 and 34 normal controls, who were referred for clinically indicated two-dimensional echocardiogram. They were referred because of the following reasons: dyspnea/peripheral edema/congestive heart failure (48 %), cerebrovascular accident (12 %), preoperative assessment (10 %), coronary artery disease (9 %), and others (21 %).The baseline clinical and echocardiographic characteristics are listed in Table 2 in case group respectively, whereas these mean values for the normal controls were 96.7 ± 15.1 ms, and 701 ± 210 cm/s2respectively. The mean values of AT and AR according to grade of LV diastolic dysfunction is showed in Table P ≤0.0001, rs =0.69) . Receiver operating characteristic (ROC) curve analysis in “derivation group” revealed that AR of E wave of mitral inflow =655 cm/s2 predicted presence of LV diastolic dysfunction with 71 % sensitivity and 65 % specificity . Application of this cutoff on test group showed 84 % sensitivity and 64 % specificity with AUC = 0.800 and P = 0.001. When considering only Grade II and III (moderate and severe) diastolic dysfunction, an AR of 750 cm/s2 predicted at least moderate diastolic dysfunction with 89 % sensitivity and 89 % specificity   but with a low sensitivity of 22 %.The mean value of E acceleration time and E acceleration rate were 85.6 ± 19.1 ms, and 1010 ± 420 cm/sThe present study showed that AR of E wave of mitral inflow has a strong and graded relation to the LV diastolic function grade, and could be used especially to identify moderate or severe LV diastolic dysfunction. This result was predictable because according to Newton’s second law there is a direct relationship between acceleration and pressure. E wave acceleration is directly determined by LA pressure and inversely related to myocardial relaxation . Thomas 2 had a 77 % sensitivity and 94 % specificity for left ventricle diastolic pressure (LVDP) >15 mmHg in patients with atrial fibrillation(AF) [2 had a suitable sensitivity and specificity for elevated LVDP according to diastolic function grade II or more. And the cut off value of 1250 cm/s2 had 100 % specificity for diastolic dysfunction of grade II or more. The difference in our cut off value and the previous one could have three reasons. First, in our study we used AR which conventionally could be measured by every machine of echocardiography, but Naughueh et.al used a computer software to measure peak of AR. Second the method of estimation of elevated LVDP was different in two studies. In our study we postulated that presence of diastolic dysfunction of grade II or more would be associated with elevated LVDP, however Naughueh et al. directly measured LVDP or LA pressure in their patients. Third, all of our patients had sinus rhythm, but the rhythm of patients in that study was AF.Despite the theoretical observations by Thomas and Weyman , AR has tion(AF) . In our The limitations of our study include its relatively small size. The ‘normal controls’ are included on the basis of absence of a history of cardiovascular disease and a normal resting two-dimensional echocardiogram. Stress tests were not performed to rule out occult coronary artery disease. We used previously published Doppler echocardiographic referenced standards to define the different grades of LV diastolic function. Cardiac catheterization was not performed to evaluate LV diastolic function. However, these reference standards were previously validated with cardiac catheterization and are widely accepted as standards for classification of LV diastolic function grade. Although the results of our study about AR are promising, before its clinical application external validation should be considered. Further studies with invasive haemodynamic measurements are needed to show if AR measurement increase the diagnostic accuracy of LV diastolic dysfunction and elevated LA pressure with respect to validated echo-Doppler parameters.AR of EARE wave of mitral inflow could be used for assessment of diastolic function, especially moderate to severe diastolic dysfunction. The cutoff value of 750 cm/s2 could deserve as suitable cutoff point with 89 % sensitivity and 89 % specificity in detection of moderate to severe diastolic dysfunction. Before its clinical application external validation should be considered.


Autosomal dominantly inherited PRKAG2 cardiac syndrome is due to a unique defect of the cardiac cell metabolism and has a distinctive histopathology with excess intracellular glycogen, and prognosis different from sarcomeric hypertrophic cardiomyopathy. We aimed to define the distinct characteristics of PRKAG2 using cardiovascular magnetic resonance (CMR).PRKAG2 mutations. On CMR, segmental analysis of left ventricular (LV) hypertrophy (LVH), function, native T1 mapping, and late gadolinium enhancement (LGE) were performed.CMR (1.5 T) and genetic testing were performed in two families harboring PRKAG2 mutation: five with an R302Q mutation (family 1), and one with a novel H344P mutation (family 2). Three of six mutation carriers had LV mass above age and gender limits  and others (with R302Q mutation) normal LV masses. All mutation carriers had LVH in at least one segment, with the median maximal wall thickness of 13 mm (range 11–37 mm). Two R302Q mutation carriers with markedly increased LV mass (203 g/m2 and 157 g/m2) showed a diffuse pattern of hypertrophy but predominantly in the interventricular septum, while other mutation carriers exhibited a non-symmetric mid-infero-lateral pattern of hypertrophy. In family 1, the mutation negative male had a mean T1 value of 963 ms, three males with the R302Q mutation, LVH and no LGE a mean value of 918 ± 11 ms, and the oldest male with the R302Q mutation, extensive hypertrophy and LGE a mean value of 973 ms. Of six mutations carriers, two with advanced disease had LGE with 11 and 22 % enhancement of total LV volume.Six individuals  had a PRKAG2 cardiac syndrome may present with eccentric distribution of LVH, involving focal mid-infero-lateral pattern in the early disease stage, and more diffuse pattern but focusing on interventricular septum in advanced cases. In patients at earlier stages of disease, without LGE, T1 values may be reduced, while in the advanced disease stage T1 mapping may result in higher values caused by fibrosis. CMR is a valuable tool in detecting diffuse and focal myocardial abnormalities in PRKAG2 cardiomyopathy. PRKAG2 cardiac syndrome is an autosomal dominantly inherited metabolic heart muscle disease characterized by left ventricular hypertrophy (LVH), progressive conducting abnormalities and ventricular pre-excitation (Wolff-Parkinson-White [WPW] syndrome) –4. The pPRKAG2 gene defect have a distinctive cardiac histopathology with excess intracellular vacuoles filled with glycogen, myocyte enlargement but without myocyte disarray typical for sarcomeric HCM ) and decreased EF 55 % [−2.2].PRKAG2 mutation, known to cause a unique defect of the cardiac cell metabolism with intracellular deposition of glycogen. We found that the distribution of LVH in PRKAG2 syndrome is eccentric. Patients with markedly increased LV mass showed a diffuse pattern of hypertrophy but predominantly in the interventricular septum. On the other hand, four patients with normal or only mildly increased LV mass exhibited a non-symmetric mid-infero-lateral pattern of hypertrophy. T1 values were lowest in patients with the R302Q mutation, LVH and no LGE. Two patients with the PRKAG2 mutation and advanced disease showed intramyocardial, patchy LGE in hypertrophic segments.We are the first to describe the comprehensive CMR findings of six individuals with PRKAG2 mutation carriers, 78 % had LVH on echocardiography with a mean LV wall thickness of 21 mm (range 13–45 mm), and varying pattern of hypertrophy within families, 46 % having concentric, 29 % asymmetric, and one distal hypertrophy, with often eccentric distributions [We found that in five patients with the R302Q mutation (family 1), LVH demonstrated a similar diffuse pattern in two patients with markedly increased LV mass, but a non-symmetric mid-infero-lateral pattern in three patients with normal LV masses. Also, one patient with the H344P mutation (family 2) presented with non-symmetric mid-infero-lateral pattern of LVH. Significant LVH in PRKAG2 patients have been demonstrated previously by echocardiography , 34. In ibutions .PRKAG2 mutations may express in the early stage with focal and mild LVH, which may change to diffuse disease in the later stage. Another explanation could be, that even in the same family and with the same mutation, there would be varying patterns of hypertrophy. Nevertheless, our study demonstrates that CMR based accurate segmental analysis of wall thickness revealed abnormal hypertrophy in all PRKAG2 mutation carriers, even in those subjects with normal LV mass.Our finding of both diffuse and non-symmetric distribution of LVH in the same family may be explained by the generally progressive nature of LVH in PRKAG2 cardiomyopathy during follow-up , and theOur study is the first one describing the behaviour of T1 or T2 times in a glycogen storage cardiomyopathy. In family 1, three males with the R302Q mutation, LVH but no LGE, presented with lower mean mid-myocardial T1 values 918 ± 11 ms) compared to mutation negative male sibling (963 ms) of their age and the mutation positive male with extensive hypertrophy and LGE (973 ms). This is in accordance with the hypothesized T1 reduction by intracellular glycogen in the absence of significant fibrosis. Theoretically, intracellular glycogen as a macromolecule with hydrophilic bonding with water would reduce T1-relaxation time, as shown in vitro , 21. Pos ± 11 ms We were unable to verify the hypothesis of inverse association between segmental T1 times and hypertrophy in non-enhanced myocardium. After adjustment to fixed effects caused by different segments on T1, the association between T1 times and hypertrophy was non-significant. This may be due to limited number of patients and the fact that LVH was predominantly located in mid-infero-lateral segments which also present lower T1 values in normal myocardium .In a previous study, it was estimated that normal native myocardial ShMOLLI T1 time is 962 ± 25 ms . PiechniAll our patients had normal T2-relaxation times. Normal T2 times exclude possible iron accumulation in the myocardium and its effect on T1 values , 38.LAMP2 gene), CMR demonstrated both RV and LV dysfunction, and extensive homogeneous LGE of the RV with concomitant patchy midwall LV involvement [In this study, patients with significant LVH and increased LV mass, had widespread LGE. In an earlier case report of a patient with large cardiomyocyte vacuoles due to extensive cytosolic accumulation of glycogen in Danon disease  with a mean age of 66 ± 9 years, which is considerably higher than our patients . Therefore, we presented both absolute and standardized values of wall thickness when appropriate. In 16 myocardial segments, there is considerable probability to achieve abnormal z-scores in some segments by change. To overcome this, we plotted the distribution of z-scores in each patient to study the consistency of values in adjacent segments.Our cohort was too small to find correlations between age, symptom duration and disease severity. We did not study the time-related changes in the myocardium. However, according to an earlier study, cardiac hypertrophy has a generally progressive nature in PRKAG2 , and thuPRKAG2 cardiac syndrome may present with eccentric distribution of LVH, involving focal mid-infero-lateral pattern in the early disease stage, and more diffuse pattern but focusing on interventricular septum in advanced cases. In patients at earlier stages of the disease, without LGE, T1 values may be reduced, while in the advanced disease stage T1 mapping may result in higher values caused by fibrosis. CMR is a valuable tool in detecting diffuse and focal myocardial abnormalities in PRKAG2 cardiomyopathy.