Concilium Cardiologicum). The three candidates presented their PhD theses at the NHI meeting in Utrecht on June 28–29th 2018. We congratulate the laureates for their excellent scientific work and their presentations during the meeting.The dissertation prize is named after Willem Einthoven, a pioneer in cardiovascular medicine who recorded the first human ECG in 1902, for which he was awarded the Nobel prize in 1924. The annual Einthoven dissertation prize is an initiative of the Netherlands Heart Institute (NHI) and the Netherlands Society of Cardiology (NVVC) to select the top three cardiovascular theses published in the year 2018. The jury received a total of 25 PhD dissertations for selection. The ranking of the theses was based upon a combination of parameters that included the curriculum vitae of the candidate, the scientific originality of the PhD thesis and its relevance for the cardiovascular field. Moreover, several objective bibliometric parameters were used that included the number of articles in citation index journals, both in PubMed and the Web of Science (WOS), the number of citations in WOS, the Hirsch index and finally the contribution of the candidate as a first author. Based upon this evaluation the jury elected the following nominees: A. Sakes, J.P. Bokma, and B.C. du Pré. The members of the jury were P. Doevendans and D.J. Duncker (Netherlands Heart Institute), H. Bosker (NVVC), I. van Gelder (CVOI) F. Martens (WCN) and M.J. Schalij  are considered the most technically challenging occlusion type that cardiovascular interventionist face. CTOs are specifically challenging, as there are older, heavily calcified complete occlusions in the coronaries with a strong blood vessel wall connection. The preferred treatment method of CTOs is percutaneous coronary intervention (PCI). Unfortunately, PCIs of CTOs remain challenging for even the most expert operators, which is evidenced not only by the low success rate in comparison to acute occlusions, but also by the high referral rate and considerably longer procedure time. The main challenge during PCI of CTOs is successfully crossing the guidewire through the CTO body into the distal lumen. Crossing is challenging as the CTO is heavily calcified and is thus able to resist large compressive forces. As a result, the small guidewire can buckle, which may eventually result in procedural failure if the CTO cannot be crossed. Furthermore, guidewire deflection by calcification cannot be actively corrected, which can result in blood vessel wall damage, subintimal crossing, and even procedural failure. The main goal of this thesis was to develop innovative prototypes that can aid the interventionist during PCI of CTOs.N through a flexible 6F catheter, with an efficiency of over 80% without illustrating any shape dependency. This is approximately 150 × more than what current guidewires can withstand and approximately 25 × more than what is needed to puncture CTOs! We are currently developing this catheter further in collaboration with Asahi Intecc (Japan) and DEAM (Amsterdam).In order to find innovative buckling prevention strategies, solutions from nature have been studied. It became apparent that using an impulse onto the CTO could have merit as it increases the buckling load of the crossing tool without the need to enlarge the diameter. Based on inspiring mechanisms found in nature, such as the chameleon’s tongue and mantis shrimp’s appendage, several ‘hammer’ catheters were developed. One of the prototypes uses a hydraulic pressure wave to transfer high-force impulses up to 43 After initial puncture, successfully crossing the CTO means active control of the crossing path, which allows for compensation of deflective forces, navigation of tortuous CTOs, and the possibility of choosing the most feasible crossing route. In order to allow for active control of the crossing path, an eight degrees-of-freedom miniature steerable tip (Ø2 mm) was developed. This ‘multisteerable’ tip allows for forming complex (S-shaped) curves and can actively counteract deflective forces. In a first experiment, this tip illustrated the benefits of actively steerable segments and was successfully combined with an optical shape-sensing fibre and forward-looking intravascular ultrasound transducer to visualise the most feasible entry point in a CTO model. In the future we will incorporate the hammer catheter into the lumen of this multisteerable tip to allow for an easy, fast, and safe PCI procedure for even the less experienced interventionist and marked improvement in quality of life and symptoms of patients suffering from CTOs.A. SakesDepartment of Biomechanical Engineering, Faculty of Mechanical, Maritime and Materials Engineering, Delft University of Technology, Delft, the Netherlandsa.sakes@tudelft.nlThis thesis focused on several clinical challenges which may occur late after surgical correction of tetralogy of Fallot. In the introduction of this thesis, anatomic features, symptoms, and early surgical management were described. Tetralogy of Fallot is the most common cyanotic congenital heart defect and surgery has allowed survival into adulthood. Nowadays, early outcomes are good, although residual lesions are common after surgical correction, depending on the techniques used. Residual lesions such as pulmonary regurgitation and surgical scars contribute to several clinical challenges which may occur late after correction of tetralogy of Fallot.Among several other topics, three important clinical challenges were studied in this thesis: (1) timing of pulmonary valve replacement, (2) risk stratification, (3) prevention and treatment of right ventricular heart failure. These topics are considered to be controversial and are relevant to the care of most adult patients born with tetralogy of Fallot. Most of the research described in this thesis was performed in collaboration with several other Dutch and international centres.Regarding the first of the three main clinical challenges. We found that lower preoperative right ventricular volumes were associated with favourable mid-to-late haemodynamic outcomes after pulmonary valve replacement. However, results from a propensity-adjusted analysis in a large international cohort suggest that early pulmonary valve replacement is associated with worse clinical outcomes compared with a conservative non-surgical approach. These results indicate that pulmonary valve replacement may be postponed in asymptomatic patients until the conservative criteria we describe in Chapter 12 of the thesis are met. Future large, long-term follow-up studies are needed to validate these results.Several chapters in this thesis focus on risk stratification in adult patients with tetralogy of Fallot. Our research revealed that QRS fragmentation was superior to QRS duration in predicting mortality, this was the first paper on prognostic relevance of QRS fragmentation in adults with congenital heart disease. Furthermore, cardiovascular magnetic resonance imaging had additional value compared with a well-established noninvasive risk model which is recommended by current guidelines. Therefore, QRS fragmentation and cardiovascular magnetic resonance imaging should be added to current recommended risk stratification models which may improve primary prevention of sudden cardiac death. Future studies are recommended to establish the role for advanced cardiovascular magnetic resonance techniques to quantify myocardial fibrosis.We performed a randomised controlled clinical trial (described in Chapter 15 of the thesis) to study the effects of the angiotensin receptor blocker losartan on right ventricular dysfunction in tetralogy of Fallot. In this trial, losartan had no significant effect on right ventricular dysfunction or secondary outcome parameters. Our results suggest that losartan should not be prescribed routinely in asymptomatic patients. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups.Overall, this thesis included several high-impact papers which are highly relevant to clinical management of adults with tetralogy of Fallot and provide a basis for future research. The studies included in this thesis involve a broad variety of subjects in a specific population and describe surgical outcomes, imaging, electrophysiology, pharmaceutical interventions and prevention/epidemiology.J.P. BokmaDepartment of Cardiology, Academic Medical Center Amsterdam, Amsterdam, The NetherlandsNetherlands Heart Institute, Utrecht, The Netherlandsj.p.bokma@amc.uva.nl.Promotor: Prof. dr. B.J. MulderCopromotor: Dr. B.J. BoumaThe earth turns around its own axis every 24 hours. As a result, life on our planet experiences daily changing circumstances such as dark/light and temperature variation. To anticipate to these changes, plants, animals, and humans possess a circadian clock that regulates 24-hour rhythms of multiple processes and functions.Circadian rhythms have been studied throughout history and already in the late 1970s, the molecular circadian clock was discovered. Its importance has been widely recognised; in 2017 the Nobel prize in physiology or Medicine was awarded to 3 circadian pioneers. So far however, biomedical research has largely ignored 24-hour rhythms. The pathophysiological role of the molecular clock has been studied in a few diseases and in most treatments, and we do not know whether time-of-day has any influence.Traditionally, research about circadian rhythms focused on the central circadian clock of the brain which regulates 24-hour rhythms via hormones and the autonomic nervous system. In the last few decades, the focus of research switched to the peripheral, molecular clock that is present in almost all body cells including cardiovascular cell types such as cardiomyocytes. Studies showed that these peripheral clocks play a major role in the cardiovascular system: they regulate approximately 10% of the cardiac transcriptome and proteome and as a result, cardiovascular functions such as electrophysiology, metabolism, and coagulation vary throughout the day. Most importantly, circadian clocks are associated with cardiovascular disease such as myocardial infarction and arrhythmias: circadian rhythmicity is involved in the incidence, pathophysiology and outcome of these acute events.in vitro model of the heart mimicking functional 24-hour rhythms. We discovered that circadian clocks and 24-hour rhythms are present in stem cells of the heart. Specifically, we found that stem cell functions that are important for cardiac repair/regenerative medicine such as apoptosis, proliferation, and the excretion of paracrine factors, fluctuate throughout the day.In this thesis, we investigated this role of circadian rhythms in cardiovascular disease. To link preclinical, molecular information of the molecular clock to the cardiovascular patient, we developed an in vivo model of myocardial infarction showed that 24-hour rhythms are present in both ischaemia and reperfusion damage. In a clinical study investigating ventricular arrhythmias, we found a 24-hour rhythm in ventricular repolarisation. We developed a new clinical parameter, QT diurnality, that quantifies this rhythm. In patients at risk of ventricular arrhythmias, we showed that patients with a high QT diurnality suffer from ventricular arrhythmias. We expect that in the near future, implementation of QT diurnality enables the prediction of ventricular arrhythmias in patients at risk.Next, we studied the role of the circadian clock in 2 common cardiac diseases, myocardial infarction and ventricular arrhythmias. Our study in an The data described in this thesis link pre-clinical studies of the molecular clock to the cardiovascular patient and shows that the circadian clock is not only involved in the pathophysiology and incidence of the cardiac disorder, but is also an important factor in prediction and treatment of cardiovascular disease.B.C. du PréDepartments of Medical Physiology and Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.E-mail: Dupre@startmail.comAimée Sakes won the first prize, Jouke Bokma the second prize and Bastiaan du Pré the third prize.


To assess the diagnostic and prognosis value of myocardial native T2 measurement in the distinction between Light-chain (AL) and Transthyretin (ATTR) cardiac amyloidosis (CA).Forty-four patients with CA  and 40 healthy subjects underwent 1.5 T cardiovascular magnetic resonance (CMR). They all underwent T1 and T2 mapping (modified Look-Locker inversion recovery), cine and late gadolinium enhancement (LGE) imaging. The Query Amyloid Late Enhancement (QALE) score, myocardial native T2, T1 and extra cellular volume fraction (ECV) were calculated for all patients.p = 0.6). Myocardial native T2 was significantly (p < 0.0001) higher in AL (63.2 ± 4.7 ms) than in ATTR (56.2 ± 3.1 ms) patients, and both higher (p < 0.001) than healthy subjects (51.1 ± 3.1 ms). Myocardial native T2 was highly correlated with myocardial native T1  and exhibited higher diagnostic performance than T1 to separate AL and ATTR patients: the area under curve (AUC) of T2 was 0.94  and the AUC of T1 was 0.77 . Myocardial native T2 did not impact overall survival in patients (HR 1.03 (0.94–1.12); p = 0.53) in contrast to ECV that was the best predictor of outcome (HR 1.66 per 0.1 increase in ECV (1.24–2.22); p = 0.0006).Of the 44 patients, 36 (82%) exhibited enhancement on LGE images. Mean QALE score of AL (7.9 ± 6) and ATTR (10.5 ± 5) patients were similar (Myocardial native T2 significantly is increased in CA, especially in AL patients in comparison to ATTR patients. Myocardial native T2 does not impact survival in CA patients in contrast to ECV that was the best predictor of outcome.Trial Registration and unique number: CNIL cardio 1778041. Date of registration: 20 December 2012. Cardiac amyloidosis (CA) is characterized by interstitial amyloid infiltration which leads to progressive thickening of cardiac walls, diastolic dysfunction, and restrictive cardiomyopathy –3. CardiAlthough CMR consistently detects CA, diagnosis of the types of amyloidosis, in particular the distinction between light chain (AL) and transthyretin (ATTR) amyloidosis, may be challenging . In mostn = 24, ATTR, n = 20, 9 mutant and 11 wild type) who underwent CMR between January 2013 and December 2014 at our center were retrospectively identified. Diagnosis and the type of systemic amyloidosis was biopsy-proven for all patients ). For patients with AL amyloidosis, cardiac involvement was histologically confirmed by EMB performed 1.2 (0–6) months after CMR. For the patients with ATTR amyloidosis, diagnosis of CA was based on significant heart retention of 99mTc-HMDP bone tracer on scintigraphy  as recently proposed in the literature  depending on the heart rate. A dedicated inversion recovery time (TI) scouting sequence was used before acquisition of LGE images to adjust the optimal TI. Phase sensitive inversion recovery (PSIR) images were systematically acquired after acquisition of LGE images because suboptimal nulling of the myocardial signal may be encountered in CA . SequencTwo reviewers, with 15 (JFD) and 3 (FR) years of experience in cardiovascular imaging, analyzed anonymously CMR images of all patients in consensus on a dedicated acquisition platform . The readers were blinded to the clinical data. LGE were scored on a five-point scale: 0: no abnormal enhancement detected within cardiac chambers, 1: doubtful enhancement within LV, 2: subendocardial enhancement of LV, 3: diffuse enhancement of LV, 4: patchy enhancement. Abnormal enhancement of RV and atria was also noted. Myocardial enhancement was also evaluated using the Query Amyloid Late Enhancement (QALE) score as previously reported . The QALpost-Gd) – (1/T1 myocardium pre-Gd)] / [(1/T1 blood pool post-Gd) – (1/T1 blood pool pre-Gd)]. Intra cellular volume (ICV) was calculated as follows: ICV = 1 – ECV. Lastly, Total amyloid volume and Total cell volume were calculated using the following formulas:The IVS was measured for all subjects on the end-diastolic short-axis cine image acquired at the middle part of the LV. LV indexed end-diastolic volume, indexed end-systolic volume, LVEF and indexed cardiac mass were calculated on cine short-axis images using a dedicated software . For myocardial native T1 and T2 measurements, the mid-ventricular short-axis and the 4 chamber images were manually contoured to outline the endocardium and epicardium, and the average T1 and T2 values were calculated for all patients using a dedicated software (cmr42). Same measurements were performed on post contrast T1 mapping images. In addition, T1 values of blood pool before and after contrast administration were calculated from a region-of-interest (ROI) placed in the blood pool cavity on the middle short-axis section. ECV was calculated using the following formula: ECV = λ (1- hematocrit), where λ = [(1/T1 myocardium 2) = ECV x LV volume.Total amyloid volume (mL/m2) = ICV x LV volume.Total cell volume  and signal intensity of chest wall muscle.Follow-up began at completion of the CMR. Dates and status of death were obtained from the medical records; as needed, details were obtained by contacting the referring physician.2 or the Fisher’s exact test, as appropriate. Differences between continuous data were tested using unpaired t-test or Mann–Whitney rank sum test for two groups comparisons, and analysis of variance (ANOVA) or Kruskal-Wallis for three groups comparisons followed by post-hoc pairwise comparisons with Bonferroni correction in case of global significance, as appropriate. Spearman’s rank correlation coefficients were calculated to assess correlation between continuous variables. Receiver operating characteristic (ROC) analysis, with corresponding measures of statistical uncertainty , was applied to myocardial native T1 and T2 and QALE score to identify optimal cut-off values for cardiac involvement based on the highest Youden index. Sensitivity and specificity were calculated using the thresholds previously defined. Overall survival was measured from the date of CMR to the date of death or last follow-up. Unadjusted survival curves were plotted by the Kaplan-Meier method, using log-rank tests to assess significance for group comparison. Unadjusted Cox proportional hazards regression models were performed to compute hazard ratios (HR) along with their 95% confidence intervals. Based on Schoenfeld residuals, all predictors were tested for the proportional-hazards assumption which was not found to be violated. For continuous variables, optimal thresholds for overall survival were determined using recursive partitioning analysis (RPA), based on the martingale residuals from a Cox model to determine the optimal value among all possible cut-points. Data were considered significant if p < 0.05. Analyses were performed using SPSS 25.0  and Stata v14.1 , using an implementation of RPA for Stata by Wim van Putten [Quantitative data are expressed as means ± SD or medians and interquartile (IQR) depending on the normality of the data. Categorical variables were described as number (%) and compared using the χn Putten .p = 0.04) and predominantly male . No significant differences were detected between AL and ATTR patients regarding biological and echocardiographic parameters. Healthy subjects were significantly younger than AL (p < 0.001) and ATTR (p < 0.001) patients and did not exhibit cardiac hypertrophy. They had higher LVEF than AL (p < 0.001) and ATTR (p < 0.001) patients. All data are reported in the Table Patients with ATTR amyloidosis were older compared with AL amyloidosis patients .Thirty-six (82%) patients exhibited enhancement of the LV on LGE images, described as subendocardial (grade 2) in 10 patients , diffuse (grade 3) in 22 patients  and patchy (grade 4) in 4 patients . Six patients  were considered as doubtful (grade 1) and 2 patients  were considered negative (grade 0). RV involvement was suspected in 21 patients  and atrial involvement was suspected in 21 patients . Mean QALE score of AL (7.9 ± 6) and ATTR (10.5 ± 5) patients did not exhibit significant difference (p < 0.05) higher in ATTR than in AL patients. Healthy subjects had significantly (p < 0.001) higher LVEF than AL and ATTR patients, and did not exhibit cardiac hypertrophy. All data are reported in the Table LV mass was significantly (p < 0.001 for both). A significant raise of myocardial native T1 was also noticed in CA patients (AL (1104 ± 54 ms); ATTR (1066 ± 42 ms)) compared to healthy subjects   higher in AL (63.2 ± 4.7 ms) than in ATTR (56.2 ± 3.1 ms) patients. A raise of myocardial native T1 was also observed in AL patients (1104 ± 54 ms) in comparison to ATTR patients (1066 ± 42 ms), but in a less significant manner (p < 0.01). AL and ATTR patients did not exhibit significant difference regarding other mapping parameters  except for total cell volume that was significantly higher in ATTR (61 ± 19 mL/m2) than in AL patients . T2 ratio did not exhibit significant differences (p = 0.2) between groups . All data are reported in Table Myocardial native T2 was significantly higher in AL and ATTR patients than in healthy subjects p = 0.001), Total cell volume  and LVEF .Myocardial native T2 was strongly correlated with myocardial native T1  Fig.  and lessp < 0.001), higher than that of T1 )  With a cut-off of 59.2 ms, the sensitivity and specificity of myocardial native T2 were 83 and 95%, respectively. One hundred percent of specificity was obtained with a cut-off of 63 ms (sensitivity 42%). Lower performances were obtained using T1: with a cut-off of 1092 ms, the sensitivity and specificity of myocardial native T1 to diagnose AL patients were 71 and 75%, respectively. One hundred percent of specificity was obtained with a cut-off of 1130 ms (sensitivity 37%). Myocardial native T1 and T2 exhibited similar performances to distinguish between patients and healthy subjects .AL patients formed the positive case group and ATTR patients were considered as negative cases. Healthy subjects were excluded to reflect clinical practice. The area under curve (AUC) of myocardial native T2 for diagnosed AL patients as opposed to ATTR patients was 0.94 . Univariate Cox regression identified the following predictors: ECV (HR 1.66 per 0.1 increase in ECV (1.24–2.22); P = 0.0006), IVS thickness (HR 1.18 per 1 mm increase in IVS thickness (1.02–1.37); P = 0.02), LVEF (HR 0.64 per 10% increase in LVEF (0.47–0.87); p = 0.005) and post contrast myocardial T1 ; p = 0.0005). For ECV, a value of 0.59 was identified by recursive partitioning as the optimal cutoff to predict overall survival: HR 5.33 (1.70–16.71), p = 0.004. Kaplan-Meier curve for patients according to ECV level is shown in Fig. Survival analysis was performed in the cohort of 42 patients with CA. In total, 18 of 42 patients died during a median follow-up of 27 months (interquartile range: 14–40 months). Myocardial native T2 was not significantly associated with overall survival in patients with CA (HR 1.03 (0.94–1.12); In this study, we reported a significant raise of myocardial native T2 relaxation time suggesting myocardial edema in patients with CA, and more pronounced in AL compared to ATTR patients. Myocardial native T2 exhibited higher performances than T1 to differentiate AL and ATTR amyloidosis but was not a predictor of survival.The question of variation of myocardial T2 in CA remains controversial in the literature with few studies addressing this topic. Using T2 mapping sequence, Sparrow et al.  did not Surprisingly, we did not find in this study a significant reduction of T2 ratio in CA patients in comparison to healthy subjects, as previously reported by our group  and otheIn the light of our results, one can also deduce that the raise of myocardial T1 in cardiac amyloidosis is not only a simple consequence of passive amyloid proteins deposit, but is also driven by myocardial edema. The high correlation between myocardial native T1 and T2 that we noticed suggests a reciprocal influence and reinforces this idea. Therefore, because of the dual origin of its signal (interstitium and myocytes), caution should be taken to use solely T1 as a direct marker of amyloid burden and as a surrogate endpoint in drug development . Its varATTR patients exhibited higher indexed LV mass and total cell volume in comparison to AL patients in our report, suggesting that extracellular deposition of amyloid proteins was associated with a concomitant cell hypertrophy in ATTR. These results are in line with Fontana et al. who reported a 18% increase of the intracellular space in ATTR vs. AL patients . NeverthFirst, the number of subjects included in this work was relatively limited and control group was younger than AL and ATTR patients, a difference that may influence (weakly) measurements of myocardial native T1 with the MOLLI sequence . Second,In this study, we reported a significant raise of myocardial native T2 in AL patients in comparison to ATTR patients. T2 separated effectively AL and ATTR patients and could be considered as an additional marker to distinguish these 2 types of CA. Although more intense than in AL amyloidosis, myocardial edema was also detected in ATTR patients suggesting that myocardial edema plays a role in the raise of myocardial native T1 in CA. As opposed to ECV, T2 did not seem to impact survival of CA patients.


Neurogenic stunned myocardium (NSM) is defined as the occurrence of cardiac abnormalities due to neurological events such as stroke, seizures, etc. These events lead to dysfunction of the autonomic nervous system (ANS) and ultimately cause injury to the myocardium. The clinical features seen in NSM include elevated troponin level, left ventricular dysfunction, and changes on the electrocardiogram (ECG). However, these features are also seen in Takotsubo cardiomyopathy as well as in an acute coronary syndrome (ACS). Hence, diagnosing the condition by clinical presentation alone is difficult. Thus, a patient of NSM who is at increased risk of developing coronary heart disease may require invasive procedures such as cardiac catheterization to rule out ACS. This review aims at raising awareness about NSM among physicians so that management of patients can be individualized. Annually, approximately 800,000 people in the US suffer from stroke, including recurrences. A person has a stroke in the country roughly every 40 seconds, and there is a stroke-related death every four minutes . Stroke Neurogenic stunned myocardium (NSM) is defined as the occurrence of cardiac abnormalities due to neurological events such as stroke, seizures, etc. These events lead to the dysfunction of the autonomic nervous system and ultimately can lead to several different types of cardiac disorders -10. LikeLike myocardial infarction, another condition with a presentation similar to NSM is Takotsubo cardiomyopathy. Both NSM and Takotsubo cardiomyopathy have similar pathophysiology and presentations. However, wall motion abnormality is a difference noted between the two. NSM is usually associated with global hypokinesis, whereas Takotsubo cardiomyopathy leads to regional wall motion abnormalities. Due to these similarities, some physicians consider them as a single condition falling under the category of stress-induced cardiomyopathy.It is challenging to differentiate between NSM and acute MI. Bulsara et al. have devised certain guidelines to help discriminate between these two similar entities in patients with subarachnoid hemorrhage. NSM can be distinguished from acute MI by the following: (1) lack of pre-existing heart disease; (2) cardiac dysfunction of recent onset with ejection fraction < 40%; (3) wall motion abnormalities which do match ECG changes; (4) low troponin levels, i.e., less than 2.8 ng/ml in patients with a low ejection fraction . HoweverPathophysiologyIt has been shown that autonomic dysfunction and adverse cardiac events after a stroke are associated with the involvement of the insular cortex of the brain. This area connects with other areas of the brain including the limbic system and helps in integrating the autonomic, motor, and sensory functions. In NSM, the insular cortex plays a key role in balancing the sympathetic and parasympathetic nervous systems.The limbic and autonomic regulatory control of the cardiovascular system is carried out by the insula, with the help of baroreceptors in the insular cortex that helps alter the blood pressure and heart rate. Any stimulation of the insula results in an alteration of these parameters. Moreover, any lesions involving the insular cortex in the brain cause an increased release of norepinephrine leading to left ventricular dysfunction. The effects seen due to the stimulation of right or left insula are different. Right insular stimulation results in sympathetic effects such as an increase in the heart rate (tachycardia) and an increase in blood pressure (hypertension). In comparison, the stimulation of the left insula results in parasympathetic effects, such as bradycardia and a reduction in blood pressure. Conversely, a stroke involving the right insular region will cause lowered sympathetic regulation and an increase in parasympathetic effects . The revThe principal mechanism of NSM is an increased sympathetic stimulation. The initiating event is an influx of catecholamines because of a lesion in the brain or due to excessive stress. Eventually, cardiac injury occurs which can be in the form of (a) ischemic insult due to inability to meet the increased myocardial demand ; (b) dirThe histological changes seen in NSM include transient myofibrillar degeneration, also known as myocytolysis. Myocytolysis is characterized by multiple foci of subendocardial hemorrhage seen around the epicardial nerves and is indicative of actual myocardial stress. As the myocytolysis affects the subendocardial region which is also the site of the cardiac conducting system, arrhythmias are seen frequently in NSM.Troponin levelsStroke patients can develop NSM which might remain asymptomatic and thus be missed. An increase in troponin levels might represent the only sign of cardiac damage in such patients and can be seen without chest pain and abnormalities on the ECG or the echocardiogram. Faiz et al. showed that approximately 53% of patients with acute ischemic stroke had raised troponin levels . HoweverRaised troponin levels can also be indicative of a poor prognosis in stroke patients. According to Ghali et al., in patients of ischemic stroke, troponin showed a sensitivity of 0.27, specificity of 0.94, and a likelihood ratio of 4.5 when it was used to predict a poor outcome. Moreover, troponin levels also showed a correlation between the severity of stroke . Jensen Electrocardiographic featuresApproximately 60%-90% of patients with cerebral infarction also demonstrate abnormal ECG findings, the most common of which is a prolonged QT interval. The second most common abnormal ECG finding in patients with cerebral infarctions is a T-wave inversion, followed by ST-segment depression. Atrial fibrillation is the most common abnormal rhythm seen in these patients, followed by sinus tachycardia. Approximately 8% of patients with cerebral infarction showed a triad of prolonged QT interval, U waves, and T-wave inversion.Arrhythmias are seen frequently in patients after a cerebrovascular stroke and are more common in patients with a co-existing cardiac disease. Other factors that increase the probability of development of arrhythmias in these patients include diabetes mellitus, hypertension, and increasing age. An independent predictor tool for the development of arrhythmias is the NIHSS score. The most common arrhythmias seen in patients with acute stroke are atrial fibrillations, followed by sinus tachycardia, premature ventricular complexes, and ventricular tachycardia.Two-dimensional (2D) echocardiographic featuresNeurogenic stunned myocardium can present with poor left ventricular function. Banki et al. evaluated patients with subarachnoid hemorrhage and cardiac dysfunction and showed that the cardiac wall motion abnormalities in these patients matched the changes seen on their ECGs .ManagementThe prevalence of asymptomatic coronary artery disease is high in patients of acute ischemic stroke. These two entities have similar risk factors and are, thus, common in the same subset of the population. Considering the coexistence of these conditions, it is essential to assess patients of stroke for cardiovascular abnormalities and dysfunction. Also, due to the impaired cognition and functional capacity of stroke patients, there is a high likelihood of asymptomatic cardiac dysfunction in them. Additionally, cardiac injury and dysfunction is an important cause of morbidity and mortality in such patients. Because of all these factors, cardiac monitoring is especially crucial in these patients with stroke .As per the American Heart Association/American Stroke Association (AHA/ASA), patients with ischemic stroke or transient ischemic attack (TIA) should be subjected to cardiovascular risk assessment, followed by aggressive risk reduction management. The guidelines also recommend that patients with multiple risk factors for coronary heart disease or a high Framingham score should be subjected to noninvasive testing for coronary artery disease. The choice of investigation can also be determined by the ACC/AHA guidelines. Lastly, the management of the patient should be individualized and modified according to the patient’s clinical scenario. However, if the cardiac dysfunction is due to NSM, coronary angiography is not recommended routinely.Against a backdrop of neurological events, cardiac abnormalities can lead to poor outcomes. The pathophysiology of such cardiac dysfunction lies in the increased release of catecholamines due to neurologic damage, eventually leading to myocardial necrosis. Several independent studies have shown that insular involvement is most likely responsible for the autonomic dysfunction in patients of stroke. The clinical features of NSM are similar to acute coronary syndrome, making it difficult to distinguish the two clinically. Moreover, no definite guidelines are currently available concerning the management of NSM. In patients who are at a high risk of developing coronary heart disease, careful risk assessment and aggressive management should be initiated to reduce morbidity and mortality in these patients.


Introduction: Systemic lupus erythematosus (SLE) myocarditis occurs in between 5% and 10%of patients with lupus. Global longitudinal strain (GLS) via speckle tracking echocardiographycan detect cardiac involvement in patients suffering from SLE. We decided to determine theechocardiographic features and subsequent early diagnosis of cardiac involvement in patientswith SLE utilizing the GLS index via speckle tracking echocardiography.Methods: In this cross-sectional study, we compared female patients with SLE of at least 2 years’duration and healthy controls in terms of the left ventricular (LV) GLS via speckle trackingechocardiography. After data collection in both groups, the GLS index and the ejection fractionwere evaluated.Results: We analyzed and compared the LV echocardiographic parameters of 33 patients withSLE (mean age=25.45±0.63 years) with those of 35 healthy controls (mean age=27±0.45 years).The apical 2-chamber view indicated a significant decrease in the LV GLS in the case group bycomparison with the healthy controls (P=0.005). The LV GLS in the apical 3-chamber view wassignificantly lower in the case group than in the control group (P=0.006). The LV GLS in theapical 4-chamber view revealed no significant difference between the case and healthy controlgroups (P=0.2). While there was a significant difference between the case and control groups visà-vis the LV GLS (P=0.02), the LV ejection fraction measured with the Simpson method showedno significant difference between the 2 groups (P=0.96).Conclusion: GLS speckle tracking echocardiography is a noninvasive method with diagnostic andprognostic values; it may, therefore, be a sensitive marker for the diagnosis of myocarditis andother cardiac involvements in patients with SLE. One of the organs reported to be involved in SLE is the heart. Several cardiac diseases have been stated to be involved in patients with SLE; these diseases include pericarditis (the most common cardiac involvement), mitral regurgitation, tricuspid valve thickening and regurgitation, valvular vegetation , myocardial dysfunction, and coronary arteries disease.20 Transthoracic echocardiography is applied to assess cardiac involvement in many autoimmune diseases such as SLE and rheumatoid arthritis. Most cardiac involvements in SLE are silent clinically, but they can cause significant illness and death.Cardiac involvement in SLE is frequently diagnosed with sensitive and noninvasive imaging methods such as echocardiography.21 We, accordingly, sought to evaluate subclinical cardiac disease with the aid of speckle tracking echocardiography in patients suffering from SLE.Screening with transthoracic echocardiography can assess the systolic and diastolic functions of the heart and can measure the indices of global longitudinal strain (GLS) and ventricular wall-motion (velocity). In addition, speckle tracking echocardiography can be drawn upon to detect myocardial dysfunction and prevent early mortality.This cross-sectional study recruited 33 female patients (age=20–30 years) with SLE of at least 2 years’ duration who referred to the Rheumatology Clinic of Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran. Patients with a history of Libman–Sacks endocarditis, a left ventricular ejection fraction (LVEF) of less than 55%, and heart failure were excluded. Thirty-five age- and sex-matched healthy controls were selected from the hospital staff. Following admission, a detailed history was obtained from the patients and clinical examinations were performed by experienced physicians. Demographic variables—including age, sex, height, and weight—were recorded. The patients and controls were also checked for the presence of classic cardiovascular risk factors such as hypertension, diabetes mellitus, dyslipidemia, smoking, and a family history of premature coronary artery disease. Additionally, patients with a history of valvular heart disease, arrhythmias, and known coronary artery disease were excluded. The clinical parameters checked encompassed the heart rate, systolic and diastolic blood pressures, a history of myocardial infarction or stroke, and congestive cardiac failure.After the collection of the baseline demographic and clinical data, all the participants were evaluated with transthoracic 2D color echocardiography and speckle tracking echocardiography by a single echocardiologist using a Philips Dimensions ultrasound system.10The LV GLS was assessed in the apical 2-, 3-, and 4-chamber views. Echocardiographic parameters, including the diameter of the 4 chambers, were measured routinely. The LV systolic function and EF were measured using the Simpson method. The reference limits of all the echocardiographic parameters were defined according to the guidelines of the American Society of Echocardiography.t test or the Mann–Whitney U test. The results are expressed as means ± standard errors (SEs). A P value of less than 0.05 was considered the minimum significant difference of means.The normal distribution of the data in the 2 groups was assessed using the Kolmogorov–Smirnov test. The comparisons of the continuous variables between the 2 groups were analyzed with the SPSS software, version 18, using the Student P = 0.005) (P = 0.006) (P = 0.2) (P = 0.02) (P = 0.96)  with those of 35 healthy controls (mean age=27±0.45 years). The results of the apical 2-chamber view showed a significant decrease in the LV GLS in the case group in comparison with the healthy controls (= 0.005) . Similar= 0.006) . In contP = 0.2) . Whereas = 0.02) , the 2 s = 0.96) .4 In an autopsy of patients with lupus, rates of cardiac involvement of between 40% and 50% have been reported, and between 7% and 10% of these cases of cardiac involvement are detected during the patients’ lifetime.23The availability of various treatment modalities has diminished the rate of death due to infections in patients with lupus. Nonetheless, death due to cardiac causes such as cardiomyopathy, arrhythmias, and heart failure plays a role as an independent factor in lupus.24One of the new methods for assessing the LV function with 2D speckle tracking echocardiography is GLS measurement. GLS measurement is a relatively new, accurate, and non-operator method to evaluate the function of the heart by comparison with the traditional methods of determining the EF.26 In the onset of cardiovascular involvement in lupus, a significant change cannot be seen in the conventional EF measurement method. A measurement of the LV GLS may detect heart disease in lupus before the occurrence of a decreased EF.Studies have also shown that GLS measurement in comparison with the EF is a good predictor of mortality in patients with heart failure.In the present study, GLS and EF parameters in patients with SLE, but without cardiac symptoms, were compared with those of healthy subjects.The results of the GLS assessment showed a significant decrease in the apical 2-, 3-, and global chamber views in the patients with SLE in comparison with the healthy subjects; nevertheless, no significant difference was found in the 4-chamber view results. Additionally, the LVEF finding in the patients with SLE indicated no significant decrease compared with the healthy controls.16 This finding is in line with the results of a study by Huang et al,27 who reported a reduction in the LV GLS in 2D echocardiography in their patients with lupus by comparison with their healthy subjects. A similar study, conducted in 2016 with the aid of speckle-tracking echocardiography to evaluate strain indices in patients suffering from lupus, indicated that the strain indices were decreased in the treatment-resistant lupus group compared with the non-resistant lupus group.28 These findings underscore the importance of strain in predicting the disease prognosis and response to treatment in patients with lupus.In light of the above findings, it can be stated that an impairment in GLS can be used as an index for evaluating ventricular functions relative to the conventional EF measurement. In fact, GLS impairment has an early diagnostic and prognostic value.30 Our research findings, in concordance with the findings of previous studies, indicate the predictive role of GLS in the LV function in patients with SLE. Several mechanisms have been suggested for cardiac involvement in patients with lupus. Indeed, chronic immune response, cytokine overactivity, and inflammatory progression contribute to cardiomyocyte apoptosis, ventricular dysfunction myocarditis, and finally heart failure. All these events increase the rate of cardiovascular mortality.33 Therefore, cardiovascular assessment in patients with lupus, even in non-symptomatic ones, appears to be crucial.A study in 2015 showed the predicting role of the GLS index in comparison with the EF index in chronic kidney disease. Cardiovascular disease is one of the causes of death in chronic kidney disease, which is mostly asymptomatic.Given the limited research in this field in Iran, we conducted the current study in order to evaluate the early diagnosis of heart disease in patients with SLE by using the GLS index. We would, however, recommend further studies with the aid of GLS index.The major limitation of the current study is the relatively small number of its participants. SLE is not a common disease and it is difficult, as such, to find patients with SLE. Another drawback of note is the single-center design of this study in a university hospital. We would recommend a multicenter study including a large number of patients with SLE in the different stages of the disease.Myocarditis and subsequent cardiac failure are a consequence of SLE. The GLS parameter in 2D speckle tracking echocardiography is a noninvasive cost-effective tool with a desirable diagnostic and prognostic value in patients with lupus myocarditis. GLS impairment was common in 2D speckle tracking echocardiography findings in our patients with lupus. Hence, it would be useful to consider screening 2D speckle tracking echocardiography in the routine care of patients with lupus to explore whether or not the GLS method would be cost-effective and beneficial for patients. Therefore, further investigations are needed on various aspects of cardiac involvement in lupus to determine the significance of GLS changes in autoimmune diseases such as lupus.All the participants signed a written informed consent before enrolment in the study, and the study protocol was approved by the Board of Research and Ethics Committee of Tehran University of Medical Sciences.None.


Botulinum toxin type A (BTX-A) injections improve muscle tone and range of motion (ROM) among stroke patients with upper limb spasticity. However, the efficacy of BTX-A injections for improving active function is unclear. We aimed to determine whether BTX-A injections with electrical stimulation (ES) of hand muscles could improve active hand function (AHF) among chronic stroke patients. Our open-label, pilot study included 15 chronic stroke patients. Two weeks after BTX-A injections into the finger and/or wrist flexors, ES of finger extensors was performed while wearing a wrist brace for 4 weeks . Various outcomes were assessed at baseline, immediately before BTX-A injections, and 2 and 6 weeks after BTX-A injections. After the intervention, we noted significant improvements in Box and Block test results, Action Research Arm Test results, the number of repeated finger flexions/extensions, which reflect AHF, and flexor spasticity. Moreover, significant improvements in active ROM of wrist extension values were accompanied by marginally significant changes in Medical Research Council wrist extensor and active ROM of wrist flexion values. In conclusion, BTX-A injections into the finger and/or wrist flexors followed by ES of finger extensors improve AHF among chronic stroke patients. Upper limb spasticity (ULS) is a common impairment after stroke, which can cause abnormal posture, pain, reduced movement, and functional impairment ,2,3,4. VClostridium, is the most potent toxin among various serotypes, and its safety is well established [Intramuscular injection of botulinum toxin type A (BTX-A) is the recommended first-line treatment for focal ULS ,6,7,8,9.ablished ,11. Its ablished ,13. Althablished ,15. Indeablished ,16. ThesSeveral explanations for the discrepancy between impairment and function have been proposed. First, most previous treatments have targeted spasticity per se, while factors other than hypertonicity are likely to be associated with active function, including stretch-sensitive paresis, overactivity of agonistic muscles, and learned non-use ,3,15. SeMany patients having ULS exhibit difficulty with finger extension, which is critical for gripping, grasping, and releasing movements. Thus, we hypothesized that relief of finger flexor spasticity following BTX-A treatment would help patients regain finger extensor strength, which would in turn improve hand function. Based on the findings of previous studies, we further hypothesized that electrical stimulation (ES) is a simple yet effective form of adjuvant therapy, as it facilitates muscle reeducation, including antagonist strengthening and agonist lengthening ,28. TherAmong the 15 included patients, 7 experienced cerebral infarction and 8 experienced intracerebral hemorrhage. Thirteen patients experienced lesions in the right hemisphere. The mean time from stroke was 12.8 ± 3.7 months. All 15 patients completed the study, and none experienced adverse events.χ2 = 6.50, p = 0.039), Action Research Arm Test (ARAT)-total , and ARAT-gross movement scores , which reflect active hand function   in the T1–T3 and T2–T3 phases. Active-FE values showed marginally significant increases during the T2–T3 phase .Repeat-finger extensor/extension (FE) values showed significant increases : χ2 = 20.18, p < 0.001), and post-hoc tests revealed significant differences in the T1–T2 and T1–T3 phases, but not in the T2–T3 phase  were accompanied by marginally significant increases in Medical Research Council WE (MRC-WE)  and AROM-WF  values. Post-hoc analyses demonstrated that AROM-WE values were higher at T3 than at T1 or T2 and that MRC-WE values significantly increased from T1 to T3. No significant changes were noted for other secondary outcomes, such as the Quick Disabilities of Arm, Shoulder, and Hand (QDASH) score .Flexor spasticity significantly decreased : T3 phase . SignifiIn the present study, we attempted to examine the efficacy of BTX-A treatment targeting finger flexor spasticity and concomitant ES for improving active hand function in the chronic phase of stroke. We found that BTX-A injections into the flexor muscles of the fingers and wrist followed by ES improved active hand function, as indicated by significant improvements in BB, ARAT , and Repeat-FE scores. These findings are in contrast to those of previous studies, which failed to demonstrate improvements in active function after BTX-A treatment among patients with chronic stroke ,30,31.These discrepancies may be explained by our concept of intervention, as we considered treatment according to spastic paresis rather than flexor muscle spasticity only ,3. OveraBotulinum toxin type A injections to finger/wrist flexors reduced involuntary activation of the flexor muscles and further led to “therapeutic weakness” . HoweverImproved balance between agonist and antagonist muscles was accomplished with proprioceptive discharge reduction via group-IA afferents ,38. BotuOn the other hand, fascicle selection was tailored to each patient, and a flexible dosing regimen was utilized to ensure the appropriate level of weakness without inadvertent over-weakness. This may explain why we observed significant changes in ARAT-gross movement and MAS-WF/finger flexor/flexion (FF) values, but not MRC-WF/FF values or functional deterioration, between T1 and T2.We subsequently utilized ES to facilitate target muscle (finger/wrist extensor) contraction, which has been difficult to achieve owing to increased flexor tone. ES enabled reeducation, stretching, and strengthening of the extensor muscles . This seSuch differences between T1–T2 and T2–T3 may explain the discrepancies between active and passive functions following BTX-A treatment . Our finIn addition, we utilized a wrist brace to maximize finger extension during ES while reducing unwanted wrist or metacarpophalangeal joint hyperextension. Full finger extension is difficult during concomitant wrist extension owing to passive tension that results from the muscle insertion pattern of two-joint finger flexor muscles. The wrist brace maintained the wrist/metacarpophalangeal joints in a neutral position to allow sufficient extension of the distal or proximal interphalangeal joints, and it may have decreased stretch-sensitive paresis of the finger extensors.In the present study, we attempted to utilize comprehensive hand-relevant outcome measures for both impairment  and active function (ARAT and BB). We also utilized measures specific to hand function, particularly finger extension . These various measures assessed at different time points helped classify the effects of our intervention in terms of spastic paresis. Recently, goal attainment scales have been used to determine individualized, focal changes following BTX-A injections . HoweverAccording to the QDASH results, no improvement in subjective upper limb function was observed, and this is likely due to the small yet significant objective change over the course of the intervention. Further studies should examine whether both subjective and objective improvements in upper limb function can be observed in select groups of patients, such as those in the subacute phase of stroke and those with some level of strength in the wrist/finger extensors.The present study had several limitations. First, as this was not a randomized controlled trial, it is difficult to conclude whether our intervention would outperform other interventions or whether the combination of BTX-A injections and ES is more effective than either approach alone. Second, we did not measure outcomes at 12 weeks, when the effects of BTX-A can no longer be observed . FinallyOur findings indicate that BTX-A injections into the finger and/or wrist flexor muscles followed by ES of finger extensors improve active hand function and impairment among patients with chronic stroke. The present results support the notion that interventions targeting spastic paresis, rather than spasticity per se, may improve active hand function.ClinicalTrials.gov .The present open-label, pilot study included 15 patients  age older than 18 years; (2) hemiplegic ULS secondary to unilateral ischemic or hemorrhagic stroke; (3) finger and wrist flexor spasticity graded at least 1+ on the MAS; and (4) stroke occurrence at least 6 months prior to enrollment. The exclusion criteria were as follows: (1) fixed contracture of the wrist or hand; (2) previous ULS treatment with neurolytic therapy, surgery, or BTX-A injection; (3) presence of any active implanted device; (4) presence of any neurological disorder causing motor deficit or spasticity, other than stroke; (5) inability to cooperate for all outcome measure-related tasks secondary to cognitive impairment or aphasia; (6) pregnancy, planned pregnancy, or lactation; and (7) contraindication for BTX-A treatment.Patients received BTX-A  injections at week 0. The dilution of BTX-A was standardized, such that each vial of BTX-A (100 U) was diluted with 2 mL of normal saline (5 U/0.1 mL). A physician with experience in BTX-A treatment performed clinical evaluations of ULS and freely selected the target muscle and dose according to the pattern and severity of ULS in each patient. BTX-A injections were then administered under ultrasonographic guidance . Injections at the flexor digitorum superficialis and profundus were administered by tailoring fascicle selection to each patient and by adopting a flexible dosing regimen. In each patient, the total BTX-A dose did not exceed 360 U. The dosages and injection sites are listed in After 2 weeks of BTX-A injections, patients received ES of finger extensors while wearing a wrist brace for 4 weeks. ES was administered 5 days per week during 30-min sessions by trained occupational therapists, using a Novastim CU-FS1 unit . During ES, each patient was seated in a chair with the affected arm resting on a table and with a small pillow supporting the pronated forearm. Cyclic ES was administered to induce muscle contractions, using biphasic pulses  delivered for 6 s , with a 12-s burst-off. Two surface electrodes (5 × 5 cm) were placed over the extensor digitorum communis. The amplitude of stimulation was adjusted to elicit adequate finger extension for a sufficient range of motion against gravity, without pain.The wrist brace  used during ES was made of soft fabric, and it covered the area from the wrist to the metacarpophalangeal joint. Two metal bars were attached to the volar and dorsal regions of the brace to immobilize the wrist in a neutral position. This immobilization ensured that ES could induce selective distal or proximal interphalangeal joint extension while overcoming unwanted simultaneous wrist or metacarpophalangeal joint extension. A Velcro strap was used to restrain the dorsal and volar sides of the brace.We recorded baseline characteristics, including sex, age, stroke type, brain lesion side, time since stroke, and handedness. Primary and secondary outcomes were assessed at baseline , immediately before BTX-A injections , and 2 weeks  and 6 weeks  after BTX-A injections, by an experienced research occupational therapist. For further screening, we evaluated changes in outcomes between T0 and T1. Patients exhibiting changes between these two time points were excluded from the study. We examined the effects of BTX-A at 2 weeks, as previous studies have indicated that BTX-A shows maximum efficacy between 1 and 2 weeks after treatment . OutcomeThe primary outcomes were changes in patient results in the BB test and ARAT between T1 and T3, which represent changes in the active function of the upper limb following the present intervention. The BB test is a reliable and validated measure of unilateral gross manual dexterity, in which participants are required to pick up a 1-inch block, lift it over a partition, and then release it within a target area as many times as possible within 60 s . The ARAHand-specific active function was assessed according to active finger extension (Active-FE), the maximum distance from the fingertip to the palm (Distance-FP), the number of repeated finger flexion/extension movements within 20 s (Repeat-FE), the rating of active thumb opposition (Thumb-opposition), and grip strength as measured using the Jamar dynamometer . Active-FE was rated using a 5-point ordinal scale  by reviewing a video clip . DistancUpper limb impairment was assessed according to MAS scores for the wrist and finger flexors/extensors (MAS-WF/WE/FF/FE), MRC grades for wrist and finger flexor/extensor strength (MRC-WF/WE/FF/FE), and active range of motion for wrist flexion/extension (AROM-WF/WE) and radial/ulnar deviation (AROM-RD/UD) as determined through goniometric measurement. Modified Ashworth Scale grades of spasticity were converted from 1+, 2, 3, and 4 to 2, 3, 4, and 5, respectively .Subjective general upper limb function was evaluated using the self-reported QDASH scale. The QDASH scale consists of 11 items regarding physical function and symptoms during the previous week, and the total scores range from 0 (no disability) to 100 (most severe disability) .p < 0.05.For all outcome measures, the Friedman test was used to determine the overall change from pre-intervention (T1) to post-intervention (T2)/follow-up (T3). When the Friedman test yielded significant results, various pairwise comparisons were performed using post-hoc Wilcoxon signed-rank tests in order to determine the effect of each intervention (BTX-A/ES). All statistical analyses were performed using SPSS 20.0 . The level of statistical significance was set at


Nuclear factor-kB is highly activated in cardiovascular disorders. However, few articles have targeted at the role of nuclear factor-kB inhibitor in heart failure.To evaluate the effects of nuclear factor-kB inhibitor pyrrolidine dithiocarbamate on cardiocyte apoptosis and cardiac function in a rat heart failure model.Animal experiment.A stable and reproducible rat heart failure model (n=64) was prepared by injecting homologous microthrombotic particles into the left ventricle of Sprague–Dawley rats while obstructing the ascending aorta to produce coronary microembolization. Rats with heart failure were randomized into untreated (HFu) and pyrrolidine dithiocarbamate-treated (HFp) groups; the latter received an intraperitoneal injection of pyrrolidine dithiocarbamate (100 mg/kg/day) 1 h prior to surgery as well as on postoperative days 1-7. The sham group comprised 32 Sprague–Dawley rats. Eight rats from each group were sacrificed on days 1, 3, 7, and 14 postoperatively. Masson’s trichrome staining was used to determine the micro-fibrotic area to indicate the severity of myocardial loss. Terminal transferase uridine triphosphate nick end labeling staining was used to detect apoptotic cardiomyocytes. Echocardiography and hemodynamics were performed to evaluate left ventricular function.Rats with heart failure exhibited pathological changes evidenced by patchy myocardial fibrosis, remarkably elevated severity of myocardial loss, and persistently reduced left ventricular function. At the end of the study, compared with the HFu group, myocardial infarct size was reduced by 28% (p=0.001), cardiocyte apoptosis was suppressed , cardiac function parameters such as left ventricular ejection fraction (80%±4% vs 61%±6%), left ventricular + dP/dt max (4828±289 vs 2918±76 mmHg.s−1), left ventricular - dP/dt max (4398±269 vs 2481±365 mmHg.s−1), and left ventricular systolic pressure (126±13 vs 100±10 mmHg) were significantly increased, and left ventricular end-diastolic pressure was reduced (18±2 vs 13±1 mmHg)  in the HFu group.Our rat model can adequately mimic heart failure via coronary vessel embolization. Moreover, pyrrolidine dithiocarbamate treatment can reduce cardiocyte apoptosis and improve cardiac function, which may be beneficial for patients with heart failure secondary to myocardial infarction. Congestive heart failure (HF) is a serious and complex clinical condition with high morbidity, disability rate, and mortality. Patients with coronary heart disease, particularly those receiving percutaneous coronary intervention, can easily become prone to HF due to coronary microembolization . TherefoThe available literature on cardiovascular disorders has documented that nuclear factor-kB (NF-kB) is highly activated ,3,4. NF-ad libitum access to water and rat chow. The study protocol observed The Guide for the Care and Use of Laboratory Animals  and received approval from the Clinical and Animal Research Ethics Committee of Medical University.Sprague Dawley (SD) rats (weighing 280-320 g) were provided from the animal center of Medical University. These animals were raised in conditions with controlled humidity, lighting cycle, and temperature and were allowed 9) were thoroughly suspended in calcium-free Dulbecco’s phosphate-buffered saline with a vortex agitator. Tail blood (500 µL per rat) was obtained and stored at room temperature to allow clot formation. The clot was then fragmented with a homogenizer and filtered using a 38 µm screen to obtain microthrombi (microthrombi-emboli), which were between 10-30 µm as measured by a micrometer.Male Sprague Dawley rats were sedated by intraperitoneal injection of ketamine (75 mg/kg) and diazepam (7.5 mg/kg) 36 h before the experiment. Prior to each injection, 7 mg of the particles  chamber with a 26-gage needle while the ascending aorta was occluded for 10 s. Sutures were used to close the thoracic cavity and skin incision. The age-matched sham group received the same surgical procedure and a phosphate-buffered saline injection of the same volume.A total of 32 Sprague Dawley rats received a sham operation and 64 rats underwent the previously described surgery to establish an HF model. Rats with HF were randomized into an untreated  and PDTC-treated  groups. The rats with HF were sacrificed at postoperative days 1, 3, 7, and 14, forming four subgroups (n=8 each). PDTC  in a 0.9% NaCl solution was intraperitoneally administrated at a dosage of 100 mg/kg/day, starting 1 h prior to surgery and continuing for 7 days postoperatively. The PDTC doses have been proved to effectively blunt NF-kB activation with no significant toxicity .The rats were sedated for the echocardiography procedure, as previously described. Echocardiography with two-dimensional and M-mode imaging modalities was conducted with a medical diagnostic system  equipped with a 10 mHz phased-array transducer. Electrocardiographic measurements were simultaneously recorded with respiratory tracings. The LV end-diastolic diameter  and the end-systolic diameter  were recorded using the M-mode tracings of the level of the chordae tendinae at the end of expiration in the LV short axis view. A cubic formula was employed to calculate the LV ejection fraction. For all parameters, at least three consecutive cardiac cycles were averaged. The echocardiographic readings were recorded and stored throughout the experiment.Hemodynamic measurements were performed under general sedation and a 20-gage polyethylene cannula was inserted from the right carotid artery into the left ventricle. The maximum change of LV pressure during isovolumic contraction (LV + dP/dt max) and relaxation (LV - dP/dt max) was calculated from the LV pressure traced with a resistance-capacitance analog differentiator and the LV systolic pressure. The hemodynamic and functional parameters were recorded in each procedure.After the harvest, the hearts were fixed in 10% formalin, embedded and cut into slices (5 µm thick). Trans-sections from the chordae tendineae, papillary muscle, mitral valve, and near-apex of the LV were subject to morphological assessment.Hematoxylin and eosin staining was performed on the sections to evaluate the general morphology. Masson’s trichrome staining showed micro-fibrotic foci at the chronic phases (14 postoperative days), indicating myocardial loss. The area taken by fibrotic foci, representing the severity of myocardial loss, was calculated with the following equation: severity of myocardial loss (%): total fibrotic area/total area of a whole section (×100). The whole section was morphologically quantified using an image processing system .in situ cell death detection kit . The apoptosis of cardiomyocytes was measured by the terminal transferase uridine triphosphate nick end labeling (TUNEL) staining. The treated myocardial tissue was heated in a sodium citrate solution and dissolved with proteinase K for DNA exposure. The resulting DNA strand breaks were labeled with a terminal transferase enzyme, with dUTP molecules conjugated to horseradish peroxidase, and visualized by immunohistochemistry. TUNEL-positive nuclei of cardiomyocytes (brownish red) were regarded as apoptotic cells from 10 random fields (≈400) per section with a total of 100 nuclei per field. The severity of apoptosis was evaluated by the apoptosis index, calculated as the number of TUNEL-positive nuclei over the total nuclei.Myocardial tissues were placed in a paraffin block and transversely cut into sections (5 μm thick) based on the instructions of an Data was expressed as mean ± standard deviation. SPSS 13.0 for Windows was used to analyze the data. Intergroup comparisons were performed by one-way ANOVA followed by Dunnett’s modified test. Statistical significance was set at p<0.05.All the animals in the sham group survived the operation. Six rats in the HFu group died within 1 week after coronary microembolization and the survivors showed various degrees of mental exhaustion, dyspnea, decreased activity and eating, and shock in severe cases. Autopsy of dead rats showed bilateral pulmonary congestion and pleural effusion, suggesting sudden cardiac death and possible death from HF. Two rats died in the HFp group.After Masson’s trichrome staining, qualitative analysis revealed multiple patchy fibrosis in the HF group on postoperative day 14. Heterogeneous distribution of transmural changes showed more involvement of the sub-endocardial rather than the sub-epicardial region . CompareThe death of cardiac muscle cells occurs in two forms: necrosis and apoptosis. Compared to the sham group, apoptosis was higher in the myocardial microinfarct zone of the HF group . On post−1 and LV - dP/dt max (2481±365 vs 4974±767 mmHg.s−1) were significantly lower in HFu rats compared to shams, while LV end diastolic pressure was higher (3±1 vs 18±2 mmHg) . At the end of the study, LV ejection fraction (80%±4% vs 61%±6%), LV + dP/dt max (4828±289 vs 2918±276 mmHg.s−1), LV - dP/dt max (4398±269 vs 2481±365 mmHg.s−1), and LV systolic pressure (126±13 vs 100±10 mmHg) were significantly higher in HFp rats compared to the HFu group, while LV end diastolic pressure was markedly lower (18±2 vs 13±1 mmHg) .Compared to their sham counterparts, the HFu rats had markedly lower left ventricular systolic pressure, LV + dP/dt max, LV - dP/dt max, and LV ejection fraction at all corresponding stages . On day These data indicate that at the acute phase, LV diastolic and systolic functions are obviously impaired in the untreated rats with HF, and deteriorate continuously during the subacute and chronic phases. In addition, LV functions in PDTC-treated rats are significantly improved at all phases.HF is associated with multiple adaptations and pathophysiological alterations. These include upgraded systemic vascular resistance, marked LV dysfunction, dilatation, and an activated neuroendocrine system. An understanding of the changes that take place during HF is critical to the study of the disease history and to the efficacy and timing of the interventions that are necessary for reversing the process, or at least retard its progression. Developing an animal model that accurately portrays HF can be of use in HF studies.Coronary microembolization plays a role in many disorders, including acute coronary syndrome with ST elevation and non-ST elevation, as well as sudden cardiac death. It often occurs after thrombolytic therapy or during coronary interventions ,13,14,15Established HF models are evaluated by cardiac function examinations including cardiac catheterization and ultrasonic cardiogram. Based on these evaluations, rats with LV end diastolic pressure >15 mm Hg are thought to have severe congestive HF . The myoAs a transcription factor sensitive to redox, NF-κB exists in cell types that have the p50/p65 heterodimer. In general, inactive NF-κB dimers are bound to the inhibitor of NF-κB proteins (IκBs) located in the cytosol. Stimuli such as reactive oxygen species (ROS) may activate NF-κB. The activated NF-κB is then translocated into the nucleus, where it activates specific target genes that regulate inflammation and apoptosis. Thus, NF-κB is a major initiator in ROS-mediated cardiomyocyte apoptosis and excessive cardiac fibrosis . AccumulIn cardiac pathology, the role of cardiac myocyte apoptosis is still speculative. However, it is intriguing that a progressive loss of cardiac myocytes can in part be compensated by fibroblast cell proliferation, which further deteriorates cardiac function. Furthermore, the degree of cardiomyocyte apoptosis is intriguingly associated with the severity of LV dilation and systolic dysfunction in acromegaly-associated cardiomyopathy in humans . Other rSince research has shown that oxidative stress has adverse effects on myocardial function ,33, this


Despite advances in heart failure treatment, this condition remains a relevant medical issue and is associated with a high morbidity and mortality. The cause of death in patients suffering from heart failure is not only a result of hemodynamic failure, but can also be due to ventricular arrhythmias. Implantable cardioverter defibrillators (ICDs) are these days the only tool to significantly reduce arrhythmic sudden death; but not all patients benefit to the same extend. In addition, cardiac resynchronization therapy (CRT) is another tool which is used in patients suffering from heart fialure. Even though both devices have been investigated in large randomized trials, both ICD and CRT remain underutilized in many countries. This brief review focuses on various aspects in this regard including a short overview on upcoming device novelties in the near future. According to current ESC guidelines, heart failure can be separated into heart failure with preserved ejection fraction , mid-range EF  and reduced ejection fraction  . The cauIn spite of these proven benefits, both ICD as well as CRT therapy remain underutilized in many countries . The reaPatients with heart failure and reduced ejection fraction LVEF < 35%) are at an increased risk of sudden cardiac death due to ventricular arrhythmias. This risk is highest in those who already suffered from previous ventricular arrhythmic events 5% are at Table 1Table 1.The situation is more complex in primary prevention. Even though current guidelines recommend the implantation of an ICD in patients suffering from heart failure with an LVEF ≤ 35% despite at least 3 months of optimal medical treatment, a NYHA class II-IVa and a predicted survival of > 1 year, there seems to be a discrepancy of the beneficial effect of an ICD depending on the underlying heart disease. Indeed, patients with ischemic heart disease have a class IA indication, while in the non-ischemic population the indication level is IB . Two larHow do these results fit together? Do we need to rethink the indication for primary prevention ICD implantation in the entire non-ischemic population? Even though a recent survey of the European Heart Rhythm Association (EHRA) has shown that already 4 months after the publication of the DANISH trial, nearly 50% of physicians changed their current practice in recommending an ICD implantation in a non-ischemic cardiomyopathy patient , a meta-On the other hand, it needs to be kept in mind that the reduction in sudden cardiac death from an ICD in this population not translating into a total-mortality benefit may not only be because of an excess in non-arrhythmogenic deaths—it may also be due to complications and morbidity of the device itself. Therefore, further investigations and developments in improving device technology are essential. The subcutaneous implantable cardioverter defibrillator (S-ICD) represents a novel model of an ICD designed to reduce the occurrence as well as the associated morbidity  of one of the most relevant lifetime risks of transvenous device systems: infection. The generator in a S-ICD is located at the left lateral chest in the space between the anterior serratus and the latissimus dorsi muscles. The lead is tunneled within the subcutaneous tissue toward the xiphoid process and from advanced alongside the sternum cranially . Large rCardiac resynchronization therapy has fundamentally changed the treatment of patients suffering from heart failure. Impaired left ventricular function often results in ventricular conduction disease, which secondarily leads to electrical and mechanical ventricular dyssynchrony further impairing hemodynamics of the ventricle . DisruptAccording to current guidelines, a CRT device is indicated in patients with stable, symptomatic (NYHA II-IVa) systolic heart failure despite 3 months of optimal medical treatment, an LVEF ≤ 35% and a QRS duration of ≥ 130 ms  and the From the MADIT-CRT and RAFT trials, there is insufficient data to recommend a CRT in patients with NYHA class I , 26.Even though a CRT device reduces mortality in correctly selected patients, it has no benefit and may cause harm if implanted in the wrong patients. The EchoCRT trial demonstrated no benefit and a signal for increased mortality if a CRT device is implanted in patients with a narrow QRS complex  .Guidelines judge a CRT device implantation in patients with a LBBB with class I indication , whereas non-LBBB situations get a class II indication. Patients with LBBB indeed seem to have a more severe type of LV electrical dyssynchrony as compared to non-LBBB situation , 29 and Atrial fibrillation (AF) was an exclusion criterion in the vast majority of CRT trials (except for the RAFT study), even though AF and heart failure regularly co-exists and patients with AF together with heart failure exhibit a worse prognosis , 32. DueOn the flip-side one needs to be aware that up to one-third of patients with a CRT device does not show a benefit over time ; indeed, HBP in the context of bradycardia indications has been shown to be a safe and successful option for patients with high burden of chronic ventricular pacing . The rolImplantable devices such as ICDs and CRTs are a cornerstone in the modern treatment of heart failure patients, reducing morbidity and mortality in this population. Continuing medical education regarding the pathophysiology, epidemiology, clinical trial results and novel technologies are of paramount importance to optimize patient selection and individual benefit. Ongoing and future studies and technological advances are aiming to improve patients' prognosis even further. Their implementation, however, will be the task of all stakeholders involved including cardiologists, general practitioners and—increasingly importantly—the patient him/herself. Only by a collaborative effort will we be able to move the field forward, and to further develop concepts to improve the prognosis of patients with heart failure.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.AB has received consultant and/or speaker fees from Abbott, Bayer, Biosense Webster, Biotronik, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Medtronic, Novartis, and Spectranetics/Philipps. JS has received consultant and/or speaker fees from Abbott, Amgen, Astra-Zeneca, Atricure, Bayer, Biosense Webster, Biotronik, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Daiichi Sankyo, Medscape, Medtronic, Merck/MSD, Novartis, Pfizer, Sanofi-Aventis, WebMD, and Zoll. He reports ownership of CorXL. JS has received grant support through his institution from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, Daiichi Sankyo, and Medtronic.


Introduction: Despite the normal systolic function at rest, cirrhotic patients often suffer from volume overload and symptoms of heart failure as they face stressful situations. This study investigated the myocardial reserve in cirrhotic patients at resting condition and peak stress by dobutamine speckle tracking echocardiography (STE) and tissue Doppler imaging (TDI).Methods: Twenty cirrhotic patients and 10 normal individuals aged 30-50 were selected randomly. For all of the participants, complete echocardiographic study of 2D, STE and TDI was done at rest and peak stress status with dobutamine. The following parameters were assessed: ejection fraction (EF), global longitudinal LV strain (GLS), strain rate in the septal basal segment and lateral wall and E’ in the septal basal segment by color-coded method.Results: At baseline, EF was higher than 55% in both groups. GLS was higher (-22.6±2.4%) in the case group than the control group (-19.2±1.9%) at resting condition. After stress, it showed a greater increase (-22.5±1.7%) in the controls compared to cirrhotic patients . In cirrhotic patients, the average strain rate in the basal septal segment decreased after stress (-1.2 ± 0.3/s to-1.1 ± 0.3/s), but it increased in the control group (-1.1 ± 0.2/s to -1.8 ± 0.2/s).Conclusion: Despite the presence of normal resting systolic function in cirrhotic patients, there was insufficient increase or even a decrease in myocardial function with stress; this may indicate the absence of sufficient myocardial reserve in cirrhotic patients. These findings would help to explain the reason for occurrence of heart failure or hemodynamic changes in cirrhotic patients. This condition is called latent heart failure or cirrhotic cardiomyopathy.Cirrhotic cardiomyopathy is a form of cardiac dysfunction in cirrhotic patients in the absence of other known cardiovascular diseases. Cirrhosis may have adverse effects on the main organs of the body. In these patients, a series of hemodynamic changes occurs in the form of increase in cardiac output and heart rate, reduction in systemic vascular resistance, reduced or normal arterial pressure, and visceral artery vasodilatation which may lead to hyper-dynamic syndromes at resting condition.5; however, most of the time, these events are subclinical.7After liver transplantation, heart failure symptoms may also appear due to the rapid increase in the venous return, volume overload, and increase in the strain of the heart. Consequently, stroke volume may reduce because of impaired myocardial contractility or reduced preload due to bleeding during surgery or fluid retention in the third space and could lead to the death of the patients after liver transplantation8Diastolic dysfunction which is more common than systolic dysfunction in cirrhotic patients occurs due to increased stiffness of the myocardium followed by hypertrophy or edema which could be due to sodium retention, fluid retention, and activation of a series of neuro-hormonal systems as well as the increased effect of fibrotic aldosterone by sodium.Although considerable advances are made regarding the pathophysiology of cirrhotic cardiomyopathy, clinical signs and its side effects, there is no certain diagnostic test for identifying the patients at risk of heart failure after liver transplant, so that it could help to act upon early diagnosis and treatment and improved prognosis of the patients. In this study, we aimed to compare the cardiac function of the cirrhotic patients who were candidate of liver transplantation with the new and advanced methods of echocardiography and compare the results with the that of the normal people to find clues for explanation of cirrhotic cardiomyopathy.9 One of the new modalities in the evaluation of myocardial performance is to measure the values of myocardial strain or regional deformation in the myocardium which is an expression in echocardiography to describe the length of certain parts of the myocardium. A new method for measuring the strain is speckle tracking echocardiography or STE.11 Therefore, we decided to measure the values of strain rate, global LV strain (as an indicator of the systolic function which is relatively independent of the load) at resting condition and in stressful conditions to have a more precise evaluation of cardiac function in cirrhotic patients.The most common method for qualitative evaluation of the LV is ejection fraction (EF); however, evaluation with the traditional two-dimensional (2D) echocardiography does not have sufficient sensitivity to diagnose the myocardial dysfunctions in the early stages.This cross-sectional study was carried out from the 21st of April to 22nd of December in 2013 in Shiraz University teaching hospital in Iran. Cirrhotic patients who were in the waiting list for liver transplantation, were referred for heart consultations, and were eligible for the study were selected by simple or convenience method. The age range of these patients was 30-50 years. The cause of cirrhosis was diverse in this study and written consent forms were obtained from all participants. Also, normal individuals were selected as the control group with an age range of 30-50 who were volunteers to be considered in the study and were eligible. Exclusion criteria included history of coronary artery disease, clinical and preclinical symptoms or evidence of coronary artery disease, underlying arrhythmias or history of arrhythmia, severe valvular disease, congenital heart diseases, EF below 55%, and diabetes. This study conforms with the declaration of Helsinki about working with human subjects and the local Ethics Committee has approved the study protocol and patients or their relatives gave informed consent.1 parameter was measured in the septal basal segment for the investigation of diastolic function using color-coded method. Also, the strain rate in the septal basal segment and lateral wall was measured using tissue Doppler imaging (TDI) and the data were stored.For all the patients and the control group, routine echocardiography was performed using Vivid E9 model device and parasternal, apical and sub-costal images were taken for all the patients while lying on their left and the dimensions of the LV were measured in systolic and diastolic phases. Then, the images were stored in three views of apical 4-ch, apical 2-ch and apical long axis with frame rates of about 50-60 and global systolic longitudinal LV strain of the LV was measured and demonstrated as bull’s eye diagram and E'Then, the patients were studied under stress condition with dobutamine according to the planned protocol and longitudinal LV strain of the left ventricle was again measured globally in the form of bull’s eye; the strain rate was also measured and stored in the septal basal segment and the lateral wall.12:Also, to study the diastolic function, E’ was studied using color-coded method and the E’s with values of ≥6 m/sec were compared . Dobutamine prescription protocol for investigating the myocardial reserve based on the guideline of the American society of echocardiography was carried out as followsFirst, dobutamine infusion starts with 5 µg/kg/min and the dosage of dobutamine was increased by 3-5 µg/kg/min every 3 minutes to reach the maximum dosage of 15-20 µg/kg/min. With this dosage of dobutamine, the LV contractility was enhanced, but the heart rate of the studied individuals did not change significantly and the parameters were recorded at the peak stress and the individuals were monitored for their ECG and blood pressure.P value < 0.05 was considered statistically significant. All data were analyzed using the statistical Package for Social Sciences, version 17.0 .For comparing the groups of patients and control in terms of global strain, strain rate and E’ values were done using Mann-Whitney test. Fisher’s exact test was used for the comparison of gender distribution and diastolic function. A total of 30 people  were examined in this study; their distribution in terms of gender and age is illustrated in In each group (liver cirrhotic patients and control group), the global longitudinal LV strain was measured at resting condition. The mean global strain for the cirrhotic patients was higher compared to the control group at resting condition which was statistically significant. However, the difference of global strain between the two groups following stress (infusion dobutamine peak according to the protocol) was not significant .The global strain variations showed less increase at peak stress in the patients group compared to the control group and it even decreased in some cases which was statistically significant. The strain rate with TDI method in the lateral and septal basal segment at resting condition showed no significant variation between the two groups. The mean strain rates at peak stress between cirrhotic and control groups were significantly different for the lateral and septal basal segment and the strain rate was higher in the control group .P value <0.001). Also, the strain rate at peak stress in the lateral wall increased in each group compared to the values at resting condition, but the increase was higher in the control group  between groups at resting condition in the septal basal segment using color-coded imaging. Even so, this parameter at peak stress was statistically significant and E’ was higher in the control group . CompariFour patients among cirrhotic patients (20%) had diastolic dysfunction and 1 person in the control group (10%) had diastolic dysfunction which showed no statistically significant discrepancy. Also in peak stress status, 6 persons among cirrhotic patients (30%) had diastolic dysfunction and all the participants in the control group had normal diastolic function and the difference was not statistically significant . TherefoAll the patients has normal systolic pulmonary artery pressure before and after stress.Our findings suggest that despite the normal or even increased EF (>55%) and global strain at resting condition in most of the cirrhotic patients, mean global longitudinal LV strain did not increase appropriately following stress stimulation (dobutamine infusion according to the protocol) and it even decreased. Moreover, diastolic function in the control group was normal at peak stress; however, 30% of the cirrhotic patients developed diastolic dysfunction following stress. In other words, both systolic and diastolic dysfunction appeared in the cirrhosis group following stress.6 Therefore, two-dimensional echocardiography is not an appropriate modality for detection of early stage of cardiomyopathy in cirrhosis, as our findings indicated.13 Consequently, using newer and more precise techniques are needed to evaluate cardiac function in cirrhotic patients.According to the obtained results in the current study, LV systolic function (EF) in all the studied cirrhotic patients and control group at resting condition was normal or higher than normal (EF > 55%). Our results were consistent with that of a recent study which assessed 44 cirrhotic patients by conventional echocardiography and TDI. In that study, despite a normal EF at resting condition, the strain rate and peak systolic tissue velocity (systolic function criteria) were decreased.9 Our results implied that according to tissue-Doppler and speckle-tracking analysis, global systolic longitudinal strain in patients with liver cirrhosis was higher than that in healthy ones at resting conditions. In contrast with our results, Sampaio et al implied that at resting condition, global systolic longitudinal strain in patients with liver cirrhosis was lower than that in healthy ones in spite of normal EF values.14Two-dimensional STI was the modality that Xu et al used to evaluate the cardiac function of cirrhotic patients. They concluded that 2D-STI can early and accurately evaluate the systolic function of liver cirrhosis compared to 2D echocardiography.14 Presence of abnormal strain rates despite normal EFs may be related to the tissue structure of the myocardium. Subendocardial fibers are at the farthest point to vascular supply; therefore, longitudinal left ventricular fibers are more susceptible to damage than radial middle fibers.14 The 2005 World Congress of Gastroenterology proposed a resting EF <55% to define systolic dysfunction in patients with cirrhosis.15 The use of EF in evaluating the systolic function has several limitations because it is not an index of contractility and depends on the volume loading, heart rate and valvular function.16 Therefore, a ‘normal’ EF may not reflect normal contractile function and this may be particularly true in cirrhosis. Our finding suggests that EF may be an insensitive  and probably late marker of systolic dysfunction in cirrhosis, identifying only patients with more severe myocardial dysfunction.The first presentation of cardiac impairment is reduced LV longitudinal in several other conditions, such as cardiomyopathy due to anthracycline consumption.17 Considering the lower costs, higher availability, and easier preformation, dobutamine stress STE is a more logical way to reveal latent myocardial dysfunction in cirrhotic patients.Inducing stress to evaluate the cardiac function may be the most precise way to reveal decreased myocardial reserve. To the best of our knowledge, our study is the first to use stress echo and speckle tracking to evaluate myocardial reserve in cirrhotic patients. Here, we have shown that despite higher values at resting condition, global longitudinal strain rate is not increased or even decreased at peak stress in cirrhotic patients as compared to controls. In the same line with our findings, pharmacological stress tests using dobutamine was used in a study with cardiovascular magnetic resonance imaging in cirrhotic patients. It was shown that during low and intermediate dose of dobutamine, the global longitudinal strain was impaired.20In our study, we also noticed that with stress 10% of cirrhotic patients developed diastolic dysfunction. Kim et al evaluated the LV systolic and diastolic functions by two-dimensional and Doppler echocardiography at rest and during peak dobutamine infusion. In agreement with our findings, their results showed that 25% of cirrhotic patients had diastolic dysfunction after dobutamine stimulation that was compatible with our findings.Our study had some limitations. As a case control study, we could not exclude the effect of various pathological conditions that had led to liver failure. However, one should notice that these effects are part of the cirrhosis and the eventual result irrespective of the cause of liver dysfunction. Also role of failure to achieve to total heart reserve as a main cause of poor myocardial reserve and inappropriate rise in Strain cannot be excluded.It can be concluded that despite the presence of normal resting cardiac function in cirrhotic patients, there is insufficient increase or even a decrease in myocardial function with stress which may indicate absence of sufficient myocardial reserve in cirrhotic patients. This may help explain why cirrhotic patients may show signs of heart failure or hemodynamic disorders following stress . In fact, these patients suffer from subclinical and latent LV disorders. Moreover, the conventional two-dimensional echocardiography is not a sensitive modality for evaluation of systolic dysfunction and myocardial reserve and using stress STE may be the logical way.The study was approved by medical ethics committee of the university (ethics No. 4955).All authors declare no competing financial interests exist.This project has been done by a grant No. 4955 from Vice-chancellor of Shiraz University of Medical Sciences. The authors are grateful to Center for Development of Clinical Research of Nemazee Hospital and Dr. Nasrin Shokrpour for editorial assistance.