To determine if left ventricular or inferior vena cava (IVC) measurements are easier to obtain on point-of-care ultrasound by anesthesiologists in preoperative patients, and to assess the relationship between preoperative cardiac dimensions and hypotension with the induction of general anesthesia.  This prospective observational study was conducted at a large academic medical center. Sixty-three patients undergoing noncardiac surgeries under general anesthesia were enrolled. Ultrasound examinations were performed by anesthesiologists in the preoperative area. To ensure that hypotension represented both a relative and absolute decrease in blood pressure, both a mean arterial pressure (MAP) < 65 mmHg and a MAP decrease of >30% from preoperative value defined this outcome. p=0.001). While high left ventricular end-diastolic diameter values were associated with a decreased odds of MAP < 65 mmHg  or a MAP decrease of >30% from baseline alone , the primary endpoint of both relative and absolute hypotension was not associated with preoperative left ventricular dimensions.  Left ventricular measurements were more likely to be acquired than IVC measurements (97% vs. 79%). Subjects without adequate images to assess IVC collapsibility tended to have a higher body mass index (33.6 ± 5.5 vs. 28.5 ± 4.5,  Preoperative cardiac ultrasound may be a more reliable way for anesthesiologists to assess patients' volume status compared to ultrasound of the IVC, particularly for patients with a higher body mass index. Decreased blood pressure can result in organ malperfusion and tissue damage. This occurs commonly with the induction of general anesthesia and initiation of positive-pressure ventilation . Given iCI) are useful, an adequate view of the IVC could not be obtained in 13.5% of patients, and more than 20% of patients experiencing hypotension were missed. This percentage may increase when patients have increased abdominal adiposity. Furthermore, IVC collapsibility index measurements have low sensitivity in the prediction of hypotension associated with general anesthesia [Preoperative ultrasound examination performed by anesthesiologists is a valuable tool for identifying patients at risk for perioperative hypotension. Increased availability, superior image quality, and improved portability have resulted in an increased utilization of point-of-care (POC) ultrasonography in the perioperative setting. Zhang and Critchley demonstrated that respiratory variation in inferior vena cava (IVC) dimensions may predict postinduction hypotension in patients undergoing noncardiac surgery . While Iesthesia . TherefoEchocardiographic measurements obtained by POC exams are a promising strategy, and these measurements may provide a useful alternative to IVC measurements in patients with increased abdominal adiposity , 6. LeftWith this in mind, this study was performed to accomplish two aims. First, we sought to compare the ability of anesthesiologists to obtain cardiac measurements compared to inferior vena cava images. Second, we assessed the feasibility of cardiac dimensions obtained immediately before surgery to identify patients at risk for postinduction hypotension.CI and that both would be associated with hypotension after the induction of general anesthesia.We hypothesized that anesthesiologists would be able to obtain cardiac views more frequently than assessing the IVCThis study was approved by the institutional review board, and written informed consent was obtained from all subjects or a legal surrogate. Adult patients scheduled to undergo noncardiac surgery using general anesthesia were screened for inclusion. Patients were excluded if they had known reduced left ventricular ejection fraction, were already admitted to the hospital, used mechanical ventilation at home, were prescribed systemic steroids, continued medications that inhibit the renin-angiotensin-aldosterone system, had preexisting wall motion abnormalities, underwent awake fiber-optic intubation, were dialysis dependent, or did not provide consent. The anesthesiologist performing the echocardiographic exam did not participate in the anesthetic management of the examined subject in order to avoid having the ultrasonographic findings from altering the induction strategy. Baseline patient characteristics were obtained from the electronic medical record.A data analysis and statistical plan was written and filed with the institutional anesthesiology clinical research committee before data were accessed. The average and standard deviation of adult male left ventricular end-diastolic diameter (LVIDd) is 50.2 ± 4.1 mm. Assuming a 40% incidence of hypotension, examining 50 patients would allow us to detect a 3.3 mm difference in means between cases and controls with 80% power and an alpha of 0.05. An additional 25% of subjects were screened to account for any potential deviation from the protocol, and thus, a total of 67 patients were enrolled in the study.Transthoracic echocardiography examinations were performed by two anesthesiologists  who routinely use echocardiography in their clinical practice. These anesthesiologists have an extensive background in the practice of advanced perioperative and critical care echocardiography. Both clinicians had at least 4 years of experience in the field, and each had personally performed more than 150 echocardiographic examinations prior to the initiation of the study. The Philips Sparq  and SonoSite X-Porte  ultrasound machines were used to conduct the exams. Findings from each examination were reviewed by the performing anesthesiologist and confirmed by the second anesthesiologist who was blinded to the findings of the first examiner. The order of the ultrasound examination was kept uniform. The sequence of the examination included parasternal long-axis view followed by the parasternal short-axis view with the subcostal IVC as the final obtained view.rd to 4th intercostal space) and subcostal imaging in the supine position. If necessary, for image optimization, left lateral decubitus positioning was utilized. The left ventricular wall thickness and diastolic chamber dimensions were obtained from the parasternal long-axis view. In accordance with the American Society of Echocardiography guidelines, left ventricular wall thickness and diastolic chamber dimensions were made at end-diastole, defined as the first video frame immediately after mitral valve (MV) closure and/or at the peak of the R wave on the electrocardiogram. Measurements were obtained at the level just below the MV leaflet tips and interventricular septum and LV posterior wall was measured at the same time and level as the LV end-diastolic dimension  and LV end-systolic area (LVESA) were obtained from parasternal short-axis view by tracing the endocardial border by planimetry, including the papillary muscles, in the end-diastolic and end-systolic frames, respectively Figures . The LVEmax) was measured as the maximum anterior-posterior dimension at end-expiration using the leading-edge technique . The minimum IVC diameter (dIVCmin) was measured at end-inspiration. For each patient, the best quality image was chosen for analysis. The collapsibility index was calculated using the built-in software available on the ultrasound systems /dIVCmax and was expressed as a percentage.The IVC was imaged in a longitudinal plane via the subcostal window. The IVC was differentiated from the aorta by visualizing its entrance into the right atrium and the hepatic vein drainage into the IVC. Respiratory variations in the IVC diameter were assessed using motion mode imaging. The maximum and minimum diameter measurements of the IVC were performed around 2 cm caudal to the hepatic vein-IVC junction. The maximum IVC diameter  received fentanyl at the time of induction. The average total dose of administered fentanyl at the time of induction was 125 mcg. 46 patients received preoperative midazolam for anxiolysis with the dose range of 1–2 mg. All patients received controlled mechanical ventilation after induction of anesthesia with a minimum positive end‐expiratory pressure (PEEP) of 5 cm HThe primary outcome was both a mean arterial pressure (MAP) < 65 mmHg and a decrease in MAP of at least 30% from the subject's preoperative value prior to the surgical incision. This a priori definition was selected to identify the presence of both absolute and relative hypotension. Secondary outcomes included the incidence of a MAP < 65 mmHg, the incidence of a MAP decrease of ≥ 30% from baseline, the total amount of time needed to complete the exam, and the frequency that adequate images were not obtainable.Exploratory data analysis techniques such as frequencies, means, medians, standard deviation, minimum and maximum, histograms, box plots, and QQ plots were used to assess the distribution of outcome measures as well as relevant predictors. Extreme values were identified and removed if they were determined to be influential. Counts and percentages were used to summarize categorical variables. The average ± the standard deviation was used to summarize continuous variables.Echocardiographic data were analyzed as continuous variables and summarized as either the mean and standard deviation or median and interquartile range as appropriate. Continuous variables were summarized using means and standard deviations and categorical ones using counts and percentages. Potential selection bias was tested by comparing those that had IVC measurements to those that did not. Similarly, we compared those that had cardiac measurements to those that did not.To test our research question related to the performance of echocardiographic variables, we used a sequential logistic regression approach where each relevant predictor was considered in a “one-at-a-time” approach, followed by a second model where gender and the interaction of gender and the predictor were added. Goodness of fit of the models was determined using AIC, SC, and −2loglikehood.A total of 67 adult patients were enrolled. Two individuals were excluded because their anesthetic plan was changed from general anesthesia to a sedation anesthetic, one subject was excluded as consent was obtained from the patient, but the patient was transferred to the operating room prior to the performance of the exam, and one subject was excluded when an unexpectedly reduced left ventricular function was appreciated during the exam.n = 32, 50.4%). n = 50). In contrast, 97% had adequate images to measure left ventricular dimensions (n = 61). Only anthropometric variables differed between those with and without images that were adequate for assessing the IVC collapsibility index. For example, those in whom the IVC could not be assessed had a higher body mass index (BMI) .Final data analysis included 63 patients, 60.3% men and 39.7% women, with a median age of 64.1 years and an average body mass index of 29.6. Of the 63 participants, 33 were classified as ASA II and 30 as ASA III based on the American Society of Anesthesiologists physical status classification system. A preoperative diagnosis of hypertension was present in about half of the study population . The average IVCCI was 36.0 ± 21.1% (The average time spent performing the echocardiography exam was 485.8 seconds (∼8 minutes). The left ventricular area was measurable in 87.3% of subjects. The average LVIDd of our study population was 4.4 ± 0.5 cm, and the average LVEDAi was 7.5 ± 1.9 cm ± 21.1% .Regarding the incidence of induction-related hypotension, 44 subjects (70%) had a MAP < 65 mmHg during induction of anesthesia while 43 (68%) had a MAP recorded that was decreased > 30% from their preoperative value. Thirty-one individuals (49%) experienced the primary outcome of both a MAP < 65 mmHg and a decrease of >30% from the preoperative value .P=0.023) and a 30% decrease in MAP from their preoperative value . The composite outcome demonstrated a similar relationship despite not reaching statistical significance . A similar relationship existed for LVEDA, although the magnitude of the effect was not as great. Higher values were associated with less hypotension defined as a MAP < 65 mmHg  and a decrease of >30% from baseline . Again, the composite outcome had a similar, although not statically significant, relationship . Regarding IVCCI, higher values were associated with a small increase in the incidence of MAP < 65 mmHg  and the incidence of a MAP decrease of > 30% from baseline . Similar patterns were observed for the composite outcome, although they did not reach statistical significance .Unadjusted logistic regression models of each of the three outcomes showed similar patterns of association of both left ventricular dimensions and IVC variability with each individual outcome . Howeverp=0.097). No other measurements remained associated with any of our criteria for hypotension with induction of general anesthesia after adjusting for gender .Crucial for future studies investigating the optimal use of perioperative POC ultrasound, we also demonstrated that measurements of cardiac dimensions were more frequently available, particularly in patients with a higher BMI. This is likely due to abdominal adiposity increasing the difficulty of IVC assessment in patients with a higher BMI. A similar pattern did not exist for left ventricular cardiac dimensions and supports developing strategies for using echocardiographic measures to identify patients at increased risk for anesthesia complications especially in populations with a high incidence of obesity.CI and hypotension with the induction of anesthesia. This relationship was found despite not controlling for any aspects of anesthesia management, which adds to the robustness of this finding. Additionally, etomidate was used as the agent of induction in the study by Zhang and colleagues, whereas our patients received propofol for induction [We also confirmed a previously described relationship between IVCnduction , thus exThe association between the incidence of hypotension and specific ventricular dimensions or IVC values did not exist when hypotension was defined as a combination of both relative and absolute thresholds. We selected this definition as our a priori primary outcome to ensure that all induction-related hypotension was clinically significant. This characterization was also selected to account for the large variability in how intraoperative hypotension is defined in the literature. For instance, Bijker and colleagues noted 140 definitions of hypotension in 130 articles and observed that the incidence of intraoperative hypotension ranged from 5 to 99% depending on the numerous threshold values . While aGiven that the individual components of our composite outcome were associated with the echocardiographic measurements, this may suggest that TTE is more sensitive for detecting less severe hypotension, although this will have to be examined by future studies. This is of importance given the findings of associations between brief periods of even mild hypotension with myocardial injury, kidney injury, and mortality , 16, 17.Point-of-care ultrasonography is rapidly being adopted by perioperative physicians. In the United States, comprehensive echocardiograms are routinely performed by the ultrasound technicians and interpreted later by the cardiologists, thus precluding its routine use in the fast-paced perioperative period. POC echocardiography on the other hand is a limited bedside investigation that is performed and interpreted by a physician at the bedside. This allows the anesthesiologist to examine cardiac status noninvasively in real time, reach rapid diagnosis, and perform repeat exams to assess response to the interventions. While this technology is being increasingly used in the perioperative period, limited data exist regarding the role of anesthesiologist-performed point-of-care studies on the intraoperative care and their association with perioperative outcomes. When conducted on patients undergoing noncardiac surgery, POC echocardiographic findings were associated with both changes in patient care and decreased postoperative adverse events –20. Curr2 to 10.6 cm2 at the time of sternal closure. The decreased LVEDA was proposed to result from inadequate preload after sternal closure [2 to 5.1 cm2 during hemorrhage involving withdrawal of blood volume of 35 ml/kg [2 and 5.6 cm2/m2 when indexed to body surface area, although 85% of the study population consisted of male patients [To our knowledge, this is the first study examining the usability of anesthesiologist-performed preoperative transthoracic echocardiography to identify echocardiographic parameters that are associated with postinduction hypotension. Left ventricular end-diastolic area and diameter measurements have been proposed to diagnose hypovolemia intraoperatively on transesophageal echocardiography (TEE), and changes in LVEDA have been noted to result in correlating changes in stroke volume and cardiac output . The lit closure . In a st closure . In pig 35 ml/kg . In cardpatients .2 or an LVEDA index of less than 5.5 cm2/m2 is proposed to indicate hypovolemia [2 has been proposed to be consistent with hypovolemia [2 or LVEDAi < 5.5 cm2/m2 with postinduction hypotension.Over time, these findings have been applied to POC cardiac ultrasonography despite lack of validation studies, and an LVEDA of less than 10 cmovolemia –28. In tovolemia . Howeverovolemia . In our Currently, limited data exist in the optimal workflow integration of POC ultrasound during the perioperative period. Perceived time constraints pose a significant challenge in the routine incorporation of POC ultrasound in the practice of anesthesiology. Our study establishes that POC cardiac ultrasound can be performed in a time-efficient manner during a routine clinical setting. The average time spent performing the echocardiography exam during our study was about eight minutes. The fastest exams in the study were performed within two minutes. The average timeframe was most likely lengthened by the examiners obtaining multiple images and attempts to obtain the perfect images for interpretation. In addition to the feasibility of anesthesiologist-performed TTE, we found that the echocardiographic images are easier to obtain than IVC measurements in certain populations and that several simple measurements appear to have a relationship with induction-related hypotension. Our findings can be used to power future studies. These findings also support the use of anesthesiologist-performed surface echocardiography especially as TTE has the advantage in screening for cardiac pathologies relevant to the practice of anesthesiology. This is highlighted by the fact that one of the enrolled patients was excluded from our analysis due to an unexpected preoperative finding of left ventricular systolic dysfunction. The abnormal cardiac findings were relayed to the intraoperative team in this case which resulted in an alteration of the anesthetic plan.Several limitations should be considered when interpreting these findings. First, by not controlling for the medications used for the induction of anesthesia, practices such as administering vasoconstrictors to patients felt to be at high risk for hypotension may have altered relationships in an unpredictable way. However, by not sharing echocardiographic measures with clinicians and studying these predictors in the setting of routine clinical practice increase the external validity of the results. Second, echocardiographic exams were performed by anesthesiologists with experience in transthoracic echocardiography. It is possible that the accuracy of the measurements could be improved if performed by level three certified cardiologists or experienced sonographers. However, again, this would not be consistent with routine clinical practice. Finally, associations that were found between echocardiographic measurements and hypotension did not persist after adjusting for patient factors. While these relationships may persist with a larger sample size, this may also reflect the relationship that exists between echocardiographic measurements and patient factors.In conclusion, we found that several echocardiographic measurements are associated with certain definitions of hypotension with the induction of anesthesia. We also demonstrated that cardiac dimensions are able to be measured more frequently than IVC dimensions, particularly in patients with a higher body surface area.


Conditions associated with states of catecholamine toxicity are pheochromocytoma, paraganglioma, Takotsubo’s cardiomyopathy, and catecholaminergic polymorphic ventricular tachycardia. This article defines these conditions along with relevant diagnostic and prognostic factors. The role of catecholamines in these conditions are compared and contrasted. Emphasis is given to the role of endothelial dysfunction as a possible etiologic factor in cardiomyopathy associated with excess catecholamines. Epinephrine, norepinephrine, and dopamine constitute the three catecholamines. The cardiac effects of catecholamines have been well recognized and described extensively in the literature. All three catecholamines have been used for the treatment of hypotension in critically ill patients. However, the excessive exposure of human myocardium to catecholamines has long been recognized as having toxic effects such as inducing myocardial necrosis . CatechoInterestingly, lunar catecholamine cardiomyopathy has been postulated as a result of catecholamine elevations in astronauts Neil Armstrong and Irwin . The toxCardiomyopathy has been reported as a phenomenon in pheochromocytoma with a prevalence of 11 % . The carCatecholamines exert inotropic, dromotropic, and chronotropic effects on the heart. Additionally, catecholamines have vasoconstrictive properties leading to an increase in afterload on the heart. Systemic net vasoconstriction results in increased myocardial oxygen demand. Placing the myocardium at risk for conditions that compromise nutrient delivery. States of catecholamine excess may even compromise blood delivery through effects on the microvasculature of the heart . There aThe microvascular dysfunction caused by catecholamines has been proposed as part of the unifying mechanism of TC . This faOther catecholamine-induced outcomes in pheochromocytoma and paraganglioma include a dilated cardiomyopathy and hypertrophic cardiomyopathy . These uA complete reversal of catecholamine cardiomyopathy has been reported within eight days of pheochromocytoma removal . HoweverExogenous infusion of norepinephrine has been reported to induce myocardial necrosis and leukocyte infiltration with degenerative changes . Many meTC is receiving more attention as a novel form of acute heart failure. Typically, apical ballooning of the ventricles resembling a Japanese octopus pot, hence the name, is seen. Most studies report the frequency of TC between 1-4% in patients presenting with the acute coronary syndrome (ACS). Individuals may experience a recurrence of TC. Regional variations in cardiac involvement exist, and biplane left ventriculography may identify focal TC . Right vImportant risk factors for TC include female sex and neurological and psychiatric disorders . TC is oSeveral efforts have been made to differentiate this condition from ACS. Highly sensitive Troponin T to creatine kinase MB ratio may provide some synergy to discriminate between TC and ACS . The IntIncreased cardiac sympathetic activity due to a variety of stressful events such as acute emotional changes, adrenergic excess states have been implicated as etiologic factors. A wide range of triggers including influenza, anti-influenza vaccination, and hypoglycemia have been implicated as etiologic factors . ExaggerPrognosis is excellent with early diagnosis and treatment. Renin-angiotensin system inhibitors may reduce episodes of TC recurrence . A high Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited channelopathy associated with an enhanced risk of arrhythmia and death . If untrA major cause of CPVT is autosomal dominant mutations in the cardiac ryanodine receptor channel (RYR2) . MutatioCatecholamines can cause these ryanodine-related channels to release calcium in diastole triggering life-threatening arrhythmias - the frequency and the complexity of the ventricular ectopy increase with the workload. Monomorphic premature ventricular complexes may be initially seen followed by bigeminy and subsequently doublets, triplets, bidirectional ventricular tachycardia to polymorphic ventricular tachycardia. These arrhythmias may be provoked during exercise testing and may degenerate into ventricular fibrillation. It should be noted that CPVT can be frequently linked to aberrant sinus node function and may also contribute to atrial tachyarrhythmias .Patients should void vigorous exercise and consider genetic testing for mutations. The use of b-blockers and flecainide are accepted treatments for this disorder. Digoxin should not be used as there is at least one case of it precipitating cardiac death . ImplantIn cases of TC, the use of catecholamines for acute circulatory support may have deleterious effects and their use is associated with increased mortality , 26. TheA state of catecholamine excess should be considered in patients presenting with an acute presentation of cardiac decompensation in the absence of ischemic or valvular etiologies. The InterTAK diagnostic score may be a useful tool in managing clinical suspicion for TC in these patients. The diagnosis of pheochromocytoma is complicated by the use of catecholaminergic agents in intensive care settings. This complication necessitates a heavier emphasis on imaging for pheochromocytoma diagnosis. A computed tomography or magnetic resonance imaging of the abdomen may be required to confirm the diagnosis of pheochromocytoma in this setting. Invasive pressure monitoring should be considered in states of catecholamine excess to manage the risk of catecholamine cardiomyopathy.


Management of a pregnant woman with complete heart block presenting during pregnancy and without pacing remains debatable. To bear up against any hemodynamic variations in peripartum period, temporary pacemakers have been advocated by some authors. Herein, we report a case of successful management of a 24 year old, pregnant woman with CHB who had an uneventful emergency caesarean delivery under spinal anesthesia after temporary pacing. She was an unbooked patient detected with CHB first time during active stage of labour. She delivered a healthy male baby and was discharged from the hospital in a stable and satisfactory condition on seventh postoperative day. Obstetric outcome in women who have undergone permanent pacemaker implanted has been reported, but there is a paucity of literature on the management of complete heart block detected for the first time during labour in pregnancy.2 We herein present a case of pregnancy with CHB detected for the first time during active stage of labour that has been managed by temporary pacemaker insertion with the co-ordinated action of cardiologist and obstetrician.Complete heart block (CHB) is a relatively rare and a potentially serious issue in pregnancy.A 24 year old, unbooked, immunized G4P3L2 IUD1 at 36weeks and 4 days period of gestation, was referred from a private hospital in view of prolonged labour with maternal bradycardia. She presented with complain of dizziness since last two days in early active stage of labour. She had irregular antenatal check up and her antenatal check up was uneventful. In all her previous deliveries, she had no card iorespiratory complain. No history of any medical illnesses, addiction or drug intake such as beta-blocker, calcium-channel blocker or digitalis. There is no significant family history. On examination at Obstetric emergency, her general condition was fair, was normotensive, with maternal bradycardia (PR = 42 bpm). Cardivascular system examination showed bradycardia and respiratory system was unremarkable. On abdominal examination, there was a single live fetus in cephalic presentation and uterine height corresponded to 36 weeks of gestation with a fetal heart rate 140 beats/minute. There was regular uterine contractions. On per vaginum examination, os was 4 centimeters dilated, cervix was 50% effaced, vertex was at -2 station , membranes was ruptured and liquor was clear. Cardiology consulation was done in view of persistent bradycardia. Electrocardiogram (ECG) was done immediately which showed sinus bradycardia, Atrio-ventricular (AV) dissociation, and ventricular rate 40% suggestive of complete heart block (CHB) .th post operative day. She was discharged from the hospital in a stable and satisfactory condition on seventh postoperative day. Later patient followed up in Gynae OPD after 6weeks in a stable condition following which she was referred to cardiologist for permanent pacemaker implantation.All her routine investigation along with cardiac enzymes, and thyroid function test was within normal limit. Echocardiagraphy was normal. Patient was shifted to cath lab and temporary pacemaker insertion (TPI) was done via Right femoral vein route  with fetal shielding and heart rate was fixed at 80bpm. Emergency cesarean section was done in view of arrest of descent and dilatation under spinal anesthesia under high risk consent. Intraoperative haemodynamics remained stable and surgery proceeded uneventfully. She gave birth to a healthy male child. The neonate did not have any rhythm disturbances. Patient was transferred to Maternal Intensive Care Unit (MICU) for observation. Postoperatively, continuous monitoring was done with pulse oximeter and invasive blood pressure. She was started on intravenous antibiotics  and thromboprophlyaxis with low molecular weight heparin. Heart rate remained steady at 46-58bpm. Rest of the post operative period was uneventful. TPI was removed under aseptic precaution on 53 The etiology of complete heart block is not completely understood yet however it's considered to be mostly congenital in origin. Most often these patients are asymptomatic; however the symptoms can also occur later in life. This is due to a variable degree of heart block. Fetomaternal outcome is favorable in asymptomatic cases and in uncomplicated bradyarrhythmias without significant underlying heart disease.4-5 Rarely, preterm birth and intrauterine growth restriction has been observed. Most of the symptoms are related to the slow heart rate resulting in hydrops foetalis, heart failure of the neonate or exercise intolerance of the child. These symptoms are present in patients with resting heart rate of 50 beats/min or less. Mortality from congenital complete heart block is highest in the neonatal period, is much lower in childhood and adolescence and increases gradually later in life. Asymptomatic pregnant patients without pacemakers may present with sudden cardiac death or heart failure during pregnancy, or may become symptomatic during labour due to valsalva induced bradycardia.CHB detected for the first time during pregnancy and delivery is a rare disease with an incidence of 1 in 20,000 live births.7 In women without a permanent pacemaker, temporary pacemakers have been routinely inserted for labour and birth probably to withstand any hemodynamic variations.8 However, the need of temporary pacemaker during labour and it's accurate timing and rate setting of pacemaker has not been objectively evaluated so far. Permanent pacemakers can be implanted at any time in pregnancy whereas short-term temporary pacemaker can be applied during delivery. Overall maternal and neonatal outcome is good in such patients.Patients with complete heart block presenting for the first time in pregnancy is a therapeutic challenge to the physician. Symptomatic patients in pregnancy should be managed with the use of cardiac pacemaker, which should be implanted whenever heart block is diagnosed. Pacemaker is needed to maintain cardiac function. However, prophylactic placement of a pacemaker is not indicated in asymptomatic patients.In our case CHB is identified at near term pregnancy with quite a low heart rate (42 beats/min) and with history of dizziness. Emergency caesarean section was carried out under temporary pacing coverage with a later plan of a permanent pacemaker implantation resulting in excellent symptom free status. To our knowledge, this is the first such case report from B P Koirala Institute of Health Sciences (BPKIHS) where close co-operation between cardiologist and obstetrician of our hospital has resulted in a happy ending by successful implantation of pacemaker in a pregnant woman. Women with asymptomatic CHB presenting at the time of labour poses a challenge to the treating Obstetrician. As suggested by our case, caesarean delivery might be safely contemplated with temporary pacing in symptomatic women with CHB. However, close monitoring with multidisciplinary approach and follow-up of cardiac function is needed in these pregnant women during labour and perioperative period.


Focal segmental glomerulosclerosis (FSGS) is a chronic glomerular disease with poor clinical outcomes. Podocyte loss via apoptosis is one important mechanism underlying the pathogenesis of FSGS. Recently, Yes-associated-protein (YAP), a key downstream protein in the Hippo pathway, was identified as an activator for multiple gene transcriptional factors in the nucleus to control cell proliferation and apoptosis. To investigate the potential role of YAP in the progression of FSGS, we examined kidney samples from patients with minimal change disease or FSGS and found that increases in podocyte apoptosis is positively correlated with the cytoplasmic distribution of YAP in human FSGS. Utilizing an established mT/mG transgenic mouse model and primary cultured podocytes, we found that YAP was distributed uniformly in nucleus and cytoplasm in the podocytes of control animals. Adriamycin treatment induced gradual nuclear exclusion of YAP with enhanced phospho-YAP/YAP ratio, accompanied by the induction of podocyte apoptosis both in vivo and in vitro. Moreover, we used verteporfin to treat an Adriamycin-induced FSGS mouse model, and found YAP inhibition by verteporfin induced nuclear exclusion of YAP, thus increasing podocyte apoptosis and accelerating disease progression. Therefore, our findings suggest that YAP nuclear distribution and activation in podocytes is an important endogenous anti-apoptotic mechanism during the progression of FSGS. An increase in podocyte apoptosis is positively correlated with the cytoplasmic distribution of YAP in focal segmental glomerulosclerosis (FSGS). YAP inhibition by verteporfin induces nuclear exclusion of YAP, thus increasing the podocyte apoptosis and accelerating disease progression. Therefore, this study suggests that YAP activation and nuclear distribution in podocytes is an endogenous anti-apoptotic mechanism during the progression of FSGS. The main manifestation of focal segmental glomerulosclerosis (FSGS) is nephrotic syndrome, a common chronic glomerular disease with poor clinical outcomes . Most ofThe Hippo pathway is an important signaling pathway regulating cell proliferation, differentiation and apoptosis. Yes-associated-protein (YAP), one key downstream effector of Hippo pathway, was recognized as an activator for multiple gene transcriptional factors in nucleus, where they bind to and activate TEAD family transcription factors, by its dephosphorylated form , 8. The YAP deletion or mutation in cap mesenchyme resulted in impairment of nephron formation and morphogenesis during renal development [Although dysregulation of Hippo pathway is closely correlated with prognosis and the survival rate in various human cancers –14, its elopment . Selectielopment . Besideselopment . These rThe current study examined the relationship between YAP localization and phosphorylation with podocyte apoptosis in kidney samples from patients with FSGS and an Adriamycin-induced FSGS mouse model, and primary cultured podocytes as well. In addition, we observed the effect of verteporfin, a YAP inhibitor, on YAP nuclear exclusion, podocyte apoptosis and the progression of FSGS. We found that YAP might be a potential therapeutic target for FSGS.NPHS2-Cre; mT/mG mice were generated by crossing NPHS2-Cre mice  with Gt(ROSA)26Sortm4Luo . Genotyping was performed according to previously described protocols [NPHS2-Cre included: 5′-GCGCTGCTGCTCCAG-3′ and 5′-CGGTTATTCAACTTGCACCA-3′, while 5′-CTTTAAGCCTGCCCAGAAGA-3′, 5′-AGGGAGCTGCAGTGGAGTAG-3’ and 5′-TAGAGCTTGCGGAACCCTTC-3′ were used to detect mT/mG. PCR conditions for mT/mG are: 94 °C for 3 min followed by 94 °C for 30 s, 58 °C for 1 min, and 72 °C for 60 s for 30 cycles, with an additional 2-min extension at 72 °C. For NPHS2-Cre: 94 °C for 3 min followed by 94 °C for 30 s, 51.7 °C for 1 min, and 72 °C for 60 s for 35 cycles, with an additional 2-min extension at 72 °C.rotocols . Male F1Adriamycin was purchased from Sigma, USA, and was administrated in mT/mG mice at several different doses  by intravenous injection (one dose at 5 weeks of age). Verteporfin was purchased from TargetMol, USA and was administrated in mT/mG mice at 100 mg/kg body wt by intraperitoneal injection every other day for 1, 2, or 3 weeks (starting from the 1st day of the Adriamycin-induced nephropathy mouse model construction). verteporfin dosages are consistent with a previous report . The mic2O2, and the antigen was retrieved in citrate buffer, following with block with 5% normal sheep serum and incubation with primary antibody at 4 °C overnight :1:50; p-YAP (S397): 1:50; activated Caspase 3: 1:100; podocin: 1:100). After washed three times in PBS, the appropriate secondary antibodies were applied for 1 h in room temperature. For immunohistochemistry, the signals were visualized using liquid DAB + substrate chromogen system , followed by counterstaining with hematoxylin and capturing images using the Vectra Camera System. For immunofluorescence staining, after incubation with the primary antibodies indicated and washing with PBS, the sections were incubated with Alexa FluorTM 549-conjugated secondary antibodies and Dylight 488-conjugated secondary antibodies for 1 h, and images were captured using the Zeiss camera. Immunoblotting and analyses were performed as previously reported [Mouse kidney was fixed by 4% paraformaldehyde for paraffin-embedded kidney sections (5 μm), which follows staining techniques after deparaffinized and rehydrated. For kidney histologic examination, H&E staining was performed using the standard methods . Immunohreported . The preSection pairs were cut into 2 µm and collected every 10 µm from the glomerulus by using a diamond knife. Twenty pairs of sections were saved per kidney. With the assumption that per podocyte has only 1 nucleus, podocyte nuclei were used as surrogates for podocytes. We used the dissector/fractionator principle for measurement of podocyte number , which, n ≥ 5 cases per group, 8 images per case).After triple immunofluorescence staining with nephrin, YAP and DAPI, podocytes were firstly confirmed by nephrin positive staining, and then the area of YAP and DAPI double-positive staining that surrounded by red nephrin staining (the area of YAP in podocyte nuclear) were counted for the numerator, which was divided by the sum of the area with DAPI that also surrounded by red nephrin staining . The positive area was calculated by Image J , and at Antibodies used in this study included YAP, p-YAP (S127), p-YAP (S397), and Caspase 3 were purchased from Cell Signaling Technology. Antibodies against β-actin and nephrin were purchased from R&D Systems. Peroxidase conjugated goat anti-mice IgG and goat anti-rabbit IgG antibody were purchased from ProteinTech Group.Serum creatinine and BUN was measured in duplicate using commercial kits according to the manufacturer’s protocol . For TUNEL labeling, mice kidney sections were fixed by 4% methanol-free formaldehyde and then were washed once with PBS, following by permeabilization with proteinase K for 10 min at room temperature. After pre-equilibrate, incubation buffer containing equilibration buffer, nucleotide mix and rTdT enzyme  were added at 37 °C for 1 h. Subsequently, after three times of wash with PBS for 5 min, DAPI (Life Technology) nuclear stain was added in mounting medium and proceed to analysis according to the manufacturer’s protocol.NPHS2-Cre; mT/mG mice at 5 weeks of age, by sieving through 100 μm filters and then 40 μm filters, following plated in type I collagen-coated dishes, cultured in DMEM/Low Glucose with 10% FBS, Insulin, Transferrin, Sodium Selenite Media Supplement, ITS (Sigma-Aldrich), Hydrocortisone, Na-3,3′, 5-Ttiiodo-L-Thyronine,100 U/ml penicillin, and 100 μg/ml streptomycin. The glomerular cells were sorted by flow cytometry and the primary podocytes were cultured at 37 °C with 95% air and 5% CO2 for at least 15 days. Primary podocytes were then exposed to Adriamycin at 0.25 μg/ml for 0, 12, 24, or 48 h. 250 nmol/L verteporfin or vehicle was applied to inhibit YAP for 0, 12, or 48 h.The glomerular cells were obtained as previously described , brieflyP < 0.05 was considered significant.The experiments were all repeated for at least three times in independent biological replicates. Data are presented as means ± SD. One-way analysis of variance was used to assess the differences between multiple groups, and Least Significant Difference (LSD) was used as the post-test to analyze difference between any two mean, and Permission on performing animal experiment for research purposes (No. 20170223-046) and the use of human tissue (No. 2017-C008) was approved by the Ethics Committee of School of Basic Medical Sciences, Fudan University, China. All procedures were carried out according to the approved guidelines.Mass et al. recently proposed that MCD is the early stage of FSGS . We thusSince YAP is an anti-apoptotic protein that binds to the TEAD transcription factor to decrease cell death, we then examined podocyte apoptosis in MCD and FSGS. TUNEL staining and quantification of TUNEL-positive cells in peripheral area of glomeruli, as well as the double-staining of activated Caspase 3 and podocyte cytoplasm marker podocin, showed more apoptotic podocytes in FSGS patients compared to MCD patients Fig. . These rmT/mG; NPHS2-Cre mice, which were generated as illustrated in the “Materials and methods” , and found the number of podocytes per glomeruli and podocyte density were decreased at the 10th week of Adriamycin treatment without change of glomerular volume /YAP was upregulated as was the active Caspase 3  and p-YAP (S397) in glomeruli was inhibited and the ratio of p-YAP (S127) to YAP was reduced by verteporfin treatment Fig. . HoweverWe then examined the morphological change of kidney and renal function. As shown in Fig. Whether podocyte injury leads to YAP nuclear exclusion, or YAP nuclear exclusion promotes podocyte injury in vivo, is still a problem to be explored . In the YAP is regulated by multiple mechanisms, such as cell–cell contact , 33, 34,Verteporfin, functioning via a reactive oxygen-dependent mechanism, was considered as a kind of small molecule for treatment of ocular photodynamic . Recent Schwartzman et al. observed that glomerular YAP expression was reduced, similar to the distribution of synaptopodin in human primary FSGS . We alsoIn summary, our study suggests that YAP activation and nuclear distribution in podocytes is an important endogenous anti-apoptotic mechanism during the progression of FSGS and targeting YAP could be a potential therapy for treatment of FSGS.Supplemental material


The increasing incidence of cardiac comorbidities in the elderly population has led to an increasing demand for vigilance of cardiac dysfunction induced by surgery. Favorable outcomes can be ensured in such cases by an increased awareness of cardiogenic complications, early identification of the problem, and appropriate treatment.This study presents 2 cases of acute pulmonary edema (PE) that were likely caused by ischemic heart disease and diastolic dysfunction in postoperative patients, following vitrectomy, in the post-anesthetic care unit.Chest x-ray and computed tomography indicated PE.Following the diagnosis of PE, patients were intubated and transferred to the intensive care unit where 20 mg furosemide was injected and 10 μg/kg/min dobutamine was infused intravenously.On postoperative day 2, the patients’ vital signs were stable and there were no signs of respiratory disturbance.Physicians should be alert to the potential development of PE as a postoperative complication in patients with left ventricular (LV) diastolic dysfunction and ischemic heart disease, even if the patient has undergone a procedure with mild hemodynamic change and minimal surgical stimulation such as vitrectomy. We propose that physicians treating elderly patients with LV diastolic dysfunction and ischemic heart disease undergoing vitrectomy should consider the use of intraoperative transthoracic echocardiogram or transesophageal echocardiogram with continuous monitoring of blood pressure, using devices such as arterial catheter devices. Left ventricular (LV) diastolic function has recently been reported as an independent predictor of the prognosis and adverse cardiac events, including PE, in patients undergoing cardiovascular and non-cardiovascular surgeries.–4 Furthermore, patients with coronary artery disease exhibit high mortality rates if they develop PE. The increasing incidence of cardiac comorbidities in the elderly population has led to an increasing demand for vigilance of cardiac dysfunction induced by surgery. The American College of Cardiology and the American Heart Association (ACC/AHA) guidelines recommend the use of risk indices for preoperative cardiac evaluations for non-cardiac surgery. On the contrary, the ACC/AHA guidelines exclude perioperative cardiovascular evaluations for patients undergoing low-risk surgeries. However, perioperative cardiovascular evaluations are needed even for patients undergoing hemodynamically stable surgeries with relatively short operation times, such as vitrectomy.Postoperative respiratory complications are associated with high mortality and morbidity. Pulmonary edema (PE) is one of the major respiratory complications and typically has a cardiogenic etiology.We believe that favorable outcomes are ensured in such cases by anticipating the possibility of the development of cardiogenic PE, early identification of the condition should it occur, and prompt administration of appropriate treatment. Herein, we present 2 cases of acute pulmonary edema that were likely caused by ischemic heart disease and LV diastolic dysfunction in postoperative patients following vitrectomy.22.1A 77-year-old man, weighing 67 kg (body mass index: 23), was diagnosed with retinal detachment and scheduled for right total vitrectomy. He had a medical history of hypertension and non-insulin-dependent diabetes with unspecified, variant angina. He also reported a 55-pack-year smoking history. Percutaneous coronary intervention (PCI) was performed ∼10 years prior to this surgery due to acute myocardial infarction; he had also experienced an episode of acute congestive heart failure (HF) with preserved ejection fraction (EF) 2 years before this surgery. The patient had a physical status score of III according to the American Society of Anesthesiologists. During preoperative evaluation, the patient described his functional capacity as good and denied experiencing any symptoms of HF. Physical examination did not reveal any signs of congestive HF. The electrocardiograph (ECG) showed non-specific T wave abnormalities with LV hypertrophy . Muscle relaxation was maintained using intermittent doses of intravenous rocuronium titrated to keep the train of 4 to <2 twitches.Upon the patient's arrival in the operating room, routine monitoring including noninvasive automated blood pressure, pulse oximetry, and electrocardiography was begun prior to premedication. Furthermore, the bispectral index (BIS) was monitored using VISTA ; sensors were placed on the frontotemporal regions of the cranium, as recommended by the manufacturer, and were connected to an electroencephalogram monitor. The values of BIS were maintained between 40 and 60 during the intraoperative period. General anesthesia was induced using propofol, and tracheal intubation was performed following rocuronium-induced muscular relaxation. Anesthesia was maintained using sevoflurane (1.5–2.0 vol%) and an air–oxygen mixture (FiO2) were 100 to 120/76 to 86 mmHg, 70 to 86 beats/min, and 99%, respectively. Blood pressure was stable at the beginning of the surgery; however, 40 minutes after anesthetic induction, it declined to a low of 80 mmHg systolic pressure. This was managed using 5 to 10 mg ephedrine and 50 μg phenylephrine, injected thrice over 30 minutes. At 30 minutes after the onset of hypotension, a radial artery catheter was placed to measure the arterial blood pressure, and a continuous intravenous infusion of 5 μg/kg/min dobutamine was initiated. Following this, the systolic blood pressure and heart rate were 100 to 120 mmHg and 80 to 100 beats/min, respectively. The patient did not have any significant electrolyte abnormalities, as determined by arterial blood gas (ABG) investigation.Blood pressure, heart rate, and peripheral oxygen saturation  without extubation, for further management. In the SICU, intravenous injection of 20 mg furosemide was administered, and infusion of 10 μg/kg/min dobutamine was continued. He received an additional dose of furosemide and his respiratory status improved over the next 12 hours. The immediate postoperative chest x-ray scan revealed bilateral vascular congestion . On arrival in the PACU, the SpOOn postoperative day 1, his vital signs were stable and there were no signs of respiratory disturbance. Follow-up chest radiography showed a decrease in pulmonary congestion. Therefore, extubation was performed, and diuretic (furosemide) and inotropic (dobutamine) treatment was discontinued. On postoperative day 3, he was transferred to the general ward in an overall stable condition and was discharged 5 days later without any complications. No abnormalities were observed during the follow-up period of 4 weeks.2.2A 74-year-old man, weighing 54 kg (body mass index: 21), was diagnosed with an epiretinal membrane and scheduled for left total vitrectomy. His medical history was significant for hypertension and non-insulin-dependent diabetes. There was no history of PCI or coronary angiography. The patient's physical status score was II according to the American Society of Anesthesiologists. During the preoperative evaluation, the patient described his functional capacity as good and denied experiencing any symptoms of HF. Physical examination did not reveal any signs of congestive HF. The preoperative ECG showed non-specific T wave abnormalities and atrial fibrillation Fig. . The patThe procedure was performed under general anesthesia and endotracheal intubation with routine monitoring as in Case 1. Anesthesia was induced using propofol, and intubation was performed following rocuronium-induced muscular relaxation. Anesthesia was maintained using sevoflurane (1.5–2.0 vol%) and an air–oxygen mixture (FiO2 0.5). Muscle relaxation was maintained using intermittent doses of intravenous rocuronium titrated to keep the train of 4 to less than 2 twitches.2 was evaluated and found to be 99%; 30 minutes after arrival, it gradually decreased to 93%. Therefore, the patient was reintubated. Suctioning of the trachea revealed pink frothy sputum. Postoperative chest radiograph was obtained immediately  contributed to the occurrence of postoperative PE. Based on our study of the two cases, we believe that cardiogenic PE can occur even in patients undergoing hemodynamically stable surgeries with relatively short operation times, such as vitrectomy. Therefore, prior identification of high-risk patients is crucial for the early diagnosis of cardiogenic postoperative complications, which will, in turn, facilitate prompt and appropriate management, thereby decreasing the postoperative morbidity and mortality.,3 The prevalence of diastolic dysfunction in the age group of ≥60 years is estimated to be 28%. In these cases, the patients had hypertension, diabetes, and LV diastolic dysfunction. LV diastolic dysfunction can contribute to the development of HF during and after surgery.–4 Preoperative LV diastolic dysfunction has recently been reported to correlate with the incidence of postoperative PE.,8 LV end-diastolic pressure is easily elevated in the presence of LV diastolic dysfunction, which subsequently results in PE. Therefore, preoperative evaluations should include not only LV systolic function but also LV diastolic function. LV diastolic function can be assessed by echocardiography. The ratio of LV early diastolic filling velocity to the peak diastolic velocity of the medial mitral annulus (E/e′) can be used as an index of LV diastolic function. LV diastolic function is considered normal when E/e′ is <8, while LV diastolic dysfunction is defined as E/e′ >15. In previous studies, the E/e′ was significantly higher in patients with PE.,9 In the cases presented here the values of E/e′ were >15  for cases 1 and 2.A high prevalence of diastolic dysfunction is observed in elderly patients with coronary artery disease, cardiomyopathies, valvular disease, hypertension, diabetes mellitus, and a variety of other systemic diseases. Weaning-induced acute hemodynamic effects may have detrimental consequences in patients with cardiovascular disease, particularly in patients with coronary artery disease. These effects may also induce localized myocardial ischemia or unmask areas of pre-existing marginal function. Myocardial ischemia has been reported as a cause of PE. Myocardial ischemia could be the main mechanism of cardiac failure during weaning; effective management of this condition may improve the success of weaning in such cases. Shifts in intravascular volume, significant operative pain, or withdrawal of anesthesia may contribute to cardiac events during the weaning period. In the cases presented in this study, perioperative stress along with myocardial ischemia could have contributed to the development of acute PE. Furthermore, diastolic dysfunction may aggravate myocardial ischemia in addition to the stress of weaning.In a clinical setting, the shift from mechanical ventilation to spontaneous breathing may induce cardiac dysfunction and is a potential etiology underlying weaning-induced PE.,12 In a clinical situation such as the acute onset of severe myocardial ischemia, PE could be induced by acute decompensated HF in susceptible patients. Acute decompensated HF typically manifests as respiratory distress with PE. Any postoperative patient with suspected PE should be evaluated for new or unstable myocardial ischemia. In the present cases, the patient had ischemic heart disease and diastolic dysfunction. Therefore, in these cases, PE could be induced from acute decompensated HF with acute onset of myocardial ischemia. Even patients with no history of HF or known cases of HF who are asymptomatic can develop clinical manifestations of HF under the stress of surgery. Therefore, it is important to evaluate all patients for known risk factors of HF, especially elderly patients with other known risk factors.,14 However, there are no guidelines for perioperative cardiovascular evaluations for patients undergoing low-risk surgeries, such as vitrectomy. Although a pre-existing cardiac disease is considered a significant risk factor for perioperative complications, there is no recommendation for perioperative monitoring in patients who are asymptomatic with LV diastolic dysfunction and ischemic heart disease. However, in light of the result of the present cases, perioperative cardiovascular evaluations and monitoring are clearly needed even for patients undergoing hemodynamically stable surgeries with relatively short operation times, such as vitrectomy.Acute decompensated HF may be precipitated by myocardial ischemia.Continuous ECG monitoring is necessary to detect myocardial ischemia. Methods of invasive monitoring, such as arterial catheter devices, in addition to standard monitoring of volume status, should be employed to avoid hypo or hypervolemia and guide fluid and diuretic administration in patients with HF caused by ischemic heart disease. We recommend that an intra-arterial catheter be inserted prior to the induction of anesthesia in all surgical patients with ischemic heart disease. Emergency intraoperative or perioperative TTE or transesophageal echocardiogram (TEE) is indicated to determine the cause of any unexplained, persistent or life-threatening hemodynamic instability. In patients at high risk for myocardial ischemia, continuous intraoperative TTE or TEE monitoring may be useful to immediately detect any new regional wall motion abnormalities suggestive of ischemia. In the present cases, intravenous crystalloid fluid infusion was administrated at approximately 2.24 to 2.78 mL/kg/h during the intraoperative period. The authors did not actively perform fluid restriction since the preoperative cardiac functions were relatively good  for both patients. There were no significant differences in the fluid in-out balance during the perioperative period. We believe that it is unlikely that the fluid administration contributed to the initial episode of acute PE as there were no significant fluid shifts observed in our patients.Excess fluid balance is also a concern with PE, especially in patients with reduced cardiac function. A continuous infusion of crystalloid may be supplemented with the administration of smaller than usual  crystalloid boluses in patients with decompensated HF.2, frequent hypotension could imply the occurrence of PE during the intraoperative period.During the intraoperative period, there was an episode of hypotension. At the time, we assumed that this hypotension was temporary. Therefore, we did not perform aggressive treatment or monitoring. Consequently, we now believe that aggressive treatment might have been necessary, considering that temporary hypotension during surgery could have been caused by cardiac depression. Moreover, invasive measurement of arterial blood pressure and the use of TEE in the intraoperative period may have been necessary to prevent the occurrence of PE. In the cases presented here, we believe that PE occurred due to the worsening of cardiac function during the weaning process with cardiac depression during surgery. Conversely, there is the possibility that PE might have occurred during the intraoperative period. Although our patient showed no decrease in SpO,12When PE was diagnosed, we used an inotropic agent, 10 μg/min/kg dobutamine, based on the conclusion that the patient had severe systolic dysfunction and low cardiac output syndrome. We also used a diuretic agent, 20 mg/12 h furosemide, due to the diagnosis of PE. Management of patients with PE due to diastolic LV dysfunction should include the maintenance of adequate preload , slower heart rate to allow an adequate diastolic filling time, and the avoidance of hypertension to decrease the afterload to the left ventricle. Furthermore, the patients discussed in this case study were elderly, which is not supportive of the diagnosis of negative pressure PE, which mainly occurs in relatively younger patients.An alternative cause of PE in the present cases may have been negative pressure PE. However, this pathogenesis is contradicted in the present cases because there were no intracranial lesions or upper airway obstructions in the perioperative period.A further prospective study for adequate perioperative monitoring and management in patients with LV diastolic dysfunction and ischemic heart disease undergoing low-risk surgeries is warranted to decrease perioperative complication, morbidity, and mortality.4Physicians should be alert to the potential development of postoperative PE in patients with LV diastolic dysfunction and ischemic heart disease, even if the patient has undergone surgeries with only mild hemodynamic changes and minimal surgical stimulation such as vitrectomy. Therefore, heightened vigilance of cardiac dysfunction is essential to prevent this perioperative complication. We propose that physicians treating elderly patients with LV diastolic dysfunction and ischemic heart disease undergoing vitrectomy should consider the use of intraoperative transthoracic echocardiogram or transesophageal echocardiogram with continuous monitoring of blood pressure, using devices such as arterial catheter devices.Conceptualizations: Yuseon Cheong, Byeongmun Hwang.Data curation: Namyoong Kim, Minsoo Kim.Formal analysis: Hee-Jeong Son, So Young Lim, Seong-Sik Kang, Jin Huh.Investigation: Byeongmun Hwang.Writing – original draft: Minsoo Kim, Byeongmun Hwang.Writing – review &editing: Byeongmun Hwang.


The present case report describes a mother and son with arrhythmogenic cardiomyopathy (ACM) with early and greater left ventricle (LV) involvement. The presence of curly hair in both, together with the resuscitated sudden cardiac death of the mother, allowed timely genetic testing, which found a pathogenic nonsense mutation of the desmoplakin gene. While asymptomatic from an arrhythmic point of view, the son’s evolution was characterized by a well-documented exercise-induced myocarditis-like stage. Arrhythmogenic cardiomyopathy (ACM) is a primary heart muscle disorder, characterized pathologically by fibro-fatty replacement of the myocardium and clinically by a propensity towards ventricular arrhythmias, most often with a genetic cause . AlthougThe family history started with the case of the patient′s mother, who, at age 38 in June 2011) experienced a resuscitated cardiac arrest (ventricular fibrillation). The electrogradiographic (ECG) tracing after resuscitation showed sinus tachycardia with microvoltated QRS complexes in the precordial leads and newly diagnosed right bundle branch block morphology with a 2 mm ST segment elevation in the lateral leads. Transthoracic echocardiography (TTE) showed mild diffuse LV hypokinesia, with an estimated LV ejection fraction (EF) of 50% and a patchy hyperechogenic appearance of the interventricular septum (IVS). The RV dimensions and function were normal, and the RV free wall had a normal morphology and contractility. Coronary angiogram and 24 h ECG monitoring were unremarkable. Late ventricular potentials on signal averaged ECG were positive, being the only ACM minor criterion [011 experIn 2018, a patient and her 13 year-old son were referred to our center for a comprehensive evaluation. We noted their particular phenotype, both having curly hair since early childhood A, withouAt that time, the mother’s ECG showed low voltage fragmented QRS complexes without any ST-T changes B. Her TTThe son’s evaluation showed an unremarkable ECG C, while p.Arg2284X (c.6850C > T) on exon 24 in both mother and son.Given the resuscitated SCD in a mother with borderline ACM criteria, as well as the curly hair of both family members, genetic testing was performed by next-generation sequencing (NGS) using a custom design based on a SeqCap EZ Solution-Based Enrichment strategy . The panel was designed to identify disease-causing mutations in 48 arrhythmia syndrome-causing genes . Target In January 2020, after prolonged and sustained exercise (skiing), the son was admitted to the local pediatric service with chest pain and palpitations, with elevated cardiac biomarkers , increased N-terminal pro-brain natriuretic peptide (NTproBNP) (841 pg/mL), and absent inflammatory markers . His TTE showed preserved biventricular function. The CMR imaging showed a mildly dilated LV (LVEDV 94 mL/m²) [The 5-month follow-up CMR showed normal biventricular size and function, with the same pattern and extent of myocardial hyperenhancement on the LGE imaging C. HoweveThis family report illustrates the peculiar, incomplete, and polymorphic presentation of a severe form of ACM, with SCD as the first symptom in the mother, as well as acute myocardial inflammation and necrosis as the first presentation in the son. Moreover, it illustrates the use of advanced cardiac imaging, a particular pattern of progression of the left dominant ACM phenotype, characterized by intermittent exercise-induced myocarditis-like hot phases, followed by resolution of acute phenomena after exercise abstinence.Two classical cardiocutaneous disorders with autosomal recessive inheritance, known as Naxos disease and Carvajal syndrome, are described, but additional cutaneous phenotypes can be linked to autosomal dominant DSP variants  and may It is currently well established that ACM clinical course is characterized by intermittent myocarditis-like episodes, designated as “hot phases” outlined by troponin rise and myocardial inflammation ,6. TheseThe frequent finding of lymphocyte infiltrates in myocardial pathology specimens of ACM patients does not necessarily indicate viral myocarditis and may be associated solely with myocyte death , which aThis case also illustrates the ability of CMR imaging to identify myocardial oedema in the acute phase of ACM, as well as its remission after exercise abstinence. We emphasize the impressive amount of LV scarring, resulting in only mild impairment of LV function and absence of acute heart failure symptoms, leading to the presumption of pre-existent fibrosis with additional recent superimposed necrosis and inflammation. The particular “ring-like” appearance of the subepicardial scar was strongly suggestive of a genetic ACM, specifically the previously diagnosed DSP mutation, as it was recently defined as an imaging hallmark for this genotype .To conclude, prompt recognition of ACM red flags in affected patients and family members, followed by genetic testing, can be life-saving. Scenarios of recurrent myocarditis advocate for a thorough investigation of a possible ACM, as the disease clinical course appears to be characterized by myocarditis-like “hot phases” that may accelerate its progression.


Dear Sir,N-Oxide with cardiovascular and all-cause mortality in hemodialysis patients’ by Zhang et al. [N-Oxide (TMAO) is a proatherogenic and prothrombotic metabolite. The article recruited 252 hemodialysis (HD) patients from China with a mean TMAO of 4.73 µg/ml (62.9 μmol/l) and divided them into a high-TMAO group (>4.73 µg/ml) and a low-TMAO group (≤4.73 µg/ml). TMAO was measured by liquid chromatography/mass spectrometry using TMAO-D9 as the internal standard. It found that a higher incidence of cardiovascular death (Log-Rank: p = 0.006) and all-cause death (Log-Rank: p < 0.001) in the high-TMAO group by Kaplan–Meier analysis. The multivariate Cox regression analysis showed that high TMAO levels were significantly associated with cardiovascular and all-cause mortality in models 1–8, which are displayed in Table 3 and Table 4.I have read with great interest the paper entitled ‘Association of trimethylamine g et al. . TrimethN-Oxide (TMAO) is an enterogenous micromolecular toxin that is mainly synthesized by the gut microflora, and which is filtered by the kidney and excreted in the urine. Plasma TMAO levels in HD patients reflect the net effect of TMAO production and clearance. HD clears TMAO at a rate similar to creatinine, with re-accumulation to plasma concentrations of approximately 100uM before the subsequent dialysis session [Trimethylamine  session . However session , which ep = 0.19) or time to cardiovascular hospitalization or cardiovascular death . Two independent, nested case-control studies conducted by Kalim et al. [p = 0.36), assessed by claim data, using a case-control design in the incident HD Accelerated Mortality on Renal Replacement cohort.Firstly, Kaysen et al. . performp > 0.05) and all-cause mortality . An additional analysis evaluating the association between TMAO quintiles and cardiovascular outcome yielded similar findings to our models utilizing ln (TMAO).Secondly, Stubbs et al. . examinep = 0.15) and were measured by liquid chromatography/mass spectrometry using TMAO-D9 as the internal standard. In whites, 2-fold higher TMAO was associated with a higher risk of cardiac death, sudden cardiac death, and any-cause death. However, in blacks, the association was nonlinear and significant only for cardiac death among patients with TMAO concentration below the median(88 μmol/l) . Above the median, there was no association with cardiac death.Finally, Shafi et al. . includeIn conclusion, I think the inconsistency of study results may partly be associated with measure methods, dialysis modes, residual renal function, intestinal microbiota, diet and the accurately defined difference between high and low levels. Further prospective studies of larger sample size and multiple centers and multiple races and multiple times to record TMAO may help to confirm the relationship and to clarify the potential utility of clinical interventions that target TMAO. Maybe TMAO difference between pre-dialysis and post-dialysis is the best indicator to evaluate the relationship.


The purpose of this study was to investigate the clinical potential of Compressed SENSE (factor 5) accelerated free-breathing three-dimensional (3D) whole heart LGE with high isotropic spatial resolution , who were referred for assessment of left ventricular myocardial viability and received free-breathing and breath-hold LGE sequences at 1.5 T in clinical routine. Two radiologists independently evaluated global and segmental LGE in terms of localization and transmural extent. Readers scored scans regarding image quality (IQ), artifacts, and diagnostic confidence (DC) using 5-point scales (1 non-diagnostic—5 excellent/none). Effects of heart rate and body mass index (BMI) on IQ, artifacts, and DC were evaluated with ordinal logistic regression analysis.Global LGE (n = 33) was identical for both techniques. Using free-breathing LGE (average scan time: 04:33 ± 01:17 min), readers detected more hyperenhanced lesions  compared to breath-hold LGE , pronounced at subepicardial localization and for 1–50% of transmural extent. For free-breathing LGE, readers graded scans with good/excellent IQ in 80.0%, with low-impact/no artifacts in 78.6%, and with good/high DC in 82.1% of cases. Elevated BMI was associated with increased artifacts (P = .0012) and decreased IQ (P = .0237). Increased heart rate negatively influenced artifacts (P = .0013) and DC (P = .0479) whereas IQ (P = .3025) was unimpaired.In a clinical setting, free-breathing Compressed SENSE accelerated 3D high isotropic spatial resolution whole heart LGE provides good to excellent image quality in 80% of scans independent of heart rate while enabling improved depiction of small and particularly non-ischemic hyperenhanced lesions in a shorter scan time than standard breath-hold LGE. Cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) imaging has become the non-invasive standard of reference for assessment of myocardial viability in different cardiac diseases –3. In isTraditionally, a two-dimensional (2D) inversion-recovery fast spoiled gradient-echo sequence is applied for LGE imaging with manually chosen inversion time (TI) to null the signal of healthy myocardium , 11. HowThe recent development of three-dimensional 3D) imaging allows data acquisition of the entire heart in a single scan without interslice gaps D imaging. In thisRecently, Compressed SENSE was introduced, which combines compressed sensing and parallel imaging using SENSitivity Encoding (SENSE) –31. CompThe purpose of this study was to investigate the clinical potential of Compressed SENSE accelerated free-breathing 3D whole heart LGE with high isotropic spatial resolution compared to standard breath-hold LGE imaging for assessment of left ventricular (LV) viability.The institutional review board approved this single-center study . Given its retrospective design, written informed consent was waived for the patient cohort.We retrospectively reviewed our internal database at our tertiary care medical center for CMR studies performed between February and November 2019. Patients were included if they received a standardized protocol in clinical routine for assessment of LV myocardial viability with known/suspected ischemic or non-ischemic cardiomyopathy including both, breath-hold and free-breathing LGE sequences. Patients were excluded in case of (I) inadequate nulling of breath-hold LGE or (II) uncertainty in assessment of global LGE in breath-hold sequences as determined by a board certified cardiovascular radiologist with eight years of experience in CMR (J.D.), and (III) a very low navigator efficiency of free-breathing LGE.The following data were obtained from the medical charts or observed during examination: Patient age, gender, body mass index (BMI) at examination date, indication for viability study, heart rate during LGE imaging, LV ejection fraction (LVEF) as assessed by short-axis (SAx) cine, and scan time for LGE sequences. Final diagnosis of cardiomyopathies was based on multidisciplinary evaluation of clinical data, laboratory examination, biopsy results if available, echocardiographic findings, and CMR examination (breath-hold LGE) by the treating cardiology consultant and a board certified cardiovascular radiologist.All CMR examinations were performed on a commercially available whole body 1.5T CMR system  equipped with a dedicated 28-channel coil for cardiac imaging, which consists of standard system-provided 12-channel posterior and 16-channel anterior coils. The clinical imaging protocol comprised 2D balanced steady-state free precession (bSSFP) breath-hold cine imaging in standard orientations (4-chamber (4Ch), 2-chamber (2Ch), 3-chamber (3Ch), and SAx) followed by admission of Gadobutrol , which was automatically injected into an antecubital vein at a flow-rate of 2 ml/s. Ten minutes after application of contrast agent, 2D gradient-echo T1-weighted sequence (Look-Locker) was used to determine TI adjusted to null LV myocardium.3 /280 × 204 × 50 mm3 , matrix 172 × 119 /176 × 133 , acquired voxel size 1.64 × 1.72 × 10 mm3, and reconstructed voxel size 1.59 × 1.59 × 10 mm3. Spectral fat suppression was used to avoid high-intensity signals from epicardial fat. Scan time was 18 s per breath-hold; to cover the SAx, two stacks were acquired.As clinical standard, electrocardiogram (ECG)-triggered (end-diastolic) 3D Cartesian T1-weighted inversion-recovery fast spoiled gradient-echo multislice breath-hold LGE sequences covering the left ventricle in standard orientations  were acquired. The following imaging parameters were applied: Slice thickness 10 mm, shot duration 170 ms, repetition time 3.5 ms, echo time 1.7 ms, flip angle 15°, field of view (FOV) 300 × 239 × 50 mm3, matrix 188 × 212 × 171, acquired voxel size 1.40 × 1.40 × 1.40 mm3, and reconstructed voxel size 0.70 × 0.69 × 0.69 mm3. In every cardiac cycle, 35 k-space lines were acquired resulting in a shot length of 150 ms in end-diastolic cardiac phase.Free-breathing whole heart 3D Cartesian LGE was acquired immediately after breath-hold LGE. Figure Philips Healthcare ) was used. Data was acquired using a balanced variable density incoherent sampling patter within high-density in the k-space center and continuously decreasing sampling density towards the k-space periphery. For image reconstruction, an iterative L1 norm minimization ensuring data consistency and sparsity in the wavelet domain in combination with regularization by coil sensitivity distribution and SENSE parallel imaging was used. Image reconstruction, which was performed with standard hardware provided by the manufacturer of the CMR system, took about 30 s. An acceleration factor of 5 was employed, resulting in a nominal scan time of 02:08 min or 04:16 min when considering 50% of navigator efficiency, and a heart rate of 60 beats per minute. Data were acquired in the transaxial plane.For acceleration of image acquisition, Compressed SENSE  used the Multiplanar-Reconstruction-(MPR) tool in a commercially available image viewer  to create reconstructions in standard orientations  with identical slice thickness as breath-hold LGE scans. Scans were than evaluated by two radiologists with four  and three  years of experience in CMR using the same IMPAX EE  workstation during separate reading sessions. Readers were blinded to clinical and patient data. The reading took place in two sessions: In the first session, the readers evaluated breath-hold LGE scans whereas in the second session, they assessed reconstructed free-breathing LGE images and its source images with the latter being free to visualize in all three directions of space using the MPR-tool. A period of four weeks between sessions was used to minimize recall bias. Readers were free to adjust window leveling.Readers assessed scans for global and segmental LGE of the LV applying the American Heart Association’s 17-segment model . HyperenUsing 5-point scales, readers scored LGE sequences in terms of image quality  and artifacts considering blurring artifacts, banding artifacts, respiratory artifacts, cardiac motion artifacts, and parallel imaging reconstruction artifacts  as well as diagnostic confidence .Statistical analysis was performed using JMP  with statistical significance being set to P < 0.05. Data are expressed as mean ± standard deviation, unless noted otherwise. Comparison of paired nonparametric variables and scan times was performed with Wilcoxon signed-rank tests. To compare the proportion of detected hyperenhanced lesions between LGE techniques, the McNemar test was applied. Cohen’s Kappa was used to evaluate interobserver agreement of detection of hyperenhanced lesions using free-breathing and breath-hold LGE sequences. The interpretation of an agreement was as follows: 0.01–0.2 slight, 0.21–0.4 fair, 0.41–0.6 moderate, 0.61–0.8 substantial, and 0.81–0.99 almost perfect agreement . InfluenSeventy-nine patients met the inclusion criteria. Thereof, four patients were excluded given inadequate nulling of breath-hold LGE, three due to uncertainty in assessment of global LGE in breath-hold sequences, and two given very low navigator efficiency of free-breathing LGE.Consequently, 70 patients  were included in this study, yielding an age of 45.8 ± 18.1 years (range 16–80 years) and BMI of 25.1 ± 4.2 (17.6–37.4). The heart rate was 70 ± 12 (48–109) beats per minute and a LVEF of 60 ± 17% (19%–85%) was observed. Scans were acquired for viability assessment of known/suspected ischemic cardiomyopathy in 19 (27.1%) and non-ischemic cardiomyopathies in 51 (72.9%) patients. Thereof, 18 (35.3%) patients were examined for evaluation of potential (peri-)myocarditis, nine (17.6%) of structural heart disease, seven (13.7%) of sarcoidosis, six (11.8%) of dilated cardiomyopathy (DCM), five (9.8%) of hypertrophic cardiomyopathy (HCM), three (5.8%) of amyloidosis, two (3.9%) of chemotherapy-induced cardiomyopathy, and one patient (2.0%) of Anderson-Fabry disease.All included imaging studies were executed successfully. Depending on patient’s heart rate and breathing frequency, free-breathing LGE took 04:33 ± 01:17 min to acquire (46.9% navigator efficiency). Breath-hold LGE sequences lasted 05:15 ± 01:23 min (P = .0104).Global LV myocardial LGE (n = 33) was identical for both techniques and readers, present in 13 patients (39.4%) with ischemic and 20 patients (60.6%) with non-ischemic cardiomyopathy (P = 1.0). Thereof, findings consistent with (peri-) myocarditis were present in 11 (55.0%) patients, sarcoidosis in three (15.0%), DCM in two (10.0%), HCM in two (10.0%), amyloidosis in one (5.0%), and chemotherapy-induced cardiomyopathy in one (5.0%) patient.Table Individual and averaged segmental LGE assessment of readers is given in Table Averaged for both readers, depiction of transmural scar was comparable between both techniques  whereas readers identified more lesions in mid-myocardial , subendocardial , and subepicardial localization  in free-breathing LGE. Further, more small lesions were depicted using free-breathing LGE than with breath-hold LGE  while identification of scars of 51–75%  and of 76–100%  of transmural extent was comparable between techniques. Figure For both techniques, an almost perfect interobserver agreement for detection of hyperenhanced lesions was observed .Concomitant pericardial LGE was identical for both techniques and readers (n = 9) with six patients presenting circular (66.7%), two LV (22.2%), and one patient right ventricular (11.1%) hyperenhancement (P = 1). Both readers detected intracardiac thrombi in three patients in both techniques (P = 1).For both readers, free-breathing LGE achieved a score of 4.1 ± 0.8 for image quality, of 4.0 ± 0.9 for artifacts, and of 4.4 ± 0.8 for diagnostic confidence. Breath-hold LGE yielded scores of 4.4 ± 0.8 for image quality (P = .0028), of 4.3 ± 0.9 for artifacts (P = .0098), and of 4.5 ± 0.8 for diagnostic confidence (P = .3125).Considering the overall distribution of scores of both readers combined, Table Table Exemplary comparisons of free-breathing and breath-hold LGE are given in Figs. In this study, we investigated the clinical potential of Compressed SENSE accelerated free-breathing 3D whole heart LGE with high isotropic spatial resolution compared to standard breath-hold LGE for assessment of LV viability. The major findings of the study are the following: 1. Free-breathing LGE enabled improved depiction of small hyperenhanced lesions of the LV myocardium, in particular of non-ischemic localization, and required a shorter scan time compared to breath-hold LGE. 2. Free-breathing LGE provided good to excellent results for diagnostic confidence, artifacts, and image quality in about 80% of examinations with the latter being independent of heart rate.3 reconstructed resolution) [3 reconstructed resolution) [3 acquired and 1.0 mm3 reconstructed resolution [3 acquired resolution in 06:10 ± 02:56 min [3 depending on patient’s size and heart rate) in approximately 4 to 6 min (depending on applied acceleration factor) using LOw-dimensional-structure Self-learning and Thresholding (LOST). However, required reconstruction of acquired data using an offline central processing unit cluster, lasting about an hour, limits its immediate application in clinical routine and feasibility for other centers [Given aforementioned limitations of breath-hold LGE, free-breathing LGE techniques are of particular interest in research and clinical practice. Previous studies have proposed different free-breathing approaches enabling high spatial resolution at 1.5 T and 3 T , 25, 26.olution) . Bratis solution  whereas 2:56 min . Akcakay2:56 min  and Bash2:56 min , respect centers , 22.3, no adaptation to patient’s specifics required) and reconstructed (0.7 mm3) voxel size in an acceptable scan time (04:33 ± 01:17 min) without extensive postprocessing. Image reconstruction took about 30 s and was performed with standard hardware provided by the manufacturer of the CMR system.In the present study, proposed Compressed SENSE accelerated free-breathing 3D whole heart LGE sequence enables high isotropic resolution in acquired  isotropic LGE techniques with different undersampling approaches was performed in the current study, which could nurture additional investigations. Finally, the possible impact of proposed free-breathing technique on final diagnosis of cardiomyopathies and further clinical decision making should be investigated in a prospective, multi-center setting, in which the order of acquisition of free-breathing and breath-hold LGE sequences is randomized to provide an unbiased evaluation.Free-breathing Compressed SENSE accelerated 3D whole heart LGE with high isotropic spatial resolution provides good to excellent image quality in 80% of scans independent of heart rate while enabling improved depiction of small hyperenhanced lesions with in particular non-ischemic localization of the LV myocardium in a shorter scan time than standard breath-hold LGE. Given its fast acquisition, wider user-independence, and omission of breath‐holds, Compressed SENSE accelerated free-breathing LGE has the potential to facilitate clinical workflow.


P/dtmax) was compared with the clinical outcome. The operators of the simulation were blinded to the clinical outcome. In six patients, the relative reduction in end-systolic volume exceeded 15% in the follow-up echocardiogram at 3 months (responders) and the remaining two patients were judged as non-responders. The simulated %ΔdP/dtmax at the best lead position could identify responders and non-responders successfully. With further refinement of the model, patient-specific simulation could be a useful tool for identifying non-responders to CRT.To identify non-responders to cardiac resynchronization therapy (CRT), various biomarkers have been proposed, but these attempts have not been successful to date. We tested the clinical applicability of computer simulation of CRT for the identification of non-responders. We used the multi-scale heart simulator “UT-Heart,” which can reproduce the electrophysiology and mechanics of the heart based on a molecular model of the excitation–contraction mechanism. Patient-specific heart models were created for eight heart failure patients who were treated with CRT, based on the clinical data recorded before treatment. Using these heart models, bi-ventricular pacing simulations were performed at multiple pacing sites adopted in clinical practice. Improvement in pumping function measured by the relative change of maximum positive derivative of left ventricular pressure (%ΔdThe online version of this article (10.1007/s00380-020-01577-1) contains supplementary material, which is available to authorized users. The safety and efficacy of cardiac resynchronization therapy (CRT) have been proved by a number of landmark studies –3, but tBecause the mechanical dyssynchrony resulting from dyssynchronous electrical activation can be an important target of therapy, various echocardiographic indices have been evaluated regarding whether they have diagnostic value additional to electrocardiogram (ECG) biomarkers. To date, none of the large trials have reported positive findings , 7. PatiComputer simulation of the heart has emerged as a novel tool in cardiology research and its applications for CRT have already been reported . Such apP/dtmax), correlated well with the clinically observed changes in ejection fraction (EF) in a retrospective study [Among these, the University of Tokyo heart simulator is a multi-scale, multi-physics heart simulator, in which the function of the heart, including patient-specific mechanics and electrophysiology, is reproduced in a three-dimensional heart model based on the molecular mechanism of the excitation–contraction coupling process –18. Okadve study . BecauseIn this study, we extended this approach to examine whether the UT-Heart heart simulator can identify non-responders to CRT based only on the clinical data recorded before the CRT implantation. The results demonstrated that the heart simulator has potential to provide additional value to the current guidelines for the selection of CRT candidates.Among the heart failure patients treated with CRT at the Kokura Memorial Hospital between April and December 2016, eight patients, whose cardiac computer tomography (CT) images were recorded before implantation, were enrolled in this study  constructed from multi-slice CT images was subdivided into finite elements. To each of these elements, molecular models of cardiac electrophysiology with a spatially detailed sarcomere model  represenTo save computational time and cost, we modeled only ventricles, and the time-varying elastance models of atria were connected with an electrical circuit analog of circulation Fig. a, the paFor each heart model, we performed CRT simulation without changing any parameters of the heart, torso, and circulation determined for the model before the treatment. Simulation was performed with the four most commonly used lead positions in each patient model. One of the pacing leads was fixed in the right ventricular apex and the other was placed in either the basal or mid-portion of the anterolateral or posterolateral segment Fig. b, c. VV All program codes were written in-house. They have been registered as intellectual property of the University of Tokyo. The computational time for a single beat was about 50 min for electrophysiological simulations and 30 min for mechanical simulations using 127 cores.Data are presented as average ± standard error of mean (SEM).In the echocardiograms taken at the three-month follow-up, significant reductions of ESV (> 15%) were observed in six patients   were all greater with case 4  was identified as the sensitive marker of CRT effect [max among the patients, we adopted the relative change in dP/dtmax (%ΔdP/dtmax) in this study and hypothesized that the patients for whom CRT fails to elicit a significant gain in %ΔdP/dtmax even at the best lead position would be the non-responders. Figure P/dtmax at the best lead position between the responders (closed circle) and the non-responders (open circle). Although the difference was small, simulated %ΔdP/dtmax value could identify the responders. To further test the predictability of %ΔdP/dtmax, we selected five patients (see Supplementary Table 3 in Online Resource 1) from the study subjects in our previous study [P/dtmax = 11.6). On the other hand, consistent with previous studies, decreases in total activation time by the pacing (Δd activation time) did not predict the response to CRT , the CRT simulation was applied to the heart models and vascular parameters before the treatment (acute effect), based on the assumption that the acute unloading effect by CRT would lead to the favorable remodeling in the remote phase, thus ignoring the remodeling processes at the cellular and tissue levels. The remodeling process and mechanisms at the cellular and tissue levels  should bmax could successfully identify the non-responders to CRT.We performed CRT simulations with individualized heart models created using data obtained only before implantations for eight patients with heart failure. Simulated changes in dP/dtSupplementary file1 (PDF 382 kb)Supplementary file2 (PDF 5414 kb)Supplementary file3 (MP4 8030 kb)Supplementary file4 (MP4 195 kb)Supplementary file5 (MP4 203 kb)Supplementary file6 (MP4 210 kb)Supplementary file7 (MP4 229 kb)Supplementary file8 (MP4 190 kb)Supplementary file9 (MP4 192 kb)Below is the link to the electronic supplementary material.


Cardiac involvement of amyloidosis can be challenging to diagnose because of the varying clinical and imaging manifestations. When present, the disease may mimic a variety of other cardiac illnesses, such as hypertrophic cardiomyopathy, left ventricular hypertrophy of any cause, heart failure with preserved ejection fraction, or hypertensive heart disease. Cardiac amyloidosis may even coexist with aortic stenosisTwo‐dimensional strain imaging of cardiac chambers has further advanced the field of echocardiography in terms of reproducible assessment of cardiac mechanical function different from the traditional estimation of left ventricular ejection fraction. One of the most intriguing discoveries in CA is the unraveling of the existence of a "cherry‐like" strain preservation pattern in the left ventricular apex (compared with other segments) with an extraordinarily high degree of spatial resolution. By taking the ratio of apical longitudinal strain versus basal and mid‐longitudinal strain, a value of over 1.3 predicted the existence of CA.P < .001). Zero points corresponded to a negative predictive value of 87%, and three points corresponded to a positive predictive value of 96% for 99 mTc‐PYP positivity. The authors have convincingly shown that as many as 96% of the patients with all the three variables present (a score of three) had positive scan results using the tracer. In contrast, only 13% of the subjects with a score of zero had a positive scan. In the latter group of subjects, other factors such as TTR mutations and carpal tunnel syndrome could help diagnose CA.The basis of the study99mTc‐PYP scintigraphy in patients suspected to have CA.In the study published in this journal,The pathophysiological basis of the apical sparing is not fully understood. Late gadolinium enhancement by CMRIt is undeniable that advanced imaging using SPECT, PET, and CMR, along with cardiac biopsies, is needed to make an accurate final diagnosis of CA. However, bedside echocardiography, using a combination of standard and speckle‐tracking imaging, may provide a reasonable, noninvasive method aiming to raise suspicion for CA. Table In a large registry‐based study involving patients from the United Kingdom and Italy, two different sets of echocardiographic scorings were used: One is the amyloid, AL score, and the other one is the increased wall thickness, IWT score. The echo measures included relative wall thickness (RWT), tricuspid annular plane systolic excursion (TAPSE), E‐wave/e’‐wave (E/e') ratio, and longitudinal strain (LS %) for the AL score. RWT, TAPSE, E/e', LS %, and septal longitudinal systolic apex‐to‐base ratio (SAB) were chosen for the IWT score. For the AL score, RWT and E/e' ratio were assigned two points, while TAPSE and LS % were given one point each. For the IWT score, RWT and SAB were given three points each, and TAPSE was graded for two points, while E/e' ratio and LS % were given one point each. For the systemic AL amyloidosis, a score of > 3 yielded an optimal sensitivity and specificity . For the increased wall thickness group, a score of > 5 had corresponding sensitivity and specificity values of 82% and 72%, respectively.It is quite intriguing to mention here that a much simpler form of a scoring system may also yield excellent sensitivity and specificity to distinguish AL from hypertrophic cardiomyopathy. Indeed, Gustavsson and colleagues have shown that an interventricular septal/posterior wall thickness ratio of < 1.6 in combination with a summed QRS voltage of < 30 mm could detect ATTR with a sensitivity of 94% and a specificity of 83%, while using these thresholds as diagnostic cutoffs.Like a host of cardiac illnesses, left atrial (LA) deformation may also be diminished in ATTR amyloidosis. Henein et alTo conclude, we are pleased that Usuku and colleagues have explored the utility of Kumamoto criteria in CA. The authors of this editorial would like to propose that larger multicenter studies are probably necessary to form a universal consensus, based on all the available published data, including the Umea and Kumamoto criteria. This would make clinical assessment and management of cardiac amyloidosis simpler and cost‐effective and avoid misdiagnosis of this life‐threatening disease.