Anemia in heart failure patients is a relatively common finding and has been linked with an increased risk of hospital admissions, morbidities, and significant mortality making its correction a significant factor in improving the quality of life and clinical outcomes in those suffering from it. This review article has discussed the multifactorial pathophysiology, including iron deficiency, longstanding inflammation, abnormal levels of human erythropoietin (Epo), and the abnormal activation of the renin-angiotensin-aldosterone system (RAAS) being the most significant. The diagnostic guidelines as well as research-based management modalities specifically with iron supplements and erythropoietin stimulating agents have also been discussed, although research done in this area has been limited and shown conflicting results. Heart failure (HF) also termed congestive heart failure is the inability of the heart to pump blood to the body. According to the electronic data gathered by the Global Health Data Exchange (GHDx) registry, the global burden of HF stands at 64.34 million cases as of 2017, whereas the current global economic burden of HF can be measured at 346.17 billion US dollars, based on an American Heart Association (AHA) estimate of 5380 US dollars per heart failure case [The World Health Organization classifies anemia as hemoglobin (Hb) levels <12 g/dL in women and <13 g/dL in men, however, the classification may differ when age, pregnancy status, altitude, and smoking status are considered [The prevalence of anemia in heart failure patients ranges from 9% to 69.6% with an increased risk of hospital admissions and mortality in nearly 46.8% of patients in comparison to 29.5% in nonanemic patients .The specific cause of anemia in heart failure patients is still unclear and has been thought to be multifactorial, with iron deficiency (IDA) and inflammation having the strongest evidence-based data .The current treatment modalities in treating anemia in patients with heart failure include the use of erythropoietic agents - epoetin-α, epoetin-β, and darbepoetin-α and intravenous or oral iron supplementation . The rolThis review article aims to establish a relationship between anemia and heart failure as well as discuss screening techniques for early diagnosis and management in such cases.PathophysiologyThe pathophysiology of anemia in heart failure patients is multi-factorial and has been linked to the presence of hematinic deficiencies, specifically iron deficiency (ID) anemia, chronic inflammation, or impaired erythropoietin levels. It can also be attributed to pseudo-anemia due to the activation of the renin-angiotensin-aldosterone system (RAAS).1. Iron Deficiency Anemia (IDA)Iron is one of the most important elements found in the human body. It is involved in erythropoiesis, transport, delivery, and utilization of oxygen, and is found in many enzymes responsible for crucial body functions . Iron deAbsolute iron deficiency is defined when total body iron levels are reduced and was identified in 15% of individuals with heart failure. ,10. ThisFunctional iron deficiency is described when iron levels are sufficient but not adequate to supply the target tissues due to maldistribution, Functional iron deficiency was found in 18% of heart failure patients. .Iron deficiency anemia in heart failure patients is a common occurrence and is linked with severity, poorer prognosis, and outcomes as evidenced in an international, multicenter cohort study conducted by Klip et al. in 2013 with 1,506 participants with chronic heart failure. Out of these 1,506, 753 participants were found to be iron deficient and 426 anemics . These pMyocardial dysfunction has been linked to chronic ID due to changes in structure and function of the myocardium due to impaired oxygen metabolism, cellular activities, and immune mechanisms . Impaire2. Chronic InflammationAnemia of inflammation is the presence of normochromic normocytic anemia in the setting of an infection, inflammatory disease, or a malignant condition. A study conducted by Opasich et al. in 2005 established a relationship between anemia and congestive heart failure . In thisThe pathophysiology behind this process is still largely unknown but is thought to be related to the increased levels of pro-inflammatory cytokines and hepcidin . EndotoxTNF-alpha and IL-6 have been shown to not only inhibit the production of erythropoietin in the kidneys via the activation of GATA 2 binding protein and nuclear factor-kB but are also involved in the suppression of erythroid progenitor cell proliferation in the bone marrow ,22. Addi3. Erythropoietin LevelsHuman Erythropoietin (Epo) is a 169 amino acid long glycoprotein hormone with a molecular mass of 30.4 kDa synthesized primarily in the peritubular fibroblasts found in the renal cortex and the liver in a fetus . DetectaThe cause for the elevated levels is multifactorial. One of the proposed causes was the chronic inflammatory state associated with heart failure ,26. The 4. Renin-Angiotension-Aldosterone System (RAAS)The RAAS is a hormonal system that is activated in response to renal hypoxia leading to the cleavage of angiotensinogen to form angiotensin I in the liver, and then angiotensin II by the angiotensin-converting enzyme (ACE) predominantly in the lungs . AngioteThe renin-angiotensin-aldosterone system (RAAS) is an important mediator in the pathophysiology of heart failure ,30. The 5. Other CausesAnemia in heart failure patients may be due to haemodilution brought upon as a consequence of sodium and water retention due to the activation of the RAAS pathway . The useThe clinical dilemma of anemia in heart failure patientsAnemia in heart failure patients has been linked with an increased risk of hospital admissions and mortality as supported by studies conducted by Schou et al. (2007)  and KomaA study conducted by Kosiborod et al. (2005) included 50,405 participants previously diagnosed with heart failure evidenced either by history or radiographic findings. An increased risk of one-year mortality rate and morbidities due to heart failure in patients with lower hematocrit was found when anemia was defined as < 40% for men and < 37% for women .Another group of studies substantiated by Anand et al. (2004) as part of the Randomized Etanercept North American Strategy to Study Antagonism of Cytokines (RENAISSANCE) trial, found the presence of anemia (Hb ≤12.0 g/dL) in 12% of the 69 participants . The parEzekowitz et al. (2003) , in anotA total of 30% out of 1,061 patients were found to have anemia (as Hb <13 g/dl in men and Hb <12 g/dl in women) in a study conducted by Horwich et al. (2002) . All theAnand et al.  and HorwEven though both studies conducted by Ezekowitz et al. and Horwich et al. used different classification criteria for the diagnosis of heart failure and anemia, both deduce higher one-year and five-year mortality rates among anemic heart failure patients as compared to their non-anemic counterparts thus establishing that anemia in heart failure patients is associated with poorer outcomes -40.Anemia has also been proposed as a marker for mortality in heart failure patients as evidenced by cohort studies conducted by Kosiborod et al. (2005)  and EzekPopulation data tableTable Diagnostic guidelines of anemia in heart failureAs per the current 2016 European Society of Cardiology (ESC) heart failure guidelines, class of recommendation I, and level of evidence C, the diagnostic investigations for newly diagnosed patients of heart failure should include the iron status, particularly the ferritin and transferrin saturation (TSAT) levels. The guidelines also recommend, although partially, the evaluation of iron levels in already diagnosed patients of HF, especially if they are symptomatic. Additionally, the guidelines also recommend the inclusion of iron status as part of the routine follow-up and post-discharge ,42.Serum ferritin and TSAT are markers for the quality and availability of stored iron and are valuable indicators of iron status . Serum fManagement of anemia in heart failure: a dilemmaAnemia in heart failure is associated with poor outcomes and mortality, as discussed earlier, making its correction a reasonable part in the management of the disease and improving its outcomes. A few modalities are available, although researches done in this area are limited and have shown conflicting results, these include the following 1. RBC TransfusionThe role of transfusion in the correction of hemoglobin levels in heart failure patients has been shown to only offer a temporary benefit with an additional risk of multiple adverse effects, making its usage limited and unsuitable for long-term management . 2. Iron SupplementationSince iron deficiency is a major cause of anemia in heart failure patients, management with iron supplements - oral (PO) and intravenous (IV) is worth looking into. Unfortunately, not many studies have been done in regards to the usage and benefits of oral iron therapy, mostly due to the reduced gastrointestinal absorption due to the high hepcidin levels seen in heart failure and its known gastrointestinal complications impacting its compliance .One of the most recent trials conducted to assess the efficacy of oral iron supplements in patients with heart failure suffering from iron deficiency anemia is the IRONOUT-HF Randomized Clinical Trial . The triThe use of intravenous (IV) iron is preferred over the use of oral iron due to its superiority as established by the IRON-HF study, a multicenter, investigator-initiated, randomized, double-blind, placebo-controlled trial . The triA double-blind, randomized, placebo-controlled study to evaluate changes in levels of NT-pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) levels in patients receiving IV iron therapy without recombinant human erythropoietin (rhEPO). All 40 One of the most recent trials conducted to understand the benefit of IV iron therapy in patients with heart failure is the AFFIRM-AHF study . This muHence, IV iron might be considered as a treatment modality for anemia in heart failure patients to improve the quality of life and functional capacity, with no change in mortality as recommended by the American College of Cardiology/American Heart Association in 2017 .3. Erythropoiesis-Stimulating Agents The use of erythropoiesis-stimulating agents (ESA), specifically recombinant human erythropoietin- epoetin-alfa and epoetin-beta and the analogue darbepoetin alfa, has been evidenced in improving anemia in chronic kidney disease and malignancies prompting exploration of their potential effects on the treatment of anemia due to heart failure .A meta-analysis comprising of 13 randomized clinical trials to assess the impact of ESA on the mortality and hospitalization in heart failure patients with anemia concluded that although ESA improved the NYHA class and quality of life, it had an insignificant effect on the mortality and hospitalization rate . Not to Another similar meta-analysis that included 11 studies comparing the ESA therapy with placebo found improved levels of hemoglobin, increased LVEF, a decrease in B-type natriuretic protein, and an improved NYHA class in the group receiving ESA . The metThe RED-HF  trial, conducted in 2013, was a randomized, double-blind trial evaluating the effects of darbepoetin alfa in patients with systolic heart failure and anemia in regard to the clinical outcomes . The triOne of the largest trials evaluating the effect of treating anemia in heart failure patients with darbepoetin alfa is the Study of Anemia in Heart Failure Trial (STAMINA-HeFT), a multicenter, randomized, double-blind, placebo-controlled trial published in 2008 . SimilarAs per the guidelines set by the American College of Cardiology/American Heart Association in 2017, ESA should not be used in patients with heart failure and anemia to improve morbidity and mortality .Anemia in heart failure patients is a significant finding and is related to poor outcomes and increased morbidity and mortality, as evidenced by the article. The aim of this article is to establish a link between the pathophysiology and the implications of anemia in patients suffering from heart failure along with a brief outlook on the treatment modalities for such patients.This article not only establishes the association of iron deficiency, chronic inflammation, erythropoietin levels, and the renin-angiotensin-aldosterone system with the development of anemia in heart failure patients but also sheds a light on the latest developments in the management, with the help of multiple evidence-based researches, of such patients. Intravenous iron supplementation was found to improve the quality of life and functional capacity, with no mortality benefit whereas studies revealed that the use of erythropoiesis-stimulating agents  in heart failure patients had little to no benefit in improving morbidity and mortality with the latest guidelines recommending against its use in these patients.We believe that this review article can provide valuable information regarding this complex topic. Furthermore, this article establishes the importance of screening and approach in the management of such patients keeping the NYHA class, hemoglobin levels and the clinical picture in mind. This review compiles the different diagnostic guidelines as per the latest recommendations by the European Society of Cardiology (ESC), 2016 and compiles the different researches in this field. Lastly, we believe further research in this complex yet important and clinically significant topic is necessary to provide a better understanding of the association between anemia and heart failure and a more systematic approach towards its diagnosis and management.


Left ventricular hypertrophy (LVH) is common among older adults. Amidst all causes, Fabry disease (FD) should be considered when LVH occurs with family history, specific clinical manifestations, or cardiac alert signs. Here, we report a case of a 76-year-old male who presented late onset concentric LVH with symptomatic high-grade atrioventricular (AV) block. After dual-chamber pacemaker implantation, interrogation revealed frequent right ventricular (RV) pacing with a wide QRS duration. The patient developed heart failure symptoms with rapid deterioration of LV systolic function. Pacing-induced cardiomyopathy (PICM) was suspected, and the pacemaker was upgraded to biventricular pacing. Further FD surveys were performed, including biochemical examinations, cardiac biopsies, and genetic sequencing, and the patient was ultimately diagnosed with a cardiac variant of FD. Particularly, we strongly suggest that physiologic pacing should be initially considered for patients with FD who have symptomatic high-grade AV block, rather than traditional RV pacing to prevent PICM. Left ventricular hypertrophy (LVH) is a common, but ominous, discovery in older adults that is associated with an increased risk of cardiovascular morbidity and mortality. Although hypertension, valvulopathies, and obesity elucidate most causes of LVH, it is crucial to consider other rare causes if unexplained LVH persists. Less common causes of LVH include numerous myocardial disorders, such as hypertrophic cardiomyopathy (HCM), infiltrative diseases, metabolic disorders, mitochondrial diseases, and some syndromic conditions ,2,3. AmiHerein we report a case of a 76-year-old male who was diagnosed as FD with symptomatic high-grade atrioventricular (AV) block. Furthermore, we have proposed an algorithm by which to evaluate patients with unexplained LVH, in order to support the diagnostic and therapeutic management of FD with high-grade AV block.In 2008, a 63-year-old male with no known underlying diseases was referred due to recurrent palpitation. A 12-lead electrocardiogram (ECG) showed sinus rhythm with ventricular pre-excitation A. SeekinFrom 2008 to 2015, the patient was repeatedly referred due to recurring unexplained palpitations and occasional retrosternal oppression. Holter monitor and TTE continued to have similar findings from his primary reports in 2008 . In 2016On the other hand, because of his constantly unexplained concentric LVH with intensified symptoms, extra investigations were launched. After excluding the common secondary causes of LVH, such as valvular heart diseases, systemic hypertension, and obesity, other rare diseases, including familial HCM, infiltrative diseases, and metabolic storage disorders, were under-differentiated. According to his clinical manifestations, ECG and TTE interpretations, FD was initially suspected. Accordingly, we began comprehensive FD survey . HoweverPRKAG2 syndrome), and mitochondrial diseases, should be thoroughly investigated. In the present case, the patient presented with late onset LVH, with symptomatic high-grade AV block and without extracardiac comorbidities, suggesting that HCM, cardiac amyloidosis, and FD were the most probable causes. Other rare diseases  usually develop at earlier ages and tend to present broad extracardiac features .,5,6.4,5,GLA pathogenic variants, but the effectiveness of this therapy is still debatable. Lastly, other novel treatments, including substrate reduction therapy, result in decreased Gb3 synthesis, which directly lower the cellular load. All gene therapy or mRNA-based therapy aims to restore the defective α-Gal A activity .,15.14,15activity . These nactivity .Symptomatic high-grade AV block should be treated following the current guidelines . After rIn FD patients receiving pacemakers, great concern exists about the adverse effect of non-physiological RV pacing with higher risk of developing PICM. From a pathophysiologic perspective, RV pacing contributes to fundamentally altered electrical pattern of ventricular activation. Disturbed electrical activation leads to impaired contraction and redistribution of myocardial strain . These eAll in all, this article focuses on two key concepts. First, physicians should keep FD in mind when noticing unexplained LVH in combination with specific cardiac alert signs. Earlier detection of the disease and initiation of FD-specific treatments leads to a superior prognosis. Secondly, we have raised a novel and important issue that physiologic pacing systems might play a crucial role in FD patients with AV block requiring pacing, especially in patients who already have impaired LV systolic function. Further, we have provided a comprehensive algorithm , based oOverall, this article focuses on two key concepts. First, physicians should keep FD in mind when noticing unexplained LVH in combination with specific cardiac alert signs. Earlier detection of the disease and initiation of FD-specific treatments leads to a superior prognosis. Second, we have raised a novel issue that physiologic pacing systems play a crucial role in patients with FD who have AV block requiring pacing, especially in patients who already have impaired LV systolic function. Furthermore, we provided a comprehensive algorithm , based o


Custodiol® and St. Thomas cardioplegia are widely employed in mini-thoracotomy mitral valve (MV) operations. One-dose of the former provides 3 h of myocardial protection. Conversely, St. Thomas solution is usually reinfused every 30 min and safety of single delivery is unknown. We aimed to compare single-shot St. Thomas versus Custodiol® cardioplegia.Primary endpoint of the prospective observational study was cardiac troponin T level at different post-operative time-points. Propensity-weighted treatment served to adjust for confounding factors.P = .01).Thirty-nine patients receiving St. Thomas were compared with 25 patients receiving Custodiol® cardioplegia; cross-clamping always exceeded 45 min. No differences were found in postoperative markers of myocardial injury. Ventricular fibrillation at the resumption of electric activity was more frequent following Custodiol® cardioplegia (Effective myocardial protection exceeding 1 h of ischemic arrest can be achieved with a single-dose St. Thomas cardioplegia in selected patients undergoing right mini-thoracotomy MV surgery. Adequate and safe myocardial protection is essential to achieve optimal results in cardiac surgery, regardless of the type of surgical procedure and the approach. Suboptimal myocardial protection during cardiopulmonary bypass is an independent predictor of perioperative adverse events, including myocardial infarction, ischemia–reperfusion injury, arrhythmias, and low cardiac output syndrome, which are associated with prolonged intensive care unit and hospital length of stay, and increased mortality .With respect to right mini-thoracotomy mitral valve (MV) surgery, the most adequate cardioplegic solution and delivery route have been widely debated. In the minimally invasive setting, the possibility to employ a single-dose cardioplegia is definitely appealing, allowing an uninterrupted operation and avoiding cumbersome and time-consuming repositioning of the atrial retractor to ensure proper delivery of the solution, and hazardous displacement of the endo-aortic clamp (EAC), when used.Both Custodiol® and St. Thomas 1 crystalloid cardioplegic solutions are currently used at our Institution in right mini-thoracotomy cardiac operations. A single dose of Custodiol® enables up to 3 h of safe cardioplegic arrest and it is consequently chosen in case prolonged aortic cross-clamping is anticipated, most commonly in case of complex MV repair –9. HowevThe aim of this study was to compare the efficacy and safety of myocardial protection provided by a single-dose administration of St. Thomas compared to Custodiol® solution in patients undergoing right mini-thoracotomy MV surgery.A single-institution, prospective observational study was performed on patients undergoing right mini-thoracotomy MV surgery and myocardial protection with a single dose of St. Thomas 1 or Custodiol® cardioplegic solutions. Patient enrollment was undertaken during a 5-year span between 2014 and 2018.Primary outcome was the evaluation of cardiac troponin T (cTn-T) levels measured at different time-points after surgery, i.e., immediately after weaning from cardiopulmonary bypass and 6, 12, and 24 h thereafter. Secondary outcomes were ventricular fibrillation as first rhythm after cross clamp release, the occurrence of post-operative myocardial infarction, postoperative creatinine kinase-myocardial band (CK-MB), creatinine kinase (CK), and lactate levels at the same time-points, the occurrence of low cardiac output syndrome, and the need for postoperative inotropic support.Patients undergoing MV surgery via right mini-thoracotomy were included in the study. Exclusion criteria were urgent or emergency surgery, left ventricular ejection fraction lower than 40%, more than mild aortic regurgitation, any history of coronary artery disease, and concomitant atrial fibrillation ablation. Associated procedures included tricuspid surgery and/or atrial septal defect closure. Reoperations were included except for prior coronary artery bypass grafting, irrespective of patent grafts. Patients requiring a second cross-clamping or who received a repeated administration of St. Thomas 1 cardioplegia for longer than expected ischemic times were also dropped out. The study protocol was reviewed and approved by the Institutional Ethics Committee .All patients were assessed with a preoperative electrocardiogram (ECG) and echocardiogram. After the surgical procedure, patients were investigated for ECG abnormalities and new-onset hypokinetic or akinetic segments at echocardiography.During the study period, minimally invasive mitral valve surgery was performed by 3 surgeons; the study was designed at the end of the learning curve of all of them.th percentile of the upper reference limit during the first 48 h with ECG abnormalities and/or angiographic or imaging evidence of new myocardial ischemia/new loss of myocardial viability [2 and systolic blood pressure lower than 90 mmHg, in conjunction with signs of tissue hypoperfusion  in the absence of hypovolemia [2. Vasoactive-inotropic score indicates the amount of cardiovascular support by various inotropes or vasopressors during the first 24 h after the surgical procedure. The score was calculated as follows: dopamine dose (μg/kg/min) + dobutamine dose (μg/kg/min) + 100 × epinephrine dose (μg/kg/min) + 10 × milrinone dose (μg/kg/min) + 10.000 × vasopressin dose (U/kg/min) + 100 × norepinephrine dose (μg/kg/min) [Postoperative myocardial infarction was defined as cTn-T value > 10 times the 99iability . Upper rovolemia . Inotrop/kg/min) . PostopeRight mini-thoracotomy approach with perfusion strategies and aortic clamping techniques used at our Institution have been previously described –19. All The choice of Custodiol® (25 ml/kg) or St. Thomas 1  cardioplegia for myocardial protection was dictated by the estimated complexity of the procedure, and thus of ischemic time, and on the surgeon’s preference. Custodiol® is primarily preferred in case of planned prolonged procedures, typically complex MV repair, because a single dose may enable up to 3 h of safe cardiac arrest before redosing; St. Thomas is usually preferred in case of planned less than 60-min procedures, such as MV replacement or simple MV repair.Both cardioplegic solutions were administered as a single dose, with no additional topical cooling, nor retrograde cardioplegia through the coronary sinus in any patient. In the Custodiol® group, hyponatremia was treated with a hemofilter on the cardiopulmonary bypass circuit, or prevented by direct aspiration of cardioplegia through a minimal right atrial incision and temporary bicaval snaring. All patients were systemically cooled to 30 °C. Clamp release was obtained at the end of appropriate air venting at a body temperature above 33 °C. All patients received 20 g of mannitol intravenously, after starting cardiopulmonary bypass and during rewarming, after reaching 33 °C or higher core temperatures.t or Wilcoxon-Mann–Whitney tests according to distribution type. Categorical variables were compared with the use of the chi-square test or Fisher exact test, as appropriate.Continuous data are presented as mean and standard deviation or median and interquartile range depending on data distribution, whereas categorical variables are presented as rate and proportion. In univariate analysis continuous variables were compared using unpaired A matched analysis using propensity score was performed to reduce possible differences between groups and obtain unbiased estimation of the treatment effect. The propensity score of receiving St. Thomas versus Custodiol® solution was estimated using multivariable logistic regression analysis with the type of solution as dependent variable. The a priori selected variables were as follows: age, gender, vasculopathy, Euroscore II, previous cardiac surgery procedures, ejection fraction, subtype of MV disease, and technique of aortic clamping. All variables were obtained before right mini-thoracotomy MV surgery. The genetic matching method without replacement was used to match patients treated with St. Thomas and Custodiol® solution . Geneticp values of 0.05 or less were considered statistically significant. Stata , R Package “MatchIt” , and SAS  software packages were used for computations.To examine the temporal effect across groups, St. Thomas solution versus Custodiol® solution during the 24-h observation period after surgery, a mixed-linear regression model for repeated measures was applied. All statistical tests were two-sided and p = 0.01). Aortic cross-clamp time exceeded 45 min in all patients, and was less than 60 min in only eight. Median cross-clamp times were 73 min  in the St. Thomas group and 80 min  in the Custodiol® group. Finally, no differences were found in the release of myocardial markers, lactate levels, and vasoactive-inotropic score at different time-points after surgery (Table During the study period, 566 patients underwent right mini-thoracotomy MV surgery at our Institution. One-hundred eighty-seven patients met the inclusion criteria for the study, with 39 and 148 patients receiving St. Thomas 1 or Custodiol® solution, respectively. Before matching, groups were not comparable with respect to age, gender, baseline creatinine, peripheral vascular disease, atrial fibrillation, EuroSCORE II, previous cardiac surgery and ejection fraction Table . No caseOur approach for right mini-thoracotomy cardiac surgery has been standardized over the last 15 years in more than 1500 cases with the use of St. Thomas type 1 or Custodiol® crystalloid solutions for myocardial protection. The type of cardioplegia is chosen according to the anticipated duration of the procedure and to the surgeon’s preference. In comparison with other cardioplegic strategies, St. Thomas or Custodiol® cardioplegia may allow the avoidance of multiple doses administration, which intrinsically necessitates repetitive repositioning of the heart and left atrial retractor for adequate cardioplegia delivery. These maneuvers are particularly tedious and time-consuming in the minimally invasive setting, and may ultimately favor the deleterious consequences of prolonged myocardial ischemia. Moreover, they can cause dislodgment of the EAC, when used, increasing the risk of myocardial suboptimal perfusion.Several studies comparing different types of cardioplegia have been reported with controversial results –25. A reOn the counterpart, other studies comparing crystalloid and cold blood cardioplegic solutions in patients undergoing right mini-thoracotomy MV operations highlighted equivalent or even better outcomes in the former in terms of mortality, myocardial injury enzyme release, arrhythmias, and early complications , 27–30. In the minimally invasive setting, a single-shot, long-lasting dose of crystalloid cardioplegia is definitely straightforward and less time-consuming; therefore, crystalloid solutions are largely preferred. Custodiol® is primarily preferred in case of planned prolonged procedures, typically complex MV repair, because a single dose may enable up to 3 h of safe cardiac arrest before redosing. However, concerns have been raised regarding the adequate myocardial protection of the Custodiol® cardioplegia when compared to other crystalloid solutions , 31. On Only few data exist in the literature regarding a direct comparison between Custodiol® and St. Thomas cardioplegia. In a recent study focused on minimally invasive MV operations, the St. Thomas solution was associated with lower postoperative cTn-T peak levels . InteresIn contrast, others have reported superior results with Custodiol® compared to repeated-dose St. Thomas 2 cardioplegia , 34. In The only significant difference recorded was a higher rate of ventricular fibrillation as first rhythm after aortic clamp release in the Custodiol® group, in analogy to previous reports which demonstrated how the Custodiol® solution may trigger ventricular fibrillation during myocardial reperfusion even when not associated with high postoperative troponin levels , 8, 24.Speculatively, the procaine contained in the St. Thomas 1 solution might have a protective role in this respect, especially if the aorta is unclamped during rewarming in near-normothermic conditions.St. Thomas solution administrated in one dose should be prefer in cases in which the ischemic time is planned to be shorter than 1 h; it allows the surgeon to maintain the benefits of a single dose crystalloid cardioplegia and allows to avoid the risk of hyponatremia and acidosis related to the Custodiol® solution, and to avoid the need for caval snaring and right atrium incision for the drainage of the solution. Our experience shows that both type of cardioplegia should be part of an effective program of minimally invasive MV surgery and the choice of the type of cardioplegia to deliver should be adapt on the surgical procedure.Main limitations of this study are the single-center observational design and the relatively small sample size. Moreover, no data regarding more sensitive tools to asses left ventricular function, such as echocardiography-based speckle-tracking strain imaging, are reported.Custodiol® and St. Thomas cardioplegic solutions are largely employed for myocardial protection during minimally invasive cardiac surgery: both allow surgeons to minimize the need for repeated dosing maintaining optimal exposure of the surgical field throughout the procedure and are congruent with the EAC setting where a blood cardioplegic solution may significantly impact the delivery line resistances and the balloon positioning. Effective myocardial protection exceeding 1 h of ischemic arrest can be achieved with a single-dose St. Thomas 1 solution. Results are comparable to Custodiol® solution in selected patients undergoing right mini-thoracotomy MV surgery.


Cross-sectional studies have reported that ventricular dilation and dysfunction are associated with adverse clinical outcome in Fontan patients; however, longitudinal changes and their relationship with outcome are not known.i), mass-to-volume ratio, and end-systolic wall stress (ESWS) were used to estimate within-patient change over time. Changes were compared for those with and without a composite outcome  as well as between patients with left (LV) and right ventricular (RV) dominance.This was a single-center retrospective analysis of Fontan patients with at least 2 cardiovascular magnetic resonance (CMR) scans without intervening interventions. Serial measures of end-diastolic volume index (EDVI), end-systolic volume index (ESVI), ejection fraction (EF), indexed mass (mass1.3/year). Compared with LV dominance, RV dominance was associated with a greater increase in ESVI (1.4 vs. 0.5 ml/BSA1.3/year), a greater decrease in EF (− 0.61%/year vs. − 0.24%/year), and a higher rate of the composite outcome (21% vs. 8%).Data from 156 patients were analyzed with a mean age at 1st CMR of 17.8 ± 9.6 years. 490 CMRs were included with median of 3 CMRs/patient (range 2–9). On regression analysis with mixed effects models, volumes and ESWS increased, while mass, mass-to-volume ratio, and EF decreased over time. With a median follow-up of 10.2 years, 14% met the composite outcome. Those with the composite outcome had a greater increase in EDVI compared to those without (4.7 vs. 0.8 ml/BSA1.3/year) may be at a higher risk of adverse outcomes and may benefit from closer surveillance. RV dominance is associated with worse clinical outcomes and remodeling compared to LV dominance.Ventricles in the Fontan circulation exhibit a steady decline in performance with an increase in EDVI, ESVI, and ESWS, and decrease in EF, mass index, and mass-to-volume ratio. Those with death or need for heart transplantation have a faster increase in EDVI. Patients with rapid increase in EDVI (> 5 ml/BSAThe online version contains supplementary material available at 10.1186/s12968-022-00884-y. Originally performed in the late 1960s, the Fontan operation provides a pathway to survival for children with single ventricle heart defects . In the The aim of current study was to analyze serial CMRs without interim interventions from a single large-volume center to characterize changes in ventricular size and function over time. The study hypothesized that significant temporal trends will exist in ventricular parameters and that the rate of change of these parameters will be associated with death or need for heart transplantation.This was a single-center retrospective analysis of all patients who had undergone a Fontan operation and had at least 2 CMR examinations without catheter-based or surgical cardiac interventions between the first and last CMR. Studies in which ventricular volumes could not be reliably measured due to artifact were excluded. Demographic and clinical data were abstracted from medical records. The study’s composite outcome was defined as death from any cause, heart transplantation, or listing for heart transplantation.1.3 [CMR examinations were performed on 1.5 T CMR scanners . Details of the study protocol in our lab have been previously published . Ventric1.3 . Ventric1.3 . The degDescriptive statistics are presented as mean ± standard deviation (SD) for continuous variables except when indicated. Categorical data are described as frequency with percentage. Where mean comparisons among independent groups are presented, a Student’s t-test or ANOVA was performed, and for comparisons of categorical variables, a Fisher exact test was performed. To evaluate whether percentage change in CMR parameters differed from zero, a one sample t-test was used. Longitudinal changes in CMR parameters were estimated using two methods. First as an annualized change per individual patient defined as (last study − first study)/number of years between the studies, and second by using a mixed effects model  to assess rates of change ± standard error (SE) over time in the overall cohort. No CMRs obtained after the occurrence of listing for transplant were included in analyses. Rates of changes in CMR parameters were compared between those with and without the composite outcome using a test of interaction. Comparisons were also performed between patients with LV and RV dominant anatomy, regardless of clinical outcome. A p-value < 0.05 was defined as statistically significant. Interobserver reliability was assessed for ventricular volumes by using a two-way mixed effects model to estimate the intraclass correlation coefficient (ICC), percent error, and coefficient of variability, and is visually depicted in the form of Bland–Altman plots. Analyses were performed using SAS  including SAS Proc Mixed, and R .Analysis included 156 Fontan patients and a total of 490 CMRs. Median date of CMR was 4/11/2010 . The median number of CMRs per patient was 3 (range 2–9). The mean age at the first CMR was 17.8 ± 9.6 years, median follow-up time after the first CMR was 10.2 years (IQR 6.1–14.5 years), and median follow-up time after the last CMR was 3.8 (IQR 2.5–6.5 years). The median time between 2 CMRs was 5 years (IQR 2.3–8.7 years). Median number of CMRs in patients with the composite outcome was 3 (IQR 2–3) compared to 2  in those without the outcome. The primary underlying cardiac diagnosis was tricuspid atresia in 21%, hypoplastic left heart syndrome in 20%, double inlet LV in 19%, double outlet RV in 12%, unbalanced common atrioventricular canal defect in 9%, small right heart structures including pulmonary atresia with intact ventricular septum in 8%, and other rare forms of functional single ventricles in the remainder. Ventricular dominance was LV in 53% and RV in 47%. 135 (87%) ventricles were D looped, 17 (11%) were L lopped, and 4 were classified as unknown.1.3 and annual decrease in mass index was higher at 1.70 g/BSA1.3. More than mild AVVR was present on the initial CMR in 14% of the cohort and more than mild semilunar valve regurgitation in 3%. Their presence was not associated with longitudinal changes in CMR variables although the analysis may have been underpowered due to small sample size  as compared to those with . Table 1.3 per year and EF (%) decreased by about 0.4 per year. Ventricular mass and mass-to-volume ratio decreased over time while ESWS increased. Those with the composite outcome of death, heart transplantation, or transplant listing demonstrated faster increase in EDVI. Patients with RV dominant hearts fared worse with faster decline in ventricular function and a higher rate of composite outcome.This study demonstrated a progressive decline in CMR-derived measurements of ventricular performance in a cohort of older children and young adults with a Fontan circulation. In particular, EDVI increased by about 1 ml/BSA1.3 per year compared to 0.8 ml/BSA1.3 in those without the outcome. Ventricular dilation may be attributable to several factors including volume loading lesions such as valvular regurgitation and aortopulmonary collaterals, as well as remodeling related to primary myocardial injury and dysfunction [Longitudinal studies using transthoracic echocardiography have shown progressive ventricular dilation and dysfunction after the Fontan operation; however, the clinical importance of these changes are not well known –19. Priofunction , 21. In 1.3/year compared to 0.5 ml/BSA1.3/year in LV dominant ventricles as well as a faster decline in EF (%) of 0.61/year compared to 0.24/year in the LV group. RV dominance was associated with a higher rate of composite outcome (21%) compared to LV (8%) a finding similar to a prior analysis of an overlapping cohort from our institution [Patients with RV dominant functional single ventricles performed worse compared to those with LV dominance in the current study. This is not surprising as an LV would be expected to perform and remodel better as a functional single ventricle as compared to an RV which has evolved to support a low-pressure and low-resistance pulmonary circulation. More longitudinal myofiber orientation in the RV is also mechanically disadvantageous for pressure generation . RV domititution . The undThe generalizability of these findings to the entire Fontan population may be limited due to a number of reasons. This is a CMR-based study and patients with pacemakers and implanted defibrillators were excluded. Only patients who had CMR studies without interim catheter or surgical interventions were included; hence, potentially sicker patients may have been excluded. The models used assumed linear changes over time; other patterns of change may be present. Associations of outcome with wall stress may differ if an alternative method of wall stress calculation were used. Effect of potential contributors to ventricular size such as aortopulmonary collateral flow, fenestrations or baffle leaks, venous collaterals, and LGE could not be evaluated in this study due to incomplete data on several initial CMRs. Despite these limitations, the study provides important overview of the trends in ventricular size and function in this population and insight into differences between LV and RV dominant hearts.1.3/year) may be at a higher risk of adverse outcomes and may benefit from closer surveillance. Patients with dominant RVs are more likely to have the composite outcome and exhibit worse remodeling compared to dominant LVs.Over a median follow-up period of 10 years, single ventricles in the Fontan circulation exhibited a steady decline in performance with an increase in EDVI, ESVI, and ESWS, and a decrease in EF, mass index, and mass-to-volume ratio. Patients with the composite outcome of death, heart transplantation, or transplant listing showed a faster increase in ventricular EDVI. Patients with rapid increase in EDVI (> 5 ml/BSAAdditional file 1. Supplementary tables to support results.


There was no difference in the diastolic and systolic functions according to myocardial thickness; however, 2D STE showed a negative correlation with the LV mass . Given that patients with GSD tend to be overweight, serial evaluation with echocardiography might be required for all types of GSD.Glycogen storage disease (GSD) is a hereditary metabolic disorder caused by enzyme deficiency resulting in glycogen accumulation in the liver, muscle, heart, or kidney. GSD types II, III, IV, and IX are associated with cardiac involvement. However, cardiac manifestation in other GSD types is unclear. This study aimed to describe whether energy deprivation and the toxic effects of accumulated glycogen affect the heart of patients with GSD. We evaluated the left ventricle (LV) wall mass, LV systolic and diastolic function and myocardial strain with conventional echocardiography and two-dimensional speckle-tracking echocardiography (2D STE) in 62 patients with GSD type I, III, VI and IX who visited the Wonju Severance Hospital in 2021. Among the GSD patients, the echocardiographic parameters of 55 pediatrics were converted into z-scores and analyzed. Of the patients, 43 (62.3%), 7 (11.3%) and 12 (19.4%) patients were diagnosed with GSD type I, type III, and type IX, respectively. The median age was 9 years , with 55 children under 18 years old and seven adults over 18 years. For the 55 pediatric patients, the echocardiographic parameters were converted into a z-score and analyzed. Multiple linear regression analysis showed that the BMI z-score ( Glycogen storage disease (GSD) consists of inherited inborn errors of metabolism caused by mutations in genes encoding enzymes involved in glucose metabolism . GSD is The metabolic diseases, such as diabetes mellitus and obesity, can cause functional or structural myocardial disease via metabolic derangement ,12. HypeThis was a single-center retrospective cohort study. The study comprised 64 patients diagnosed with GSD using next generation sequencing and liver biopsy, who visited the Wonju Severance Hospital between March 2021 and April 2022. Patients were grouped by GSD type, and two patients (one with GSD type VI and one with an unknown type) were excluded as they could not be compared. The patient’s GSD type, age, height, weight, sex, and laboratory findings were recorded at the time of echocardiographic assessments. Body mass index (BMI) was calculated as weight (kilograms) divided by height (meters) squared, and then for children under the age of 18 years, the BMI z-score was calculated using the Centers for Disease Control and Prevention (CDC) growth charts. According to CDC criteria a z-score ≥ 1.45 (85 percentile) was defined as overweight, and a z-score ≥ 2 was defined as obesity.A single experienced pediatric echocardiographer performed transthoracic echocardiography using a Philips EPIQ 5c system . Myocardial mass and left ventricle (LV) systolic function were measured using the M-mode at short axis view. Doppler signal quality was enhanced by lowering the Nyquist limit to 10–30 cm/s, using the lowest wall filter setting with minimal optimal gain, decreasing Doppler sample volume size to 5 mm, and optimizing the sweep speed to at least 100 mm/s.2 and 43–95 g/m2, respectively [LV mass was calculated using the LV wall thickness and the LV cavity diameter measured during end diastole. For optimal LV mass indexing, according to previous studies, younger children aged < 8 years and children and adolescents aged <19 years were indexed by dividing the LV mass by height (meters) increased to a power of 2.0 and 2.7, respectively. Adults aged >19 years were indexed by dividing the LV mass by body surface area (BSA) ,15,16. Tectively . The LV ectively ,19. The The echocardiographic evaluation is confounded by the effect of age, body weight, and height. All echocardiographic parameters, which have different normal reference values according to age, were converted into z-scores and analyzed for comparison. The BSA-adjusted z-score described by Dallaire et al. was used for left-sided pulse-wave Doppler and tissue Doppler imaging . The RV p < 0.05.In pediatric patients, the echocardiographic parameters were compared with the z-sore adjusted for age, weight, and height, and seven adult patients were excluded from the analysis. All statistical analyses were conducted using the Statistical Package for the Social Sciences, version 25.0 . For continuous variables, medians with interquartile ranges (IQRs) were calculated and compared using analysis of variance. (ANOVA) was used to analyze the difference between the three groups, and post-hoc Bonferroni analysis was used for subsequent analysis. Pearson’s correlation for parametric data was used to assess the relationship between the BMI z-score, LV mass, heart function, and laboratory findings. Significant variables were further analyzed using the stepwise methods of multiple linear regression analysis to isolate predictors of an increase in LV mass. All tests were two tailed, and statistical significance was set at Sixty-four patients with GSD visited our institution during the study period. One patient with GSD type VI and another one with GSD of unknown type were excluded from the analysis. Thus, 62 patients were included in the study. The clinical and demographic characteristics of the patients are listed in p =0.037), interventricular septum diameter (IVSd) z-score (p < 0.001), and LV posterior wall thickness diameter (LVPWd) z-score (p < 0.001) were relatively high in the patients with GSD type III. In this study, most of the pediatric patients had normal LV mass z-scores, except for two patients (GSD types I and III) with an LV mass z-score >2. One patient with a normal LV mass z-score had an IVSD z-score of >2 and had GSD type I. Analysis of diastolic and systolic function showed no significant differences between the GSD types. Four patients had an E/A z-score less than −2 and 15 had an E/e’ z-score greater than 2 , HDL (p = 0.036) and CK (p = 0.005) correlated with the LV mass z-score in children (p = 0.022) and CK (p = 0.020) predicted an increased LV mass z-score, regardless of GSD type  was slightly increased without obesity, and his E/A ratio (0.78) was revered. EF was preserved, but the average GLS showed a relatively low value of −17.5% (2) was increased above the normal range with a BMI of 19.3. In addition, she showed diastolic dysfunction indicated by E/A (2.34) and E/e’ (8.73). RV function, EF, FS, and strain remained within normal ranges. In laboratory findings, AST and ALT were slightly increased.f −17.5% . The labThe heart has complex metabolic processes to use energy to maintain its function. If this metabolic process is disrupted, heart function or structure is affected. The exact mechanisms of cardiac manifestations are currently unknown; however, they seem to correlate with the accumulation of by-products, toxic effects, and lack of energy ,23,24,25In this study, 62 patients were examined, including children and adults. Pediatric patients (age < 18 years) accounted for 76% of all patients, and there was a greater number of male (62%) than female patients. These findings were similar to the results of the GSD prevalence study based on the Health Insurance Review and Assessment Servis (HIRA) research in Korea . It was In the analysis comparing echocardiography parameters of cardiac function including tissue Doppler, EF and FS did not differ with GSD type. As previously reported, type III showed a tendency of thicker myocardium compared to that in patients with other GSD types. However, two patients with GSD type I, including one child and one adult, showed increased LV mass above the normal range. This suggests that, besides the characteristics of the GSD type, there may be other factors that affect the heart. These patients showed hyperuricemia, lactic acidosis, dyslipidemia, and increased AST and ALT due to poor metabolic control.The LV mass index z-score was independent of age, gender, and laboratory findings, except for CK. In our study, the BMI z-score and CK showed a significant association with LV hypertrophy in GSD. As the age-adjusted BMI increased, the LV mass and LV wall thickness also increased. This finding was similar to those of previous studies that showed an association between obesity and LV hypertrophy in the general population . Patientp = 0.038), and a higher TG was associated with a higher E/e’ z-score . Considering that the proportion of patients aged less than 10 years was higher in our study than in other studies that evaluated diastolic function in children with obesity, serial echocardiography evaluation is necessary for assessing functional changes in the heart as these pediatric patients mature. As a measurement to evaluate systolic function, EF and FS were maintained within normal ranges and were not related to myocardial thickness. However, the strain z-score decreased as the LV mass increased. In general, EF is useful for more easily evaluating LV systolic function but has limitations in predicting functional capacity and prognosis [In children, although there were patients with LV mass index z-scores above the normal range, systolic and diastolic heart function remained in the normal range. There was no difference in LV function according to LV mass change, which is inconsistent with the findings of previous studies suggesting a decrease in LV diastolic function associated with LV hypertrophy in children with obesity in the general population ,29. Thisrognosis ,33. 2D Srognosis ,35,36. OAmong adults, there were two patients with LV diastolic dysfunction and a slight increase in LV mass index. Neither of them had any symptoms or cardiovascular disease, including hypertension. The single male adult patient with GSD type I showed diastolic dysfunction and reduced strain despite a relatively young age of 25 years. His disorder had not been properly managed for a long time, and it is possible that he had cardiac injury due to metabolic abnormality. This suggests that echocardiography is needed to evaluate cardiac involvement in all types of GSD, not only in the types already known to be associated with cardiac involvement.Numerous studies have evaluated cardiac function in GSD types II and III. However, to our knowledge, this is the first study to use standard echocardiography and 2D STE in patients with GSD types I, III, and IX. Our study is meaningful in that it assessed the cardiac evaluation of a relatively large number (n = 64) of patients with GSD in a single center in Korea. It is already known that cardiomyopathy occurs due to cardiac deposition of glycogen in some GSD types. In this study, there was no significant myocardial injury in patients with GSD according to laboratory findings and increased BMI. However, our study showed subclinical functional change in the heart according to myocardial thickness with 2D STE or hypertrophy and GSD type. The associations between BMI and E/A and TG level and E/e’ in our results suggest the need for further research and follow-up on functional changes using echocardiography in patients with GSD, especially those who are overweight. LV diastolic dysfunction could precede LV systolic dysfunction and is known as a contributor to mortality from cardiovascular disease in people with obesity. GLS could also be an early marker for LV dysfunction. Regular screening with echocardiography, including wall thickness measurement and diastolic functional evaluation, and 2D STE allows for the early diagnosis of subclinical heart changes in patients with GSD.This study had some limitations. First, there was no healthy control group. The study could not establish whether there are differences in heart structure and functional changes in patients with GSD compared with those in the general population. Second, there may have been selection bias due to the differences in the number of patients between types. Third, a one-off blood test has limitations in representing a patient’s previous metabolic status. However, the study is meaningful in that overall echocardiography was performed on a large number of patients with GSD, including GSD type I, and subtle cardiac structure changes in subclinical states were measured through 2D STE.There is still no specific curative treatment for GSD. The management of GSD varies with GSD type, and lifelong management is required to control symptoms or avoid possible complications, such as liver failure and cardiomyopathy. Since metabolic disease is often related to heart dysfunction and structural change, our results showed the effects of metabolic aberration on the hearts of patients with GSD. In our study, metabolic abnormalities, such as hyperuricemia, lactic acidosis, and dyslipidemia, caused by GSD did not have a significant effect on the function of the heart structure; however, there was a significant change in myocardial thickness with weight gain. Given that patients with GSD tend to be overweight or obese, steady cardiac evaluation through echocardiography is required for all types of GSD patients, including types not known to be associated cardiac involvement. Not only the evaluation of myocardial thickness, but also the evaluation of diastolic function and 2D STE will enable early detection of subclinical cardiac dysfunction. Future studies with a larger number of adult patients will be able to observe the long-term effects of metabolic abnormalities on the heart of patients with GSD. In addition, it is necessary to find out whether diet, optimal metabolic control, and exercise management in patients with GSD have a positive effect on changes in cardiac structure and function through follow-up echocardiography.


Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease with potential cardiovascular involvement. Layer-specific strain (LSS) analysis is a new method that allows early detection of subtle left ventricular (LV) systolic dysfunction. The aim of this study was to evaluate LV systolic function in patients with SLE using conventional echocardiographic measurements and longitudinal strain (LS) and circumferential strain (CS) by LSS. Furthermore, the association between echocardiographic parameters and the occurrence of cardiovascular events was assessed.A total of 162 patients with SLE (the SLE group) who underwent a dedicated multidisciplinary assessment, including echocardiography, were analyzed at the time of their first visits. The control group consisted of 68 age- and sex-matched healthy subjects. LS and CS on endocardial, mid-myocardial, and epicardial layers at 17 cardiac segments were measured. Transmural strain gradient was calculated as the differences in systolic strain between the endocardial and epicardial layers.P < 0.05); LV LS and CS gradient were all lower than control subjects (P < 0.05). During a median follow-up period of 83 months (interquartile range: 64–95 months), 59 patients (36.4%) developed cardiovascular events. Using multivariate Cox regression analysis, we found that LV endocardial LS  and CS  demonstrated independent associations with cardiovascular events; whereas LV ejection fraction was not significantly associated with cardiovascular events. The Kaplan–Meier survival curves showed that patients with SLE with lower LV endocardial LS and CS  experienced higher cumulative rates of cardiovascular events compared with those with higher LV endocardial LS and CS.Compared with control subjects, patients with SLE had significantly lower LV ejection fraction, LS, and CS values in all layers (In patients with SLE, LV systolic function measured by LV endocardial LS and CS were significantly lower than that of the control group and were associated with cardiovascular events, potentially representing a new technology to improve risk stratification in these patients Systemic lupus erythematosus (SLE), which usually occurs in young females, is associated with high cardiovascular morbidity and mortality , 2. Cardechocardiography is currently proposed as a more sensitive approach to detecting subclinical myocardial dysfunction than conventional echocardiography parameters such as left ventricular ejection fraction (LVEF) and fractional shorting . Using tPatients were consecutively recruited from the Department of Rheumatology at the Affiliated Hospital of Hangzhou Normal University for an extensive multidisciplinary from January 2010 and October 2020 and underwent echocardiographic analysis. All patients fulfilled the 2012 American College of Rheumatology (ACR)/Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE [The control group consisted of 68 age- and sex-matched healthy subjects who were identified from the echocardiography database with normal heart structure. The study was approved by the institutional ethics committee.Demographic and clinical data, including age, sex, height, weight, heart rate, systolic and diastolic blood pressures, SLE characteristics, duration of SLE, comorbidities, and CVD-related risk factors such as smoking, hypertension, diabetes mellitus, dyslipidemia, obesity, and a family history of premature coronary artery disease, were recorded. Specific disease-related characteristics at baseline echocardiographic examination were also reported, including SLE disease activity index 2000 (SLEDAI-2000), positive antinuclear antibody, anti-double-stranded deoxyribonucleic acid, extractable nuclear antigen, antiphospholipid antibodies, reduced creatinine clearance, and elevated C-reactive protein. Patients were followed from the baseline examination of CVD, which was defined as coronary artery disease requiring revascularization, cerebrovascular accident, hospitalization for heart failure, pulmonary embolism, aortic aneurysm and dissection, and development of sustained ventricular or supraventricular arrhythmias. The time till cardiovascular events was calculated from the date of the baseline echocardiographic examination.2, and peak tricuspid regurgitation velocity > 2.8 m/sec [Comprehensive transthoracic echocardiography was performed using an IE33 or Epiq 7C  ultrasound system. Examinations were performed with subjects in the left lateral recumbent position. Using the modified biplane Simpson’s formula, LVEF was calculated from measurements of end-diastolic volume (EDV), end-systolic volume (ESV), and stroke volume (SV). Interventricular septum diastolic (IVSd), LV end-diastolic diameter (LVEDd), and posterior wall thickness (PW) were measured from the parasternal long axis using 2D imaging. Relative diastolic wall thickness (RWT) was calculated as the ratio between the sum of IVSd and PW and the LVEDd. LV mass (LVM) was calculated using the formula described by Lang et al. . Left at.8 m/sec . Systoli.8 m/sec .After a standard echocardiographic study, the apical long-axis, four- and two-chamber views, and the basal, middle, and apical short-axis planes were scanned using a high frame rate (at least 50 frames/sec) in routine grayscale B-mode for speckle-tracking imaging. These images were stored digitally. All images were obtained while the subjects held their breaths and were stored in a cine loop format for four consecutive beats. The software automatically tracked the myocardial motion during the cardiac cycle. Myocardial tracking echocardiographic was performed using a Qlab multiparameter analysis workstation . The apical long-axis, four-, and two-chamber heart images were analyzed to obtain the peak endocardial, mid-myocardial, and epicardial LS of 17 segments and their corresponding curves, the bull’s eye diagram. The basal, middle, and apical short-axis dynamic images of the LV were traced and used to calculate the LV three-layer CS  with 95% confidence interval (CI) are presented. Receiver operating characteristic (ROC) curve analysis was also performed to predict cardiovascular events in patients with SLE. The Kaplan–Meier survival method was used to analyze the cumulative event rates between two groups of patients divided by the cutoff values of LV three-layer LS and CS. Inter- and intra-observer reproducibility was assessed using intraclass correlation coefficients (ICC). All statistical analyses were 2-tailed; P < 0.05 was considered to indicate a statistical significance.Statistical analyses were performed using SPSS, version 22.0 . Continuous variables are described by mean ± standard deviation for normally distributed variables, and median with interquartile range for non-normally distributed variables, between two groups were compared using P < 0.05). Mild disease activity was found in 38.2% (n = 62) of patients with SLE, while 34.0% (n = 55) had moderate disease activity, and 27.8% (n = 45) had high disease activity. The prevalence of comorbidities for patients with SLE were: 30.2% (n = 49) had hypertension, 22.8% (n = 37) had hypercholesterolemia, 4.3% (n = 7) had diabetes mellitus, and 7.4% (n = 12) had a family history of premature coronary artery disease. Antiphospholipid antibodies were observed in 28 patients (17.3%) and anti-double-stranded deoxyribonucleic acid in 68 patients (42.0%).A total of 168 patients with SLE and 68 healthy subjects were initially included in this study, but six patients with SLE were later excluded because of poor endocardial definition. Clinical characteristics of the overall population are presented in Tables P = 0.007), whereas IVSd, LVEDd, PW, EDV, ESV, SV, RWT, and LVM in patients with SLE were significantly higher than that of healthy control subjects. The LV diastolic function, E, e’, and E/e’ were significantly lower in patients compared with healthy controls, and sPAP was significantly higher in patients with SLE, but the prevalence of LV diastolic dysfunction was only seven patients (4.3%) in the overall population. In addition, the LV LS and CS of different myocardial layers in patients with SLE and healthy controls are shown in Table P < 0.001; LS gradient: -3.4 ± 0.9 vs. -4.5 ± 1.0, P < 0.001; endocardial CS: -29.7 ± 3.7 vs. -33.1 ± 3.1, P < 0.001; CS gradient: -17.3 ± 1.1 vs. -18.5 ± 1.1, P < 0.001).Baseline echocardiographic characteristics of the overall population are presented in Table tients 4.% in the tients 4.% in the P < 0.001), as did age , systolic blood pressure , SLEDAI-2000 score , sPAP , and endocardial LS . On the contrary, positive antiphospholipid antibodies, IVSd, LVEF, LVM, LS gradient, and LS gradient were not significantly associated with cardiovascular events. In multivariate Cox regression analysis, factors were chosen on the basis of their significance in univariate analysis; in addition to those, the following additional factors were included in the model: age, systolic blood pressure, SLEDAI-2000 score, sPAP, and LV endocardial LS and CS. In this model LV endocardial LS and endocardial CS  were independent association with cardiovascular events.During a median follow-up period of 83 months , 59 patients (36.4%) developed cardiovascular events. The cardiovascular events included 17 (10.5%) coronary artery diseases requiring revascularization, 14 (8.6%) cerebrovascular accidents, nine (5.5%) hospitalization for heart failure, six (3.7%) pulmonary embolism, four (2.4%) aortic aneurysm and dissection, and nine (5.5%) development of sustained ventricular or supraventricular arrhythmias. Cox proportional HR analysis revealed few statistically significant associations between clinical and echocardiographic data of patients with SLE and the risk of cardiovascular events ; meanwhile, patients with lower LV endocardial CS had higher cumulative rates of cardiovascular events compared to patients with an absolute higher value of endocardial CS ≥ 29.0% LV systolic function in patients with SLE was significantly lower compared to healthy control subjects on routine echocardiography and LSS technology; (2) in these patients, LV endocardial LS and CS were independently associated with the occurrence of cardiovascular events, whereas conventional echocardiographic parameters of LV structure and systolic function were not.SLE is one of the strongest risk factors for CVD , 2, whicPatients with SLE have up to a 10- fold risk of cardiovascular morbidity and mortality compared to the general population, and cardiac involvement still accounts for most of the deaths . PreviouIn this study, conventional echocardiographic and LSS technique parameters such as sPAP, LV endocardial LS, and endocardial CS were significantly associated with cardiovascular events in univariate analysis, while mid-myocardial and epicardial strains and transmural strain gradient were not significantly associated with outcome. Only LV endocardial LS and CS were significantly associated with cardiovascular events in multivariate analysis. In addition, the results of ROC analysis revealed the statistical significance of LSS technique parameters in the prediction of cardiovascular events. LV endocardial LS and CS were more powerful and had better predictive power; LV endocardial CS had the highest HR and the most prominent areas under the curves. Therefore, LV endocardial strains may be able to reflect not only subclinical myocardial involvement at an early stage but also an overall increase in risk for cardiovascular events in patients with SLE. Even when LV systolic function seems normal under conventional echocardiographic parameters, micro- and macrovascular abnormalities might affect LV endocardial strains and can lead to cardiovascular events. Recently, the association of subclinical LV myocardial dysfunction by layer-specific LS could better predict significant stenosis in the coronary artery supplying the surrounding territory in patients with suspected stable angina pectoralis and normal LV wall motion . In a loLV endocardial LS and CS could be considered as a new tool to diagnose subclinical (primary) myocardial involvement and to optimize individual patient management and risk stratification.There are some limitations to this study that should be acknowledged. In this study, we enrolled SLE patients with CVD-related risk factors ; therefore, the results cannot be applied to an SLE population without CVD-related risk factors. We could not exclude the possibility that pulmonary hypertension contributes to impaired LV myocardial function in patients with SLE. Further study should be conducted to include a larger cohort of patients in a multicenter setting to clarify these results.To the best of our knowledge, this is the first study to explore the association between LSS technique parameters and the development of cardiovascular events in patients with SLE. LV systolic function is significantly lower than healthy control subjects on routine echocardiography and LSS technology. The LV endocardial LS and CS have better than the other two layers strain predictive value for cardiovascular events, which indicates especial endocardial is crucial for clinical management and may significantly improve risk stratification in the early evaluation of early evaluation myocardial involvement for patients with SLE.


In subgroup analysis, the HTN-DM group showed a significantly higher ECV (0.260 ± 0.023) than the control  and HTN  groups. Overall postT1 and ECV of the LV had significant correlation with eGFR . Septal segments show higher preT1 and ECV but lower postT1 than lateral segments at the mid-ventricular and basal levels. ECV is significantly affected by HTN, DM, and eGFR, even in asymptomatic subjects.To evaluate variations in pre-contrast (preT1) and post-contrast (postT1) myocardial T1 values and extracellular volume fraction (ECV) according to left ventricular (LV) segments and to find correlations between them and cardiovascular risk factors. The 233 asymptomatic subjects  underwent cardiac magnetic resonance imaging with preT1 and postT1 mapping on a 1.5-T scanner. T1 values and ECVs were evaluated according to LV segments, age, sex, and estimated glomerular filtration rate (eGFR). Based on the presence of hypertension (HTN) and diabetes mellitus (DM), subjects were subdivided into the control, HTN, DM, and HTN and DM (HTN-DM) groups. T1 values and ECV showed significant differences between septal and lateral segments at the mid-ventricular and basal levels ( Recent research has found that “diffuse” fibrosis is more intimately correlated with poor outcomes, such as mortality or hospitalization, than “focal” fibrosis3. Even though the biopsy is the gold standard for confirming MF, native and post-contrast T1 mapping via the modified look-locker inversion recovery (MOLLI) sequence has become a foundational method for detecting MF and infiltrative processes5. Native T1 value and extracellular volume fraction (ECV) on cardiac magnetic resonance imaging (CMR) correlate well with the histological quantification of MF on a region-of-interest (ROI) basis9.Myocardial fibrosis (MF) is closely linked to various adverse cardiovascular events11. However, they have not been evaluated segmentally, which could serve as reference values to evaluate localized myocardial abnormalities.According to meta-analyses, pooled means of T1 values and ECV in normal subjects showed almost the same ECV and heterogeneous T1 values, and hypertension (HTN) yielded native T1 values and ECV similar to normal subjects16. As pressure overload of the left ventricle (LV) induces accelerated collagen synthesis and breakdown, MF is followed by left ventricular hypertrophy (LVH) in hypertensive heart disease17. One of the hallmarks of diabetic heart disease is diffuse interstitial MF, generated by increased collagen type III in the perimysium and perivascular regions18. Decreased glomerular filtration causes various organs to produce pro-fibrotic substances, leading to progress MF19. However, few studies have demonstrated alterations of T1 values and ECV in subjects with subclinical manifestations of those cardiovascular risk factors.Recent reports have described a possible correlation between MF, demonstrated by elevated native T1 or ECV, and cardiovascular risk factors, such as HTN, diabetes mellitus (DM), and chronic renal diseaseTherefore, this study aimed to report the variation in pre-contrast and post-contrast myocardial T1 values  and ECV according to LV segments and evaluate any correlation between T1 values and cardiovascular risk factors in asymptomatic subjects.p < 0.05).The baseline characteristics and CMR LV measurements of the subjects and subgroups divided by their status of cardiovascular risk factors are shown in Table p < 0.001). The ICC (0.64–0.80) for T1 value of each apical segment was significantly poorer than that (0.79–0.88) of each basal and mid-ventricular segment . PreT1, postT1, and ECV of global LV myocardium were 989 ± 41 ms, 454 ± 38 ms, and 0.245 ± 0.024, respectively.The mean T1 values and ECV with standard deviations for all 16 American Heart Association segments are shown in Fig. p < 0.05, Table p < 0.05, Table PreT1 and ECV revealed significantly higher values in the septal wall than in the lateral wall at the basal and mid-ventricular levels of the LV myocardium . However, postT1 showed no significant difference between male and female subjects (p ≥ 0.061).PreT1, postT1, and ECV of global LV myocardium in male were 984 ± 40 ms, 457 ± 36 ms, and 0.241 ± 0.021, respectively. Those in female were 1029 ± 25 ms, 443 ± 51 ms, and 0.280 ± 0.026, respectively. PreT1 and ECV were significantly higher in women than in men in all LV segments  and no significant correlation . In total population nor each sex group, there was no significant linear correlation between the age and T1 values or ECV .There was no statistically significant difference in T1 values and ECV of the four age groups divided into quantiles   . BMI nor dyslipidemia did not affect T1 values and ECVs statistically in the entire population and each subgroup (p > 0.05). PostT1 and ECV of the LV in the control group showed significant correlations to estimated glomerular filtration rate (eGFR) .A dot scatter plot of ECV with error bars indicating two standard deviations from the average reveals that the HTN-DM group showed significantly higher ECV (0.260 ± 0.023) than the control group  and the HTN group  was associated with preT1 and ECV in an animal model of MF23.MF is commonly associated with cardiac hypertrophy and failure and is associated with worsening ventricular systolic function, abnormal cardiac remodeling, and increased ventricular stiffness in animal models11. In a recent study, normal myocardial T1 reference ranges were reported as follows; at 3-T: 1129–1309 ms and at 1.5-T: 933–1020 ms  and 965–1054 ms , which tend to be similar to our findings24.In a pooled summary of 954 healthy subjects from the literature, 3-T showed longer T1 than 1.5-T with MOLLI variant sequences by approximately 100–200 ms. ECV of the healthy subjects was consistent among the studies (25–27%), irrespective of subject factors, sequences, vendors, and contrast types25. Lateral wall is more vulnerable to partial volume effects which may be a potential cause of the lower preT1 and ECV and the higher postT1 in the lateral segments.29. In addition, considering low reproducibility of apical T1 values, it may be reasonable to measure T1 values in basal to middle septal walls28.Our finding included segmental variations in T1 values and ECV, especially between septal and lateral segments. Motion during the T1 map acquisition may induce a poor T1 model fit and falsely deviated T1 values and ECV, because T1 maps are generated from a sequential series of images31. However, further investigations into this theory should be warranted as the T1 and ECV differences between septal and lateral walls might be subtler than those between normal and overt myocardial disease33.Based on the result that preT1 and ECV were substantially higher in the septal wall than in the lateral wall at the basal and mid-ventricular levels of the LV myocardium, the thresholds of T1 and ECV for detecting MF or infiltrative disease at the lateral wall might be different from those at the septal wall. If the pathologic development and progression of myocardial disease are gradual, the very initial involvement of sarcoidosis or myocarditis at the lateral wall might be underestimated based on the reference values of the septal wall35. The myocardial perfusion difference between the septum and non-septal wall might also contribute to the variations in native T137.Given that cardiac diseases with MF, such as hypertrophic cardiomyopathy, dilated cardiomyopathy, and pulmonary HTN, show increased native T1 and ECV, and late gadolinium enhancement (LGE), more frequently at the septal wall, it might be possible that the fibrotic remodeling of the LV starts earlier at the septum than the lateral wall40.On the other hand, in terms of LV anatomy or pathophysiology, there is no obvious consensus associated with variation of native T1 or ECV between septal and lateral segments. The cardiac skeleton and septal branches of the coronary artery may be partly accountable for increased T1 and ECV in the basal septum42. Especially, a previous study demonstrated that estradiol attenuates myocardial hypertrophy43. Similar to prior literature, our observations of higher preT1 and ECV of females than those of males may suggest that sex hormones affect myocardial histology44. However, since the proportion of females in this study is small (9.9%), that result should be extrapolated carefully, considering other studies with balanced sex distribution.Sex hormones may influence myocardial structure and function47. Rauhalamm et al.26 and Liu et al.45 demonstrated a linear correlation between age and T1 values and ECV. According to Rosmini et al., native myocardial T1 decreased slightly with age, while ECV did not change with age47. In our study, aging was not a significant factor affecting T1 values and ECV, which is consistent with a previous study by Dabir et al.27.There is inconsistency in association of age with T1 values and ECV in the published studies48. Our findings are consistent with the literature, since LVH was contained in the exclusion criteria of our study. Patients with HTN LVH had higher ECV and longer native T1 than HTN non-LVH and control subjects48. According to Venkatesh et al., in a study of 1,813 subjects who underwent CMR, HTN-induced remodeling was related to enhanced replacement and diffuse fibrosis49. In an animal study, the ECV and native T1 value of the myocardium in 18 hypertensive swine increased over three months, even though no LGE was found at any of the imaging times23.Our results showed that there was no significant difference in ECV between the HTN and control groups. According to previous reports, T1 mapping revealed increased diffuse MF in well-controlled HTN patients, but the increase was small and only occurred with LVH50. Furthermore, our study showed HTN-DM group showed significantly high ECV than the control and HTN groups, which provides a clue about a synergetic effect on ventricular fibrosis of DM and HTN. DM appears to enhance fatty acid metabolism, decrease glucose oxidation, and change intracellular signaling, leading to cardiac structure and function alterations, based on prior research53. Ventricular fibrosis is a common structural and histological hallmark of DM, primarily owing to the deposition of collagen and advanced glycation end-products resulting from altered intracellular signaling and metabolic disturbances54. In a study of 135 patients with DM, ECV was significantly different from that of control subjects, while native T1 was not significantly different55. ECV values correlated with HbA1c levels in DM56. The group with HbA1c ≥ 7.0 had a significantly higher ECV value than the control subjects and the lower HbA1c group (HbA1c < 7.0). There was no statistically significant difference in the native T1 value and postT1 value among the three groups56. The lack of significance between the control and DM groups in ECV can be explained by Hb A1c below 7.2 in our research population.According to Levelt et al., there were no significant differences in native myocardial T1 values and ECV between the patients with DM and the control subjects, indicating the absence of fibrosis in a similar context as our study58. According to Edward et al., patients with chronic kidney disease had increased native T1 values and ECV compared with the control and hypertensive subjects59.In our study, in the control group, eGFR significantly correlated not with preT1 linearly but with postT1 proportionally and ECV inversely. This interesting finding suggests that postT1 may be associated with the degrees of renal clearance of contrast agent. Increased renal clearance of contrast agent could facilitate washout of contrast agent in myocardium and then increase myocardial postT1 valuesn = 25), DM and HTN (n = 29), and female subjects (n = 23). Especially, a relatively narrow range of age distribution concentrated in the 50 s resulting from the consecutive data collection could lower the reliability about the insignificant association between age and T1 values or ECV. Low ICCs for measurement of apical segments are ascribed to small ROIs and image inhomogeneity associated with motion.The limitations of this study include the retrospective cross-sectional study design, the relatively small number of subjects with DM  or cooperation (n = 40), lack of optimal T1 mapping (n = 22), and previous history of myocardial infarction (n = 5), localized T1 abnormality and LGE suspicious for myocardial infarction or cardiomyopathy (n = 12), LVH defined as LV wall thickness > 13 mm at least 1 segment or indexed end-diastolic mass > 91 g/m2 in males and > 77 g/m2 in females (n = 9)61. A total of 233 subjects were included  with a 32-channel phased-array receiver coil during repeated breath-holds. After localization, cine images of the LV mass were acquired using a steady-state free precession (SSFP) sequence with 8–10 contiguous short-axis slices to cover the entire LV with a slice thickness of 6 mm and a 4-mm gap. Standard delayed gadolinium-enhanced imaging was acquired using the phase-sensitive inversion recovery (PSIR) technique after injecting 0.15 mmol/kg gadobutrol  in 10–12 continuous short-axis images of 6 mm thickness with a 4-mm slice gap. Inversion delay times were typically 280–360 ms. Three short-axis images were acquired using the MOLLI sequence before and 15 min after administering gadolinium . Image analysis of T1 maps was performed by two experienced cardiac radiologists  blinded to the clinical information. ROIs were drawn on 16 LV segments and blood pools manually  endorsed by the European Association for Cardiovascular Imaginglly Fig. . Areas oECV was calculated using the following equations:ΔR1 = 1/T1 time post-contrast—1/T1 time pre-contrast,myocardium/ΔR1blood,λ = ΔR165.Hct refers to the hematocrit measured in venous blood sampled on the same day of the MRI scan acquisition 2). SBP and DBP were measured after the subject had rested for at least 5 min. Blood samples were collected from the antecubital vein after overnight fasting. Total cholesterol, high-density lipoprotein, triglyceride (TG), fasting plasma glucose (FPG), and serum creatinine (Cr) levels were measured using enzymatic or colorimetric methods. The eGFR was calculated using a formula from the Modification of Diet in Renal Disease study: eGFR (mL/min/1.73 m2) = 186.3 × (Cr)—1.154 × (age)—0.203 × (0.742 for women)66. Body surface area (BSA) was calculated as follows: 0.20247 × height (m)0.725 × weight (kg)0.425 (Dubois formula). HTN was diagnosed when a person’s SBP in the office or clinic was ≥ 140 mmHg and/or their DBP was ≥ 90 mmHg following repeated examinations67. DM was diagnosed using the following criteria: occasional plasma glucose value of ≥ 200 mg/dL (≥ 11.1 mmol/L), FPG of ≥ 126 mg/dL (7.0 mmol/L) (fasting time 8–12 h), oral glucose tolerance test 2-h value in venous plasma ≥ 200 mg/dL (≥ 11.1 mmol/L), HbA1c ≥ 6.5% (≥ 48 mmol/mol Hb), and impaired fasting glucose for the fasting glucose range of 100–125 mg/dL (5.6 mmol/L- 6.9 mmol/L) in venous plasma68.The clinical information of the subjects was obtained from medical records and laboratory findings on the day of CMR acquisition. BMI was calculated as weight (kg) divided by the square of the height  HTN group, (2) DM group, (3) HTN-DM group, and (4) control group. The control group was defined as subjects who did not have HTN and DM. We evaluated whether there were any differences in T1 values and ECV between the subgroups.t-test. Wilcoxon rank sum test and Mann Whitney U-test were used to analyze the differences between non-continuous variables. According to normality of distribution, analysis of variance or Kruskal–Wallis test was applied for multiple group comparison. For the trend analysis, Jonckheere-Terpstra test was adopted. The relationships between T1 values and cardiovascular risk factors were studied using simple correlation analysis with Pearson correlation coefficient (r). Inter-observer agreement was quantified using ICCs for all subjects. The threshold for statistical significance was set at p = 0.05 in the two-tailed tests.All analyses were conducted using SPSS 26  and Rex . Categorical variables were reported as percentages and continuous variables are presented as means with standard deviations. The differences between continuous variables were analyzed using the independent or paired Supplementary Information.