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Peripartum cardiomyopathy (PPCM) is a rare pregnancy-associated dilated cardiomyopathy occurring in the last month of pregnancy and five months postdelivery, which presents with features of cardiac failure. Diagnosis is based on characteristic echocardiographic findings and elevated cardiac biomarkers and has significant mortality and morbidity when undiagnosed and untreated. Atypical presentations in earlier gestations are rare and associated with risk factors. Here we present a case of PPCM diagnosed in the second trimester in a post in vitro fertilization (IVF) twin pregnancy to emphasize the importance of considering the diagnosis of PPCM in all cases of unexplained cardiac failures during pregnancy in previously healthy patients, especially in the presence of risk factors.

Takotsubo cardiomyopathy is characterised by left ventricular apical ballooning, in the absence of coronary artery disease, and classically occurs at times of intense stress. Due to the striking preponderance of Takotsubo cardiomyopathy occurring in postmenopausal women, it has been postulated that female sex hormones may also be implicated in its pathogenesis. This case report describes the first case of Takotsubo cardiomyopathy associated with the initiation of dydrogesterone (a synthetic retroprogesterone) in a premenopausal woman.

Pacing-induced cardiomyopathy (PICM) consists of heart failure (HF) associated with a drop in the left ventricular ejection fraction (LVEF) in the setting of high-burden right ventricular pacing, with presentation that may range from subclinical to severe. Time to manifestation can go from weeks to years after device implantation. Treatment typically consists in an upgrade to a cardiac resynchronisation therapy (CRT) or His bundle pacing (HisP). Several risk factors for PICM have been described and should be considered before pacemaker (PM) implantation, as thorough patient selection for de novo CRT or HisP, may preclude its manifestation. We present the case of an 82-year-old patient presenting with acute congestive HF and new severely reduced LVEF, 30 days following dual chamber PM implantation for high-grade atrioventricular block. Treatment with HF medication and upgrade to a CRT permitted rapid resolution of the symptoms and normalisation of the LVEF at 1-month follow-up.

Rare variants in JPH2 have been associated with a range of cardiac disease, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmias, and sudden cardiac death (SCD); however, our understanding of how variants in JPH2 correspond to specific modes of inheritance and correlate clinical phenotypes has not been comprehensively explored. In this systematic review, we assess current case reports and series that describe patients with JPH2 variants and cardiac disease. We identified a total of 61 variant-positive individuals, approximately 80% of whom had some form of cardiac disease, including 47% HCM, 18% DCM, and 14% arrhythmia/SCD. In analyzing the 24 probands described in the studies, we found that autosomal recessive, loss-of-function variants are associated with severe, early onset DCM, while autosomal dominant missense variants are associated with a wider range of cardiac disease, including HCM, arrhythmia, SCD, and cardiac conduction disease.

Background: Many patients in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) had a significant improvement (> 10%) in the left ventricular ejection fraction (LVEF) during the course of the study, but the factors and outcomes associated with such improvement are uncertain. Methods: We examined factors and rates of mortality, cause-specific mortality, and implantable cardioverter defibrillator (ICD) shocks associated with improvement in LVEF by analyzing patients in the SCD-HeFT who were randomized to placebo or an ICD and who had an LVEF checked during follow-up. Results: During a median follow-up of 3.99 years, of 837 patients who had at least two follow-up LVEF measurements, 276 (33%) patients had > 10% improvement in LVEF and 561 (67%) patients had no significant change in LVEF. Factors significantly associated with LVEF improvement included female sex, white race, history of hypertension, a QRS duration < 120 ms, and beta-blocker use. Improvement in LVEF was associated with a significant improvement in survival. There was no significant association between improvement in LVEF and cause-specific death, but there was a significant association between improvement in LVEF and reduced risk of receiving appropriate ICD shocks. Conclusions: About a third of patients in this analysis, who were randomized to placebo or an ICD in SCD-HeFT, had a significant improvement in LVEF during follow-up; improvement in LVEF was associated with improved survival but not with cause-specific death, and with decreased likelihood of receiving appropriate ICD shocks.

Takotsubo cardiomyopathy (TCM) secondary to an infusion reaction is extremely rare in the literature. Here, we present an unusual case of TCM in a patient with cervical squamous cell carcinoma who presented with acute hypoxic respiratory failure following the initiation of the first-cycle paclitaxel infusion therapy.

Introduction The etiology of sudden cardiac death (SCD) in young people continues to attract much attention. This meta-analysis aimed to identify the most frequent causes of SCD in individuals aged ≤35 years, the differences between athletes and non-athletes and geographic areas. Methods Studies published between 01/01/1990 and 01/31/2020 and evaluating post-mortem the aetiology of SCD in young individuals (≤35 years) were included. Individuals were divided into athletes and non-athletes. Studies that did not report separate data between athletes and non-athletes were excluded. Results Thirty-four studies met the inclusion criteria, and a total population of 5,060 victims of SCD were analyzed (2,890 athletes, 2,170 non-athletes). Comparing the causes of SCD between athletes and non-athletes, non-ischemic left ventricular scar (NILVS) (5.1% vs. 1.1%, p=0.01) was more frequent in the former, while coronary artery disease (CAD) (19.6% vs. 9.1%, p=0.009), arrhythmogenic cardiomyopathy (ACM) (11.5% vs. 4.7%, p=0.03) and channelopathies (8.4% vs. 1.9%, p=0.02) were more frequent in the latter. In studies published in the last decade, hypertrophic cardiomyopathy (HCM) (p=0.002), dilated cardiomyopathy (p=0.047), and anomalous origin of coronary arteries (AOCA) (p=0.009) were more frequently the causes of SCD in athletes while aortic dissection (0.022) was the cause in non-athletes. HCM (p=0.01) and AOCA (p=0.004) were more frequently the causes of SCD in the US while ACM (p=0.001), structurally normal heart (p=0.02), and channelopathies (p=0.02) were more frequent in Europe. Conclusions Among the causes of SCD, NILVS was the more frequent cause in athletes, while CAD, ACM and channelopathies were more frequent causes in non-athletes. The causes of SCD differ between the US and Europe.

BACKGROUND: Black women have greater than a three-fold risk of pregnancy-associated death compared to White women; cardiomyopathy is a leading cause of maternal mortality. OBJECTIVES: This study examined racial disparities in health outcomes among women with peripartum cardiomyopathy. STUDY DESIGN: Retrospective cohort of women with peripartum cardiomyopathy per the National Heart, Lung, and Blood Institute definition from January 2000–November 2017 from a single referral center. Selected health outcomes among Black and White women were compared; primary outcome was ejection fraction at diagnosis. Secondary outcomes included cardiovascular outcomes, markers of maternal morbidity, resource utilization, and subsequent pregnancy outcomes. RESULTS: Ninety-five women met inclusion criteria: 48% Black, 52% White. Nearly all peripartum cardiomyopathy diagnoses were postpartum (95.4% Black, 93% White, p=0.11). Ejection fraction at diagnosis was not different between Black and White women (26.8% ± 12.5 vs 28.7% ± 9.9, p=0.41). Though non-significant, fewer Black women had myocardial recovery to EF ≥ 55% (35% vs 53%, p = 0.07); however, 11 (24%) of Black women vs 1 (2%) White woman had an ejection fraction ≤ 35% at 6 – 12 months postpartum (p < 0.01). More Black women underwent implantable cardioverter defibrillator placement: n = 15 (33%) vs n = 7 (14%), p=0.03. Eight women (8.4%) died in the study period, not different by race (p = 0.48). Black women had higher rates of healthcare utilization. In the subsequent pregnancy, Black women had a lower initial ejection fraction (40% vs 55%, p = 0.007) and were less likely to recover postpartum (37.5% vs 55%, p = 0.02). CONCLUSIONS: Black and White women have similar mean ejection fraction at diagnosis of peripartum cardiomyopathy, but Black women have more severe left ventricular systolic dysfunction leading to worse outcomes, increased resource use, and lower ejection fraction entering the subsequent pregnancy.

Pheochromocytoma, is a rare neuroendocrine tumor, which usually presents as hypertension. We report a young male patient, who presented with intracerebral hemorrhage and intractable hypertension. On further evaluation, for uncontrolled secondary hypertension, he was diagnosed to have right adrenal pheochromocytoma. After hemodynamic stabilization, laparoscopic adrenelectomy was performed. Pheochromocytoma crisis presenting as intracerebral hemorrhage and cardiomyopathy is an uncommon phenomena. Even though it is a crisis, it is not a surgical emergency. Proper preoperative hemodynamic stabilization is essential before surgery is performed. An experienced anesthetist, to manage intraoperative fallacies, is warranted. Postoperatively, they must be on lifelong follow-up to watch for recurrence.

Takotsubo cardiomyopathy (TCM) is a transient acute cardiac disorder often associated with QT prolongation, but this rarely leads to torsades de pointes (TdP). Additionally, it is a rare complication of catheter ablation. Here we report a case of TCM that developed after catheter ablation for common atrial flutter, which led to TdP. The patient was an 85-year-old male who had persistent supraventricular tachycardia, which was considered atrial flutter. The patient was hospitalized for congestive heart failure. Although the response to diuretic administration was unfavorable, heart failure improved with the combined use of rate control by landiolol. Catheter ablation was performed because of the possibility of tachycardia-induced cardiomyopathy. Tachycardia disappeared following ablation to the cavotricuspid isthmus, but the patient complained of severe pain during the ablation. Approximately 2 h after the treatment, the patient's heart failure re-exacerbated. The next day, electrocardiogram confirmed a marked QT prolongation, and TdP occurred. Although the phenomenon we experienced is rarely reported, it should be considered a complication following catheter ablation. Adequate analgesia, care for anxiety about treatment, and evaluation of cardiac condition after treatment are considered important.

OBJECTIVE Based on cybernetics, a large system can be divided into subsystems, and the stability of each can determine the overall properties of the system. However, this stability analysis perspective has not yet been employed in electrocardiogram (ECG) signals. This is the first study to attempt to evaluate whether the stability of decomposed ECG subsystems can be analyzed in order to effectively investigate the overall performance of ECG signals, and aid in disease diagnosis. METHODS We used seven different cardiac pathologies (myocardial infarction, cardiomyopathy, bundle branch block, dysrhythmia, hypertrophy, myocarditis, and valvular heart disease) to illustrate our method. Dynamic mode decomposition (DMD) was first used to decompose ECG signals into dynamic modes (DMs) which can be regarded as ECG subsystems. Then, the features related to the DMs stabilities were extracted, and nine common classifiers were implemented for classification of these pathologies. RESULTS Most features were significant for differentiating the above-mentioned groups (value

This study aimed to explore the diagnostic value and the correlation of the combined detection of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) with sepsis-induced cardiomyopathy (SIC).Admitted to our hospital from January 2017 to January 2019, 96 patients with SIC (a study group) and 90 patients with sepsis (a control group) were enrolled. The three cytokines were determined and the diagnostic value of their combined detection for SIC was analyzed.The cytokines were remarkably higher in the study group (p.001). The combined detection of the three had a better diagnostic value for SIC (p.001). The three cytokines were independent risk factors for the death of patients with SIC.IL-1β, IL-6, and TNF-α in SIC patients rise markedly. The combined detection of the three has a better predictive value for patients with SIC and is closely related to the patients' prognoses, so it may be crucial in diagnosing and treating the disease.

Cardiac dysfunction after subarachnoid hemorrhage (SAH) is described as Takotsubo or reverse Takotsubo cardiomyopathy that shows transient left ventricular wall motion abnormalities with electrocardiogram (ECG) changes. ST change followed by T inversion is a common ECG finding complicated with these disorders, left bundle branch block (LBBB) may be a potential ECG pattern which is seen. In this case, we describe the clinical profile and outcomes of a patient with LBBB and reverse Takotsubo cardiomyopathy after anesthetic induction, which was scheduled as an emergent external ventricular drainage after SAH. This is the first report of an LBBB pattern in reverse Takotsubo cardiomyopathy.

Trastuzumab-induced cardiomyopathy is a known complication of its use in breast cancer treatment. However, cardiac complications of trastuzumab without left ventricular systolic dysfunction have been rarely reported. These include left bundle branch block, sinus node dysfunction, and ventricular tachycardia. We herein report a case of a 47-year-old female with human epidermal growth factor receptor 2-positive, stage IV breast cancer without a history of cardiovascular disease. During treatment with trastuzumab emtansine (T-DM1), she presented with out-of-hospital cardiac arrest and was resuscitated by automated cardioverter defibrillator (AED). Emergent cardiac catheterization revealed no organic obstruction and coronary vasospasm in her coronary arteries, and no left ventricular systolic dysfunction. Ventricular fibrillation (VF) was documented by an event memory of AED. T-DM1 was withdrawn and implantable cardioverter defibrillator was implanted. Thereafter, VF or life-threatening arrhythmia were not documented for 36 months until her death by breast cancer. We concluded that the etiology of her VF event was T-DM1-induced cardiotoxicity. We believe this is the first report of life-threatening VF event without cardiomyopathy induced by T-DM1.

The prognosis of several lymphoid malignancies has improved through development of novel therapies, combination with traditional chemotherapies, and delineation of appropriate therapeutic sequencing. Toxicities that are arising because of prolonged or multiple sequential therapeutic interventions are becoming increasingly impactful. Among the broad spectrum of complications that patients with lymphoid malignancies may experience, cardiovascular toxicities are significant in terms of morbidity and mortality. The entire cardiovascular system can be affected, but cardiomyopathy, heart failure, and arrhythmias remain of greatest concerns with the use of anthracyclines, hematopoietic stem cell transplantation, and radiation therapy in patients with lymphoid malignancies. These aspects will be covered in this article within the framework of case-based discussions. Key to the management of cardiovascular complications in patients with lymphoid malignancies is awareness and preparedness across the cancer continuum. Baseline risk stratification helps to direct surveillance and early intervention efforts before, during, and after cancer therapy, which are paramount for the best possible outcomes. Along these lines, the overall goal is to enable the best possible therapies for lymphoid malignancies without the complications of clinically significant cardiovascular events.

Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications.

Takotsubo syndrome (TS) is a reversible form of cardiomyopathy characterized by transient systolic dysfunction with regional wall motion abnormalities and absence of coronary artery obstruction, which can be precipitated by severe emotional or physical stress. Its clinical presentation is similar to that of acute coronary syndrome. However, TS presenting with atrioventricular (AV) block with ventricular asystole is rarely reported. In this article, we describe the case of a postmenopausal woman who experienced near cardiac arrest due to high-degree AV block. Although transthoracic echocardiography revealed left ventricular dysfunction with severe global hypokinesia, coronary angiography and cardiac magnetic resonance imaging showed normal coronary arteries without myocardial scarring. The patient's condition improved after permanent pacemaker implantation and medical treatment for heart failure. Echocardiography and pacemaker analysis at two-month follow-up revealed normalization of heart function and cardiac rhythm, and the patient was finally diagnosed with TS.

Sepsis is a clinical syndrome caused by a dysregulated host response to infection that can lead to multiple organ dysfunction and death. Cardiovascular abnormalities are frequent in sepsis and may result in myocardial injury unrelated to coronary artery disease. Myocardial calcification is a rare complication of sepsis, which shows rapid-onset extensive myocardial calcifications. We present a case of a 67-year-old man who developed severe sepsis complicated with shock, acute renal failure, and acute respiratory distress syndrome. Initial chest computed tomography (CT) on admission showed normal left ventricular (LV) myocardial attenuation. However, serial chest CT demonstrated a gradual increase of the LV myocardial attenuation, which ultimately resulted in extensive myocardial calcification within 6 weeks. Sepsis-related myocardial calcification is usually found in patients with severe sepsis complicated with hemodynamic failure requiring vasopressors, acute renal failure necessitating renal replacement therapy, and acute respiratory distress syndrome. Although the prognostic significance of this pathology is unclear, it may be a precursor to long-term irreversible cardiomyopathy or an arrhythmogenic substrate that induces life-threatening arrhythmias. Therefore, patients who have survived the acute phase of severe sepsis need to be monitored carefully for signs of this complication by an imaging modality such as CT.

Background Developmental disorders associated with Becker muscular dystrophy (BMD), possibly resulting from a lack of dystrophin in the brain, have been reported, but their importance is not fully understood. We report a case of a BMD patient who had been socially withdrawn due to mental retardation and autism spectrum disorder and could not receive appropriate medical services, resulting in delayed detection of severe cardiomyopathy and embolic strokes which developed as complications of BMD. Case report: The case is a 41-year-old male. In elementary school, he was the slowest runner in his class and had poor grades. He started missing school due to bullying in junior high school and had been socially withdrawn for 24 years. He developed difficulty walking due to progressive muscle weakness in the extremities and lost ambulation at age 36. At age 41, he was referred to our hospital by public health support services to address his social withdrawal. Muscle biopsy led to the diagnosis of BMD. Psychological examination revealed mild mental retardation and autism spectrum disorder, which may have resulted in social isolation. He had severe cardiomyopathy and asymptomatic cerebral infarction due to heart failure. Conclusion In BMD patients, developmental disorders can potentially hinder access to appropriate medical treatment. BMD is an important differential diagnosis for physically disabled children with developmental disorders. Early intellectual and psychological interventions and evaluation of complications are important for improving patient prognosis and quality of life.

BACKGROUND AND PURPOSE Small molecule BGP-15 has been reported to alleviate signs of heart failure and improve muscle function in murine models. Here, we investigated the acute and chronic effects of BGP-15 in a rabbit model of atherosclerotic cardiomyopathy. EXPERIMENTAL APPROACH Rabbits were maintained on standard chow (Control) or atherogenic diet (HC) for 16 weeks. BGP-15 was administered intravenously (once) or orally (for 16 weeks), to assess acute and chronic effects. Cardiac function was evaluated by echocardiography, endothelium-dependent vasorelaxation was assessed, and key molecules of the protein kinase G (PKG) axis were examined by ELISA and Western blot. Passive force generation was investigated in skinned cardiomyocytes. KEY RESULTS Both acute and chronic BGP-15 treatment improved the diastolic performance of the diseased heart, however, vasorelaxation and serum lipid markers were unaffected. Myocardial cGMP levels were elevated in the BGP-15-treated group, along with preserved PKG activity and increased phospholamban Ser16-phosphorylation. PDE5 expression decreased in the BGP-15-treated group, and the substance inhibited PDE1 enzyme. Cardiomyocyte passive tension reduced in BGP-15-treated rabbits, the ratio of titin N2BA/N2B isoforms increased, and PKG-dependent N2B-titin phosphorylation elevated in the BGP-15-treated group. CONCLUSIONS AND IMPLICATIONS Here we report that BGP-15-treatment improves diastolic function, reduces cardiomyocyte stiffness, and restores titin compliance in a rabbit model of atherosclerotic cardiomyopathy by increasing the activity of the cGMP-PKG axis. As BGP-15 is proven to be safe, it may have clinical value in the treatment of diastolic dysfunction.

Transthyretin amyloid cardiomyopathy (ATTR‐CM) is caused by the cardiac deposition of insoluble amyloid fibrils formed by misfolded transthyretin proteins and is associated with various cardiac symptoms, such as progressive heart failure, conduction disturbance, and arrhythmia. The implementation of 99mtechnetium (99mTc)‐labelled bone radiotracer scintigraphy for diagnosing ATTR‐CM has enabled accurate diagnosis of the disease with high sensitivity and specificity and positioned this diagnostic modality as an integral part of disease diagnostic algorithms. In 2020, 99mTc‐pyrophosphate scintigraphy received exceptional approval for Japanese national health insurance reimbursement as a diagnostic method of ATTR‐CM. Nevertheless, the utility of 99mTc‐labelled bone radiotracer scintigraphy and the importance of an early diagnosis of suspected ATTR‐CM using this technique have yet to be internalized as common practice by general cardiologists, and guidance on daily clinical scenarios to consider this technique for a diagnosis of suspected ATTR‐CM is warranted. In this review, we discuss the utility of 99mTc‐labelled bone radiotracer scintigraphy for the early diagnosis of ATTR‐CM based on published literature and the outcomes of an advisory board meeting. This review also discusses clinical scenarios that could support early diagnosis of suspected ATTR‐CM as well as common pitfalls, correct implementation, and future perspectives of 99mTc‐labelled bone radiotracer scintigraphy in daily clinical practice. The clinical scenarios to consider 99mTc‐labelled bone radiotracer scintigraphy in daily practice may include, but are not limited to, patients with a family history of the hereditary type of disease; elderly patients (aged ≥60 years) with unexplained cardiac findings (e.g. cardiac hypertrophy associated with abnormalities on an electrocardiogram, heart failure with preserved ejection fraction associated with unexplained left ventricular hypertrophy, and heart failure with reduced ejection fraction associated with atrial fibrillation and left ventricular hypertrophy); and patients with cardiac hypertrophy associated with diastolic dysfunction, right ventricular/interatrial septum/valve thickness, left ventricular sparkling, or apical sparing. Cardiac hypertrophy and persistent elevation in cardiac troponin in elderly patients are also suggestive of ATTR‐CM. 99mTc‐labelled bone radiotracer scintigraphy is also recommended in patients with characteristic cardiac magnetic resonance findings (e.g. diffuse subendocardial late gadolinium enhancement patterns, native T1 increase, and increase in extracellular volume) or patients with cardiac hypertrophy and bilateral carpal tunnel syndrome.

Kidney international 101(2), 256-273 (2022). doi:10.1016/j.kint.2021.10.025, Published by Elsevier, New York, NY

Inherited cardiomyopathies are a major cause of mortality and morbidity worldwide and can be caused by mutations in a wide range of proteins located in different cellular compartments. The present review is based on Dr. Ju Chen’s 2021 Robert M. Berne Distinguished Lectureship of the American Physiological Society Cardiovascular Section, in which he provided an overview of the current knowledge on the cardiomyopathy-associated proteins that have been studied in his laboratory. The review provides a general summary of the proteins in different compartments of cardiomyocytes associated with cardiomyopathies, with specific focus on the proteins that have been studied in Dr. Chen’s laboratory.

Krüppel-like factors (KLFs) are DNA-binding transcriptional factors, which regulate various pathways that pertain to development, metabolism and other cellular mechanisms. KLF5 was first cloned in 1993 and by 1999, it was reported as the intestinal-enriched KLF. Beyond findings that have associated KLF5 with normal development and cancer, it has been associated with various types of cardiovascular (CV) complications and regulation of metabolic pathways in the liver, heart, adipose tissue and skeletal muscle. Specifically, increased KLF5 expression has been linked with cardiomyopathy in diabetes, end-stage heart failure, and as well as in vascular atherosclerotic lesions. In this review article, we summarize research findings about transcriptional, post-transcriptional and post-translational regulation of KLF5, as well as the role of KLF5 in the biology of cells and organs that affect cardiovascular health either directly or indirectly. Finally, we propose KLF5 inhibition as an emerging approach for cardiovascular therapeutics.

The article presented the etiological and pathophysiological features of non-compaction cardiomyopathy. Types of clinical course and prognosis were considered. We have described the interpretation of the results of modern instrumental techniques used in the diagnosis of cardiomyopathy. In the end of article, there is a clinical case from the practice of the authors on the diagnosis and treatment of young female patient with non-compaction cardiomyopathy, probably hereditary form.

Mitochondrial diseases (MD) include an heterogenous group of systemic disorders caused by sporadic or inherited mutations in nuclear or mitochondrial DNA (mtDNA), causing impairment of oxidative phosphorylation system. Hypertrophic cardiomyopathy is the dominant pattern of cardiomyopathy in all forms of mtDNA disease, being observed in almost 40% of the patients. Dilated cardiomyopathy, left ventricular noncompaction, and conduction system disturbances have been also reported. In this article, the authors discuss the current clinical knowledge on MD, focusing on diagnosis and management of mitochondrial diseases caused by mtDNA mutations.

Diabetic mellitus (DM) is a common degenerative chronic metabolic disease often accompanied by severe cardiovascular complications (DCCs) as major causes of death in diabetic patients with diabetic cardiomyopathy (DCM) as the most common DCC. The metabolic disturbance in DCM generates the conditions/substrates and inducers/triggers and activates the signaling molecules and death executioners leading to cardiomyocyte death which accelerates the development of DCM and the degeneration of DCM to heart failure. Various forms of programmed active cell death including apoptosis, pyroptosis, autophagic cell death, autosis, necroptosis, ferroptosis and entosis have been identified and characterized in many types of cardiac disease. Evidence has also been obtained for the presence of multiple forms of cell death in DCM. Most importantly, published animal experiments have demonstrated that suppression of cardiomyocyte death of any forms yields tremendous protective effects on DCM. Herein, we provide the most updated data on the subject of cell death in DCM, critical analysis of published results focusing on the pathophysiological roles of cell death, and pertinent perspectives of future studies., Graphical abstract This review article provides the research evidence for the presence and role of various types of cell death in diabetic cardiomyopathy, as well as the perspectives of future studies.Image 1

While much has been written about the syndrome of diabetic cardiomyopathy, clinicians and research scientists are now beginning to realize that an entirely unique syndrome exists, albeit with several commonalities to the diabetic syndrome, that being obesity cardiomyopathy. This syndrome develops independent of such comorbidities as hypertension, myocardial infarction and coronary artery disease; and it is characterized by specific alterations in adipose tissue function, inflammation and metabolism. Recent insights into the etiology of the syndrome and its consequences have focused on the roles played by altered intracellular calcium homeostasis, reactive oxygen species, and mitochondrial dysfunction. A timely and comprehensive review by Ren, Wu, Wang, Sowers and Zhang (1) identifies unique mechanisms underlying this syndrome, its relationship to heart failure and the recently identified incidence of COVID-19-related cardiovascular mortality. Importantly, the review concludes by advancing recommendations for novel approaches to the clinical management of this dangerous form of cardiomyopathy.

Dystrophin deficiency results in cardiomyopathy and fibrosis with variable onset. Little is known about electrocardiographic abnormalities in Becker muscular dystrophy and their relationship to underlying cardiac pathology. We hypothesized QRS fragmentation is associated with myocardial fibrosis on cardiac magnetic resonance imaging in Becker muscular dystrophy patients. We retrospectively evaluated 44 patients, and extracted data from clinically obtained electrocardiogram and cardiac magnetic resonance. Ventricular function and presence or absence late gadolinium enhancement representing myocardial fibrosis were recorded from imaging. Nearly half (19/42, 45%) of patients interrogated had myocardial fibrosis on cardiac magnetic resonance. Total number of electrocardiogram leads with QRS fragmentation (median 1 vs 4, p 0.001) and either right or left axis deviation from median was significantly increased (13.6 vs. 44.8°, p 0.001) in patients with myocardial fibrosis. Decreased leftward voltage in V6 correlated to both increased fibrosis and decreased cardiac function (p 0.01). The positive likelihood ratio for underlying myocardial fibrosis in patients with two of the three findings on electrocardiogram was 8.47 (p 0.0001). QRS fragmentation and axis deviation on electrocardiography are strongly predictive of myocardial fibrosis in Becker muscular dystrophy and may inform the use of advanced imaging in evaluation of these patients.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by a homozygous GAA triplet repeat expansion in the frataxin gene. Cardiac involvement, usually manifesting as hypertrophic cardiomyopathy, can range from asymptomatic cases to severe cardiomyopathy with progressive deterioration of the left ventricular ejection fraction and chronic heart failure. The management of cardiac involvement is directed to prevent disease progression and cardiovascular complications. However, direct-disease therapies are not currently available for FRDA. The present review aims to describe the current state of knowledge regarding cardiovascular involvement of FRDA, focusing on clinical-instrumental features and management of cardiac manifestation.

In the wide phenotypic spectrum of cardiomyopathies, sudden cardiac death (SCD) has always been the most visible and devastating disease complication. The introduction of implantable cardioverter-defibrillators for SCD prevention by the late 1980s has moved the question from how to whom we should protect from SCD, leaving clinicians with a measure of uncertainty regarding the most reliable option to guide identification of the highest-risk patients. In this review, we will go through all the available evidence in the field of arrhythmic expression and arrhythmic risk stratification in the different phenotypes of cardiomyopathies to provide practical suggestions in daily clinical management.

Takotsubo syndrome is an acute reversible heart failure syndrome, most frequently seen in postmenopausal women and precipitated generally by significant emotional stress or physical illness. A sudden sympathetic activation seems to play a key role in the pathophysiology, but growing evidence is emerging about the role of inflammation in the subacute and chronic phases. An incidence of life-threatening complications occurring in the acute phase and at long-term follow-up has been demonstrated, comparable with the acute coronary syndrome. Multimodality imaging could be useful to stratify in-hospital and long-term prognosis. The efficacy of specific medical treatments in long-term follow-up should be investigated.

Highlights • Knowledge of the genetic etiologies of cardiomyopathies has created novel opportunities for treatments. • Emerging treatments targets include gene therapy, myofilament function, protein quality control, and metabolism. • Consideration of the genetic cause, biophysical context, and cardiomyopathy disease stage will be critical to the success of these novel treatments., Summary The primary etiology of a diverse range of cardiomyopathies is now understood to be genetic, creating a new paradigm for targeting treatments on the basis of the underlying molecular cause. This review provides a genetic and etiologic context for the traditional clinical classifications of cardiomyopathy, including molecular subtypes that may exhibit differential responses to existing or emerging treatments. The authors describe several emerging cardiomyopathy treatments, including gene therapy, direct targeting of myofilament function, protein quality control, metabolism, and others. The authors discuss advantages and disadvantages of these approaches and indicate areas of high potential for short- and longer term efficacy., Central Illustration

Background Most COVID-19 infections result in a viral syndrome characterized by fever, cough, shortness of breath, and myalgias. A small but significant proportion of patients develop severe COVID-19 resulting in respiratory failure. Many of these patients also develop multi-organ dysfunction as a byproduct of their critical illness. Although heart failure can be a part of this, there also appears to be a subset of patients who have primary cardiac collapse from COVID-19. Objective Conduct a systematic review of COVID-19-associated myocarditis, including clinical presentation, risk factors, and prognosis. Discussion Our review demonstrates two distinct etiologies of primary acute heart failure in surprisingly equal incidence in patients with COVID-19: viral myocarditis and Takotsubo cardiomyopathy. COVID myocarditis, Takotsubo cardiomyopathy, and severe COVID-19 can be clinically indistinguishable. All can present with dyspnea and evidence of cardiac injury, although in myocarditis and Takotsubo this is due to primary cardiac dysfunction as compared to respiratory failure in severe COVID-19. Conclusion COVID-19-associated myocarditis differs from COVID-19 respiratory failure by an early shock state. However, not all heart failure from COVID-19 is from direct viral infection; some patient's develop takotsubo cardiomyopathy. Regardless of etiology, steroids may be a beneficial treatment, similar to other critically ill COVID-19 patients. Evidence of cardiac injury in the form of ECG changes or elevated troponin in patients with COVID-19 should prompt providers to consider concurrent myocarditis.

The genetic background of congenital heart diseases (CHDs) is extremely complex, heterogenous, and still majorly to be determined. CHDs can be sporadic or familial. In this article we discuss in detail the phenotypic spectrum of selected genes including MYH7, GATA4, NKX2-5, TBX5, and TBX20. Our goal is to offer the clinician a general overview of the clinical spectrum of the analyzed topics that are traditionally known as causative for CHDs but we underline in this review the possible progressive functional (cardiomyopathy) and electric aspects (arrhythmias) caused by the genetic background.

Introduction Autosomal dominant mitochondrial DNA depletion syndrome (MTDPS-12A) is characterized by severe hypotonia from birth due to a mutation in the adenine nucleotide translocator 1 (ANT1). Case report A 4-year-old female patient diagnosed with neonatal-onset mitochondrial disease, who had good cognitive function while receiving antiepileptic treatment, presented with sudden-onset status epilepticus with facial and limb myoclonus persisting for more than 30 min. Subsequently, she developed epileptic encephalopathy. Brain MRI showed progressive ventricular enlargement and marked white matter atrophy. She was unable to perform verbal communication or make eye contact and fingertip movements. She lacked any signs of cardiomyopathy. Sanger sequencing demonstrated a heterozygous de novo mutation of c.239G>A (p.Arg80His) in SLC25A4. Her right quadriceps muscle tissue showed lowered complexes I, III, and IV activities and mitochondria DNA depletion (mitochondria/nuclear DNA: 14.6 ± 2.2%) through the quantitative polymerase chain reaction. She was definitively diagnosed with MTDPS-12A. Conclusion Status epilepticus causes encephalopathy in patients with MTDPS-12A. Reducing the energy requirement on the cardiac muscle and brain may be a treatment strategy for patients with MTDPS-12A. Therefore, seizure management and preventive treatment of status epilepticus are considered to be important for maintaining neurodevelopmental outcomes.

Ivabradine increases stroke volume, but does not have a negative impact on blood pressure (BP). Thus, a patient with low BP can benefit from treatment with ivabradine. A 72-year-old Japanese woman with asthma and chronic bronchitis presented with dyspnea. Her heart rate (HR) was 126 beats per minute and an electrocardiogram showed sinus tachycardia. The chest X-ray showed cardiomegaly and pulmonary congestion. A transthoracic echocardiogram (TTE) showed reduced left ventricular ejection function (LVEF) and severe functional mitral regurgitation (MR). We diagnosed her with inappropriate sinus tachycardia (IST) and heart failure (HF) due to tachycardia-induced cardiomyopathy. After resolving the pulmonary congestion with diuretics, we administered a minimum dose of bisoprolol, which resulted in re-exacerbation of the HF. Because IST was persistent, we initiated treatment with ivabradine. As soon as ivabradine was started, the HR decreased, the BP gradually increased, and HF compensation was achieved. Bisoprolol was continued and losartan was started. In summary, we used ivabradine for a patient with tachycardia, low BP, a low LVEF, and severe MR. By optimizing the medical therapy, exercise tolerance improved and she was discharged. The serum brain natriuretic peptide was significantly reduced and TTE showed an improved LVEF and reduced MR.

Broad cellular functions and diseases including muscular dystrophy, arrhythmogenic right ventricular cardiomyopathy (ARVC5) and cancer are associated with transmembrane protein43 (TMEM43/ LUMA). The study aimed to investigate biological roles of TMEM43 through genetic regulation, gene pathways and gene networks, candidate interacting genes, and up- or downstream regulators. Cardiac transcriptomes from 40 strains of recombinant inbred BXD mice and two parental strains representing murine genetic reference population (GRP) were applied for genetic correlation, functional enrichment, and coexpression network analysis using systems genetics approach. The results were validated in a newly created knock-in Tmem43-S358L mutation mouse model (Tmem43S358L) that displayed signs of cardiac dysfunction, resembling ARVC5 phenotype seen in humans. We found high Tmem43 levels among BXDs with broad variability in expression. Expression of Tmem43 highly negatively correlated with heart mass and heart rate among BXDs, whereas levels of Tmem43 highly positively correlated with plasma high-density lipoproteins (HDL). Through finding differentially expressed genes (DEGs) between Tmem43S358L mutant and wild-type (Tmem43WT) lines, 18 pathways (out of 42 found in BXDs GRP) that are involved in ARVC, hypertrophic cardiomyopathy, dilated cardiomyopathy, nonalcoholic fatty liver disease, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease were verified. We further constructed Tmem43-mediated gene network, in which Ctnna1, Adcy6, Gnas, Ndufs6, and Uqcrc2 were significantly altered in Tmem43S358L mice versus Tmem43WT controls. Our study defined the importance of Tmem43 for cardiac- and metabolism-related pathways, suggesting that cardiovascular disease-relevant risk factors may also increase risk of metabolic and neurodegenerative diseases via TMEM43-mediated pathways.

Trimethylamine N-oxide (TMAO) is a gut microbiota metabolite derived from trimethylamine- containing nutrient precursors such as choline, L-carnitine, and betaine, which are rich in many vegetables, fruits, nuts, dairy products, and meats. An increasing number of clinical studies have demonstrated a strong relationship between elevated plasma TMAO levels and adverse cardiovascular events. It is commonly agreed that TMAO acts as an independent risk factor and a prognostic index for patients with cardiovascular disease. Although most animal (mainly rodent) data support the clinical findings, the mechanisms by which TMAO modulates the cardiovascular system are still not well understood. In this context, we provide an overview of the potential mechanisms underlying TMAO-induced cardiovascular diseases at the cellular and molecular levels, with a focus on atherosclerosis. We also address the direct effects of TMAO on cardiomyocytes (a new and under-researched area) and finally propose TMAO as a potential biomarker and/or therapeutic target for diagnosis and treatment of patients with cardiovascular disease.

Background Dilated cardiomyopathy (DCM) is a well-described entity for heart failure (HF) with reduced left ventricular ejection fraction (LVEF). Recently, drugs and other substance of abuse have been recognized as potential triggers for DCM. The aim of this study was to assess the survival in patients under 65 years old with toxic cardiomyopathy (TCM). Left ventricular remodeling and the potential usefulness of left ventricular assist device (LVAD) was also assessed. Methods Single center retrospective study from January 2003 to August 2019 at a tertiary care cardiology center identified 553 patients younger than 65 years old with LVEF Results Two hundred and one patients (36%) had a diagnosis of idiopathic DCM. Further analysis identified 38 patients (19%) for which a TCM was the most likely etiology (amphetamine [50%], cocaine [37%], anabolic steroids [8%], and energy drinks [5%]). Despite a mean LVEF of 17±8% at presentation, most patients (n=27, 71%) had an event-free survival with guideline-directed medical therapy, and 61% (n=23) recovered a LVEF ≥40% after a median follow-up of 21±23 months. Seven patients (18%) required a LVAD and 1 (3%) patient a transplantation. All LVAD were explanted or decommissioned after a median support time of 11±4 months following partial or complete LVEF recovery. Conclusion TCM induced by substance abuse is a frequent cause of HF accounting for almost 20% of all patients with DCM of unknown etiology under 65 years of age. Treatment must be tailored on an individual basis. Mechanical circulatory support demonstrated its usefulness in carefully selected patients.

The prevalence of sarcoidosis-related cardiomyopathy is increasing. Sarcoidosis impacts cardiac function through granulomatous infiltration of the heart, resulting in conduction disease, arrhythmia and/or heart failure. Diagnosis of cardiac sarcoidosis can be challenging and requires clinician awareness as well as differentiation from overlapping diagnostic phenotypes such as other forms of myocarditis and arrhythmogenic cardiomyopathy. Clinical manifestations, extracardiac involvement, histopathology, and advanced cardiac imaging can all lend support to a diagnosis of cardiac sarcoidosis. Mainstay therapy for cardiac sarcoidosis is immunosuppression, however no prospective clinical trials exist to guide management. Patients may progress to developing advanced heart failure or ventricular arrhythmia, for which ventricular assist device therapies or heart transplantation may be considered. The existing knowledge gaps in cardiac sarcoidosis call for an interdisciplinary approach to both patient care and future investigation to improve mechanistic understanding and therapeutic strategies.

Objectives This study aimed to determine the feasibility of using radioablation for arrhythmogenic a substrate modification. Background Stereotactic body radiation therapy (SBRT) is a promising therapy for ventricular tachycardia (VT) refractory to catheter ablation. Methods A total of 6 male patients (median age 72 years) with ischemic cardiomyopathy (left ventricular ejection fraction 20% [interquartile range (IQR): 16%-25%]) and VT refractory to antiarrhythmic medications and catheter ablations underwent SBRT to extensive scar substrate. In addition to electroanatomical mapping, 5 of 6 patients had computed tomography segmentation using MUSIC (Institut Hospitalo-Universitaire l’Institut de Rythmologie et Modelisation Cardiaque, Bordeaux, France). Regions of wall thinning Results The median planning target volume was 319 (IQR: 280-330) mL. Device-treated or sustained VT episodes were not significantly reduced by radioablation (median 42 [IQR: 19-269] to 29 [IQR: 0-81]; P = 0.438). However, a reduction in device shocks was observed from 12 (IQR: 3-19) to 0 (IQR: 0-1) (P = 0.046). Over a follow-up period of 231 (IQR: 212-311) days, 3 patients died of end-stage heart failure and 3 of 6 patients had possible adverse events (heart failure exacerbation, pneumonia, and an asymptomatic pericardial effusion). Conclusions Substrate modification using SBRT assisted by computed tomography segmentation is feasible for treatment of VT in patients with ischemic cardiomyopathy. Although a significant reduction in device shocks was observed, suboptimal VT burden reduction and significant mortality rate in this cohort of patients with advanced cardiomyopathy underscore the need to improve mechanistic understanding for antiarrhythmic effects to guide dosing and targeting of scar substrates.

Takotsubo cardiomyopathy (TCM) associated with left ventricular outflow tract (LVOT) obstruction in the event of an ST-elevation myocardial infarction (STEMI) is a rare cause of hypotension during percutaneous coronary intervention (PCI). Herein, we describe a 57-year-old woman who presented with STEMI and underwent PCI. She developed hypotension which worsened during inotropic therapy. Echocardiography revealed evidence of LVOT obstruction in the setting of TCM. Therefore, inotropic support was promptly discontinued. Beta blockers and phenylephrine were rapidly administrated, resulting in improved blood pressure and stabilisation of the patient.

Takotsubo cardiomyopathy (TCMP) is an important, though under-recognised, syndrome which mimics acute coronary syndrome (ACS) presenting with similar clinical, biochemical and ECG features. A 68-year-old man was referred as ACS for emergency coronary angiography; however, a history of lethargy, weight loss and electrolyte abnormalities prompted further investigations. Angiography was postponed, adrenal insufficiency confirmed and steroid replacement commenced. Echocardiography demonstrated reduced left ventricular (LV) function (45%) with regional wall motion abnormalities, although angiography confirmed unobstructed arteries. Steroid replacement induced a rapid improvement in symptoms and LV function. Few cases of TCMP associated with adrenal insufficiency have been reported. This appears to be the first case describing TCMP precipitated by new-onset secondary adrenal insufficiency following long-term steroid use in a male patient, and highlights the importance of considering TCMP in patients presenting with suspected ACS. Here, prompt recognition and treatment of a serious underlying disorder prevented a potentially life-threatening Addisonian crisis.

Mitochondrial diseases are rare, often go undiagnosed and can lead to devastating cascades of multisystem organ dysfunction. This report of a young woman with hearing loss and gestational diabetes illustrates a novel presentation of a cardiomyopathy caused by a previously described mutation in a mitochondrial gene, MT-TL1. She initially had biventricular heart dysfunction and ventricular arrhythmia that ultimately recovered with beta blockade and time. She continues to participate in sport without decline. It is important to keep mitochondrial diseases in the differential diagnosis and understand the testing and management strategies in order to provide the best patient care.

In the last years, the field of inheritable ventricular arrhythmia disease modelling has changed significantly with a push towards the use of novel cellular cardiomyocyte based models. However, there is a growing need for new in vivo models to study the disease pathology at the tissue and organ level. Zebrafish provide an excellent opportunity for in vivo modelling of inheritable ventricular arrhythmia syndromes due to the remarkable similarity between their cardiac electrophysiology and that of humans. Additionally, many state-of-the-art methods in gene editing and electrophysiological phenotyping are available for zebrafish research. In this review, we give a comprehensive overview of the published zebrafish genetic models for primary electrical disorders and arrhythmogenic cardiomyopathy. We summarise and discuss the strengths and weaknesses of the different technical approaches for the generation of genetically modified zebrafish disease models, as well as the electrophysiological approaches in zebrafish phenotyping. By providing this detailed overview, we aim to draw attention to the potential of the zebrafish model for studying arrhythmia syndromes at the organ level and as a platform for personalised medicine and drug testing.

Amaç: Bu çalışma, tip 1 tirozinemi hastalarında kardiyomiyopati sıklığını ve rutin olarak kullanılan nitisinon tedavisine yanıtını retrospektif olarak değerlendirmeyi amaçlamıştır.Gereç ve Yöntem: Tanımlayıcı ve kesitsel olan bu çalışmadaki olgular, tek bir metabolizma ünitesinin takibinde olan Tirozinemi Tip 1 hastalarıdır. Çalışmanın önceliği tanı anında “anormal ekokardiyografik bulguların varlığını” ve nitisinon tedavisinin bu bulgulara etkisini değerlendirmektir. Bulgular: Çalışmaya alınan 54 hastanın 21'i (%38,9) kız, 33'ü (%61,1) erkekti. 41 hasta tanı anında ekokardiyografi ile değerlendirildi. Dokuzunda (%21,9) farklı şiddette hipertrofik kardiyomiyopatik değişiklikler mevcuttu. Takip döneminde yapılan ikincil ekokardiyografik incelemeler, nitisinon tedavisinin kardiyak durumda iyileşmeye sebep olduğunu ortaya koydu. On üç hasta takipleri bıraktı. Geriye kalan 41 hastanın 10’u (%24,4) kaybedildi, 31 (%75,6) hasta ise hayatta kaldı. Ekokardiyografik değişiklikleri olan hastalar, ekokardiyografik anormalliği olmayan hastalarla karşılaştırıldığında, plazma aspartat aminotransferaz (AST), total bilirubin ve direkt bilirubin konsantrasyonları açısından istatistiksel olarak anlamlı farklılıklar bulundu Sonuç: Kardiyak bulgusu olmayanlar da dahil olmak üzere tüm tirozinemi tip 1 hastalarında ekokardiyografik inceleme yapılmalıdır. Kardiyomiyopatinin varlığı kötü bir prognoza işaret edebilir. Nitisinonun tip 1 tirozinemili hastalarda kardiyomiyopati üzerinde olumlu bir etkisinin olduğu bulunmuştur., Purpose: This study aimed to retrospectively evaluate the frequency of cardiomyopathy and its response to routinely used nitisinone treatment in patients with tyrosinemia type 1.Materials and Methods: Participants of this descriptive cross-sectional study were Tyrosinemia Type 1 patients who were under the care of a single metabolic unit. The primary outcome of the study was “presence of abnormal echocardiographic findings” at diagnosis and the impact of nitisinone treatment on the detected findings.Results: Of the 54 patients enrolled in the study, 21 (38.9%) were female and 33 (61.1%) were male. 41 patients were evaluated using echocardiography at the time of diagnosis. 9 (21.9%) of them had hypertrophic cardiomyopathic alterations varying in severity. In the follow-up period, second echocardiographic examinations revealed improvements in cardiac alterations while on nitisinone treatment. Thirteen patients dropped out of follow-up. Of the remaining 41 patients, 10 (24.4%) patients died in the follow-up period, whereas 31 (75.6%) remained alive. Plasma aspartate aminotransferase (AST), total bilirubin, and direct bilirubin concentrations were significantly higher in patients witj normal cardiac evaluation.Conclusion: Echocardiographic examination should be done in all tyrosinemia type 1 patients including those with an absence of cardiac manifestations. The presence of cardiomyopathy may indicate a poor prognosis. Nitisinone is found to have a positive impact on cardiomyopathy in patients with type 1 tyrosinemia.

Wilms tumor (WT) is the most common malignant kidney tumor in children. High blood pressure is seen in up to 55% of children with WT. However, hypertensive cardiomyopathy with congestive heart failure due to WT is remarkably rare, with only several cases reported worldwide. In this report, a pediatric case of WT with hypertension causing hypertensive cardiomyopathy and congestive heart failure is presented. An 8-month-old male child with abdominal distension was seen by his primary physician. He was referred to our hospital for further examination and treatment. Abdominal contrast-enhanced computed tomography demonstrated a weakly enhancing, large abdominal mass, which was larger than 12 cm. Two-dimensional transthoracic echocardiography showed a diffuse hypokinetic left ventricle. The patient was diagnosed with cardiomyopathy caused by hypertension. Open surgical resection of the mass was successfully performed. His postoperative course was uncomplicated, and the patient was successfully discharged. The plasma renin activity was maintained at a high level even after left nephrectomy, suggesting that the right kidney was likely the source of renin secretion. Mechanical compression of the right renal blood vessels by a greatly enlarged left kidney can cause right renal ischemia, which activates renin excretion. Nephrectomy can be an effective treatment for a WT patient with hypertension causing hypertensive cardiomyopathy, and then cardiac function will be improved within several weeks. We recommend routine echocardiography surveillance in patients with WT. This report can help pediatric surgeons become more familiar with cardiomyopathy caused by WT.