Although not frequent in the pediatric population, ischemia could occur in children due to several congenital and acquired disease. Stress imaging is key for the non-invasive evaluation of myocardial abnormalities and perfusion defect in this clinical setting. Moreover, beyond ischemia assessment, it can provide complementary diagnostic and prognostic information in valvular heart disease and cardiomyopathies. When performed using cardiovascular magnetic resonance, it could detect, in addition, myocardial fibrosis and infarction, increasing the diagnostic yield. Several imaging modalities are currently available for the evaluation of stress myocardial perfusion. Advances in technologies have also increased the feasibility, safety and availability of these modalities in the pediatric age group. However, despite the established role of stress imaging and its increasing use in daily clinical practice, there are currently no specific guidelines, and little data are available in the literature on this topic. The aim of this review is to summarize the most recent evidence on pediatric stress imaging and its clinical application with a focus on the advantages and limitations of each imaging modality currently available. The evaluation of physiological or pathological changes occurring during myocardial stress is of paramount importance in the pediatric population . Data coEchocardiography is a non-invasive cardiovascular imaging technique that uses ultrasound waves to generate images. This tool has the advantage of being widely accessible, radiation free and inexpensive. Echocardiography can give information regarding cardiac anatomy, systolic and diastolic function, providing a simultaneous assessment of cardiac valves. The use of a stressor  can complement standard assessment with information about myocardial ischemia.In the pediatric scenario, encouraging data on stress echocardiography utility have been collected in a plethora of pathologies such as post-transplant coronary vasculopathy; anomalous origin of coronary arteries; coronary abnormalities in KD; coronary reimplantation due to arterial switch or Ross operations; valvular heart diseases; evaluation of pulmonary vascular disease; timing of intervention when a conduit dysfunction is present; evaluation of vascular obstructive disease such as coarctation; single ventricles or systemic right ventricle (RV); and previous exposure to a cardiotoxic chemotherapy agent .Stress echocardiography can be performed with both a pharmacological stressor or through an exercise test. In the first scenario, two types of pharmacologic stressors are available: those that increase myocardial oxygen consumption  and those that cause coronary vasodilatation . In general, dobutamine is used more than dipyridamole, but the choice of stressor type is linked to the experience and availability of the single center.Dobutamine stress echocardiography (DSE) creates a positive inotropic and chronotropic effect on the heart which leads to increased myocardial oxygen demand.Dobutamine infusion starts at 5 mcg/kg/min and is increased at 3-min intervals to 10, 20, 30, 40, and 50 mcg/kg/min. If the maximal target heart rate (HR), defined as 85% of the maximal HR for age, is not reached, a low dose of atropine (0.01 mg/kg) can be added for a maximum of 0.25 mg per dose and 1–2 mg in total. Esmolol can be used to reverse adverse reactions.Vasodilator agents are contraindicated in advanced atrioventricular blocks, marked hypo- or hypertension, sinus bradycardia, active bronchoconstrictive or bronchospastic disease with regular use of inhalers, and known hypersensitivity to the components. Instead, contraindications to dobutamine include severe hypertension, unstable angina pectoris, severe aortic valve stenosis, complex cardiac arrhythmias, hypertrophic obstructive cardiomyopathy, myocarditis, endocarditis, or pericarditis. Finally, atropine use is not allowed in case of narrow-angle glaucoma, myasthenia gravis, and obstructive uropathy or gastrointestinal disorders. Side effects of dipyridamole are chest pain, headache, dizziness and rarely myocardial infarction, ventricular tachycardia, and transient ischemic attack. Similarly, high-dose dobutamine may cause chest pain and palpitations but also myocardial infarction, ventricular fibrillation, and sustained ventricular tachycardia . ExercisChildren younger than 8 years are usually unable to cooperate and, for this reason, they are often referred to a pharmacological stress test with either general anesthesia or mild sedation; as previously mentioned, when they are older or able to cooperate, an exercise test is usually preferred.In pharmacological stress tests, resting images are usually acquired at baseline and subsequently during stress after each increase in drug dose. In ESE, images are acquired at baseline, during incremental exercise and early within 60 sec of peak exercise, given the rapid drop in peak HR in children compared to adults.Regardless of the type of protocol used, images at rest, during stress, and in the recovery period are required. The echocardiographic images must allow the best visualization of regional and global myocardial motion . GeneralDespite the several advantages named so far, echocardiography has some limitations. Suboptimal acoustic windows can significantly decrease the quality of the images acquired, particularly in patients with previous chest surgery. Furthermore, the presence of left bundle branch block, pre-existing wall motion abnormalities, malignant cardiac arrhythmias , hemodynamically significant LV outflow tract obstruction, and severe systemic hypertension are other important contraindications.Finally, stress echocardiography needs adequate and specialized training compared to the rest of echocardiography, limiting the access to this modality at center with higher expertise ,10.Stress testing in nuclear cardiology for myocardial perfusion imaging involves a stress test  and a scintigraphic scan of the heart, with the administration of a radiopharmaceutical. Scintigraphic images are obtained after myocardial stress and in rest conditions  with theThe main clinical indications of stress testing imaging in pediatric nuclear cardiology are represented by KD to evaluate myocardial ischemia and/or myocardial infarction  12,13],,13,12,13In nuclear cardiology, stress testing may be performed with physical stressors (such as cycle ergometer) or pharmacological stressor or the combination of the two. Pharmacological stress is usually preferred in children since tests with physical stressors require high compliance from patients .Adenosine is the most used pharmacological stressor in pediatric patients : adenosiStress testing imaging may be obtained by means of single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after the injection of radiopharmaceuticals: for the injected dose, it is important to underline that the ALARA (“as low as reasonably achievable”) principle must be followed in order to minimize radiation exposure. In general, a dose reduction could be performed with algorithms (for example “European association of nuclear medicine (EANM) dose calculator”) or with the EANM Dosage Card ,25,26.SPECT images are acquired with a gamma camera: a two-head gamma camera—preferably one with an L configuration, using a 180-degree rotation from the right anterior oblique to left posterior oblique; moreover, the utilization of pinhole or converging collimators may be useful in pediatric patients in order to optimize SPECT imaging with an improved spatial resolution .99mTc-2-methoxyisobutylisonitrile (99mTc-Sestamibi), 99mTc-1,2-bis[bis(2-ethoxyethyl) phosphino] ethane (99mTc-Tetrofosmin), and thallium-201 (201Tl) chloride. 99mTc-Sestamibi and 99mTc-Tetrofosmin are cationic complexes that diffuse passively through the capillary and cell membrane: the myocardial uptake of these radiopharmaceuticals augments with increase in perfusion, reflecting myocardium viability  Ammonia ([13N]NH3) in children after arterial switch operation for the transposition of great arteries [13N]NH3 is required due to the short half-life of this radiopharmaceutical (9.96 min) [13N]NH3 in clinical practice.PET imaging has a higher spatial resolution in comparison to SPECT; furthermore, this imaging technique may provide an accurate quantitative data of myocardial blood flow. Nonetheless, few reports in the literature concerning stress testing imaging in pediatric nuclear cardiology are available: these reports are mainly focused on PET with ..65].In neonates and young children, non-ionic iodinated contrast agents are injected at a dose of 2 mL/kg to a maximum amount of 100 mL. The injection could be at 1 mL/s but might be increased to 2 mL/s in patients with a large intracardiac communication . In adults, 1.5 mL/kg is generally injected at a rate of 3–4 mL/s. In ECG-synchronized CT, the scan delay is determined through the bolus-tracking technique. The region of interest (ROI) in pediatric patients is positioned in the left ventricle at a threshold attenuation of 200 HU. In adult patients, the ROI is sited in the ascending or descending aorta, and the attenuation threshold is set at 140–180 HU .Dual-source CTCA scanners implementation  drastically diminished cardiac and respiratory motion artifacts. They offer diagnostic images even at higher heart rates (>80 bpm). Therefore, exams performed for most indications can be acquired without sedation and during free breathing ,64.As with other myocardial perfusion imaging exams , the myocardial CT perfusion protocol consists of an acquisition during stress, which is caused by the administration of pharmacological agents such as adenosine, to induce vasodilation. A resting acquisition, and a third delayed acquisition, which can be performed in cases where a late-contrast-enhanced evaluation of myocardial scars is desired. Heart rhythm and symptoms are monitored throughout the whole exam ,66.In detail, after scouting images and testing bolus, adenosine can be administrated at an infusion rate of 140 μg/kg/min . Three mDespite the premises and the promising techniques implemented in adults, several issues should be addressed and discussed when dealing with pediatric patients, especially when neonates. Firstly, stress imaging techniques cannot be applied/implemented when sedation is contextually administrated. Therefore, a certain collaboration during myocardial perfusion CTCA imaging is needed; this depends on the patients’ age and compliance; children are usually more compliant when >6–7 years old. If they are >4 years old, each exam should be tailored to every single patient. In addition, given the incremental radiation dose exposure for stress CTCA imaging, the risks and benefits of each exam should be carefully balanced. Finally, the stress SPECT or PET protocols with 6-min adenosine infusion have been demonstrated to be superior to 3-min ones in the detection of coronary artery disease (CAD) in adults, while uncertainty persists regarding the relationship between ischemia and exercise-induced abnormalities in myocardial perfusion imaging in children. Ischemic echocardiographic and ECG changes may have a different stage in pediatric patients with Kawasaki disease, coronary arteries abnormalities (both origin and course) or myocardial bridges and fistulas. To date, it is unclear whether the “ischemic cascade” concept that has been found to be so helpful in the diagnosis and management of typical adult atherosclerotic CAD applies with equal validity to these anatomically and physiologically distinct conditions . TherefoAll advantages and disadvantages of the single cardiovascular imaging method are summarized in Transposition of the great arteries (TGA) is a complex congenital heart disease characterized by ventricular arterial discordance that is treated in the first weeks of life with an ASO operation where the aorta is transacted and reconnected to the left ventricle (LV) and pulmonary artery to the RV. In this delicate procedure, coronary buttons are created and reimplanted onto the aorta . This laAssessment with stress imaging is therefore mandatory to evaluate ischemia in this clinical scenario. Hui et al. demonstrated in a cohort of 31 ASO patients that DSE was able to unmask wall motion abnormalities in 74% of patients n = 23). Myocardial perfusion scan was subsequently performed in 22 patients, confirming perfusion defects in the dysfunctional segments in 77% (n = 17) of them . Another. MyocardAlthough there is no consensus regarding the appropriate timing for these examinations, Sterrett et al. recommended serial myocardial perfusion stress testing during periods of growth; every 3 years and before high school sports participation .Coronary artery vasculopathy (CAV) in one of the most common consequences of heart transplantation, with angiography currently representing the gold standard for the assessment of this disease. However, this method is invasive with possible, even life-threatening, complications. Stress imaging therefore represents a valuable alternative in this setting and is currently recommended by expert consensus . DSE hasKD is a systemic inflammatory vasculitis that tends to affect small vessels and that frequently involves coronary arteries causing coronary artery dilation and aneurysms . It is cAnomalous origin of a Coronary Artery (AOCA) is one of the most common causes of sudden cardiac death, with intramural or inter-arterial course of the left coronary artery being the highest risk variants . CCTA isAlthough atherosclerotic disease is very rare in children, patients with homozygous familial hypercholesterolemia can have severe coronary artery disease with myocardial infarction even at a pediatric age . For theCoronary microvascular dysfunction (CMD) may represent one of the causes of chest pain even in pediatric patients, particularly in the context of congenital heart disease or long-standing type 1 diabetes mellitus . AlthougOf note, in the adult population, the measurement of FFR retrospectively or prospectively from simple invasive coronary angiography images has led to the defniton of the quantitative flow ratio (QFR). This is a new important parameter to detect the presence of inducible ischemia. However, in the pediatric population where the main coronary disease is not coronary arteriosclerosis, this has still not been applied. Given its great results, it could be an important future resource that could be used in these patients ,99.Evaluation of cardiac performance and perfusion during stress condition is key in several congenital and acquired conditions. Although the role of stress testing is already established in the pediatric population, there are currently no specific clinical guidelines for this age group. Different imaging modalities can be used for stress evaluation, each one with its advantages and disadvantages. Echocardiography is a widely available, radiation-free, and low-cost technique that can be used during either pharmacological or exercise stress. Despite representing the first-line stress imaging modality, its accuracy could be significantly reduced in patients with poor acoustic windows, particularly after chest surgery. Nuclear imaging can overcome this drawback; technological evolution with improved detectors and the advent of hybrid machines (SPECT/CT and PET/CT) have reduced the amount of radiation exposure with improved diagnostic accuracy. Similarly, the advent of dual source CT scanners along with high-pitch modality have significantly reduced the overall amount of radiation needed to obtain CTCA and stress perfusion CT in children. However, acquiring stress images with CT could be particularly challenging in non-compliant children, and the modality requires the use of an iodinated contrast agent which is contraindicated in patients with severe chronic kidney disease. Stress CMR represents a valuable non-invasive imaging alternative with very few limitations represented by the high cost of the modality, long acquisition time and the relative contraindication in patients with some metallic devices. Its unique tissue characterization properties along with the complete absence of radiation make CMR particularly appealing when assessing young patients, often requiring serial imaging evaluation. The options available are therefore several and always more often integrated in a multi-modality approach. Clinicians should be aware of the strengths and limitations of each modality in order to choose the best technique and one which is most likely able to answer the clinical question. Finally, beyond diagnostic performance and limitations, particularly in the pediatric age group, local expertise and availability are crucial factors when deciding which is the most suitable stress test to perform.


Myocardial fibrosis resulting from the excessive deposition of collagen fibers through the myocardium is a common histopathologic finding in a wide range of cardiovascular diseases, including congenital anomalies. Interstitial fibrosis has been identified as a major cause of myocardial dysfunction since it distorts the normal architecture of the myocardium and impairs the biological function and properties of the interstitium. This review summarizes current knowledge on the mechanisms and detrimental consequences of myocardial fibrosis in heart failure and arrhythmias, discusses the usefulness of available imaging techniques and circulating biomarkers to assess this entity and reviews the current body of evidence regarding myocardial fibrosis in the different subsets of congenital heart diseases with implications in research and treatment. The history of congenital heart disease (CHD) is a history of hope and success. Since the first ligation of a patent ductus arteriosus accomplished by Gross and Hubbard on August 8, 1938  has gone from the role of innocent bystander to a preeminent position in the pathogenesis of long-term cardiovascular complications, mainly HF. The MI is not a passive entity, but rather a complex and dynamic microenvironment that undergoes constant turnover: it ensures structural myocardial integrity, executes the repair response after injury, provides the means for force transmission throughout the cardiac cycle, translates myocyte shortening into overall ventricular pump function and facilitates communication between cells .The accumulation of fibrillar collagen in the interstitial space, the so-called myocardial interstitial fibrosis, has been identified as a major cause of myocardial dysfunction. It not only distorts this normal architecture but also impairs its biological function and properties.The term “interstitial myocardial disease” was first coined in 1989 by Weber  in referAltered hemodynamic conditions are a common feature of most CHDs, both before and after palliation or complete repair. Therefore, MF is expected to be one of the main maladaptative mechanisms behind the progressive deterioration of ventricular function in our patients and a potential therapeutic target.This paper aims to summarize current knowledge about MF in terms of pathophysiology, diagnostic tools and potential treatments, focusing on the CHD population.For a simplified description, the myocardium can be dichotomized into two components. The cellular component is mainly represented by cardiomyocytes, occupying 75% of the myocardium but only conforming one-third of the cell population. The rest is constituted of endothelial cells, vascular smooth muscle cells, fibroblasts, macrophages and mast cells.. The non-cellular component of the myocardium is also located in the interstitial space and mainly comprises fibrillar collagen (95% of the extracellular matrix) but has also other constituents: proteoglycans, glycosaminoglycans and different bioactive signaling molecules , 5.Among the cellular constituents, fibroblasts are responsible for the synthesis and maintenance of cardiac connective tissue. Fibroblasts can migrate to areas of damaged myocardium  where they trans-differentiate into myofibroblasts, which are crucial cells for cardiac remodeling and fibrosis . A myriaAs for non-cellular components, fibrillar collagen is the cornerstone, with five isoforms in the myocardial interstitium: collagen type I, III, IV, V and VI. Type I collagen is the predominant, representing 80% of the total. It offers the greatest tensile strength (comparable to steel) and represents the major determinant of myocardial stiffness. Type III collagen has more elastic characteristics, representing 10% of collagens, and the other types constitute the remaining 10% , 10.reparative, replacement or focal myocardial fibrosis (FMF) develops as a healing mechanism at the site of a previous myocardial injury . The necrotic tissue is replaced by collagen fibrils that are cross-linked to provide mechanical stability in response to cardiomyocyte loss. On the other hand, reactive diffuse myocardial fibrosis (DMF) is characterized by a diffuse deposition of excess fibrous tissue relative to the mass of cardiomyocytes. In this case, MF appears as an accumulation of collagen fibers between individual cardiomyocytes and cardiomyocyte fascicles and around the intramyocardial vessels. As a result, the highly organized architecture of the myocardial interstitium is replaced with a thickened, poorly organized structure , the so-called collagen cross-linking, will influence the resistance to degradation by matrix metalloproteinases (MMPs) and will also have an impact on myocardial stiffness.Finally, it is well known that, coming from different embryonic origins, the left ventricle (LV) and the right ventricle (RV) respond distinctly to normal and abnormal loading conditions . TherefoInterstitial MF has classically been related to the development of diastolic impairment since an excessive accumulation of insoluble collagen in the ECM leads to an abnormally stiff myocardium see .In a physiological state, collagen fibers form a deformable elastic structure that stores energy when deformed from its neutral position during systolic contraction. Lengthening of the myocardium during diastole is then facilitated by the release of potential energy stored during systolic compression of these fibers, generating a suction effect that allows early diastolic filling .When extracellular viscoelastic properties are impaired this suction effect is compromised. This leads to a higher dependence on atrial contraction and elevated filling pressures to maintain the stroke volume, which can also cause venous congestion and ultimately result in congestive heart failure.Aside from the absolute amount of collagen, myocardial stiffness also depends on the characteristics of the fibers in the extracellular matrix. Thus, a higher fiber linkage and a higher proportion of type I collagen have also been correlated with impaired diastolic parameters in echocardiography, elevated peptides or elevated filling pressures in right heart catheterization –27.In this setting, MF might just be part of the reparative response to the loss of contractile mass, becoming a marker of more advanced cardiomyopathy . Howevervia several mechanisms, constituting an important arrhythmic substrate. Beyond re-entry tachycardias around macroscopic scars , DMF interferes with myocardial electrophysiology by slowing down action potential propagation, initiating re-entry, promoting after-depolarizations, and increasing ectopic automaticity  methodologies for the detection of MF are based on the concept that fibrosis increases the extracellular space . As prevThere are two major CMR techniques used for MF assessment: late gadolinium enhancement (LGE) imaging and T1 mapping/extracellular volume (ECV) fraction calculation.LGE is a CMR technique that identifies areas of discrete replacement fibrosis. Image acquisition is typically performed 10–20 min after administration of a gadolinium-based contrast agent. In damaged myocardial tissue, where there has been a significant localized expansion of the extracellular matrix, the distribution volume of the contrast agent is increased and the wash-out delayed .LGE requires spatial heterogeneity to detect focal fibrosis, being a dichotomous method. It has the advantage that it analyzes the entire cardiac image, without focusing on a specific area, so it could be more sensitive for overall fibrosis burden, even though it requires a greater amount of fibrosis to be detectable visually .ECV mapping quantifies MF by measuring the extracellular compartment depicted by the myocardial uptake of contrast relative to plasma . ECV repECV has advantages over LGE, being intrinsically quantitative and able to assess both focal and diffuse fibrosis. However, although fibrosis is certainly a cause of increased ECV, it is not the only one, as extracellular space expansion may be due to other causes  , 42, 43.Even so, ECV is the most widely used imaging biomarker for interstitial fibrosis  as it haBoth ECV and T1 are quantitative measures that can allow us to grade disease activity, monitor progress and guide treatment . HoweverMF is the final common pathway of a variety of congenital lesions. It is found in both the right and left ventricles and is not limited to areas of surgical scarring or within a coronary distribution  (FMF), bSeveral studies have characterized MF by CMR in CHD , 55; howCHD patients present certain peculiarities and common challenges to CMR when studying MF, such as wide and abnormally shaped QRS complexes, breath-holding difficulties, metallic artifacts from sternal wires and transcatheter devices, as well as pathology focused on the thin-walled RV .Multiple circulating biomarkers of collagen metabolism have been described, but only a few molecules have demonstrated an association between the biomarker levels and histologically assessed myocardial collagen deposition or collagen cross-linking –61 see . A positThe biomarkers that have shown more consistent results and a higher pathological correlation with MF upon biopsy are the carboxy-terminal propeptide of type I procollagen (PICP), the amino-terminal propeptide of type III procollagen (PIIINP) and the ratio of serum carboxy-terminal telopeptide of type I collagen to serum matrix metalloproteinase-1 (CITP:MMP-1ratio) , 40. ThePICP is generated during the extracellular maturation of the collagen molecule by conversion of procollagen type I into collagen type I by the enzyme bone morphogenetic protein-1 or procollagen carboxy-terminal proteinase .Serum levels of PICP have been associated with various findings: myocardial deposition of collagen type I fibers in HF patients ; correlaMost serum PIIINP is generated during the extracellular conversion of procollagen type III to collagen type III by the enzyme procollagen amino-terminal proteinase . An assoOnce the collagen molecule is mature, the spontaneous self-assembling of molecules results in the formation of collagen fibrils. In a second step, the formation of intra- and intermolecular covalent bonds, cross-links, between lysine residues ensues.Collagen cross-linking determines the resistance of collagen fibers to MMP degradation; therefore, the highly cross-linked type I collagen fibers have increased resistance to degradation by MMP1, producing a reduction in collagen type I telopeptide (CITP) levels and, thereby, a decreased CITP:MMP1 ratio. Thus, the serum CITP:MMP-1 ratio inversely correlates with myocardial collagen cross-linking .A low CITP:MMP-1 ratio has been associated with a higher risk of hospitalization for HF and cardiovascular mortality in hypertensive patients , 69. It Myocardial fibrosis is the final common pathway of a variety of CHDs due to the multiple procedures and situations of volume and pressure overload to which these hearts are subjected throughout their lives. The current evidence regarding myocardial fibrosis in specific congenital heart conditions will be reviewed in this chapter, focusing on the most common congenital cardiac disorders.There is histological evidence of increased interstitial collagen deposition in patients with tetralogy of Fallot (TOF). Existing data suggest that chronic exposure to cyanosis and pressure overload play a role in the development of MF before repair . UnloadiIn 2006, Babu-Narayan et al. , publishRV LGE has been related to RV diastolic dysfunction  and fragDMF has also been studied in patients with TOF. Chen and colleagues  found a Elevated RV and LV ECVs have been associated with older age, age at TOF repair, neurohormonal activation, longer QRS duration, shorter six-minute walk distance, larger left atrial volume and adverse outcomes, including death, congestive heart failure and arrhythmias , 75, 76.There are some studies with negative results. Using native T1 mapping, Yigit et al. , found fAs for circulating biomarkers, patients with repaired TOF exhibit a pattern of excessive collagen synthesis and dysregulated degradation, with elevated circulating PICP and PIIINP levels and PICP:CITP ratio, a positive correlation between collagen synthesis biomarkers (PICP and PIIINP) and RV end-diastolic volumes (EDV) and a negative correlation with RV systolic function , 79.Atrial switch operation in patients with D-transposition leaves the RV as the systemic pump , 90, as via MRI . This could imply that DMF is present in the early stages of the disease and even in the absence of macroscopic scars.Recently, CMR studies with T1 mapping techniques for DMF characterization yielded interesting results. Plymen and colleagues  found a Broberg and co-workers  studied More intriguing results focusing on the subpulmonic LV were published recently , 104. AsThe arterial switch operation (ASO) is the current procedure of choice for patients born with D-TGA. In this population, the systemic LV is usually believed to be normal –110. HowIndeed, in the last few years, data with speckle tracking echocardiography have emerged suggesting that a mild impairment of LV function may be more common than previously thought –114.A single-center CMR cohort study  in 220 pDiastolic function may also be impaired. Some studies found slight differences in terms of ventricular stiffness and diastolic parameters when compared with healthy controls, but still within the normal range, and in the absence of an established LV hypertrophy . This covia activation of hypoxia-inducible factors  and different stages of the fibrotic process (more static vs. more dynamic) may coexist in the same individual and identification of the specific or dominant type of fibrosis would be important for the selection of the anti-fibrotic approach. Timely detection of fibrosis and determination of its state could potentially help diagnose and halt HF progression.There are several potential novel therapeutic strategies for MF coming from the idiopathic pulmonary fibrosis armamentarium , some of them showing promising results in preliminary studies . HoweverWhile current experimental studies and even clinical trials [pirfenidone is currently being tested in the PIROUETTE  phase IIWhile the prognostic role of preoperative myocardial fibrosis in patient outcomes after valvular replacement has been extensively studied , 134, thThe RV and LV have distinct fibrotic responses and, therefore, may require different therapeutical approaches . PirfeniWider availability of diagnostic methods to evaluate MF is needed. In recent years, cardiac computed tomography angiography (CTA) has yielded good results for MF assessment. An excellent correlation between ECV evaluated by CTA and by CMR has been shown in animal models, healthy volunteers and HF patients , 143. CTOn the other hand, new targeted approaches that have shown promising results for collagen detection in other organs, such as the novel molecular magnetic resonance contrast agents utilized in liver studies, might be applicable in heart diseases .In summary, understanding HF pathophysiology lies beyond the mere assessment of cardiac function. In-depth consideration of myocardial structure and function at the tissue level, particularly of the myocardial interstitium, provides additional and crucial insight and may drive the development of new therapies. MF, particularly diffuse interstitial fibrosis, constitutes an emerging and promising therapeutic target in HF secondary to acquired heart conditions. Due to intrinsic particularities , MF seems to play a determinant role in the development of HF and arrhythmias in CHD. Further studies in the field are needed to shed light on this exciting and promising area of research in CHD.


This study evaluated the prognostic value of staging right heart failure in patients with significant tricuspid regurgitation (TR) undergoing tricuspid valve (TV) surgery.Patients with significant TR who underwent TV surgery were divided into 4 right heart failure stages according to the presence of right ventricular (RV) dysfunction and clinical signs of right heart failure: stage 1 was defined as no RV dysfunction and no signs of right heart failure; stage 2 indicated RV dysfunction without signs of right heart failure; stage 3 included RV dysfunction and signs of right heart failure; and stage 4 was defined as RV dysfunction and refractory signs of right heart failure at rest.A total of 278 patients  were included, of whom 34 (12%) patients were classified as stages 1 and 2, 141 (51%) as stage 3 and 103 (37%) as stage 4 right heart failure. The majority of patients (91%) had TV surgery concomitant to left-sided valve surgery or coronary artery bypass grafting and 95% underwent TV annuloplasty. Cumulative survival rates were 89%, 78% and 61% at 1 month, 1 year and 5 years, respectively. Stages 1 and 2 and stage 3 were independently associated with better survival compared to stage 4 .Patients with significant TR undergoing TV surgery and diagnosed without advanced right heart failure have better survival as compared to patients with right heart failure. The prognostic implications of severe tricuspid regurgitation (TR) have been reported in several patient cohorts and left untreated, severe TR is associated with poor survival . The prognostic implications of severe tricuspid regurgitation (TR) have been reported in several patient cohorts and left untreated, severe TR is associated with poor survival , 2. CurrPatients with significant TR who subsequently underwent TV surgery, after multidisciplinary discussion in the Heart Team applying the prevailing guidelines for surgical valvular intervention , 4, betwThe institutional review board of the Leiden University Medical Centre approved the observational design and retrospective analysis of clinically acquired data (IRB: CME 10/053—18 May 2010) and waived the need for patient written informed consent.Baseline demographic, clinical, laboratory and echocardiographic variables were evaluated at the time of first diagnosis of significant TR on transthoracic echocardiography. Demographic characteristics included age, sex and body surface area. Clinical characteristics included symptoms of heart failure, relevant medical history and comorbidities and heart failure medication. Risk scores for predicting survival were calculated  and images were digitally stored for offline analysis . M-mode, 2-dimensional and colour and continuous- and pulsed-wave Doppler data were acquired from the parasternal, apical and subcostal views, according to current guidelines . Left veet al.  diagnosed with significant TR, who subsequently underwent TV surgery were included in the analysis. At the time of first diagnosis of significant TR on echocardiography, 34 patients (12%) were in stages 1 and 2, 141 patients (51%) were in stage 3 and 103 patients (37%) were in stage 4  functional class, peripheral oedema and diuretic use.The mean left ventricular ejection fraction was 44 (15)%, and concomitant significant aortic stenosis or mitral regurgitation was present in 22% and 54% of patients, respectively  were found across the different stages of right heart failure .P = 0.002).During a median follow-up of 75 (IQR: 19–114) months and a median follow-up index of 0.75 (IQR: 0.16–1.00), after TV surgery was performed, 147 deaths (53%) occurred. The cumulative survival rates were 89%, 78% and 61% at 1 month, 1 year and 5 years, respectively. The Kaplan–Meier curves for overall survival according to the different right heart failure stages are shown in Fig. Univariable and multivariable Cox regression analyses for all-cause mortality are presented in Table The aim of the present study was whether a staging algorithm of right heart failure is associated with outcomes, analysed individually as well as corrected for variables that have been associated with outcome in valvular heart disease; and not to build a prediction model. The main findings of the present study are two-fold: (i) the majority of patients with significant TR are referred for surgical intervention at a late stage, with symptoms and signs of right heart failure, and (ii) stages 1 and 2 and stage 3 of right heart failure are associated with better outcomes after surgery compared to stage 4.P < 0.001), despite a higher comorbidity burden with time; however, mortality rates remained higher when compared to those of other valve interventions. Congestive heart failure with NYHA functional class I–III symptoms as well as congestive heart failure with NYHA functional class IV symptoms were independently associated with increased mortality risk, odds ratio: 1.236  and 1.938 , respectively [et al. showed that among 449 patients with severe TR undergoing TV surgery 47% presented with NYHA functional class III or IV heart failure symptoms. Moreover, NYHA functional class IV was independently associated with an increased risk of all-cause mortality and with the occurrence of the composite end-point of death, TV reoperation and congestive heart failure [et al. [Timing of surgical intervention for severe TR remains challenging. Current guidelines recommend (preferably) surgical TV repair in patients with symptomatic severe TR and in patients with a dilated TV annulus who undergo left-sided valve surgical intervention , 4. Howeectively . Kim et  failure . Further [et al.  investigConsidering the relatively high mortality of TV surgery, there is a need for a better selection of patients with severe TR who may benefit from surgical TV intervention. Given that both NYHA functional class heart failure symptoms and RV function are independently associated with outcome after TV surgery, this study evaluated the prognostic value of a staging system, which integrates both variables. This novel staging system proved to be independently associated with outcomes and is easily applicable in clinical practice to guide decision-making regarding (earlier) referral for TV surgery.Transcatheter TV interventions, which are considered less invasive than surgery and have been proven safe and effective in reducing TR, provide a potential future therapeutic option for high-risk patients who were previously deemed inoperable . Albeit First, this study is limited by its retrospective design from a single tertiary centre with a limited number of patients and the results need to be confirmed in larger, prospective cohorts. Second, it is important to acknowledge the limitations in the evaluation of the staging system of RV dysfunction and right heart failure due to the complex RV geometry. Third, symptoms of right heart failure are subjective and other signs of right heart failure  might be incremental in the clinical evaluation. Fourth, time from the initial diagnosis of significant TR to TV surgery may significantly influence peri- and postoperative mortality. Accounting for this limitation, the time delay from diagnosis to surgery was included in the multivariable Cox regression analysis. Fifth, the current cohort included a few patients undergoing isolated TV surgery, which did not allow detailed analyses. This could be of interest for future research. Sixth, the design of the study did not allow any prediction statement. Applying the current staging system in future research to develop a prediction model, would be outstanding research. Seventh, clinical follow-up was left at the discretion of the treating physician without systematic clinical follow-up.Patients with significant TR are referred for surgical intervention at a late stage of right heart failure. The survival after surgical TV intervention is better among patients with stages 1 and 2, and stage 3 right heart failure compared to patients in stage 4.EJCTS online.Jan Stassen received funding from the European Society of Cardiology (ESC Training Grant App000064741). Steele C. Butcher received funding from the European Society of Cardiology (ESC Research Grant App000080404).Conflict of interest: The Department of Cardiology, Heart Lung Centre, Leiden University Medical Centre, has received unrestricted research grants from Abbott Vascular, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Medtronic and Novartis. This work was funded by an unrestricted research grant from Edwards Lifesciences (IISUSTHV2018017). Nina Ajmone Marsan received speaker fees from Abbott Vascular and GE Healthcare. Jeroen J. Bax received speaker fees from Abbott Vascular and Edwards Lifesciences. Victoria Delgado received speaker fees from Abbott Vascular, Edwards Lifesciences, GE Healthcare, Medtronic, MSD and Novartis. The remaining authors have nothing to disclose.All relevant data are within the manuscript and its supporting information files and are available on reasonable request to the corresponding author.Xavier Galloo: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Writing—original draft. Jan Stassen: Formal analysis; Investigation; Methodology; Writing—review & editing. Steele C. Butcher: Conceptualization; Formal analysis; Investigation; Methodology; Validation; Writing—review & editing. Maria Chiara Meucci: Formal analysis; Investigation; Methodology; Writing—review & editing. Marlieke F. Dietz: Conceptualization; Data curation; Formal analysis; Investigation; Writing—review & editing. Bart J.A. Mertens: Conceptualization; Methodology; Resources; Software; Writing—review & editing. Edgard A. Prihadi: Formal analysis; Investigation; Methodology; Writing—review & editing. Pieter van der Bijl: Formal analysis; Investigation; Visualization; Writing—review & editing. Nina Ajmone Marsan: Conceptualization; Data curation; Formal analysis; Funding acquisition; Supervision; Writing—review & editing. Jerry Braun: Methodology; Supervision; Visualization; Writing—review & editing. Jeroen J. Bax: Conceptualization; Data curation; Project administration; Supervision; Writing—review & editing. Victoria Delgado: Conceptualization; Data curation; Formal analysis; Project administration; Supervision; Writing—review & editing.European Journal of Cardio-Thoracic Surgery thanks Francesco Ancona, Michele Di Mauro, David Schibilsky and the other, anonymous reviewer(s) for their contribution to the peer review process of this article.ezac290_Supplementary_DataClick here for additional data file.


Anastomotic leakage remains the most feared complication in colorectal surgery. Various intraoperative tests evaluate bowel perfusion and mechanical integrity of the colorectal anastomosis. These tests reduce the risk of postoperative anastomotic leakage; however, the incidence remains high. Diverting loop ileostomy mitigates the damage if anastomotic leakage occurs. Nevertheless, ileostomy has a significant rate of complications, reducing patients’ quality of life, and requiring an additional operation. We evaluated six consecutive cases where bowel rest with total parenteral nutrition was used instead of diverting loop ileostomy. All colorectal anastomoses were at high risk of postoperative anastomotic leakage. Total parenteral nutrition was administered for the first seven days postoperatively. There were no serious complications during the recovery period, and no clinical postoperative anastomotic leakage was detected. All patients tolerated total parenteral nutrition. Bowel rest with total parenteral nutrition may be a feasible option in high-risk left-sided colorectal anastomosis and a possible alternative to a preventive loop ileostomy. Further studies are necessary to evaluate it on a larger scale. Anastomotic leakage (AL) remains one of the most feared complications in colorectal surgery. Despite immense research effort and practice changes, the percentage of AL remains high . A diverConsecutive patients undergoing elective left-sided colorectal resection with high-risk primary anastomosis  who agreed to participate were included. The central venous line was placed during anaesthesia, and patients underwent bowel rest with TPN for the first seven postoperative days.TPN consisted of 1477 mL SmofKabiven, 10 mL of Addaven, 10 mL of Soluvit N, and 10 mL of Vitalipid N. The infusion starting speed was 30 mL/hour on the first postoperative day, 45 mL/hour on the second, and 62 mL/hour on the third until the seventh postoperative day.Complete blood count, C-reactive protein (CRP), and electrolyte concentrations were monitored daily. After TPN, on the eighth postoperative day, patients were allowed to drink and eat liquid food.The primary outcome of the study was the AL rate. Secondary outcomes included postoperative morbidity rate and tolerance of TPN. Postoperative complications were graded by the Clavien–Dindo classification.Six patients were included in the study. Patient details are described in We present an alternative to diverting loop ileostomy by using bowel rest and TPN in high-risk left-sided colorectal anastomoses. There was no AL detected, and all patients tolerated bowel rest with TPN.Colorectal surgeons aim to create safe anastomosis by ensuring adequate bowel perfusion and mechanical integrity of the anastomosis. Several studies showed the benefit of bowel perfusion (indocyanine green) and mechanical integrity (air-leak and methylene blue) testing in reducing postoperative AL ,7,8. UnfOne of the recommendations for enhanced recovery after surgery (ERAS) is early postoperative oral nutrition . TherefoIn conclusion, bowel rest with total parenteral nutrition may be a feasible option in high-risk left-sided colorectal anastomosis and a possible alternative to a preventive loop ileostomy. Further studies are necessary to evaluate it on a larger scale.


We quantified total exposure to TMAO (AUC-TMAO) and classified individuals by the blood draw at which they experienced their maximal TMAO concentration (TMAO-response groups). We related AUC-TMAO to the 16S rRNA microbiome, to two SNPs in the exons of the FMO3 gene , and to a priori plasma metabolites. We observed varying TMAO responses (timing and magnitude) and identified a sex by age interaction such that AUC-TMAO increased with age in females but not in males . Few relationships between AUC-TMAO and the fecal microbiome and FMO3 genotype were identified. We observed a strong correlation between AUC-TMAO and TNF-α that depended on TMAO-response group. These findings promote precision nutrition and have important ramifications for the eating behavior of adults who could benefit from reducing TMAO exposure, and for understanding factors that generate plasma TMAO.Plasma trimethylamine n-oxide (TMAO) concentration increases in responses to feeding TMAO, choline, phosphatidylcholine, L-carnitine, and betaine but it is unknown whether concentrations change following a mixed macronutrient tolerance test (MMTT) with limited amounts of TMAO precursors. In this proof-of-concept study, we provided healthy female and male adults ( The circulating metabolome consists of metabolites that are absorbed directly from the diet, produced by human metabolism, and/or that are derived from the metabolism of the gut microbiome . StudiesTMAO can be absorbed directly by consuming foods containing TMAO or it can be formed via the microbial metabolism of choline, phosphatidylcholine, L-carnitine, and betaine to trimethylamine gas (TMA) ,6,7. TMATo investigate whether dietary components influence plasma TMAO concentrations, researchers have compared foods with different TMAO precursors  , foods w2 who were unmedicated for cardiometabolic diseases [Addressing this gap, we leveraged the cross-sectional Nutritional Phenotyping Study, which deeply phenotyped male and female adults aged 18-65 years and with a BMI of 18 to 44 kg/mdiseases . Individn = 49) and female (n = 48) participants were randomly selected from each sex-age-BMI bin  from the Nutritional Phenotyping Study for postprandial metabolomics assessment. This resulted in studying the metabolism of 30 adults aged 18–33 years, 32 adults aged 34–49 years, and 35 adults aged 50–65 years. The present cohort was multi-ethnic but was mostly represented by participants who self-identified as White (67%). This was similar to the 2020 California Census (71.1% White) [Participant characteristics are described in % White) . AverageThe composition of the standard mixed macronutrient tolerance test (MMTT) is provided in p-value = 0.244). Compared to fasting, average plasma TMAO remained elevated 3 h after consuming the MMTT  and then significantly decreased from 3 h to 6 h (p = 0.011) to concentrations similar to baseline at 4.76 ± 4.00 µM. The average fold change was 4.43-fold, but individual responses were highly variable with the maximum fold change of 23 starting at 11 µM and decreasing to 0.46 µM.We first assessed whether plasma TMAO concentration responded to a mixed macronutrient tolerance test (MMTT) with limited amounts of TMAO-precursors in a cohort of adults unmedicated for cardiometabolic diseases . Fastingp-value = 0.0112) such that AUC-TMAO increased with age in females but not in males  nor fasting plasma cystatin C , a marker of kidney function. This suggests that the observed changes in postprandial TMAO concentration are not driven by renal function. AUC-TMAO was correlated to fasting plasma TMAO concentration (r = 0.5), which was stronger in males (r = 0.6), than in females (r = 0.41)  was calculated for each participant using the trapezoid rule. A significant sex by age interaction was related to AUC-TMAO  B.p-value = 0.597), age , or BMI . At a given blood draw, differences in plasma TMAO concentration by TMAO-response group were observed . Further, 30 min after the MMTT, the average TMAO concentration in the peak-30m group was 10.05 ± 7.13 µM, which was significantly higher than that in each of the other groups . Three hours after the MMTT, participants in the peak-3h group had a significantly higher TMAO concentration than each of the other groups at 11.26 ± 11.88 µM.We noted individual variation in TMAO response to the MMTT. Although the average maximum TMAO concentration was recorded 3 h postprandially, the timing of the peak concentrations was variable by participant. We classified the participants according to the point where TMAO concentrations were maximally elevated . This reobserved . For exap < 0.001). Overall, the four distinct response types allowed us to utilize a precision nutrition approach by asking if relationships between health parameters differed by TMAO response type.Overall exposure to TMAO (AUC-TMAO) also varied by TMAO-response group. Participants whose maximal TMAO concentration was observed at 30 min or 3 h had the greatest quantified exposure to TMAO concentration over the 6 h window , Faith’s phylogenetic diversity , observed OTUs , Pielou’s evenness , and AUC-TMAO. In contrast, fasting TMAO concentration was significantly associated with Shannon diversity  suggesting that postprandial changes in TMAO are likely driven by factors independent of gut diversity captured by 16S rRNA based analysis of microbial diversity in the stool.After identifying distinct postprandial TMAO response types we interrogated the role of the gut microbiome using 16S rRNA sequence data isolated from stool collected prior to consuming the MMTT. We hypothesized that there could be compositional differences associated with differences in postprandial TMAO generation including its timed appearance and total amount . To evalWe then assessed whether there were compositional differences between TMAO-response groups while controlling for sex and age. PERMANOVA analysis was assessed to test differences by TMAO-response group with relation to dissimilarity matrices calculated using weighted UniFrac, unweighted UniFrac, and Bray Curtis methods. With each statistic, no compositional differences were observed.p-value = 0.759).Choline TMA-lyase, the enzyme that utilizes choline and generates TMA is more abundant in Firmicutes than Bacteroidetes. The mean ratios of the relative abundances of Firmicutes to Bacteroidetes by individuals in the peak-0m, peak-30m, peak-3h, and peak-6h groups were 8.25 ± 11.44, 10.28 ± 12.94, 8.82 ± 8.94, and 6.70 ± 8.19 features, respectively, and were not statistically different. Similarly, abundances of Firmicutes were not significantly related to total exposure to TMAO in the 6 h window  and two genera that were more abundant in the above-median group (genera eggerthella and clostridium) (lactobacillus and catenibacterium) to 59% (clostridium) of participants.Lastly, we assessed the relative abundance of microbes related to AUC-TMAO by dichotomizing the cohort using the median AUC-TMAO concentration of 29.25 µM/h. Differential abundance analysis via the DESeq2 likelihood ratio test revealed four genera that were more abundant in the below-median group (genera tridium) . In all p-value = 0.289; rs2266780, Chi square = 0.05, p-value = 0.820).FMO3 oxidizes TMA to TMAO, and individuals with monogenic FMO3 variants may experience low-penetrance-associated predispositions such as increased plasma TMA concentrations . We hypop-value = 0.120; rs2266780 p-value = 0.824). Although not statistically significant at SNP rs2266782 (G>A) , the median (interquartile range) of AUC-TMAO for genotypes GG, GA, and AA increased to 26.41 (21.37–40.66), 29.45 (22.99–35.00), and 40.20 (23.55–59.46) µM/h, respectively. Likewise, no significant differences by genotype were identified for SNP rs2266780 (A>G). The median concentration for individuals with the AA genotype was 28.37 µM/h (21.49–40.13) while it was 32.30 µM/h (22.43–38.48) for individuals with the AG genotype and 30.88 µM/h (25.11–36.33) for individuals with the GG genotype.When evaluating the relationship between genotype and AUC-TMAO, we observed a trend between increased concentration with variant alleles A,B, but p-value = 0.752). Similarly, in males at SNP rs2266780 (A>G), the median AUC-TMAO increased with copies of the variant G allele but did not reach statistical significance . Males with the genotype AA had a median AUC-TMAO of 29.35 (22.15–39.83) µM/h, compared to 31.07 (22.54–37.70) and 35.86 (35.86–35.86) µM/h for AG and GG males. In females, the effect of genotype varied and neither SNP reached statistical significance . At rs2266782 (G>A), GG females had similar AUC-TMAO as females with the GA genotype at 28.69 (23.81–48.43) and 28.18 (20.20–32.55) µM/h, which was less than females with the AA genotype at 37.74 (24.33–58.94) µM/h. When we tested a dominant model such that one G allele could rescue the wildtype phenotype, the trend approached statistical significance . At rs2266780 (A>G) in females, median AUC-TMAO values included 27.47 (20.46–39.64) µM/h for the AA genotype, 32.30 (24.50–39.81) µM/h for the AG genotype, and 25.89 (24.33–31.82) µM/h for the GG genotype.We stratified this analysis by biological sex and observed non-significant differences by genotype in both sexes. However, median AUC-TMAO tended to increase more prominently with the variant allele in males than females. In males at SNP rs2266782 (G>A), the median (interquartile range) of AUC-TMAO was 23.76 (20.93–36.23), 30.34 (27.07–37.13), and 42.66 (31.52–54.79) µM/h with genotypes GG, GA, and AA . Tukey’s post hoc test revealed marginal differences as females with the genotype rs2266782(G>A)-rs2266780(A>G) AA-AA had higher AUC-TMAO than those with the genotype GA-AA . No associations were observed in males.Because the SNPs were often in linkage disequilibrium, we next assessed the effect of allelotype, or genotype at both SNPs simultaneously . In the Biliary phosphatidylcholines are released to aid in lipid digestion and chylomicron production . KnowingTo assess which metabolites followed a similar metabolic pattern to TMAO, we correlated the AUC of the a priori metabolites to AUC-TMAO. We selected the AUC variables because they represent all blood draws. Additionally, we reasoned that if the metabolites traveled in a similar pattern to TMAO then their AUC would be related. The complete correlation results are presented in p-value = 0.044). Next, we expanded our analysis to assess whether exposure to plasma TMAO over the 6 h postprandial window related to total exposure to CVD biomarkers over the same window. Similar to assessments at the fasting time point, TNF-α remained the only statistically significant biomarker related to AUC-TMAO . This suggests that in healthy adults, fasting measurements of cardiometabolic biomarkers provide similar insights to characterizing metabolic responses of the biomarkers over a 6 h window.We previously assessed the relationship between fasting plasma TMAO concentration and CVD biomarkers including clinical chemistry markers and inflammatory markers in this generally healthy cohort . We founp-value = 0.002), AUC-insulin , AUC-interleukin 6 (AUC-IL6) , AUC-C-reactive protein (AUC-CRP) , and TMAO were identified in individuals in the peak-0m group. In contrast, individuals in the peak-30m group had a strong direct association with AUC-TNF-α , which was not present in the other groups. Together, our results suggest that postprandial TMAO dynamics may relate to different underlying health states in generally healthy adults.Finally, in line with precision nutrition approaches, we assessed whether these relationships differed by TMAO response type. Interestingly, many differences by TMAO-response group were identified that were masked when assessing the cohort as one . SignifiWe present evidence that plasma TMAO concentration responds to a high-fat MMTT with minimal amounts of choline  and betaine (0.755 mg) in adults unmedicated for cardiometabolic diseases. We found that TMAO response to the MMTT was individualized such that the rate and total amount of TMAO generated ranged from rapid appearance and clearance of TMAO to slow. To understand what may be driving this phenomenon, we interrogated the roles of the fecal microbiome, the FMO3 genotype, and the plasma metabolome. Further, we assessed the relationship between postprandial exposure to TMAO and cardiometabolic biomarkers such as cholesterol, glucose, insulin, triglycerides, and inflammation.In the healthy cohort, TMAO concentrations increased on average four-fold with postprandial concentrations averaging above 6 µM. Prospective literature consistently reports that in adults with cardiometabolic risk, fasting TMAO concentrations above approximately 5–6 µM are associated with increased cardiometabolic events over a multi-year period ,24. In hOur data demonstrated that individual’s TMAO response to a high-fat MMTT was highly variable. Assigning participants to a TMAO-response group based on the blood draw at which they experienced their maximal TMAO concentration, we observed four distinct groups. We sought to assess whether these groups were uniquely defined by their fecal microbiomes, their FMO3 genotype, or aspects of their plasma metabolome. Fasting TMAO concentration was significantly correlated to α-diversity metrics, but AUC-TMAO and TMAO-response group showed no relation. Further, compositional differences between response groups were also not identified. Overall, compositional differences assessed through diversity analyses were not associated with postprandial changes  in TMAO concentration. Fecal microbiome community abundance may be a poor tool for predicting the duration and magnitude of postprandial TMAO concentrations. Part of the explanation for this might be that the small intestine microbiome, which has the highest probability of encountering the MMTT during the postprandial window tested, may not be completely captured by the distal stool microbiota. Additionally, potential variations in gastric emptying and general gastrointestinal motility among participants could impact the “contact time” between the postprandial meal bolus and the incompletely captured small-intestine microbial community. The utility of the fecal microbiome in predicting fasting TMAO concentrations has been questioned previously. Ferrell et al. used metagenomics to determine the association between TMA-lyase, the bacterial enzyme that converts choline to TMA, and TMAO and found no relation, concluding that TMA-lyase gene count number is not a predictive marker of enzyme activity . Given tWe assessed two missense SNPs in exons of the FMO3 gene under the assumption that the SNPs influenced FMO3 activity. This assumption is supported by the literature relating the SNPs to decreased affinity to TMA, resulting in increases of the malodorous metabolite TMA . We relaPhosphatidylcholines are released to aid in digestion and may serve as a source of choline. Over the 6 h window, we identified three phosphatidylcholines  and one negatively correlated lysophoshpatidylcholine (LPC) that were significantly related to plasma TMAO exposure. Interestingly, the concentrations of the PCs decreased from fasting to 30 min but then followed dynamics similar to TMAO such that individuals with early rises in TMAO concentration also experienced early rises in PC concentration. Other studies have identified non-metabolic links between PCs, LPCs, and TMAO. Untargeted metabolomics and RNA expression experiments in mice consuming a high-fat diet with or without the microbial TMA-lyase inhibitor iodomethylcholine (IMC) identified that TMA may be a key regulator of the microbiome’s circadian rhythm . AlthougTo comprehensively evaluate the postprandial TMAO response, we evaluated bile acids, which play a critical role in lipid digestion, have been demonstrated to influence the composition of the gut microbiome, and are related to TMAO through the FXR receptor, which regulates FMO3 . The priWe also evaluated the microbial-derived metabolites kynurenine, indoxyl sulfate (indSO4), and p-cresol sulfate (p-cresolSO4). In addition to being associated with cardiometabolic diseases, the metabolites are often derived from similar animal-protein food sources as TMAO . KynurenTMAO response to a high-fat MMTT may have important ramifications for eating behavior. Time restricted eating (TRE) is a dietary pattern with a window of unrestricted feeding followed by a longer window of fasting and considers aligning feeding with circadian rhythm . TRE is -/-) mice given water supplemented with 1.3% choline displayed high plasma TMAO concentrations and upregulated expression of inflammatory genes including TNF-α [-/- mice. However, in LDLR-/- mice treated with an antisense nucleotide to knockdown FMO3, TMAO levels were reduced but TNF-α expression remained significantly higher than that in the control [In the generally healthy cohort, we identified a robust association between AUC-TMAO and TNF-α in the full cohort and in the peak-30m and peak-6h groups. The relationship between TMAO and inflammation has been described. In an atherogenic mouse model, LDL receptor knockout (LDLRng TNF-α . In the  control . The treWe found that the relationship between exposure to TMAO (AUC-TMAO) and fasting versus AUC-cardiometabolic markers was similar. However, by assessing individuals by their TMAO response type, we observed group-specific relationships between AUC-TMAO and cardiometabolic markers that were hidden when assessing the whole cohort. For example, participants in the peak-0m group had inverse relationships with insulin and IL-6 identified in the sub-analysis. Assessing metabolism via MMTTs may reveal disease states that have not presented as clinical symptoms, which may make them extremely useful in preventative health care.Our study is limited by the number of participants with postprandial plasma values and the time points and total duration postprandial metabolism were measured. Furthermore, postprandial metabolism is continuous, and our sampling scheme at 30 min, 3 h, and 6 h postprandially likely resulted in missing true peak concentrations in each subject. We observed that participants in the peak-30m and peak-3h groups had the highest exposure to postprandial TMAO over the 6-h interval, but we did not fully capture TMAO exposure in participants in the peak-6h group whose concentrations had not resolved to baseline levels. Further, quantifying TMA would have provided further insights to the kinetics of TMAO generation but was not measured. We chose to group participants by the blood draw at which they experienced their peak TMAO concentration because we were interested in capturing differences in metabolic responses. This strategy resulted in similar-sized groups that did not differ by sex, age, or BMI, which satisfied our objective; however, an unsupervised grouping strategy, such as hierarchical clustering, may have better captured metabolic response types. Additionally, our genotyping strategy only captured two characterized missense FMO3 SNPs that can be inherited independently. Other SNPs have been described to affect FMO3 activity and may have provided a more complete surrogate of FMO3 activity . The cohOverall, these results suggest that TMAO concentration changes in response to a high-fat MMTT. We assessed whether these changes related to the composition of the gut microbiome, the FMO3 genotype, and the plasma metabolome. We identified select phosphatidylcholines, bile acids, and uremic toxins that related to total TMAO exposure. We identified unique response types such as early or late responders and found that some metabolites followed similar patterns. We also used the response types to identify associations with CVD biomarkers that were hidden when assessing the whole cohort. We show that the strong correlation between TMAO and TNF-α persists in the postprandial state but depends on TMAO response type. Overall, these findings promote precision nutrition and have important ramifications for the eating behavior of adults who could benefit from reducing TMAO exposure, and for understanding factors that generate plasma TMAO.2) used during recruitment.The Nutritional Phenotyping Study has been previously described in depth ,22,40,41Ethnicity was self-reported from a questionnaire with 12 categories: Hispanic or Latino/a, Black or African American, Asian, East Asian, South Asian, Southeast Asian, Middle Eastern, American Indian or Alaska Native, Native Hawaiian or Pacific Islander, decline to respond and other. Eighty-eight of the ninety-seven participants reported one ethnicity, while seven people reported two ethnicities, three people reported three ethnicities, and one person declined to respond. Due to the scarcity of many groups, we categorized people who reported Middle Eastern, Pacific Islander, Native Indian, or Other as “Other”. We also categorized individuals who reported multiple Asian ethnicities as “Asian”.A detailed protocol describing the reasoning, nutrient composition, and distribution of the MMTT has been published . The MMTA detailed protocol describing how the stool sample was acquired, transported, processed, as well as how the DNA from the stool sample was isolated, amplified, and sequenced has been previously described ,39.The 16S sequencing data were processed using Qiime2 (v2019.10) and analyzed using RStudio (v4.1.0) . In QiimTMAO and the plasma metabolome were measured using tandem mass spectrometry on an API 6500 QTRAP  using the MxP Quant 500 kit . Metabolites detected through flow infusion acquisitions were processed in the MetIDQ Oxygen, with peak area used for quantification. Metabolites detected through chromatographic acquisitions were imported into MultiQuant v 3.2 (Sciex) and peak integrations were manually curated. An in-house python script was generated to correct for acquisition ion mass truncation and output header inconsistencies between MetIDQ and MultiQuant. Fasting plasma was analyzed for 362 participants randomized onto five plates. Postprandial samples for a subset of 104 participants were randomized onto four additional plates. The analysis of a single subaliquot of NIST Standard Reference Material 1950: Metabolites in Human Plasma  was processed on each plate along with method blanks, manufacturer provided quality control plasma dilutions, and 7-point calibration curves for a subset of metabolites. Replicate analyses of 22 fasting plasma samples were included on plate five to further assess analytical precision. Data was normalized to the median of four mid-range quality control (QC2) solutions analyzed on each plate prior to exportation from MetIDQ. Of the 630 metabolites evaluated, 381 passed all quality control measures. A total of 97 participants had complete TMAO data and were included in the study. For analytes passing all quality control parameters, the overall replicate precision for analytes with concentrations greater than the limit of detection (LOD) was ~30 ± 1% (mean ± SEM) for both intra- and inter-plate replicates, but ranged from 12 to 56% for metabolite classes, with bile acids, diacylglycerols, and indole derivatives showing the worst precision. Across NIST replicates, 6.1% of 380 metabolites were above the LOD and 1.9% of 313 metabolites with concentrations greater than the limit of quantification had replicate precision of <30%, respectively.Human blood was collected at fasting (0 min), 30 min, 3 h, and 6 h after consuming the MMTT. Blood was transported from the collection room to the laboratory on ice, and immediately processed to plasma or serum. Samples were stored at −80 °C. Plasma chemistry including glucose, triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol were measured on the COBAS INTEGRA 400 Plus Analyzer  following the manufacturer’s instructions. Insulin was measured on the COBAS E 411  following the manufacturer’s instructions.Concentrations of the inflammatory markers have been described . Tumor nTo quantify participants total exposure to metabolites or clinical biomarkers, the area under the curve (AUC) was calculated on raw variables using the trapezoid rule . A totalTo capture differences in TMAO-related metabolism, TMAO response types were categorized by the blood draw at which the participant had their highest TMAO concentration. Four groups were established including “peak-0m”, “peak-30m”, “peak-3h”, and “peak-6h”.DNA was extracted from whole blood using a PAXgene Blood DNA kit  as previously described . SNPs rsp-value < 0.05. For questions with multiple comparisons, false positives were controlled using the Benjamini and Hochberg  method at a significance threshold of p-value < 0.05. Analyses were conducted on a MacBook Pro running MacOS Monterey software with 16 GB of memory.Statistical analyses were conducted in R Studio (v4.1.0). Before calculating parametric statistics, the variable’s distribution was tested using the Shapiro Wilk test. Variables were considered normally distributed if their W-statistic was greater than 0.95. Non-compliant variables were transformed via the natural log. Relationships between continuous variables were assessed using linear regression and controlled for a sex-by-age interaction. The sex-by-age interaction was assessed with type 2 sums of squares from the R package car (v3.1-0). Beta values are reported from natural log-transformed variables. Differences in the means between groups was assessed via the Student’s t-test or ANOVA followed by Tukey’s post-hoc test. A chi-square test was used to assess the relationship between the TMAO-response groups and categorical variables. Correlations were completed via the Spearman method. Significance was set at Plasma TMAO responds to a high-fat MMTT with minimal amounts of choline and betaine. Variation in postprandial responses was observed such that some participants experience no, slow, or prolongated rises in TMAO concentrations. The composition of the gut microbiome had limited power to distinguish differences between response type as did FMO3 genotype characterized by two common SNPs. Distinct responses in the plasma metabolome were detected by TMAO-response group including correlations to select phosphatidylcholines and two secondary bile acids. TMAO response type was associated with the inflammatory marker TNF-α and TMAO-response group revealed hidden relationships to cardiovascular biomarkers. Assessing postprandial responses may be a better tool to predict cardiometabolic disease risk than values measured at fasting and should be assessed in healthy and diseased adults. Further, expanding foods that are considered TMAO precursors from choline, phosphatidylcholine, L-carnitine, and betaine to meals that produce a large release in biologically derived phosphatidylcholines like fatty meals should be considered. Lastly, eating behaviors, such as TRE, should be tested to reduce TMAO exposure and long-term CVD risk.


Ventricular assist devices (VAD) have gained popularity in the pediatric population during recent years, as more and more children require a heart transplant due to improved palliation methods, allowing congenital heart defect patients and children with cardiomyopathies to live longer. Eventually, these children may require heart transplantation, and ventricular assist devices provide a bridge to transplantation in these cases. The FDA has so far approved two types of device: pulsatile and continuous flow (non-pulsatile), which can be axial and centrifugal. Potential eligible studies were searched in three databases: Medline, Embase, and ScienceDirect. Our endeavor retrieved 16 eligible studies focusing on five ventricular assist devices in children. We critically reviewed ventricular assist devices approved for pediatric use in terms of implant indication, main adverse effects, and outcomes. The main adverse effects associated with these devices have been noted to be thromboembolism, infection, bleeding, and hemolysis. However, utilizing left VAD early on, before end-organ dysfunction and deterioration of heart function, may give the patient enough time to recuperate before considering a more long-term solution for ventricular support. Congenital abnormalities, especially congenital heart defects (CHD), are the leading cause of infant mortality associated with congenital disabilities, occurring in almost 1% of live births .The advancement of ventricular assist devices (VADs), envisioned as a temporary bridge to transplant therapy and preferred over the escalation of conventional therapy, has significantly impacted the management of heart failure in CHD and cardiomyopathies . AccordiPediatric mechanical circulatory support is again receiving attention due to the rising number of sick children with end-stage heart failure ,4,5. ThiThe search was performed in Medline (PubMed), Embase, and ScienceDirect databases using several prespecified keywords and MeSH terms (in the case of Medline database): ventricular assist device, pump, artificial ventricles, congenital heart disease, heart defect, cardiomyopathies, children, and pediatric.The following inclusion criteria were considered for eligibility assessment of individual studies: children aged <18 years were analyzed, full-text available online, and randomized and observational studies reporting original data regarding VAD use in the pediatric population (including efficacy and safety end-points). Studies available only as abstracts, letters, studies that analyzed adult patients, and those which did not meet the inclusion criteria were excluded from the present review. Two independent authors evaluated retrieved studies for eligibility in a two-step process. In the first step, titles and abstracts were screened for inclusion and exclusion criteria. Only studies that fulfilled all inclusion criteria were appraised in the second step as full-text.When available, we extracted the following data from included studies: year of publication, the number of patients included and their age, the weight of enrolled participants, the type of VAD used, and reported efficacy and safety outcomes.Following the screening process and eligibility assessment, included studies were critically discussed and analyzed. Concerning safety outcomes, the main complications associated with VAD use in children encompassed thromboembolism, infection, bleeding, and hemolysis . Several® pediatric VAD is a mechanical circulatory support device for pediatric patients [The Berlin Heart EXCORpatients ,10,11. Epatients .A study conducted between August 2015 and July 2016 in Suita, Japan, showed satisfactory results on four pediatric patients with idiopathic dilated cardiomyopathy using this device. The EXCOR device was used to implant left ventricular assist devices (LVADs) in patients with end-stage heart failure. At the time of surgery, the typical patient was eight months old and weighed 4.8 kg. All patients made it through the median follow-up of 7.3 months . Two patients received heart transplants, while the other two are stable hemodynamic candidates on a waiting list [® 2000 system . Six days later, she underwent EXCOR implantation. Nonetheless, five days after the device implantation, she developed intracranial bleeding that required emergently removal of the hematoma. She was on LVAD support for 310 days without any issues; she received a heart transplant. Paresthesia is still in the left side of the upper and lower extremities, but no central neurological sequelae are present. The second case was of a 4-month-old infant with idiopathic DCM. Her left ventricular ejection percentage (LVEF) was 17% at the time, and her left ventricular diastolic diameter (LVDd) was 50.4 mm. She had cardiac resynchronization therapy (CRT) for left ventricular asynchrony when she was five months old [Case one was of an 11-month-old infant with idiopathic dilated cardiomyopathy (DCM) on mechanical respiratory support and treated with inotropic agents. Her hemodynamic state deteriorated while waiting for the device to be implanted, necessitating immediate central extracorporeal membrane oxygenation (ECMO) with the Endumonths old . DespiteThe third case was a 4-month-old infant (weight 4.9 kg) with idiopathic DCM. He was administered inotropic medication  and was on mechanical ventilator support. A total of 44 days after admission, his ventricular function gradually severed, leading to EXCOR implantation. He was afterward diagnosed with associated Barth syndrome. Cyclic neutropenia is a significant comorbidity of this disease, raising the risk of nosocomial infections ,20. The ® 2000 system started ECMO support immediately, and her left atrium was ventilated via a percutaneous transfemoral catheter through a patent foramen ovale (PFO). Even though these surgeries helped her hemodynamic condition, thoracic compartment syndrome in some way impeded her ability to recover her breathing. As a result, 12 days following the start of ECMO, it was necessary to switch to central ECMO using the Endumo 2000 system and EXCOR pediatric inflow and outflow cannula. The PFO was sealed off, and the atrial venting catheter was withdrawn. Her respiratory function was restored after four days of central ECMO support, enabling conversion to the EXCOR pump under local anesthetic without mechanical right heart support. She is currently in a stable condition without any neurological issues while waiting for a heart transplant.A 1-month-old baby (weighing 3.0 kg) with idiopathic DCM and cardiogenic shock was the fourth patient involved in the research. This patient experienced severe respiratory failure caused by pneumonia and cardiogenic lung edema. The EndumoAnother study examining the outcomes of 204 Berlin EXCOR VAD implantations performed in North America between 2007 and 2010 found that some children receiving sustained BiVAD support may have fared better with LVADs alone. The EXCOR Pediatric device assisted 204 patients during the trial [In order to assess the changes in heart transplant waiting list mortality following the adoption of the Berlin Heart EXCOR, a retrospective, single-center analysis was carried out in the Netherlands involving all juvenile patients (18 years) awaiting transplantation. Based on the availability of the BH EXCOR in the center, patients were divided into two groups: era I  and era II  .p = 0.06) and transplantation rates  did not differ significantly from one period to the other. Cerebrovascular accidents (CVAs), which affected eight (29%) of the juvenile ventricular assist device (VAD) group, were the primary cause of death in 11 (39%) children. In addition, 14 (or 50%) of the young VAD patients made it to transplantation. The most common adverse events in VAD patients were CVA—occurring in 14 cases and happening in most cases (68%) within 30 days of implantation—and bleeding that necessitated a re-thoracotomy in 14, also occurring in all cases within 30 days of implantation.A total of 87 patients, 15 in the era I and 72 in era II, were included. In period I and period II, one patient (7%) and 13 (18%), respectively, needed extracorporeal membrane oxygenator support. Overall mortality  is a compact, extracorporeal, pneumatically driven system for left, right, or biventricular support.n = 1), restrictive cardiomyopathy brought on by endocardial fibroelastosis (n = 1), and Ebstein abnormality (n = 1) were the underlying heart conditions. All the children were in the New York Heart Association’s class IV range and needed an inotrope. The goal was to use the Medos device as bridge to transplantation because recovery was no longer possible in any of the cases. All children presented with compromised end-organ dysfunction; they were intubated and mechanically ventilated.A study performed at University Hospital Münster, Münster, Germany, described three neonates that were treated from December 1996 to March 1997 . DilativIn the early use of the Medos system, the atria were punctured using the Inflow cannulas of the Medos device. An encircling suture was used to insert left-sided cannulas via the interatrial groove and right-sided cannulas into the right atrium. After surgery, protamine was always used in place of heparin. Full heparinization was initiated 4 to 12 h after surgery during the first implant phase (Medos system), and activated clotting time was maintained between 160 and 200 s. The patients did not receive any antiplatelet medication. All patients could be stabilized with univentricular mechanical support; no perioperative complications were recorded.All three infants with the Medos system required additional observation of bleeding and evacuation of mediastinal blood clots on postoperative days 4, 7, and 21, respectively. In all neonates, severe thromboembolic events were observed. Two children were afflicted by hemiplegia, but they completely recovered; the third child had an obstruction in the right pulmonary artery and was treated with a recombinant tissue plasminogen activator. As a consequence of the research procedures, two neonates developed infectious complications. In one instance, the infection was successfully treated with antibiotics; in the other, the patient died from multiple organ failure. Two of the three patients carried out a successful bridge to transplant procedures.n = 11), (II) ECLS in cardiopulmonary resuscitation (CPR) (n = 7), and (III) extracorporeal membrane oxygenation (ECMO) in acute respiratory distress syndrome (ARDS) (n = 4). Mechanical circulatory support was provided for an average of 4 days (0–18 days), and 12 patients (or 75%) were successfully weaned off it. However, four of these children (or 25%) died following weaning, with a median survival period of 15 days (6–28 days). The overall survival rate was 50%, and none of the eight survivors suffered neurological damage before being sent home. No severe bleeding, thromboembolic issues, or device failure were reported.A study that looked at a group of 16 children—with a range of ages from 0.1 to 55 months and median weights of 3.2 kg (2.5–14 kg) and 0.9 months (median) showed that the Medos system is secure and efficient for supporting circulation in kids . The Med®, CentriMag®, and PediMag®  offer a choice for doctors caring for young children with ventricular failure. These centrifugal pumps are magnetically levitated, have low prime volumes and negligible hemolysis, and are permitted for 30 days by the Food and Drug Administration. However, these devices have inherent risks because they necessitate concurrent anticoagulation control [The blood pumps Thoratec control .These devices have been successfully used in patients with right-sided failing Fontan physiology. Both decreased inferior vena cava pressure, while CentriMag did not increase superior vena cava pressure in a recently published in vitro model .One study investigated the multicenter use of Thoratec devices in children and adolescents and found similar mortality as in adults, with an increased chance of neurologic complications if the left atria were cannulated .Conway et al. reported a single center ten-year experience with the PediMag device. This study included 37 patients suffering from congenital heart diseases, cardiomyopathy, or after transplant. The median weight was 8.9 kg in the study group, and the median duration of device use was 12 days. A total of 45% of patients required ECMO support before PediMag use. Frequent complications included bleeding (24%), neurologic events (18%), and infection (15%). A total of 21% of children were successfully weaned from support, 42% required long-term VAD support, 12% required transplantation, 9% were switched to ECMO, and 5% died . HoweverA new, compact centrifugal ventricular assist device is the HeartMate III. Due to its decreased pump thrombosis and stroke rates, it is widely utilized in pediatrics. HeartMate III was successfully used as a bridge to transplantation in an adolescent with failing Fontan circulation, according to research from Children’s Hospital in Minneapolis, Minnesota . The devO’Connor et al. reported a single-center 3 year experience with this device in adult and pediatric patients suffering from dilated cardiomyopathy or congenital heart defects, some with Fontan physiology. No stroke or pump thrombosis was reported in this study, which the older participants could partly explain. This study’s survival rate was also very high—97% .Encouraging results with this device were also reported by Trezzi et al. . This stThe Impella device is a catheter-based, miniature ventricular assist device. It is placed by retrograde femoral artery access into the left ventricle across the aortic valve. At a maximum rate of 2.5 to 5.0 L/min, the device helps to maintain systemic circulation by pumping blood from the left ventricle into the ascending aorta. This raises overall systemic cardiac output while virtually immediately and sustainably unloading the left ventricle. Although this device does not have enough pediatric-related expertise, it can help with RV function and is only utilized for short-term ventricular support ,33.In one multicentric trial, nearly 160 pediatric patients with acute ventricular failure or dysfunction or those undergoing high-risk catheter-based procedures had their systemic circulation supported by an Impella device . The casRegardless of size or age, 85% of the patients were maintained with Impella 2.5 and CP devices, usually via femoral access. In 38% of cases, repositioning of the device was required. A patient received support for a maximum of 51 days, with a median of 45 h. Most patients had their devices removed because of ventricular recovery (41%) or a change in mechanical support (31%).Within 30 days after the implant, 12 of the 38 patients (32%) passed away. Six of the twelve deaths happened after the Impella was removed, including five patients who had switched to other devices . Eight patients experienced severe reactions, the most important being bleeding and hemolysis.The implantation of the Impella device unloaded the LV volume, which reduced the LV wall stress, improved the coronary flow, and reduced the myocardial oxygen consumption. Almost 40% of patients were able to be explanted for ventricular recovery, suggesting that using temporary support early on, such as Impella, before CGS and end-organ dysfunction worsen, may give patients enough time to recover before switching to a more permanent form of ventricular supportA ventricular assist device helps to circulate a patient’s blood when the heart can no longer provide hemodynamic support. It is a pump attached between the heart and the aorta or pulmonary artery. This device’s functions include relieving strain on the heart and ensuring adequate peripheral circulation for optimal organ function. This provides the necessary energy for healing processes while reducing heart work and oxygen consumption, allowing the patients to heal the impaired myocardial segments faster or live longer until transplantation .Although the operative techniques have improved, myocardial dysfunction can result from complex congenital heart disease interventions involving the left and right ventricles . This leAn assessment of the possible hazards and benefits of the intervention should be used to determine the best time to implant a VAD in pediatric patients. The many factors influencing the VAD risk profile, such as patient age/size ,38,39, aOnly a few cases of ventricular assist devices in smaller children (20 kg) have been reported. First, when adult-sized devices are used in children, low flow rates may concern thromboembolic problems due to technological considerations ,48,49,50The demand for pediatric ventricular assist devices is growing despite a lack of sufficiently small valves adapted for children. They provide the opportunity for remedial surgeries for numerous previously incurable kinds of congenital cardiac disease. Moreover, it increases the rate of success of pediatric heart transplantation. A surgical infrastructure that includes a children’s intensive care unit and a constantly open laboratory for monitoring coagulation status is required for optimal outcomes ,52.Both pulsatile and non-pulsatile LVADs, sometimes called continuous flow LVADs, are FDA approved.While continuous flow devices employ a motor to continuously discharge the blood to the systemic circulation at the same rates, pulsatile LVADs mirror the heart’s natural rhythmic movement. Continuous flow LVADs also comprise two categories: axial flow (HeartMate II Left Ventricular Assist Device) and centrifugal flow (HeartWare Ventricular Assist System) ,53.These devices have been used most frequently in children with cardiomyopathies, cardiogenic shock, and complex heart malformations, such as the Ebstein anomaly or hypoplastic left heart syndrome.Although VAD therapy in children was associated consistently with better outcomes in clinical studies ,11,14, uPediatric patients with end-stage heart failure can successfully transition from early left ventricular assist device support placement to heart transplantation. Additionally, we demonstrated that early LVAD use, prior to the deterioration of heart function and end-organ failure, may provide enough time for recovery before thinking about a more long-term kind of ventricular support. As a result of the development of dependable, more compact LVAD technology with a better morbidity profile may now be used more frequently, leading to better results. This makes VAD support a stand-alone therapy for medically resistant heart failure needing hospitalization, combined with the ability to return patients to their homes.


It is a spongy morphological appearance of the myocardium that occurs largely in the LV.We discuss here a case of 19 years old female with no known past medical history who present with Shortness of breath (SOB) and left sided weakness following delivery.Bedside Echocardiography demonstrated Left ventricular trabiculation with reduced ejection fraction. While brain Computed tomography showed acute ischemic stroke primly due to non-compaction cardiomyopathy as the embolic. Patient was discharged after successfully managed.Left ventricular non-compaction cardiomyopathy (LVNC) is characterized by progressive ventricular trabeculation and deep intratrabecular recesses caused by the functional arrest of myocardial maturation, which is a rare case of congenital cardiomyopathy. Our patient had isolated non-compaction cardiomyopathy of the type that was complicated by an acute ischemic stroke and was treated accordingly.It is usually associated with congenital heart disease, but isolated left ventricular non-compaction cardiomyopathy is very uncommon. •Adults with left ventricular noncompaction are at risk for significant consequences such stroke, HF, arrhythmia, and mortality.•No evidence-based guidelines for preventing thromboembolic events in isolated left ventricular noncompaction.•Transthoracic echocardiography remains the most commonly used method for LVNC diagnosis. She had no chronic diseases as well as a known family history. In an emergency, the vitals were as follows: Spo2 82, glucose 97, Bp 120/60, and a pulse of 150bpm.On cardiac examination; there was tachycardia, normal heart sound, with no added sounds..On lung auscultation, there were reduced breath sounds. Other systems were unremarkable except for left-sided weakness and grade 2 lower limb edema. 12 electrocardiography (ECG) showed non-sustained ventricular tachycardia and a pulse of 180bpm figure (3)Bedside echocardiography was done to exclude postpartum cardiomyopathy as the cause of her symptoms.The echocardiography showed trabeculation of the left ventricles, and heart failure reduced ejection fraction (35–40%), as shown in The patient was transferred to the Intensive care unit (ICU) and the amiodarone loading dose, potassium replacement, aspirin , and furosemide infusion with continuous positive airway pressure (CPAP) were started. On day two after stabilization of the patient, a brain CT scan showed an acute ischemic infarct 3LVNC) is a rare type of primary hereditary cardiomyopathy that happens when the ventricular myocardium stops developing during embryogenesis . It is aIn one large group of adult patients, the prevalence of LVNC was 0.014%. The majority of people with LVNC remain asymptomatic; roughly two-thirds of them develop heart failure as a result of ventricular dysfunction, although embolic events, arrhythmias, and sudden cardiac death are less prevalent .No sustained ventricular tachycardia (NSVT) is described as 3  or more successive beats occurring below the atrioventricular node with an RR interval of 600 ms (100 beats/min) and lasting 30 seconds . Given tStroke/Embolic in patients with LVHT/NC is not always cardioembolic; it can also have an atherosclerotic origin. In individuals with LVHT/NC without AF or left ventricular systolic failure, cardioembolic strokes or emboli are infrequent .Due to the rarity of the disease , there aEchocardiographic, cardiac magnetic resonance (CMR), and computed tomography (CT) imaging criteria can be used to make the diagnosis of this cardiomyopathy. However, none of these imaging methods has been standardized to provide a definitive diagnosis .Because it is widely available, easily interpreted, and inexpensive, transthoracic echocardiography remains the most commonly used method for LVNC diagnosis .The ratio of the non-compacted layer to the compacted layer thickness (T/C) is one of the most often used criteria for diagnosis, with a ratio of >2 at end-diastole being regarded as diagnostic . Due to In comparison to patients with DCM, those with LVNC had comparable risks of cardiovascular mortality, all-cause mortality, thromboembolic consequences, and ventricular arrhythmias . This ca4Adults with left ventricular noncompaction are at risk for significant consequences such HF, stroke, arrhythmia, and mortality.Anticoagulation is not advised as a preventative measure because of the risk of thromboembolism.According to our hospital rule, Ethical approval is only required in articles but not case reports.There is no funding source for this study.All authors contributed toward writing, analysis, drafting, and revising the paper and they gave final approval of the version to be published, and agree to be accountable for all aspects of the work.I declare that there is no competing interest related to the study, authors, other individuals, or organizations.1Name of the registry: Not applicable2Unique Identifying number or registration ID: Not applicable3Hyperlink to your specific registration (must be publicly accessible and will be checked): Not applicableSaid Abdirahman Ahmed.informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Written N/A.Not commissioned, externally peer-reviewed.