The microecological environment of the gastrointestinal tract is altered if there is an imbalance between the gut microbiota phylases, resulting in a variety of diseases. Moreover, progressive age not only slows down physical activity but also reduces the fat metabolism pathway, which may lead to a reduction in the variety of bacterial strains and bacteroidetes’ abundance, promoting firmicutes and proteobacteria growth. As a result, dysbiosis reduces physiological adaptability, boosts inflammatory markers, generates ROS, and induces the destruction of free radical macromolecules, leading to sarcopenia in older patients. Research conducted at various levels indicates that the microbiota of the gut is involved in pathogenesis and can be considered as the causative agent of several cardiovascular diseases. Local and systematic inflammatory reactions are caused in patients with heart failure, as ischemia and edema are caused by splanchnic hypoperfusion and enable both bacterial metabolites and bacteria translocation to enter from an intestinal barrier, which is already weakened, to the blood circulation. Multiple diseases, such as HF, include healthy microbe-derived metabolites. These key findings demonstrate that the gut microbiota modulates the host’s metabolism, either specifically or indirectly, by generating multiple metabolites. Currently, the real procedures that are an analogy to the symptoms in cardiac pathologies, such as cardiac mass dysfunctions and modifications, are investigated at a minimum level in older patients. Thus, the purpose of this review is to summarize the existing knowledge about a particular diet, including trimethylamine, which usually seems to be effective for the improvement of cardiac and skeletal muscle, such as choline and L-carnitine, which may aggravate the HF process in sarcopenic patients. As a result, dysbiosis reduces physiological adaptability, boosts inflammatory markers, creates ROS, and induces the destruction of free radical macromolecules, leading to sarcopenia in older patients [The human intestine microbiota is primarily comprised of four phyla: proteobacteria, firmicutes, actinobacteria, and bacteroidetes . An imbapatients ,4. As agpatients . In a mupatients .Sarcopenia may be induced by heart failure via common pathogenetic pathways and mechanisms influenced by each other, such as physical activities, malnutrition, and hormonal changes. Prevalence levels are significantly greater in individuals with heart failure (HF), ranging between 19.5 and 47.3% [2+ and cardiovascular health, and highlights the potential pathophysiological pathways through which Mg2+ depletion may increase the development, progression, and maintenance of CVD. Indeed, hypomagnesemia has a detrimental effect on cardiovascular health, as it is linked with an increased prevalence of hypertension, type 2 diabetes, dyslipidemia, atherosclerosis, arrhythmias, and coronary artery disease [Conversely, the development of heart failure may be favored by Sarcopenia via various mechanisms such as pathological ergoreflexes. It can be considered as a paradox that the association of sarcopenia is not visible with a sarcopenic cardiac muscle, while non-functional hypertrophy is displayed by cardiac muscles. In addition, cardiac hypertrophy can be considered as the normal mechanism of cardiac adaptation to the conditions of a rise in systemic demand. Cardiac dysfunctions can be caused by a hypertensive state in pregnancy and even in athletes via the heart’s physiological hypertrophy or via pathological hypertrophy, which can be triggered by various factors such as hemodynamic stress of irregular and prolonged nature, i.e., a hypertensive condition . Cardiac disease , all of  disease .Enhanced muscle reflex has a significant link with peripheral muscle wastage and, additionally, the overactivity of muscle reflex can be considered consistent with the idea that the development of a syndrome is linked to the muscle’s peripheral maladaptive changes. There are some important factors, such as progressive age, associated with sarcopenia and the change in gut microbiota diversity. Dysbiosis can also be considered as an independent cardiovascular risk factor and as responsible for heart failure in elderly people. Minimal investigations have been conducted in elderly patients regarding the actual mechanisms, such as concerning cardiac mass alteration and dysfunction, which are considered equivalent with cardiovascular diseases. They can be concluded as the downward spiral of dysregulation regarding exercise of the skeletal muscle, which is suggested by the hypothesis of muscle and can be correlated with certain vicious cycles in heart failure in which, initially, there are adaptive physiological responses that are gradually converted into maladaptive responses . Thus, tCertain databases such as Medline, Mendeley, Google Scholar, Public Library of Science, PubMed, ScienceDirect, and Springer Link were considered and searched through for the literature review, searching for studies that were potentially relevant and in which certain keywords were used both alone and in conjunction. Certain keywords that were significant and were used for the search of literature were ‘Sarcopenia’, ‘Epidemiology of sarcopenia’, ‘Mechanism of sarcopenia mediated heart failure’, ‘Involvement of dysbiosis in sarcopenia’, ‘Pathogenesis of heart failure’, ‘Reactive oxygen species-mediated mitochondrial dysfunction, ‘Relationship of choline and L-carnitine for muscle function improvement’ or ‘Role of TMA and TMAO in heart failure, in combination with ‘heart failure and dysbiosis’, ‘Immunogenic profile in sarcopenia and heart failure’, and ‘ergoreflx mechanism in sarcopenia associated heart failure’. In this review, only papers in English were considered. The reference list of the papers found were also screened for related articles not detected by the initial search strategy.Sarcopenia can be referred to as the gradual loss in mass of skeletal muscle, the loss of its strength, and the loss of functions performed, and it is now considered as the major factor of negative effects of health in the later period of life . In factThe authors established a link between health status, diet, and microbiota. To be more precise, the composition of the microbial population was predominantly influenced by fruit, meat, and vegetable intake. Additionally, a higher proportion of two dominant phyla, namely Firmicutes (64%) and Bacteroidetes 23%), comprise up to 90% of the overall gut microbiota in older people who are living in long-term care facilities ,17,18). %, compriIn addition, the maintenance of sarcopenia is supported by the insufficient nutritional system and aged immune system, which play key roles in stimulating the activation of chronic inflammation ,25. In cCholine/L-carnitine was investigated as an ergogenic aid for improving the training ability of a stable athletic population due to its pivotal role in the oxidation of fatty acids and energy metabolism. Beneficial impacts on acute physical performance, such as increased power production and increased intake of maximum oxygen, were observed in earlier research studies and further studies show the beneficial influence of L-carnitine as a dietary supplementation in the post-exercise recovery process. L-carnitine has been shown to alleviate the injury of muscles and condenses’ cellular damage markers, and muscle soreness attenuation is accompanied by free radical formation .In 2013, researchers first demonstrated that a molecular metabolite, namely trimethylamine-N-oxide (TMAO) isolated from the microbiota of the gut, predicted that 4007 healthy cardiac patients will be enduring elective coronary angiography with an excepted increased risk of cardiovascular accidents . TMAO isChange in the microbiota composition of the gut caused by sarcopenia and heart failure can alter the circulating levels of TMAO. Moreover, it has been identified that hypertension patients experience an alteration in intestinal microbiota diversity. Experiments conducted on rats who were treated with angiotensin II revealed that intestinal biota species were less diverse and when compared to regulated rats, the Firmicutes to Bacteroidetes ratio was increased ,45. MoreRuminococcus is due to the high fat and high protein diet [One research study found that eight Firmicute and Proteobacteria species have absorbed more than 60% of the production of choline of TMA, including Escherichia fergusonii, Clostridium asparagiforme, C. hathawayi, C. sporogenes, Edwardsiella tarda Anaerococcus hydrogenalis, Proteus penneri, and Providencia rettgeri . Akkermaein diet , and addein diet ,56. ThusMechanisms of heart failure pathophysiological pathways are quite intricate and include inflammatory reaction, hemodynamics irregularity, cardiac remodeling, neuroendocrine system stimulation, etc. Traditionally, the key causes of heart failure are supposed to be the activation of the pathways of the neuroendocrine system, which include the natriuretic peptide system, renin-angiotensin-aldosterone cascade, and sympathetic nervous system, which lead to a pathologic myocardial remodeling process series including apoptosis, extracellular matrix deposition, myocardial hypertrophy, and resultant fibrosis ,58. HencAdditionally, an independent cohort of ambulatory individuals with persistent systolic HF supports our results and provides new insights on the link between the three phosphatidylcholine metabolic isomers, namely TMAO, choline, and betaine, considering echocardiographic determinants and the associations between both renal and inflammatory biomarkers. Numerous noteworthy discoveries have been made. To begin, we found that TMAO had a superior predictive value to choline and betaine in patients with chronic systolic heart failure, regardless of the cardio-renal parameters. Second, rather than LV systolic dysfunction, we found associations between all three metabolites and LV diastolic dysfunction. Thirdly, the very low correlations between TMAO, choline, and betaine in many well-characterized inflammatory biomarkers and in their distinct associations with endothelial dysfunction indicators indicated the existence of a separate pathophysiological mechanism. Notably, the increased TMAO levels seen in individuals with renal insufficiency or diabetes mellitus suggest an underlying metabolic deficiency associated with those disease states rather than a systemic inflammatory response. Nonetheless, the relationship between increased TMAO and both HF severity and adverse outcomes, irrespective of other cardio-renal indices, argues for a possible harmful molecular link between the gut microbiota pathway that generates TMAO and the development and/or progression of HF. Notably, this is a cohort of ambulatory stable heart failure patients with left ventricular systolic dysfunction and with an annualized mortality of 7.1% , which is not dissimilar to that seen in published clinical trials. Taken together, our results validate the clinical relevance of TMAO levels in heart failure and indicate that further research is needed to elucidate the association’s molecular underpinnings. However, after tuning for the parameters of renal function, the capacity of the TMAO to independently forecast is lost, likely due to the substantial correlations between the parameters of renal function (approximate glomerular filtration rate and urea) and TMAO. These findings indicate that a higher degree of “backward failure” (congestion associated with scarring or ischemia) rather than “forward failure” (or reduced perfusion) may be linked with the main metabolic deficiency underlying the observed correlations. Consistent with this, correlations between choline and renal function indices were seen for both choline and TMAO, although the link between TMAO and adverse outcomes in individuals persisted even after adjusting for renal function. The purpose of this study was to investigate the connection between (1) the intestinal microbiota-dependent analyte TMAO and its dietary precursors, namely and choline and betaine, and (2) echocardiographic indicators in sarcopenic patients with chronic systolic heart failure ,81 Figu.Sarcopenia is common in cases of heart failure, leading to inadequate disease prognosis. While the pathophysiology of muscle wastage is quite complicated in heart failure, multiple pathogenetic mechanisms tend to be shared by sarcopenia and heart failure, and they can benefit from strategies of standard treatment focused on a nutritional, physical, and pharmacological approach. In recent years, several studies have identified a clear correlation between CVDs and the microbiota of the gut. We already know that TMAO, a gut microbiota metabolite, may have fresh perspectives and insights regarding how heart failure is supported by the microbiota of the gut. These findings provide a good opportunity for controlling heart failure via addressing the microbiota of the gut, including through the use of updated probiotics, prebiotics, dietary therapy, and FMT. Moreover, emerging research from different groups and clinical findings reveal the association between the dysfunction of the microbiota of the gut, the TMAO circulation, and the susceptibility of heart failure, indicating a fresh and desirable therapeutic target for HF treatment. Furthermore, excessive intake of a diet such as choline or L-carnitine, which contain intermediate precursor TMA for TMAO, should be carefully used in elderly people who have dysbiosis with muscle disorders. Future research studies are warranted.


Cardiac sarcoidosis (CS) is a widely underdiagnosed yet clinically significant form of granulomatous myocarditis associated with significant morbidity and mortality. Clinical presentation ranges from silent cardiac involvement detected on imaging to cardiomyopathy or sudden cardiac death. Diagnosis of CS remains challenging due to the lack of sensitivity and specificity of any single diagnostic method, underscoring the importance of elevated clinical suspicion and the use of multimodality imaging to guide diagnosis and treatment. In this review, we discuss the epidemiology, pathogenesis, clinical features, and diagnosis of this clinically evading and enigmatic disease. The prevalence of CS has been increasing over the past two decades, likely due to utilization of advanced cardiac imaging.4 However, CS continues to remain underdiagnosed as a reversible cause of cardiomyopathy and arrhythmias. In this review, we discuss the epidemiology, pathogenesis, clinical features, and diagnosis of CS with the purpose of increasing awareness about this disease since timely diagnosis and treatment can lead to better outcomes.Diagnosis of cardiac sarcoidosis (CS) remains challenging as it requires a combination of clinical and radiological findings in addition to histologic evidence of noncaseating granulomas with exclusion of any other potential causes of such histologic findings.1 The highest incidence has been reported in Scandinavian countries, with an estimated 11.5 cases per 100,000 individuals. In the United States (US), it ranges from 8 to 11 per 100,000 people and is reported to be lower in other parts of the world, including Canada  and East Asian countries such as South Korea .5 Similarly, reported prevalence ranges from 140 to 160 per 100,000 in Sweden and Canada, to 1 and 5 per 100,000 in South Korea, Taiwan and Japan.5 A US national healthcare database analysis between 2010 and 2013 revealed a three-times higher prevalence among Black Americans  compared with Whites , and a lower prevalence in Hispanics and Asians . The highest prevalence was noted among Black American women .6 The Black Women’s Health Study estimated the average annual incidence among Black American women to be as high as 71 per 100,000 and a prevalence of nearly 2%.7 Mortality also is reported as higher among women and Black Americans.8The incidence and prevalence of sarcoidosis varies widely across the globe and has been reported to be higher in populations of northern European and African American descents.9 followed by extra-thoracic sites such as lymph nodes, skin, heart, spleen, liver, and other organs and tissues.3 Disease usually occurs in patients aged 25 to 45 years, with a second peak occurring in women > 50 years in Japan and European countries.10The lung is the most commonly involved organ system, occurring in more than 90% of patients with sarcoidosis,12 Moreover, up to half of the cases of cardiac involvement might present as isolated CS.4 Prevalence of CS has increased over the years as evidenced by studies in Finland showing a greater than 20-fold increase in detection between 1988 and 2012.4 Similarly, the US rate of transplantation for CS increased from 0.1% to 0.5% between 2011 and 2014.13 Use of advanced imaging modalities that aid prompt detection of CS potentially elucidates this increasing prevalence.Cardiac involvement can occur with multisystem sarcoidosis or may be the initial and only manifestation of the disease. Studies estimate 5% of patients with sarcoidosis have clinically manifest CS and up to a third have clinically silent disease as detected in imaging and autopsy studies.14 Implicated infectious agents include mycobacteria, Propionibacterium, Borrelia burgdorferi, Rickettsia helvetica, Epstein-Barr virus, and human herpes virus 8.15 Workers in lumbering and wood processing industries who are exposed to industrial organic dust showed elevated risk of sarcoidosis.16 Further clues on the role of environmental agents are drawn from observations indicating an increased incidence of sarcoidosis-like granulomatous pulmonary disease in World Trade Center survivors.18Although the inciting antigenic trigger is yet to be identified, several factors are implicated in the pathogenesis of CS, including genetic susceptibility coupled with immune dysregulation, prior history of infections, and occupational or environmental factors. Human leukocyte antigen (HLA) alleles in the major histocompatibility complex gene are influential in the disease’s course. For example, HLA-DR17(3) is most associated with sarcoidosis in a White population, DRB1*03 is associated with spontaneous resolution, and HLA-DR15(2) or DR14(6) are associated with a chronic disease course.19 The multinucleated giant cells are initially foreign body type (with haphazardly arranged nuclei) and later become Langhans type . They may contain cytoplasmic inclusions, particularly Schaumann bodies or asteroid bodies.20 The immunological basis responsible for sarcoid generation is primarily driven by an exaggerated TH1 cell response with production of cytokines, including interleukin (IL)-2, interferonγ, and IL-12.21 This is followed by an anti-inflammatory TH2 type response marked by the presence of IL-4, IL-5, IL-10, and IL-13 cytokines.20 Interestingly, the development and disappearance of cardiac granulomas parallels the presence of these cytokines in the specified order.22 Fibrotic transformation of chronic granulomas is mediated by the switch to TH2 type response with contribution from platelet-derived growth factor-B, insulin-like growth factor 1, and insulin-like growth factor binding protein-related protein 2.23 Recent studies also demonstrate the role of Th17 cell mediated production of IFN-γ in pathogenesis of sarcoidosis and suggest imbalances in Tregs and Th17 cell response to be an added mechanism.24Formation of discrete noncaseating granulomas consisting of epithelioid histiocytes and multinucleated giant cells surrounded by lymphocytes, plasma cells, and fibroblasts is the histological hallmark of sarcoidosis.25 Granulomas are frequently found in the basal interventricular septum, left ventricular (LV) free wall, right ventricle, and atria.29 With disease progression, the granulomatous inflammation elicits a repair response with scarring, different from the scarring seen in myocardial infarction, which is patchy rather than maximal in the subendocardial region or transmural.20 While distribution of granulomas in the interventricular septum results in conduction blocks that may be responsive to steroid therapy, patchy myocardial scarring provides a nidus for ventricular tachyarrhythmias, focal aneurysms, and systolic or diastolic LV dysfunction.In CS, myocardium is usually involved with endocardium or epicardium as an extension of the disease.30 Consequently, patients present with a history of dizziness, near-syncope or syncope, palpitations, fatigue, dyspnea, or other symptoms of congestive heart failure (HF).Cardiac sarcoidosis can present as (1) asymptomatic disease incidentally detected on screening in the setting of pulmonary/systemic sarcoidosis, (2) clinically manifest CS along with symptomatic or asymptomatic extra-CS, or (3) isolated CS. The cardinal manifestations of CS include high-grade atrioventricular (AV) blocks, ventricular tachycardias (VT) potentially resulting in sudden cardiac death (SCD), and cardiomyopathy. Rarer presentations include atrial arrhythmias, papillary muscle dysfunction and mitral regurgitation, constrictive pericarditis, pericardial effusion, or mimics of myocardial ischemia.30 These result from direct granulomatous inflammation of the septum involving the conduction system. Sustained or nonsustained VT has been reported in 2% to 42% patients with CS, while SCD may present in 12% to 65%.30 The most common mechanism of VT is re-entry from scar formation, while some studies also point to a role of active inflammation.32 Due to the patchy nature of the myocardial inflammatory process, multiple morphologies of VT also may be present. Occurrence of frequent premature ventricular contractions or polymorphic VT raises suspicion for active inflammation.31 VT often is the first manifestation of CS and predicts mortality.32Conduction abnormalities are the most common clinical manifestation of CS (12-62% of patients) and can present as bundle branch blocks (right or left), AV blocks of varying degrees, or even sinus arrest.31 Granulomatous infiltration of the myocardium can result in wall motion abnormalities in a noncoronary distribution, valvular regurgitation, LV dysfunction, LV wall thinning, aneurysmal dilation, scarring, or wall rupture. Moreover, reduced ventricular compliance from LV stiffening leads to diastolic dysfunction. Right ventricular (RV) dysfunction can result from granulomatous inflammation or more commonly as a consequence of LV dysfunction and sarcoid-induced pulmonary hypertension.29 One study showed a 3% incidence of HF in CS, twice that of the general population. Moreover, HF at presentation or RV involvement is associated with poor clinical outcomes.34CS cardiomyopathy has a prevalence of 10% to 30% and can manifest as left, right, or biventricular-systolic or diastolic dysfunction in the early inflammatory or late fibrotic stages.18fluorine-fluorodeoxyglucose-postrion emission tomography (FDG-PET) have emerged as invaluable tools to aid disease detection as well as follow disease activity and response to treatment. Here we describe findings associated with CS on various testing modalities.Diagnosis of CS is clinically challenging due to the lack of sensitivity or specificity of any modality in isolation. Hence, multiple diagnostic tests need to be interpreted with the clinical context in mind. Tissue histology using endomyocardial biopsy remains the gold standard for definitive diagnosis. Advanced cardiac imaging techniques such as cardiac magnetic resonance (CMR) imaging and 31 Other nonspecific electrocardiogram (EKG) changes hinting at cardiac involvement in patients with sarcoidosis are axis deviation, abnormal Q waves (pseudoinfarct pattern), and ST changes in noncoronary patterns.35 VT can be the only presentation in sarcoidosis36 and can predict onset of heart failure in CS patients.37Abnormalities on electrocardiography prompting suspicion and further imaging for CS include right bundle branch block, advanced or complete AV blocks, and ventricular arrhythmias, including ventricular tachycardia or fibrillation.38 The most specific finding on echocardiography is basal ventricular septum thinning included as part of the Japanese Circulation Society (JCS) diagnostic criteria.35 It is defined as the thinning of the ventricular septum at 10 mm below the aortic annulus and/or the ratio of this measure to the thickness of the normal ventricular septum of ≤ 0.6.35 Other commonly reported abnormalities include ventricular aneurysm formation, myocardial thickening from edema or infiltration mimicking myocardial hypertrophy, unusual wall motion abnormalities in noncoronary patterns, and papillary muscle dysfunction.39 Moreover, echocardiography may also determine left atrial dysfunction, pulmonary hypertension, RV dysfunction, and the degree of diastolic dysfunction.40 Speckle tracking echocardiography can potentially enhance the yield of screening. A recent meta-analysis highlighted the utility of global longitudinal strain (GLS) imaging in predicting subclinical myocardial involvement and major cardiac events.41Echocardiography plays an important role in screening for CS but has low sensitivity and specificity as a diagnostic tool.40 Moreover, several known cardiac markers such as atrial natriuretic peptide, brain natriuretic peptide (BNP), high-sensitivity cardiac troponin T and I, and N-terminal proBNP have also been studied in CS.42 Interestingly, studies show that troponin levels can predict risk of arrhythmias, and levels often decrease with improvement in cardiac function and inflammation after treatment.45 Elevated BNP levels also have been reported as a marker of cardiac involvement in patients with extracardiac sarcoidosis.45 Markers of inflammation, including serum levels of soluble IL-2 receptors, neopterin and cytokines such as IL-1α, IL-2, IL-12 p40, and IFN-γ have been evaluated as markers of disease activity in small studies although sensitivity and specificity have been poor.40 The utility of biomarkers in clinical practice remains limited, and most are still being studied in research protocols.Established markers of systemic sarcoidosis such as angiotensin converting enzyme (ACE) can be elevated in CS.47 In one study, CMR detected subclinical disease in 9.3% of asymptomatic patients without EKG abnormalities and in 4.7% of patients without any abnormalities at initial evaluation.48 Both acute and chronic stages can be discerned with different technical aspects of CMR. Late gadolinium enhancement (LGE) is the most reliable tool in CMR assessment. There is no pathognomonic distribution pattern for CS. However, studies show LGE in mainly subepicardial or midmyocardial areas of the basal septum and LV lateral wall with extension into the RV.51 Rarely, LGE also can be subendocardial, mimicking an infarct pattern.49 While LGE helps detect more chronic phases of diseases attributed to fibrosis or scarring, T2 mapping detects increased water content or edema in areas of active inflammation.46 A meta-analysis by Zhang et al. estimated the sensitivity and specificity for CS diagnosis by CMR at 95% and 92%, respectively.52 Among patients with extra-CS, CMR has shown diagnostic accuracy and independently predicted mortality, VT, and HF hospitalizations in those with cardiac symptoms and/or an abnormal EKG .48 In patients with known or suspected CS, a pooled analysis of 760 patients showed that the presence of LGE in CMR increased likelihood of death from any cause and of future arrhythmogenic events.53CMR is considered the initial step in evaluation of CS due to its superior spatial resolution, ability to provide tissue characterization, and simultaneous structural and functional evaluation of the heart.18FDG-PET imaging has become an important part of the multimodality approach used to diagnose and follow treatment response in CS. PET imaging serves as an indicator of ongoing inflammation. The principle follows uptake of 18FDG, a glucose analogue, into cells in macrophage-rich areas via the glucose transporter (GLUT); the GLUT is then metabolized to form 18FDG-6-phosphate, whose further intracellular metabolism via glycolytic pathway is terminated, resulting in metabolic trapping that enables detection using imaging techniques. The test involves suppressing glucose uptake in the normal myocardial cells, thus allowing for detection of uptake by inflammatory cells with increased metabolic activity. A joint expert consensus report of the Society of Nuclear Medicine and Molecular Imaging and American Society of Nuclear Cardiology recommend use of cardiac PET for CS diagnosis in the following clinical scenarios: (1) patients with histological evidence of extracardiac sarcoid or positive screening test for CS; (2) unexplained, new-onset significant conduction abnormality such as second- or third-degree AV conduction block in a patient < 60 years; (3) idiopathic sustained ventricular tachycardia; and (4) patients on treatment for CS to guide therapy.54 In the absence of recent whole-body PET imaging or the presence of clinical suspicion for extra-CS, a concomitant whole-body PET study should be performed, or at least imaging of chest, liver, and spleen to detect any extracardiac involvement that could be accessed to confirm a histologic diagnosis.54 Moreover, in patients in whom MRI is contraindicated and in advanced renal disease, PET can be a useful diagnostic tool.5599mTc-labeled tracers or 201Tl) along with 18F-FDG uptake (Table 1). Uptake patterns on PET imaging suggestive of CS include focal and focal on diffuse uptake, whereas suppression of uptake or a diffuse pattern points to normal physiological uptake.55 Rest perfusion images are classified as normal or abnormal, with regional myocardial perfusion further categorized as mild, moderate, or severely reduced. Moreover, quantitative analysis using standard uptake value can add to the diagnostic utility, although thresholds for this are still under investigation.57 A recent systematic review showed that the sensitivity of 18F-FDG-PET in the diagnosis of CS ranges from 27% to 100% with a similar specificity (28-100%) and is dependent on disease activity.47 A meta-analysis by Youssef et al. evaluating 18FDG-PET imaging for CS revealed a sensitivity and specificity of 89% and 78%, respectively.58 The presence of both perfusion and metabolic abnormality on PET and focal RV uptake has been associated with a 3-fold increase in adverse events including death or VT.33 In addition to RV involvement, uptake in basal anterolateral area of LV in steroid-naïve patients was predictive of adverse outcomes.59Inflammatory activity in CS using PET is interpreted both visually and quantitatively. Visual interpretation involves simultaneous evaluation for presence of myocardial perfusion defect  the day before the study followed by at least 12 to 18 hours of fasting before testing.18FDG-PET imaging have a complementary role in the diagnosis and management of CS since both evaluate slightly different aspects of the disease. The greater specificity and negative predictive value of CMR combined with its ability to help rule out other diagnoses make it an ideal initial screening test.46 Imaging with FDG-PET/CT is warranted in equivocal or negative CMR findings in the setting of high clinical suspicion or in cases with CMR findings with highly probable CS to detect active inflammation and plan further therapy.49 Visual reduction in the intensity and extent of myocardial inflammation on follow-up 18FDG-PET imaging and indices, such as Standard Uptake Value, show utility in monitoring response to therapy.62 The exact timing to repeat PET imaging is unknown; however, 4 to 6 months post initiation of treatment has been suggested.38 Moreover, the Heart Rhythm Society (HRS) indicates use of CMR to determine eligibility for implantable cardioverter defibrillator (ICD) placement with indications being reduced LV ejection fraction (35%) after immunosuppressive therapy (Class I) or if LGE is present in patients with LV ejection fraction 35% to 49% after immunosuppression (Class IIb).3Advanced imaging modalities help increase the diagnostic yield, bear prognostic implications, and help direct therapy. CMR and 65 Several factors impact yield, including technique, the patchy distribution of lesions having increased predilection for left heart favoring midmyocardial and subepicardial areas, and stage of disease.66 If performed during chronic stages, granulomas and lymphocytic infiltration tend to disappear and are replaced by fibrosis.35 EMB is required for confirmation of diagnosis in absence of extracardiac histological diagnosis and isolated cardiac sarcoidosis and to rule out other causes of fulminant cardiomyopathy, such as giant cell myocarditis. In addition to histological evaluation, concurrent staining with Grocott staining for fungal infection and Ziehl-Neelsen staining for acid-fast microorganisms should be conducted as indicated.35 The presence of epithelioid giant cells in myocardial biopsy samples is strongly suggestive of cardiac sarcoidosis.35 Electroanatomic mapping-guided EMB helps increase diagnostic yield up to 41%, with additional benefit from cardiac imaging.66 The prognostic yield of EMB remains uncertain, with different studies providing contrasting results.66The identification of epithelioid noncaseating granulomas in cardiac tissue specimen is considered definitive for diagnosis of CS after exclusion of alternative diagnoses. However, the diagnostic yield of electromyocardial biopsy (EMB) in CS is low, estimated at 20% to 30%.67 Lung or lymph node biopsies obtained through transbronchial needle aspiration (TBNA), endobronchial biopsy, transbronchial lung biopsy, and, more recently, endosonography with nodal aspiration, either endobronchial ultrasound-guided TBNA or esophageal ultrasonography with fine-needle aspiration, can aid in pathological confirmation of diagnosis. Depending on the system involved, cutaneous biopsies, eye examination, and further imaging may be indicated.67Evaluation for extracardiac involvement in patients with suspected CS is crucial and may often be the only feasible approach to establishing a histologic diagnosis. Chest radiography or high-resolution computed tomography (HRCT) can demonstrate bilateral hilar or mediastinal lymphadenopathy along with lung parenchymal findings of nodular and patchy ground-glass opacities, pale infiltrates, and cyst formation that distribute along the lymphatic vessels, suggestive of pulmonary sarcoidosis. HRCT in pulmonary sarcoidosis also demonstrates very fine to fine nodular shadows along the peribronchovascular sheaths, interlobular septa and pleural surface, and tracheal wall thickening, while more advanced cases develop fibrosis and traction bronchiectasis.Figure 1).68 Since histologic evidence of noncaseating granulomas in the myocardium can be difficult to establish, CS is typically diagnosed based on clinicopathological findings in conjunction with imaging and extracardiac tissue histology. Three sets of diagnostic criteria have been prescribed by professional societies based on expert consensus. Diagnostic criteria commonly used in practice include the HRS criteria and the Japanese Ministry of Health and Welfare/JCS criteria (Table 2).Diagnosis of sarcoidosis requires a compatible clinical and radiologic presentation, pathologic evidence of noncaseating granulomas, and exclusion of other diseases with similar findings  revised the 1999 WASOG Sarcoidosis Organ Assessment Instrument, which replaced the dated ACCESS (A Case Control Etiology of Sarcoidosis Study) sarcoidosis organ assessment instrument. Based on expert opinion consensus, they categorized the likelihood of organ involvement as either (A) highly probable; likelihood of sarcoidosis causing this manifestation of at least 90%; (B) probable; likelihood of sarcoidosis causing this manifestation of between 50% and 90%; or (C) possible; likelihood of sarcoidosis causing this manifestation of less than 50%.69 In 2017, the JCS further revised their 2006 criteria to guide diagnosis based on a histological or clinical basis.42 Important diagnostic clues such as fatal ventricular arrhythmia (sustained ventricular tachycardia and ventricular fibrillation), abnormal ventricular anatomy, and advanced cardiac imaging findings  were incorporated into major criteria, reflecting the significance of these manifestations in CS.42 Moreover, diagnosis in the clinical group did not mandate biopsy findings of sarcoidosis from cardiac or extracardiac tissue, a significant change from previous recommendations. The 2017 JCS guidelines also prescribe criteria to diagnose isolated CS.42The HRS recommendations described criteria for “definite” or histological, requiring myocardial biopsy findings, and “probable” or clinical diagnosis, necessitating biopsy proven sarcoid in an extracardiac site.70 Recognizing iCS as a distinct clinical entity, the JCS laid out criteria for clinical or histological diagnosis (Table 3).35 Reported prevalence ranges widely from 3.2% to 54%. Table 4 summarizes characteristics of studies on iCS published after 2010.77 Patients with iCS usually present with advanced heart disease and have worse survival outcomes, explained by late diagnosis.4 iCS patients present with LV systolic dysfunction or sudden cardiac death more often than patients with extracardiac sarcoidosis with cardiac involvement.64 While EMB confers definitive diagnosis, advanced imaging modalities are preferred for their higher yield , and aiding extracardiac sarcoidosis detection. Signs of extracardiac sarcoidosis such as lymphadenopathy can manifest later, although its relevance to treatment and prognosis is unclear.70Isolated CS (iCS) is characterized by cardiac involvement in the absence of clinical, histological, or imaging findings of extracardiac disease.80 Differentiation is vital because it carries implications in treatment and prognosis. Table 5 lists the differential diagnosis one must keep in mind when ruling in or out sarcoidosis.Several conditions mimic CS presentation. These differential diagnoses can be clarified using histology or imaging modalities.Figures 2 and 3.CS remains a challenge to diagnose, and diagnostic testing needs to be tailored to the clinical scenario in which it is being used. Clinicians may encounter three main clinical scenarios that trigger further testing for CS: (1) patients with clinical features suggestive of CS, ie, new heart block under age 60 years, nonischemic cardiomyopathy with electrocardiographic or echocardiographic features suggestive of CS, or idiopathic VT with known extracardiac sarcoidosis; (2) patients with clinical features suggestive of CS without known extracardiac sarcoidosis; and (3) patients with known extracardiac sarcoidosis without clinical features of cardiac involvement. We suggest a practical approach to diagnostic testing in these scenarios as shown in 18FDG-PET. The HRS guidelines recommend screening for CS in patients with a history of extracardiac sarcoidosis and those under 60 years presenting with unexplained Mobitz II or third-degree AV block and VT of unknown etiology.3 In patients with previously diagnosed extracardiac sarcoidosis, the diagnosis of CS can be made with relative ease if clinical features and imaging findings consistent with CS are present. The challenge often arises in patients with a clinical syndrome suspicious for CS but without a diagnosis of extracardiac sarcoidosis. Prior to labeling these cases as isolated cardiac sarcoidosis, a thorough search for extracardiac sarcoidosis must be undertaken with whole body PET imaging, skin exam, eye exam for uveitis, and biopsies if lymph node, lung, or liver involvement are suspected. In cases of isolated cardiac sarcoidosis, in addition to searching for extracardiac involvement, a comprehensive search for any other potential clinical mimics or causes of myocarditis must be performed.In patients with suspected CS based on their clinical presentation, CMR remains the initial test of choice and can be used to guide further testing with 48 A recent large observational study assessing cardiac outcomes in 12,042 sarcoidosis patients (without prior CS diagnosis) noted a higher risk of cardiovascular events, including incident HF, HF-related death, and composite outcomes inclusive of ICD implantation, ventricular arrhythmias, and cardiac arrest. This affirms the necessity of early recognition of CS in this population.81 Utilization of advanced imaging techniques in this population remains debated outside of research studies due to limited knowledge regarding the impact of treatment in asymptomatic individuals, particularly given the risks of immunosuppression.It is suggested that patients with known extracardiac sarcoidosis without symptomatic cardiac involvement undergo periodic assessment for CS with appropriate history and EKG.CS is an under-recognized cause of nonischemic cardiomyopathy and arrhythmias. CS can present as the initial, or even the only, manifestation of sarcoidosis and is associated with adverse outcomes. Diagnosis of CS remains challenging and requires a combination of clinical, radiologic, and histologic evidence. Advanced imaging techniques including CMR and FDG-PET are increasingly being used for diagnosis and guiding treatment in CS. Additional studies are required to improve diagnostic accuracy in cases of isolated cardiac sarcoidosis and to inform screening guidelines and the care of patients with asymptomatic cardiac involvement.Cardiac sarcoidosis is an under-recognized but treatable cause of cardiomyopathy and arrhythmias.Diagnosis of cardiac sarcoidosis is challenging and requires a combination of clinical, radiologic, and histologic findings.Endomyocardial biopsies have low sensitivity for diagnosis of cardiac sarcoidosis, and use of imaging or electroanatomic mapping guidance can help improve diagnostic yield.Clinical vigilance for cardiac sarcoidosis is important due to high risk of morbidity and mortality if left untreated.


Myocardial infarction often leads to progressive structural and electrophysiologic remodeling of the left ventricle. Despite the widespread use of β-adrenergic blockade and implantable defibrillators, morbidity and mortality from chronic-phase ventricular tachyarrhythmias remains high, calling for further investigation on the underlying pathophysiology. Histological and functional studies have demonstrated extensive alterations of sympathetic nerve endings at the peri-infarct area and flow-innervation mismatches that create a highly arrhythmogenic milieu. Such accumulated evidence, along with the previously well-documented autonomic dysfunction as an important contributing factor, has stirred intense research interest for pharmacologic and non-pharmacologic neuromodulation in post-infarction heart failure. In this regard, aldosterone inhibitors, sacubitril/valsartan and sodium-glucose cotransporter type 2 inhibitors have shown antiarrhythmic effects. Non-pharmacologic modalities, currently tested in pre-clinical and clinical trials, include transcutaneous vagal stimulation, stellate ganglion modulation and renal sympathetic denervation. In this review, we provide insights on the pathophysiology of ventricular arrhythmogenesis post-myocardial infarction, focusing on sympathetic activation. Myocardial infarction (MI) often leads to substantial loss of contractile tissue, despite prompt revascularization in the acute phase. Due to the high incidence of coronary artery disease, progressive left ventricular (LV) dilatation and dysfunction post-MI constitutes the most frequent cause of heart failure, which is associated with high morbidity and mortality. Recent evidence demonstrates that heart failure post-MI remains a major health-related problem worldwide, diagnosed in 20–30% of patients one year after the acute event, with the rates steadily rising thereafter . In addiThe extent of myocardial necrosis after acute coronary occlusion and the resultant LV dilatation and dysfunction are the most important predictors of long-term outcome. In this regard, the widespread use of acute reperfusion strategies in recent years has had major impact on the incidence of SCD post-MI . ThromboMyocardial necrosis alters loading conditions and triggers a cascade of events, frequently referred to as LV remodeling . CommencThe autonomic nervous system consists of a complex set of neurons that regulate different systems, aiming at maintaining homeostasis by adapting to changes of the external and internal environment. During emotional stress or exercise, the sympathetic nervous system increases heart rate, conduction velocity and contractility, allowing for the increased metabolic demand. Increased sympathetic drive also occurs as an adaptive response in heart failure, enhancing the contractility of the healthy myocardium. However, this action is associated with several maladaptive mechanisms that increase arrhythmogenesis in the long-term, a process that has been attracting major research interest for decades.Chronically elevated sympathetic drive affects a number of ionic currents (referred to as ionic remodeling), resulting in global alteration of LV electrophysiologic properties . For insThe widespread use of β-blockers has been a major advance in the treatment of post-MI patients during the past decades. These agents exert anti-ischemic actions by reducing myocardial metabolic demand and by prolonging diastolic perfusion time secondary to their actions on the sinus node. Moreover, β-blockade obviates action potential changes and increases the threshold for ventricular fibrillation, counterbalancing the pro-fibrillatory effects of myocardial ischemia or sympathetic activation . Based oSympathetic responses entail two major components, namely increased circulating catecholamines from the adrenal medulla, as well as local norepinephrine release from sympathetic nerve endings, elicited by central activation. The pathophysiologic and clinical significance of such distinction has been largely overlooked, a notion likely attributed to the well-studied downstream-effects of β-blockade. Nevertheless, several pieces of recent data highlight the implications of such disparate electrophysiologic effects of sympathetic activation . For exaIn the process of infarct healing, the area of abnormal myocardial blood flow in the peri-infarct tissue is often surrounded by larger areas, characterized by regional impairment of neuronal catecholamine uptake . Such imdecreased denervation of viable myocardium around the infarct scar, as sympathetic nerve fibers are more susceptible to ischemia than cardiomyocytes. Interestingly, denervated myocardial regions display excessive responses to catecholamines  inhibitors. In these paradigms, the issue of ameliorating central sympathetic activation has been raised, strongly reinforcing previous considerations.Spironolactone  or eplerThe recent PARADIGM-HF trial examined the efficacy of angiotensin receptor/neprilysin inhibition in patients with heart failure and reduced ejection fraction ; compareSodium-glucose co-transporter type 2 inhibitors are glucose-lowering agents that promote glucosuria, independent of the action of insulin. Recent multicenter clinical trials reported reduced cardiovascular mortality in diabetic patients with LV dysfunction ; the mecPrompt revascularization of the infarct-related coronary artery decreases the necrotic area. Unfortunately, treatment delays are frequent, particularly in elderly patients or diabetics; hence, post-MI heart failure remains a common clinical entity, characterized by evolving structural and electrophysiologic milieu. Despite β-blockade, the incidence of VTs and SCD are high, as current risk-stratification algorithms cannot accurately identify patients that benefit from ICDs.Several pieces of evidence point towards a crucial role of sympathetic activation on arrhythmogenesis that accompanies progressive post-MI LV remodeling. Examining the complex pathophysiology, a broad spectrum of pre-clinical and clinical studies is currently under way, addressing various aspects of the underlying mechanisms. Non-pharmacologic therapies are intensely investigated, introducing neuromodulatory approaches for post-MI heart failure. Beyond β-blockade, direct pharmacologic approaches were initially disfavored after the disappointing results of moxonidine, but the robust data of SCD reduction by aldosterone antagonists, by sacubitril/valsartan or, more recently, by the sodium-glucose cotransporter type 2 inhibitors have broadened the therapeutic horizon. The pathophysiologic role of the autonomic nervous system is an intriguing topic, with promising clinical applications in the chronic phase of MI.


Levosimendan exerts positive inotropic and vasodilatory effects. Currently, its effects on right heart function remain uncertain. This systematic review and meta-analysis is intended to illustrate the impacts of levosimendan on systolic function of the right heart in patients with heart dysfunction. We systematically searched electronic databases  up to November 30, 2020, and filtered eligible studies that reported the impacts of levosimendan on right heart function. Of these, only studies whose patients suffered from heart dysfunction or pulmonary hypertension were included. Additionally, patients were divided into two groups (given levosimendan or not) in the initial research. Then, RevMan5.3 was used to conduct further analysis. A total of 8 studies comprising 390 patients were included. The results showed that after 24 h of levosimendan, patients’ right ventricular fractional area change , tricuspid annular plane systolic excursion  and tricuspid annular peak systolic velocity  were significantly increased compared to the control group. And there is an increasing trend of cardiac output in levosimendan group  .Furthermore, patients’ systolic pulmonary arterial pressure  and mean pulmonary arterial pressure  were both significantly decreased, whereas changes in pulmonary vascular resistance  were not significant. Our study shows that in patients with heart dysfunction, levosimendan improves systolic function of the right heart and decreases the pressure of the pulmonary artery. Compared to the left heart, the right heart has a limited influence on systemic diseases; thus, clinicians and researchers have not been very concerned about this facet in the past. However, poor right ventricular (RV) function has been confirmed as an independent prognostic marker for mortality in patients with heart dysfunction3. Right heart dysfunction develops for various reasons, primarily on of these three: (1) primary RV myocardial dysfunction, such as RV myocardial infarction due to coronary thrombosis and arrhythmogenic right ventricular cardiomyopathy (ARVC); (2) volume overload, such as right-sided valvular insufficiency and congenital heart diseases; and (3) pressure overload, including pulmonary hypertension, acute left ventricular (LV) failure and acute lung injury/hypoxia6. Right heart failure has a poor prognosis7. Furthermore, scholars8 have found that RV failure was associated with a high mortality rate, even exceeding LV failure, by observing the survival of patients with pulmonary arterial hypertension.Heart failure (HF) is a syndrome characterized by impaired ventricular filling and/or ejection function due many diseases, pulmonary and/or systemic congestion, and insufficient blood perfusion of organs and tissues. HF comprises heart dysfunction accompanied by clinical symptoms. HF has become a major cause of mortality and morbidity2+ sensitizer and K+ channel opener levosimendan is considered a safer choice of inotropic drug than other traditional drugs10. As a novel anti-HF drug, it plays an important role in enhancing myocardial contractility and distending systemic vasculature. In fact, it has been proven that levosimendan does indeed have the ability to improve left heart function in patients with heart dysfunction13. However, its influences on right ventricular systolic function and right ventricular load are not completely understood. Even though a number of published studies have reported the relationship between levosimendan and the right heart system, the small sample size in a single study, incomplete analysis parameters and different designed protocols have resulted in inconsistent conclusions. Therefore, a systematic review and meta-analysis is indispensable for synthesizing the evidence pertaining to the efficacy of levosimendan for RV function in patients with heart dysfunction by Doppler echocardiography and right heart catheterization.Catecholamines and phosphodiesterase inhibitors are often used in patients with acute decompensated HF, but the impact of these medications on prognosis is still controversial because they might lead to an increased risk of mortality. Under such circumstances, the CaWe systematically searched pertinent original research documents from PubMed, The Cochrane Library, Embase, and Web of Science. The search time was from the time of each database’s inception to November 2020. Combinations of the following keywords were used to retrieve articles: “levosimendan”, “right heart or right ventricular (failure)”, “pulmonary hypertension”, “pulmonary embolism”, “perioperative” and “congenital heart disease”. The original research type was restricted to clinical controlled research published in English.Studies were included that met the following criteria: (1) the subjects of the studies were patients with heart dysfunction, and a majority of patients (≥ 70%) with heart function were classified as NYHA III/IV or patients with pulmonary hypertension (mPAP ≥ 25 mmHg before treatment); (2) in the treatment group, levosimendan was administered via intravenous infusion at a rate of 0.1–0.2 μg/kg/min for 24 h, with or without load; and the intervention measures for the control group were intravenous placebo, dopamine or prostaglandin; (3) observed endpoints included pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), tricuspid annulus plane systolic excursion (TAPSE), tricuspid annulus peak systolic velocity (S’), and right ventricular fraction area change (RVFAC) using Doppler echocardiography or right heart catheterization to assess the outcomes; and (4) the observation time was within 1 month after using levosimendan for the first time.The exclusion criteria were as follows: (1) the subjects of the original studies were nonhuman; (2) the types of original studies were case reports, reviews, letters, comments, or conference abstracts; and (3) ongoing trials or literature with insufficient data from original studies.Two investigators (Yaoshi Hu and Zhe Wei) independently searched and screened the literature according to the inclusion and exclusion criteria and then extracted and verified the data. Disagreements were discussed in detail and resolved together with a third investigator (Chaoyong Zhang) if necessary or by contacting the original author. The following content was extracted from the included literature: (1) basic characteristics of the original studies, including first author, year of publication, study design, etc.; (2) sample size of the original studies; and (3) intervention strategies and study duration; (4) clinical end points and adverse events, etc.14. In addition, we conducted a quality assessment of cohort studies according to the Newcastle–Ottawa Scale (NOS), which primarily included selection, comparability and outcome evaluation. This method uses the 0–9 score scale, and studies with scores ≥ 6 are considered to be of high quality. However, the above quality assessment was not used as an exclusion criterion for eligible studies.The quality of the included studies  was independently evaluated by two authors (Yaoshi Hu and Zhe Wei) using the Jadad scale, and any differences were resolved through discussion and adjudication. This method adopts the 0–5 score method, and trials scored one point for each area addressed. A score ≤ 2 was considered low-quality research, and ≥ 3 was considered high-quality research2 analysis were used to test heterogeneity among studies included in the pooled analysis. In the case of no significant difference , a fixed-effects model was used for pooled analysis. Otherwise, we tried our best to identify possible sources of heterogeneity first, and then the random effects model was used for subsequent analysis . Moreover, subgroup analysis or sensitivity analysis can be performed if necessary15.For each study’s data, changes before and after treatment in the levosimendan and control groups were calculated. Then, we reported changes in the mean ± standard deviation (SD). Missing SD values were imputed based on the mean and SD of the changes reported in the original studies. According to the method mentioned in Chapter 16.1.3.2 of the Cochrane Handbook for Systematic 5.1.0 (Updated March 2011), a correlation coefficient (R) of 0.5 was adopted to calculate the standard deviation of the change. Subsequent meta-analysis was conducted using RevMan software . The weighted mean difference (WMD) and 95% confidence interval (CI) were used to represent continuous data. If the 95% confidence interval does not overlap 0, the result is considered statistically significant. The Q test and I23.As illustrated in Fig. There was a total of 8 original studies included, comprising 7 RCTs and 1 prospective cohort study. All literature was published from 2005 to 2019. The sample size was 390 cases in total, including 216 cases in the levosimendan group and 174 cases in the control group. Among trials reporting the study participants’ gender and age, there were 283 male patients (72.56%) and 107 female patients (27.44%). The mean ages of patients receiving levosimendan ranged from 49.6 to 69.9 years and from 45.7 to 72.6 years in the control group. All patients in the intervention group were administered levosimendan with or without a 10-min intravenous bolus infusion at 6–12 μg/kg, followed by a continuous 24-h infusion at 0.1–0.2 μg/kg/min, whereas patients in the control group started with infusion of placebo, dopamine or prostaglandin E1 for 24 h. Of these, 3 studies used levosimendan versus placebo, 2 studies used levosimendan versus dobutamine, 1 study used prostaglandin E1 in the control group, and patients in the control group did not receive any additional drug in the remaining 2 studies. Patient outcomes were assessed by Doppler echocardiography (4 RCTs and 1 prospective cohort study) or right cardiac catheterization (3 RCTs).The trials varied in quality assessment from low to high. Three trials were classified as high quality (Jadad score ≥ 3 or NOS score ≥ 6), and 5 trials were classified as low quality (Jadad score = 2). More characteristics of the included articles are described in Table For each study, we calculated changes between pretreatment and posttreatment in both groups, reported as the mean ± SD. The meta-analysis results are shown as follows.23 were included with 207 patients investigating changes in TAPSE after levosimendan or control treatment. These four studies showed an overall heterogeneity of I2 = 57% and P < 0.1, implying a moderate level of heterogeneity; hence, a random effects model was adopted. The results suggested that levosimendan did not significantly increase TAPSE in the overall analysis [WMD = 0.68 cm, 95% CI , P = 0.13, Fig. 20 had a greater impact on the results compared to others’. We speculated that it was the cause of the moderate heterogeneity. After excluding the study, a total of 148 patients participated in the research. These three studies showed a low level of heterogeneity , hence a fixed effects model was adopted. The results suggested that levosimendan significantly increased TAPSE in the overall analysis [WMD = 1.26 cm, 95% CI , P = 0.007, Fig. For tricuspid annular plane systolic excursion (TAPSE), a total of 4 studies23 involving 153 patients investigated changes in RVFAC after levosimendan or control treatment. These three studies showed an overall heterogeneity of I2 = 47% and P = 0.15, implying a low level of heterogeneity among studies; hence, a fixed effects model was adopted. The results suggested that levosimendan significantly increased RVFAC levels in the overall analysis [WMD = 3.17%, 95% CI , P < 0.00001, Fig. For right ventricular fractional area change (RVFAC), 3 studies21 involving 229 patients investigated changes in S’ after levosimendan or control treatment. These four studies showed an overall heterogeneity of I2 = 16% and P = 0.31, implying a low level of heterogeneity among studies; hence, a fixed effects model was adopted. The results suggested that levosimendan significantly increased S’ in the overall analysis [WMD = 0.86 cm/s, 95% CI , P = 0.0002, Fig. For tricuspid annular peak systolic velocity (S’), 4 studies23 were included, involving 269 patients, investigating changes in sPAP after levosimendan or control treatment. These five studies showed an overall heterogeneity of I2 = 15% and P = 0.32, implying a low level of heterogeneity among studies; hence, a fixed effects model was adopted. The results suggested that levosimendan significantly decreased sPAP in the overall analysis [WMD = − 5.57 mmHg, 95% CI , P < 0.00001, Fig. For systolic pulmonary artery pressure (sPAP), a total of 5 studies22 involving 93 patients investigated the changes in mPAP after levosimendan or control treatment. These two studies showed an overall heterogeneity of I2 = 0% and P = 0.69, implying a low level of heterogeneity among studies; hence, a fixed effects model was adopted. The results suggested that levosimendan significantly decreased mPAP in the overall analysis [WMD = − 1.01 mmHg, 95% CI , P = 0.002, Fig. For mean pulmonary artery pressure (mPAP), 2 studies22 involving 93 patients investigated changes in PVR after levosimendan or control treatment. These two studies showed an overall heterogeneity of I2 = 66% and P = 0.09, implying a moderate level of heterogeneity among studies; hence, a random effects model was adopted. For this analysis, the results suggested that levosimendan did not significantly reduce PVR in the overall analysis [WMD = − 55.88, 95% CI , P = 0.47, Fig. For pulmonary vascular resistance (PVR), 2 studies22 involving 93 patients investigated changes in PVR after levosimendan or control treatment. These two studies showed an overall heterogeneity of I2 = 89% and P = 0.002, implying a high level of heterogeneity among studies; hence, a random effects model was adopted. For this analysis, the results suggested that levosimendan did not significantly increase CO in the overall analysis [WMD = 1.06, 95% CI , P = 0.09, Fig. For cardiac output (CO), 2 studies22, for which we performed a descriptive analysis.Among the 8 studies included, safety issues were reported in 5 studies21 reported a number of incidents related to surgical safety, such as operation time, length of stay in the ICU, number of IABP implants, and mortality, but the results showed no significant difference between the levosimendan and control groups. Another study18 reported that no adverse events occurred in either group. To the best of our knowledge, the most common adverse reactions to levosimendan are hypotension, headache, and ventricular tachycardia. However, these adverse reactions were rarely observed in the included studies. Although Yanbo Wang20 mentioned in his study that systolic and diastolic blood pressure within 24 h after medication exhibited a downward trend compared to before medication, overall blood pressure levels were still within the normal range. Moreover, there was no significant difference between the two groups. According to Cristina Giannini’s study21, there were no reports of any related arrhythmia during patient hospitalization. Only 3 cases of new onset atrial fibrillation occurred, one in the control group and two in the levosimendan group, but there was no significant difference between the groups. Kleber. F. X16 reported the incidence of various adverse events in response to levosimendan in detail. In his study, a total of 19 patients (65 adverse events) were recorded, of which 11 patients (61%) and 8 patients (80%) were in the levosimendan group and control groups, respectively. Four patients (8 episodes) in the levosimendan group developed hypotension, resulting in dose reduction in three patients, while no hypotension occurred in the control group. Headache was reported by 4 patients . The proportions of drug-related or serious adverse events in the levosimendan (33%) group and the control (30%) group were parallel. Deddo Moertl22 also reported adverse events of hypertension. In the levosimendan group, 12 patients (34%) were administered a reduced dose of medicine due to hypotension. Moreover, during the 24-h infusion, levosimendan had to be withdrawn in 3 patients, which was attributed to serious hypotension and elevated serum creatinine.Two studies24 also compared the RV function of the two groups to a certain degree, it emphasized on rather the comparison of the LV systolic function than the RV. And there were just small sample sizes, incomplete analysis parameters, and different analysis methods and proposals in some other researches, having made it difficult to compared results. As such, we conducted this study. In this study, the comparison of RVFAC and S’ between the two groups were added to replace the LVEF in the previous. Moreover, this study included more initial studies on the comparison between two groups, which made it more convincing. Our meta-analysis included a total of 8 studies with a combined study population of 390 patients and provides evidence that levosimendan decreases both the mPAP and sPAP in patients with heart dysfunction. Meanwhile, the drug also increased levels of RVFAC and TAPSE, as well as tricuspid annular peak systolic velocity. And there is an increasing trend of cardiac output in levosimendan group. However, we failed to offer evidence that levosimendan reduces PVR.To the best of our knowledge, this is the first systematic review and meta-analysis that comprehensively illustrates the efficacy of levosimendan for RV function in patients with heart dysfunction, including pulmonary artery pressure, pulmonary vascular resistance, tricuspid annular plane systolic excursion, tricuspid annular peak systolic velocity, right ventricular fractional area change and cardiac output. Although the previous meta-analysis20 had a greater impact on the results compared to others’. We reviewed the original literature once again and found that their measurement method was similar to that reported in other researches, but the results of measured TAPSE were much lower than the normal value or even the value of others, which led to the change value (mean ± standard deviation) of TAPSE being smaller. What’s more, there were no significant differences in the sample size or baseline characteristics of patients included  between Yan's research and others’, which was believed not to lead to such a remarkable difference. Considering from the perspective of clinical heterogeneity, we speculated the existence of measurement or recording errors in Yan’s study, and tended that it was the cause of moderate heterogeneity. We tried to contact the author via email for further confirmation but failed. After excluding this study, the remaining three studies showed a low level of heterogeneity (I2 = 0%), and the results suggested that levosimendan significantly increased TAPSE in the overall analysis. In addition, there were also moderate levels of heterogeneity among studies in the analysis of PVR (I2 = 66%) and CO (I2 = 89%). Regrettably, the included studies were too few to perform sensitivity analysis to explore the source of heterogeneity. Therefore, we used the random effects model and found that levosimendan did not reduce PVR or increase CO in such patients. For FAC, sPAP, mPAP and tricuspid annular peak systolic velocity, the results were regarded as reasonably reliable due to the low heterogeneity. Although the results of mPAP and PVR were inconsistent with the previous analysis24, in the view of the lower heterogeneity (I2: 0% vs. 92%), primitive data types as well as the rationality of statistical methods, it could be thought that the results of the current study were more reliable to a certain extent.There was moderate heterogeneity in the current meta-analysis among studies in the analysis of TAPSE (57%), and the results suggested that levosimendan did not significantly increase TAPSE in the overall analysis. Sensitivity analyses of the outcomes from the four studies implied that Yan’s data25. At present, echocardiography is the most commonly used method in clinical practice for evaluating RV function. RVFAC and TAPSE are typically regarded as symbols of the longitudinal function of the RV. According to the 2010 ASE guidelines, it is easy to obtain the value of TAPSE from echocardiography, which can be used as a routine measurement index of RV function. Decreased TAPSE (< 16 mm) is associated with weakened RV systolic function26. Moreover, technicians are also able to evaluate RV function by calculating the value of RVFAC via a related formula. RV systolic dysfunction is considered when RVFAC < 35%26. In addition, the tricuspid annular peak systolic velocity (S’) can be harvested quickly and repeatedly at the same time. If the value of S’ is slower than 11.5 cm/s, it predicts an RV ejection fraction less than 45% with a sensitivity of 90% and a specificity of 85%27. Similarly, in regard to PAH patients, De Castro, S. reported in his article that a value of S' less than 9.5 cm/s was the optimal value for predicting RVEF < 40%28. On the other hand, right heart catheterization is also a major and widely used measurement to estimate RV load, which provides key information, such as PVR, sPAP, mPAP, CO, etc.Assessment of RV function is more challenging, and the relevant parameters are harder to establish than those of the left ventricle as a result of the irregular and complex geometric morphology of the RV7. Over time, people have paid increasing attention to the right heart, from anatomy to pathophysiology to function. The geometric morphology of the RV is complex and irregular and is composed of the inflow tract , trabecular apex myocardium and funnel part. Systemic venous blood return is received by the right atrium, passes through the tricuspid valve to the RV and is finally pumped into the pulmonary circulation through the pulmonary valve. The pressure of pulmonary circulation is much lower than that of systemic circulation, so the wall of the RV is much thinner than that of the LV. As pulmonary vascular resistance and pulmonary arterial pressure increase, the myocardial contractility of the RV will also be enhanced up to four- to fivefold to maintain stroke volume29. This compensatory mechanism is called the "coupling" of the ventricle and its load, which is achieved primarily by myocardial hypertrophy. As the disease progresses, cardiac output is maintained by relying on RV cavity diastole and increased heart rate6. Then, RV decompensates, and "decoupling" occurs30. Eventually, it comes into RV dysfunction, even right heart failure. As mentioned above, the causes of right heart failure vary; hence, the management of right heart failure should aim at the pathogenic factors of the primary disease. Additionally, it is a key step to follow a three-pronged approach: enhancing RV myocardial contractility, decreasing afterload, and optimizing volume load31.In patients with heart dysfunction, even systemic diseases, RV failure usually accounts for the leading cause of mortality. Right heart failure has a much worse prognosis than left heart failure33. At this point, levosimendan could be used not only as an inotrope but also as an inodilator in clinical practice. Moreover, levosimendan has several advantages over traditional inotropes: (1) the positive effect of contractility is not related to the increasing concentration of intracellular calcium, so myocardial oxygen consumption will not increase; (2) if beta-blockers are given, the effect is not compromised; (3) the action is prolonged by forming active metabolites; and (4) the agent has a beneficial effect on peripheral organ (kidney and liver) perfusion and function via vasodilation35. Furthermore, it has been confirmed that levosimendan subserves heart failure in some practical studies. For instance, repeated intravenous levosimendan benefited patients with advanced heart failure by reducing hospitalization and mortality rates38. A meta-analysis comprising 1065 patients with acute heart failure/cardiogenic shock revealed that levosimendan-treated patients with acute coronary syndrome appeared to have haemodynamic benefit but did not identify an adverse effect on worsening heart failure or mortality39.Levosimendan, described as a novel anti-heart failure agent, has two major pharmacological mechanisms. It exerts a positive inotropic effect by binding to cardiac troponin C and enhancing the sensitivity of cardiac muscle to calcium; additionally, it exerts a vasodilator effect by mediating the opening of ATP-dependent potassium channels in smooth muscle cells of blood vessels 40 identified an increase in RVEF and LVEF, as well as an improved RV diastolic index, in 47 patients with acute compensatory heart failure. Additionally, they observed the recovery of neurohormones and alleviation of symptoms, manifested as a significant decrease in serum NT-pro BNP levels and NYHA class. In the study performed by Fatma Alibaz-Oner et al.41, the impact of levosimendan on RV systolic and diastolic parameters, isovolumic myocardial acceleration (IVA) and peak myocardial velocity during isovolumic contraction (IVV) derived from tissue Doppler imaging was evaluated in 30 patients with ischaemic heart failure. Their data suggested a favourable effect of levosimendan therapy on RV systolic function due to the significant increase in IVA and IVV.Our pooled analysis showed that levosimendan improved RV systolic function for enhancing RVFAC and TAPSE, as well as tricuspid annular peak systolic velocity. Actually, some previous studies have also shown that patients' right heart function could be improved after levosimendan. Asli Kurtar Mansiroglu et al.42. Additionally, pulmonary arterial pressure decreases in part as a result of the amelioration of LV function. Certainly, the agent could also enhance RV contractility similar to that of the LV. Leppikangas et al.43 also reported that after continuous infusion of Levosimendan for 24 h, cardiac index (CI) and stroke volume index (SI) were significantly enhanced. As mentioned in our results, levosimendan could enhance RV contractility. It is all known that stroke volume (SV) is affected by preload, myocardial contractility, and afterload. And the regulation of the pumping function of the heart by changing the myocardial contractility, independent of the other two, is called homometric regulation. In the case of a constant heart rate, CO is positively related to SV. Accordingly, SV and even CO should be theoretically increased, as a result of enhancement of RV systolic function. Intriguingly, the consistent conclusion was not observed in our pooled analysis. There were two possible explanations for this outcome. One is that levosimendan also exerts vasodilatory effects, leading to the reduction of preload, which cause a similar consequent on SV and CO based on heterometric autoregulation. The other is the statistical limitations for small sample size aggregated or the original research. Second, levosimendan exerts vasodilating effects on the pulmonary arterial system, resulting in a reduction in PVR and PAP44. Therefore, the RV afterload is reduced, and the mechanical efficiency is improved. Previously, it was reported that PVR was reduced after levosimendan by Slawski et al.45. However, our pooled analysis demonstrated that there was only a reduction in PAP but not PVR. Of note, the difference in the dose of levosimendan used might be a possible reason for these differences. Undeniably, we included only a few studies in the analysis of PVR, which weakens the persuasiveness of the results. Third, it is believed that levosimendan improves ventricular-vascular coupling of the RV, combining the dual benefits of pulmonary vasodilatation and positive inotropy23.Levosimendan improves RV systolic function through a variety of mechanisms. First, due to the positive inotropic effect, levosimendan increases LVEF and LV filling pressures, which might exert favourable effects on RV systolic functionUndoubtedly, our research has several limitations. First, our study’s data were extracted from other studies. Due to the inherent limitations of these studies, such as heterogeneity with respect to data selection, our pooled results might have produced some biases towards positive results. Second, high heterogeneity of PVR was observed, and the sources of this heterogeneity remain unknown and are attribute to the few numbers of included studies. The low number of clinical studies, small samples of each included study, and low-quality trials weaken the conviction of the results to a certain extent. Third, although our study showed that levosimendan was beneficial for RV function in some respect, the follow-up time was too short to verify the long-term efficacy of the drug. Forth, the most common etiology of patients enrolled are heart failure , but we failed to obtain specific information of these patients. Thus, it limits us to perform further subgroup analysis. However, the results might suggest that levosimendan is effective for RV failure caused by all kinds of heart failure. Surely, further large-scale, multicentre strict RCTs and more pertinent evaluation parameters  are required to verify the positive effects of this drug.Our meta-analysis provides evidence that levosimendan improves the systolic function of the right heart and decreases the pressure of the pulmonary artery in patients with heart dysfunction. However, the current meta-analysis was based on observational studies. Due to the lack of other evaluation parameters, these conclusions should be interpreted with caution.


Eruptive seborrheic keratoses (ESK) is a benign skin condition that has beenassociated with malignant and nonmalignant diseases. We conducted asystematic review of reported cases of ESK to identify and summarizeassociated comorbidities.MEDLINE and Embase were searched from database inception (1946) to July 31,2020 for original articles describing ESK with or without a co-occurringcondition. Subject demographics, as well as details of ESK and associateddiagnoses were extracted from 76 articles  representing 92 patients.n = 70/92) of patients with ESK had aco-occurring malignancy, 4.3% (n = 4/92) presented with anonmalignant condition, 9.8% (n = 9/92) experienced ESK asan adverse drug reaction, and 9.8% (n = 9/92) did notreport any underlying medical condition. ESK preceded a cancer diagnosis in76.1% (n = 70/92) of patients with a mean latency period of4.0 months (range: 0.25-9 months). The most common malignancies associatedwith ESK were cutaneous T-cell lymphoma and gastrointestinal adenocarcinoma . ESKpreceded nonmalignant conditions or no disease in 14.1% (n= 13/92) of patients with a mean latency period of 3.1 months (range: 0.75-6months). Drug-induced ESK occurred in 9.8% (n = 9/92) ofpatients with a mean latency period of 7.1 weeks after changingmedication.In total, 76.1% (Although the role of ESK as a paraneoplastic cutaneous marker is debated,healthcare providers should consider screening for underlying malignancy inpatients presenting with ESK. Larger studies are needed to confirm its roleas a marker for disease. Histopathologic examination shows proliferation of keratinocytes withkeratin-filled cysts. Treatment is not required but can be considered if the lesions aresymptomatic or for cosmetic reasons. Treatment options include cryotherapy, shaveexcision, electrodessication, hydrogen peroxide, and laser treatment.Eruptive seborrheic keratoses (ESK) is a rare dermatological disorder characterizedby the rapid appearance of several benign pigmented skin lesions. ESK presents aswell-demarcated round or oval lesions with a verrucous surface. It is diagnosedclinically although in rare cases, a biopsy can be used to differentiate ESK fromother benign and malignant lesions. ESK has also been reported as an adverse drug reaction. Although there have been clinical reviews about ESK, to our knowledge therehave been no systematic reviews to-date.Although ESK is a benign condition, it has been associated with malignant andnonmalignant conditions, including gastrointestinal adenocarcinoma, viral infection,and inflammatory skin conditions.Given its potential role as an early marker of cancer or other illnesses, it isimportant for healthcare workers to promptly identify ESK and to understand itsassociated conditions. The goal of this systematic review is to identify andsummarize malignant and nonmalignant conditions in patients with ESK. The secondaryobjective is to report outcomes and characteristics of ESK after medication use. No language restrictions and no publication period restrictions wereapplied. Variations of the following keywords were used for the search:“Leser-Trelat”, “Stucco keratoses,” “Seborrheic keratoses,” or “Lichenoidkeratosis” in combination with “eruptive,” “abrupt,” explosive,” and“sudden.”MEDLINE and Embase were searched from database inception (1946) to July 31, 2020using the OVID interface in accordance with the Preferred Reporting Items forSystematic Review and Meta-Analysis guidelines.Original articles that described ESK in association with other medical conditionswere included if they met the following criteria: (1) included patientsdiagnosed with ESK, (2) if latency period was described, only patients with anESK latency period of less than a year were included, and (3) were observational. Thefollowing studies were excluded: (1) animal and in vitro studies, (2) systematicreviews or review articles, and (3) commentaries.The literature search was conducted by 2 independent reviewers (S.M. and R.P.L.)who reviewed the list of titles, abstracts, and full texts to identify eligiblestudies. Discrepancies between the 2 reviewers were discussed and if a consensuswas not reached, a 3rd reviewer (A.M.) was consulted and a final decision wasmade. Reference lists from included articles were reviewed to identifyadditional studies that were not found in the initial search.Supplemental File 1. This review used a descriptive analysis ofobservational studies.Data collection was independently conducted by 2 reviewers (S.M. and R.P.L.), whoreviewed and extracted data from included studies. Discrepancies between the 2reviewers were discussed and if a consensus was not reached, a 3rd reviewer(A.M.) was consulted and a final decision was made. Outcome measures are definedin  Quality appraisal was performed by S.M. and R.P.L. using Murad et al.(case reports and case series) and the Newcastle-Ottawa scale (case control studies). If a consensus was not reached, a 3rd reviewer (A.M.) was consulted and afinal decision was made. .The level of evidence for all include articles were assessed by S.M. and R.P.L.according to the Oxford Centre for Evidence-Based Medicine.In total, 26 case reports and case series were scored as good (5 + points), 32fair , and 15 poor  using the Murad et al. scale. Allincluded case control studies scored as good (6 + points) using theNewcastle-Ottawa scale.Supplementary Figure S1, Supplemental Tables S3-S5). Overall, 92.1% (n = 70/76) of studies hada level of evidence of 5, 6.6% (n = 5/76) had a level ofevidence of 4, and 1.3% (n = 1/76) had a level of evidence of3b. Of the 92 patients that were included in the analysis, the mean age was 60.3years (range: 13-92 years) and among patients in whom sex was reported, 47.3%(n = 35/74) were female and 52.7% (n =39/74) were male. In total, 76.1% (n = 70/92) of patients withESK had a co-occurring malignancy, 4.3% (n = 4/92) had acoinciding nonmalignant condition, 9.8% (n = 9/92) did notreport any underlying medical condition, and 9.8% (n = 9/92)experienced ESK as an adverse drug reaction.After screening the titles and abstracts of 366 articles, the full texts of 253studies were reviewed. In total, 76 studies met the inclusion criteria and wereused for data collection and analysis (n = 70/83) had an underlying neoplastic condition witha mean age of 62.8 (range: 20-92) years . Patients were diagnosed with solidmalignancies , hematological malignancies, both ,or specifics were not reported . The mostcommon hematological malignancy was cutaneous T-cell lymphoma and the most common solid tumor wasgastrointestinal adenocarcinoma . On average,ESK appeared 4.0 months (range: 0.25-9 months) before a cancer diagnosis.Comorbidities were reported in 32.9% (n = 23/70) of cancerpatients with the most common being hypertension = 5/23, 21.7%), obesity, and diabetes mellitus. Following cancer treatment, 19 patientsexperienced improvement in their ESK lesions. Among these patients, completeresolution was reported in 42.1% (n = 8/19) of patients with amean resolution period of 6.7 months and partial resolution was reported in57.9% (n = 11/19) of patients with a mean resolution period of3.4 months.Of the 83 patients who reported ESK with an associated condition, the majority. ESK was a rare occurrence amongst bothcancer patients and controls with a prevalence rate of 0.3% to 2.3% and 0.0% to8.0%, respectively. Given the low incidence rate, an association between ESK andmalignancy could not be made.Despite the temporal relationship observed between the development of ESK and acancer diagnosis in smaller studies, larger case control studies found norelationship between ESK and the incidence of cancer (n = 13/92) of patients with a mean age of 44.9 years(range: 13-74 years). The mean latency period between ESK onset and presentationwas 3.1 months (range: 0.75-6 months). These patients presented with variousdiseases. Specifically, ESK co-occurred with erythrodermic pityriasis rubrapilaris (n = 1), diabetes mellitus (n = 1),secondary syphilis (n =1) and human immunodeficiency virus(n = 1).ESK coincided with nonmalignant diseases or no disease in 14.1%(n= 9/92) of patients (n = 2/9) of patientsand after starting synthetic estrogens in 22.2% (n = 2/9). Aprior cancer diagnosis was made in 55.6% (n = 5/9) ofpatients.ESK was described as an adverse effect to medication in 9.8% (patients . Of thes Our data found that 76.1% (n = 70/92) of reported casesoccurred in patients that were subsequently diagnosed with a malignancy. Inaccordance with previous literature, we found that ESK was most commonly associatedwith cutaneous T-cell lymphoma and gastric adenocarcinoma. To support their uncontrolled proliferation, cancer cells produce growthfactors which bind to receptors on cell membranes that drive intracellular growthsignalling. Activation of the epidermal growth factor receptor (EGFR) family is ahallmark of many cancers. EGFR are found in keratinocytes and can be activated by epidermal growthfactor (EGF) or transforming growth factor α (TGF-α). Growth factor secretion from the tumor may drive keratinocyte growth via EGFRsignaling, resulting in ESK. Supporting this hypothesis, seborrheic keratoseslesions from a melanoma patient showed increased EGFR levels compared to control skin. Although increased EGF levels were not observed in ESK patients, TGF-α levelswere elevated and became undetectable after treatment, suggesting that TGF-α is themain driver of ESK. In addition, TGF-α have previously been shown to be upregulated in precursorlesions of gastric carcinomas. Thus, it is plausible that ESK may be correlated with EGFR mediatedproliferation of keratinocytes caused by growth factors secreted by the tumor.ESK is a rare, benign, and underdiagnosed skin disease that may be associated withmalignant or nonmalignant conditions. Another criticism of ESK’s link to malignancy is that the incidence of bothseborrheic keratoses and cancer is higher in older patients. While the majority of patients were elderly in our analysis, we found that31.4% (n = 22/70) of patients who had ESK prior to a cancerdiagnosis were under the age of 60. Moreover, 27.1% (n = 19/70) ofcancer patients reported resolution of ESK following treatment, although this didnot always correlate with regression of the tumor. Of the 4 reports that notedrecurrence of ESK in cancer patients, all were associated with a relapse of theprimary cancer or a new malignancy. These data suggest that there is a temporal relationship between ESK andmalignancy that may not be strictly due to increased age.ESK’s role as a paraneoplastic cutaneous marker is debated in the literature.Although case control studies found no association between ESK and malignancy, theincidence of ESK was low in both patient and control groups. Given the small samplesize, no conclusions could be made on the association between ESK and malignancy. In some cases, a diagnosis of ESK was made by visual appearance alone andimages were not available for our assessment. In 58.7% (n = 54/92)of cases, the ESK latency were based on patient self-reports, which may beunreliable. Moreover, the number of ESK patients with no associated disease may beunderestimated because of reporting bias. Additionally, other reports have notedinflammation of preexisting seborrheic keratoses following treatment with chemotherapy. Although we excluded these reports from our analysis on drug-induced ESK, itis possible that patients noticed an inflammation of previously unrecognizedseborrheic keratoses, rather than the eruption of new ones. Of the included studiesdescribing drug induced ESK, none prove causality . It is difficult to attribute a link between ESK and treatmentas 55.6% (n = 5/9) of patients who developed drug induced ESK werealso diagnosed with cancer. Moreover, this may also have contributed tomisclassification bias. Finally, data on ESK resolution was unavailable in 68.5%(n = 63/92) of patients, which limits our analysis.Our systematic review has several limitations. Firstly, the definition of ESK variedbetween studies and most articles were case reports or case series, with an overallmean evidence level of 4.9.Despite these limitations, our study demonstrates that ESK precedes malignant andnonmalignant conditions and has also been reported as an adverse drug reaction.Results from future studies will be important in determining if there is a causativelink between ESK and disease. Further studies are required to understand theprevalence of ESK and its associated conditions.Click here for additional data file.Supplemental material, Online supplementary file 1, for Eruptive SeborrheicKeratoses Are Associated With a Co-Occurring Malignancy in the Majority ofReported Cases: A Systematic Review by Sara Mirali, Asfandyar Mufti, RafaelPaolo Lansang, Muskaan Sachdeva and Jensen Yeung in Journal of CutaneousMedicine and Surgery