In recent years, direct oral anticoagulants (DOAC) have accumulated evidence of efficacy and safety in various clinical scenarios and are approved for a wide spectrum of indications. Still, they are currently used off-label for left ventricular thrombus owing to a paucity of evidence. For the same reason, there is a lack of guideline indication as well. Our work is based on an exhaustive analysis of the available literature and provides a structured and detailed update on the use of DOACs in patients with left ventricle thrombus. The safety and efficacy of DOACs were analyzed in particular clinical scenarios. As far as we know, this is the first paper that analyzes DOACs in this approach. In recent years, direct oral anticoagulants (DOAC) have accumulated evidence of efficacy and safety in various clinical scenarios and currently have a wide spectrum of indications. Studies of DOACs in patients with atrial fibrillation (AF) have shown that they reduce the risk of stroke and systemic embolism equal to or better than vitamin K antagonists (VKA), with a similar or lower bleeding risk, and are currently preferred over VKA in patients eligible for a DOAC. Left atrial (LA) or left atrial appendage (LAA) thrombi are identified in up to 10% of patients with AF and current guidelines recommend anticoagulant therapy for at least three weeks upon their detection ,3,4. MorIn the ventricle, thrombus formation reflects the presence of factors that represent Virchow’s triad, namely local myocardial injury, stasis of blood flow due to reduced wall motion and dilation of the heart chamber, and hypercoagulability . HoweverMost data related to LV thrombosis come from patients with acute myocardial infarction, especially those with anterior localization and akinetic apex that provide the perfect milieu for thrombosis. However, LV thrombus complicates both ischemic and non-ischemic cardiomyopathies, and there is little evidence of the latter. DOACs are currently used off-label for left ventricular thrombus owing to a paucity of evidence. For the same reason, there is a lack of guideline indication as well.Evaluating the efficiency and safety of DOACs compared to VKA by including all patients with LV thrombi has the advantage of an analysis of a large number of cases but is hampered by the uneven distribution of the etiological substrate. Our work aims to fill this gap. Based on an exhaustive analysis of the available literature, we provide a structured and detailed update on the use of DOACs in particular clinical scenarios. As far as we know, this is the first paper that analyzes DOACs in this approach.Early LV thrombosis is a common complication of acute myocardial infarction (MI), especially in patients with anterior or extensive ST-elevation myocardial infarction (STEMI) and a reduced LV ejection fraction. The cardiomyocytes’ ischemia and necrosis lead to wall motion abnormalities such as hypokinesia, akinesia, or dyskinesia that favor blood stasis within LV. Moreover, collagen exposure and subendothelial inflammation act as triggers for platelet aggregation and activation of coagulation . In the first three months after an acute coronary event, the risk of LV thrombus occurrence and, consequently, cardioembolism, is the highest. The widespread use of percutaneous coronary intervention (PCI) in patients with STEMI has dramatically reduced the incidence of thromboembolic events related to LV thrombosis, from 22.3% before the PCI era to 5.5% in the PCI era . The useBefore DOACs were available, warfarin was the only oral anticoagulant used for the treatment of LV thrombosis post-acute MI. The minimum duration of the anticoagulant treatment is 3–6 months, and the imaging confirmation of thrombi resolution allows the discontinuation of anticoagulation ,10. HoweThe successful use of DOACs in post-STEMI LV thrombosis has already been reported. The complete resolution of a 26 mm × 16 mm LV thrombus was obtained after 18 days of treatment with dabigatran added to dual antiplatelet therapy (DAPT) . The resSince these first case reports, multiple evidence of efficiency and safety has been added. DOACs were used in both STEMI and non-ST-elevation myocardial infarction (NSTEMI) patients complicated with LV thrombosis, and in cases with available follow-up, the outcome was generally favorable. The thrombus resolution was confirmed in 82% of patients at a 1-year follow-up and in 86.1% of patients after a median follow-up period of 2.2 years . The resThe most recent meta-analysis to date comparing DOACs with VKA included over 2000 patients with LV thrombus and showed that post-acute MI patients had a lower risk of stroke or systemic embolism, and bleeding if they used a DOAC and not VKA . Fang etThere are data suggesting that DOACs allow a quicker resolution of LV thrombus than VKA . Still, The full thrombus resolution was documented in some patients after more than one year of treatment . In otheSince nowadays much emphasis is placed on prevention, the role of DOACs has been studied in this setting as well. Low-dose rivaroxaban was added to standard DAPT in patients with anterior STEMI treated by primary PCI and it reduced the LV thrombi formation at a 30-day follow-up .Myocarditis is an inflammatory disease of the myocardium, usually resulting from common viral infections with cardiac tropism. Adenoviruses, enteroviruses, and herpesviruses are most commonly involved . HoweverViral myocarditis evolves in three stages. First, the viruses enter cardiomyocytes and activate the innate immune response. Second, viral replication occurs and activates the acquired immune response. Finally, the evolution might mean a full recovery or the development of dilated cardiomyopathy . While sIn animal models, viral myocarditis was associated with an increased myocardial tissue factor expression and activity . ProinflEosinophils are granulocytes with roles in inflammation and immunological responses. After activation, eosinophil degranulation takes place, with the release of proteins involved in the production of free radicals, cell necrosis, and the induction of apoptosis . EosinopThe thrombotic stage occurs when the mean duration of eosinophilia is 10 months . The proCurrent guidelines recommend initial treatment with unfractionated heparin (UFH) or low-molecular-weight heparins (LMWH) and bridging with VKA, with warfarin as the antithrombotic therapy of choice for intracardiac thrombi. Although the minimum duration of VKA treatment is three months , the lenHypertrophic cardiomyopathy (HCM) is a myocardial disease with a genetic substrate, characterized by a particular pattern of LV hypertrophy. 2DS2-VASc score and even when sinus rhythm is restored [Atrial fibrillation is a common complication of HCM. Due to this association, patients with concurrent HCM and AF have an increased risk of developing atrial thrombi ,51. Consrestored ,53. Morerestored . However, the presence of AF is not mandatory for the onset of LV thrombosis. In a short series of five cases of HCM and LV thrombus, only one patient had AF . Of noteOccasionally, patients with HCM and AF can simultaneously develop thrombi in LA and LV, thereby having an extremely high thromboembolic risk. In a patient with AF and a history of gastrointestinal bleeding while on warfarin, discontinuation of anticoagulant therapy resulted in thrombosis in both the left atrial appendage and LV. The ventricular thrombus was attached to the chordal apparatus of the posterior mitral valve . In thisBased on the distribution of hypertrophy, there are several phenotypes, such as symmetric, asymmetric, apical, and focal . Of morpHypokinetic/akinetic and aneurismal areas are prone to thrombi formation and are associated with a high risk of thromboembolic events. One study investigating intracardiac thrombosis in patients with heart failure reported that all five patients with HCM and LV aneurysm also had LV thrombosis . In a coLV thrombosis in HCM patients in sinus rhythm is a rare incidence. Still, a 40 mm apical thrombus was identified at the level of an LV apex aneurysm . The preWhile patients with HCM and AF DOACs showed similar embolic and bleeding rates to VKA ,62,63, lThe long-term action of elevated heart rate causes both diastolic and systolic LV dysfunction. The LV is dilated and has decreased contractility. Structural remodeling and myolysis are contributors to wall-thinning and the loss of contractile force. What is particular about tachycardia-induced cardiomyopathy is the reversible nature of dilated cardiomyopathy and the heart failure that it produces. In the case of a patient who presents both tachyarrhythmia and dilated cardiomyopathy with LV systolic dysfunction, the differential diagnosis between tachycardia-induced cardiomyopathy and tachycardias secondary to cardiomyopathy is extremely difficult and often possible only after heart rate control . There are few case reports on LV thrombus in this setting ,67,68. ITakotsubo cardiomyopathy is a stress-induced heart disease characterized by sudden and usually transient regional LV systolic dysfunction. The adrenaline surge leads to coronary spasm and microcirculation dysfunction, resulting in acute myocardial impairment. The echocardiographic feature is “apical ballooning”, the result of the abnormal motion of the apical and midventricular walls that appear akinetic or dyskinetic compared to the basal segments . There iFurthermore, platelet and coagulation cascade activation and myocardial inflammation are present in the acute phase. Sometimes, persistent low-grade inflammation has been identified, and it is assumed that it may contribute to long-term cardiac dysfunction . A signiLV thrombus is rare, occurring in only 1–2% of cases . PatientWhen LV thrombus is present, patients with Takotsubo cardiomyopathy should receive anticoagulant treatment for at least three months or until LV function is restored . Before In 2018, the non-vitamin K antagonist oral anticoagulants were introduced in the International Expert Consensus Document on Takotsubo Syndrome as a therapeutic option in patients with LV thrombus and/or embolization . AlthougDuring the last three years of the COVID-19 pandemic, an important number of reports of thrombotic and thromboembolic events were collected, especially venous thromboembolism. COVID-19-associated coagulopathy is very complex and multifactorial. It partially overlaps but never perfectly matches with any of the following: sepsis-induced coagulopathy, disseminated intravascular coagulation, hemophagocytic syndrome, hemophagocytic lymphohistiocytosis, antiphospholipid syndrome, and thrombotic microangiopathy . Acute cTo date, LV thrombosis in COVID-19 patients was associated with acute MI ,91,92 anExtreme thrombotic events have been reported in COVID-19 patients. A 17-year-old patient, otherwise healthy, experienced heart failure with reduced ejection fraction (HFrEF) and LV thrombus in the context of a severe multisystem inflammatory syndrome associated with COVID-19 . SimilarThe high thrombotic risk determined by COVID-19 is reflected by the case of a 30-year-old woman with HFrEF who developed recurrent thrombosis in the LV and bilateral arterial embolism of lower limbs while on a therapeutic dose of apixaban, one month after infection with SARS-CoV-2 . The treThere are few reports of successful use of DOACs in patients with LV thrombus and acute or recent SARS-CoV-2 infection . Still, These studies include a larger number of cases and allow for estimating the rate and speed of thrombi resolution, the prevalence of ischemic and hemorrhagic events during treatment with DOACs, and a comparative analysis with VKA.A meta-summary of 36 case reports of DOAC use in patients with LV thrombosis found that thrombus resolution was achieved in 87.9% of cases, after a median duration of treatment of 30 days . This thAn extensive literature search and analysis of the available data found that thrombus resolution was achieved in 75%, 86.2%, and 90% of patients receiving dabigatran, rivaroxaban, or apixaban, respectively . CompletIn the last two years, small retrospective studies comparing DOACs with VKA published their results. Some showed similar rates of LV thrombus resolution, systemic thromboembolic events, and bleeding events with DOACs compared to VKA ,110. In The results of three randomized clinical trials were recently published. Rivaroxaban 20 mg od was assessed in patients with newly diagnosed LV thrombus and compared to warfarin. Thrombus resolution was better with rivaroxaban than warfarin at all follow-ups, especially at a 1-month follow-up (71.79% vs. 47.5%) . RivaroxThe most robust data are provided by several meta-analyses, and all reached a similar conclusion. A meta-analysis of 6 studies, including 408 patients on DOAC and 1207 patients on VKA, compared the efficacy and safety of DOACs with that of VKA in patients with LV thrombus and highlighted that thrombus resolution, embolic events, and bleeding events were similar between the 2 groups . Herald Thrombus usually forms in large LV with systolic dysfunction, in aneurysms, or in areas with wall motion abnormalities such as hypokinesia or akinesia. Although thrombosis in an LV with a normal ejection fraction is rare, this particular situation should not be forgotten or ignored ,60. The The difficulties of VKA treatment lie in the multiple food and drug interactions, the unpredictable anticoagulant effect, the narrow therapeutic range, the need for frequent monitoring of the anticoagulant effect through blood tests, and the slow onset of the effect, which requires bridging therapy. DOACs are an enticing alternative to VKA because they do not have these shortcomings. Moreover, DOACs perform better than VKA in different clinical settings . CurrentA dilated LV with parietal kinetic abnormalities is an environment characterized by low flow and low-shear stress, which is favorable for thrombosis. The same hemodynamic condition that predisposes to the formation of thrombi in the LV is also found in the left atrial appendage. Starting from this similarity, from the favorable outcomes in patients with AF , and froThe mechanism of action could be an advantage of DOACs over VKA. Rivaroxaban prevents thrombosis but may favor the dissolution of established thrombi by direct inhibition of free and thrombus-bound factor Xa . RivaroxIt is well-known that between inflammation and thrombosis exists a bidirectional relationship . InflammThe data gathered so far show that DOACs are an alternative to VKA, having a rate of resolution of thrombi, and ischemic and hemorrhagic risks at least equal to that of VKA . They haThere were several reports of a lack of thrombus resolution and even thrombus formation in the LV during anticoagulant therapy, DOACs included ,139,140.Our study has several limitations arising from the studied literature. Firstly, only one DOAC has been studied in randomized clinical trials for this indication. Most data come from case reports and retrospective analysis which are subject to inherent biases. Secondly, DOACs were used in various dosing regimens and often in combination with one or two antiplatelet agents. This heterogeneity makes it very difficult to identify the most appropriate therapeutic strategy for the treatment of LV thrombosis. Thirdly, the assessment of thrombus resolution was not performed at standardized time intervals, and therefore a comparison between DOACs regarding the time required for thrombus resolution remains a desideratum for future studies. The anticoagulant treatment is of utmost importance in patients with left ventricle thrombus to prevent disabilities and death resulting from systemic embolism. Our thorough analysis of the available literature showed that DOACs can be an option for the treatment of LV thrombus regardless of the substrate. Considering the considerable amount of evidence accumulated so far, we expect a change in the guidelines soon. Our study found that apixaban was prescribed at 2.5 mg/5 mg bid, dabigatran at 110 mg/150 mg bid, edoxaban at 30 mg/60 mg od, and rivaroxaban at 15 mg/20 mg od, depending on creatinine clearance, age, and weight. In a few patients with concomitant pulmonary embolism, anticoagulants were administered according to the related guideline specifications. Available recommendations advocate a treatment period of at least 6 months, but the optimal duration is not well-known. Further prospective studies are needed to better guide the treatment of these patients.


Anthracyclines are a widely used class of chemotherapy in pediatric and adult cancers, however, their use is hampered by the development of cardiotoxic side-effects and ensuing complications, primarily heart failure. Clinically used imaging modalities to screen for cardiotoxicity are mostly echocardiography and occasionally cardiac magnetic resonance imaging. However, the assessment of diastolic and global or segmental systolic function may not be sensitive to detect subclinical or early stages of cardiotoxicity. Multiple studies have scrutinized molecular nuclear imaging strategies to improve the detection of anthracycline-induced cardiotoxicity. Anthracyclines can activate all forms of cell death in cardiomyocytes. Injury mechanisms associated with anthracycline usage include apoptosis, necrosis, autophagy, ferroptosis, pyroptosis, reactive oxygen species, mitochondrial dysfunction, as well as cardiac fibrosis and perturbation in sympathetic drive and myocardial blood flow; some of which have been targeted using nuclear probes. This review retraces the pathobiology of anthracycline-induced cardiac injury, details the evidence to date supporting a molecular nuclear imaging strategy, explores disease mechanisms which have not yet been targeted, and proposes a clinical strategy incorporating molecular imaging to improve patient management. In another study of doxorubicin treated mice, increased 18F-FDG myocardial uptake had a direct correlation with histologically determined myocardial redox stress  . They fux stress .18F-FDG uptake in patients treated with anthracyclines. Borde et al. observed in lymphoma patients treated with doxorubicin-based chemotherapy a higher post-therapy 18F-FDG uptake than before treatment    (n = 337 consecutive patients) that Hodgkin’s lymphoma (n = 52) was associated with a higher cardiac 18F-FDG uptake  whereas non-Hodgkin’s lymphoma (n = 57) and non-lymphatic cancer (n = 228) were not. Interestingly, the authors observed that the increase in cardiac 18F-FDG uptake in Hodgkin’s lymphoma was not determined by prior chemotherapy and/or serum glucose levels, however, with the caveat that patient preparations were not optimized or standardized for cardiac 18F-FDG PET imaging, in addition to the retrospective nature of the study  . Similar= 0.012) . Though = 0.012) . Additio < 0.01) . Heckman < 0.01)  demonstrhe study . A signiiability . Further signals . Whereas signals , these pP = 0.02)  cycle and can thus serve as a metric to quantify myocardial oxygen consumption. A preclinical model of chronic doxorubicin treatment in rats (2 mg/kg IV weekly for 6 weeks) observed that doxorubicin decreased myocardial oxygen consumption reserve  . 11C- acorubicin .11C-acetate uptake to assess myocardial oxidative metabolism and myocardial blood flow in patients treated with anthracyclines (2 every 3 weeks for 15 weeks (cumulative dose of 300 mg/m2). The investigators observed that compared to baseline, there was no significant change in resting myocardial blood flow during or after completion of doxorubicin treatment. Similarly, no significant changes were noted in Kmono, an index of myocardial oxygen consumption  is another PET tracer that could circumvent this limitation by utilizing a sulfur atom in its backbone that prevents it from undergoing further β-oxidation  , which was associated with a 7% and 9.5% drop in ejection fraction and fractional shortening, respectively, that was also only significant 2 weeks post-treatment ,1Htriazole-4-ethylene]triphenylphosphonium bromide (18F-MitoPhos)  . Animal reatment . While plication . In livetivation . These fitoPhos) . In a LaM involves the radiolabeled lipophilic cation 18F-tetraphenylphosphonium (18F-TPP+)  . Using aribution . Additioessments , paving essments . These t18F]6-{4-phenyl}-5-methyl-5,6-dihydrophenanthridine-3,8- diamine (18F-DHMT), an analog of the superoxide indicator dihydroethidium, has previously been identified as a promising PET radiotracer of ROS generation (18F-DHMT uptake 4 weeks post treatment which preceded degradation in LVEF that was significant only 6 weeks post treatment (P = 0.0012)  between LV 18F-DHMT uptake and LVEF as well as a direct correlation  between LV 18F-DMHT and LV ESV. These results suggest that 18F-DHMT may be a viable radiotracer for early assessment of cardiotoxicity that precedes left ventricular systolic dysfunction.[neration . In a ch 0.0012) . CorrelaDox intercalates in the DNA and induces single- and double-strand DNA breaks in target cells in a topoisomerase (Top)-2-dependent manner . By prodAdult cardiomyocytes express Top-2β but not Top-2α , and TopAnthracyclines triggers various cell death mechanisms , 2, thoum99Tc-annexin-V was scrutinized by Bennink et al. in an acute doxorubicin-induced cardiotoxicity rat model. Doxorubicin treated rats displayed a significant increase in myocardial m99Tc-annexin-V uptake, with longer doxorubicin treatment regimens corresponding to an even higher uptake , a phospholipid that is translocated from the inner to the outer leaflet of the plasma membrane early in apoptosis. r uptake . Furtherce times .18F-ICMT-11, 11C-WC-98, and 18F-WC-IV-3 have demonstrated high caspase-3 affinity in vitro but all exhibited poor specificity in vivo models, likely due to the dicarbonyl moiety caspase binding region of isatin being recognized by other proteases such as cathepsins  and maximal (420–600 mg/m2) cumulative doxorubicin doses. Whereas an abnormal heart-to-lung 111In-antimyosin uptake ratio was observed with both doxorubicin dosages, maximal exposure to doxorubicin led to a more pronounced 111In-antimyosin uptake with a ratio of 2.02 ± 0.3 (P < 0.01) and was associated with a significant ≥10% decrease in LVEF , a norepinephrine analog that shares with it similar release and uptake mechanisms, can be used to identify areas of abnormal adrenergic innervation in the myocardium. Approximately 80–90% of norepinephrine released at sympathetic nerve terminals is taken up again via norepinephrine transporter uptake-1 , a significant decrease in cardiac 123I-MIBG uptake was detected at week 4, which correlated with histologically examined myocardial tissue damage (123I-MIBG with 18F-FDG in a chronic doxorubicin-induced cardiotoxicity rat model (15 mg/kg cumulative dose) indicated that 18F-FDG uptake decreased significantly in doxorubicin treated groups at weeks 4 and 6 (4.2 ± 0.5%ID/g vs. 9.2 ± 0.8%ID/g at week 6), which correlated with LVEF  (123I-MIBG heart-to-mediastinum (H/M) ratio between groups was detected earlier at week 2 , maintained at weeks 4 and 6, but was not correlated with LVEF decrease at week 6 . While promising, a limiting point of these preclinical studies is the large variability in anthracycline doses and temporal administration patterns which may lead to systemic toxicity in animals.e damage . A compa= 0.002) . In cont123I-MIBG uptake were proposed as an index for stratifying prognosis and risk in patients with chronic heart failure , which also corresponded with a significant (≥10%) reduction in LVEF. A similar reduction in ejection fraction was not detected in patients at intermediate cumulative doxorubicin doses (240–300 mg/m2), though 25% of patients exhibited slight decreases in 123I-MIBG uptake that were not significant compared to baseline. A study by Laursen et al. , and H/Mearly – a measure of the anatomical distribution of functioning myocardial adrenergic neurons . No association was observed between follow-up decreases in LVEF and WOR (P = 0.5). Moreover, in a study of asymptomatic patients who had completed anthracycline treatment ≥2 years prior, 123I-MIBG uptake did not differ between anthracycline treated patients (cumulative anthracycline dose 257.6 ± 117.1 g/m2) and control patients, as assessed either by mean H/Mlate – which reflects overall neuronal functioning, i.e., the product of norepinephrine uptake, storage, and release  – or WOR   . These rEx vivo biodistribution studies 3 weeks after chronic doxorubicin treatment in rats found no change in cardiac uptake of the norepinephrine analog 11C-meta-hydroxyephedrine (11C-HED) or the phosphodiesterase-4 inhibitor (R)-11C-rolipram   . On the  in rats .99mTc-MUGA imaging is an accurate method to assess ventricular contraction. While generally avoided in pediatric patients due to radiation concerns, m99Tc-MUGA may be used to monitor cardiotoxicity in adult patients due to its high accuracy and low inter-observer variability  using 13N-ammonia, Nehmeh et al. reported decreased MFR 1-year post-radiation in 50% of breast cancer patients (n = 4) receiving radiotherapy and anthracycline  – calculated as the stress/rest ratio of myocardial blood flow – 3 days after initial doxorubicin treatment, with 13 out of 54 patients exhibiting low cardiotoxicity threshold (>20% decline in MFR) (13N-ammonia (15O-water (18F-flurpiridaz (Microvascular dysfunction is a possible complication of AIC . The SPEreatment . Hardenbto SPECT –109. In acycline . However in MFR) . Importa-ammonia , 15O-wat5O-water  and 18F-rpiridaz , 113 shorpiridaz .68Ga-fibroblast activation protein inhibitor (FAPI) is a robust fibroblast PET tracer that was initially developed to detect high FAP-expressing, cancer-associated fibroblasts. In a retrospective study of n = 32 patients, Siebermair et al. evaluated the cardiac uptake of 68Ga-FAPI in a heterogenous population of cancer patients treated with various anticancer therapies (n = 185) and confirmatory (n = 44) consecutive cohorts of patients with cancer metastasis who had FAPI-positive PET scans, Heckmann et al.  and activation of the NLRP-3-caspase-1 pathway  . Previou pathway –130. Spe pathway . This in pathway .While cancer affects more than one in three people over their lifetime, improved long-term cancer survival has led to an increase in the incidence of adverse cardiac side-effects of cancer treatments . The U.SDespite the continued discovery of alternative chemotherapeutic strategies, and their known cardiotoxic side-effects, anthracyclines remain a mainstay of many cancer treatments , 140. InWhile echocardiography continues to be the most widely used tool for AIC monitoring, it is important to consider the limitations and advantages of each modality when selecting the proper screening exam for an individual patient. Echocardiography enjoys attractive features such as wide availability, rapid interpretation, lack of ionizing radiation exposure and relatively low cost which have firmly established it as the staple of AIC monitoring . HoweverIn contrast, automated segmentation and ventricular volume algorithms offer precise and accurate evaluations of chamber function in cardiac MRI and multi-detector gated cardiac CT. However, cardiac MRI is more expensive and less widely available at many clinical centers. It is also a time-consuming exam that requires significant patient cooperation and can be undermined by rapid heart rates, arrhythmias, or by the presence of intrathoracic hardware such as implantable pacemakers or defibrillators that can introduce excessive signal artifact , 153.Cardiac CT is also challenged by susceptibility to gating artifacts with rapid or irregular heart rhythms, need for iodinated contrast which is limiting in patients with kidney disease, as well as less robust data on the assessment of muscle strain or mechanics that can indicate early toxicity as compared to echocardiography or cardiac MRI .Lastly, although largely fallen in clinical desuetude, patients with poor echocardiographic acoustic windows and contraindications to MRI or CT imaging may be referred for a radionuclide MUGA scan. This modality has proven to be a viable alternative to cardiac MRI or CT in patients where the precision or accuracy of echocardiographic measurements are in question, and thus remains a clinical option when choosing a strategy to monitor for AIC , 156. HoWhereas the utility of perfusion-based imaging and myocardial blood flow quantitation for the detection of sub-clinical or early AIC has been studied in several small trials, additional research is needed to bring the evidence to the level of routine clinical utility. In particular, PET-derived myocardial blood flow has been examined as a potential marker of patients who may be at increased risk for AIC , 158. WhSimilarly, although no societal guidelines exist for routine myocardial perfusion imaging of patients undergoing anthracycline based chemotherapy regimens, the high correlation of CAD and subsequent acute coronary syndromes in cancer patients often prompts clinicians to screen patients with intermediate or high risk of CAD prior to initiation of therapy. In one retrospective analysis of 6.5 million cases of acute coronary syndromes, 9% of the patients had a diagnosis of cancer, either active or in remission, suggesting that pre-chemotherapy evaluation and revascularization, if indicated, may be appropriate in this patient group .18F-FDG and 68Ga-FAPI are used for cancer staging or progression evaluation. Retrospective analyses of these clinical studies suggest abnormal myocardial uptake in certain patients, paving the way for dedicated cardiac studies to detect and monitor AIC. There is also an opportunity to investigate these probes for oncologic and cardiac assessment in tandem. Doing so, however, will require patients to have a standardized preparation and clinicians to follow a more rigid imaging protocol that adheres to both oncologic and cardiac quality control requirements.Several of the probes discussed in this review such as Echocardiography, including the segmental assessment of myocardial function by strain or displacement vectors, remains the first imaging modality of choice for AIC screening. Therefore, we posit a complementary role – dependent on the imaging targets – for the clinical utilization of nuclear molecular imaging applications in cardio-oncology, that we separate into two aims: 1) improving the prediction of AIC development in the setting of a normal echocardiogram, and 2) improving AIC reclassification in the setting of an abnormal echocardiogram . The cliAnthracycline-induced cardiotoxicity involves a broad range of pathophysiological pathways that lead to cardiomyocyte injury and that may be further complicated by cardiomyopathy and heart failure. Mechanisms implicated in the disease process, as well as molecular responses thereto, can be probed for nuclear imaging, e.g., metabolic dysfunction, cardiomyocyte death, sympathetic innervation, and changes in myocardial blood flow. Detecting these AIC-induced processes at a subclinical level, prior to the onset of irreversible cardiac impairment, may provide clinicians with valuable information permitting changes in chemotherapeutic strategies and/or timely initiation of cardioprotective strategies.JJ, JP, and RP wrote the manuscript. JJ drew the figures and wrote the table. All authors read and approved the final manuscript.


Ovarian hyperstimulation syndrome (OHSS) is a complication of assisted reproductive technology (ART) for infertility. Given the potential for significant morbidity, it is important for emergency medicine (EM) residents to be able to recognize and initiate treatment for this disorder.A high-fidelity human patient simulator was used, with availability of bedside ultrasound. PGY 1–4 EM residents participated in this case of a 28-year-old female patient undergoing treatment for infertility who presented to the emergency department with shortness of breath and near syncope. Workup revealed a diagnosis of OHSS. After the simulation, we surveyed residents on their knowledge of OHSS prior to participation in the simulation. We also asked about their confidence in caring for a patient with OHSS pre- and postsimulation based on a 5-point Likert scale.not at all comfortable, 5 = extremely comfortable; p < .001).A total of 24 EM residents completed this simulation case. Prior to participating in the simulation experience, 62% of residents reported that they had heard of OHSS, and 17% of residents had previously managed a patient with OHSS. After participating in the simulation, residents’ comfort with managing a patient with OHSS increased from 1.7 to 3.7 points (1 = OHSS is a rare but important complication of ART that many EM residents have not treated in the clinical environment. As the presenting symptoms may mimic other diagnoses, obtaining a detailed history and utilizing bedside ultrasonography are essential to diagnosing and correctly treating these patients. Ovarian hyperstimulation syndrome (OHSS) is a potential complication of ART, affecting 20%–30% of patients undergoing ART.4 In addition, a woman who has previously had OHSS is at increased risk of a repeat occurrence.Certain women are at higher risk for OHSS. Risk factors include younger age, history of polycystic ovarian syndrome, gonadotropin releasing hormone agonist cycles, and a high oocyte retrieval number.1Clinical manifestations of OHSS can be varied. Women with mild OHSS  are likely to be managed in the outpatient setting. Moderate OHSS is characterized by the presence of ascites on imaging and laboratory studies notable for leukocytosis and hemoconcentration. Severe OHSS includes additional clinical symptoms , laboratory abnormalities , and worsened hemoconcentration and leukocytosis.MedEdPORTAL, which complements the current resource, discusses the pathophysiology of OHSS and the contributing hormones.5 Our resource is unique in applying the pathophysiology of OHSS to the clinical setting and challenging learners to astutely evaluate, diagnose, and treat an undifferentiated emergency department patient with OHSS.A clear understanding of the pathophysiology of OHSS is important to identify and treat its clinical and laboratory features. Ovarian hyperstimulation leads to the release of vasoactive factors that contribute to capillary leakage and third spacing. This leads to tissue edema as well as hypovolemia. A prior publication in As the use of ART continues to increase, it is important that emergency medicine (EM) residents receive training in the diagnosis and management of OHSS. Our residents train in institutions with robust reproductive endocrinology departments, so some have seen a case of OHSS during their training. While moderate/severe OHSS is rare, EM residents should be exposed to the diagnosis, as we expose them to many other rare but potentially life-threatening diagnoses during their training. Several of the symptoms of OHSS can mimic other life-threatening conditions . Simulation provides the optimal active learning environment to teach this topic and highlights many key principles important in the care of any unstable patient. This case was developed to target EM residents of all levels, recognizing that more senior residents would have an increased likelihood of having encountered a case of OHSS in clinical care.6 Then, the cases were designed to achieve the objectives.The Harvard affiliated EM residency incorporated a robust simulation curriculum as a core aspect of its didactics program. Each session was assigned an overarching topic and theme and included a combination of mannequin-based simulation cases, procedure practice stations, and small-group activities. While the list of procedural topics remained relatively constant, the topics for the mannequin-based cases were frequently rotated. Cases were developed using the backwards design model, by which the faculty and residency leadership initially identified the desired objectives.This simulation was designed by EM faculty members with both clinical and academic interests in reproductive health, medical simulation, and medical education to address an identified need. After the objectives had been determined, the case, including the initial history and physical examination as well as the flow of the case, was designed. Additionally, we identified the necessary supplies and stimuli to create a realistic experience.The simulation was performed in the STRATUS Center for Medical Simulation at Brigham and Women's Hospital during the Harvard affiliated EM obstetrics and gynecology session . The lea•High-fidelity female mannequin (low-fidelity mannequin can be used)•Noninvasive blood pressure cuff•Pulse oximeter•Monitor that can be connected to the simulator to display the heart rhythm, heart rate, pulse oximetry, respiratory rate, and blood pressure•Nasal cannula oxygen tubing•Intravenous line start supplies•Intravenous fluids•Chest radiography with bilateral pleural effusions •EKG stimulus •Lab results sheet •Ultrasound simulator with radio-frequency identification chips loaded •Ultrasound video clips demonstrating enlarged ovaries and pelvic free fluid , free flWe recommend the following equipment to implement this simulation case:During each simulation, the facilitator divided the learners into groups of approximately four EM residents working as a team during the scenario. An EM attending physician facilitated the simulation, serving as the voice of the patient and providing relevant history and physical exam findings when asked. A simulation technician was responsible for changing the vital signs during the simulation based on the actions taken by the team as well as for projecting radiology studies .Within the simulation center, learners participated in the simulation in our human patient simulation room, which was set up to reflect a typical room in our emergency department. The residents entered the room, and the facilitator told them that they would be caring for a 28-year-old female patient who was presenting to the emergency department with shortness of breath and near syncope. After setting the stage for the scenario, the facilitator left the room and sat with the simulation specialist behind a one-way mirror. The facilitator used an intercom system to communicate with the learners and provide history as the patient. After a chest X-ray had been requested, the image  was projDuring the scenario, the facilitator made note of the critical actions . We also asked residents about their agreement with a statement that the ultrasound clips enhanced the educational value of the case scenario, based on a 5-point Likert scale . In addition, learners were asked for narrative comments about the simulation scenario.EM education faculty developed a postsimulation survey  that wasA total of 24 EM residents participated in this simulation. With regard to postgraduate year, 10 were first-year residents, five were second-year residents, six were third-year residents, and three were fourth-year residents.Fifteen residents (62%) reported having heard of OHSS prior to the simulation, seven residents (29%) had not heard of OHSS, and two residents (8%) were unsure. Four residents (17%) reported having previously cared for a patient with OHSS, while the remainder had not.not at all comfortable, 5 = extremely comfortable). Postscenario, learners’ comfort increased to a mean of 3.7 (p < .001). Learners felt that the ultrasound video clips added value to the scenario .With regard to their comfort managing a patient with OHSS, learners reported their prescenario comfort at a mean of 1.7 on a 5-point Likert scale . This case could also be used in an oral boards–style format if no mannequin is available.As our residents had received training in point-of-care ultrasound, many of them reached for it early in their patient evaluations to aid in diagnosis and treatment. Because we embedded the ultrasound clips on chips attached to the mannequin, they were able to be read by the ultrasound probe when applied to the correct area on the mannequin and displayed for the learners. While this provided an added level of reality, the simulation can be used by educators without access to this technology. The ultrasound clips can be displayed on a computer monitor for interpretation, or a verbal description of the findings can be provided to the learners if video display is not available.Another limitation is in the curriculum's assessment, which relied on learners’ self-reported confidence in managing OHSS as opposed to objective observation in a follow-up scenario after the training. Learner confidence has limitations as a measurement of competence. We used the critical action checklist as a guide for the facilitator during the scenario and to assist with debriefing, but we did not record or analyze the number of critical actions achieved by each group of learners. Our critical action checklist could be used in this capacity. In addition, to avoid revealing the case diagnosis ahead of the simulation, questions assessing residents’ self-perception of their knowledge of OHSS and comfort managing a patient with OHSS prior to the simulation were included on the postsimulation survey. This could have introduced both response bias and order effect bias in our results.In summary, OHSS is a complication of ART that EM physicians are likely to encounter in clinical practice, as the number of people using this technology continues to increase. This simulation provides an excellent opportunity to explore the symptoms, clinical and laboratory manifestations, and treatment options for OHSS. The value of the simulation was highlighted by our learners. While the simulation was limited to EM residents, it could also be applicable for OB/GYN residents and physician assistants who work in an emergency department setting.OHSS Simulation.docxSimulation Labs, Chest X-ray, & EKG.docxUS Clip - Pelvis.mp4US Clip - RUQ.mp4US Clip - LUQ.mp4Critical Actions.docxDebriefing Materials.docxOHSS Survey.docxAll appendices are peer reviewed as integral parts of the Original Publication.


Chest radiation therapy (RT) is known to be associated with cardiotoxicity. However, the changes in myocardial tissue characterization with radiation-induced cardiotoxicity are not well-understood.This study sought to assess the changes in left ventricular function and tissue characterization using cardiovascular magnetic resonance (CMR) in patients receiving RT.Between June 2015 and July 2018, we enrolled patients with breast, lung cancer, or lymphoma with plan to receive chest radiation after chemotherapy. CMR was performed using a 1.5T scanner at baseline and 6 months after RT. Myocardial volume, function, strain analysis using feature tracking, and tissue characterization including late gadolinium enhancement (LGE), T1, T2, T1ρ (rho), and extracellular volume fraction (ECV) were measured and compared using non-parametric methods.p = 0.004), and elevated T2  and T1ρ values . Two patients had LGE. There was no significant difference in the average T1 values or ECV. There was a trend toward lower LV ejection fraction and global longitudinal strain (GLS). At 6-month follow-up after RT, there were no significant changes in all the CMR parameters.The final cohort consisted of 16 patients, 11 of whom completed both baseline and follow-up CMRs. Patients were matched to 10 healthy controls. At baseline prior to RT, compared to controls, patients had lower global circumferential strain (GCS) (15.3 ± 2.2% vs.18.4 ± 2.1%, At 6-month following chest radiation therapy, there was no change in LV and RV EF, LV and RV GLS, LV GCS, and myocardial tissue characterization using LGE, T1, ECV, T2, and T1ρ in a small cohort of patients. However, the baseline T2 and T1ρ were elevated and LV GCS was reduced compared to controls indicating ongoing myocardial edema and subclinical dysfunction post-chemotherapy. As survival continues to improve following treatment for cancer, there is an increasing concern for long-term treatment-related toxicity. In the management of thoracic malignancies, systemic therapy and radiation are associated with cardiotoxicity. Radiation therapy (RT) is an important component of curative treatment in about half of patients with cancer . HoweverThe etiology of RIHD is not well-understood  althoughCardiovascular magnetic resonance utilizes a multiparametric approach for myocardial evaluation. Left ventricular (LV), global longitudinal strain (GLS), and circumferential strain (GCS) by CMR feature tracking is a more sensitive measure of systolic function and can be used to identify sub-clinical LV dysfunction . ElevatePatients with breast cancer, lung cancer, or lymphoma receiving chest radiation between June 2015 and July 2018 at our institution were considered eligible for this sub-study . Patient2; spatial resolution = 1.97 × 1.97 mm2, parallel imaging factor = 2. Late gadolinium imaging was obtained using routine 2D inversion recovery sequences with the following parameters: TE = 3.3 ms; slice thickness = 8 mm with 2 mm gap; bandwidth = 130 Hz/pixel; flip angle = 15, field-of-view = 320–380 mm; spatial resolution = 1.5 × 1.5 mm.Cardiovascular magnetic resonance was performed before RT and at 6 months after RT using a 1.5 scanner . For patients with breast cancer and lymphoma, chemotherapy was administered before baseline CMR, while the lung cancer patients received chemotherapy during RT. Retrospectively gated cine images of the short axis of the heart were obtained using steady-state free precession (SSFP) for biventricular volumes and function. Sequence parameters include TE (echo time)/TR (repetition time) = 1.07/2.2 ms; slice thickness = 8 mm with 2 mm gap; bandwidth = 930 Hz/pixel; flip angle = 59°; field-of-view = 320-380 mm2; spatial resolution = 1.7 × 1.7 mm2; slice thickness = 8 mm; bandwidth = 1,085 Hz/pixel; parallel imaging factor = 2. T2 maps were acquired using a T2-prepared SSFP sequence with the following sequence parameters at end-systole: T2-preparation durations = 0, 24, and 55 ms; TE/TR = 1.37/2.64 ms; flip angle = 70°; field-of-view = 320 × 380 mm2; bandwidth = 1,185 Hz/pixel, spatial resolution = 1.9 × 2.3 mm, slice thickness = 8 mm; parallel imaging factor = 2. Motion corrected T1ρ maps were acquired at the same location and eight T1ρ weighted images with different spin locking pulse duration (TSL) was performed: TSL = 2, 10, 18, 26, 34, 42, 50 ms, B1 = 400–500 Hz, spatial resolution = 1.4 × 1.4 mm2, slice thickness = 6 mm, flip angle = 70°, TE = 1.45 ms, TR = 2.9 ms, bandwidth = 900 Hz/pixel, linear k-space phase encoding ordering, parallel imaging with acceleration factor = 2.All mapping sequences were obtained at the basal and mid ventricular short axis. Native T1 maps were acquired using a modified Looker-Locker Inversion Recovery (MOLLI) sequence (Siemens Work-in-Progress 448B) using the 5(3)3 scheme before and 4(1)3(1)2 scheme after contrast injection in diastole with the following sequence parameters: TE = 1.03 ms; minimum TI = 100 ms; TI increment = 80 ms; flip angle = 35°, field-of-view = 320–380 mmLeft ventricular and right ventricular (RV) endocardial and epicardial borders were manually traced on short-axis slices according to Society of Cardiovascular Magnetic Resonance (SCMR) recommendations using Qmass software  . PapillaU-test between the two groups and Kruskal–Wallis H (K) test among the three groups. For ranked variables, significant differences were analyzed using the Chi-square test. A p-value of < 0.05 was considered statistically significant. Data analyses were performed using the SPSS 17.0 .Continuous variables were expressed as mean ± SD. Categorical variables were presented as absolute numbers or percentages. For continuous variables, significant differences were analyzed using the Mann-Whitney A total of 18 patients met eligibility criteria and underwent baseline CMR . One patp = 0.004) and a trend toward lower LV ejection fraction (EF) . The T2 and T1ρ values were elevated in these patients compared with controls at baseline . No significant difference in the average T1 values was observed in these patients (1018.4 ± 30.7 ms) compared to the control group . No significant differences were found in the right ventricle for ventricular volumes, function, and RV longitudinal strain  based chemotherapy and six patients with non-AC based chemotherapy. Five patients received chemotherapy  during radiation. At baseline, when compared to controls, patients who underwent RT had reduced LV GCS at baseline , 3-dimensional conformal RT (3DCRT) in 25 and 44% of the patients, respectively. 3D CRT was exclusively used in the setting of breast cancer and lymphoma. Proton therapy was used in 31% of the patients with either passive scattering (12% of the patients) which produces a broad beam of proton delivery or with active scanning (19% of the patients) which uses several small pencil beams throughout the target volume . The aveThere was excellent intra and inter-observer reproducibility with the ICC ranging from 0.892–0.964 for T1, T2, and T1ρ values .We prospectively evaluated for early cardiac toxicity following RT using CMR to identify subclinical functional and structural changes. Prior to chest RT, we have found reduced GCS, elevated T2 and T1ρ values in patients compared to controls indicating myocardial edema and subclinical functional changes after chemotherapy. After RT, a 6-month follow-up CMR showed no change in LV and RV EF, LV and RV GLS, LV GCS, T1/ECV, T2, and T1ρ values.All patients in this study received chemotherapy prior to RT and 11/17 patients received anthracycline-based chemotherapy. When compared to controls, patients who underwent chemotherapy had elevated T2 and T1ρ values at baseline, which were possibly related to chemotherapy and active inflammation/fibrosis . Both T2p < 0.01 for both) and LV stroke volume index reduced and more patients had LGE at 1.5 years compared to baseline  (A few studies in patients receiving anthracycline-based chemotherapy have shown elevated T1 and ECV which can occur as early as 3 months after initiation of therapy –28. Howe < 0.01) . The meaSeveral other studies utilized LGE/T1 sequences to detect fibrosis post-RT. Ricco et al.  studied The time to development of fibrosis with RT is not well-known but based on previous studies and our current study, it does not seem to develop until after 6 months of radiation therapy and is heart-dose dependent. Additional tissue characterization markers such as T2 and T1ρ may indicate ongoing myocardial edema that was a consequence of chemotherapy, but the long-term implications of these findings will need to be studied in the future.Our study has several limitations. First, our sample size is small with a few different types of cancers/chemotherapy regimens and radiation fields. Second, patients did not have baseline CMR prior to chemotherapy. The mean cardiac dose in our cohort is low considering that less than 5% of lung cancer patients have mean cardiac doses below 10 Gy. To further study myocardial tissue changes in RT, a larger population study is needed.Six-month follow-up CMR in patients undergoing chest radiation therapy showed no change in LV and RV EF, LV and RV GLS, LV GCS, LGE, T1/ECV, T2, and T1ρ values. Prior to chest RT, we found reduced GCS, and elevated T2 and T1ρ values in patients after chemotherapy as compared to controls. Contemporary chest radiation with a low heart dose may not have short-term effects on the heart although future studies are needed to confirm these findings.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by IRB at University of Pennsylvania. The patients/participants provided their written informed consent to participate in this study.All authors participated in the writing and/or final review and approval of this manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Patients with higher miRNAs values at baseline  appear to have a higher probability of developing adverse events at 12 months of follow-up. ROC curves outlined for each variable confirmed their good predictive value ; the group of three miRNAs also proved to have a better predictive value for MACE together than separately (AUC = 0.862). Moreover, adding each of the miRNAs  or all together over the myocardial work indices in the regression models improved their prognostic value. In conclusion, both myocardial work indices  and three miRNAs  have the potential to be used as prognostic markers for adverse events after acute myocardial infarction. The combination of miRNAs and MW indices (measured at baseline) rather than each separately has very good predictive value for MACE in young STEMI patients (C-statistic 0.977).Acute ST elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality worldwide despite continuous advances in diagnostic, prognostic and therapeutic methods. Myocardial work (MW) indices and miRNAs have both emerged as potential prognostic markers in acute coronary syndromes in recent years. In this study we aim to assess the prognostic role of myocardial work indices and of a group of miRNAs in young patients with STEMI. We enrolled 50 young patients (<55 years) with STEMI who underwent primary PCI and 10 healthy age-matched controls. We performed standard 2D and 3D echocardiography; we also calculated left ventricular global longitudinal strain (GLS) and the derived myocardial work indices. Using RT-PCR we determined the plasmatic levels of six miRNAs: miR-223-3p, miR-142-3p, miR-146a-5p, miR-125a-5p, miR-486-5p and miR-155-5p. We assessed the occurrence of major adverse cardiac events (MACE) at up to one year after STEMI. Out of 50 patients, 18% experienced MACE at the one-year follow-up. In a Cox univariate logistic regression analysis, myocardial work indices were all significantly associated with MACE. The ROC analysis showed that GWI, GCW and GWE as a group have a better predictive value for MACE than each separately (AUC 0.951,  Ischaemic heart disease remains to this day a leading cause of morbidity and mortality worldwide ,2. AlthoPatients with an acute coronary syndrome at a young age are at high risk for other future major cardiovascular events; therefore, an optimal follow-up and preventive strategies are of paramount importance in this population category  ConsiderLeft ventricular systolic function is one of the most important and used prognostic marker after STEMI. It is traditionally expressed by left ventricular ejection fraction (LVEF), based on systolic and diastolic volume changes. However, LVEF is subjective, there are technical limitations and inconsistency, impaired reproducibility and a high interobserver variability . MyocardEchocardiographic assessment of myocardial work may further improve the evaluation of myocardial function. This non-invasive method is based on a standardised LV pressure curve adjusted to arterial pressure. Myocardial work parameters offer an estimation of LV systolic function taking into account loading conditions; therefore, this method is very promising for evaluating the failing heart and predicting prognosis ,15. TherIn recent years, microRNAs (miRNAs) have appeared as promising diagnostic and prognostic markers involved in the pathophysiology of cardiovascular diseases . Many stIn this study, we tested six miRNAs , known to be associated with coronary artery disease from previous research. MiR-233-3p is almost exclusively of platelet or megakaryocyte origin ; the bioConsidering all the above, we hypothesised that both myocardial work parameters and the six miRNAs might play a role in predicting outcome patients with acute coronary syndromes; therefore, we propose to assess their value as prognostic markers in young patients (<55 years) with STEMI.We enrolled in this prospective study young patients (<55 years old) with STEMI admitted to our hospital (in 2019–2020) and treated by primary PCI. We first selected 89 consecutive STEMI patients, excluded 23 of them for being >55 years, 10 were excluded due to poor acoustic window and 6 were lost during follow-up, leaving a final study group of 50 . We also2), chronic liver failure (defined as a Child–Pugh score of 3), chronic respiratory failure (defined as PO2 < 50 mmHg and/or PCO2 > 50 mmHg), patients with addictions, poor compliance or those who refused to sign the informed consent were excluded.Patients with previous myocardial infarction or cardiac surgery, recent stroke (within six months), recent surgery or trauma (within 6 months), active malignancy or autoimmune diseases, chronic renal failure  ,20.The quantification of noninvasive myocardial work was performed using a commercially available software package .LV strain data were acquired using 2D speckle-tracking echocardiography by manually tracing the LV endocardial border in the apical long-axis, 2 and 4-chamber views. The peak LV pressure was measured using the patient’s brachial cuff blood pressure recordings with the peak systolic LV pressure assumed to be equal to the peak arterial pressure. An LV pressure–strain curve was then automatically constructed using a reference curve provided by the software package and adjusted to the different cardiac cycle phases using valvular event timing . LV myocardial work was calculated by integrating the product of the rate of segmental shortening and instantaneous LV pressure over time, thus obtaining myocardial work as a function of time during systole and isovolumic relaxation .Global work index (GWI)—the area within the global LV pressure–strain loop , representing the total LV work performed in a single cardiac cycle.Global constructive work (GCW)—the myocardial work performed during the shortening of a myocardial segment in systole and during lengthening in isovolumic relaxation, representing the total work contributing to the pump function.Global wasted work (GWW)—the negative myocardial work performed during the lengthening of a myocardial segment in systole or during shortening in isovolumic relaxation, and which therefore does not contribute to LV ejection.Global work efficiency (GWE)—the sum of the constructive work in all LV segments, divided by the sum of the constructive and wasted work in all LV segments; it is expressed as a percentage: GCW/(GCW + GWW).The following parameters were obtained from this analysis ,53,54:Glg) for 15 min at −4 °C within 30 min of collection and then aliquoted in Eppendorf tubes (300 µL each) and frozen at −80 °C immediately.Whole blood samples harvested in EDTA tubes were obtained by peripheral venous puncture in the first 24–48 h after admission for STEMI. All blood samples were collected after primary PCI, in all patients. Plasma was separated from blood samples after centrifuging , following the manufacturer’s instructions. A quantity of 25 fmol of synthetic cel-miR-39 was added to each sample during miRNA purification as previously described .The plasmatic levels of (hsa)-miR-223-3p (ID 002295), hsa-miR-146a-5p (ID 000468), hsa-miR-486-5p (ID 001278), hsa-miR-125a-5p (ID 002198), hsa-miR-142-3p (ID 000464) and hsa-miR-155-5p (ID 002623) were determined by TaqMan technology. Reverse-transcription was performed with a pool of TaqMan miRNA-specific stem-loop primers on a Veriti PCR system. Real-time quantitative PCR was performed using the hydrolysis probes of miRNA TaqMan assays on a ViiA7 real-time PCR system  and for each sample, triplicate measurements were done on 384-well reaction plates.The data were analysed using ViiA7 Software v1.2 with the automatic Cq setting. The expression level of each miRNA was determined relative to that of exogenously added cel-miR-39-2p (ID 000200) as previously reported .According to the European society of cardiology practice guidelines , invasivPatients were followed up for up to one year after STEMI. At 6 months, we performed a more detailed follow-up—clinical examination, standard echocardiography—and at one year, a telephone follow-up.All included patients were followed up for one year after the acute ischemic event. The one-year follow-up consisted of a telephone questionnaire whereas at 6 months, a more detailed examination was performed. At 6 months of follow-up, we performed a clinical examination, electrocardiography, an echocardiographic evaluation and blood harvesting to assess specific biomarkers (miRNAs).During this one year of follow-up, we assessed the occurrence of MACE. In this study, MACE was defined as death from cardiovascular causes, heart failure requiring hospital admission or repeat PCI/CABG due to ischaemia/infarction .It is important to mention that all patients received optimal medical therapy at hospital discharge, according to current clinical practice guidelines .2 tests were used to compare continuous and categorical variables. To determine the predictors of MACE, we performed a Cox univariate regression, further incorporating the statistically significant variables in a multivariate analysis. An ROC analysis (receiver operating curve) was used to determine the AUC (area under the curve) representing the predictive power of the tested parameters. We also determined cut-off values for the significant variables using the Youden index. To further test the added values of miRNAs over myocardial work indices, we constructed prediction models and compared their statistical power using the C statistic and Akaike information criterion (AIC). We considered p under 0.05 as statistically significant.We performed the statistical analysis using SPSS software  and GraphPad software . We presented the categorical data as percentages and the continuous variables as means. A Kolmogorov–Smirnov test and Mann–Whitney U-test were used for normal and non-normal distribution of data, respectively. Student t and XWe included 50 young patients (<55 years), mean age of 44.78, with STEMI treated by primary PCI and 10 healthy control subjects . Patients were divided into MACE group  and non-MACE group . The baseline characteristics of the entire study group divided according to the presence or absence of MACE are detailed in p = 0.000), more impaired LVGLS  and higher 2D LVEDV  and 2D LVESV  at baseline.Echocardiographic parameters measured at baseline are reported in Regarding medical treatment, there was no significant difference between MACE and no-MACE groups.Echocardiography was performed both at baseline and at 6 months of follow-up. The echocardiographic parameters measured at follow-up are depicted in p < 0.005). All of the miRNAs associated with cardiovascular disease tested in this study were significantly upregulated in STEMI compared to the control group: miR-233-3p (p = 0.04), miR-142-3p (p = 0.009), miR-155-5p (p = 0.001), miR-486-5p (p = 0.001), miR-125a-5p (p = 0.013) and miR-146a-5p (p = 0.029). miRNA levels at baseline and at 6 months of follow-up are depicted in Patients with STEMI had significantly higher levels of miRNA when compared to the control group (p = 0.006) and miR-142-3p with gender . miR-223-3p and miR-146a-5p both correlated with the Killip class .We tested the correlations between miRNAs and cardiovascular risk factors —no significant correlations were observed. Interestingly, miR-125a-5p inversely correlated with age ; miR-142-3p ; miR-4865p  and miR-146a-5p . The 2D LVEF values inversely correlated with miR-223-3p  and miR-146a-5p (Pearson −0.299. p = 0.035). miR-146a-5p inversely correlated with myocardial work indices—GWI , GCW  and GWE . A few of the correlations are depicted below  and glycaemic levels (p = 0.047). As expected, patients with MACE had a higher Killip class.No significant differences between the two groups regarding cardiovascular risk factors, clinical or angiographic characteristics were observed. There were a few differences in laboratory data—patients with MACE had higher CK-MB levels  and GWE  contributed significantly to the model—All four myocardial work indices  were independent predictors for MACE at follow-up. They remained significant MACE predictors after adjustment for age, gender, 2D LVEF, LV dispersion and LV GLS. Moreover, after checking for collinearity, we obtained that GWI, GWE and GCW had a better predictive value as a group than separately. In the multivariate Cox regression analysis of the three variables, only GWI , p = 0.001 for GCW; AUC 0.812 (95% CI), p = 0.004 for GWW and AUC 0.932 (95% CI), p < 0.0001 for GWE, as shown in p < 0.0001. The highest AUC was obtained for the combination of the three parameters GWI, GCW and GWE, with AUC 0.951, p < 0.0001, proving a better prediction ability than each variable separately , parately .For each variable we determined a cut-off value, based on the maximum value of the Youden index as follows: 799 mmHg%  for GWI, 1232 mmHg%  for GCW, 186 mmHg%  for GWW and 82.5%  for GWE as shown in p < 0.0001), LV mechanical dispersion  and 3D LVEF . Considering this, GWI and GWE are better at predicting an outcome in this patient group than the standard parameters.For comparison, we performed an ROC analysis for classical echocardiographic MACE predictors: LV GLS , miR-142-3p (p = 0.022) and miR-146a-5p (p = 0.000). Introducing the variables in a multivariable Cox regression model , only miR-146a-5p remained independently associated with MACE .Using a Cox binary univariate regression analysis, we tested the predictive potential of these markers and found that only three of the circulating miRNAs were significantly associated with the primary endpoint (MACE) in young STEMI patients: miR-223-3p , p = 0.031 for miR-142-3p and AUC 0.848 (95% CI), p = 0.001 for miR-146a-5p . According to this analysis, the three miRNAs had good prediction abilities for MACE with an AUC greater than 0.7: AUC 0.832 (95% CI), -146a-5p . For eacA Kaplan–Meier analysis showed the survival curves for the risk of MACE with respect to miR-223-3p, miR-142-3p and miR-146a-5p expression. Patients with higher miRNA levels at baseline had a higher probability of MACE at follow-up  proved to have a better prognostic potential than the three miRNAs  . HoweverTo further test the added value of miRNAs as prognostic markers, we built two logistic models: model 1 included myocardial work indices  and model 2 included sex, age and myocardial work indices. We determined the ability of each miRNA and of the combination of miRNAs to improve the predictive value of the three models.Each of the three miRNAs and their associations added value to all the proposed predictive models as depicted below .To support our findings, we compared the prediction potential of the combination of the three miRNAs with myocardial indices and the combination of the three miRNAs with LVGLS and 2D LVEF and in each case, the combination of miRNAs with myocardial work parameters yielded the best AIC and C-statistic.This was the first study to assess the potential prognostic value of a group of miRNAs together with new echocardiographic parameters  in predicting adverse events/MACE in a group of young patients with STEMI.We focused our attention on young adults with STEMI considering its increasing prevalence in this group. The diagnosis of AMI at a younger age exerts a significant health, socioeconomic and psychological burden not only upon the patient but also upon the entire community. Finding a good prognostic marker might help improve the stratification risk and prognosis in these patients.Recently, the LV myocardial work analysis was proposed as a new method for evaluation of LV systolic function. Combining LV pressure–strain loops derived from GLS and blood pressure measurements, this new method takes into account the loading conditions . Even thPrevious studies evaluated the clinical applications of this new method of assessing systolic function in various cardiovascular diseases. In ischaemic heart disease, myocardial work indices have proved to have good diagnostic value in a few studies. Guo et al. demonstrated that regional myocardial work measured by echocardiography exhibited a good diagnostic value in detecting significant myocardial ischaemia compared to the standard fractional flow reserve approach (measured invasively in the catheterisation laboratory) . The useIn our study cohort of young STEMI patients treated by primary PCI, we found that myocardial work parameters measured noninvasively were independent predictors of MACE at one-year follow-up.p = 0.007; 1493 at baseline vs. 1663.29 at follow-up for GCW p = 0.089, 87 at baseline vs. 90 at follow-up, for GWE p = 0.004) but with little to no changes in GWW  results, consistent with a recent study [We first assessed the evolution of MW in time in the entire cohort. At follow-up, we observed that GWI, GCW and GWE values were higher than baseline  at baseline was an independent predictor of MACE. Furthermore, in the Kaplan–Meier analysis, patients with higher levels of miR-223-3p in the acute setting had a higher probability of developing MACE at follow-up . These results are consistent with Schulte et al. [We obtained that a value of miR-233-3p expression over the cut-off value , p = 0.031, and determined an optimal cut-off value of 1115  for MACE prediction. In good agreement with these data, a strong predictive potential for subsequent cardiovascular events was proved in our previous study on multiple vascular atherosclerotic patients with peripheral artery disease [miR-142-3p, known to be involved in atherosclerosis  and isch disease . It is wSTEMI patients with miRNAs values higher than the cut-off points  appeared to have a higher probability of developing MACE in a Kaplan–Meier analysis. The increased plasma levels of the three miRNAs could be used to predict unfavourable outcomes in STEMI patients.As far as we know, this is the first study to assess the power of a group of miRNA and myocardial work indices to predict the occurrence of MACE after STEMI in young patients. In this study, we found that both miRNAs and myocardial work parameters had good prognostic power in the studied population.miR-223-3p, miR-142-3p and miR-146a-5p had incremental prognostic value over myocardial work indices and together, they could better predict unfavourable outcomes than each separately. The addition of each of the three miRNAs over myocardial work indices  in a Cox multivariate regression analysis, yielded a higher AIC and C-statistic than those of the myocardial indices alone (the best model between two was chosen based on the likelihood ratio test).Our findings hold great potential for future treatment monitoring and personalised patient management according to risk stratification.Our study had several limitations. The first limitation is the small sample population (due to the age threshold of the study group and COVID 19 pandemic)—the performance and precision of predictions may have been affected. Second, another limitation is related to the lack of a comparison group of older STEMI patients. Third, at one year, we only had a telephonic follow-up available due to COVID-19 pandemic restrictions.Larger further studies are required to validate our findings.Despite these limitations, our study holds great potential, considering the obtained results and their further possible utility as MACE predictors in a young population.Myocardial work indices and the three miRNAs tested in this study  have a promising prognostic potential, as independent markers and also as a group, in young STEMI patients. The complementary use of miRNAs has incremental prognostic value over the tested echocardiographic parameters .miRNAs together with myocardial work indices are better at predicting MACE than each separately and have the potential to be used as prognostic biomarkers; this might further facilitate risk stratification and the guidance of clinical care, improve secondary prevention and even lower cardiovascular mortality in young patients after STEMI.


Since the first pacemaker was implanted, nearly 60 years have passed. Since then, pacemaker technology has made major advancements that have increased both its safety and effectiveness in treating people with bradyarrhythmias. The repeated stimulation of cells in specialized "pacemaker" regions of the mammalian heart and the transmission of stimulus via the ventricles serve as evidence that the electrical function of the mammalian heart is necessary for a regular mechanical (pump) role. The development of action potentials in individual cardiac cells is linked to myocardial electrical activity and the heart's regular cooperative electrical functioning. A container or pulse initiator that houses the battery and electronics, as well as lines that connect to the myocardium to deliver a depolarizing pulse and detect intrinsic cardiac stimulation, are all parts of a pacemaker. Defibrillators could be used with artificial hearts that have electrical pacemakers integrated into them in order to treat arrhythmia, heart failure, and cardiac arrest. Modern pacemakers have units for supporting patients with other disorders like "heart failure," which happens when the heart does not pump as forcefully as it should. While many pacemakers are effective in treating different types of arrhythmias (irregular heartbeats), they also have units for treating them. Despite significant advancements and the development of novel therapies, cardiovascular illnesses have remained the world's leading cause of death and morbidity for a decade . SeveralIt has been almost six decades since the initial pacemaker was placed. Since then, pacemaker technology has advanced significantly, boosting its safety and potency in treating individuals with bradyarrhythmias. Despite advancements, pacemaker therapy continues to be analogous with considerable peri- and post-procedural problems .Leadless pacemaker therapy is a revolutionary method that addresses lead and pocket-associated issues in standard transvenous pacemaker treatment and was recently launched in clinical trials. These leadless pacemakers are independent, single-chamber suitable ventricular pacemakers inserted by a femoral percutaneous route .Physiology The heart is a metrical electromechanical pump whose operation relies on the origination and transmission of action potentials, tailed by relaxation and a phase of refractoriness until a succeeding stimulus is produced. Inward (Na+ and Ca2+) and outward (K+) impulse-transporting ion channels are consecutively switched on and off during myocardial action potentials. Action potential waveforms vary in separate parts of the heart due to variances in Na+, Ca2+, and K+ channel articulation. These variations add up to a typical, unidirectional impulse circulation and the creation of usual cardiac rhythms .The electrical function of the mammalian heart is required for a regular mechanical (pump) role, as evidenced by the successive stimulation of cells in specialized "pacemaker" areas of the heart and the transmission of stimulus via the ventricles. The creation of action potentials in discrete cardiac cells is attributed to myocardial electrical venture, and normal cooperated electrical working of the whole heart. Changes in channel function caused by inherited or acquired illness impact the action potential repolarization and can result in life-threatening arrhythmias .Tissue engineering When the heart cannot keep up, technology comes up with a solution: an artificial pacemaker, a medical apparatus that provides electrical activity to keep the heartbeat stable. Artificial pacemakers have been used to treat various heart diseases that cause them to beat abnormally since the late 1950s, and they come with varying degrees of programmability.Pacemakers comprise a pulse initiator or can accommodate the battery and electronics, as well as lines that pass from the can to the myocardium to impart a depolarizing pulse and ascertain intrinsic cardiac stimulus. Insulation materials separate the conductor cables and the lead tip electrodes. The leads might be concentric (a tube within a tube) or co-radial, depending on the relationship between the wires (side-by-side coils). Active  or passive lead attachment to the myocardium . Short-circuiting causes high impedance (fracture) or low impedance (insulation breach) depending on how conductor elements and insulation materials are disrupted. When a potential difference (voltage) is enforced between the two electrodes, the pacing starts to ensue ,9.The devices are made entirely of FDA-approved biocompatible materials; nevertheless, they are non-biodegradable and will persist in the patient's body for the rest of their lives until they are removed. Although not always harmful, there are times when the existence of old-fashioned electrical implants within the tissue is dispensable. If these non-biodegradable devices become a regular place, they could represent a danger to the patient's life ,10.Pacemakers today use activity sensors  to measure the patient's movement. However, these sensors are frequently insufficient to deliver real-time automated heart rate variation to the wearer. It might fluctuate depending on the rate of respiration; for example, current pacemakers are not sensitive enough to monitor and process specific brain activities related to heart rate control. As a result, even if the patient is cycling, the pacemaker indicates that they are at rest since precise signals are not refined. When a neuronal circuit at the base of the brain depreciates due to age or disease, it fails to provide the correct signals for the heart to pump correctly .Hybrid technique Substituted hearts with built-in electrical pacemakers could be employed as a defibrillator in the event of arrhythmia or failure, as well as in the event of cardiac arrest. Of course, they would be merged accompanied by a network of electrodes that can provide a complete account of the organ's condition ,12.Tian and colleagues provided the first example of a hybrid technique. A planar, slim, penetrable, and electronic mesh with amalgamated silicon nanowire field-effect transistors was created via lithography (nanoFETs). By removing an underlying sacrificial layer, this apparatus was subsequently removed from the silicon wafer and transformed into a discrete device. The mesh was designed to be highly penetrable, and its thin thickness of 2mm made it incredibly pliable and convenient to handle in 3D as shown in Figure Two present-day examples have revealed the use of electrospun fiber scaffolds as the membrane and dielectric of the electronic net in order to construct a hybrid tissue made of biodegradable electronics . The synThe Micra Transcatheter Pacing System and the Nanostim Leadless Cardiac Pacemaker  are now leadless pacing systems in clinical use . Both the devices are self-sufficient and can single chamber pace sensing, and rate reaction supply The Nanostim L.C.P got the C.E. mark in October 2013 . HoweverCardiac resynchronization therapyIn patients with left ventricular (LV) dysfunction, choosing the suitable implanted cardioverter defibrillator (ICD) or cardiac resynchronization treatment (CRT) device might be difficult . ACC/AHADespite the promising results of CRT in bradycardia patients, not all patients experiencing RV pacing develop LV dysfunction; some may be impervious to the pacing-induced systolic dyssynchrony. Because CRT is expensive and has a high rate of complications, not every patient should receive it. It is crucial to pick people susceptible to systolic dyssynchrony from repeated ventricular pacing in bradycardia. Even though it might be ideal to find baseline indicators of pacing-induced systolic dyssynchrony, there is not enough information to guide patient selection . AnotherCRT is a costly therapy, which makes reimbursement difficult . The relCRT is now used in patients with congenital heart disease with various HF phenotypes , hypertrophic cardiomyopathy, pulmonary hypertension causing RV failure, and HF with intact ejection fraction . A multiComplications Since the transcatheter aortic valve replacement (TAVR) technology is applied to healthier and lower-risk groups, the implications and anticipations of procedure-related problems, together with the requirement of permanent pacemaker (PPM) installation, need to be determined . Due to All patients had paravalvular aortic regurgitation after PHV implantation. Echocardiography suggested that the PHV stent frame may not be ideally positioned against the sick native valvular structures in the area of calcific nodules. Even though the initial improvement in left ventricular function and clinical status following consolation of the aortic valve blockage was unaffected by paravalvular aortic regurgitation, severe paravalvular aortic regurgitation may have a deteriorating effect on long-term clinical outcomes succeeding PHV implantation. Future developments in stent design, such as larger maximal stent diameters, may lessen the frequency and graveness of paravalvular aortic regurgitation ,31.Other crucial factors to take into account with any valve-replacement procedure include issues such as postoperative stroke, valve degeneration, PVL, and conduction abnormalities. With combined rates of 2.7 percent at 30 days and 4.8 percent at prolonged follow-up, the occurrence of postoperative neurological events was less and appeared to correspond to the previously described prevalence of strokes for traditional AVR . To moreFuture prospects Although there have been considerable advancements in the domain, each variety of tissue under investigation has its own set of hurdles that must be addressed before it can be used in clinical settings. The idea of incorporating electronics into all types of synthetic tissues has a lot of potential for improving tissue development and function ,33.While many modern pacemakers are effective in treating various types of arrhythmias (irregular heartbeats), they have units for supporting patients with other disorders such as "heart failure", which occurs when the heart does not pump as powerfully as it should ,35.In pacemaker (PM) patients, high abidance to remote monitoring (RM) improves outcomes; yet adherence remains unsatisfactory without a bedside console newer-generation PMs using Bluetooth low-energy (BLE) technology can communicate straightaway with patient-controlled intelligent devices via an app ,37. A smart pacemaker is a sophisticated device that can detect even the smallest irregularity in the functioning of the heart. These smart pacemakers then not only help in rectifying the abnormality in the heart and reestablishing normal body functions but also alert the patients and their physicians about the patient's cardiac health. Hence, allowing them to take appropriate measures for the same. This feature of smart pacemakers had helped bring down the mortality rate in today's world.The sector of biomedical electronic installs has progressed from the times of rigid implantable pacemakers to micro- and nanoscale, delicate electronic webs having traits as small as single cells and mechanical characteristics compared to the softest tissues. We have been able to bypass the considerable organic-inorganic hurdle that customarily subsists in joining electronics, tissues, and organs thanks to rapid breakthroughs in the sphere of flexible and stretchable electronics. These advancements have made it possible to counteract the detrimental effects that a foreign implant may have on a tissue and its denial by the body. The electronics could be removed after the organ function has been reinstated, and there is no obligation for ongoing inspection or mediation. On the other hand, if the existence of the electronics does not impair tissue behavior, they may be left in place indefinitely to ameliorate the patient's standard of life. The evolution of these sorts of substitutions would not only assist minimized donor organ scarcity but would also lessen the necessity for persistent follow-ups and operations. For carefully chosen individuals with heart failure, cardiac resynchronization treatment (CRT) is a beneficial therapeutic. Recent research indicates that re-coordinating left ventricular dyssynchrony may not be how CRT delivers the majority, if not all, of its advantages. Other probable mechanisms of effect that may differ from patient to patient and over time include atrioventricular resynchronization, decreased mitral regurgitation, and avoidance of bradycardia. No one treatment target exists; hence it is unlikely that any one metric will be able to predict benefit with any degree of accuracy. The purpose of this article was to create awareness among the medical society about smart pacemakers.