In patients with atrial fibrillation, the left atrial appendage may serve as the site of thrombus formation due to stasis that occurs within the appendage because of its shape and trabeculations. Although thrombus formation can be reduced by using anticoagulants, this may be contraindicated in some patients. The need for a better alternative treatment prompted the study of left atrial appendage occlusion for thromboembolism prophylaxis. Due to this, procedures that excise or occlude the left atrial appendage have gained attention because of their ability to prevent thromboembolic events. This article provides a comprehensive review of the left atrial appendage and its associated procedures’ clinical utility. The left atrial appendage (LAA) is an anatomical outpouching of the left atrium . Found wIn patients with atrial fibrillation (AF), the LAA may serve as site of thrombus formation due to the stasis that occurs within the appendage because of its shape and trabeculations. About 90% of atrial thrombi among patients with non-rheumatic atrial fibrillation and 60% among rheumatic mitral valve disease patients originate in the LAA . Due to During the third week of gestation, the LAA begins to develop as a remnant of the embryonic left atrium, while the branches of the primordial pulmonary vein forms the remaining portion of the left atrium .Following four weeks of gestation, the primitive atrium starts moving toward its ultimate location. The ensuing cellular protrusion phase solidifies the basal mesodermal layer and forms the trabeculae or pectinate muscles leading to the rough endocardium. The ultrastructural and physiological characteristics of the LAA are distinct from the left atrium . A connection of paired cardiac mesoderm that fuses to form a two-cell thick tubular heart is where the beginning and ultimate location of the left atrial appendage and its surrounding structures originate .From a pro-myocardial plate of cells that slowly forms into a three-dimensional tubular formation, it folds into an area that develops into a heart, residing in what will eventually become the pericardial space. The left atrial appendage begins to emerge as early as in these stages of embryonic growth .During the fourth week of embryonic development, the structurally and physiologically distinct LAA is derived from the left wall of the primary atrium. Further development of the left atrium occurs around six weeks of embryonic life .Unlike the right appendage, which is broad and triangular with a wide junction, the LAA is a finger-like, long, tubular, hooked structure, which is usually crenelated and has a narrow junction with the venous component of the atrium. The extent of the pectinate muscles enables appendages to be designated as morphologically right or left .Located within the pericardium, the LAA is a blind-ended pouch emerging from the left atrium, which makes its spatial relationship of importance. The structures surrounding the LAA include (1) the superiorly directed pulmonary artery; (2) the tip of the appendage, oriented toward the left ventricle free wall pointing inferomedially; (3) the left phrenic nerve running over the appendage; (4) fibers of Bachmann’s bundle toward the LAA arising from the medial aspect of the atrial roof; (5) the left superior pulmonary vein superiorly; and (6) the mitral valve inferiorly .The LAA cellular composition can vary both in composition and density since it contains both endocardial and epicardial layers that are structurally complicated by a disarray of myocyte orientation .Evora et al. noted that the LAA morphology is the substrate for generating thrombi due to its direct connection to the left-sided circulation . The hea“Lobe classification” into four types of LAA was first described by Veinot et al., in which they determined the orifice diameter, width, length, and number of lobes. The dominant type, which occurred in 54% of the hearts, is composed of two lobes, while 23% of the hearts studied have a three-lobed LAA. The third type, which occurred in 20% of the hearts, is a one-lobed appendage, while the fourth type, occurring in 3% of the examined heart, are four-lobed appendages .Having more complex internal characteristics, a variable number of lobes with the absence of a dominant lobe, a more irregular shape of orifice, and a short length, the “cauliflower” morphology was noted by Beigel et al. to be most often associated with an embolic event. The “cactus” has a foremost central lobe and the secondary lobes arise from it superiorly and inferiorly. The “windsock” has a dominant lobe as its primary structure with the location and number of secondary or even tertiary lobes varying. The most common morphology, “chicken wing”, has a dominant lobe that presents with a sharp bend in its proximal or middle part, folding back on itself, and may present with secondary lobes .The anatomy of the left atrial appendage facilitates its function as a receptacle during left ventricular systole, a blood drain from the pulmonary veins to the left ventricle in early diastole, a contractile room that assists in late diastolic left ventricular filling, and an early systolic suction source . Early sThe LAA has an initial passive phase of emptying in protodiastole and another active phase of emptying during left atrial contraction and a monophasic pattern of filling . During It is when disruptions in this normal flow happen that pathology arises. The flow pattern in patients with atrial fibrillation is marked by a rapid alternation of emptying and filling, with lower velocities . Furtherp = 0.008), disruptions in LAA peak flow velocities, and fractional area change with the occurrence of thrombus formation secondary to blood stasis. Compared to low-risk individuals, atrial fibrillation patients with hypertension (moderate risk) are at risk of atrial appendage thrombi  and reduced flow velocity  [Zabalgoitia et al. associated LAA peak flow velocities of ≤20 cm/s  . A study= 0.003) .2DS2-VASc score was created to assess the risk of stroke or other thromboembolic events among non-anticoagulated patients with non-valvular atrial fibrillation. It uses clinical parameters  and clinical history of diabetes, hypertension, congestive heart failure, thromboembolism, and vascular disease to risk stratify non-valvular atrial fibrillation patients as low- (0), intermediate- (1), and high-risk (≥2) [Non-treatment and even undertreatment with oral anticoagulation of patients with atrial fibrillation resulted in a high incidence of stroke . The CHAisk (≥2) .Currently, the modality of choice for evaluating LAA is transesophageal echocardiography (TEE). Other non-invasive imaging modalities such as cardiac magnetic resonance (CMR), multi-detector computed tomography (MDCT), and intracardiac echocardiography (ICE) can also be used. The different imaging modalities can be found in Transesophageal echocardiography is the main echocardiographic modality used in assessing the LAA. Other types include intracardiac echocardiography and Doppler echocardiography. TEE has high sensitivity and specificity (close to 100%) in assessing the presence of atrial thrombi . The useICE is a less sensitive alternative in the absence of TEE . MultiplDoppler echocardiography is often used for functional evaluation of the LAA to better assess the LAA and the risk of thromboembolism . To exclMulti-detector computed tomography (MDCT) produces 3D volumetric data of the whole heart, which can be reconstructed along different cardiac phases and planes to give an accurate evaluation of the LAA anatomy. Recent advances in MDCT now allow 3D imaging, high spatial and temporal resolution, and quantitative assessment to allow successful identification of LAA thrombi and non-dense clearing spontaneous echocardiographic contrast (SEC), as shown using TEE ,41,42,43CMR is a non-invasive imaging modality, which is used as an alternative for those cases in which TEE is not feasible, such as in patients with unsuccessful TEE probe insertion. This imaging modality visualizes the LAA size and function accurately, and can also detect thrombi in patients with atrial fibrillation . Tissue The left atrial appendage poses significant risk for thromboembolism in patients with atrial fibrillation . Treatme2DS2-VASc ≥ 2) and with contraindications to oral anticoagulants (OACs) due to a history of significant bleeding like intracranial bleeding [The EHRA/European Association of Percutaneous Cardiovascular Interventions expert consensus statement on catheter-based LAAO has identified five patient categories in whom LAAO should be considered with regard to its risks and benefits. Clinically, the most widely recognized indication for LAAO is stroke prevention in patients at high thromboembolic risk (CHAbleeding . 2DS2-VASc ≥ 2) and the increased bleeding risk associated with systemic OACs in three patient groups: (1) patients with a HAS-BLED score ≥3, (2) patients requiring the prolonged period of triple anticoagulant and antiplatelet therapy for severe coronary artery disease treated with stents, and (3) patients with end-stage renal dysfunction (creatinine clearance 15–30 mL/min). The decision to implant LAAO is still an individualized risk–benefit evaluation with novel oral anticoagulants (NOACs) being still the main strategy of choice [Another indication is stroke prevention in high-thromboembolic-risk patients  undergoing pulmonary vein isolation that are planning to discontinue OAC use after ablation [The last indication according to the EHRA consensus on potential indication for LAAO is in patients at high thromboembolic risk , cardiovascular mortality , all-cause mortality , and non-procedure-related major bleeding  when compared to OACs [Multiple randomized control studies have indicated that the WATCHMAN device is non-inferior to warfarin therapy for patients with increased risk of clotting ,63,64. Fp < 0.001 for noninferiority; p = 0.003 for superiority) [Amplatzer Amulet was approved for LAAO in 2021. It consists of a braided nitinol mesh disk and lobe connected by a waist . Clinicariority) .p = 0.019) [The Lariat system is a combination of percutaneous and epicardial LAA closure using a soft tissue snare. Via percutaneous access, a magnet-tipped catheter is placed in the LAA as a guide for the snare that is delivered via the pericardium. Currently, this device has 510 K clearance from the FDA . Despite= 0.019) . Multipl= 0.019) . The cli®. Individual techniques have been well described elsewhere, so here we will discuss surgical obliteration as a whole. It is common for patients with atrial fibrillation undergoing cardiac surgery to receive concomitant LAA obliteration. The techniques for obliteration include excision, stapler removal, running sutures, and the use of specialized devices such as AtriClipn = 10,633) suggested that those who underwent surgical LAAO were more likely to have early post-operative atrial fibrillation than those who did not undergo LAAO, without significant change in risk of stroke or mortality [A recent meta-analysis by Tsai et al. concluded that when compared to patients who underwent cardiac surgery , those who received LAAO concomitantly had a significantly reduced risk of stroke and all-cause-mortality, without increased risk of bleeding . Anotherortality . A studyortality . A randoortality . There hWhether carried out percutaneously or surgically, left atrial appendage closure is not without risk. The major risks for percutaneous procedure include cardiac effusion/tamponade, stroke, and device-associated thrombi . Based oA study by Simard et al. identified the following as risk factors for device-associated thrombi: hypercoagulability disorders, renal impairment, pericardial effusion, implantation depth >10 mm from the pulmonary vein limbus, and non-paroxysmal AF . MoreoveIncomplete closure of the LAA is not uncommon with a surgical approach. This results in a patent communication, which only exacerbates the risk of stroke. In addition to this, the left circumflex artery is often proximal to the site of obliteration, necessitating mastery of surgical anatomy and skills.The clinical results of LAA occlusion in comparison to oral anticoagulation were explored in multiple studies. p = 0.001) [In the LAAOS III study, which first explored the prevention of ischemic stroke or systemic embolism in patients who had LAAO coupled with usual post-operative care, including oral anticoagulants, systemic embolism or ischemic stroke occurred in 114 participants (4.8%) in the LAAO group and 116 participants (7.0%) in the non-occlusion group. This showed a significant reduction in risk of ischemic stroke or systemic embolism  .It is noteworthy to highlight multiple randomized controlled trials, including PREVAIL, PROTECT AF, and PRAGUE 17, which have shown the efficacy and safety of LAAO in comparison to medical management . The PROIn the PREVAIL trial, stroke or death at 18 months was found to occur in 0.064 in the LAAO group compared to 0.063 in the warfarin group, which did not reach the pre-established non-inferiority criteria for the trial . The ratp value for non-inferiority = 0.004) [The PRAGUE17 trial showed that LAAO was non-inferior to NOAC. The Amplatzer Amulet or WATCHMAN device was used for the LAAO, while the control group was given antiplatelet therapy for 3 months. The primary clinical findings showed that the net outcome of CV death, stroke, TIA, systemic embolism, etc., was similar in both treatment groups  .p = 0.005) and all-cause mortality  [After 3.8 years of follow-up, the combined outcome of preventing stroke, systemic embolism, and cardiovascular death among LAAO patients was shown to be non-inferior and superior to those of warfarin patients in the PROTECT AF trial, 8.4% vs. 13.9%, respectively . There was reduced cardiovascular mortality  .The LAA is clinically important because it is a major site of thrombus formation in atrial fibrillation and mitral valve disease. Due to the LAA’s properties and relations, it may be utilized as a decompression chamber in cases where left atrial pressure is increased. The exact pathogenesis of thrombus formation is not yet known, but it is hypothesized that the stasis of blood flow within the LAA is a key factor.Occlusion of the LAA is a good alternative to warfarin for stroke prophylaxis. However, it will not prevent every episode of thromboembolism, especially in patients with mitral valve disease. This is important because patients with left ventricular failure and valvular disease may be more affected.Alternative treatments need to be explored to further understand how to create more effective outcomes for thromboprophylaxis in patients with atrial fibrillation. This will help determine which course of treatment should be selected, as well as how to manage significant adverse effects from the specific treatments.


The introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors in the management of heart failure with preserved ejection fraction (HFpEF) may be regarded as the first effective treatment in these patients. However, this proposition must be evaluated from the perspective of the complexity of clinical outcome endpoints in heart failure. The major goals of heart failure treatment have been categorized as: (1) reduction in (cardiovascular) mortality, (2) prevention of recurrent hospitalizations due to worsening heart failure, and (3) improvement in clinical status, functional capacity, and quality of life. The use of the composite primary endpoint of cardiovascular death and hospitalization for heart failure in SGLT2 inhibitor HFpEF trials flowed from the assumption that hospitalization for heart failure is a proxy for subsequent cardiovascular death. The use of this composite endpoint was not justified since the effect of the intervention on both components was clearly distinct. Moreover, the lack of convincing and clinically meaningful effects of SGLT2 inhibitors on metrics of heart failure-related health status indicates that the effect of this class of drugs in HFpEF patients is essentially restricted to an effect on hospitalization for heart failure. In conclusion, SGLT2 inhibitors do not represent a substantial breakthrough in the management of HFpEF. Heart failure is the cardiovascular epidemic of the 21st century . A distiPrevalence of heart failure in the general population is 1–2% . The preThe data in the previous paragraph are not in contradiction with the fact that the natural history of HFrEF is more severe than the natural history of HFpEF. The natural history is the progression of a disease process over time, in the absence of treatment. It ends with death or resolution of the disease but can also persist in the presence of reduced function or disability of the patient. Inhibition of the renin-angiotensin-aldosterone system, ß-receptor blockade, and neprilysin inhibition by sacubitril improve survival and decrease hospitalizations in patients with HFrEF ,18,19. ISGLT2 inhibitors were initially developed as novel oral glucose-lowering agents that improve glycemic control independently of insulin secretion by inducing glucosuria. The SGLT2 inhibitors also result in a modest reduction in blood pressure and body weight. The pharmacology of this class of anti-diabetic agents is discussed in detail in +/K+ ATPase [In the kidney and the intestine, glucose transport across epithelial cells occurs via active transport, which is achieved by sodium-glucose cotransporter proteins . The abs+ ATPase . The incIn the kidneys, 100% of the filtered glucose in the glomerulus is reabsorbed under physiological conditions along the nephron. SGLT has two main types. SGLT1 accounts for glucose absorption from the small intestine and to a minor extent also contributes to glucose reabsorption in the kidney, while SGLT2 is responsible for the reabsorption of most of the filtered glucose in the kidney. SGLT1 is an integral membrane protein that has low-capacity and high-affinity characteristics and is mainly expressed in the intestine . In typeIn healthy individuals, the renal tubules are capable of reabsorbing nearly 100% of filtered plasma glucose. Hyperglycemia results in an increased amount of filtered glucose, which is reabsorbed until the maximal capacity for the reabsorption of tubules is reached. The renal threshold of glucose refers to a particular plasma glucose concentration, beyond which glucose is eliminated in the urine  . In diabPhlorizin, known since the nineteenth century for causing glucosuria, was later proven to be a potent inhibitor of SGLT1 and SGLT2 ,32. ThisCurrently, four SGLT2 inhibitors are licensed by both the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA): canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. They differ pharmacologically from each other mainly by the relative selectivity for SGLT2 over SGLT1, which amounts to approximately 260-fold for canagliflozin , 1200-foMultiple clinical trials have demonstrated the capacity of SGLT2 inhibitors to improve glycemic control in type 2 diabetes. When SGLT2 inhibitors were used as monotherapy or in addition to other anti-hyperglycemic therapies in type 2 diabetic patients, their fasting plasma glucose and glycated hemoglobin (HbA1c) were significantly reduced ,45. SGLTThe SGLT2 inhibitor-induced elevated urinary glucose excretion led to a loss of approximately 75 g of glucose or 300 kilocalories per day . TreatmeAs SGLT2 reabsorbs sodium and glucose at the same time, the administration of SGLT2 inhibitors also results in a natriuretic effect, which is most prominent in the first 2–3 days. Subsequently, natriuresis gradually returns to baseline levels over the course of several weeks. A median (interquartile range) plasma volume change from the baseline of −7.3% (−12.4% to −4.8%) was observed after 3 months of treatment . Subsequp = 0.0002) [p < 0.001) and in the empagliflozin 25 mg group  at week 12 [Blood pressure reduction by SGLT2 inhibitors is thought to be mediated by osmotic diuresis and mild natriuresis ,57. More 0.0002) . In the  week 12 .Studies in experimental animal models of atherosclerosis have shown that SGLT2 inhibition attenuates the progression of atherosclerosis by a plenitude of mechanisms. These mechanisms include the inhibition of vascular inflammation, decreased oxidative stress, reversal of endothelial dysfunction, reduction in foam cell formation, and the prevention of platelet activation . The maj+/H+ exchanger-3 located in the distal segment of the proximal tubule, contributing to natriuresis. Second, Na+-K+-2Cl− cotransporters in the macula densa may also be inhibited by SGLT2 inhibitors, leading to the inhibition of glomerulotubular feedback. In addition, Na+/H+ exchanger-4, in the thick ascending limb of Henle, is also inhibited by SGLT2 inhibitors [+/H+ exchanger-1 [+/H+ exchanger-11 is a potential target of SGLT2 inhibitors [SGLT2 inhibitors have also shown to exert effects that are independent of their interaction with SGLT2 receptors, which are termed off-target effects ,70. Firshibitors ,70. In thanger-1 ,72. Morehibitors .Adverse effects of SGLT2 inhibitors include the risk of genital mycotic infection and volume depletion-related events ,75. DapaIn the Canagliflozin Cardiovascular Assessment Study (CANVAS), canagliflozin was shown to be associated with a higher risk of bone fracture and lower limb amputation . HoweverType 2 diabetes mellitus is associated with an elevated risk of cardiovascular disease, and cardiovascular mortality is the primary cause of mortality in these patients ,84. GlucSince 2015, large-scale clinical trials have been launched to evaluate a potential impact of SGLT2 inhibitors on cardiovascular outcomes. In p < 0.001 for non-inferiority, p = 0.04 for superiority) in the empagliflozin group, mainly driven by a 38% reduced risk of cardiovascular death . Hospitalization for heart failure was also significantly reduced by 35% with empagliflozin , suggesting a potential for preventing heart failure hospitalization in diabetics. Additional subgroup analyses revealed a consistent effect of empagliflozin on cardiovascular mortality and hospitalization for heart failure regardless of the baseline risk of heart failure in type 2 diabetes [In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients—Removal of Excess Glucose (EMPA-REG OUTCOME) trial , patientdiabetes .p < 0.001 for non-inferiority, p = 0.02 for superiority), while reductions in all-cause mortality and cardiovascular death were not significant. Hospitalization for heart failure as a secondary outcome was reduced by 33% . Post hoc analysis of CANVAS showed no clear difference in the effects on HFrEF versus HFpEF events [The CANVAS study  assessedF events .p < 0.001 for non-inferiority, p = 0.17 for superiority). The risk of cardiovascular death or hospitalization for heart failure was significantly lower in the dapagliflozin group , mainly as a result of a great reduction in hospitalization for heart failure , similar to that as observed in the EMPA-REG OUTCOME trial and the CANVAS trial.In the Dapagliflozin Effect on Cardiovascular Events—Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial  in patiep < 0.001 for noninferiority), at a dose of either 5 mg or 15 mg. Further analyses demonstrated only a significant reduction in hospitalization for heart failure .The Evaluation of Ertugliflozin efficacy and safety cardiovascular outcomes trial (VERTIS-CV)  involvinIn conclusion, the non-inferiority in relation to MACE indicated the cardiovascular safety of SGLT2 inhibitors in patients with type 2 diabetes with prior cardiovascular disease or at elevated risk for cardiovascular disease. Empagliflozin and canagliflozin have further shown cardiovascular benefits by significantly reducing the risk of MACE. Notably, all four mentioned SGLT2 inhibitors have demonstrated potential in decreasing hospitalization for heart failure in diabetic patients, which has motivated further research into SGLT2 inhibitors in heart failure patients. Furthermore, studies were extended to patients without type 2 diabetes.Nevertheless, hospitalization for heart failure is only one particular clinical outcome endpoint in the treatment of chronic heart failure. Indeed, the treatment of heart failure is directed toward different goals. In order to make a comprehensive interpretation of the currently available evidence regarding the effects of SGLT2 inhibitors in heart failure, the therapeutic goals of heart failure treatment need to be accurately defined. Heart failure endpoints need to be precisely circumscribed and the rationale behind composite endpoints needs to be explored. These topics are discussed in depth in Clinical endpoint adjudication requires unambiguous definitions. Objective criteria have been developed, contributing to the standardization of definitions ,93,94,95The progress of heart failure management has been partially based on the development of deeper insights into the pathophysiology of heart failure and the concomitant development of new paradigms. Since William Withering first described heart failure as “dropsy” in the 18th century, it had been regarded as an edematous disease until 1960s. Diuretics were accordingly used as the main treatment to stimulate fluid excretion via urine . In the The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) in 1987 was a landmark trial that assessed all-cause mortality as the primary endpoint . PatientAll-cause mortality is the most clear-cut endpoint. Cardiovascular mortality includes deaths that result from an acute myocardial infarction, sudden cardiac death, death due to heart failure, death due to stroke, death due to cardiovascular procedures, death due to cardiovascular hemorrhage, and death due to other cardiovascular causes . Since oWhen the incidence of death or cardiovascular death is not high, the execution of clinical trials with all-cause mortality or cardiovascular mortality as the endpoint becomes problematic from the perspective of statistical power. As the rate of mortality in chronic heart failure appears to be declining  and is aComposite endpoints, the combination of two or more study outcomes into a single composite measure, have been increasingly used in the past decades as a primary efficacy measure in heart failure trials . The advf Inhibitor Ivabradine Trial), no significant effect of ivabradine was observed on cardiovascular mortality whereas a significant impact of ivabradine on the primary composite endpoint of cardiovascular death or hospital admission for worsening heart failure was demonstrated  [p < 0.001) [A typical primary composite endpoint in heart failure trials is the composite of cardiovascular mortality and heart failure hospitalization, which is regarded as a cause-specific composite endpoint. Since the beginning of the 21st century, most studies of disease-modifying treatments for chronic heart failure have indeed employed the composite endpoint of cardiovascular mortality and hospitalization for heart failure ,117,118  0.0001) . Similar< 0.001) .In chronic conditions such as heart failure, hard clinical endpoints like all-cause mortality or cardiovascular mortality and a softer endpoint like hospitalization for worsening heart failure are not the only meaningful efficacy measure. Patients who are alive and not hospitalized can still have a poor clinical status, functional capacity, or quality of life . From thThe evaluation of heart failure-related health status was assessed by means of short-to-intermediate-term studies. In contrast to long-term trials focusing on mortality and hospitalization, these trials focusing on symptoms and clinical status were frequently inconsistent . MeasureSeveral approaches for the evaluation of clinical status have been applied. The direct assessment of symptoms examines the presence and severity of specific symptoms  during specified levels of effort  . The NYHThe cardiovascular trials of SGLT2 inhibitors in type 2 diabetes discussed in In p < 0.001) (The DAPA-HF (The Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial in 2019 investigated the efficacy of dapagliflozin in patients with established heart failure and a reduced ejection fraction (ejection fraction of 40% or less) regardless of type 2 diabetes mellitus status . The ris< 0.001) . Worseni< 0.001) . Separat< 0.001) . This stp < 0.001), regardless of the presence or absence of diabetes [The EMPEROR-Reduced  trial, published shortly after the DAPA-HF trial, assessed the cardiovascular efficacy of empagliflozin in HFrEF patients (ejection fraction of 40% or less). Administrating empagliflozin 10 mg once daily on top of the standard heart failure therapies efficaciously lowered the risk of cardiovascular death or hospitalization for heart failure  ,139. Howp < 0.001), indicating its potential in ameliorating symptoms among heart failure patients [In addition, both trials also assessed the functional outcomes by means of the KCCQ, but they evaluated different domains of KCCQ and the duration of the observation period was also distinct. In the DAPA-HF study, the KCCQ total symptom score was measured. The use of dapagliflozin resulted in a greater increase in the total symptom score on the KCCQ at month 8 compared to the baseline  in favor of canagliflozin, demonstrating a statistically significant amelioration in symptom burden in patients with heart failure of all types after a 12-week treatment of canagliflozin. HFrEF patients accounted for 40.4% of the study population, in which the mean difference in the changes of scores was 4.0 points (95% CI −1.0–9.0).The CHIEF-HF  was patient centered and conducted in a completely remote fashion . This trCollectively, these data indicate that dapagliflozin and canagliflozin but not empagliflozin had a statistically significant effect on heart failure-related health status in HFrEF patients. Whether the observed impact is clinically meaningful is a matter of debate. Given the importance of symptoms, function, and quality of life to patients, more clinical trials assessing the functional impact of SGLT2 inhibitors are ongoing. The DETERMINE-Reduced  and the p < 0.001), which was independent of the presence or absence of diabetes. The effect on the primary endpoint was mainly driven by a 29% lower risk of hospitalization for heart failure . The risk of cardiovascular death was not significantly different between the empagliflozin and placebo groups . Subgroup analyses suggested that patients with an ejection fraction of 40% to 49% benefited most from the cardiovascular effects of empagliflozin. The primary outcome reduction was not significant in the group with an ejection fraction of 60% or more.The EMPEROR-Preserved  trial was carried out to evaluate the effects of empagliflozin on major heart failure outcomes in heart failure patients with an ejection fraction greater than 40% . SGLT2 ip < 0.001), without a difference in benefit among patients with an ejection fraction of 60% or more and those with an ejection fraction of less than 60%. The effect of dapagliflozin on the primary outcome was consistent in subgroups with or without type 2 diabetes. There was no significant effect of dapagliflozin on cardiovascular mortality. Collectively, the reduction in the primary composite endpoint in the two HFmrEF and HFpEF patients was mainly driven by a markedly lower risk of hospitalization for heart failure, while cardiovascular deaths in both trials were not substantially reduced in the SGLT2 inhibitor treatment group.Recently, the DELIVER  trial revealed the cardiovascular effects of dapagliflozin in patients with HFmrEF (ejection fraction between 41% and 49%) or HFpEF (ejection fraction of 50% or more) . DapagliA prespecified analysis of the DELIVER trial examined the efficacy of dapagliflozin in the group of heart failure patients with improved ejection fraction, defined as patients whose ejection fraction improved from 40% or less to more than 40% . This pop = 0.027) and on all-cause mortality  among the 8474 patients with HFrEF [A meta-analysis of the DELIVER and EMPEROR-preserved trials was prespecified in the DELIVER academic statistical analysis plan and preregistered with PROSPERO (CRD42022327527) before unmasking of the DELIVER trial results . Importath HFrEF .p = 0.009; mean placebo-corrected difference between baseline and month 8 among survivors 2.4 points; 95% CI 1.5–3.4) [p = 0.001), was improved, together with an amelioration of the 6-min walk test  after a 12-week dapagliflozin treatment [p value for interaction = 0.35) [Similarly, as in the HFrEF trials, studies on HFmrEF and HFpEF patients also carried out more detailed evaluations of heart failure-related health status. In the EMPEROR-Preserved, no significant improvement in the quality-of-life score on KCCQ at 52 weeks was observed . The DEL1.5–3.4) . Dapagli1.5–3.4) . The KCCreatment . In the  = 0.35) . The ong = 0.35)  and EMPE = 0.35)  trials wTherapeutic classes are defined based on the mechanism of action. Drugs of a particular class share a single mechanism, but at the same time, all drugs have multiple actions that may be favorable and unfavorable. The more similarities between the agents within a pharmacologic class in terms of chemical structure, pharmacodynamics, and pharmacokinetics, the greater the likelihood of shared class effects . In the There is a certain degree of heterogeneity in the definitions of endpoints in the existing studies, impeding a comparison of the current evidence.Meaningful differences in the defining components of composite endpoints exist between the DAPA-HF and EMPEROR-Reduced trials ,118. TheRegarding the evaluation of heart failure-related health status, both HFrEF trials used KCCQ as the endpoint, but DAPA-HF employed the change in the total symptom score on KCCQ from the baseline to 8 months whereas EMPEROR-Reduced chose to use change in a clinical summary score on KCCQ from the baseline to 52 weeks. DAPA-HF measured a statistically substantial improvement in the score in the dapagliflozin group, in contrast to the EMPEROR-Reduced where no significant difference between the empagliflozin group and the placebo group was observed. This discordance in functional benefits between empagliflozin and dapagliflozin can potentially indicate drug-specific effects rather than class-specific effects, although the difference in duration of observation might also play a role. Nevertheless, the real issue here is that it is questionable whether a clinically relevant benefit on KCCQ was observed in any of these trials.p < 0.0001) [The EMPEROR-Preserved and DELIVER trials on HFmrEF and HFpEF patients have generally adopted the definition of primary endpoints from the EMPEROR-Reduced and DAPA-HF trials, respectively ,138. Pos 0.0001) . HoweverIn the two major outcome trials of dapagliflozin and empagliflozin on HFrEF patients, cardiovascular death as one component of the primary composite outcome was only significantly reduced in the DAPA-HF trial. Specifically, the risk reduction in cardiovascular mortality was 18%  in DAPA-HF  and a noRegarding the profile of the study population, the DAPA-HF trial primarily enrolled patients with mild-to-moderate degrees of left ventricular systolic dysfunction , while tAs mentioned before, the subgroup analyses in EMPEROR-Preserved showed that the primary outcome was not significantly reduced in the group with the ejection fraction of 60% or more . FurtherBased on the currently available clinical trial data, the effects on clinical endpoints in chronic heart failure data represent predominantly class-specific effects rather than drug-specific effects. It cannot entirely be excluded that minor differences between individual drug members of the class exist based on the data presented in p = 0.0054). The interpretation of clinical trial results with hierarchical composite endpoints will become more complex since it will be less clear what drives a statistical difference. Very disparate categories are integrated in one composite endpoint. When the mortality assessment time window is short, the influence or contribution of mortality on the composite is diminished relative to a patient-centered outcome like dyspnea. Detailed criticisms have been provided by Brown and Ezekowitz [The application of SGLT2 inhibitors in the treatment of acute heart failure was outside the focus of this review. A recent review concluded that currently available studies including six randomized trials and two real-world studies provide conflicting results concerning the true efficacy of SGLT 2 inhibitors in the setting of acute heart failure . Intereszekowitz .Hierarchical clinical composite endpoints certainly do not solve the main problems associated with classical composite clinical endpoints. Both strategies merge event types, which lead to a loss of information, and both do not provide event-specific estimates of the effect . Brown aIn general, patients that are included in clinical trials are not entirely representative of patients in clinical practice. Although many other reasons may contribute to the infrequent prescription of certain classes of heart failure drugs in the real world , differeIn this review, the progress from SGLT2 inhibitors being evaluated as anti-diabetic agents to SGLT2 inhibitors being assessed as a therapy for chronic heart failure was illustrated. SGLT2 inhibitors with glucose-lowering effects independent of augmented insulin secretion have shown cardiovascular benefits in cardiovascular safety studies in patients with type 2 diabetes mellitus. The positive effect on hospitalization for heart failure stimulated further research into the effects of SGLT2 inhibitors on heart failure outcomes. This was realized by large-scale clinical trials performed in different categories of heart failure patients, with defined endpoints compiled in line with the therapeutic goals of heart failure management. SGLT2 inhibitors exerted a statistically significant effect on the primary outcome in both the HFrEF and HFpEF trials. The effect on hospitalization for heart failure was unequivocal, whereas the effect on cardiovascular mortality was both statistically and clinically insignificant with the exception of the DAPA-HF trial. The composite endpoint of cardiovascular death and hospitalization of heart failure/worsening heart failure was used as the primary endpoint in the clinical trials. This was not justified in both HFpEF trials, and this field illustrates the problem of using composite endpoints when the effect is driven by less serious components. The only consistent result is an effect on heart failure hospitalization, and this component should not have been combined with cardiovascular mortality.In addition to evaluating the first two therapeutic goals of heart failure treatment being reducing mortality and preventing hospitalization for heart failure, the third goal concerning the heart failure-related health status was also assessed by means of the KCCQ. To date, heart failure-related health status has mainly been analyzed as a secondary outcome; more large-scale trials assessing functionality and health status as the primary outcome endpoint are ongoing. Up until now, there have been no convincing data that there is a clinically meaningful improvement in the heart failure-related health status of these patients. Statistically significant improvements in certain metrics do not necessarily indicate a clinically meaningful effect.Whether there is or is not a clinically meaningful impact of SGLT2 inhibitors on heart failure-related health status is further being evaluated in ongoing trials ,142,148.


Conventional selection criteria are not consistently able to discriminate between responders and non-responders to cardiac resynchronization therapy (CRT). The objective of this study was to evaluate the usefulness of quantitative gated single-photon emission computed tomography (SPECT) in predicting the response to CRT. This prospective cross-sectional study included 25 patients with advanced congestive heart failure who underwent quantitative gated SPECT before and after CRT implantation. Patients with the left ventricular (LV) lead positioned at the latest activation segment away from the scar had a significantly higher chance of responding than those with the lead positioned at a different area. Responders were likely to have a phase standard deviation (PSD) value of >33°, with 86.6% sensitivity and 90% specificity, and a phase histogram bandwidth (PHB) value of >153°, with 100% sensitivity and 80% specificity. Quantitative gated SPECT can help refine patient selection for CRT implantation, using PSD and PHB cutoff points, in addition to guiding the positioning of the LV lead. Phase analysis using gated SPECT was recently evaluated for the assessment of LV dyssynchrony, and a quantitative gated SPECT (QGS) algorithm (from Cedars-Sinai) has been used to provide quantitative parameters for the assessment of LV mechanical dyssynchrony.This study sought to explore the clinical value of QGS in predicting the response to CRT.The present study included 30 patients with advanced congestive heart failure who were eligible for CRT implantation according to the European Society of Cardiology guidelines of pacing released in 2013; patients with symptomatic heart failure despite optimal pharmacological therapy, New York Heart Association (NYHA) functional class III, and ambulatory class IV; and patients with a left ventricular ejection fraction (LVEF) of ≤35%, sinus rhythm, and a QRS duration of ≥120 ms for left bundle branch block (LBBB) morphology or ≥150 ms for non-LBBB morphology.Patients with a life expectancy of <1 year, pregnant women, patients with atrial fibrillation, and patients with previously implanted pacemakers were excluded.This study was approved by the Ain Shams University ethical committee and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients.Data collection was completed for all patients, including history-taking with an emphasis on age, sex, risk factors , and a history of previous events (including previous acute coronary syndromes or coronary angiography). Patients were asked about heart failure symptoms, their functional class according to the NYHA classification, and history of current heart failure medications. A questionnaire was also given to patients to examine their quality of life (QOL) using the Arabic version of the Minnesota Living with Heart Failure questionnaire (MLHFQ). The QRS duration was calculated for all patients using 12-lead electrocardiography (ECG), and the QRS morphology was recorded.All eligible patients underwent resting ECG gated SPECT with technetium (Tc)-99m sestamibi at baseline prior to CRT implantation and at 6 months post-CRT implantation to determine global systolic synchrony parameters, the segment with latest mechanical activation, the extent of perfusion defect, and scar burden; the estimation of LVEF and LV volumes (end-diastolic volume [LVEDV] and end-systolic volume [LVESV]) was also carried out.3The resting images were acquired 1 h after intravenous injection of 20–30 mCi of Tc-99m sestamibi using a dual-headed cardiac dedicated gamma cameral system  equipped with a low-energy high-resolution parallel hole collimator operating in continuous rotation around 360° according to the local protocol of the nuclear cardiology laboratory. An ECG R-wave detector was used to provide gating to acquire 8 emission frames per cardiac cycle.7 The presence of a large total perfusion defect encompassing ≥30% of the LV was diagnosed as ischemic cardiomyopathy.8Visual and semiquantitative analyses were used to obtain a score to represent perfusion for each of the 17 segments of the myocardium based on 3 short-axis slices and a representative long-axis slice to depict the apex. Each segment was scored according to the degree of radiotracer uptake. The defect size was expressed as a percentage of the LV, as previously validated in a phantom model.Automated computer-generated LV volumes and LVEF were obtained from short-axis slices of electrocardiographically gated rest myocardial perfusion SPECT datasets using the AutoQUANT (QGS) software program .3Reconstructed images were analyzed using a modified version of the QGS algorithm  that provides quantitative parameters for the assessment of LV dyssynchrony. In the present study, a histogram and polar map were constructed from the phase value for the entire LV. The phase standard deviation (PSD) and phase histogram bandwidth (PHB) were calculated and examined as the global dyssynchrony parameters, and the segment with the latest mechanical activation was identified..9All patients underwent CRT implantation, and all leads were implanted transvenously by physicians who were blinded to the results of the SPECT examination. No intraoperative hemodynamic evaluation was performed. The pacing leads were connected to a CRT implantable device . Then, after CRT implantation, biplane fluoroscopy was performed using orthogonal views (left anterior oblique at 60° and right anterior oblique at 30°). The images were analyzed to determine the anatomic location of the LV lead using the 6-segment model The LV lead position was determined using fluoroscopy and classified retrospectively according to the results of the SPECT analysis to be concordant or discordant with the site of the most-delayed mechanical activation determined prior to implantation. The lead was considered concordant when it was found to be adjacent to the latest contracting segment of the LV assessed using SPECT. On the other hand, the LV lead was considered discordant if it was placed in any other coronary sinus tributary that was not adjacent to the latest contracting LV segment.Patients were assessed 6 months after CRT implantation for the following: NYHA functional class; QOL, using a questionnaire according to the MLHFQ; and QGS to determine LV volumes, LVEF, and global dyssynchrony indices to define the response to CRT.10Responders were defined as patients with a ≥5% improvement in LVEF as well as an improvement of ≥1 NYHA class, whereas non-responders were defined as patients who showed no improvement or a <5% improvement in LVEF and no improvement in NYHA class.t test when the data were parametric or the Mann–Whitney test when the data were non-parametric, and comparisons between paired data were performed using a paired t test. Pearson and Spearman correlation coefficients were used to assess the relationships between 2 parameters in the same group. Logistic regression analysis was used to assess predictors of CRT response after implantation.Data were coded and entered into SPSS version 22  for analysis. Qualitative data were presented as numbers and percentages. The chi-squared test was used to compare qualitative data, while Fisher’s exact test was only used when the expected count in any cell was <5. Quantitative data are presented as means, standard deviations, and ranges. Comparisons between 2 groups with quantitative data were performed using an independent P ≤ .05 was considered statistically significant.Receiver-operating characteristic (ROC) curves were constructed to determine cutoff values for PSD and PHB. The confidence interval was set to 95%, and the margin of error accepted was set to 5%. Table 1. The mean MLHFQ score was 68 ± 15 points and 68% of cases were NYHA class III, whereas 32% were NYHA class IV. The mean QRS duration was 156 ± 12 ms with 56% of cases having an LBBB morphology. The mean echocardiographic-derived LVEF was 21.6% ± 5.2%.Thirty patients were enrolled in this study; however, 2 patients died and contact was lost with 3 patients. Therefore, a total of 25 patients fulfilled the inclusion criteria and completed the 6-month follow-up assessments. The mean age was 49 ± 9 years, with 56% of the population being male and 44% of cases having an ischemic etiology. The distribution of risk factors is shown in . ECG findings revealed that the incidence of LBBB was significantly higher in the responder group, whereas the QRS duration showed no significant difference between the 2 groups.These 25 patients were subdivided according to the criteria for CRT response into 2 groups: responders (n = 15) and non-responders (n = 10). Both groups were comparable in terms of demographic data and risk factor distribution. The assessment of symptoms and QOL revealed that the responders showed significant degrees of NYHA class III and IV compared to the non-responders, whereas there were no significant differences in QOL .A comparison of the myocardial perfusion data of both groups showed that the responder group had significantly smaller LV volumes (LVEDV and LVESV) at baseline. The responder group also presented a greater baseline degree of mechanical dyssynchrony as determined using phase analysis. On the other hand, patients in the responder group had a significantly smaller perfusion defect. In the responder group, there was also a significantly higher percentage of patients with coronary sinus lead position concordant with the area of latest activation and not adjacent to scar tissue P < .001). Considering SPECT parameters, the responder group showed significant improvements in the dyssynchrony indices (P < .001) and significant reverse remodeling with improvements in LVEF .At the 6-month follow-up, both groups were compared using MLHFQ scores and SPECT parameters. The responder group showed significant improvements in the MLHFQ score compared to the non-responder group  negatively correlated with the change in LVEF. This implies that a lower MLHFQ score (better QOL) correlates with improved LVEF, and the lower the dyssynchrony indices (better synchrony), the greater the improvement in LVEF. On the other hand, the baseline QRS duration was not significantly correlated with the change in LVEF .In the present study, univariate regression analysis for predictors of CRT response revealed that non-ischemic etiology and baseline NYHA (III rather than IV) are predictors of such. Baseline SPECT-derived parameters that predict CRT response include smaller baseline LV volumes (LVEDV and LVESV), higher dyssynchrony indices (PSD and PHB), lower total perfusion defects, and placing the LV lead adjacent to the SPECT-determined latest activation and away from the scar .In the present study, ROC analysis was performed to determine the cutoff value of dyssynchrony indices to predict CRT response. A cutoff value for PSD of 33°, with a sensitivity of 86.6% and specificity of 90% , was determined. Therefore, patients with PSD > 33° were likely to be responders. A cutoff value for PHB of 153°, with a sensitivity of 100% and a specificity of 80% , was also determined, and patients with PHB values > 153° were likely to be responders 11 Current guidelines for biventricular pacing adopt the electrographic criteria in terms of QRS duration and morphology that reflect electrical rather than mechanical dyssynchrony. However, based on these criteria, 30% of patients undergoing CRT implantation are non-responders. Efforts have been made to decrease non-responder rates, including improving patient selection, optimizing the correction of electrical and mechanical dyssynchrony, and improving postimplant care.12 Echocardiographic techniques, such as tissue Doppler and strain rate imaging, have been used to identify mechanical dyssynchrony. However, these methods have some disadvantages as they lack reproducibility and the ability to differentiate between responders and non-responders to CRT.13An important aspect in the management of heart failure is to obtain and maintain optimal electrical activation of the cardiac chambers as well as atrioventricular synchrony.3 Thus, using reproducible SPECT dyssynchrony indices to address the mechanical dyssynchrony has been suggested to refine the criteria for CRT response. The assessment of LV mechanical dyssynchrony using phase analysis of gated myocardial perfusion SPECT was feasible in all patients using 2 selected indices—namely, PSD and PHB. As CRT is indicated to synchronize ventricular pacing, CRT will fail to produce tangible results if the baseline dyssynchrony is below a certain threshold. We explored the potential of baseline dyssynchrony indices to predict the response to CRT. In the present study, a cutoff point of 33° for PSD was detected, with a sensitivity of 86.6% and specificity of 90%, whereas a cutoff point for PHB of 153° was detected, with a sensitivity of 100% and specificity of 80%. These results are close to those from Azizian et al., who reported cutoff points of 21° for PSD and 112° for PHB, respectively.14 In addition, it was demonstrated that the improvement in mechanical dyssynchrony indices significantly correlated with the improvement in LVEF, a result which is quite similar to that highlighted in the VISION-CRT study.15SPECT has been used to determine dyssynchrony indices using phase analysis, which has been shown to be reproducible and has the potential to predict the response to CRT.15 Prior to CRT, it seems logical to select the position of the LV lead insertion in the coronary sinus vein as one adjacent to the latest electromechanical activation–viable segment to achieve optimal resynchronization.16 The priority is to achieve a stable LV lead position with a suitable threshold in the absence of diaphragmatic pacing in the posterolateral area. All LV leads were positioned in the mid-LV segment in the right anterior oblique projection to avoid apical insertion of the LV lead, as the MADIT-CRT study showed that the apical position is less effective and even harmful, increasing the risk of death.17 In the present study, positioning the LV lead concordant with the latest activation segment was a predictor of CRT response. These results agree with those concluded in the study by Boogers et al. using SPECT and similarly in the TARGET trial with speckle-tracking site analysis.19 Nevertheless, in the VISION-CRT study using SPECT, the investigators failed to show this association that was possibly attributed to a lack of operator blinding to the echo information of sites of scar that could have influenced the lead positioning decision.15 It is also noteworthy that reliable echocardiographic measurements require expertise in order to obtain consistent and reproducible results.SPECT imaging is not only capable of dyssynchrony evaluation but also allows simultaneous assessment of LV perfusion and function. In addition, it can assess myocardial scar location and severity for optimizing CRT in patients with heart failure.21 Additionally, patients with non-ischemic cardiomyopathy are more likely to be responders than those with ischemic cardiomyopathy.22 In the present study, the total defect size that reflects scar burden was significantly larger in the non-responder group. This finding is supported by Adelstein et al. and Sciagrà et al., who reported that patients with extensive resting perfusion defects had a limited clinical response to CRT.23 This may be explained by the direct correlation between LV scar and LV dyssynchrony. Samad et al. used SPECT imaging to show that the presence of LV scar and its extent were independent predictors of mechanical dyssynchrony.24 In addition, Ludwig et al. proposed that PSD values were increased by the presence of scar tissue.25Extensive scar tissue in the LV may hinder the response to CRT. Accordingly, patients with extensive scarring in the LV were less likely to be responders to CRT.27In the present study, the relationship between the scar and LV lead position had a significant impact on CRT response. Within the responder group, only 27% of patients had the LV lead concordant to the scarred area, while 80% of patients in the non-responder group had the lead concordant to the scarred area. This result was similar to the findings reported by Leyva et al. and Bleeker et al., who found that placing the LV lead away from the scar tissue gave clinically better results after implantation of CRT. This could be due to the fact that scar tissue could not respond or contract compared to non-scar tissue; therefore, placing the LV lead adjacent to scar tissue would result in an impaired response.30 In addition, a lower response in patients with NYHA class IV is similar to that reported by De Sisti et al., which could be attributed to the more adverse remodeling and higher baseline dyssynchrony in patients with NYHA class IV.31 The presence of LBBB morphology has been shown to be significantly higher in the responder group, which is commensurate with the guideline recommendations. In the present study, responders showed a significantly smaller heart (lower EDV and ESV) at baseline, which is supported by the findings reported by Azizian et al., who found that responders showed less dilatation in the LV than non-responders, although the difference was not statistically significant.14 In addition, significant reverse remodeling was observed in the responder group after CRT implantation compared to the non-responder group, consistent with the results of the study by Boogers et al.18It is noteworthy that other factors that influence the CRT response were demonstrated in the study. The responder group had a significantly higher proportion of female patients, NYHA III (rather than IV), non-ischemic etiology, LBBB morphology, and baseline smaller LV volumes. The higher female sex prevalence in the present study is consistent with the findings reported by Cheng et al., which is possibly explained by the greater rates of non-ischemic etiology and deaths from pump failure rather than sudden cardiac death in female patients.This study has some limitations that need to be reinforced by more specific larger studies in order to contribute to clinical practice. One of the limitations is the unfeasible application of multivariate analysis due to the small number of patients enrolled.In conclusion, SPECT represents a “one-stop shop” non-invasive imaging modality that has the potential to refine patient selection for CRT implantation and predict and optimize the CRT response. It not only enables assessment of mechanical dyssynchrony with reproducible indices but also allows for simultaneous assessment of LV perfusion and function. In addition, it can assess myocardial scar location and severity and guide placing of the LV lead adjacent to the gated SPECT-derived latest activation segment and away from the scarred area to achieve a better response.


Cardiotoxicity is a potential prognostically important complication of certain chemotherapeutic agents that may result in preclinical or overt clinical heart failure. In some cases, chemotherapy must be withheld when left ventricular (LV) systolic function becomes significantly impaired, to protect cardiac function at the expense of a change in the oncological treatment plan, leading to associated changes in oncological prognosis. Accordingly, patients receiving potentially cardiotoxic chemotherapy undergo routine surveillance before, during and following completion of therapy, usually with transthoracic echocardiography (TTE). Recent advancements in AI-based cardiac imaging reveal areas of promise but key challenges remain. There are ongoing questions as to whether the ability of AI to detect subtle changes in individual patients is at a level equivalent to manual analysis. This raises the question as to whether AI-based left ventricular strain analysis could provide a potential solution to left ventricular systolic function analysis in a manner equivocal to or superior to conventional assessment, in a real-world clinical service. AI based automated analyses may represent a potential solution for addressing the pressure of increasing echocardiographic demands within limited service-capacity healthcare systems, in addition to facilitating more accurate diagnoses.This clinical service evaluation aims to establish whether AI-automated analysis compared to conventional methods (1) is a feasible method for assessing LV-GLS and LVEF, (2) yields moderate to good correlation between the two approaches, and (3) would lead to different clinical recommendations with serial surveillance in a real-world clinical population.r = 0.541) in GLS between AI automated assessment compared to conventional methods. The LVEF quantification between methods demonstrated a strong correlation (r = 0.895). AI-generated GLS and LVEF values compared reasonably well with conventional methods, demonstrating a similar temporal pattern throughout echocardiographic surveillance. The apical-three chamber view demonstrated the lowest correlation (r = 0.423) and revealed to be least successful for acquisition of GLS and LVEF. Compared to conventional methodology, AI-automated analysis has a significantly lower feasibility rate, demonstrating a success rate of 14% (GLS) and 51% (LVEF).We observed a moderate correlation ( Cardiotoxicity is a significant, potential complication of certain chemotherapeutic agents that can lead to either preclinical or overt heart failure. In some cases, chemotherapy must be withheld when cardiac function, primarily left ventricular (LV) systolic function, becomes significantly impaired to protect cardiac function at the expense of a change in the oncological treatment plan and associated changes in prognosis . AccordiEchocardiographic indices such as left ventricular ejection fraction (LVEF) by Simpson's Biplane method has traditionally been used to assess changes in LV systolic function. However, in the modern era of speckle tracking echocardiography (STE), strain quantification has rapidly evolved into a valuable tool for the early detection of cardiotoxicity during oncological therapy and has since been incorporated into international guidance , 4.p < 0.0001); twenty-six patients  developed cardiotoxicity, and of these patients, 5  developed symptoms of heart failure (HF). Significant LVEF reduction (≥8%) was detected in 15% of patients that developed subsequent cardiotoxicity, whereas upon the application of strain analysis, the incidence rate increased to 78%. Among the patients that later developed HF, all had a reported GLS of less than −19%  has been the most studied strain parameter with the largest body of literature supporting its diagnostic and prognostic value , 6. One While strain quantification with speckle tracking echocardiography represents a sensitive method for assessing LV function, this postprocessing analysis remains laborious, time-consuming and is subject to significant inter- and intra-observer variability, related to reproducibility of contouring cardiac structure by manual and even semi-automated contouring. In recent years, the emergence of artificial intelligence (AI) in echocardiography has generated much interest among the cardiac imaging community. The technology is rapidly evolving but is yet to be widely adopted into clinical practice. Recent evidence has revealed promising findings, demonstrating that the application of AI enables data analysis free from human operator bias, accelerated workflow and quantification, along with high feasibility rate in the absence of operator input. One multicentre study which assessed LVEF and longitudinal strain using visual, manual and fully AI-automated-methods  reported a high feasibility 98%) of AI-automated assessment  and low bias of −1.4 ± 0.3% (p < 0.01) with an estimated level of agreement (LOA) of ±3.7% when comparing AI-automated vs. conventional methodology , suggesting that the application of AI is potentially comparable to human expert performance using conventional methodology  a feasible method for assessing LV-GLS and LVEF, (2) correlates well with conventional methods, and (3) whether AI analysis would lead to different clinical recommendations during serial surveillance in a real-world clinical population.This single-centre audit and service evaluation retrospectively reviewed all HER2 + breast cancer patients that underwent TTE surveillance and trastuzumab therapy between January 2019 and October 2022 at the Royal Wolverhampton NHS Trust (UK) and assessed the evaluation of cardiac function against international cardio-oncology guidance . Informed consent was not required due to the retrospective nature of the clinical audit and evaluation. Patients undergoing combination therapy including anthracycline were excluded from the study. Patients with atrial fibrillation or other form of arrhythmias during the echocardiographic studies were also excluded. To reflect real-world patient population and feasibility, patients with partially suboptimal endocardial border definition were not excluded. Clinical characteristics of our cohort were collected from the image reporting system and hospital records and are summarised in 648 TTE studies acquired from 142 oncology patients that received trastuzumab echocardiographic surveillance between 2019 and 2022 were retrospectively evaluated. All echocardiographic studies within our British Society of Echocardiography (BSE) accredited imaging laboratory were comprehensive studies which complied with BSE cardio-oncology guidelines. Echo imaging was performed by BSE accredited echocardiographers using commercial equipment .AI-automated and conventionally measured GLS and LVEF were assessed from standard apical four- (A4C), three- (A3C), and two-chamber (A2C) cine loops in accordance with BSE guidance.AI-automated assessments (GLS and LVEF) were performed on individual echocardiographic studies using an AI-based platform . The investigators submitted individual clinical studies required for analysis from the local hospital archiving system to the AI pipeline (Ultromics SaaS). Individual views are identified and classified with the existing convolutional neural network (CNN) model and subsequently processed by a U-Net based architecture for view-specific LV contouring, myocardial segmentation, and myocardial motion tracking to compute GLS and LVEF in the absence of manual adjustments .Conventional GLS assessment was performed in a semi-automated fashion from the apical four-, three- and two-chamber LV-focused cine images in dedicated conventional software . Upon detection of the endocardial border, the software automatically established a region of interest (ROI) and calculated the strain values of the selected view. The BSE-accredited or similarly experienced operator manually adjusted the ROI to optimise tracking if deemed necessary and strain values were recalculated to reflect this adjustment. Where image quality was insufficient to permit strain assessment of all three views, then a global strain value could not be calculated. Conventional LVEF was manually performed using the Simpson's biplane method of discs (Modified Simpson's rule) for LV volumes and LVEF calculation. End-diastole was defined as the frame following mitral valve closure or the frame in which the cardiac dimension is largest, in preference to the onset of the QRS. End-systole was defined as the frame preceding mitral valve opening or the time in the cardiac cycle in which the cardiac dimension is smallest, respectively. This protocol was performed using the LV-focused A4C and A2C views.n (%). Linear regression analysis was performed to evaluate the relationship between GLS and LVEF when assessed by either conventional or AI-automated methods. Bland-Altman analysis was used to assess the levels of agreement and quantify systemic differences between assessments. Comparison of mean values between the automated and conventional groups were performed using the paired sample student t-test. Analysis of variance (ANOVA) was used to compare the means of three of more groups. For all statistical tests performed, a p-value less than 0.05 was regarded as statistically significant. Statistical analyses were performed using IBM SPSS Statistics version 29 .Continuous variables were expressed as mean ± standard deviation and categorical variables were presented as The patient cohort included 142 patients which had undergone a total of 648 echocardiographic studies as part of their oncological therapy cardiac surveillance. The population comprised 140 females (99%), with mean age 59 ± 13 years (range 28–89 years). Oncological diagnoses predominantly comprised breast cancer (84%), but also included gastric (13%) and oesophageal cancer (3%). Patient demographic and clinical characteristics are summarised in AI-generated GLS and LVEF values were acquired in 14% and 51% of all studies, respectively. Representative examples of normal and abnormal GLS studies analysed by AI-generated and conventional assessment are shown in p = 0.028). Whilst the success rate of deriving longitudinal strain from the A3C via the conventional method was also low, the failure rate was superior to that of AI. Factors contributing to suboptimal image quality, particularly affecting the A3C, included challenging body composition, tachyarrhythmias, ectopy, limited rib space and previous mastectomy.Technical failure to derive strain from the A3C was therefore the main reason for the low rate of success in obtaining AI-generated GLS  and disagreement  with small biases (Mean GLS in whole cohort was −17.9 ± 2.2% (AI) vs. −19.1 ± 2.0% . Mean LVEF in the whole cohort was 61.6 ± 5.7% (AI) vs. 60.7 ± 4.9% . Linear regression and Bland-Altman analysis for GLS revealed moderate correlation  and A4C/A2C  strain  views for strain between AI-automated and conventional methods . The weakest correlation  and widest limits of agreement among each individual apical view were observed in the A3C view.Mean longitudinal strain values from specific apical views were −18.7 ± 2.9% and −19.0 ± 2.6% (A4C) ,B, −18.1 methods ,B. In cot-test. Conventional and AI-automated values followed a similar temporal pattern in patients receiving trastuzumab therapy for both GLS and LVEF irrespective of the cardiotoxic cohort or the total study population . At 12- (T4) and 15-months (T5), AI-automated values demonstrated improvements in GLS and LVEF. Similar trends were observed from the conventional method although the degree of improvement is shown to be smaller in LVEF at 15-months. There were no significant differences observed between the AI-automated and conventional methods for GLS. For LVEF, there was a significantly lower LVEF from the conventional method . Based on the GLS and LVEF criteria  and 51% (LVEF).While the introduction of speckle tracking has provided exciting opportunities in the field of cardiac imaging, its clinical application is rendered meritless if performed by unexperienced or suboptimally trained practitioners. Like any echocardiographic technique, there is a steep learning curve with performing and interpreting echocardiograms . InterprThere is emerging data suggesting that a fully automated AI assessment could potentially reduce post-processing time with high reproducibility and reduced risk imposed by human-software interaction. However, in the presence of significant knowledge gaps the technology may fall short of this potential. Presently, semi-automated assessments are in clinical use and accepted as a standard, feasible method for LV strain assessment, supported by evidence from numerous studies have supported the use of these methods –16. HoweFurthermore, research to date has rarely explored the application of AI-automated assessment in cancer therapy-related cardiac dysfunction but instead has largely focused on ischaemia-related cardiac abnormalities. Given that cancer therapy-induced heart failure carries a worse prognosis compared to heart failure related to other causes , the neeThe present findings reveal that the current version of AI-automated GLS possess some limitations in feasibility, achieving successful acquisition of GLS in only 14% of all studies. The higher rate of success demonstrated from conventional methods (38%) suggests either that the AI-automated approach is inferior to the semi-automated approach or that the semi-automated approach is overly generous in the studies to which it is applied. The unifying consideration here is that of a threshold for acceptability for an echo study to be amenable to either of the assessment methods. We speculate that the two approaches accept image qualities of different levels. Standardising this threshold is not necessarily a straight-forward proposition as even with a group of selected studies, the AI-automated system is using different approaches to strain assessment than in the semi-automated system.In either analysis approach, the acquisition of GLS requires the strain values of three individual apical views. The present study found that the A3C view was the most frequently limiting view followed by the A2C (46%) in preventing a GLS assessment. These findings are in keeping with a study by Kawakami et al. which examined the automated tracking quality in each individual LV segments . The stuIn contrast to previous studies that excluded echo studies where image quality were deemed substandard , the prePrevious validation studies , 14, 19 Although our reported values were lower compared to the literature, this may be influenced by the preselection of subjects with segments suited for assessment in previous studies. Our findings also demonstrated that serial monitoring of trastuzumab-treated oncology patients with AI-assisted technology to detect subtle changes in LVEF and GLS may be done with similar certainty to conventional assessment with the values generated from both methods being largely similar.A significant difference in LVEF was observed at one timepoint although this may be attributed to smaller sample size at the final follow-up. Further work will be required to assess longitudinal echocardiographic trends in addition to correlation between AI-automated and conventional analyses, and there may be systematic differences in absolute values whether related to the vendor or system used.In the cardiotoxic cohort, while the sample size was small, both methods demonstrated a similar temporal trend highlighting the potential for AI-automated methods to reliability detect LV functional deterioration. Such findings suggest that AI-automated LV assessments represent a valuable method of serial echocardiographic monitoring in longitudinal patient care and can build a case for future prospective studies in this area.There are a few potential limitations associated with the present analysis that deserves to be mentioned. First, we only studied patients in sinus rhythm, thus data could not be extrapolated from patients with irregular heart rhythms. Additionally, our study included a relatively small sample size. Despite this, our patient cohort included all patients during the study period to reflect a real-world clinical setting and is the first to study functional changes in this specific patient cohort, thereby providing valuable insight into the application of AI-automated analysis in serial echocardiographic studies in trastuzumab-treated patients. Our report and early insights thereby provide a basis for future studies to expand upon. Second, the potential vendor differences in AI-imaging software for strain and LVEF analysis due to differences in AI-algorithms should be noted. Third, is the lack of gold standard reference to compare our strain and EF measurements. However, the primary objective was to determine the level of correlation between AI-automated and conventional methods thus identifying the “true” reference value is of lesser significance. We therefore used the current clinically accepted semi-automated approach as the comparator. Finally, the analysis was conducted retrospectively which meant that it suffered from the inherent limitations of a restrospective study design. Nevertheless, this report describes a straightforward comparision of imaging as opposed to patient outcomes, thus selection bias is of lesser relevance.With increasing echocardiographic demands surpassing clinical capacity in the face of a shortage of echocardiographers, there is now an urgent need for the active incorporation of AI guided technology to assist, or potentially substitute the need for operator input into analysis of advanced echocardiographic techniques. Consequently, software solutions must possess the accuracy to where it could be confidently applied irrespective of the GLS experience of the operator. There are a number of challenges in the widespread clinical implementation of AI echocardiography, none of which are considered insurmountable.The future appears positive for the application of AI in echocardiography and significant advances are anticipated to address the current knowledge gaps. Future work should explore whether: (1) AI-based assessment is superior to less experienced humans, (2) image rejection threshold appropriateness, (3) accuracy and reproducibility of automated, semi-automated and manually generated data, and (4) improvements in post-processing time and overall workflow on echocardiography services.Despite enthusiasm for the application of AI technology in healthcare, it is yet to be widely embraced in the echocardiographic community. Due to significant limitations and knowledge gaps in automation, AI technology in echocardiography remains premature for clinical use if adopted completely independent of operator intervention. Instead, at present, it could be a useful unbiased “second opinion” for “experienced” practitioners. Our analysis is supportive of prospective studies into the utility and application of AI-based analysis of heart function by echocardiography in patients receiving potentially cardiotoxic chemotherapy.


This study aims at exploring biventricular remodelling and its implications for outcome in a representative patient cohort with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI).P = 0.001]. In contrast, LVGLS as well as the conventional parameters LV ejection fraction (LVEF) and RV fractional area change (RVFAC) did not differ (P = ns). Kaplan–Meier analyses indicated a reduced survival probability when RVGLS was below the −14.6% cutpoint (P < 0.001). Lower RVGLS was associated with higher mortality  independent of LVGLS, LVEF, RVFAC, and EuroSCORE II. Addition of RVGLS clearly improved the fitness of bivariable and multivariable models including LVGLS, LVEF, RVFAC, and EuroSCORE II with potential incremental value for mortality prediction. In contrast, LVGLS, LVEF, and RVFAC were not associated with mortality.Pre-interventional echocardiographic examinations of 100 patients with severe AS undergoing TAVI were assessed by speckle tracking echocardiography of both ventricles. Association with mortality was determined for right ventricular global longitudinal strain (RVGLS), RV free wall strain (RVFWS) and left ventricular global longitudinal strain (LVGLS). During a median follow-up of 1,367  days, 33 patients (33%) died. RVGLS was lower in non-survivors [−13.9% (−16.4 to −12.9)] than survivors [−17.1% (−20.2 to −15.2); In patients with severe AS undergoing TAVI, RVGLS but not LVGLS was reduced in non-survivors compared to survivors, differentiated non-survivors from survivors, was independently associated with mortality, and exhibited potential incremental value for outcome prediction. RVGLS appears to be more suitable than LVGLS for risk stratification in AS and timely valve replacement.  MyocCurrent guidelines recommend aortic valve replacement in severe symptomatic AS or in severe asymptomatic AS with associated LV systolic dysfunction defined as impaired LV ejection fraction (LVEF <50%) . The proS') have shown inconsistent results regarding outcome association in patients undergoing transcatheter aortic valve implantation (TAVI) , tricuspid annular plane systolic excursion (TAPSE), and RV lateral wall tissue velocity (n (TAVI) –23. Analn (TAVI) . Similarn (TAVI) .This study aims at exploring the role of RVGLS vs. LVGLS assessed by STE for outcome prediction in a representative patient cohort with severe AS undergoing TAVI.2.2.1.2 or indexed AVA <0.6 cm2/m2) undergoing TAVI between 2008 and 2019 were retrospectively identified from the prospective AS registry of the University Heart Center Zurich. Patients were included when a comprehensive echocardiographic examination was available within three months prior to TAVI allowing complete strain analysis of both ventricles. A flow diagram  examinations were performed using commercially available equipment . Echocardiographic measurements were made by certified specialists according to current recommendations –28. CalcTomTec ImageArena Cardiac Performance Analysis (Version 4.6) was used for offline STE measurements of both ventricles according to current recommendations , 27. EndApical 2- (A2C), 3- (A3C) and 4-chamber (A4C) views were used for measuring LVGLS. End-diastole was set at the last frame before mitral valve closure and end-systole at the last frame before aortic valve closure. LVGLS is indicated as average peak systolic strain based on the 16-segment model. Focused RV views were used for measuring RV strain . End-dia2.3.Reproducibility was tested on 15 echocardiographic examinations by two observers to investigate inter-observer agreement and repeated by the main observer with a difference of 3 months between the first and the second measurement to determine intra-observer agreement. Concordance correlation coefficient was used for assessing reproducibility (inter-observer agreement) and repeatability (intra-observer agreement). These results are reported in 2.4.The date of the echocardiography examination before TAVI  marks the date of study inclusion. The date of the TAVI procedure indicates the start of follow-up. All-cause mortality was defined as the primary endpoint. Patient survival status was evaluated through patient records and/or phone calls.2.5.pROC (version 1.18.0) package. Kaplan–Meier survival curves and log-rank tests of time-to-event data were analysed with the survminer (version 0.4.9) package; variables were either dichotomised at their optimal cutpoint according to the ROC curve or according to the literature. For some analyses, variables were divided into tertiles or quartiles. Association with all-cause mortality was analysed in uni- and multivariable Cox regression models. Proportional hazard assumptions were assessed for all models using the scaled Schoenfeld residuals. Variables with clinical relevance such as age, sex, EuroSCORE II, STS score, AS severity, LVEF, RVFAC were included in multivariable models regardless of their significance level in univariable models and tested for sensitivity. A further sensitivity analysis was performed excluding periprocedural deaths from the total number of events. Cox regression analysis of variance (Cox-ANOVA) was used to test model fit. The chi-squared (χ2) log-likelihood ratio and Harrell's C-statistic were used to examine the incremental value of predictors in the multivariable model compared to the nested univariable model. Collinearity between variables in the regression models was tested using Spearman's correlation and variance inflation factor tests. Standard mean difference (SMD) was used for determining the representativeness of the study cohort compared to the overall registry population. SMD values of 0.2, 0.5, and 0.8 are considered to represent small, medium, and large differences, respectively . Continuous variables were compared with the Mann–Whitney–Wilcoxon test, categorical variables with Fisher's exact test. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutpoint value for distinguishing survivors from non-survivors, and model discrimination was summarised by area under the curve (AUC). The AUC from models was compared with the DeLong method using ectively , 31. Sta3.3.1.N = 1,467; SMD 0.0–0.4; 3.2.RVFAC [40.5% (37.8–44.0)] and LVEF [58.5% (53.0–64.3)] were preserved among the study population. In contrast, longitudinal deformation of both ventricles was impaired (RVGLS [−16.5% (−19.8 to −13.8)]; RVFWS ; The concordance correlation coefficient for assessing intra- and inter-observer variability was each 0.8 for LVGLS, each 0.9 for RVGLS, and 0.9 and 0.8 for RVFWS, respectively .3.3.P = 0.001 and −15.7% [−18.3 to −12.8]; P = 0.002, respectively) compared to survivors , while LVGLS did not differ  and RVFWS  differentiated survivors from non-survivors, while that for LVGLS did not (P = 0.243). Kaplan–Meier analyses indicated a higher survival probability when the population was dichotomised according to the cutpoint value for RVGLS (P < 0.001) and for RVFWS .During a median follow-up time of 1,367  days, 33 patients (33%) died, of which 23 (23%) due to a cardiovascular cause. There was no significant difference in survival between women and men . Among tP = 0.003; ANOVA χ2 9.27; χ2P = 0.002] and RVFWS (data not shown) with an increased mortality risk, while this was not the case for LVGLS  or the conventional echocardiographic parameters ; rameters . BivariaP = 0.005] and RVFWS  were associated with mortality independent of LVGLS and EuroSCORE II. There was a significant interaction between RVGLS and LVGLS regarding the association with mortality . In contrast, RVFWS and LVGLS did not interact significantly in terms of association with mortality . The highest C-index [0.69 (0.58–0.80)] of the multivariable models was observed for the model containing RVFWS, LVGLS, their interaction, and the EuroSCORE II. However, this is no higher than the greatest univariable C-index and there were only small differences in C-index between the multivariable models. Finally, a sensitivity analysis was performed by replacing EuroSCORE II with either STS score, age and sex, or parameters defining AS severity , revealing most compelling results for models including EuroSCORE II (data not shown).A multivariable Cox regression analysis was performed to test for a possible interaction between LVGLS and RVGLS or RVFWS, respectively, with inclusion of EuroSCORE II to account for possible confounders . RVGLS [4.This study demonstrates that in patients with severe AS undergoing TAVI (1) RV strain was lower in non-survivors than survivors; (2) RV strain was associated with mortality after TAVI; (3) RV strain was an independent predictor of mortality; and (4) RV strain improved the fitness of bivariable and multivariable models with potential incremental value for association with mortality. In contrast, none of the LV parameters was associated with mortality nor useful for predicting outcome in this cohort.The present data indicate that RVGLS, but not LVGLS, is an independent predictor of mortality in patients with severe AS undergoing TAVI. Previous studies observed that pre-interventional RV strain plays a role in predicting outcomes in such patients , 23, 32.LVGLS almost invariably exhibited clearly reduced values in the present cohort, regardless of survival status during follow-up, and did not even tend to be associated with mortality. This observation is consistent with some reports , 37, 38,RVFAC, TAPSE, and LVEF were not associated with outcome in the present cohort, which is consistent with previous observations and emphasises that longitudinal deformation as well as other strain-derived parameters such as ventricular twist are much more sensitive tools for detecting ventricular remodelling , 18, 42.Timely assessment of RV longitudinal strain seems to be crucial for recognising the extent of myocardial remodelling in response to AS. Appropriate clinical decision-making early in the disease course may decrease the risk of irreversible myocardial damage and improve survival after aortic valve replacement.4.1.Assessment of RV systolic function is an integral part of every echocardiographic examination. RV strain is obtained from the RV focused apical view with little additional effort. However, care must be taken in the real-wold setting to ensure that all methodological requirements are met in order to perform a reliable deformation analysis. Impaired RV longitudinal strain indicates increased mortality in patients with severe AS after valve replacement and emerges as an important parameter to improve the prognostic understanding of these patients. Hence, RV longitudinal strain should be measured in patients with severe AS and its reduced values should promote the decision to replace the aortic valve for avoiding persistent cardiac remodelling and reduced outcome after intervention.4.2.This study is limited by its retrospective single-center design; however, the cohort is representative of a typical TAVI population and the number of patients included, although limited, is reasonable to address the research question. A selection bias cannot be excluded because inclusion criteria involved the quality of echocardiographic examinations as well as several additional parameters. Although multivariable models were generated, it cannot be excluded completely that unobserved confounding factors affected the results. The predictive performance, as measured by AUC, was greater for the parameters of interest than for EuroSCORE II, which contains several predictors important to understanding individual prognosis. Due to the limited amount of data, the EuroSCORE II was used as a single predictor and its individual components were not re-estimated with the data at hand, tipping the comparison in favor of the new parameters. More data on this population is needed to develop true clinical prediction models with limited risk of overfitting and performance overoptimism.5.In patients with severe AS undergoing TAVI, RV longitudinal strain was lower in non-survivors than survivors and independently associated with mortality after TAVI. RV longitudinal strain improved the fitness of clinical and echocardiographic models with potential incremental value for mortality prediction. LVGLS was not associated with mortality in the current dataset. Hence, RV longitudinal strain may be incorporated in risk stratification of patients with severe AS and trigger timely aortic valve replacement.


Objective This study is aimed to assess the prognostic value of diastolic left ventricular mechanical dyssynchrony (LVMD) measured by gated-single photon emission computed tomography (GSPECT) myocardial perfusion imaging (MPI) in post-myocardial infarction (MI).Subjects and Methods The study was conducted on 106 post-MI from January 2015 to January 2019. First, the indices of diastolic LVMD phase standard deviation (PSD) and histogram bandwidth (HBW) of post-MI were measured using the Cardiac Emory Toolbox. Subsequently, the post-MI patients were followed up, and the primary endpoint was major adverse cardiac events (MACEs). Finally, the prognostic value of dyssynchrony parameters for MACE was analyzed by the receiver-operating characteristics curve and survival analyses.Results With the cut-off values of 55.5 degrees of PSD, the sensitivity and specificity in prediction of MACE were 75% and 80.8%, with the cut-off values of 174.5 degrees of HBW, the sensitivity and specificity were 75% and 83.3% respectively. There was a significant difference of time to MACE between groups of PSD less than 55.5 degrees and more than 55.5 degrees. PSD, HBW, and left ventricle ejection fraction (LVEF) assessed on GSPECT were significant factors in the prediction of MACE.Conclusion Diastolic LVMD parameters of PSD and HBW derived from GSPECT are significant prognostic factors in predicting MACE in post-MI patients. Left ventricular mechanical dyssynchrony (LVMD) is defined as the disparity in regional contraction timing, which can be a cause of decreased ejection function. LVMD is a consequence of various cardiac diseases including coronary artery disease (CAD) and myocardial infarction (MI). The role of LVMD has been investigated for several decades and significant prognostic implications of LVMD were reported across a variety of diseases.Currently, advances in image processing software allow to assess diastolic LVMD on gated single photon emission computed tomography (GSPECT) myocardial perfusion imaging (MPI), which are supposed to be more objective than those on tissue Doppler imaging.The study was conducted on 106 post-MI patients who admitted to our institution from January 2015 to January 2019. MI was diagnosed according to the third universal definition of MIThe present study protocol was reviewed and approved by the Institutional Review Board of Central Military Hospital 108  and informed consent was obtained from each patient before being included in the study.99mTc-Sestamibi (0.31 mCi/kg). Electrocardiogram-gated images were obtained using eight frames/second. SPECT image was acquired using a step-and-shoot method for 30 seconds per step, with 6-degree interval. Images were reconstructed on 128 × 128 matrices. Raw data of rest MPI were processed using the Myovation Evolution software . Quantitative analyses of perfusion and LVEF were performed using the QPS/QGS 2012 software . Summed rest score (SRS) greater than 13 was defined as severe perfusion defect, and LVEF of 40% or less was defined as severely decreased LVEF.GSPECT MPI was performed using a dual-head gamma camera . A 2-day protocol was used to acquire stress  and rest MPI as described on the European Association of Nuclear Medicine guidelines.On GSPECT MPI, phase analysis was performed using the Emory Cardiac Toolbox  integrated on vendor-supplied analysis package  to derive diastolic LVMD as mentioned in a previous study.Post-MI patients were followed up within 12 months after discharging from hospital. Complete history taking, physical examination, laboratory test, and electrocardiogram were performed. The primary endpoint was major adverse cardiovascular event (MACE). Currently, MACE is defined as cardiac death, MI, and hospitalization due to heart failure.t-test. The optimal cut-off value, sensitivity, and specificity of each diastolic LVMD parameters for cardiac events prediction were calculated using receiver-operating characteristic (ROC) curve analysis, and diagnostic power was assessed using the area under the curve (AUC). Logistic regression analysis was used to determine the significant parameters of diastolic LVMD to predict MACE. Estimating for time to MACE was analyzed by using Kaplan–Meier methods. The significance threshold was set atp-value less than 0.05.Commercial software packages were used for statistical analysis . The relationship between PSD, HBW. and ejection fraction (EF), summed rest scored (SRS) in post-MI was evaluated using Student'sp < 0.001,The general characteristics of patient population are shown inp < 0.001) and AUC of PSD was 0.872  . Similarly, the significant difference in the mean time of MACE was seen between HBW of 174.5 or greater and less than 174.5 degrees . A representative case is shown inIn the ROC curve analysis for MACE prediction, AUC of HBW was 0.851  . The op 0.001) . The Ka 0.001) . The meOur study reported the relationship between diastolic LVMD and EF, SRS derived from GSPECT MPI. It has been reported that the more diastolic LVMD is seen with the more perfusion defect due to MI, and the size of myocardial perfusion defect is one of independent predictors for LVMD.This study showed the value of PSD and HBW as the predictors for MACE of post-MI patients. Diastolic LVMD could predict the outcome in heart failure patients undergoing CRT and it is associated with adverse outcomes in CAD patients.Our study evaluated the predictive value of diastolic LVMD assessed by GSPECT MPI in post-MI patients. Tian et al reported that PSD and HBW were not predictors of cardiac mortality in patients who underwent to GSPECT MPI 3 months after MI.Recently, GSPECT MPI became a more popular approach than before, and it can be easily used to assess diastolic LVMD in patients with heart failure and CAD. A few previous studies have showed that high PSD and HBW indicating diastolic LVMD on GSPECT MPI can assist the clinicians to select appropriate candidates for CRT and assess the treatment response.The limitation of this study is the time of follow-up was not long enough to estimate the overall survival. It was challenging to follow up the patients from different regions of country for long term because many patients could not be admitted to our hospital due to social distancing during the COVID-19 pandemic. In addition, the limited number of enrolling patients (106 post-MI patients) may impact the results of our study due to selection bias.Diastolic LVMD indices including PSD and HBW can be easily assessed by GSPECT MPI, and can be effective prognostic factors for predicting MACE.