In acute coronary syndrome (ACS) patients, restoring epicardial culprit vessel patency and flow with percutaneous coronary intervention or coronary artery bypass grafting has been the mainstay of treatment for decades. However, there is an emerging understanding of the crucial role of coronary microcirculation in predicting infarct burden and subsequent left ventricular remodelling, and the prognostic significance of coronary microvascular obstruction (MVO) in mortality and morbidity. This review will elucidate the multifaceted and interconnected pathophysiological processes which underpin MVO in ACS, and the various diagnostic modalities as well as challenges, with a particular focus on the invasive but specific and reproducible index of microcirculatory resistance (IMR). Unfortunately, a multitude of purported therapeutic strategies to address this unmet need in cardiovascular care, outlined in this review, have so far been disappointing with conflicting results and a lack of hard clinical end-point benefit. There are however a number of exciting and novel future prospects in this field that will be evaluated over the coming years in large adequately powered clinical trials, and this review will briefly appraise these. In patients presenting with an acute coronary syndrome (ACS), protective mechanical and pharmacological interventions are aimed at infarct size reduction, reperfusion of viable myocardium, and attenuation of necrosis leading to heart failure . Historip < 0.001) and MVO was the strongest predictor of MACE with incremental prognostic value over infarct size and LV ejection fraction [Advances in the treatment of STEMI patients has led to a progressive decline in mortality over several decades, with one-year cardiac mortality after primary PCI at 7–8% . Howeverfraction .The overwhelming evidence for the prognostic significance of MVO underpins the need for strategies to protect or restore coronary microcirculatory flow. To date, there has been a paucity of cardioprotective therapies targeting MVO. Moreover, the translation of potential strategies  into improved clinical outcomes has been disappointing due to difficulties with clinical trial design and a lack of hard clinical end-point benefit . In thisMVO is defined as the inability to reperfuse the coronary microcirculation (microvessels < 200 µm diameter) in a previously ischaemic myocardial territory, despite restoration of epicardial vessel patency. There are several interdependent mechanisms underlying MVO and myocardial injury , which aCoronary microvascular dysfunction (CMD) is a mismatch of myocardial blood supply and oxygen consumption due to coronary microvessel dysfunction and can occur with or without obstructive coronary artery disease (CAD) and/or myocardial diseases . The keyPre-existing CMD is often present in ACS patients before their index event, which can result in an increased risk of significant MVO and poor cardiovascular outcomes. Furthermore, pre-existent CMD likely represents an important pathological contributor of MVO, as studies have demonstrated that coronary flow is attenuated by up to 50% in non-culprit arteries during acute myocardial infarction (AMI), both before and after primary PCI, suggesting global rather than regional myocardial microcirculatory dysfunction . Indeed,Various genetic factors also play a role in modulating adenosine-induced vasodilatation and subsequent microcirculatory function. The 1976T.C polymorphism of the adenosine 2A receptors gene is related to a higher prevalence of MVO, and genetic variations in regions of the VEGFA and CDKN2B-AS1 genes have been associated with CMD. Patients with MVO also have a more compact fibrin network, suggesting a genetically mediated resistance to clot permeability and lysis .Ischaemic injury is a well-described mechanism for cardiomyocyte cell death, especially if the period of myocardial ischaemia lasts over 3 h in duration. Ischaemia to the microcirculation results in capillary damage, endothelial protrusions/blebs which occlude the capillary lumen, decreased endothelial nitric oxide synthase (eNOS) vasodilator release, and increased endothelin-1 vasoconstrictor release. Furthermore, ischaemia induces disruption of the endothelial glycocalyx barrier and destabilization of interendothelial cell junctions resulting in extravascular erythrocytes, adhesion and influx of inflammatory cells, and interstitial myocardial oedema which compresses capillaries and small arterioles, further reducing flow through these dysfunctional vessels in a vicious cycle ,3,16. IfAfter a prolonged period of ischaemia, reperfusion of the affected region potentiates further injury to the microvasculature. Reperfusion stimulates reactive oxygen species (ROS) production by mitochondria, which subsequently results in increased membrane permeability, calcium overload, endothelial swelling, and cell disruption. An influx of leucocytes, platelets, and neutrophil-platelet aggregates after reperfusion exacerbates vessel lumen obliteration, coronary microvascular constriction, oxidative stress injury, and release of proteolytic enzymes and pro-inflammatory mediators which drive further MVO ,2,3,16. Distal coronary microembolisation is the final key mechanism underpinning myocardial injury and MVO. The spontaneous or iatrogenic (PCI-induced) rupture of atherosclerotic epicardial plaque releases particulate debris which, together with superimposed microthrombi, embolises distally into the coronary microcirculation. This microvascular plugging by inflamed plaque fragments contributes to MVO (represented as the coronary no-reflow phenomenon), and subsequent peri-procedural MI. In STEMI, distal embolization of thrombotic microemboli and atherothrombotic debris has been increasingly recognised as an important mechanism contributing to coronary microcirculatory impairment. In an extensive microscopic examination of 25 cases of sudden death due to acute coronary thrombosis, Falk provided conclusive support for spontaneous, mainly thrombotic, distal embolization leading to occlusion of small intramyocardial arteries and microinfarctions . FurtherCoronary no-reflow describes the inability to reperfuse regions of previously ischaemic myocardium after the restoration of flow in the occluded coronary artery, and angiographically can be visualised as impaired penetration of contrast distally into the myocardium ,16. It iInflammatory activation is triggered by myocardial ischaemia and necrosis; mediating tissue healing, scar formation and ventricular remodelling, and serving as a potent contributor to cardiac MVO ,31. AfteThe diagnosis of MVO is made using both non-invasive and invasive tools, with incidence rates ranging from 10% angiographically to 60% using CMR . The disaAngiographyThrombolysis in myocardial infarction (TIMI) flow is a widely recognised angiographic visual scoring system from 0 to 3 grading epicardial coronary flow, ranging from no flow to complete antegrade flow to the distal vessel which is associated with less MVO, smaller infarct size, fewer MACE, and better survival ,16. AlthbCoronary physiologyd) multiplied by the hyperaemic Tmn (IMR = Pd × Tmn). IMR is an appealing diagnostic technique as it can be measured immediately during primary PCI and thereby identify high-risk patients requiring more intensive follow-up or early intervention with novel therapies targeting MVO and aimed at microvascular recovery. A meta-analysis found that IMR is significantly higher in patients with CMR-determined MVO [p < 0.01). IMR has also been shown to predict infarct size, 3-month echocardiographic wall motion score, and peak creatinine kinase and troponin levels better than TIMI grade or CFR [p = 0.027) and at three years  compared to those with IMR ≤ 40 [−1 s indicative of CMR-determined MVO  [Invasive assessments of coronary epicardial and microvascular function can be performed with an intracoronary sensor-tipped guidewire . Coronarined MVO . In STEMe or CFR ,52,53. IIMR ≤ 40 . HMV is ity 63%) . Althougity 63%) ,55, its ity 63%) .cIntracoronary ECGp = 0.005) on contrast-enhanced CMR assessed day 4 post-STEMI; as well as infarct size, non-viable mass, peak creatinine-kinase and left ventricular remodelling at 3 months post-STEMI.Intracoronary ECG has also been proposed as an early, simple and objective method of diagnosing MVO and predicting infarct zone recovery “real-time” during primary PCI, thereby identifying patients suitable for potential therapeutic interventions or careful follow-up . In a stAfter primary PCI, incomplete ST-elevation resolution has been related to MVO and portends a worse clinical outcome , althougMyocardial perfusion positron emission tomography (PET), based on radiotracers labelled with isotope-emitting positrons, represents a well-validated imaging modality for the identification of CMD with high diagnostic accuracy, temporal resolution, and sensitivity. Rest and stress PET allows for quantification of indices of microvascular dysfunction such as absolute myocardial blood flow (MBF), myocardial perfusion reserve , and coronary flow reserve  ,60. HybrFinally, CMR is the gold standard non-invasive diagnostic modality for MVO, allowing multislice imaging with high tissue contrast and spatial resolution, enabling quantification and localization of MVO and infarct size, as well as regional contractile function. On contrast-enhanced CMR, MVO is identified as a dark hypointense core (lack of gadolinium enhancement) during first pass <2 min) or after conventional late 10–15 min) gadolinium enhancement of the affected myocardium. First pass (early) MVO is more sensitive than late MVO to subtle microvascular injury, as the latter often underestimates severity. However, the prognostic utility of early MVO for the prediction of postinfarction MACE is lower, as late MVO represents severely disturbed microcirculation and hence correlates more strongly with worse outcomes [0–15 min  min or aOver the course of several years, many therapies have been trailed to prevent as well as treat MVO, and this represents an ongoing unmet need in interventional cardiology. However, unfortunately, there still exists no treatment which has convincingly demonstrated benefit in an adequately powered randomised control trial with clinical endpoints. Regardless, we will summarise various treatments which have been investigated as well as possible future directions in the field.Pre-clinical data has shown that third-generation beta-blockers  may reduce infarct size and protect the coronary microcirculation . IntraveSeveral studies have proposed that acute statin treatment may mitigate MVO via pleiotropic effects such as improvement in endothelial function, coronary microvascular dilatation, and anti-inflammatory and anti-thrombotic mechanisms. However, the evidence regarding this remains conflicting. Chronic ongoing statin therapy at the time of STEMI is associated with a lower rate of coronary no-reflow, and more favourable LV ejection fraction and ventricular remodelling . In 171 p = 0.009) but not TIMI flow grade and MBG  or MACE at 30 days  compared to placebo. At one-year follow-up, however, the adenosine cohort had reduced MACE and better LV remodelling compared to placebo or the nitroprusside arm. In contrast, however, the REFLO-STEMI trial [Adenosine is a potent direct vasodilator of the coronary microcirculation and also has a range of purported pleiotropic effects including anti-inflammatory properties against neutrophils, inhibition of platelet aggregation, antiapoptotic effects, and stimulation of angiogenesis . HoweverMI trial  of 247 SAtrial natriuretic peptide (ANP) suppresses endothelin-1 production and acts on the reperfusion injury salvage kinase (RISK) cardioprotective pathway which is involved in ischaemic preconditioning, thereby exerting possible favourable effects on MVO . In the p = 0.003) on CMR compared to controls, and this was further reinforced in a smaller study of 58 patients where the absolute mass of delayed hyperenhancement (suggestive of MVO on CMR) in exenatide-treated patients was significantly reduced compared to controls (p < 0.01) [p = 0.662) [Exenatide, a glucagon-like peptide-1 agonist, has been proposed to reduce infarct size and preserve cardiac function in pre-clinical models, by reducing myocardial apoptosis and oxidative stress. Unfortunately, human trials have been limited by conflicting results. In an initial study of 172 STEMI patients , the exe < 0.01) . However= 0.662) .p = 0.03) compared to later therapy in the catheterisation lab. The ON-TIME 2 trial [p = 0.03) measured with CMR at 30 days was reduced by bolus intracoronary abciximab delivered to the infarct lesion site compared to placebo. Finally, in AIDA STEMI [Current practise guidelines  recommen 2 trial  of 984 S 2 trial  of 452 aDA STEMI , the onlp = 0.002) [Experimental data has also examined the role of P2Y12 inhibitors in reducing MVO and infarct size when administered at the onset of reperfusion or earlier. In a small study of 84 STEMI patients who received upstream clopidogrel treatment prior to PCI, there was a significantly lower rate of MVO on CMR  . However= 0.002) . In the = 0.002) , pre-hos= 0.002)  of 110 S= 0.002) .p < 0.03) and less MVO (p = 0.05) in the therapy cohort. In the much larger POST trial of 700 STEMI patients, however, 4 cycles of 60-s angioplasty balloon inflation-deflation did not improve myocardial reperfusion (MBG), ST-elevation resolution, or MACE at 30 days [p = 0.66), or CMR-evaluated infarct size, myocardial salvage index, the extent of MVO, or LV ejection fraction at 3 months.Ischaemic conditioning, defined by either repeated brief episodes of mechanical ischaemia/reperfusion before PCI or at the onset of reperfusion, has been proposed as a cardioprotective therapy in several clinical studies, by increasing myocyte resistance to ischaemic injury. Post-conditioning refers to interrupted reperfusion with alternating brief coronary artery re-occlusion-reperfusion cycles. In a study of 118 STEMI patients, patients in the treatment arm demonstrated better ST-elevation resolution and smaller CMR-determined infarct size, but no difference in clinical outcomes at 15 months . In a tr 30 days . Finally 30 days , involvip = 0.03) and hence infarct size as assessed by myocardial perfusion imaging [p = 0.04) and heart failure  at over three years follow-up [p = 0.32), i.e., cardiac death or heart failure hospitalisation, at 12 months.On the other hand, remote ischaemic post-conditioning (RIPC), using several cycles of brief limb ischaemia and reperfusion, has shown some promise in smaller studies but not larger trials powered for hard outcomes. In the CONDI trial of 333 STEMI patients, four cycles of 5-min arm (blood pressure cuff) ischaemia alternating with reperfusion during ambulance transport pre-PCI improved myocardial salvage  and ST-elevation resolution  [p < 0.001) and ST-elevation resolution  [p = 0.009) for patients receiving aspiration thrombectomy [p < 0.0001), post-procedural MBG (p < 0.0001), less distal embolisation (p < 0.0001), and significant 30-day mortality benefit  [Initial smaller studies evaluating manual thrombus aspiration, purported to improve myocardial perfusion and attenuate MVO by reducing distal embolisation of atherothrombotic debris, showed promising results but this did not translate into a benefit in larger trials. In the small REMEDIA trial of 100 STEMI patients, manual aspiration improved MBG  . Similar< 0.001)  in the tmbectomy . In a me = 0.04) .p = 0.63), hospitalisation for recurrent myocardial infarction , or stent thrombosis  [p = 0.57), recurrent myocardial infarction hospitalisation , and stent thrombosis  [p = 0.86) but stroke within 30 days was higher in the thrombectomy arm compared to controls  [p = 0.043) and reduced MACE (p = 0.011) at 6 months [p = 0.008) and TIMI flow grade (p = 0.006) but not MBG (p = 0.81), mortality (p = 0.06) or MACE (p = 0.75) at 30 days.However, in the much larger TASTE trial of 7244 STEMI patients, there was no difference at 30 days between the aspiration thrombectomy arm and controls in all-cause mortality  . These f = 0.51) . Similar = 0.02) . On the 6 months . In the 6 months . Here, tbDeferred coronary stenting in STEMIp = 0.006) and intraprocedural thrombotic events (p = 0.01). Of the 52 patients randomised to deferred stenting, recurrent STEMI occurred in 2 patients before the planned second procedure. Myocardial salvage index at 6 months was also lower in the deferred cohort compared to controls (p = 0.031), but there was no difference in CMR-assessed MVO at two days (p = 0.155).Importantly, there has also been an examination of whether deferred stenting  might reduce no-reflow and salvage myocardium in high-risk STEMI patients, particularly in the DEFER-STEMI pilot trial . ComparicIntermittent Coronary Sinus Occlusionp < 0.001) and lower infarct size on CMR at 6 months  [Pressure-controlled intermittent coronary sinus occlusion (PICSO) has been proposed as a means of improving microvascular perfusion and reducing MVO, by redistributing venous blood to the border zone of ischaemic myocardium, thereby enhancing washout of injurious agents in the microcirculation and inducing the release of vascular endothelial growth factors . In the = 0.006) . There ip < 0.001), CFR  and TIMI frame count . In a subsequent larger study of 95 patients by the same authors [p < 0.001) and IMR  that correlated with reduction in infarct size  and improvement in left ventricular ejection fraction  at 6 months. However, another recent study of 76 anterior STEMI patients compared the effects of intracoronary tenecteplase to abciximab during primary PCI, and found better angiographic parameters including cTFC  and TIMI flow grade (p = 0.03) in the abciximab cohort two days later, as well as no difference in infarct size on CMR at four months follow-up (p = 0.33) [p = 0.32) or 10-mg and placebo . Interestingly, higher prothrombin concentrations in the alteplase group suggested that the undesired procoagulant effect of fibrinolytic therapy via thrombin activation may have contributed to microvascular thrombosis, especially in patients with inadequate therapeutic anticoagulation with unfractionated heparin.There is a growing body of evidence supporting the hypothesis that intracoronary thrombolysis improves microvascular perfusion in STEMI patients, by induction of fibrinolysis and inhibition of red cell and platelet aggregation contributing to MVO. In a landmark study, 41 STEMI patients were randomized to low-dose intracoronary streptokinase (STK) (250 kU) immediately post-PCI or no additional therapy . Intraco authors , patient = 0.33) ,117. Fur = 0.33) , was stowww.clinicaltrials.gov; Unique Identifier NCT02894138) of 80 patients  and the RESTORE-MI trial  of up to 800 patients (IMR > 32 randomised to low-dose tenecteplase or placebo). In RESTORE-MI, a large phase 3 double-blinded placebo-controlled multicentre randomised trial, initially 243 patients will be recruited in a 1:1:1 fashion  as part of a dose-finding and cardiac MRI study to evaluate infarct size at 6 months. Subsequently, after determining the optimal tenecteplase dose with a significant infarct size reduction but no substantial predisposition to adverse events such as bleeding, a larger study of 800 randomised patients (with IMR > 32 post-PCI) will aim to determine whether low-dose tenecteplase improves cardiovascular mortality and heart failure rehospitalisation at 24 months compared to placebo.Two ongoing trials will stratify enrolment and patient selection based on IMR after primary PCI, hoping to identify the specific STEMI patient population most at risk of clinically significant MVO and therefore most likely to derive benefit from putative therapies. These two trials are the OPTIMAL study  and “no-flow” area (p < 0.05) in the ischaemic region, reduced infarct size (p < 0.001) after 3 h of reperfusion, and ameliorated LV remodelling (p < 0.05) [It is well established that NETs are induced during ischaemia-reperfusion and distal microembolisation post-PCI and correlate with infarct size ,28, and  < 0.05) . FurtherITF-1697 is a C-reactive protein-derived tetrapeptide which, based on pre-clinical studies, was proposed to reduce reperfusion injury to hence MVO. However, in a randomised dose-finding study of 402 patients undergoing primary PCI, there was no difference in TIMI flow, cTFC, MBG, ST-elevation resolution, enzymatic infarct size, or clinical outcome between the placebo or treated patients . Enhancep = 0.021) over median 3.7 years follow-up, and there was a dose-dependent reduction in heart failure hospitalisation and heart failure-related mortality (p = 0.037) [p = 0.046) or heart failure hospitalisation (p = 0.011), although again there was no data with respect to MVO.A multitude of anti-inflammatory therapies have also been evaluated in patients with ACS, but despite early encouraging results in pre-clinical models, to date, none have convincingly demonstrated attenuation of MVO . IL-1 in= 0.037) , althoug= 0.037) ,125. In = 0.037) , anakinrp = 0.15), but there was a lower incidence of heart failure  and a possible favourable effect in early anterior STEMI patients (p < 0.05) on subgroup analysis, but these need further confirmation in larger trials.The CHILL-MI study of 120 STEMI patients aimed to evaluate the cardioprotective effects of hypothermia using a combination of cold saline rapid infusion and endovascular cooling starting pre-PCI and up to 1 h after reperfusion . Here, tp = 0.04), indicating amelioration of oxidative stress, but no difference in CMR-determined infarct size (p = 0.73) versus placebo [Emerging data suggest that severe MVO and IMH post-PCI, with residual myocardial iron deposition, can lead to ongoing inflammation and adverse LV remodelling. Experimental studies suggest deferoxamine iron chelation may limit ROS generation, and hence reduce ischaemia-reperfusion injury and subsequent infarct size. In a small study of 60 STEMI patients, however, there was a significant reduction in plasma F(2)-isoprostane levels post-PCI in the treated cohort  in patients undergoing PCI will aim to determine whether temanogrel is a safe and effective treatment of MVO, with the primary outcome being a change in IMR.Finally, temanogrel is an investigational selective 5-HT2A receptor inverse agonist designed to inhibit serotonin-mediated amplification of platelet aggregation and vasoconstriction. The upcoming ARENA study (The crucial role of the microcirculation in determining short-term and long-term prognostic clinical outcomes after an ACS is manifest in the literature and continues to emerge as an untapped frontier for potential future therapies. Unfortunately, efforts to date aimed at improving outcomes in patients with MVO have been met with limited success, most likely because it is a multifactorial process with several interdependent underlying pathophysiological mechanisms. There is clearly an unmet need to develop novel strategies to maintain or restore microvascular perfusion in ACS patients, and these strategies require further investigation in large well-powered clinical trials with hard endpoints.


Aims: Left ventricular global longitudinal strain (GLS) by cardiac magnetic resonance feature tracking (CMR-FT) analysis has shown an incremental prognostic value compared to classical parameters in non-ischemic dilated cardiomyopathy (NICM). However, less is known about the role of right ventricular (RV) GLS. Our objective was to evaluate the prognostic impact of RV-GLS by CMR-FT analysis in a population of NICM patients.Methods: In this multicenter study, we examined NICM patients evaluated with a comprehensive CMR-FT study. Major cardiac events (MACEs) were considered as the study primary outcome measure and were defined as a composite of (a) cardiovascular death, (b) cardiac transplant or destination therapy ventricular assist device, (c) hospitalization for life-threatening ventricular arrhythmias or implantable cardiac defibrillator appropriate intervention. Heart failure (HF) related events, including hospitalizations and life-threatening arrhythmia-related events were considered as secondary end-points. Receiver operating time-dependent analysis were used to calculate the possible additional effect of RV-GLS to standard evaluation.Results: We consecutively enrolled 273 patients. During a median follow-up of 39 months, 41 patients (15%) experienced MACEs. RV-GLS and LV late gadolinium emerged as the strongest prognostic CMR-FT variables: their association provided an estimated 3-year MACEs rate of 29%. The addition of RV-GLS significantly improved the prognostic accuracy in predicting MACEs with respect to the standard evaluation including LGE . On competing risk analysis, RV-GLS showed a significant ability to reclassify overall both HF-related and life-threatening arrhythmia-related events, regardless of LV and RV ejection fraction.Conclusions: In NICM patients, RV-GLS showed a significant prognostic role in reclassifying the risk of MACEs, incremental with respect to standard evaluation with standard prognostic parameters. The implementation of prognostic stratification in non-ischemic dilated cardiomyopathy (NICM) is a demanding issue in clinical practice . NICM paWe retrospectively analyzed all the consecutive patients with a diagnosis of NICM based on current international criteria , with anAll the available and readable ECGs were systematically and retrospectively analyzed by three clinicians . The ECG analysis was performed according to the main important acknowledged parameters and measured by standardized measurements .Declaration of Helsinki . All cine images were acquired using a balanced, steady-state, free precession (SSFP) sequence during an expiratory breath-hold. Short-axis cine images from cardiac base to apex, and long-axis cine images in 2-, 3-, and 4-chamber views were obtained using the following scan parameters: TE/TR/flip-angle = 1.5 ms/3.0 ms/60°, slice thickness = 8 mm, gap = 2 mm (Intera); TE/TR/flip-angle = 1.0 ms/2.3 ms/60°, slice thickness = 8 mm, gap = 2 mm (Magnetom Avanto). LGE imaging was carried out using a standard LGE technique: two-dimensional segmented breath-held fast low-angle shot inversion recovery sequences  were applied 10–15 min after contrast agent intravenous administration (gadopentate (Gd-DTPA) or gadobenate dimeglumine  in the same views of the cine images; inversion times were adjusted to null normal myocardium using Look-Locker sequence. To exclude artifacts, images were repeated in 2 separate phase-encoding directions.All post processing analysis were performed using CVi42® software . Ventricular volumes and systolic function were measured by planimetry of endocardial borders, on short-axis cine images, excluding papillary muscles from the myocardium. LV end-diastolic volume (EDV), LV end-systolic volume (ESV), RVEDV, and RVESV were calculated by summation of these images (“Simpson's rule”). LV mass was calculated by subtracting endocardial from epicardial volume at end-diastole and multiplying by 1.05 g/cm3. Ventricular volumes and LV mass were indexed to body surface area. The LVEF and RVEF were calculated by dividing the stroke volume (EDV minus ESV) by the EDV of the respective ventricle . LV focaFor LV short- and long-axis FT analysis, a modified 16-segment LV model derived from the standard American Heart Association 17-segment model was applied omitting the apical cap. An expert operator manually delineated LV endocardial and epicardial borders in all standard cine SSFP short- and long-axis images, with the initial contour set at end-diastole. Values of 2D longitudinal, circumferential and radial peak strain were calculated. For RV strain analysis, we used the 4-chambers view to determine peak global longitudinal strain and 3 short-axis views  for global radial and circumferential strain . EndocarMajor cardiovascular events (MACEs) were considered as the study primary outcome measure and were defined as a composite of: (a) cardiovascular death, (b) cardiac transplant or destination therapy ventricular assist device for end-stage heart failure (HF), (c) hospitalization for life-threatening ventricular arrhythmias or implanted cardioverter defibrillator appropriate intervention on sustained ventricular tachycardia >185 beats per minute or ventricular fibrillation . Seconda2) or Fisher exact test for dichotomous variables, as appropriate. The linear correlation between LVEF-LVGLS, RVEF-RVGLS, LVGLS-RVGLS and LVEF-RVEF was evaluated by means of Pearson's Correlation Coefficient. Kaplan-Meier survival curves and cumulative incidence curves (considering the competing risk of death) were estimated to evaluate the possible association of the considered CMR variables with respect to time to the primary outcome measures and secondary outcome measures, respectively. In the absence of established cut-off values for LV-GLS and RV-GLS at CMR-FT analysis from the literature, median values of our study cohort were used as a cut-off in order to visually compare survival curves and cumulative incidences. Conversely, recognized cut-offs from the literature were used for LVEF and RVEF. Log-rank test and Gray tests were used to assess differences across groups . Cross-validation was used to choose the optimal value for the tuning parameter lambda1 of the penalized ML estimation. Since it is not possible to estimate the standard errors of the regression coefficients from the penalized estimation (Continuous variables were expressed as median and interquartile range (IQR) . Differences between two groups were compared using Mann-Whitney U test for continuous variables and the chi-square  and R statistical software version 3.3.2 , libraries “cmprsk,” “coxphf” and “timeROC.”Finally, we compared the predictive performance of these models in terms of time-dependent ROC curves, that estimates a AUC suitable for censored data . Interobp = 0.001; RV-GLS −15.8% vs. −20%, p = <0.001 respectively. Finally, we found moderate to strong correlations between the major CMR variables  followed for a median follow-up of 39 months (IQR 20-71). During follow-up, 49 MACEs occurred: 10 cardiovascular deaths (nine due to HF and one sudden cardiac death), 16 cardiac transplants, four VAD implantations, 15 appropriate ICD interventions, and four hospitalizations due to life-threatening arrhythmias. Because only the first event was censored, 41 MACEs  were eligible for statistical analysis. No other cause of death other than cardiovascular were found in the present population. Finally, 44 patients were hospitalized due to HF during follow-up. ariables .At CMR-FT evaluation, we found that LGE, LV end-diastolic volume, LVEF, RVEF, LV-GLS and RV-GLS were all associated to MACEs, as shown at univariable analysis . Multivap = 0.03 vs. model (a); model (c), including model (b) plus the RV-GLS as a continuous variable, further increased the AUC to 0.76 (0.66–0.86), p = 0.03 vs. model (b) , the “clinical model,” showed the prognostic power of NYHA class III-IV and sinus rhythm , the “clinical model” plus LGE, increased the AUC to 0.71 (0.61–0.82), odel (b) .Consistently with multivariable analysis, RV-GLS >-19.1%  was significantly associated to higher rates of MACEs, independently to RVEF and LVEF. Of note, LV-GLS did not show the same prognostic value .The simultaneous presence of LGE and RV-GLS >-19.1% was associated to particularly poor outcomes (estimated 3-year and 5-year MACEs rate of 29% and 37% respectively). On the contrary, patients without LGE and with preserved RV-GLS (<-19.1%) showed. a very good prognosis, with an estimated 3-year and 5-year MACEs rate of 1% .Concerning secondary outcomes measures, RV-GLS >-19.1% was associated to higher rates of cardiovascular mortality, HF-related events, and life-threatening arrhythmia-related events. Therefore, RV-GLS was capable of predicting also individual components of MACEs . MoreoveAll the ICC for CMR-FT measurements and RVEF are reported in The present study shows for the first time an independent prognostic role of FT-derived RV-GLS, when added to standard clinical parameters and comprehensive CMR evaluation, in a large cohort of Caucasian NICM patients: in Our population included “recently onset NICM patients”  and allowed us to explore the possible prognostic impact of RV function (and in particular RV-GLS) over the LV function in the initial, crucial phases of the medical treatment in NICM patients. In fact, RV improvements under therapy might be faster than LV reverse remodeling, as previously suggested , and migThe prognostic impact of RV-GLS emerged in predicting the MACEs, independently from LVEF, RVEF and respect its counterpart LV-GLS , and botCompared to standard clinical and CMR features, the possible additive significance of RV strain was widely unexplored, despite RV dysfunction is a known prognostic tool in NICM, when measured by RVEF . DespiteRV is a crescent-shaped structure. Traditionally, RV is divided in 3 anatomical regions: (1) inlet; (2) apex; (3) outlet. The thin RV free wall is histologically arranged in two main layers, the superficial  and a more represented subendocardial sheet . Physiologically, RV function is preload-based. It guarantees a nearly constant stroke volume streamlining blood flow in a low impedance circulation. RV stroke volume is generated by the coupling with the LV (20–40%) and by intrinsic RV contraction which, probably due to the predominantly longitudinal architecture, is mainly developed by vertical shortening . This asMany contributors may lead to RV dysfunction (RVD) in NICM: (1) LV dysfunction; (2) pressure overload due to pulmonary hypertension; (3) mitral regurgitation; (4) the cardiomyopathic process itself. On the other hand, given the strict ventricular interdependence, RVD might further impair LV function thereby aggravating prognosis of NICM patients , 28.Despite CMR is recognized as the gold standard technique for RV systolic function assessment, tissue deformation analysis might identify subtle RV dysfunction, undetectable by RVEF . This haRV-GLS was demonstrated to be a prognostic feature in our NICM population, independently from LV function, measured by both LVEF and LV-GLS , 31. TheGiven its ability to detect myocardial scar tissue, the presence of LGE is currently recognized as the most powerful CMR prognostic finding in NICM , 4, 33. This study suffers by the common referral and inclusion biases of retrospective observational studies. Despite the study population is the largest NICM population in which RV-GLS prognostic impact has been evaluated during an adequate follow-up period, the present results cannot be generalized to all NICM patients. Furthermore, an external validation is cohort might be required to confirm the hypothesis generated by our model regarding the use of RV-GLS in clinical practice. The results of internal validation  only partially overcome this limit. To date, Feature Tracking RV GLS is not validated because of the lack of large studies based on this method. We assessed reproducibility between high-trained expert in cardiovascular imaging and the results were consistent and reliable. However in future, large studies are needed to confirm these data and to compare CMR data to echocardiographic data. Important variables were not routinely performed, with a high rate of missing values, especially regarding NTproBNP, which could not be used for analysis. Also, some CMR data were not systematically available in both centers, such as both atrial volumes. Although CMR is crucial for NICM assessment, it was not performed in all the patients who eventually received a diagnosis of NICM in the two centers involved, especially in the first years of enrollment period. This, however, is a real-world limitation and the present results highlight how the availability of this methodic should be further implemented. LGE has been treated as a categorical variable since its quantification is not definitely validated in literature. Despite the penalized multivariable procedure adopted, multivariable analysis results should be used as hypothesis generating, due to the limited number of events. Furthermore, due to the retrospective nature of the study, multivariable analysis has not been performed for secondary endpoints. We acknowledge that ICD appropriate interventions do not always correspond to SCD, however they have been considered in the MACEs and in the arrhythmia-related end-points due to the relevance of this event in the natural history of the disease, as previously reported . Even thIn recently-onset NICM patients, FT-derived RV-GLS impairment emerges as strongly associated with MACEs. Given this, RV-GLS appears to be a promising tool able to further re-classify patient's risk independently from LVEF, RVEF and LV-GLS and potentially incremental if compared to LGE. Furthermore, RV-GLS might be a tool for implementing the prediction of arrhythmia- and HF-related events in patients with LVEF >35% and of HF-related events in patients with LVEF <35%. In conclusion, a comprehensive CMR-FT study, always complementary to an advanced systolic and diastolic echocardiographic evaluation, should be systematically performed in patients with NICM, including RV-GLS, in order to globally improve the prognostic stratification and therapeutic management of this population.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Institutional Ethical Boards of Trieste and Padua Cardiovascular Departments. The patients/participants provided their written informed consent to participate in this study.MC: conception and design of paper, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript. ACi and MMe: design of the analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript. GB: statistical analysis. GV, MMa, MB, LP, MAC, ACa, MD, and BG: analysis and interpretation of data and drafting of the manuscript. CB, DS, and SI: critical revision of the manuscript. GS and MP: drafting of the manuscript and critical revision of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: The objective was to evaluate the normal value of left ventricular myocardial strain using the computed tomography feature-tracking technique and to explore the correlation between myocardial strains and cardiac function parameters. Methods: Participants suspected of coronary heart disease were selected from 17 August 2020 to 5 November 2020 to undergo coronary computed tomography angiography using a third-generation dual-source CT scanner. Data were imported into a commercial software (Medis) after multiphase reconstruction. The cardiac function parameters, radial (Err), circumferential (Ecc), and longitudinal strain (Ell) of the left ventricle were recorded. Results: A total of 87 normal subjects were enrolled, including 41 males and 46 females. For healthy subjects, the global radial strain (GRS), circumferential strain (GCS), and longitudinal strain (GLS) of the left ventricle were 74.5 ± 15.2%, −22.7 ± 3.0%, and −26.6 ± 3.2%, respectively. The Err and Ecc absolute values (|Ecc|) were the largest at the apex, and the |Ell| gradually increased from the base to the apex. The Err and |Ecc| were the largest in the lateral and inferior wall, respectively. |Ell| showed a clockwise decrease from the lateral wall in the short axis. Meanwhile, the GRS and |GLS| in females were higher than that in males. Multiple linear regression analysis showed that both SV and LVEF were the independent determinants of GRS, GCS, and GLS. BMI and CO were the independent determined factors of GCS. Conclusions: At a reasonable radiation dose, CT feature-tracking is a feasible and reproducible method to analyze left ventricular myocardial strain. Left ventricular myocardial strain in normal subjects varies in gender, segments, levels, and regions. Myocardial strain is defined as heart deformation during the systolic process, including radial strain (Err), circumferential strain (Ecc), and longitudinal strain (Ell) . FeatureTherefore, this study evaluates the normal values of the left ventricular myocardium strain by FT-CT. In addition, the correlations between myocardial strain and cardiac function parameters, gender, and age are analyzed to explore the feasibility and repeatability of the application of this technique, which could provide an important reference for clinical research and applications.An ethics committee institution of Tongji Medical College of Huazhong University of Science and Technology approved the study. People suspected of coronary heart disease (CAD) underwent coronary computed tomography angiography (CCTA) from 17 August 2020 to 5 November 2020, from which normal cases without coronary artery abnormality were selected. The exclusion criteria based on history were as follows: (1) electrocardiogram (ECG) abnormalities 2 weeks before the CT examination ; (2) coronary heart disease, cardiomyopathy, valvular heart disease, and other cardiovascular diseases; (3) history of revascularization; (4) history of hypertension, diabetes, or dyslipidemia. The exclusion criteria based on cardiac CT reports were as follows: (1) coronary artery calcification score >0; (2) coronary artery stenosis (≥1% lumen stenosis); (3) poor cardiac CT image quality.CT was performed using a Siemens third-generation dual-source CT scanner . Participants were trained to inhale and hold their breath before the examination. Retrospectively, the ECG-gated coronary computed tomography angiography (CCTA) scanning parameters were as follows: detector collimation 192 × 0.6 mm, gantry rotation time 0.25 s/r, pitch 0.15, and slice 0.75 mm. Automatic tube voltage technology  and intelligent tube current scanning technology  were used to automatically determine tube voltage and current. The reference tube voltage range was 100 kv, and reference tube current was 350 mAs. According to the weight of subjects, a total of 30–60 mL iopromide  was injected into the median cubital vein, followed by diluted contrast and a saline flush. Diluted contrast was mixed saline solution with a ratio of 2:8, and the injection rate was 2–4 mL/s. The monitored region of interest was placed at the aortic root, and the trigger threshold of coronary artery CTA automatic scanning was set at 100 HU. When the density within the region of interest reached the threshold, scanning was automatically triggered, and the scanning time was 5–6 s. Twenty phases were reconstructed in 5% steps of the RR interval within the full window. The data constructive section thickness was 0.75 mm, the increment was 0.5 mm, the reconstruction kernel was Bv40, and the model-based iterative reconstruction  was at a strength level of 3. The effective radiation dose was 4.0 ± 1.4 mSv (range: 1.9–6.7 mSv), equal to DLP (dose-length product) multiplied by 0.014.The 20-phase images were imported to a commercial software package  to analyze the myocardial strain. Based on the American Heart Association 16-segment model for the left ventricle, the left ventricular basal, middle, and apex segments were selected for strain analysis. The end-diastole and -systole of the left ventricle was determined on the short- and long-axis sections, and the endocardial and epicardial borders were manually delineated, respectively. The deformation of myocardial movement was obtained by automatically tracking the continuous contour of the endocardial and epicardial borders throughout the cardiac cycle. In addition, the parameters of cardiac function were recorded, including the left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), stroke volume (SV), cardiac output (CO), left ventricular ejection fraction (LVEF), and global and regional segment myocardial strain. The anterior wall of the left ventricle included segments 1, 2, 6, 7, 8, 12, and 13. The septal wall of the left ventricle included segments 2, 3, 8, 9, and 14. The inferior wall included segments 3, 4, 5, 9, 10, 11, and 15. The lateral wall included segments 5, 6, 11, 12, and 16. The Err and Ecc were measured in the short axis of the heart, and the Ell was an average value measured in the long axis  of the heart .Thirteen subjects were randomly selected from the study’s total sample. The myocardial strain was measured independently by two radiologists with more than 5 years of experience in the diagnosis of cardiovascular diseases. In addition, one observer measured the myocardial strain after 2 weeks. The inter-observer and intra-observer interclass correlation coefficients (ICCs) of the global radial strain (GRS), global circumferential strain (GCS), and global longitudinal strain (GLS) were calculated separately to assess repeatability.t-tests were used to compare two groups of normally distributed variables. One-way analysis of variance was used to compare multiple groups. Furthermore, Bonferroni and Tamhanes were used for post-hoc comparisons between the two groups. Pearson’s and Spearman correlation coefficients were implemented for evaluating correlations between continuous variables as appropriate. In addition, multivariable linear regression was further used to analyze the relationship between the parameters and myocardial strain. Finally, repeatability between observers was evaluated with 13 randomly selected patients using ICCs. p < 0.05 (two-tailed) was considered statistically significant.Statistical analysis was performed using SPSS v21.0. The normality of the distributions for all continuous variables was tested using the Shapiro-Wilk test. The normal distribution data were described as the means ± standard deviation, whereas the non-normally distribution data were expressed as medians (interquartile ranges) and categorical variables were expressed as frequencies (percentages), respectively. Independent sample student’s p < 0.05). Cardiac function parameters, including LVEDV, LVESV, SV, LVEF, CO, and heart rate (HR), did not differ between the sexes, respectively (p > 0.05)  .In this study, 4176 strain values of myocardial segments were measured. After excluding segments with poor image quality and abnormal local myocardial strain due to severe myocardial bridge, 4134 values were statistically analyzed. The global and segment myocardial strain values of the left ventricle are shown in The myocardial strain in different parts of the left ventricle is shown in The myocardial strain in different ventricular walls of the left ventricle is shown in p < 0.05; GLS: (−27.3 ± 2.6)% vs. (−25.8 ± 3.6)%, p < 0.05; GCS: (−23.0 ± 3.1)% vs. (−22.3 ± 2.9)%, p = 0.286). The differences in myocardial strain on segment and region of the left ventricle in gender are shown in There were differences in the left ventricular GRS, GLS, and GCS based on the gender of the participant . The GRSp < 0.05). While GCS and GLS were negatively correlated with age respectively . GCS and GLS were significantly positively correlated with BMI respectively . In addition, LVEDV and LVESV were negatively correlated with age , respectively. There was no significant difference in the GRS, GCS, and GLS among all age groups  and significantly positively correlated with LVEF . GCS was significantly positively correlated with LVESV  and significantly negatively correlated with SV, LVEF, and CO . There was a significantly negative correlation with GLS, SV, and LVEF .The correlation between left ventricular myocardial strains and left ventricular function parameters is shown in p = 0.004; GCS: β = −0.115, p < 0.001; GLS: β = −0.14, p = 0.003) and LVEF  were the independent determinants of GRS, GCS, and GLS. The GRS of females was 8.174% higher than males, and the GLS was −1.653% lower than males. BMI  and CO  were the independent determined factors of GCS.Furthermore, univariate and multivariate regression analysis for global myocardial strains and clinical indicators and cardiac function parameters are shown in The ICC values in the intra-observer analysis were 0.575, 0.900, and 0.891 for GRS, GCS, and GLS, respectively. Finally, the ICCs were 0.325, 0.853, and 0.787 for GRS, GCS, and GLS, respectively, in the inter-observer analysis .It is important to understand the normal global structural and functional parameters of the left ventricle, which is the basis for evaluating cardiovascular diseases. Furthermore, it is worth applying a measurement technique in the research of reference values, as this helps the timely clinical discovery of abnormalities, diagnosis, and treatment.The normal values of the left ventricular myocardial strains quantified by FT-CT reveal significant differences in gender and segments and correlate with clinical characteristics and left ventricular function. This study shows that the GRS, GCS, and CLS of the left ventricle were 74.5 ± 15.2%, −22.7 ± 3.01%, and −26.6 ± 3.2%, respectively, in healthy individuals. The absolute values measured by FT-CT were higher than the normal values measured by Cao  and Liu Our study shows that there were differences in the three short axes of the left ventricular regional myocardial strains. The Err and Ecc of the left ventricle were the highest in the apex and lowest in the middle, which agrees with the results of Ecc measured by Taylor  using FTIn addition, significant differences in regional myocardial strains were observed among different segments and walls of the left ventricle, which agrees with previous studies ,15,16. TIt has been reported that left ventricular myocardial strains partly differ between genders and age groups in healthy subjects ,10,19. TIn addition, this study found a significant positive correlation between GRS and age, and a negative correlation between LVEDV, LVESV, and age. The literature shows that with increasing age, LVEDV shrinks significantly and myocardial mass decreases, leading to a significant increase in the left ventricular (LV) mass/LVEDV ratio. Then, LV remodeling occurs, with an increase in myocardial stiffness and a decrease in compliance and diastolic function, which results in a compensatory thickening of the LV myocardium during systole, eventually leading to the increase of GRS . MeanwhiAnother significant positive correlation was revealed between left ventricular GCS, GLS, and BMI in healthy individuals, and similar results have not been reported in the literature. Whether GCS and GLS based on cardiac CT can become early warning indicators to quantify the health status of obese people remains to be studied.In this study, GCS and GLS had good intra-observer and inter-observer reproducibility, and GRS measurements were less stable. The poor reproducibility of the radial parameters may be caused by the quantification of the radial strain, which depends on the simultaneous motion of the endocardium and epicardium. Furthermore, the density contrast at the epicardial border is less pronounced than at the endocardial border. Moreover, there are more myocardial trabeculae in the apical region. The compression and drainage of blood from the trabeculae at the end of systole alter the voxel appearance in this region, making accurate tracking challenging . FinallyThis study has some limitations. First, it is a single-center, single-race study. Therefore, the sample size of males and females were unequal, and there is a possibility that some gender differences were magnified or inadequately detected. Considering the limited overall sample size and the number of samples from youth and elderly groups, the results of myocardial strain between groups stratified by age may require further analysis by expanding the sample size. Second, this study did not perform a concordance test between myocardial strain measured using CT FT techniques and other imaging techniques. However, previous studies have shown good concordance between CT FT techniques, ultrasound speckle-tracking techniques, and FT-CMR to assess myocardial strain in patients with cardiovascular disease. Lastly, the radiation dose was relatively high due to the use of a retrospective electrocardiogram gated scan. However, we used techniques (CarekV and CareDose) to reduce the radiation dose and ensure a one-stop evaluation of coronary anatomy and myocardial strains at a comparable dose. In addition, compared with the radiation dose described by the authors of  and the Conclusively, using the CT FT technique to assess left ventricular myocardial strain in healthy individuals is feasible and reproducible. In the future, the overall sample size can be increased to quantify the reference values of LV myocardial strain in different age groups. Furthermore, given the rapidity and convenience of CT examination, using CT to quantitatively assess myocardial strain differences by gender and segment should improve the quantitative diagnosis of cardiovascular diseases, such as coronary heart disease and cardiomyopathy.


Embora se saiba que a fração de ejeção (FE) do ventrículo esquerdo (VE) medida por eletrocardiograma seja preservada em pacientes com acromegalia, não há informação suficiente sobre deformação longitudinal global e deformação do átrio esquerdo (SLG-VE e SAE). O objetivo deste estudo foi avaliar as funções do ventrículo esquerdo (VE) e do átrio esquerdo (AE) por ecocardiograma strain (ES) em pacientes com acromegalia. Este estudo incluiu 50 pacientes com acromegalia na forma ativa da doença e 50 controles saudáveis com idade, sexo e área de superfície corporal similares. Além dos ecocardiogramas de rotina, medições de SLG-VE e SAE foram realizadas com o ES.2 de aumento no nível de IMVE aumenta a probabilidade de redução de SLG-VE em 6%. Os valores dos SAE e SLG-VE foram significativamente mais baixos em pacientes com acromegalia . Na análise bivariada, a pressão arterial sistólica, o pró-hormônio N-terminal do peptídeo natriurético cerebral, o fator de crescimento semelhante à insulina tipo 1, e detectou-se que os níveis de IMVE tinham correlação positiva com SAE e SLG-VE . O nível de IGF-1 tinha forte correlação com SAE e SLG-VE ; 48% dos pacientes com acromegalia têm SLG-VE reduzido (<20%). O índice de massa do ventrículo esquerdo (IMVE) determina independentemente a presença de SLG-VE reduzido, e cada 1g/m Embora a fração de ejeção de VE seja normal em pacientes com acromegalia, os valores de SAE e SLG-VE são significativamente mais baixos. Além do aumento em IMVE, outro achado do envolvimento cardíaco pode ser a redução de SAE e SLG-VE. Portanto, além do ecocardiograma de rotina, SAE e SLG-VE podem ser úteis para avaliar os sinais iniciais de envolvimento cardíaco antes da ocorrência de alterações cardíacas irreversíveis. Os parâmetros de deformação do átrio esquerdo (AE) e deformação longitudinal global do ventrículo esquerdo (SLG-VE) demonstraram estar fortemente correlacionados às funções sistólicas do AE e do VE em cenários clínicos diferentes, respectivamente.8 Demonstrou-se que muitos pacientes com fração de ejeção de VE (FEVE) normal têm redução da função sistólica do VE com o uso do SLG-VE.10Strain é uma medida de deformação em relação a uma potência em uma substância. Ele é definido em dimensões radiais, circunferenciais e longitudinais. A avaliação da deformação miocárdica por ecocardiograma strain (ES), em termos de um ecocardiograma de rastreamento de manchas bidimensional (2D-STE) ou imagem por Doppler tecidual  pode oferecer informações incomparáveis sobre as funções ventriculares regionais e globais.14 Recentemente, um número limitado de estudos avaliou a deformação de AE e SLG-VE em pacientes com acromegalia e FEVE preservada.8 Foram obtidos resultados contraditórios nesses estudos. Detectou-se, em dois estudos conduzidos pelos mesmos autores, a redução do SLG-VE;9 enquanto outro estudo relatou que o SLG-VE era semelhante ao dos pacientes de controle saudáveis.5 A avaliação das medidas de deformação do AE em pacientes com acromegalia foi realizada com 3D-STE em um estudo; entretanto, não se obtiveram informações claras sobre a alteração da deformação global no AE.8Em pacientes com acromegalia, a função sistólica é avaliada com FEVE. Entretanto, deficiências em FEVE só são vistas em etapas posteriores da doença e na minoria dos pacientes.Devido à viabilidade de medições simultâneas da deformação de AE e SLG-VE, além do ecocardiograma tradicional, este estudo teve o objetivo de avaliar as funções do VE e do AE com ES em pacientes com acromegalia ativa e FEVE preservada.1 A remissão da acromegalia foi definida como um GH sérico suprimido por glicose abaixo de 0,38 μg/litro (<1 mU/litro), um GH sérico abaixo de 1,9 μg/litro(<5 mU/litro), e IGF-1 normal para a idade.1 Pacientes com histórico de doença arterial coronariana (DAC) e infarto do miocárdio, arritmia cardíaca, insuficiência cardíaca sistólica ou FEVE <50%, doença de válvula cardíaca, embolia pulmonar, disfunção da tireoide, gravidez (comprovada ou suspeita), malignidade, e disfunção renal e hepática, e pacientes que se recusaram a participar do estudo não foram incluídos. O comitê de ética local aprovou o protocolo do estudo , e foi obtido o consentimento informado por escrito de cada um dos participantes.Neste estudo transversal, 50 pacientes  com acromegalia ativa  e idade, sexo, índice de massa corporal (IMC) e área de superfície corporal (ASC) correspondentes a 50 pacientes de controle saudáveis . Pacientes acima dos 18 anos de idade com acromegalia ativa foram cadastrados no estudo. Os pacientes incluídos no estudo são apresentados no fluxograma   . InformApós a avaliação do histórico médico detalhado e um exame físico completo, as características de linha de base dos pacientes, incluindo idade, sexo, hipertensão (HT), diabetes mellitus (DM), hiperlipidemia, tabagismo atual, histórico familiar de doenças cardíacas e medicamentos, foram registradas para todos os pacientes. Os parâmetros de IMC e ASC dos participantes foram calculados.Os níveis de glicose, nitrogênio ureico sanguíneo, creatinina, colesterol total, colesterol de lipoproteína de baixa densidade, colesterol de lipoproteína de alta densidade, triglicérides, aspartato aminotransferase, alanina aminotransferase, leucócitos, hemoglobina, proteína C-reativa sensível alta, e peptídeo natruriético pró-cérebro N-terminal (NT-proBNP) foram medidos utilizando-se um analisador químico automático  com os kits comerciais apropriados (Abbott). O GH sérico foi avaliado por um analisador químico automático  utilizando-se os kits comerciais apropriados (Abbott) e o valor de referência do GH estava entre 0,014 -5,219 ng/ml. O IGF-1 sérico total foi avaliado por um analisador químico automático  utilizando-se os kits comerciais apropriados (Abbott) e o valor de referência do IGF-1 varia de acordo com idade e sexo. Os níveis de GH e IGF-1 foram medidos ao mesmo tempo do exame ecocardiográfico para cada um dos sujeitos.American Society of Echocardiography (Sociedade Americana de Ecocardiografia).15 O diâmetro diastólico do VE, o diâmetro sistólico do VE, a espessura do septo interventricular (SIV), a espessura da parede posterior (PP), e o diâmetro diastólico do AE foram medidos a partir da imagem do eixo longo paraesternal de janelas de imagem bidimensionais. A fórmula de Devereux foi utilizada para a medição da massa do VE.16 Em seguida, o índice de massa do VE (IMVE) foi calculado dividindo-se a massa do VE pela ASC. O valor do IMVE >115 gr/m2em homens e >95 gr/m2 em mulheres foram considerados hipertrofia do VE.17A avaliação ecocardiográfica foi feita utilizando-se um transdutor de 2,5-3,5 MHz EPIQ 7C . A avaliação ecocardiográfica foi realizada durante a primeira semana para pacientes que atenderam aos critérios de inclusão. Avaliações ecocardiográficas de todos os pacientes foram realizadas em posição de decúbito lateral esquerdo com monitoramento de pressão arterial e eletrocardiográfico. Todas as imagens foram obtidas em pelo menos 3 ciclos repetitivos do eixo paraesternal longo e curto padrão, cortes apicais de 4 câmaras, de 5 câmaras, e 2 câmaras de acordo com as sugestões da European Society of Cardiology (Sociedade Europeia de Cardiologia).18 Segmentos com qualidade de imagem insuficiente e ciclos cardíacos contendo batimentos prematuros foram excluídos das medições.No procedimento de ES, todos os pacientes tinham ritmo sinusal normal. Os parâmetros de deformação miocárdica de AE e VE foram calculados utilizando-se STE sobre imagens em escala de cinza bidimensionais. Foram registradas imagens apicais de 4 câmaras (A4C), apicais de 2 câmaras (A2C) e apicais de 3 câmaras (A3C) em escala de cinza bidimensionais após a expiração após prender o fôlego. Pelo menos três ciclos cardíacos foram registrados para cada imagem, e prestou-se atenção para se considerar pelo menos 60-80 fps, de acordo com as diretrizes da O software QLAB versão 10.5  foi utilizado para as análises de VE e AE. O software seguiu automaticamente os movimentos da parede durante todo o ciclo cardíaco após o endocárdio do VE ter sido marcado quadro a quadro pelo método de desenho manual  nas imagens bidimensionais. Os valores de SLG-VE foram calculados a partir das imagens com 2D-STE. Após a marcação manual de 2 partes basais e 1 parte apical do VE, as bordas endocárdicas restantes foram automaticamente marcadas pelo software e a borda epicárdica apropriada também foi automaticamente desenhada. Quando os contornos de VE desenhados automaticamente não eram adequados para análise, as bordas foram corrigidas manualmente para permitir uma análise adequada. Após a análise, o software dividiu os registros de A2C, A3C, A4C do VE em modelos de seis segmentos, e o modelo de 18 segmentos foi usado para calcular o SLG-VE   .19 Foram obtidas imagens do AE em corte de quatro câmeras utilizando-se marcos anatômicos-padrão para garantir a aquisição ideal e evitar o encurtamento com ecocardiograma bidimensional convencional, em índices de quadros relativamente altos (60–80 fps). O contorno endocárdico do AE foi iniciado na borda endocárdica do anel mitral até a borda endocárdica do AE, extrapolando pelas veias pulmonares, e/ou orifícios de apêndices de AE, até o anel mitral oposto por um radiologista experiente, cego em relação às informações clínicas. O software então gerou automaticamente uma silhueta de AE epicárdica, que delineou uma região de interesse em cada um dos cortes apicais. O ajuste manual da região de interesse foi permitido para incluir toda a camada miocárdica do AE, seguido de um rastreamento segmentar automático. Após o rastreamento, os índices de deformação do AE, tais como da deformação longitudinal e suas primeiras curvas SR de derivação foram obtidas a partir de uma vista apical de quatro câmaras.20 Utilizamos uma onda R como ponto de partida (ligação R-R) para análise da deformação. A deformação longitudinal e as curvas de índice de deformação foram geradas em todos os segmentos, e a média dos segmentos foi calculada para os pontos de tempo correspondentes . Os dados foram expressos como média ± DP para variáveis contínuas e porcentagens para variáveis categóricas. O teste de Shapiro-Wilk foi utilizado para testar a normalidade e um p-valor >0,05 foi definido como dado normalmente distribuído. Variáveis contínuas que apresentaram distribuição normal foram comparadas utilizando-se o teste T de Student e ANOVA, enquanto o teste U de Mann-Whitney e o teste de Kruskal-Wallis foram usados para amostras não distribuídas normalmente. Variáveis categóricas e frequências foram comparadas pelo teste Qui-quadrado. A significância estatística foi definida como um p-valor <0,05 para todas as comparações. Neste estudo, os parâmetros que foram diferentes em pacientes com <20% para SLG-VE foram encontrados em análise univariada. Portanto, retroativamente: A análise de regressão logística (RL) foi realizada para se determinar os parâmetros que determinaram de forma independente pacientes com SLG-VE <20%. As correlações de Pearson e Spearman foram usadas para examinar a relação entre variáveis contínuas. Variáveis com um p-valor <0,05 na análise bivariada foram testadas na análise de regressão linear. Os resultados foram expressos como p-valor e razão de risco (RR) no IC de 95%.Foram incluídos no estudo cinquenta e oito pacientes com acromegalia ativa. Foram excluídos do estudo oito pacientes que atenderam aos critérios de exclusão e que não puderam realizar o exame ecocardiográfico ideal. Dos pacientes incluídos no estudo, 45 eram pacientes recorrentes de acromegalia. Dos demais pacientes, três eram pacientes pós-cirurgia sem remissão, e dois estavam fazendo tratamento médico sem remissão. Os dados do estudo foram divididos em dois grupos, com e sem acromegalia (pacientes de controle saudáveis). Os coeficientes kappa de Cohen que avaliaram a variabilidade interobservador e intraobservador estavam acima de 90% de todas as medições de ecocardiogramas.Quando os dados demográficos foram comparados entre os grupos do estudo: idade, sexo, IMC e ASC eram semelhantes entre os grupos. Determinou-se que a frequência de HT e DM em pacientes com acromegalia era de 28% e 32%, respectivamente. Em termos de parâmetros clínicos, as pressões arteriais sistólica e diastólica, e a frequência cardíaca eram mais altas em pacientes com acromegalia. Identificou-se que os níveis de glicemia plasmática, NT-proBNP, IGF-1 e hormônio de crescimento eram significativamente mais altos em pacientes com acromegalia. Parâmetros de outros laboratórios eram semelhantes entre os dois grupos   .Identificou-se que os valores de SIV, espessura diastólica final da PP, e IMVE eram significativamente mais altos em pacientes com acromegalia   . Determ2 x 94,6 gr/m2 e p <0,008). Na análise de regressão logística multivariada, detectou-se que o valor de IMVE e os níveis de IGF-1 fazem a previsão independente do valor de SLG-VE reduzido . De acordo com essa análise, cada aumento de 1 gr/m2 no valor de IMVE e cada aumento de 1 ng/dL nos níveis de IGF-1 aumenta a probabilidade de diminuição de SLG-VE em 6% e 5,6%, respectivamente.Quando o valor limite foi tomado como <20% para SLG-VE, detectou-se que os níveis de SLG-VE eram reduzidos em 48% do grupo com acromegalia. Quando os dados demográficos, clínicos e laboratoriais de pacientes com acromegalia SLG-VE normal e reduzida foram comparados, determinou-se que pacientes com SLG-VE baixo tinham índices mais altos de HT  e valores mais altos de IMVE .25 A doença consiste em 3 fases: i) aumento da contratilidade do VE e do ventrículo direito (VD) e HVE acompanhado do aumento da IGF-1, ii) disfunção diastólica resultante de redução da elasticidade do VE, iii) aparência típica de cardiomiopatia com dilatação do VE e diminuição de FEVE.26 A diminuição de FEVE e dilatação do VE, que são o terceiro estágio da doença, são vistas apenas em 1 a 10% dos pacientes com acromegalia.14 Entretanto, é importante avaliar as funções do VE desses pacientes com um novo método diagnóstico já desde o estágio 1, antes da ocorrência de alterações cardíacas irreversíveis.A acromegalia é uma das causas secundárias do HT. A HT e a DM são comuns nesses pacientes devido aos efeitos metabólicos da doença.30 A mortalidade cardiovascular aumenta em pacientes com acromegalia.2 Foi demonstrado que os valores de SLG-VE reduzidos estão associados a morte súbita cardíaca e arritmia potencialmente fatal.31 O fato de que o ES é facilmente acessível e barato dá uma vantagem importante em relação aos outros métodos. Entretanto, a limitação mais importante é que a qualidade da imagem deve ser muito boa. Embora o ES seja usado frequentemente para a avaliação inicial das funções do VE; nos últimos anos, muitos estudos avaliaram as funções do AE com ecocardiograma strain.4A avaliação da função sistólica do VE com SLG-VE é relativamente nova e ainda não é muito comum. O SLG-VE é mais utilizado para avaliar o envolvimento cardíaco subclínico ou silencioso de doenças sistêmicas com FEVE normal.7 O primeiro estudo foi realizado por Volschan et al.5 , em 2017, em 37 pacientes com acromegalia ativa, e detectou-se que o valor de SLG-VE não variou nem aumentou sem significância estatística em comparação aos pacientes de controle. Em outro estudo realizado em 2018, relatou-se que houve uma diminuição no valor do SLG-VE nos pacientes com acromegalia e essa situação estava relacionada a HVE.7 Em outro estudo, realizado e publicado muito recentemente pelos mesmos autores, relatou-se que o SLG-VE era reduzido em pacientes com acromegalia, da mesma forma que o estudo anterior.6 Este estudo corrobora dois estudos que demonstram que o valor de SLG-VE é reduzido em pacientes com acromegalia. Além dos estudos anteriores, também demonstramos uma redução significativa no SLG-AE no mesmo grupo de pacientes. O valor de corte para o SLG-VE reduzido foi aceito como <20%.15 Neste estudo, 48% dos pacientes com acromegalia ficavam <20%. Em outras palavras, as funções sistólicas do VE de metade dos pacientes deste estudo com acromegalia estavam comprometidas. Identificou-se que o IMVE e o IGF-1 tinham uma forte associação com o SLG-VE reduzido em pacientes com acromegalia.7 Os níveis de GH e IGF-1 sérico não estavam relacionados em pacientes com SLG-VE reduzido nos mesmos estudos.7 Neste estudo, assim como no estudo anterior, identificou-se que o IMVE previa pacientes com SLG-VE reduzido. Além disso, os níveis de IGF-1 estavam significativamente relacionados ao SLG-VE reduzido. Neste estudo, identificou-se que cada aumento de 1 gr/m2 de IMVE aumentava o risco de SLG-VE reduzido em 6%. Além disso, cada aumento de 1 ng/dL nos níveis de IGF-1 aumenta a probabilidade de diminuição de SLG-VE em 5,6%. O IMVE, que é o achado mais objetivo do envolvimento cardíaco em pacientes com acromegalia, também é o parâmetro mais proximamente associado ao SLG-VE reduzido. Portanto, a intervenção de HT, DM e IMVE o mais cedo possível pode ser a forma mais lógica de retardar a disfunção sistólica futura em pacientes com acromegalia.Vários estudos avaliaram o SLG-VE em pacientes com acromegalia e FEVE normal e foram obtidos resultados contraditórios.28 Determinou-se que a frequência de HT e DM em pacientes com acromegalia era de 28% e 32%, respectivamente. A prevalência de HT foi significativamente mais alta em pacientes com SLG-VE reduzido. Isso indica que o SLG-VE é afetado pela presença de HT. O segundo mecanismo pode ser a heterotrofia do VE e fibrose miocárdica devido ao aumento do IGF-1 em pacientes com acromegalia sem HT e DM.25 O aumento do valor de IGF-1 pode estar associado à atividade da doença e envolvimento cardíaco. Neste estudo, o nível de IGF-1, que era um dos parâmetros mais importantes da atividade da doença acromegalia, tinha uma forte correlação com o SLG-VE.O SLG-VE comprometido em pacientes com acromegalia pode ser explicado por dois mecanismos fisiopatológicos. O primeiro é o efeito de HT e DM. A redução do SLG-VE foi demonstrada anteriormente com os efeitos cardíacos de HT e DM mesmo no período assintomático antes de qualquer doença CV.32 Em um estudo anterior, relatou-se que o volume e as funções mecânicas do AE eram semelhantes aos dos pacientes de controle saudáveis e os níveis de GH e IGF-1 séricos não foram associados à função mecânica do AE em pacientes com acromegalia.32 Em outro estudo recente, um aumento no volume do AE foi relatado em pacientes com acromegalia.8 Em nosso estudo, o volume do AE ainda não foi avaliado, mas o diâmetro diastólico do AE era aumentado em pacientes com acromegalia.Há dados limitados sobre a função e o tamanho do AE em pacientes com acromegalia.8 Kormanyos et al.8 relataram uma redução nos valores de deformação segmentar médios e globais, e uma redução no valor de deformação circunferencial de AE. Um achado semelhante foi demonstrado para o átrio direito em outro estudo pelos mesmos autores.33 Relatou-se que o nível de IGF-1 e o valor de deformação circunferencial do AE tinham uma correlação positiva.8 Nosso estudo foi o primeiro a demonstrar a redução do SAE e sua correlação forte e positiva com o IGF-1, que é um dos parâmetros de atividade da doença.Embora não haja estudos na literatura avaliando o SAE com 2D-STE em pacientes com acromegalia, as imagens da deformação de AE foram realizadas em apenas um estudo com 3D-STE.1 Entretanto, os prognósticos não foram avaliados. Além disso, o efeito do tratamento de SLG-VE e SAE não foi avaliado devido à ausência de um acompanhamento. Neste estudo, não tivemos informações sobre o insight fisiopatológico do SLG-VE reduzido devido à ausência de avaliação histopatológica com biópsia miocárdica. A apneia do sono é comum em pacientes com acromegalia,1 e tem um efeito adverso nas funções de VE. Entretanto, não foi possível fazer a polissonografia em todos os pacientes. Os tipos de envolvimento cardíaco mais importantes são HVE e fibrose miocárdica em pacientes com acromegalia. A fibrose miocárdica é mais bem avaliada por imagens por ressonância magnética cardíaca. Se tivesse sido possível realizar as imagens por ressonância magnética cardíaca, teria sido possível avaliar a associação entre realce tardio pelo gadolínio e SLG-VE e SLG-AE. A disfunção diastólica também era comum  em pacientes com acromegalia.34 Portanto, não avaliamos a disfunção diastólica nesses grupos de pacientes.Como um estudo não randomizado de centro único, esta coorte de pacientes pode ser diferente da de outros centros. O tamanho da amostra é relativamente pequeno e os resultados do estudo precisam ser confirmados ensaios prospectivos multicêntricos grandes no futuro. A mortalidade e a morbidade cardiovasculares são altas em pacientes com acromegalia.8 Neste estudo, foram medidos apenas o diâmetro do VE e o diâmetro diastólico final do AE. Se o índice de volume do AE e do VE também tivesse sido medido, poderia haver alterações, especialmente nos parâmetros relacionados a SLG-AE.Estudos anteriores demonstraram que o volume do VE e do AE e o índice de volume aumentou em pacientes com acromegalia.Embora a FEVE seja normal em pacientes com acromegalia, SAE e SLG-VE detectados com 2D-STE são significativamente reduzidos e têm uma relação próxima aos níveis de IGF-1 plasmático. Além do aumento em IMVE, outro achado do envolvimento cardíaco pode ser a redução de SAE e SLG-VE. Portanto, além do ecocardiograma de rotina, SAE e SLG-VE podem ser úteis para avaliar os sinais iniciais de envolvimento cardíaco antes da ocorrência de alterações cardíacas irreversíveis em pacientes com acromegalia. 1 Chronic high IGF-1 levels cause specific structural and functional changes.1 If left untreated, it causes mortality, and the most common cause of mortality is cardiovascular (CV) diseases.2Acromegaly is a chronic disease characterized by increased Insulin-like growth factor 1 (IGF-1) synthesis in the liver due to a growth hormone (GH) secreting pituitary adenoma, and excessive protein synthesis and excess tissue growth due to these hormones.3 Deformation imaging can even detect minimal functional changes and provides early stage diagnosis. Left atrium (LA) deformation parameters and left ventricular global longitudinal strain (LV-GLS) have proven to be strongly correlated with LA and LV systolic functions in different clinical scenarios, respectively.8 It has been demonstrated that many patients with normal LV ejection fraction (LVEF) have reduced LV systolic function with the use of LV-GLS.10Strain is a measure of deformation against a power in a matter. It is defined in radial, circumferential, and longitudinal dimensions. Assessment of myocardial deformation by strain echocardiography (SE), in terms of two-dimensional speckle tracking echocardiography (2D-STE) or tissue Doppler imaging , can provide peerless information on both regional and global ventricular functions.14 Recently, a limited number of studies have evaluated LV-GLS and LA strain in patients with acromegaly and preserved LVEF.8 Contradictory results were obtained in these studies. LV-GLS was found to be decreased in two studies conducted by the same authors;9 whereas, another study reported LV-GLS to be similar to healthy controls.5 Evaluation of LA deformation measures in patients with acromegaly with 3D-STE have been performed in a study; however, no clear information was provided regarding the change in global LA strain.8In patients with acromegaly, systolic function is evaluated with LVEF. However, impairment in LVEF is only seen in the later stages of the disease and in the minority of patients.Due to the feasibility of simultaneous measurements of LA deformation and LV-GLS, in addition to traditional echocardiography, this study aimed to evaluate the LV and LA functions with SE in patients with active acromegaly and preserved LVEF.1 Remission of acromegaly was defined as a normal glucose-suppressed serum GH less than 0.38 μg/liter (<1 mU/liter), a serum GH less than 1.9 μg/liter (<5 mU/liter), and a normal IGF-1 for age.1 Patients with a history of coronary artery disease (CAD) and myocardial infarction, cardiac arrhythmia, systolic heart failure or LVEF <50%, heart valve disease, pulmonary embolism, thyroid dysfunction, pregnancy (known or suspected), active malignancy, and kidney and liver dysfunction, as well as patients who refused to participate in the study were not included in the study. The local ethics committee approved the study protocol , and written informed consent was taken from each participant.In this cross-sectional study, 50 patients  with active acromegaly  and age, gender, body mass index (BMI), and body surface area (BSA) matched with 50 healthy controls . Patients aged over 18 years with active acromegaly were enrolled in the study. The patients included in the study are shown in the flow-chart   . CurrenAfter the assessment of detailed medical history and a complete physical examination, the baseline characteristics of the patients, including age, sex, hypertension (HT), diabetes mellitus (DM), hyperlipidemia, current smoking status, family history of cardiac disease, and medications were recorded for all patients. Participants’ BMI and BSA parameters were calculated.Glucose, blood urea nitrogen, creatinine, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglyceride, aspartate aminotransferase, alanine aminotransferase, white blood cells, hemoglobin, high sensitive C reactive protein, and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured using an automated chemistry analyzer  with appropriate commercial kits (Abbott). Serum GH was assessed by an automated chemistry analyzer , using appropriate commercial kits (Abbott) and reference value of GH was between 0.014 -5.219 ng/ml. The serum total IGF-1 level was assessed by an automated chemistry analyzer , using appropriate commercial kits (Abbott), and the reference value of IGF-1 varies according to age and sex. Serum GH and IGF-1 levels were measured at the same time of echocardiography examination for each subject.15 LV diastolic diameter, LV systolic diameter, interventricular septum (IVS) thickness, posterior wall (PW) thickness, LA diastolic diameter were measured from the parasternal long axis image from two-dimensional image windows. Devereux formula was used for LV mass measurement.16 Afterwards LV mass-index (LVMI) was calculated by dividing LV mass to BSA. LVMI value > 115 gr/m2in men and > 95 gr/m2in women were considered LV hypertrophy.17Echocardiographic evaluation was made by using a 2.5-3.5 MHz transducer EPIQ 7C . Echocardiographic evaluation was performed within the first week for patients who met the inclusion criteria. Echocardiographic evaluations of all patients were performed in the left lateral decubitus position with electrocardiography and blood pressure monitoring. All images were taken with at least 3 repetitive cycles from the standard parasternal long and short axis, apical 4 chamber, 5 chamber, and 2 chamber views according to the suggestions of the American Society of Echocardiography.18 Segments with insufficient image quality and cardiac cycles containing premature beats were excluded from the measurements.In the SE procedure, all patients were in normal sinus rhythm. LA and LV myocardial deformation parameters were calculated by using STE over two-dimensional gray scale images. Two-dimensional gray scale apical 4 chambers (A4C), apical 2 chambers (A2C), and apical 3 chambers (A3C) were recorded after expiration by holding one’s breath. At least three cardiac cycles were recorded for each image, and attention was paid to consider at least 60-80 fps, according to the guidelines of European Society of Cardiology.QLAB version 10.5  software was used for LV and LA analyses. The software has automatically followed the wall movements throughout the entire cardiac cycle after the LV endocardium has been marked frame by frame with manual drawing method  on the two-dimensional images. LV-GLS values were calculated from the images with 2D-STE. After manually marking 2 basal and 1 apical parts of LV, the remaining endocardial borders were automatically marked by the software and the appropriate epicardial border was also automatically drawn. When the automatically drawn LV boundaries are not suiTable for analysis, the borders were manually corrected for proper analysis. After analysis, the software divided LV A2C, A3C, A4C recordings to six segments, and an 18-segment model was used to calculate LV-GLS   .19 Apical four chamber view images of the LA were obtained using standard anatomic landmarks to ensure optimal acquisition and avoid foreshortening with conventional 2-dimensional echocardiography, at relatively high frame rates (60–80 fps). The LA endocardial border tracing was started at the endocardial border of the mitral annulus, to the LA endocardial border, extrapolating across the pulmonary veins, and/or LA appendage orifices, up to the opposite mitral annulus side by experienced echocardiographers blinded to clinical information. The software then automatically generated an epicardial LA silhouette, which delineated a region of interest in each apical view. Manual adjustment of the region of interest was allowed to encompass the entire LA myocardial layer, followed by automated segmental tracking. After tracking, the LA deformation indices, such as longitudinal strain and its first derivation SR curves, were obtained from a non-foreshortened apical four chamber view.20 We used the R wave as a starting point (R-R gating) for deformation analysis. Longitudinal strain and strain rate curves were generated in all segments, and the average of the segments was calculated for the corresponding time points . Data are expressed as mean ± SD for continuous variables and percentage for categorical variables. The Shapiro-Wilk test was used to test normality, and a p-value >0.05 was defined as normally distributed data. Continuous variables that showed normal distribution were compared using the Student’s t test and ANOVA, whereas the Mann-Whitney U and Kruskal-Wallis tests were used for non-normally distributed samples. Categorical variables and frequencies were compared by means of the chi-square test. Statistical significance was defined as a p-value <0.05 for all comparisons. In our study, parameters that differed in patients with <20% for LV-GLS were found in univariate analysis. Therefore, Backward: LR logistic regression analysis was performed to determine the parameters that independently determined patients with <20% for LV-GLS. Pearson’s and Spearman’s correlation were used to examine the relationship between continuous variables. Variables with a p-value <0.05 in the bivariate analysis were tested in the linear regression analysis. Results were expressed as the p-value and hazard ratio (HR) in a 95% CI.Fifty-eight patients with active acromegaly were included in the study. Eight patients who met the exclusion criteria and could not perform ideal echocardiographic examination were excluded from the study. Forty-five patients included in the study were De novo acromegaly patients. The other three patients were after surgery without remission and two patients were on medical treatment without remission. The study data were divided into two groups, with and without acromegaly . Cohen kappa values that evaluate interobserver and intraobserver variability were over 90% for all echocardiography measurements.When demographic data were compared between the study groups; age, gender, BMI, and BSA were similar between the groups. The frequency of HT and DM in patients with acromegaly was determined to be 28% and 32%, respectively. In terms of clinical parameters, systolic and diastolic blood pressures and heart rate were higher in patients with acromegaly. Plasma glucose, NT-proBNP, IGF-1, and growth hormone levels were found to be significantly higher in patients with acromegaly. Other laboratory parameters were similar between the two groups   .IVS and PW end-diastolic thickness and LVMI values were found to be significantly higher in patients with acromegaly   . LV dia2vs 94.6 gr/m2and p <0.008). In the multivariate logistic regression analysis, it was found that the LVMI value and IGF-1 levels independently predict the reduced LV-GLS value . According to this analysis, every 1 gr/m2increase in LVMI value and every 1 ng/dL increase in IGF-1 level increases the probability of decreased LV-GLS by 6% and 5.6%, respectively.When the limit value was taken as <20% for LV-GLS, it was found that LV-GLS levels were decreased in 48% of the acromegaly group. When the demographic, clinical, and laboratory data of patients with decreased and normal LV-GLS acromegaly were compared, it was determined that patients with low LV-GLS had higher rates of HT (45.8% vs 11.5% and p = 0.008) and higher LVMI values .25 This disease consists of 3 phases; i) an increase in LV and right ventricle (RV) contractility and LVH accompanied by increased IGF-1, ii) diastolic dysfunction as a result of decreased LV elasticity, iii) typical cardiomyopathy appearance with LV dilatation and decreased LVEF.26 LVEF decrease and LV dilatation, which is the 3rd stage of the disease, are seen in only 1-10% of the patients with acromegaly.14 However, it is important to evaluate LV functions of these patients with a new diagnostic method as early as stage 1, before irreversible cardiac changes occur.Acromegaly is one of the secondary causes of HT. HT and DM are common in these patients due to the metabolic effects of the disease.30 Cardiovascular mortality increases in patients with acromegaly.2 Decreased LV-GLS values have proven to be associated with sudden cardiac death and life-threatening arrhythmia.31 The fact that SE is easily accessible and inexpensive gives it an important advantage over other methods. However, the most important limitation is that the image quality must be very good. Although SE was used frequently to evaluate LV functions in the first place; in the last few years, many studies evaluated LA functions with strain echocardiography.4Evaluation of LV systolic function with LV-GLS is relatively new and still quite uncommon. LV-GLS is mostly used to evaluate subclinical or silent cardiac involvement of systemic diseases with normal LVEF.7 The first study was conducted by Volschan et al.5 in 2017 in 37 patients with active acromegaly, and it was found that the LV-GLS value did not change or even increased with no statistical significance when compared to healthy controls. In another study conducted in 2018, it was reported that there was a decrease in LV-GLS value in acromegaly patients, and this situation was related to LVH.7 In another study conducted and published very recently by the same authors, LV-GLS was reported to be lower in patients with acromegaly, similar to the previous study.6 Our study supports two studies showing that the LV-GLS value is decreased in patients with acromegaly. In addition to previous studies, we also showed a significant decrease in LA-GLS in the same patient group. The cut-off value for reduced LV-GLS was accepted as <20%.15 In our study, 48% of the patients with acromegaly were under <20%. In other words, LV systolic functions of half of the patients with acromegaly were impaired. Increased LVMI and IGF-1 were found to be strongly associated with decreased LV-GLS in acromegaly patients.7 Serum IGF-1 and GH levels were not related in patients with reduced LV-GLS in the same studies.7 In our study, similar to the previous study, LVMI was found to predict patients with reduced LV-GLS; moreover, IGF-1 levels were significantly related to reduced LV-GLS. In our study, it was found that every 1 gr/m2increase in LVMI increased the risk of reduced LV-GLS by 6%. In additional to this, every 1 ng/dL increase in IGF-1 level increased the probability of decreased LV-GLS by 5.6%. LVMI, which is the most objective finding of the cardiac involvement in patients with acromegaly, is also the most closely associated parameter with decreased LV-GLS. Therefore, intervention to HT, DM, and LVMI as early as possible may be the most logical way to delay future systolic dysfunction in patients with acromegaly.Several studies have evaluated LV-GLS in patients with acromegaly and normal LVEF, and contradictory results have been obtained.28 In our study, the prevalence of HT and DM in patients with acromegaly is 28% and 32%, respectively. The prevalence of HT was significantly higher in patients with decreased LV-GLS. This indicates that LV-GLS is affected by the presence of HT. The second mechanism may be LV heterotrophy and myocardial fibrosis due to increased IGF-1 in patients with acromegaly without HT and DM.25 An increased IGF-1 value may be associated with disease activity and cardiac involvement. In our study, the IGF-1 level, which is one of the most important parameters of acromegaly activity, was strongly correlated with LV-GLS.Impaired LV-GLS in patients with acromegaly can be explained by two pathophysiological mechanisms. The first is the effect of HT and DM. LV-GLS reduction has been demonstrated previously with the cardiac effects of HT and DM even in the asymptomatic period before any CV disease.32 In a previous study, it was reported that LA volume and mechanical functions were similar to healthy controls, and serum IGF-1 and GH levels were not associated with LA mechanical function in patients with acromegaly.32 In another recent study, an increase in LA volume was reported in patients with acromegaly.8 In our study, LA volume was not evaluated, but LA diastolic diameter was increased in patients with acromegaly.There is limited data on LA function and size in patients with acromegaly.8 Kormanyos et al.8 reported that LA global and mean segmental strain values were increased and LA circumferential strain values was decreased. A similar finding was demonstrated for right atrium in another study by the same authors.33 It has been reported that the IGF-1 level and the LA circumferential strain value were positively correlated.8 Our study was the first to demonstrate a decrease in LAS, and its strong and positive correlation with IGF-1, which is one of the disease activity parameters.Although there is no study in the literature evaluating LAS with 2D-STE in acromegaly patients, LA strain imaging was performed in only one study with 3D-STE.1 However; we did not evaluate the prognosis. In addition, the effect of treatment on LV-GLS and LAS was not evaluated due to the absence of follow-up. In our study, we did not have the information regarding the pathophysiologic insight of reduced LV-GLS due to the lack of histopathological evaluation with myocardial biopsy. Sleep apnea is common in patients with acromegaly,1 and it has an adverse effect on LV functions. However, we were not able to do polysomnography in all patients. The most important types of cardiac involvement are LVH and myocardial fibrosis in patients with acromegaly. Myocardial fibrosis can be best assessed with cardiac magnetic resonance imaging. If we had been able to perform cardiac magnetic resonance imaging, we would have been able to evaluate the association of late gadolinium enhancement with LA-GLS and LV-GLS. Diastolic dysfunction was also common (50.5%) in patients with acromegaly.34 Therefore; we did not evaluate the diastolic dysfunction in these patients groups.As a single-center non-randomized study, our patient cohort might be different from other centers. The sample size is relatively small and our results need to be confirmed in future, large multi-center prospective trials. CV mortality and morbidity are high in patients with acromegaly.8 In our study, we only measured LV diameter and LA end-diastolic diameter. If we also measured the LA and LV volume index, there could be changes especially in the parameters related to LA-GLS.It was shown in previous studies that LA and LV volume and volume index increased in patients with acromegaly.Although LVEF is normal in patients with acromegaly, LAS and LV-GLS detected with 2D-STE are significantly lower and are closely related to plasma IGF-1 levels. Apart from an increase in LVMI, another finding of cardiac involvement may be the decrease in LAS and LV-GLS. Therefore, in addition to routine echocardiography, LAS and LV-GLS may be useful to evaluate early signs of cardiac involvement before the occurrence of irreversible cardiac changes in patients with acromegaly.