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Primary aldosteronism (PA) is associated with increased prevalence of metabolic disorders (impaired glucose and lipid metabolism and insulin resistance), but also with more frequent cardiovascular, renal and central nervous system complications.Biochemical and clinical parameters were retrospectively analysed for 40 patients with PA caused by aldosterone-producing adenoma (APA) and compared to the control groups of 40 patients with nonfunctioning adrenal adenoma (NFA) and essential hypertension (HT), and 20 patients with adrenal Cushing syndrome (CS) or subclinical CS (SCS).Systolic, diastolic and mean arterial blood pressures were significantly higher in the PA group (p=0.004; p=0.002; p=0.001, respectively) than in NFA+HT group. PA patients had longer hypertension history (p=0.001) than patients with hypercorticism and all had hypokalaemia. This group showed the smallest mean tumour diameter (p0.001). The metabolic syndrome was significantly less common in the PA group (37.5% vs. 70% in CS+SCS and 65% in NFA+HT group; p=0.015), although there was no significant difference in any of the analysed metabolic parameters between groups. PA group was found to have the most patients with glucose intolerance (81.8%), although the difference was not significant. The mean BMI for all three groups was in the overweight range. Patients with PA had higher microalbuminuria and a higher tendency for cardiovascular, renal and cerebrovascular events, but the difference was not significant.Our results support the importance of the early recognition of primary aldosteronism on the bases of clinical presentation, as well as an increased screening intensity.Primarni aldosteronizam (PA) je praćen povećanom prevalencom metaboličkih poremećaja, (oštećen glukozni i lipidni metabolizam i insulinska rezistencija), ali i češćim kardio vaskularnim, renalnim i komplikacijama centralnog nervnog sistema.Analizirane su retrospektivno biohemijske i kliničke karakteristike 40 pacijenata sa PA zbog aldosteron-produkujućeg adenoma (APA) i upoređene sa kontrolnim grupama od 40 pacijenata sa afunkcionim adrenalnim adenomom (NFA) i esencijalnom hipertenzijom (HT), i 20 pacijenata sa adrenalnim Cushing-ovim sindromom (CS) ili subkliničkim CS (SCS).Sistolni, dijastolni i srednji arterijski pritisci su bili značajno viši u grupi sa PA (p=0,004; p=0,002; p=0,001, redom) nego u grupi NFA+HT. PA pacijenti su imali dužu istoriju hipertenzije (p=0,001) nego pacijenti sa hiperkorticizmom i svi su imali hipokalemiju. Ova grupa je imala najmanji srednji prečnik tumora (p0,001). Metabolički sindrom je bio značajno ređi u PA grupi (37,5% vs. 70% u CS+SCS i 65% u NFA+HT grupi; p=0,015), mada nije bilo značajne razlike u bilo kom analiziranom metaboličkom parametru među grupama. U PA grupi je nađen najveći procenat pacijenata sa glikoznom intolerancijom (81,8%), mada razlika nije bila značajna. Srednja vrednost BMI za sve tri grupe je bila u rangu prekomerne težine. Pacijenti sa PA su imali veći stepen mikroalbuminurije, veću tendencija ka javljanju kardiovaskularnih, renalnih i cerebrovaskularnih događaja, ali razlika nije bila značajna.Naši rezultati podržavaju značaj ranog prepoznavanja primarnog aldosteronizma na osnovu kliničke prezentacije, ali i povećanog korišćenja skrininga.

Background Recent studies showed that coronary flow velocity reserve (CFVR) measurement by transthoracic Doppler echocardiography (TTDE) during inotropic stimulation with dobutamine (DOB), in comparison to vasodilation with adenosine, provides more reliable functional evaluation of myocardial bridging (MB). However, the adequate cut-off value of CFVR during DOB for diagnosing functional significant MB has not been fully established. Purpose The purpose of the study was to evaluate the adequate cut-off value of TTDE- CFVR during DOB for diagnosis of functional significant MB. Methods This prospective study included 79 patients (54 males, mean age 55±10 years) with angiographic evidence of isolated MB on the left anterior descending artery (LAD) and systolic compression ≥50% diameter stenosis. Exercise stress-echocardiography test (ExSE) and TTDE-CFVR in the distal segment of LAD during DOB infusion (DOB: 10–40μg/kg/min) were performed in all patients. Percent diameter stenosis (DS) of MB at end-systole and end-diastole were analyzed using quantitative coronary angiography. Results Exercise-SE was positive for myocardial ischemia in 22/79 (28%). CFVR during peak DOB was significantly lower in SE-positive group in comparison to SE-negative group (1.94±0.16 vs. 2.78±0.53, p Conclusion A cut-off value Funding Acknowledgement Type of funding sources: None.

Introduction In patients with angina and no obstructive coronary artery disease (ANOCA), different mechanisms of ischaemia, epicardial spasm, microvascular spasm, and impaired microvascular dilatation frequently coexist. The aim was to assess CFVR changes during coronary vasoconstrictor and vasodilator stimuli in patients with ANOCA. Methods In a prospective single center study, we enrolled 29 ANOCA patients (age 59.6±11 years, 27 females) with previously normal angiograms. All underwent SE testing with hyperventilation (HYP, respiratory rate of 30 per min for 5') followed by supine bicycle exercise (HYP+EXE); and adenosine CFV evaluation (ADO 140 mcg/kg in 1 min) on the other day. Coronary flow velocity (CFV) was assessed in distal LAD by Transthoracic Doppler echocardiography. The ratio of peak/rest changes of CFV during HYP in LAD was taken as an index of vasoconstriction, and CFV reserve was evaluated after EXE. An abnormal response to HYP was a CFV ratio Results The double product increased during HYP, in comparison to rest (13213 vs 10517, p Conclusion In patients with ANOCA, HYP+EXE is a more powerful ischemic stress than HYP alone. In over one-half of patients HYP+EXE unmasks abnormalities in CFVR response and/or regional wall motion, likely unmasking the underlying endothelium dependent microcirculatory dysfunction with enhanced vasoconstriction in 44% of the patients and mixed vasoconstriction and reduced relaxation in 65%. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): University Clinical Centre of Serbia, Faculty of Medicine

Background Coronary flow velocity reserve (CFVR) and heart rate reserve (HRR) during vasodilator stress echocardiography (SE) assess coronary microvascular function and cardiac sympathetic reserve respectively. Both CFVR and HRR can be impaired in hypertrophic cardiomyopathy (HCM). Objectives To evaluate the prognostic value of CFVR and HRR during vasodilator SE in HCM. Methods We enrolled 244 HCM patients (age=51±15 years, 116 men) studied with vasodilator SE from 1999 to 2019 in 5 certified centers. Stress modality was either adenosine (Ado, 0.14 mg/kg/min in 2', n=171) or dipyridamole (Dip, 0.84 mg/kg in 6', n=73). Left ventricular outflow tract obstruction was present at rest in 80 patients (33%). We assessed CFVR in left anterior descending coronary artery (by TTE in 225, and TEE in 19 patients) and HRR (peak/rest heart rate). Abnormal values of HRR were based on receiver operating characteristics for Ado and Dip separately calculated. All patients completed the follow-up. Results CFVR was 2.17±0.46 for Dip and 2.13±0.43 for Ado (p=ns); HRR was 1.36±0.19 for Dip and 1.10±0.16 for Ado (p Conclusions A reduced CFVR and blunted HRR during vasodilator SE identify distinct phenotypes and show independent value in predicting outcome in HCM patients. Funding Acknowledgement Type of funding sources: None. Figure 1. Kaplan-Meier spontaneous event-free survival curves based on HRR and CFVR. Kaplan-Meier survival curves (considering spontaneous events) in patients stratified with the abnormal HRR and/or CFVR. Number of patients at risk per year is shown.

Purpose: Graves’ orbitopathy (GO) is an inflammatory autoimmune disorder of the orbit and while the antiphospholipid antibodies (aPL) Abs were associated with the markers of inflammation in the antiphospholipid syndrome (APS), there is no literature that investigate the presence of aPL Abs in GO. We analyzed the prevalence of aPL Abs and the differences between aPL (+) and aPL (−) subgroups of GO patients. Methods: Study included consecutive patients with GO (66 with Graves’ (GD), 10 with Hashimoto (HD), and 8 were euthyroid). Anticardiolipin (aCL) and anti-beta 2glycoprotein I (aβ2gpI) Abs were measured by ELISA. Results: aPL Abs were present in 9/84 (10.71%) patients. The IgM aβ2gpI Abs were present in 8/66 and in 1/10 patients with GD and HD. The IgG aCL Abs were present in one GD patient, and IgM aCL were present in 3/66 GD and in 1/10 patients with HD. In GD group, anti-Tg Abs were in positive correlation with aβ2gpI IgG (p = 0.000) and with anti-TPO Abs (p = 0.016). In HD group, anti-Tg Abs were in positive correlation with IgM aCL (p = 0.042), while anti-TPO Abs were in positive correlation with aβ2gpI IgM (p = 0.014). Conclusion: This study is the first report of the aPL Abs presence in GO patients. The anti-thyroid Abs were linked to aPL suggesting that their presence is not the sole consequence of hyperstimulation of autoreactive B-lymphocytes. Larger studies are necessary to confirm potential cause-effect relations. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Funding Acknowledgements Type of funding sources: None. Introduction Since mitral regurgitation (MR) is a very common finding in patients with hypertrophic cardiomyopathy (HCM), the evaluation of the mitral valve anatomy and the degree of MR is of utmost importance in this population. However, data regarding the prognostic value of different degrees of MR in HCM remains scarce. Purpose The aim of this study was to determine whether the presence of a higher degree of MR affects: 1) long term prognosis; 2) clinical and echocardiographic presentation of HCM patients. Material and Methods We included prospectively 102 patients, diagnosed with primary asymmetric HCM. The degree of MR was determined echocardiographicaly according to current recommendations of the American Association of Echocardiography. According to the MR severity, patients were divided into 2 groups: Group 1 (n = 52) with no/trace or mild MR and Group 2 with moderate or moderate to severe MR. All patients had clinical and echocardiographic examination, 24-hour Holter ECG and NT pro BNP analysis performed. The primary outcome was a composite of: 1) HCM related death or sudden death; 2) hospitalization due to acute heart failure; 3) sustained ventricular tachycardia; 4) ischemic stroke. Results Patients with higher MR degree had more frequent chest pain (p = 0.039), syncope (p = 0.041) and NYHA II functional class (p 10), as well as higher levels of NT pro BNP (p = 0.001). By Kaplan-Meier analysis we demonstrated that the event free survival rate during follow up of median 75 (IQR 48-103) months was significantly higher in Group 1 compared to the Group 2 (79% vs. 46%, p Conclusion Presence of moderate, or moderate to severe MR was associated with poor long-term outcome of HCM patients. These results indicate the importance of an adequate MR assessment and detailed evaluation of the mitral valve anatomy in the prediction of complications and adequate treatment of patients with HCM. Abstract Figure.

Purpose: Whereas antithyroid drugs (ATD) are the preferred treatment modality for Graves’ hyperthyroidism (GH), there is still controversy about the optimal regimen for delivering ATD. To evaluate whether ‘Block and Replace’ (B + R) and ‘Titration’ (T) regimes are equivalent in terms of frequency of euthyroidism and Graves’ Orbitopathy (GO) during ATD therapy. Methods: A prospective multicentre observational cohort study of 344 patients with GH but no GO at baseline. Patients were treated with ATD for 18 months according to B + R or T regimen in line with their institution’s policy. Results: Baseline characteristics were similar in both groups. In the treatment period between 6 and 18 months thyrotropin (TSH) slightly increased in both groups, but TSH was on average 0.59 mU/L (95% CI 0.27–0.85) lower in the B + R group at all time points (p = 0.026). Serum free thyroxine (FT4) remained stable during the same interval, with a tendency to higher values in the B + R group. The point-prevalence of euthyroidism (TSH and FT4 within their reference ranges) increased with longer duration of ATD in both groups; it was always higher in the T group than in the B + R group: 48 and 24%, respectively, at 6 months, 81 and 58% at 12 months, and 87 and 63% at 18 months (p < 0.002). There were no significant differences between the B + R and T regimens with respect to the fall in thyrotropin binding inhibiting immunoglobulins (TBII) or thyroid peroxidase antibodies (TPO-Ab). GO developed in 15.9% of all patients: 9.1 and 17.8% in B + R group and T group, respectively, (p = 0.096). GO was mild in 13% and moderate-to-severe in 2%. Conclusion: The prevalence of biochemical euthyroidism during treatment with antithyroid drugs is higher during T compared to B + R regimen. De novo development of GO did not differ significantly between the two regimens, although it tended to be higher in the T group. Whether one regimen is clinically more advantageous than the other remains unclear.

Background Coronary chronic total occlusion (CTO) is characterized by the presence of collateral blood vessels which can provide additional blood supply to CTO-artery dependent myocardium. Successful CTO recanalization is followed by significant decrease in collateral donor artery blood flow and collateral derecruitment. Purpose Study aim was to assess time-dependent changes in coronary flow reserve (CFR) in collateral donor artery after CTO recanalization and identify factors that influence these changes. Methods Our study enrolled 31 patients with CTO scheduled for percutaneous coronary intervention (PCI). Non-invasive CFR was measured before PCI in collateral donor artery, and 24h and 6 months post-PCI in CTO and collateral donor artery. Gated SPECT MIBI was performed before PCI, while quality of life was assessed by Seattle angina questionnaire (SAQ) pre-PCI, and 6 months after PCI. Results Collateral donor artery showed significant increase in CFR 24h after CTO recanalization compared to pre-PCI values (2.30±0.49 vs. 2.71±0.45, p=0.005), which remained unchanged after 6 months (2.68±0.24). Maximum baseline blood flow velocity of the collateral donor artery showed significant decrease measured 24h post-PCI compared to pre-PCI values (0.28±0.06 vs. 0.24±0.04m/s), and remained similar after 6-months. There was no significant difference in maximum hyperemic blood flow velocity pre-PCI, 24h and 6 months post-PCI. CFR change of the collateral donor artery 24h post-PCI compared to pre-PCI values showed inverse correlation with left ventricle ejection fraction (LVEF) measured on SPECT. CFR changes showed no correlation with the changes in quality of life assessed by SAQ post-PCI compared to pre-PCI. Conclusions Significant increase in CFR of the collateral donor artery was observed within 24h after successful recanalization of CTO artery, which maintained constant after the 6 months follow-up. This increase was largely driven by the significant reduction in the maximum baseline blood flow velocity within 24h after CTO recanalization compared to pre-PCI values. Our results suggest that possible benefit of CTO recanalization could be the improvement in physiology of the collateral donor artery. Funding Acknowledgement Type of funding source: None

Background Patients with ischemia and no obstructive coronary artery disease (INOCA) are a heterogeneous group and an unmet diagnostic challenge. Noninvasive Doppler is a feasible tool to assess coronary flow velocity (CFV) in left anterior descending coronary artery (LAD) during stress echocardiography (SE). Aim To assess CFV response during coronary vasoconstrictor and vasodilator stimuli in INOCA patients. Methods In a prospective single center study, we enrolled 16 INOCA patients (age 60±12 years, 15 females) with previously normal angiograms. All underwent SE testing with hyperventilation (HYP, respiratory rate of 30 per min for 5') followed by supine bicycle exercise (HYP+EXE); and adenosine CFV evaluation (ADO, 0.84 mg/kg in 1 min) on the other day. The ratio of peak/rest changes of CFV during HYP in LAD was taken as an index of vasoconstriction, and CFV reserve was evaluated after EXE. An abnormal response to HYP was a CFV ratio Results The double product increased during HYP, in comparison to rest (13 337 vs 9858, p Conclusion In INOCA patients, HYP+EXE is a more powerful ischemic stress than HYP alone and unmasks abnormalities in regional wall motion and/or CFV response in over one- half of patients, likely unmasking the underlying abnormal coronary vasomotor response of large epicardial and/ or small coronary vessels. INOCA patients show profound heterogeneity of coronary vasomotor responses which can be detected with a combined vasodilator - vasoconstrictor SE approach with CFV assessment. The clarification of underlying coronary microcirculatory heterogeneity is the prerequisite for a personalized treatment, and can be easily extracted from CFV-SE. Normal INOCA hearts are all alike, every abnormal heart is abnormal in its own way. Funding Acknowledgement Type of funding source: None

Background Previous studies have shown that left bundle branch block (LBBB), as a relatively common electrocardiographic (ECG) abnormality, represents the condition with often non benign and sometimes adverse outcome. Purpose The Aim of our study was to determine the predictive value of a stress echocardiography test in patients with LBBB. Methods Our study population included 189 patients (88 male, 46.6%, mean age 63.08±9.65) with diagnosed left bundle branch block who performed stress echocardiography (SECHO) according to Bruce protocol. Median follow-up of the patients was 56 months (IQR 48–71 months) for the occurrence of cardiovascular death and non-fatal myocardial infarction, repeat revascularization (coronary artery bypass grafting-CABG or percutaneous coronary intervention-PCI). Results Out of 189 patients, 32 (16.9%) patients had positive, while 157 (83.1%) patients had negative SECHO test. During the follow up period 28 patients had major adverse cardiac event: 1 nonfatal myocardial infarction, 6 heart failure hospitalizations, 5 CABGs, 8 PCIs, while 8 patients had cardiac death. Using the Cox regression analysis, univariate predictors of adverse cardiac events were diabetes mellitus (HR 4.530 [95% CI 1.355–15.141], p=0.014), PCI (HR 4.288 [95% [95% CI 2.010–9.144], p Conclusion Patients with LBBB and negative SEHO test have good prognosis. Patients with history of CAD and diabetes mellitus and LBBB are at increased risk for future events and need periodical reassessment. Funding Acknowledgement Type of funding source: None

Background Relevant number of all stress echocardiography results are non-diagnostic or inconclusive. Such importance cannot be ignored as previous studies have shown that these patients have higher risk for adverse events. Non-invasive transthoracic Doppler derived coronary flow reserve (CFR) of left anterior descending (LAD) artery, as additional test, is an effective tool to predict adverse cardiac events in various clinical settings. Purpose The aim of this study was to investigate the value of CFR of LAD in predicting outcome. Methods 122 patients, (35,8% with previous MI) with nondiagnostic stress echocardiography results (target heart rate not reached, chest pain without ECG and echo changes) and with inconclusive stress echocardiography results (target heart rate reached, chest pain with ECG changes and without echo changes) were referred for transthoracic Doppler echocardiographic CFR assessment of LAD. CFR was calculated as the ratio between maximal hyperemic and baseline coronary flow velocity. CFR ≤2 was considered abnormal. All patients were followed for major adverse cardiac events (MACE): nonfatal myocardial infarction, hospitalization, revascularization (CABG or PCI) and death. Results Measured values of CFR LAD were in the range 1,52- 4,00 (mean: 2,4±0.44). CFR LAD was abnormal in 22 (18%), and preserved in 100 patients (82%). During median follow-up of 23 months (interquartile range 9–35), 14 patients underwent revascularization (2 had CABG, 12 had PCI). There were no myocardial infarctions, hospitalizations or cardiovascular deaths in the follow-up period. Patients with lower CFR values (CFR≤2) had a higher event rate and shorter event free survival time compared to those with CFR>2, event rate (9/22, 40,9% vs 5/98 5,1%; p Conclusions Preserved CFR of LAD (>2.0) predicts excellent survival in patients with non-diagnostic and inconclusive stress echocardiography. Funding Acknowledgement Type of funding source: None

Background A reduction in coronary flow velocity reserve (CFVR) related to coronary microvascular dysfunction is a major mechanism for ischemia in hypertrophic cardiomyopathy (HCM). Hypothesis To assess the functional correlates and prognostic value of CFVR during stress echocardiography (SE) in HCM. Methods We enrolled 201 HCM patients (age 51±14 years, 105 male, 52%; maximal wall thickness: 18±3 mm) studied with CFVR during exercise (n=33, 16.4%), dipyridamole (n=89, 44.3%) or adenosine (n=79, 39.3%) SE in 6 certified centers. CFVR was assessed using pulsed wave Doppler sampling in left anterior descending coronary artery. All patients completed the clinical follow-up. Results During SE mean value of CFVR was 2.11±0.46. No patients showed regional wall motion abnormalities during stress. LV outflow tract obstruction (LVOTO) was present in 34 (16.9%) patients at rest and in 47 (23.4%) at peak stress. CFVR was inversely related to age (r=−0.229, p=0.001) and maximal wall thickness (r=−0.197, p=0.031). During a median follow-up of 26 months (IQ range: 12–48 months), 75 events in 63 patients occurred: 10 deaths, 33 new hospital admission for acute heart failure, 8 sustained ventricular tachycardias and 24 atrial fibrillations. Patients in the lowest tertile (≤1.88) showed the worse prognosis with higher incidence of follow-up events compared to median tertile (1.89–2.29) and highest tertile (≥2.30) (see figure). At multivariable analysis, NYHA functional class (HR: 2.234, 95% CI: 1.398–3.517, p=0.001), presence of LVOTO at rest (HR: 2.958, 95% CI: 1.074–3.570, p=0.028) and lowest tertile of CFVR (HR: 2.144, 95% CI: 1.126–4.081, p=0.011) were the independent predictors of follow-up events. Conclusions In HCM patients, reduction in CFVR is associated to a clearly worse outcome. The spectrum of prognostic stratification is expanded if the response is titrated according to a continuous scale. Figure 1 Funding Acknowledgement Type of funding source: None

Background Percutaneous coronary intervention of chronic total occlusion (PCI CTO) can reduce angina and the need for bypass surgery, however, it is still not clear how it effects the myocardial function. Conventional echocardiography is subjective and experience-dependent while tissue Doppler imaging together with strain imaging provides a more objective assessment of myocardial contractility. Purpose Our aim was to access the effectiveness of percutaneous coronary intervention (PCI) along with optimal medical therapy (OMT) on myocardial function. Methods We compared two groups of patients. The first group of patients underwent PCI CTO with OMT while the second group of patients only received OMT (control group). The echocardiographic exam was performed before randomization and after 24 months of follow-up. Doppler time intervals- isovolumetric relaxation time (IVRT), isovolumetric contraction time (IVCT) and ejection time (ET) were measured from mitral inflow and left ventricular outflow Doppler tracings. Myocardial performance index (MPI) is equal to the sum of the IVRT and IVCT divided by the ET. Velocity of early mitral filling wave (E) was measured and divided by average peak early diastolic annular velocity (e'). Peak longitudinal strain was assessed in 17 left ventricular segments. Time intervals from start Q/R on electrocardiogram to peak negative strain during the cardiac cycle were assessed. Mechanical dispersion was defined as the standard deviation of this time interval from 17 left ventricular segments, reflecting myocardial contraction heterogeneity Results Comparing the groups at follow up, there was no significant change in ejection fraction (EF), diastolic function, and mechanical dispersion, however, there was improvement in GLS and MPI (Table 1). Conclusion Global longitudinal strain as a parameter of systolic function and Myocardial performance index as a parametar of global systolic and diastolic function are sensitive markers that can detect subtle improvement in myocardial function after recanalisation of CTO. Funding Acknowledgement Type of funding source: None

Background Two-dimensional (2-D) volumetric exercise stress echocardiography (ESE) provides an integrated view of preload reserve through end-diastolic volume (EDV) and left ventricular contractile reserve (LVCR) through end-systolic volume (ESV) changes. Purpose To assess the dependence of stroke volume (SV) and cardiac output (CO) upon LVCR EDV changes and heart rate (HR) during ESE. Methods We prospectively performed semi-supine bicycle or treadmill ESE in 1,344 patients (age 59.8±11.4 years; 550 female; ejection fraction = 62.5±8%) referred for known or suspected coronary artery disease in 20 quality controlled laboratories of 16 countries from 2016 to 2019. SV was calculated at rest and peak stress from raw measurement of LV EDV and ESV by biplane Simpson rule, 2-D echo. LVCR was the stress-rest ratio of force (systolic blood pressure by cuff sphygmomanometer/ESV, abnormal values Results By selection, all patients had negative SE by wall motion criteria. Of the 1,344 patients included in the study, 448 belonged to the lowest tertile of CO increase. Of them 326 (73%) achieved HR reserve Conclusion Patients with normal CO reserve during exercise usually have a fast, compliant and strong heart. Abnormal CO reserve is associated with heterogeneous hemodynamic responses, with slow, stiff and/or weak hearts. The clarification of underlying hemodynamic heterogeneity is the prerequisite for a personalized treatment, and can be easily extracted from a standard 2-D volumetric SE. Hearts with normal CO are all alike; every heart with abnormal CO is abnormal in its own way. CO % changes in subsets (*p Funding Acknowledgement Type of funding source: None

BACKGROUND/AIMS The most effective and safe treatment protocol for Graves' orbitopathy (GO) needs to be further assessed. The aim of the present study was to evaluate the efficacy, safety and outcome of parenteral versus parenteral and oral glucocorticoid (GC) protocols in euthyroid patients with untreated and active moderate to severe GO. METHODS This was a retrospective observational study in 140 patients comparing intravenous GC pulses only (IVGC group, 74 patients, 51 ± 11 years) with historical controls of combined oral and intravenous GC therapy (CombGC group, 66 patients, 49 ± 10 years, P = ns). IVGC therapy included infusions of 500 mg of methylprednisolone weekly for the first six weeks, followed by infusions of 250 mg weekly for the remaining six weeks (cumulative dose 4.5 g). CombGC therapy included 500 mg of methylprednisolone in 500 mL of saline solution for two alternative days, followed by oral prednisone tapering dose repeated each month for the next 5 months (cumulative dose 10.2 g). RESULTS The overall success of the treatment was 43/66 (65%) in the CombGC group and 37/73 (51%, P = .071) in the IVGC group. Deterioration of GO developed in four (6%) patients during CombGC therapy and in nine (12%, P = .214) patients during IVGC therapy. After 6 months, relapse of GO was observed in 10/37 (26%) in the IVGC group, whereas none of the patients in CombGC had a relapse (P < .001). There were significantly more side effects in the CombGC versus IVGC group (49/66, 74% vs 28/74, 38%, P < .001). CONCLUSIONS Our data suggest that CombGC therapy was more efficient with significantly less relapse rate, but with more side effects in comparison to IVGC therapy.

Background Percutaneous coronary intervention of chronic total coronary occlusion (PCI of CTO) is proved to reduce symptoms of angina and long term survival. Purpose This study aimed to assess systolic and diastolic left ventricular function with standard echocardiographic indices. Methods We analyzed total of 46 CTO patients (age 58 ± 9, 73% male). Measures were obtained with the transducer in the apical four-chamber view. Doppler time intervals were measured from mitral inflow and left ventricular outflow Doppler tracings by pulsed wave Doppler. The isovolumetric relaxation time (IVRT) was measured from closure of the aortic valve to opening of the mitral valve. The isovolumetric contraction time (IVCT) was measured from closure of the mitral valve to opening of the aortic valve. Ejection time (ET) was measured from the opening to the closure of the aortic valve on the LV outflow velocity profile. Myocardial performance index (MPI) is simple method for evaluation of overall cardiac function and is independent of heart rate and blood pressure. MPI was equal to the sum of the IVRT and IVCT divided by the ET. Velocity of early mitral filling wave (E) was measured and divided by average peak early diastolic annular velocity (e") which was measured as average value between septal and lateral side of the mitral annulus using Doppler tissue imaging. The E/e’ ratio was calculated to estimate the LV filling pressures Results Six months after PCI of CTO patients showed no change in ejection fraction (EF) (55.69 ± 8.56% vs. 54.83 ± 8.44%, p = 0.10). MPI was significantly decreased (0.676 ± 0.99 vs. 0.632 ± 0.96 p Conclusion PCI of CTO improves overall cardiac function, particularly diastolic function in patients with reduced ejection fraction.

Background Percutaneous coronary intervention for chronic total occlusion (PCI CTO) is still high risk procedure and it is doubtful will it become standard of care. There is evidence that it can reduce angina but even silent ischemia represent ischemic burden that ultimately lead to left ventricle remodeling and electrical instability. Purpose Our aim was to access effectiveness of percutaneous coronary intervention (PCI) when added to optimal medical therapy (OMT) on myocardial function. Methods We compared two groups of pts. First patients with percutaneous coronary intervention of chronic total occlusion with optimal medical therapy and second group - patients with only optimal medical therapy (control group). Echocardiographic exam was performed before randomization and after 6 months of follow-up. Doppler intervals- isovolumetric relaxation time (IVRT), isovolumetric contraction time (IVCT) and ejection time (ET) were measured. MPI (Myocardial performance index) is equal to the sum of the IVRT and IVCT divided by the ET. Velocity of early mitral wave (E) was divided by average peak early diastolic annular velocity (e"). Peak longitudinal strain was assessed in 17 left ventricular segments. Time intervals from start Q/R on electrocardiogram to peak negative strain during the cardiac cycle were assessed. Mechanical dispersion was defined as the standard deviation of this time intervals from 17 segments, reflecting myocardial contraction heterogeneity. Results A total of 94 age matched CTO patients (48 in PCI + OMT group and 46 in OMT) were analyzed. Changes in ejection fraction (EF), diastolic function represented by E/e", global cardiac function represented by MPI, global longitudinal strain (GLS) and myocardial dispersion changes were compared between groups. At follow up between groups in there was no significant change in ejection fraction (EF), diastolic function, GLS and mechanical dispersion, but there was improvement in MPI. Conclusion Myocardial performance index is sensitive marker which can detect subtle improvement in global myocardial function after recanalization of chronic total occlusion.. Variable PCI + OMT (n = 46) OMT (n = 48) ΔOMT vs. ΔPCI + OMT p value baseline At 6month follow up P value baseline At 6month follow up P value EF (%) 55.69 ± 8.56 54.83 ± 8.44 0.10 50.22 ± 11.71 51.42 ± 10.45 0.06 0.71 MPI 0.676 ± 0.99 0.632 ± 0.96

Background Heart rate recovery (HRR) has been shown to predict cardiovascular and all-cause morbidity and mortality in different populations. Recent studies have indicated the CHA2DS2-VASc score can be used as predictor of mortality in patients with coronary artery disease, without atrial fibrillation. However, the relation between these two parameters has not yet been documented. The Aim: The aim of this study was to determine the relation between CHA2DS2-VASc score and impaired heart rate recovery in patients without inducible myocardial ischemia. Methods Our study comprised of 2699 consecutive patients (1319 male, 42.8%, average age 60 ± 11 years) who underwent treadmill exercise testing (stress echocardiography or stress echocardiography) according to Bruce protocol for the assessment of myocardial ischemia. We excluded patients with the systolic heart failure (left ventricle ejection fraction Results Out of 2699 patients, 378 (12.3%) had a positive test and they were excluded from further analysis. Of the remaining 2321 patients, 251 (10.8%) had an impaired HRR, whereas 2070 (89.2%) had normal HRR. Previously known coronary artery disease (previous myocardial infarction, percutaneous coronary intervention or coronary artery bypass graft surgery) had 78 (3.4%) patients. Patients with impaired HRR had significantly higher CHA2DS2-VASc score (3.1 ± 1.3 vs 2.3 ± 1.2, p Conclusion CHA2DS2-VASc score is an independent predictor of impaired HRR in patients without inducible ischemia.

Background Coronary collateral circulation exerts protective effects on myocardial ischaemia due to coronary artery disease and can be promoted by exercise with heparin co-administration. Whether this arteriogenetic effect is accompanied by functional improvement of left ventricle during stress and lessening of angina symptoms remains unknown. Aims To evaluate the anti-ischaemic efficacy of heparin plus exercise in coronary artery disease. Methods In a prospective, single-centre, randomized, double-blind study we recruited 32 ‘no-option’ patients (27 males; mean age 61 ± 8 years) with stable angina, exercise-induced ischaemia and coronary artery disease not suitable for revascularization. All underwent a two-week cycle of exercise (two exercise sessions per day, five days per week) and were randomized (n = 16 per group) to intravenous placebo (0.9% saline) versus unfractionated heparin (5.000 IU intravenously), 10 min prior to exercise. We assessed Canadian Cardiovascular Society angina class, stress electrocardiogram and echo parameters (wall motion score index) and computed tomography angiography for collaterals. Results After two-week cycle, Canadian Cardiovascular Society class statistically decreased in both groups (heparin plus exercise group: 2.6 ± 0.7 to 1.9 ± 0.7, p Conclusion A two-week, 10-test cycle of heparin plus exercise is better than exercise in improving angina class, myocardial ischaemia and collaterals by computed tomography angiography.

Background Coronary collateral circulation (CCC) exerts protective effects on myocardial ischemia due to coronary artery disease (CAD), but the anti-ischemic, pro-CCC effects of exercise (E) with or without heparin (H) co-administration remain unclear. Purpose To establish the anti-ischemic functional efficacy of 2-week cycle of E-to-ischemia twice daily, with or without unfractionated i.v. H immediately before E, in patients with “no-option” CAD Methods In a prospective, single-center, parallel group study design we recruited 32 “no-option” patients (27 males; mean age of 61±8 years) with at least one chronically occluded coronary artery and stable angina, refractory to optimal medical management, not suitable for revascularization therapy and with E-induced ischemia. All underwent a 2-week cycle of E (2 E test per day, 5 days a week, for 2 weeks) and were randomized, with a double-blind design, to i.v. placebo (0.9% saline) versus unfractionated H (100 IU/kg up to a maximum of 5.000 IU iv, 10 min prior to E). Seattle stable angina questionnaire (SAQ), 12-lead E-ECG for time-to-ischemia (treadmill exercise testing), and MDCT angiography for CCC imaging (Rentrop score, from 0= absent to 3= full opacification of occluded vessel) were assessed at entry and re-assessed after treatment for symptomatic, ECG, and anatomic end-points respectively. Results In H+E group (n=16), time to 1 mm ST segment depression (ST-D) increased, and CCC improved, p0.05) (see table). Clinically important change of more 10 points in SAQ was observed regarding physical limitation, angina stability and disease perception in H+E patients, and in only angina frequency in E group. The ECG and angiographic results Heparin + Exercise Placebo + Exercise Rentrop baseline 0.73±0.88 1.06±1.06 Rentrop 2-week 1.6±0.99* 1.19±1.05 Time to ST-D base (s) 269±64 273±176 Time to ST-D 2-week (s) 328±65* 306±151 *p Conclusion A 2-week, 10 E test cycles are well tolerated and effective particularly with H in ameliorating symptoms, E-induced ischemia and CCC in “no-option” CAD patients with refractory angina.

Background Coronary collateral circulation exerts protective effects on myocardial ischemia due to coronary artery disease (CAD) and can be promoted by exercise (E) with heparin (H) co-administration. Whether this arteriogenetic effects is accompanied by functional improvement of left ventricle (LV) during stress remains unknown. Purpose To establish the stress-induced functional effects on LV regional and global function of 2-week cycle of H+E in patients with “no-option” CAD. Methods In a prospective, single-center, double-blind, randomized, parallel-group study we recruited 32 “no-option” patients (27 males; mean age of 61±8 years), with stable angina and CTO, refractory to OMT, not suitable for revascularization and with E-induced ischemia. All underwent 2-week cycle of E (2 E test per day, 5 days a week) and were pre-treated with i.v. 0.9% saline or unfractionated H (100 IU/kg up to maximum of 5.000IU, 10 min prior to E). Canadian Class Score (CCS) and 12-lead E-ECG for time-to-1 mm ST-segment depression were assessed at entry and after treatment. LV function was evaluated during treadmill exercise with conventional and advanced imaging indices: Wall Motion Score Index (WMSI); Ejection Fraction (EF); Force (systolic blood pressure/end-systolic volume); Global Longitudinal Strain (GLS). Results Post-treatment exercise-time and CCS improved in both groups. In H+E patients exercise-time improved from 369.8±107.8 sec to 475.3±114.6 sec (p=0.001) while in E patients improved from 384±152.7 sec to 464.8±134.1 sec (p=0.019). CCS score changed in H+E from 2.6±0.7 to 1.9±0.7 (p=0.000), and in E group from 2.4±0.7 to 2.1±0.9 (p=0.046). At peak exercise, H+E was different from E group for EF and GLS (see Table). Effects of H+E on SE parameters H+E p P+E p *H+E vs P+E STRESS Time 0 vs Time 1 Time 0 vs Time 1 Time 0 Time 1 WMSI 1.377 vs 1.279 0.005 1.404 vs 1.376 0.290 0.626 0.255 EF (%) 60.9 vs 64.8 0.016 61.2 vs 57.8 0.284 0.943 0.016 Force (mmHg/mL) 6.36 vs 6.5 0.158 5.82 vs 4.68 0.209 0.760 0.098 GLS (%) −16.96 vs −18.50 0.001 −15.79 vs −15.60 0.380 0.325 0.027 SE = stress echocardiography; H+E = heparin+exercise; P+E = placebo+exercise; Time 0 = before randomization; Time 1 = after 2-week therapy cycle. *p values. Conclusion A 2-week, H+E cycle is associated with improvement in regional and global LV function during exercise, concordantly shown by conventional (WMSI, EF) and advanced (GLS) echocardiographic indices of LV function. This integrates and supplements the classical objective index based on ST-segment depression, unable to localize and quantify the functional consequences of therapy on myocardial ischemia.

Background The specific role of non-invasive functional testing in a risk stratification of patients with incomplete revascularization after primary percutaneous coronary intervention (pPCI) still needs to be evaluated. The aim of our study was to assess negative prognostic value of stress echocardiography (SECHO) after successful pPCI and incomplete revascularization of non-culprit lesions. Methods Our study consisted of 202 patients (mean age 59±10 years, male 142) successfully treated with pPCI, who performed SECHO according to Bruce protocol in order to assess residual ischemia in coronary artery with non-culprit lesion. Duke treadmill score, functional capacity (Metabolic Equivalents - METs), achieved target heart rate (THR), heart rate recovery (HRR), wall motion score index (WMSI) and ejection fraction were interrogated in all patients. Slow HRR was defined as ≤18 beats/min. Median follow-up of the patients was 70 months (IQR 55–83 months) for the occurrence of cardiovascular death and non-fatal myocardial infarction. We also assessed the independent predictors for the occurrence of the adverse events. Results Out of 202 patients, 42 (20.8%) had positive SECHO test, 4 patients (1.98%) had died due to non-cardiac causes and 7 patients (3.5%) were lost to follow-up. From the remaining 149 patients with negative SECHO, 13 (8.7%) had an adverse event (7 cardiovascular deaths and 6 non-fatal MI). Negative predictive value of SECHO test was 91.3%. Univariate predictors of adverse events were slow HRR (HR 4.343 [95% CI 1.473–14.011], p=0.008), and not achieved THR (HR 0.322 [95% CI 0.105–0.985], p=0.047). By multivariate analysis, only slow HRR remained independent predictor of adverse events (HR 3.324 [95% CI 1.013–10.906], p=0.048). Conclusion SECHO test has excellent negative prognostic value in patients with incomplete revascularization of non-culprit lesions after successful pPCI. Still, particular care should be taken to the patients with slow HRR and negative SECHO due to increased risk for the occurrence of adverse events. Acknowledgement/Funding Ministry of Education and Science of the Republic of Serbia (Grant No III41022)

Background Hypertrophic cardiomyopathy (HCM) patients with blunted force-frequency relationship assessed with pacing during cardiac catheterization are at greater risk of adverse events. Left ventricular contractile reserve (LVCR) based on force can be obtained noninvasively during exercise stress echocardiography (ESE). Purpose To evaluate the prognostic correlates of force-based LVCR during ESE in HCM. Methods We enrolled 332 HCM patients (age 51±15 years, 193 males, New York Heart Association, NYHA, Class I-III, EF 68±9%, maximal wall thickness 20±5 mm, left ventricular outflow tract gradient, LVOTG, present at rest in 34 pts, 10%) referred for ESE in 7 quality-controlled labs. SE assessment included LVOTG (mm Hg), LV Force (systolic blood pressure by cuff sphygmomanometer + LVOTG/LV end-systolic volume assessed with 2-D, mmHg/ml) and LVCR (peak/rest ratio of LV Force). LV volumes were measured from apical biplane (4- and 2-chamber) views with Simpson method when feasible (n=290) or with linear Teichholz (T) method from parasternal (long- or short-axis) view (n=42). All patients were followed-up. Results Force values were 8.5±6.7 at rest and 15.0±13.7 mmHg/mL at peak stress (P Figure 1. HCM-LVCR Conclusion A non-invasive evaluation of LVOTG, systolic blood pressure and LV end-systolic volume during ESE allows to assess force-based LVCR in HCM. Lower LVCR is associated with greater risk of events at follow-up.

To evaluate the hypothesis that breast arterial calcification (BAC) may predict coronary artery disease (CAD) severity.The study comprised 102 women45 years (mean age 62±8 years) referred for digital mammography after coronary angiography. BAC was assessed using the Likert scale and CAD severity was assessed using the SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery trial) score.In comparison to the low SYNTAX score group (≤22) patients with a intermediate-to-high SYNTAX score (22) were older (p=0.001), they more often had hypercholesterolaemia (p0.001), diabetes (p=0.021), and a history of smoking (p=0.048). They also had a statistically higher level of fasting blood glucose (p0.001), glycated haemoglobin (HbA1C; p0.001), triglycerides (p=0.002), fibrinogen (p=0.001), whereas high-density lipoprotein (HDLc) was lower than in the group with a SYNTAX score ≤22 (p=0.005). BAC was significantly higher in patients with a SYNTAX score22 (p0.001). At multivariate analysis, BAC (odds ratio [OR] 34.24, 95% confidence interval [CI]: 8.05-145.7, p0.001), hypercholesterolaemia (OR 22.65, 95% CI: 4.18-122.81, p0.001) and fibrinogen (OR 2.55, 95% CI: 1.28-5.07, p=0.008) were independent predictive factors for patients with intermediate-to-high SYNTAX score.In women45 years, there was a significant correlation between the severity of CAD as evaluated by the SYNTAX score and BAC as evaluated by the Likert scale. BAC, hypercholesterolaemia, and fibrinogen may be used as an additional diagnostic tool to predict the presence and severity of CAD.

The increased secretion of thyroid gland hormones affects the cardiovascular system by increasing heart rate and often by increasing systolic and diastolic blood pressure. We examined the influence of elevated thyroid hormone on blood pressure. Blood pressure monitoring was performed prior to the introduction of therapy in people with increased FT4 and on therapy when FT4 was in the normal range. We analyzed 32 people, of which 26 women had normal blood pressure values measured by blood pressure monitoring. Average age 45 and body mass index 27 kg/m2. Blood pressure was measured by monitoring blood pressure for 24 hours. On average, before the introduction of the therapy, it was 133/83 mmHg P 96 / min. The blood pressure on average on therapy with tireosuppressive was 128/82 mmHg P 74 / min. The Wilcoxon-Mann-Whitney paired test shows a significant P

Introduction. In interpreting thyroid hormones results it is preferable to think of interference and changes in concentration of their carrier proteins. Outline of Cases. We present two patients with discrepancy between the results of thyroid function tests and clinical status. The first case presents a 62-year-old patient with a nodular goiter and Hashimoto thyroiditis. Thyroid function test showed low thyroid-stimulating hormone (TSH) and normal to low fT4. By determining thyroid status (ТSH, T4, fT4, T3, fT3) in two laboratories, basal and after dilution, as well as thyroxine-binding globulin (TBG), it was concluded that the thyroid hormone levels were normal. The results were influenced by heterophile antibodies leading to a false lower TSH level and suspected secondary hypothyroidism. The second case, a 40-year-old patient, was examined and followed because of the variable size thyroid nodule and initially borderline elevated TSH, after which thyroid status showed low level of total thyroid hormones and normal TSH. Based on additional analysis it was concluded that low T4 and T3 were a result of low TBG. It is a hereditary genetic disorder with no clinical significance. Conclusion. Erroneous diagnosis of thyroid disorders and potentially harmful treatment could be avoided by proving the interference or TBG deficiency whenever there is a discrepancy between the thyroid function results and the clinical picture.

Introduction: The most common cause for persistent elevation of TSH levels in hypothyroid patients treated with levothyroxine is poor compliance. The Levothyroxine Absorption Test (LAT) is usually confirmed this phenomenon called 'pseudo-malabsorption'. Case report: 60-year-old female, weight 60kg, BMI 24.3kg/m2, presented with sleepiness, tiredness, fatigue and forgetfulness. Her skin was very dry and flaky. She had low tolerance of effort, poor appetite with weight oscillation around 2kg, constipation and sometimes heartburn. Hypothyroid for ten years after radioiodine treatment of Graves' disease. Her TSH levels were higher than normal, TSH 20-70mIU/L, in spite of efforts to adjust the dose (different LT4 preparations). In last two years her daily LT4 dose was 900 (15 µg/kg), 3x300mcg, 500+400mcg. Comorbidities: depression, angina, hypertension, absolutely arrhythmias (with inadequate INR in last two months). Before testing TSH 33.6mIU/L, FT4 4.25 pmol/L. Standard (1000 µg) LAT was performed under supervision. TSH, T4 and FT4 were measured 2h, 4h, 6h and 24h upon LT4 administration. Baseline values were TSH 26.92 mIU/L; FT4 4.4pmol/L; T4 41.5pmol/L. The lack of TSH fall with slight T4 and FT4 increase, significantly below expected AUC, pointed an inadequate absorption. It was started with 300 µg LT4 oral suspension, after testing. The presence of fat in the stool and positive antiparietal antibodies increased suspicion to malabsorptiv syndrome. EGDS was performed, PH finding confirmed H. pylori positive chronic atrophic gastritis, without morphological elements for GSE. Eradication treatment and IPP were introduced. After four weeks her thyroid hormones were TSH 1.63 mIU/L; FT4 26.6pmol/L, FT3 3.87pmol/L. Conclusion: LAT is useful for identifying much rare malabsorption. The adequate treatment lead to proper substitution and avoidance of no rationale increase of levothyroxine dose.

UVOD: Nefrolitijaza se sve vise smatra sistemskom bolescu koja je udružena sa hronicnom bubrežnom insuficijencijom i kostanim poremecajima. Ako se ne leci to je hronicna bolest sa stopom ponavljanja vise od 50% za 10 godina. Pacijenti sa cistinurijom imaju visoku stopu rekurentne kalkuloze. PRIKAZ SLUCAJA: Tridesetsedmogodisnja pacijentkinja žalila se na bolove u levoj slabini sa sirenjem prema napred pri naglom ustajanju prilikom ispitivanja zbog rekurentne kalkuloze. U 24. godini ustanovljena je kalkuloza desnog bubrega i zbog hidronefroze i anurije urađena je nefrektomija. Poslednje tri godine, bar jednom godisnje, imala je anuriju a litoklast kalkulusa u pelvicnom delu levog bubrega rađenje 2009. i 2011.g. U maju 2009. prvi put je pregledana od strane nadležnog endokrinologa kada je PTH bio blago povisen 70,8 (15-65ng/l), uz uredan jonizovani kalcijum u serumu. Kvantitativne analize 24h urina pokazale su uredne vrednosti kreatinin klirensa, proteinurije, natriureze, kaliureze, normalne vrednosti kalciurije, fosfaturije, oksalurije, urikozurije i citraturije. U hormonskim analizama granican PTH 66 (10-65ng/L) i deficit vitamina D (15,3ng/L). Analiza hemijskog sastava kalkulusa ukazala je da se radi o cistinskim kalkulusima. Testiranjem sina i same pacijentkinje u Institutu za zdravstvenu zastitu majke i deteta 'dr Vukan Cupic', na osnovu povecanog izlucivanja cistina, lizina, ornitina i arginina u 24h urinu, kod pacijentkinje je potvrđena cistinurija. Savetovanaje prevencija formiranja kalkulusa (povecan unos tecnosti na 4-4,5l/d, alkalizacija urina tabletama kalijum-citrata, uz monitoring pH urina test trakama i kontrolu kalemije) uz terapiju Vigantol kapima zbog hipovitaminoze D. ZAKLJUCAK: Prevencija kalkuloze je moguca nakon pravilno postavljene dijagnoze. Zato je važno da se utvrdi uzrok nefrolitijaze.

Objective To construct a predictive score for the development or progression of Graves’ orbitopathy (GO) in Graves’ hyperthyroidism (GH). Design Prospective observational study in patients with newly diagnosed GH, treated with antithyroid drugs (ATD) for 18 months at ten participating centers from EUGOGO in 8 European countries. Methods 348 patients were included with untreated GH but without obvious GO. Mixed effects logistic regression was used to determine the best predictors. A predictive score (called PREDIGO) was constructed. Results GO occurred in 15% (mild in 13% and moderate to severe in 2%), predominantly at 6–12 months after start of ATD. Independent baseline determinants for the development of GO were clinical activity score (assigned 5 points if score > 0), TSH-binding inhibitory immunoglobulins (2 points if TBII 2–10 U/L, 5 points if TBII > 10 U/L), duration of hyperthyroid symptoms (1 point if 1–4 months, 3 points if >4 months) and smoking (2 points if current smoker). Based on the odds ratio of each of these four determinants, a quantitative predictive score (called PREDIGO) was constructed ranging from 0 to 15 with higher scores denoting higher risk; positive and negative predictive values were 0.28 (95% CI 0.20–0.37) and 0.91 (95% CI 0.87–0.94) respectively. Conclusions In patients without GO at diagnosis, 15% will develop GO (13% mild, 2% moderate to severe) during subsequent treatment with ATD for 18 months. A predictive score called PREDIGO composed of four baseline determinants was better in predicting those patients who will not develop obvious GO than who will.