Prognostic Relevance of Left Ventricular Global Longitudinal Strain in Patients With Heart Failure and Reduced Ejection Fraction
2023; Elsevier BV; Volume: 202; Linguagem: Inglês
10.1016/j.amjcard.2023.06.058
ISSN1879-1913
AutoresSurenjav Chimed, Jan Stassen, Xavier Galloo, Maria Chiara Meucci, Juhani Knuuti, Victoria Delgado, Pieter van der Bijl, Nina Ajmone Marsan, Jeroen J. Bax,
Tópico(s)Cardiac Imaging and Diagnostics
ResumoPatients with heart failure (HF) and reduced ejection fraction (HFrEF) are complex patients who often have a high prevalence of co-morbidities and risk factors. In the present study, we investigated the prognostic significance of left ventricular (LV) global longitudinal strain (GLS) along with important clinical and echocardiographic variables in patients with HFrEF. Patients who had a first echocardiographic diagnosis of LV systolic dysfunction, defined as LV ejection fraction ≤45%, were selected. The study population was subdivided into 2 groups based on a spline curve analysis derived optimal threshold value of LV GLS (≤10%). The primary end point was occurrence of worsening HF, whereas the composite of worsening HF and all-cause death was chosen for the secondary end point. A total of 1,873 patients (mean age 63 ± 12 years, 75% men) were analyzed. During a median follow-up of 60 months (interquartile range 27 to 60 months), 256 patients (14%) experienced worsening HF and the composite end point of worsening HF and all-cause mortality occurred in 573 patients (31%). The 5-year event-free survival rates for the primary and secondary end point were significantly lower in the LV GLS ≤10% group compared with the LV GLS >10% group. After adjustment for important clinical and echocardiographic variables, baseline LV GLS remained independently associated with a higher risk of worsening HF (hazard ratio 0.95, 95% confidence interval 0.90 to 0.99, p = 0.032) and the composite of worsening HF and all-cause mortality (hazard ratio 0.94, 95% confidence interval 0.90 to 0.97, p = 0.001). In conclusion, baseline LV GLS is associated with long-term prognosis in patients with HFrEF, independent of various clinical and echocardiographic predictors. Patients with heart failure (HF) and reduced ejection fraction (HFrEF) are complex patients who often have a high prevalence of co-morbidities and risk factors. In the present study, we investigated the prognostic significance of left ventricular (LV) global longitudinal strain (GLS) along with important clinical and echocardiographic variables in patients with HFrEF. Patients who had a first echocardiographic diagnosis of LV systolic dysfunction, defined as LV ejection fraction ≤45%, were selected. The study population was subdivided into 2 groups based on a spline curve analysis derived optimal threshold value of LV GLS (≤10%). The primary end point was occurrence of worsening HF, whereas the composite of worsening HF and all-cause death was chosen for the secondary end point. A total of 1,873 patients (mean age 63 ± 12 years, 75% men) were analyzed. During a median follow-up of 60 months (interquartile range 27 to 60 months), 256 patients (14%) experienced worsening HF and the composite end point of worsening HF and all-cause mortality occurred in 573 patients (31%). The 5-year event-free survival rates for the primary and secondary end point were significantly lower in the LV GLS ≤10% group compared with the LV GLS >10% group. After adjustment for important clinical and echocardiographic variables, baseline LV GLS remained independently associated with a higher risk of worsening HF (hazard ratio 0.95, 95% confidence interval 0.90 to 0.99, p = 0.032) and the composite of worsening HF and all-cause mortality (hazard ratio 0.94, 95% confidence interval 0.90 to 0.97, p = 0.001). In conclusion, baseline LV GLS is associated with long-term prognosis in patients with HFrEF, independent of various clinical and echocardiographic predictors. Heart failure (HF) with reduced ejection fraction (HFrEF) is the most common type of HF and is associated with a poor prognosis, even when being compared with other types of HF including HF with midrange or preserved ejection fraction (EF).1Chioncel O Lainscak M Seferovic PM Anker SD Crespo-Leiro MG Harjola VP Parissis J Laroche C Piepoli MF Fonseca C Mebazaa A Lund L Ambrosio GA Coats AJ Ferrari R Ruschitzka F Maggioni AP Filippatos G Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.Eur J Heart Fail. 2017; 19: 1574-1585Crossref PubMed Scopus (452) Google Scholar,2Meta-analysis Global Group in Chronic Heart Failure (MAGGIC)The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis.Eur Heart J. 2012; 33: 1750-1757Crossref PubMed Scopus (585) Google Scholar Left ventricular (LV) EF, estimated with 2-dimensional (2D) echocardiography, is the most frequently used imaging technique for the diagnosis and management of HFrEF.3Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Flachskampf FA Foster E Goldstein SA Kuznetsova T Lancellotti P Muraru D Picard MH Rietzschel ER Rudski L Spencer KT Tsang W Voigt JU Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.J Am Soc Echocardiogr. 2015; 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145: e876-e894PubMed Google Scholar However, the assessment of LV systolic performance with 2D LVEF has several limitations, including its reliance on geometrical assumptions.6Cikes M Solomon SD Beyond ejection fraction: an integrative approach for assessment of cardiac structure and function in heart failure.Eur Heart J. 2016; 37: 1642-1650Crossref PubMed Scopus (213) Google Scholar Moreover, LVEF underestimates LV forward stroke volume in patients with mitral and aortic regurgitation, because of retrograde flow into the left atrium (LA) or LV, respectively.7Ng ACT Delgado V Bax JJ Application of left ventricular strain in patients with aortic and mitral valve disease.Curr Opin Cardiol. 2018; 33: 470-478Crossref PubMed Scopus (8) Google Scholar LV global longitudinal strain (GLS) is a noninvasive, sensitive marker to detect subtle LV systolic dysfunction and can at least partially overcome the limitations that are associated with the assessment of LV systolic performance by 2D LVEF.8Cikes M Sutherland GR Anderson LJ Bijnens BH The role of echocardiographic deformation imaging in hypertrophic myopathies.Nat Rev Cardiol. 2010; 7: 384-396Crossref PubMed Scopus (71) Google Scholar, 9Ewe SH Haeck ML Ng AC Witkowski TG Auger D Leong DP Abate E Ajmone Marsan N Holman ER Schalij MJ Bax JJ Delgado V Detection of subtle left ventricular systolic dysfunction in patients with significant aortic regurgitation and preserved left ventricular ejection fraction: speckle tracking echocardiographic analysis.Eur Heart J Cardiovasc Imaging. 2015; 16: 992-999PubMed Google Scholar, 10Kamperidis V Marsan NA Delgado V Bax JJ Left ventricular systolic function assessment in secondary mitral regurgitation: left ventricular ejection fraction vs speckle tracking global longitudinal strain.Eur Heart J. 2016; 37: 811-816Crossref PubMed Scopus (71) Google Scholar In addition, it has proved its incremental diagnostic and prognostic value over 2D LVEF in multiple cardiovascular diseases, including valvular heart disease and different cardiomyopathies, which are also frequently noted in patients with HFrEF.1Chioncel O Lainscak M Seferovic PM Anker SD Crespo-Leiro MG Harjola VP Parissis J Laroche C Piepoli MF Fonseca C Mebazaa A Lund L Ambrosio GA Coats AJ Ferrari R Ruschitzka F Maggioni AP Filippatos G Epidemiology and one-year outcomes in patients with chronic heart failure and preserved, mid-range and reduced ejection fraction: an analysis of the ESC Heart Failure Long-Term Registry.Eur J Heart Fail. 2017; 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15: 808-817Crossref PubMed Scopus (592) Google Scholar Therefore, the assessment of LV systolic function with LV GLS could be more accurate than an LVEF-based approach. The prognostic value of LV GLS, however, has never been evaluated in a real-life, large cohort of patients with HFrEF. The present study, therefore, aims to evaluate the prognostic value of LV GLS in a large cohort of patients with HFrEF. From an ongoing registry of patients with chronic HF (Leiden University Medical Center, Leiden, The Netherlands) and first echocardiographic diagnosis of LV dysfunction, defined as an LVEF ≤45%, patients ≥18 years who presented between November 1993 and June 2020 were identified. Patients who had a diagnosis of active cancer at baseline or who died within the first 30 days of follow-up were excluded. Patients underwent complete clinical and echocardiographic evaluation at the time of the echocardiogram on which an LVEF ≤45% was first documented. Baseline clinical data were collected as documented in the departmental information system (EPD-Vision, Leiden University Medical Centre, Leiden, The Netherlands) at the time of the first echocardiogram on which an LVEF ≤45% was documented. Baseline clinical data including demographic data, cardiovascular risk factors, co-morbidities, and laboratory results were collected as recorded at the date of the index echocardiography. According to the departmental routine clinical workflow, which is based on the European Society of Cardiology guideline recommendations,4McDonagh TA Metra M Adamo M Gardner RS Baumbach A Böhm M Burri H Butler J Čelutkienė J Chioncel O Cleland JGF Coats AJS Crespo-Leiro MG Farmakis D Gilard M Heymans S Hoes AW Jaarsma T Jankowska EA Lainscak M Lam CSP Lyon AR McMurray JJV Mebazaa A Mindham R Muneretto C Francesco Piepoli M Price S Rosano GMC Ruschitzka F Kathrine Skibelund A ESC Scientific Document Group2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure.Eur Heart J. 2021; 42: 3599-3726Crossref PubMed Scopus (3284) Google Scholar most patients were initiated on guideline-directed medical therapy (GDMT) or received up-titration of GDMT during the first year after echocardiographic diagnosis of HF with LVEF ≤45%. Accordingly, GDMT was presented within 1 year after the index echocardiography. Similarly, data on invasive procedures including percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, implantable cardioverter-defibrillator (ICD), cardiac resynchronization therapy (CRT), and valvular intervention (surgical or transcatheter) were also presented within 1 year after the index echocardiography. All data used in the current analysis were collected for routine clinical purposes and handled anonymously. Written informed consent was waived by the Institutional Review Board. The investigation conforms to the principles outlined in the Declaration of Helsinki.13Rickham PP Human experimentation. Code of ethics of the World Medical Association. Declaration of Helsinki.Br Med J. 1964; 2: 177Crossref PubMed Google Scholar The index echocardiography was the first examination on which a reduced LVEF (≤45%) was diagnosed. All patients were examined in the left lateral decubitus position using a commercially available echocardiography system (Vivid 7, E9, and E95, GE Vingmed Ultrasound, Horten, Norway). M-mode and 2D images were obtained and saved in a cine-loop format for offline analysis (EchoPac 202 and 203, GE Vingmed Ultrasound, Horten, Norway). The LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) were measured on the apical 4-chamber and 2-chamber views and LVEF was calculated according to Simpson's biplane method.3Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Flachskampf FA Foster E Goldstein SA Kuznetsova T Lancellotti P Muraru D Picard MH Rietzschel ER Rudski L Spencer KT Tsang W Voigt JU Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.J Am Soc Echocardiogr. 2015; 28 (e14): 1-39Abstract Full Text Full Text PDF PubMed Scopus (7588) Google Scholar LA volume was measured on the apical 4-chamber and 2-chamber views at LV end-systole using the biplane method of disks3Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Flachskampf FA Foster E Goldstein SA Kuznetsova T Lancellotti P Muraru D Picard MH Rietzschel ER Rudski L Spencer KT Tsang W Voigt JU Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.J Am Soc Echocardiogr. 2015; 28 (e14): 1-39Abstract Full Text Full Text PDF PubMed Scopus (7588) Google Scholar and indexed for body surface area (left atrial volume index). The severity of mitral regurgitation (MR) and tricuspid regurgitation was evaluated and graded according to current recommendations.14Baumgartner H Hung J Bermejo J Chambers JB Edvardsen T Goldstein S Lancellotti P LeFevre M Miller Jr, F Otto CM Recommendations on the echocardiographic assessment of aortic valve stenosis: a focused update from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.J Am Soc Echocardiogr. 2017; 30: 372-392Abstract Full Text Full Text PDF PubMed Google Scholar, 15Lancellotti P Tribouilloy C Hagendorff A Popescu BA Edvardsen T Pierard LA Badano L Zamorano JL Scientific Document Committee of the European Association of Cardiovascular ImagingRecommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging.Eur Heart J Cardiovasc Imaging. 2013; 14: 611-644Crossref PubMed Scopus (1170) Google Scholar, 16Zoghbi WA Adams D Bonow RO Enriquez-Sarano M Foster E Grayburn PA Hahn RT Han Y Hung J Lang RM Little SH Shah DJ Shernan S Thavendiranathan P Thomas JD Weissman NJ Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography developed in collaboration with the Society for Cardiovascular Magnetic Resonance.J Am Soc Echocardiogr. 2017; 30: 303-371Abstract Full Text Full Text PDF PubMed Scopus (1834) Google Scholar Echocardiographic loops which had at least 40 frame rates per second and no foreshortening were selected for 2D speckle-tracking echocardiography-derived LV GLS measurements from the apical long-axis, 4-chamber, and 2-chamber views.3Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Flachskampf FA Foster E Goldstein SA Kuznetsova T Lancellotti P Muraru D Picard MH Rietzschel ER Rudski L Spencer KT Tsang W Voigt JU Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.J Am Soc Echocardiogr. 2015; 28 (e14): 1-39Abstract Full Text Full Text PDF PubMed Scopus (7588) Google Scholar The region of interest was automatically generated and manually adjusted to the myocardial thickness. LV GLS was subsequently averaged from 17 LV segments. LV GLS measurements in which the regional tracking was suboptimal on more than 2 myocardial segments were excluded from analysis. LV GLS values were reported as positive values. The primary end point was worsening HF. The secondary end point was the composite of worsening HF and all-cause mortality. Data on mortality were obtained from the departmental cardiology information system (EPD-Vision, Leiden University Medical Centre, The Netherlands), which is linked to the governmental death registry database. Worsening HF was defined as the first hospital admission for worsening signs and symptoms of HF or a visit to the emergency department which required intensification of intravenous diuretics after the index echocardiography. Data on worsening HF were acquired by review of medical records which were archived in the departmental information system. Follow-up time was calculated from the date of index echocardiography at which LVEF ≤45% was first documented. All patients were followed up until the occurrence of the study end point, loss of follow-up, or September 2021. Normally distributed continuous variables (assessed by the Shapiro-Wilk test and distribution histograms) are presented as mean ± SD and non- normally distributed variables as median and interquartile range (IQR). Categorical variables are presented as frequencies and percentages. To illustrate the change in hazard ratio (HR) for the primary and secondary end point across the range of baseline LV GLS, a spline curve was plotted. A baseline LV GLS value >10% was derived from the spline curve analysis, representing the value where the HR for the end point was >1 (Figure 1). Furthermore, baseline clinical and echocardiographic variables were compared between patients having an LV GLS ≤10% versus >10%. Continuous variables were compared using the independent samples t test when normally distributed, whereas the Mann–Whitney U test was used to compare continuous variables that were not normally distributed. Categorical variables were compared using chi-square tests. Univariable and multivariable Cox proportional hazard regression models were constructed to determine the relation between individual variables and study end points, and HRs with 95% confidence intervals (CIs) were reported. Variables that had a significant association with the univariable analysis (p <0.05) were included in the multivariable model. To check the incremental value of baseline LVEF and LV GLS, 2 step multivariable analysis was constructed. In the first step, baseline LVEF was included in the multivariable analysis together with other significant variables, while baseline LV GLS was introduced into the second multivariable analysis. Additional unadjusted and adjusted spline curves were built to illustrate the change in HR across the spectrum of LVEF and LV GLS versus risk of worsening HF and the composite of worsening HF and all-cause mortality with overlaid CIs. The 5-year event-free survival rates were estimated by the Kaplan–Meier method and differences between groups were compared with the log-rank test. All statistical tests were 2-sided, and a p <0.05 was considered to be statistically significant. Statistical analysis was performed using SPSS for Windows version 25.0 (IBM Corporation, Armonk, New York) and R version 4.2.0 (survival package v3.1-12, splines2 package v0.3.1, Greg package v1.3.4 and survminer 0.4.9 package, R Foundation for Statistical Computing, Vienna, Austria). A total of 1,873 patients (mean age 64 ± 12 years, 75% male) with a first echocardiographic diagnosis of LVEF ≤45% were included in the present study. Baseline characteristics of the overall population and according to the LV GLS groups are listed in Table 1. Patients with LV GLS ≤10% were more likely older (65 ± 12 vs 62 ± 13 years, p <0.001), and the prevalence of diabetes mellitus (23% vs 17%, p <0.001), arterial hypertension (42% vs 36%, p <0.001), hyperlipidemia (30% vs 27%, p = 0.044), coronary artery disease (56% vs 53%, p = 0.040), chronic kidney disease (29% vs 16%, p 10%. In contrast, patients with LV GLS ≤10% were less likely to have a family history of coronary artery disease (22% vs 31%, p <0.001) and previous history of myocardial infarction (MI) (45% vs 67%, p 10%.Table 1Baseline characteristicsOverall patient population (n=1873)LV GLS ≤10% (n=1211)LV GLS >10% (n=662)p-valueAge (years)64±1265±1262±13<0.001Male, n (%)1405 (75%)903 (75%)502 (76%)0.546BSA (m2)1.98±0.221.98±0.231.97±0.200.184Current smoker, n (%)409 (22%)236 (20%)173 (26%)0.006Ex-smoker, n (%)427 (23%)291 (24%)136 (21%)0.019DM, n (%)385 (21%)275 (23%)110 (17%)<0.001Arterial hypertension, n (%)742 (40%)507 (42%)235 (36%)<0.001Hyperlipidemia, n (%)537 (29%)360 (30%)177 (27%)0.044Family history of CAD, n (%)479 (26%)271 (22%)208 (31%)<0.001CAD, n (%)1029 (55%)676 (56%)353 (53%)0.040MI, n (%)989 (53%)545 (45%)444 (67%)<0.001COPD, n (%)174 (9%)131 (11%)43 (7%)0.134CKD, n (%)462 (25%)355 (29%)107 (16%)<0.001AF, n (%)451 (24%)345 (29%)106 (16%)0.001Hemoglobin (g/dl)14.8±2.514.7±2.514.9±2.30.208eGFR (ml/min/1.73 m2)72±2668±2679±24<0.001PCI, n (%)553 (30%)336 (28%)217 (33%)0.022CABG, n (%)385 (21%)283 (23%)102 (15%)<0.001ICD implantation, n (%)573 (31%)456 (38%)117 (18%)<0.001CRT implantation, n (%)355 (19%)302 (25%)53 (8%)<0.001Valvular intervention, n (%)399 (21%)300 (25%)99 (15%)0.016Beta-blocker, n (%)1332 (71%)840 (69%)492 (74%)0.287ACEi/ARB, n (%)1375 (73%)845 (70%)530 (80%)<0.001MRAs, n (%)479 (26%)399 (33%)80 (12%)<0.001Ca2+ channel antagonist, n (%)216 (12%)121 (10%)95 (14%)0.011Diuretics, n (%)954 (51%)765 (63%)189 (29%)<0.001OACs, n (%)791 (42%)612 (51%)179 (27%)<0.001Anti-arrhythmic, n (%)262 (14%)213 (18%)49 (7%)<0.001Digoxin, n (%)156 (8%)132 (11%)24 (4%)<0.001Statin, n (%)1260 (67%)774 (64%)486 (73%)0.001LVEDV (ml)146±72160±77120±51<0.001LVESV (ml)102±58116±6376±35<0.001LVEF (%)31±8.729±8.436±6.7<0.001LAVi (ml/m2)37±2041±1930±20<0.001Moderate-to-severe MR, n (%)638 (34%)493 (41%)145 (22%)<0.001Moderate-to-severe TR, n (%)418 (22%)332 (27%)86 (13%)<0.001LV GLS (%)9.1±4.06.7±2.213.4±2.8<0.001Values are mean ± SD.ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation. Open table in a new tab Values are mean ± SD. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation. After the initial echocardiographic diagnosis of LVEF ≤45%, invasive procedures (including PCI, CABG, ICD, and CRT implantation and valvular interventions [surgical or transcatheter]), were performed within 1-year if indicated. Patients with LV GLS ≤10% were more likely to be treated with CABG (23% vs 15%, p <0.001), ICD implantation (38% vs 18%, p <0.001), CRT implantation (25% vs 8%, p 10%. Similarly, GDMT was started or intensified within 1 year, and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (70% vs 80%, p <0.001), calcium channel antagonists (10% vs 14%, p = 0.011) and statins (64% vs 73%, p = 0.001) were significantly lower, whereas use of mineralocorticoid antagonists (33% vs 12%, p <0.001), diuretics (63% vs 29%, p <0.001), oral anticoagulants (51% vs 27%, p <0.001), antiarrhythmic therapies (18% vs 7%, p <0.001) and digoxin (11% vs 4%, p 10% group. LVEDV (160 ± 77 ml vs 120 ± 51 ml, p <0.001), LVESV (116 ± 63 ml vs 76 ± 35 ml, p <0.001), and LA volume index (41 ± 19 ml/m2 vs 30 ± 20 ml/m2, p 10% group. The presence of moderate-to-severe MR (41% vs 22%, p <0.001) and tricuspid regurgitation (27% vs 13%, p 10%. During a median follow-up of 60 (IQR 27 to 60) months, 256 patients (14%) experienced worsening HF. Cumulative event rates for worsening HF at 5 years follow-up were significantly higher in the LV GLS ≤10% group (20%, CI 18% to 22%) compared with the LV GLS >10% group (95%, CI 7% to 11%) (p 10% (log-rank p <0.0001) (Figure 1, Figure 2). The association between baseline LV GLS and worsening HF was tested using univariable and multivariable Cox proportional hazard models (Table 2, Table 3). Baseline LVEF was significantly associated with worsening HF in the univariable analysis (HR 0.97, 95% CI 0.96 to 0.98, p 35% was associated with decreased risk of worsening HF in a spline curve (Figure 3, light blue spline curve). However, the parameter lost the significant association when adjusted for other significant covariates (HR 1.01, 95% CI 0.97 to 1.05, p = 0.541). When adjusted for other significant predictors, baseline LVEF was not associated with risk of worsening HF in spline curve analysis (Figure 3, light blue spline curve).Table 2Univariable and multivariable analysis for worsening HFUnivariable analysisMultivariable analysis without LV GLSMultivariable analysis with LV GLSHR95% CIp-valueHR95% CIp-valueHR95% CIp-valueAge1.000.99-1.010.757Male1.310.97-1.770.081BSA1.260.73-2.180.405Current smoker0.910.67-1.230.525Ex-smoker1.170.88-1.560.286DM1.320.99-1.770.059Arterial hypertension1.100.85-1.420.469Hyperlipidemia1.000.76-1.310.975Family history of CAD1.080.82-1.430.585CAD1.481.12-1.960.0061.090.76-1.580.6351.070.73-1.550.739MI1.040.80-1.350.772COPD1.360.93-1.970.110CKD1.451.09-1.930.0110.770.46-1.300.3270.750.45-1.270.284AF1.230.94-1.630.135Hemoglobin*10 unit increase. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systolic volume; LVEF = left ventricular ejection fraction; LV GLS = left ventricular global longitudinal strain; MI = myocardial infarction; MRA = mineralocorticoid receptor antagonist; MR = mitral regurgitation; OACs = oral anticoagulants; PCI = percutaneous coronary intervention; TR = tricuspid regurgitation.1.061.00-1.130.061eGFR*10 unit increase. ACEi = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BSA = body surface area; CABG = coronary artery bypass graft; CAD = coronary artery disease; CI = confidence interval; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; HR = hazard ratio; ICD = implantable cardioverter-defibrillator; LAVi = left atrial volume index; LVEDV = left ventricular end-diastolic volume; LVEDV = left ventricular end-systol
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