CLINICAL INVESTIGATIONS LEFT VENTRICULAR STRAIN MECHANICS AND FUNCTION
Longitudinal Myocardial Strain Alteration Is Associated with Left Ventricular Remodeling in Asymptomatic Patients with Type 2 Diabetes Mellitus Laura Ernande, MD, PhD, Cyrille Bergerot, MD, Nicolas Girerd, MD, Helene Thibault, MD, PhD, Einar Skulstad Davidsen, MD, Pierre Gautier Pignon-Blanc, MD, Camille Amaz, MsC, Pierre Croisille, MD, PhD, Marc L. De Buyzere, PhD, Ernst R. Rietzschel, MD, PhD, Thierry C. Gillebert, MD, PhD, Philippe Moulin, MD, PhD, Mikhael Altman, MD, and Genevieve Derumeaux, MD, PhD, Lyon, Cre teil, and Nancy, France; Bergen, Norway; Ghent, Belgium
Background: In normal subjects, left ventricular (LV) dimensions have been shown to decrease over time, while wall thickness is increasing. The aim of this study was to investigate LV remodeling in a cohort of patients with type 2 diabetes mellitus during a 3-year follow-up period and its potential association with decreased longitudinal systolic strain (εL). Methods: One hundred seventy-two patients with type 2 diabetes without overt heart disease were prospectively enrolled and underwent echocardiography with speckle-tracking imaging to assess global LV εL at baseline and at 3 years. The associations between alteration in εL (defined as jεLj < 18%), LV geometry at baseline, and LV remodeling over time were evaluated. Results: Among the 172 enrolled patients, 154 completed 3-year follow-up. At baseline, patients with εL alteration had higher LV end-systolic volumes (28 6 11 vs 23 6 9 mL, P < .001) and relative wall thicknesses (RWT; 0.44 6 0.06 vs 0.40 6 0.07, P = .008) compared with those with normal εL. At 3-year follow-up, RWTs remained stable in both groups. LV volumes significantly decreased in patients with normal εL but not in patients with εL alteration. Multivariate analysis showed that εL alteration was independently associated with LV end-systolic volume (b = 5.0, P = .006) and RWT (b = 0.03, P = .03) at baseline and with changes in both LV end-diastolic volume (b = 19.1, P = .001) and LV end-systolic volume (b = 2.6, P = .047) over 3 years. Conclusions: In patients with type 2 diabetes, εL alteration was associated with higher RWT and LV volumes and with the absence of decreases in LV volumes over time, which might be an early sign of adverse LV remodeling. (J Am Soc Echocardiogr 2014;27:479-88.) Keywords: Left ventricular remodeling, Myocardial strain, Diabetes mellitus
Diabetes mellitus is associated with an increased risk for heart failure, even in the absence of coronary artery disease or hypertension, because diabetes itself is responsible for the development of diabetic cardiomyopathy.1,2 This pathology is responsible for increases in both cardiovascular morbidity and mortality.1,2 We and others have shown that patients with diabetes exhibit decreased left ventricular (LV) systolic strain compared with euglycemic subjects.3-6 It was speculated that such an abnormality could be
considered an early marker of diabetic cardiomyopathy. However, the potential impact of these subtle abnormalities on the evolution of LV function and LV geometry remains unknown. Indeed, the association between abnormal systolic strain in patients with diabetes and cardiac remodeling over time has never been investigated. Recently, large cohort studies have underlined the influence of diabetes on cardiac LV remodeling over the lifetime.7-9 Although in normal subjects, the aging process is associated with a progressive
From the Service des Explorations Fonctionnelles Cardiovasculaires & Centre d’Investigation Clinique, Louis Pradel Hospital, Lyon, France (L.E., C.B., H.T., de Me decine de Cre teil, P.G.P.-B., C.A., G.D.); INSERM U955, Team 8, Faculte dicale, Universite Paris-Est Cre teil, Cre teil, Institut Mondor de Recherche Biome France (L.E., M.A., G.D.); INSERM, Centre d’Investigations Cliniques 9501, de Lorraine, CHU de Nancy, Institut Lorrain du Cœur et des Universite Vaisseaux, Nancy, France (N.G.); CarMeN INSERM Unit 1060, Claude Bernard Lyon 1 University, Lyon, France (H.T., P.M.); Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (E.S.D.); CREATIS, UMR CNRS Jean Monnet Saint-Etienne, CHU 5220, INSERM U1044, Universite de Lyon, Lyon, France (P.C.); Department of Saint-Etienne, Universite
Cardiology, Ghent University, Ghent, Belgium (M.L.D.B., E.R.R., T.C.G.); and Department of Endocrinology, Louis Pradel Hospital, Lyon, France (P.M.). This study was supported by the Association of French Language for the Study of Diabetes Mellitus and Metabolic Diseases (D20515). ve Derumeaux, MD, PhD, Faculte de Me decine Reprint requests: Genevie Lyon-Est, CarMen INSERM Unit 1060, 8, Avenue Rockefeller, 69373 Lyon Cedex 8, France (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.01.001
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Abbreviations
ACE = Angiotensinconverting enzyme
ARB = Angiotensin receptor blocker
εL = Longitudinal systolic strain HbA1c = Glycosylated hemoglobin
LV = Left ventricular LVEDV = Left ventricular enddiastolic volume LVEF = Left ventricular ejection fraction
LVESV = Left ventricular endsystolic volume RWT = Relative wall thickness
Journal of the American Society of Echocardiography May 2014
increase in LV wall thickness and a decrease in LV cavity dimensions, the presence of diabetes induces a more pronounced increase in LV wall thickness but the absence of a proportional decrease in cavity dimensions.7 We hypothesized that in patients with type 2 diabetes mellitus, alterations in longitudinal systolic deformation are associated with LV remodeling. Therefore, the aim of this study was to investigate LV remodeling in a cohort of patients with type 2 diabetes mellitus during a 3-year follow-up period and its potential association with alteration in longitudinal systolic strain (εL).
METHODS Study Population Between February 2006 and June 2009, 172 consecutive patients with type 2 diabetes referred to the outpatient Department of Endocrinology at our institution were prospectively included. The inclusion criteria were (1) age between 35 and 75 years, (2) oral antidiabetic or insulin treatment, and (3) LVejection fraction (LVEF) > 50%. Exclusion criteria were (1) symptoms, signs (clinical or electrocardiographic), or history of heart disease; (2) presence of regional LV wall motion abnormalities; (3) absence of sinus rhythm; (4) history of cardiomyopathy, coronary artery disease, or valvular heart disease; (5) severe renal failure, defined as creatinine clearance < 30 mL/min; (6) echocardiographic images unsuitable for quantification; (7) severely uncontrolled diabetes, defined as glycosylated hemoglobin (HbA1c) > 12% or glycemia > 3 g/L; and (8) uncontrolled blood pressure at rest (defined as blood pressure > 180/100 mm Hg). All patients underwent exercise stress tests, stress echocardiography, or myocardial perfusion scintigraphy within the month before inclusion to exclude silent ischemia. Among the 172 enrolled patients, seven declined to repeat the echocardiographic examination, two were censored because of cancer treated with chemotherapy, two died (one sudden death and one pancreatic cancer), one had stress cardiomyopathy, and six had nonfatal myocardial infarctions and/or underwent revascularization. The remaining study population consisted of 154 patients. All subjects provided informed consent to participate, and the study was approved by the ethics committee of our institution. Study Design All patients underwent physical examinations, standard echocardiography, and biochemical analysis on the same day at baseline and after 3 years. Echocardiography Resting transthoracic echocardiography was performed in the left lateral decubitus position using a commercially available ultrasound
system (Vivid 7 or 9; GE Medical Systems, Oslo, Norway). All acquisitions were digitally stored in raw-data format from at least three consecutive heartbeats for offline analysis (EchoPAC; GE Vingmed Ultrasound AS, Horten, Norway), which was performed by two experienced observers blinded to the other data (L.E., C.B.). LV wall thickness was measured from M-mode images from the parasternal long-axis view according to the recommended criteria.10 Total LV wall thickness was calculated as the sum of septal wall thickness and posterior wall thickness.7 LV mass was determined as recommended10 using Devereux’s formula11 and indexed to body surface area. Relative wall thickness (RWT) was calculated as (2 posterior wall thickness at end-diastole)/LV end-diastolic diameter.10 LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) and LVEF were calculated from the apical four-chamber and two-chamber views using the modified biplane Simpson’s method.10 Using pulsed-wave Doppler, mitral inflow velocities, peak early (E) and late (A) diastolic velocities, the E/A ratio, and E-wave deceleration time were measured. The annular early diastolic velocity (e0 ) was assessed at the lateral and septal sites of the mitral annulus using pulsed-wave Doppler tissue imaging. The average e0 value (from the lateral and septal sites) was used to calculate the E/e0 ratio. Left atrial area was measured in an apical four-chamber view using planimetry, and left atrial volume was assessed as previously described.12 Strain Analysis by Speckle-Tracking Imaging Speckle-tracking analysis was performed using a dedicated software package (EchoPAC).4 Peak εL was measured in the apical fourchamber and two-chamber views (frame rate, 70–80 frames/sec) The endocardial border was manually traced from an end-systolic frame. The software automatically detected the epicardial border, and the region of interest was manually adjusted to include the entire myocardial wall. Thus, the software tracked the contour throughout the entire cardiac cycle frame by frame. The quality of tracking was verified both automatically and visually, and the region of interest was modified and corrected by the observer if judged necessary to obtain optimal tracking. The software automatically divided the LV walls into six segments for each view and calculated the segmental strain values. Each segmental peak εL value was collected, and the average of longitudinal segmental strain values was calculated for each patient and presented as εL. Alteration in εL was defined as jεLj < 18% and normal εL as jεLj $ 18% (mean value 2 standard deviations in normal subjects), as previously published by our group,4 in accordance with others13 and as reported in the American Society of Echocardiography and European Association of Echocardiography consensus statement on techniques for the quantitative evaluation of cardiac mechanics (Figure 1).14 Reproducibility To define reproducibility, 15 patients were randomly selected in the population study. In these patients, LV dimensional measurements by M-mode echocardiography, LV volumes, and εL analysis were repeated 3 months apart by the same observer and performed by a second observer. The first observer (L.E.) was blinded to previous measurements during the second analysis, and the second observer (C.B.) was blinded to measurements of the first observer. A minimum of six cardiac cycles were available for each measurement (three cardiac cycles per loop and at least two loops for each view), and the reader was allowed to select the best cardiac cycle each time and to repeat and average the measurement if judged necessary.
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Figure 1 Longitudinal systolic deformation measurement by speckle-tracking imaging in an apical four-chamber view (top) and two-chamber view (bottom). The endocardial border was manually traced from an end-systolic frame. The software automatically divided the LV walls into six segments for each view and calculated the segmental strain values. The maximal systolic strain values of each segment are shown on the left, and strain values during an entire cardiac cycle in each segment are shown on the right. The white curve represents the mean value of strain during the cardiac cycle in the considered view. (A) Longitudinal strain analysis in a patient with normal systolic strain (εL = 25.7%) and (B) in a patient with strain alteration (εL = 16.8%). Intraobserver and interobserver variability was calculated as the absolute difference divided by the average of the two measurements for each parameter and is expressed as a relative value (percentage of variability).15 Biochemistry Blood samples were taken for the biochemical analysis of renal function, triglycerides, total cholesterol, and HbA1c. Microalbuminuria was measured by immunonephelometry.
Statistical Analysis Analyses at Baseline. Normality of the continuous data was tested using a graphical method based on a histogram and quantilequantile plot analysis. If non-normal distribution was suspected, we further performed a Kolmogorov-Smirnov test. Continuous and normally distributed data are presented as mean 6 SD. Continuous data deviating from the normal distribution are presented as median (interquartile range), and categorical variables are presented as frequencies and percentages. Differences in baseline characteristics
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between patients with and without εL alteration were tested using unpaired Student’s t tests for normally distributed data, Wilcoxon’s rank-sum tests for data deviating from the normal distribution, and c2 tests for categorical variables. A simple linear regression analysis was used to assess associations between characteristics at baseline and LVESV and RWT. In the setting of linear regression, an increase of one unit of the independent variable (i.e., the explanatory variable) results in an increase of b of the dependent variable (i.e., the result variable) on an additive scale (i.e., b is added to the intercept). Association with the following baseline characteristics was tested for the two dependent variables (LVESV and RWT): age, gender, body mass index, diabetes duration, presence of a hypertension, dyslipidemia, smoking, peripheral artery disease, retinopathy, heart rate, insulin therapy, sulfonylureas, angiotensinconverting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy, HbA1c, microalbuminuria, LV thickness, and εL alteration. Then, backward selection was used to select variables independently associated with LVESV and RWT at baseline. To test whether the association between the presence of εL alteration and LVESV varied according to gender, we introduced an interaction term, gender εL alteration, to the analysis. Variables associated with P values < .10 in a simple linear regression were selected to be included in the model. Association between εL Alteration and LV Remodeling during Follow-Up. Paired t tests for normally distributed data, Wilcoxon’s matched-pairs tests for data deviating from the normal distribution, and McNemar’s tests for categorical variables were used to assess changes between baseline and follow-up in each group according to the presence or the absence of εL alteration. The association between baseline characteristics and LV volume changes during follow-up was tested using bivariate linear regression with the absolute difference between LV volume at baseline and 3-year follow-up as the dependent variable. In these models, the tested baseline variable was entered as the independent variable along with LV volume at baseline. Association with the following prespecified baseline characteristics was tested: age, gender, body mass index, diabetes duration, presence of a hypertension, dyslipidemia, smoking, peripheral artery disease, retinopathy, insulin therapy, sulfonylureas, ACE inhibitor or ARB therapy, HbA1c, microalbuminuria, LV thickness, LVEF, and εL alteration. Then, backward selection was used to determine variables independently associated with changes in LV volume during the follow-up period. To test whether the association between εL alteration and LV volumes varied according to gender, we introduced an interaction term, gender εL alteration, to the analysis. Variables associated with P values < .10 in the bivariate linear regression were selected to enter the model. The multivariate models were systematically adjusted for LV volume at baseline. P values < .05 were considered statistically significant. Statistical analyses were performed using SPSS version 17.0.0 (SPSS, Inc, Chicago, IL).
RESULTS Patients’ Characteristics at Baseline The mean age of the study population was 58 6 8 years, with a mean diabetes duration of 13 6 8 years and a mean HbA1c level of 7.7 6 1.3%. Treatment included metformin for 110 patients (71%) and insulin therapy for 70 patients (45%) (Table 1). Among the 154 patients, 36 (23%) had εL alteration (defined as jεLj < 18%). Diabetes duration was similar in the two groups. Blood pres-
Journal of the American Society of Echocardiography May 2014
sure was in the normal range in both groups. No difference was observed regarding HbA1c and renal function. Patients with εL alteration were more likely treated with renin-angiotensin system inhibitors, were less likely to be treated with sulfonylureas associated with a trend toward more frequent use of insulin therapy, and had a higher level of microalbuminuria compared with patients with a normal εL. LV Geometry and Function at Baseline Patients with εL alteration had higher LVESV and LVESV indexed to body surface area than patients with normal εL (Table 1). In addition, despite similar LV wall thicknesses and LV mass indices in the two groups, RWTs were also higher in patients with εL alteration compared with patients with normal εL. As determined by the inclusion criteria, LVEFs were in the normal range in both groups but were lower in patients with εL alteration than in those with normal εL (67 6 7% vs 71 6 7%, respectively, P = .002). Of note, the conventional diastolic functional parameters were not different in patients with and without εL alteration. Determinants of LV Geometry at Baseline Multivariate analyses were performed to evaluate the independent association between εL alteration and LV geometric parameters (Table 2). After controlling for age, gender, body mass index, diabetes duration, presence of hypertension, dyslipidemia, smoking, peripheral artery disease, retinopathy, systolic blood pressure, heart rate, insulin therapy, sulfonylureas, ACE inhibitor or ARB therapy, HbA1c, microalbuminuria, and LV wall thickness, εL alteration was independently associated with higher LVESV (b = 5.0, P = .006) and higher RWT (b = 0.03, P = .024) at baseline. Because of the collinearity of the two variables, hypertension but not ACE inhibitor or ARB therapy was initially entered in the multivariate model testing the independent associations with RWTat baseline. When ACE inhibitor or ARB therapy was entered in the model, the results remained essentially unchanged: εL alteration was independently associated with higher RWT (b = 0.03, P = .02). Of note, the association between εL alteration and LVESV was not gender specific at baseline (P = NS for the interaction term). LV Remodeling at 3-Year Follow-Up In the whole population, RWT remained stable (0.41 6 0.07 at baseline and 0.41 6 0.07 at 3 years, P = .47), but both LVEDV (79 6 22 mL at baseline and 76 6 22 mL at 3 years, P < .0001) and LVESV (24 6 9 mL at baseline and 21 6 9 mL at 3 years, P = .04 and P < .0001, respectively) decreased at 3-year follow-up. These changes in LV geometry were associated with a slight increase in LVEF (70 6 7% at baseline to 72 6 7% at 3 years, P = .002). Whereas patients with normal εL displayed small but significant decreases in LV volumes at 3 years (LVEDV, 78 6 21 to 73 6 22 mL, P = .001; LVESV, 23 6 8 to 20 6 8 mL, P < .001), LV volumes did not change in patients with εL alteration (LVEDV, 84 6 24 and 88 6 18 mL, P = .21; LVESV, 28 611 and 26 610 mL, P = .38; Figure 2). No change occurred in LV mass index, LV wall thickness, or RWT in either group (P = NS for all). Of note, women with εL alteration tended to show increased LV volumes, whereas women with normal εL had significantly decreased LV volumes at follow-up (Figure 2). During follow-up, εL remained in the normal range in patients with normal εL (20.8 6 1.8% at baseline vs 20.0 6 2.6% at 3 years, P = .02) and did not improve in patients with εL alteration at baseline (17.7 6 1.2% at baseline vs 17.1 6 2.5% at 3 years, P = .69).
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Table 1 Characteristics at baseline of the total population and according to the presence or the absence of longitudinal strain alteration Variable
Clinical characteristics Age (y) Men BMI (kg/m2) Diabetes duration (y) Treated hypertension Dyslipidemia Current smokers Peripheral artery disease Retinopathy Systolic blood pressure (mm Hg) Heart rate (beats/min) Medications Metformin Sulfonylureas Glitazones Insulin ACE inhibitors or ARBs Statins Antiplatelet agents Biologic characteristics HbA1c (%) Triglycerides (mmol/L) Total cholesterol (mmol/L) eGFR (mL/min/1.73 m2) Microalbuminuria (mg/L) Echocardiographic characteristics LV dimensions Total LV wall thickness (mm) LV mass index (g/m2) RWT 2D/speckle-tracking imaging LVEDV (mL) LVEDVi (mL/m2) LVESV (mL) LVESVi (mL/m2) LVEF (%) εL (%) LV diastolic function E/A ratio mDT (msec) E/e0 ratio LA volume (mL)
Total population (n = 154)
Normal strain (jεLj $ 18%) (n = 118)
Altered strain (jεLj < 18%) (n = 36)
58 6 8 88 (57%) 29.5 6 4.4 13 6 8 80 (52%) 90 (58%) 26 (17%) 51 (33%) 33 (21%) 132 6 16 75 6 11
58 6 8 60 (51%) 29.1 6 4.3 13 6 8 58 (49%) 71 (60%) 18 (15%) 39 (33%) 25 (21%) 131 6 16 74 6 12
57 6 8 28 (78%) 30.6 6 4.9 13 6 7 22 (61%) 19 (53%) 8 (22%) 12 (33%) 8 (22%) 135 6 18 78 6 10
.51 .003 .09 .84 .11 .30 .21 .37 .48 .20 .07
110 (71%) 64 (42%) 33 (21%) 70 (45%) 89 (58%) 89 (58%) 45 (29%)
87 (74%) 55 (47%) 28 (24%) 50 (42%) 61 (52%) 69 (58%) 32 (27%)
23 (64%) 9 (25%) 5 (14%) 20 (56%) 28 (78%) 20 (56%) 13 (36%)
.21 .02 .17 .07 .002 .52 .18
7.7 6 1.3 1.8 6 1.4 4.7 6 1.1 83 6 19 24 (11–69)
7.8 6 1.3 1.8 6 1.4 4.8 6 1.1 83 6 22 18 (10–60)
7.4 6 1.4 1.8 6 1.4 4.5 6 1.0 83 6 19 42 (15–148)
.17 .93 .17 .96 .045
20 6 3 93 6 18 0.41 6 0.07
20 6 3 92 6 19 0.40 6 0.07
21 6 2 95 6 17 0.44 6 0.06
79 6 22 42 6 10 24 6 9 13 6 5 70 6 7 19.8 6 2.4
77 6 20 79 6 22 23 6 9 12 6 4 71 6 7 20.8 6 1.8
85 6 24 79 6 22 28 6 11 14 6 5 67 6 7 17.7 6 1.2
1.0 6 0.2 240 6 54 9.7 6 2.7 46 6 13
1.0 6 0.3 240 6 51 9.8 6 2.8 45 6 13
1.0 6 0.2 239 6 61 9.3 6 2.6 47 6 14
P*
.12 .48 .008 .08 .50
Longitudinal Myocardial Strain Alteration Is Associated with Left Ventricular Remodeling in Asymptomatic Patients with Type 2 Diabetes Mellitus Laura Ernande, MD, PhD, Cyrille Bergerot, MD, Nicolas Girerd, MD, Helene Thibault, MD, PhD, Einar Skulstad Davidsen, MD, Pierre Gautier Pignon-Blanc, MD, Camille Amaz, MsC, Pierre Croisille, MD, PhD, Marc L. De Buyzere, PhD, Ernst R. Rietzschel, MD, PhD, Thierry C. Gillebert, MD, PhD, Philippe Moulin, MD, PhD, Mikhael Altman, MD, and Genevieve Derumeaux, MD, PhD, Lyon, Cre teil, and Nancy, France; Bergen, Norway; Ghent, Belgium
Background: In normal subjects, left ventricular (LV) dimensions have been shown to decrease over time, while wall thickness is increasing. The aim of this study was to investigate LV remodeling in a cohort of patients with type 2 diabetes mellitus during a 3-year follow-up period and its potential association with decreased longitudinal systolic strain (εL). Methods: One hundred seventy-two patients with type 2 diabetes without overt heart disease were prospectively enrolled and underwent echocardiography with speckle-tracking imaging to assess global LV εL at baseline and at 3 years. The associations between alteration in εL (defined as jεLj < 18%), LV geometry at baseline, and LV remodeling over time were evaluated. Results: Among the 172 enrolled patients, 154 completed 3-year follow-up. At baseline, patients with εL alteration had higher LV end-systolic volumes (28 6 11 vs 23 6 9 mL, P < .001) and relative wall thicknesses (RWT; 0.44 6 0.06 vs 0.40 6 0.07, P = .008) compared with those with normal εL. At 3-year follow-up, RWTs remained stable in both groups. LV volumes significantly decreased in patients with normal εL but not in patients with εL alteration. Multivariate analysis showed that εL alteration was independently associated with LV end-systolic volume (b = 5.0, P = .006) and RWT (b = 0.03, P = .03) at baseline and with changes in both LV end-diastolic volume (b = 19.1, P = .001) and LV end-systolic volume (b = 2.6, P = .047) over 3 years. Conclusions: In patients with type 2 diabetes, εL alteration was associated with higher RWT and LV volumes and with the absence of decreases in LV volumes over time, which might be an early sign of adverse LV remodeling. (J Am Soc Echocardiogr 2014;27:479-88.) Keywords: Left ventricular remodeling, Myocardial strain, Diabetes mellitus
Diabetes mellitus is associated with an increased risk for heart failure, even in the absence of coronary artery disease or hypertension, because diabetes itself is responsible for the development of diabetic cardiomyopathy.1,2 This pathology is responsible for increases in both cardiovascular morbidity and mortality.1,2 We and others have shown that patients with diabetes exhibit decreased left ventricular (LV) systolic strain compared with euglycemic subjects.3-6 It was speculated that such an abnormality could be
considered an early marker of diabetic cardiomyopathy. However, the potential impact of these subtle abnormalities on the evolution of LV function and LV geometry remains unknown. Indeed, the association between abnormal systolic strain in patients with diabetes and cardiac remodeling over time has never been investigated. Recently, large cohort studies have underlined the influence of diabetes on cardiac LV remodeling over the lifetime.7-9 Although in normal subjects, the aging process is associated with a progressive
From the Service des Explorations Fonctionnelles Cardiovasculaires & Centre d’Investigation Clinique, Louis Pradel Hospital, Lyon, France (L.E., C.B., H.T., de Me decine de Cre teil, P.G.P.-B., C.A., G.D.); INSERM U955, Team 8, Faculte dicale, Universite Paris-Est Cre teil, Cre teil, Institut Mondor de Recherche Biome France (L.E., M.A., G.D.); INSERM, Centre d’Investigations Cliniques 9501, de Lorraine, CHU de Nancy, Institut Lorrain du Cœur et des Universite Vaisseaux, Nancy, France (N.G.); CarMeN INSERM Unit 1060, Claude Bernard Lyon 1 University, Lyon, France (H.T., P.M.); Department of Heart Disease, Haukeland University Hospital, Bergen, Norway (E.S.D.); CREATIS, UMR CNRS Jean Monnet Saint-Etienne, CHU 5220, INSERM U1044, Universite de Lyon, Lyon, France (P.C.); Department of Saint-Etienne, Universite
Cardiology, Ghent University, Ghent, Belgium (M.L.D.B., E.R.R., T.C.G.); and Department of Endocrinology, Louis Pradel Hospital, Lyon, France (P.M.). This study was supported by the Association of French Language for the Study of Diabetes Mellitus and Metabolic Diseases (D20515). ve Derumeaux, MD, PhD, Faculte de Me decine Reprint requests: Genevie Lyon-Est, CarMen INSERM Unit 1060, 8, Avenue Rockefeller, 69373 Lyon Cedex 8, France (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.01.001
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Abbreviations
ACE = Angiotensinconverting enzyme
ARB = Angiotensin receptor blocker
εL = Longitudinal systolic strain HbA1c = Glycosylated hemoglobin
LV = Left ventricular LVEDV = Left ventricular enddiastolic volume LVEF = Left ventricular ejection fraction
LVESV = Left ventricular endsystolic volume RWT = Relative wall thickness
Journal of the American Society of Echocardiography May 2014
increase in LV wall thickness and a decrease in LV cavity dimensions, the presence of diabetes induces a more pronounced increase in LV wall thickness but the absence of a proportional decrease in cavity dimensions.7 We hypothesized that in patients with type 2 diabetes mellitus, alterations in longitudinal systolic deformation are associated with LV remodeling. Therefore, the aim of this study was to investigate LV remodeling in a cohort of patients with type 2 diabetes mellitus during a 3-year follow-up period and its potential association with alteration in longitudinal systolic strain (εL).
METHODS Study Population Between February 2006 and June 2009, 172 consecutive patients with type 2 diabetes referred to the outpatient Department of Endocrinology at our institution were prospectively included. The inclusion criteria were (1) age between 35 and 75 years, (2) oral antidiabetic or insulin treatment, and (3) LVejection fraction (LVEF) > 50%. Exclusion criteria were (1) symptoms, signs (clinical or electrocardiographic), or history of heart disease; (2) presence of regional LV wall motion abnormalities; (3) absence of sinus rhythm; (4) history of cardiomyopathy, coronary artery disease, or valvular heart disease; (5) severe renal failure, defined as creatinine clearance < 30 mL/min; (6) echocardiographic images unsuitable for quantification; (7) severely uncontrolled diabetes, defined as glycosylated hemoglobin (HbA1c) > 12% or glycemia > 3 g/L; and (8) uncontrolled blood pressure at rest (defined as blood pressure > 180/100 mm Hg). All patients underwent exercise stress tests, stress echocardiography, or myocardial perfusion scintigraphy within the month before inclusion to exclude silent ischemia. Among the 172 enrolled patients, seven declined to repeat the echocardiographic examination, two were censored because of cancer treated with chemotherapy, two died (one sudden death and one pancreatic cancer), one had stress cardiomyopathy, and six had nonfatal myocardial infarctions and/or underwent revascularization. The remaining study population consisted of 154 patients. All subjects provided informed consent to participate, and the study was approved by the ethics committee of our institution. Study Design All patients underwent physical examinations, standard echocardiography, and biochemical analysis on the same day at baseline and after 3 years. Echocardiography Resting transthoracic echocardiography was performed in the left lateral decubitus position using a commercially available ultrasound
system (Vivid 7 or 9; GE Medical Systems, Oslo, Norway). All acquisitions were digitally stored in raw-data format from at least three consecutive heartbeats for offline analysis (EchoPAC; GE Vingmed Ultrasound AS, Horten, Norway), which was performed by two experienced observers blinded to the other data (L.E., C.B.). LV wall thickness was measured from M-mode images from the parasternal long-axis view according to the recommended criteria.10 Total LV wall thickness was calculated as the sum of septal wall thickness and posterior wall thickness.7 LV mass was determined as recommended10 using Devereux’s formula11 and indexed to body surface area. Relative wall thickness (RWT) was calculated as (2 posterior wall thickness at end-diastole)/LV end-diastolic diameter.10 LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) and LVEF were calculated from the apical four-chamber and two-chamber views using the modified biplane Simpson’s method.10 Using pulsed-wave Doppler, mitral inflow velocities, peak early (E) and late (A) diastolic velocities, the E/A ratio, and E-wave deceleration time were measured. The annular early diastolic velocity (e0 ) was assessed at the lateral and septal sites of the mitral annulus using pulsed-wave Doppler tissue imaging. The average e0 value (from the lateral and septal sites) was used to calculate the E/e0 ratio. Left atrial area was measured in an apical four-chamber view using planimetry, and left atrial volume was assessed as previously described.12 Strain Analysis by Speckle-Tracking Imaging Speckle-tracking analysis was performed using a dedicated software package (EchoPAC).4 Peak εL was measured in the apical fourchamber and two-chamber views (frame rate, 70–80 frames/sec) The endocardial border was manually traced from an end-systolic frame. The software automatically detected the epicardial border, and the region of interest was manually adjusted to include the entire myocardial wall. Thus, the software tracked the contour throughout the entire cardiac cycle frame by frame. The quality of tracking was verified both automatically and visually, and the region of interest was modified and corrected by the observer if judged necessary to obtain optimal tracking. The software automatically divided the LV walls into six segments for each view and calculated the segmental strain values. Each segmental peak εL value was collected, and the average of longitudinal segmental strain values was calculated for each patient and presented as εL. Alteration in εL was defined as jεLj < 18% and normal εL as jεLj $ 18% (mean value 2 standard deviations in normal subjects), as previously published by our group,4 in accordance with others13 and as reported in the American Society of Echocardiography and European Association of Echocardiography consensus statement on techniques for the quantitative evaluation of cardiac mechanics (Figure 1).14 Reproducibility To define reproducibility, 15 patients were randomly selected in the population study. In these patients, LV dimensional measurements by M-mode echocardiography, LV volumes, and εL analysis were repeated 3 months apart by the same observer and performed by a second observer. The first observer (L.E.) was blinded to previous measurements during the second analysis, and the second observer (C.B.) was blinded to measurements of the first observer. A minimum of six cardiac cycles were available for each measurement (three cardiac cycles per loop and at least two loops for each view), and the reader was allowed to select the best cardiac cycle each time and to repeat and average the measurement if judged necessary.
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Figure 1 Longitudinal systolic deformation measurement by speckle-tracking imaging in an apical four-chamber view (top) and two-chamber view (bottom). The endocardial border was manually traced from an end-systolic frame. The software automatically divided the LV walls into six segments for each view and calculated the segmental strain values. The maximal systolic strain values of each segment are shown on the left, and strain values during an entire cardiac cycle in each segment are shown on the right. The white curve represents the mean value of strain during the cardiac cycle in the considered view. (A) Longitudinal strain analysis in a patient with normal systolic strain (εL = 25.7%) and (B) in a patient with strain alteration (εL = 16.8%). Intraobserver and interobserver variability was calculated as the absolute difference divided by the average of the two measurements for each parameter and is expressed as a relative value (percentage of variability).15 Biochemistry Blood samples were taken for the biochemical analysis of renal function, triglycerides, total cholesterol, and HbA1c. Microalbuminuria was measured by immunonephelometry.
Statistical Analysis Analyses at Baseline. Normality of the continuous data was tested using a graphical method based on a histogram and quantilequantile plot analysis. If non-normal distribution was suspected, we further performed a Kolmogorov-Smirnov test. Continuous and normally distributed data are presented as mean 6 SD. Continuous data deviating from the normal distribution are presented as median (interquartile range), and categorical variables are presented as frequencies and percentages. Differences in baseline characteristics
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between patients with and without εL alteration were tested using unpaired Student’s t tests for normally distributed data, Wilcoxon’s rank-sum tests for data deviating from the normal distribution, and c2 tests for categorical variables. A simple linear regression analysis was used to assess associations between characteristics at baseline and LVESV and RWT. In the setting of linear regression, an increase of one unit of the independent variable (i.e., the explanatory variable) results in an increase of b of the dependent variable (i.e., the result variable) on an additive scale (i.e., b is added to the intercept). Association with the following baseline characteristics was tested for the two dependent variables (LVESV and RWT): age, gender, body mass index, diabetes duration, presence of a hypertension, dyslipidemia, smoking, peripheral artery disease, retinopathy, heart rate, insulin therapy, sulfonylureas, angiotensinconverting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy, HbA1c, microalbuminuria, LV thickness, and εL alteration. Then, backward selection was used to select variables independently associated with LVESV and RWT at baseline. To test whether the association between the presence of εL alteration and LVESV varied according to gender, we introduced an interaction term, gender εL alteration, to the analysis. Variables associated with P values < .10 in a simple linear regression were selected to be included in the model. Association between εL Alteration and LV Remodeling during Follow-Up. Paired t tests for normally distributed data, Wilcoxon’s matched-pairs tests for data deviating from the normal distribution, and McNemar’s tests for categorical variables were used to assess changes between baseline and follow-up in each group according to the presence or the absence of εL alteration. The association between baseline characteristics and LV volume changes during follow-up was tested using bivariate linear regression with the absolute difference between LV volume at baseline and 3-year follow-up as the dependent variable. In these models, the tested baseline variable was entered as the independent variable along with LV volume at baseline. Association with the following prespecified baseline characteristics was tested: age, gender, body mass index, diabetes duration, presence of a hypertension, dyslipidemia, smoking, peripheral artery disease, retinopathy, insulin therapy, sulfonylureas, ACE inhibitor or ARB therapy, HbA1c, microalbuminuria, LV thickness, LVEF, and εL alteration. Then, backward selection was used to determine variables independently associated with changes in LV volume during the follow-up period. To test whether the association between εL alteration and LV volumes varied according to gender, we introduced an interaction term, gender εL alteration, to the analysis. Variables associated with P values < .10 in the bivariate linear regression were selected to enter the model. The multivariate models were systematically adjusted for LV volume at baseline. P values < .05 were considered statistically significant. Statistical analyses were performed using SPSS version 17.0.0 (SPSS, Inc, Chicago, IL).
RESULTS Patients’ Characteristics at Baseline The mean age of the study population was 58 6 8 years, with a mean diabetes duration of 13 6 8 years and a mean HbA1c level of 7.7 6 1.3%. Treatment included metformin for 110 patients (71%) and insulin therapy for 70 patients (45%) (Table 1). Among the 154 patients, 36 (23%) had εL alteration (defined as jεLj < 18%). Diabetes duration was similar in the two groups. Blood pres-
Journal of the American Society of Echocardiography May 2014
sure was in the normal range in both groups. No difference was observed regarding HbA1c and renal function. Patients with εL alteration were more likely treated with renin-angiotensin system inhibitors, were less likely to be treated with sulfonylureas associated with a trend toward more frequent use of insulin therapy, and had a higher level of microalbuminuria compared with patients with a normal εL. LV Geometry and Function at Baseline Patients with εL alteration had higher LVESV and LVESV indexed to body surface area than patients with normal εL (Table 1). In addition, despite similar LV wall thicknesses and LV mass indices in the two groups, RWTs were also higher in patients with εL alteration compared with patients with normal εL. As determined by the inclusion criteria, LVEFs were in the normal range in both groups but were lower in patients with εL alteration than in those with normal εL (67 6 7% vs 71 6 7%, respectively, P = .002). Of note, the conventional diastolic functional parameters were not different in patients with and without εL alteration. Determinants of LV Geometry at Baseline Multivariate analyses were performed to evaluate the independent association between εL alteration and LV geometric parameters (Table 2). After controlling for age, gender, body mass index, diabetes duration, presence of hypertension, dyslipidemia, smoking, peripheral artery disease, retinopathy, systolic blood pressure, heart rate, insulin therapy, sulfonylureas, ACE inhibitor or ARB therapy, HbA1c, microalbuminuria, and LV wall thickness, εL alteration was independently associated with higher LVESV (b = 5.0, P = .006) and higher RWT (b = 0.03, P = .024) at baseline. Because of the collinearity of the two variables, hypertension but not ACE inhibitor or ARB therapy was initially entered in the multivariate model testing the independent associations with RWTat baseline. When ACE inhibitor or ARB therapy was entered in the model, the results remained essentially unchanged: εL alteration was independently associated with higher RWT (b = 0.03, P = .02). Of note, the association between εL alteration and LVESV was not gender specific at baseline (P = NS for the interaction term). LV Remodeling at 3-Year Follow-Up In the whole population, RWT remained stable (0.41 6 0.07 at baseline and 0.41 6 0.07 at 3 years, P = .47), but both LVEDV (79 6 22 mL at baseline and 76 6 22 mL at 3 years, P < .0001) and LVESV (24 6 9 mL at baseline and 21 6 9 mL at 3 years, P = .04 and P < .0001, respectively) decreased at 3-year follow-up. These changes in LV geometry were associated with a slight increase in LVEF (70 6 7% at baseline to 72 6 7% at 3 years, P = .002). Whereas patients with normal εL displayed small but significant decreases in LV volumes at 3 years (LVEDV, 78 6 21 to 73 6 22 mL, P = .001; LVESV, 23 6 8 to 20 6 8 mL, P < .001), LV volumes did not change in patients with εL alteration (LVEDV, 84 6 24 and 88 6 18 mL, P = .21; LVESV, 28 611 and 26 610 mL, P = .38; Figure 2). No change occurred in LV mass index, LV wall thickness, or RWT in either group (P = NS for all). Of note, women with εL alteration tended to show increased LV volumes, whereas women with normal εL had significantly decreased LV volumes at follow-up (Figure 2). During follow-up, εL remained in the normal range in patients with normal εL (20.8 6 1.8% at baseline vs 20.0 6 2.6% at 3 years, P = .02) and did not improve in patients with εL alteration at baseline (17.7 6 1.2% at baseline vs 17.1 6 2.5% at 3 years, P = .69).
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Table 1 Characteristics at baseline of the total population and according to the presence or the absence of longitudinal strain alteration Variable
Clinical characteristics Age (y) Men BMI (kg/m2) Diabetes duration (y) Treated hypertension Dyslipidemia Current smokers Peripheral artery disease Retinopathy Systolic blood pressure (mm Hg) Heart rate (beats/min) Medications Metformin Sulfonylureas Glitazones Insulin ACE inhibitors or ARBs Statins Antiplatelet agents Biologic characteristics HbA1c (%) Triglycerides (mmol/L) Total cholesterol (mmol/L) eGFR (mL/min/1.73 m2) Microalbuminuria (mg/L) Echocardiographic characteristics LV dimensions Total LV wall thickness (mm) LV mass index (g/m2) RWT 2D/speckle-tracking imaging LVEDV (mL) LVEDVi (mL/m2) LVESV (mL) LVESVi (mL/m2) LVEF (%) εL (%) LV diastolic function E/A ratio mDT (msec) E/e0 ratio LA volume (mL)
Total population (n = 154)
Normal strain (jεLj $ 18%) (n = 118)
Altered strain (jεLj < 18%) (n = 36)
58 6 8 88 (57%) 29.5 6 4.4 13 6 8 80 (52%) 90 (58%) 26 (17%) 51 (33%) 33 (21%) 132 6 16 75 6 11
58 6 8 60 (51%) 29.1 6 4.3 13 6 8 58 (49%) 71 (60%) 18 (15%) 39 (33%) 25 (21%) 131 6 16 74 6 12
57 6 8 28 (78%) 30.6 6 4.9 13 6 7 22 (61%) 19 (53%) 8 (22%) 12 (33%) 8 (22%) 135 6 18 78 6 10
.51 .003 .09 .84 .11 .30 .21 .37 .48 .20 .07
110 (71%) 64 (42%) 33 (21%) 70 (45%) 89 (58%) 89 (58%) 45 (29%)
87 (74%) 55 (47%) 28 (24%) 50 (42%) 61 (52%) 69 (58%) 32 (27%)
23 (64%) 9 (25%) 5 (14%) 20 (56%) 28 (78%) 20 (56%) 13 (36%)
.21 .02 .17 .07 .002 .52 .18
7.7 6 1.3 1.8 6 1.4 4.7 6 1.1 83 6 19 24 (11–69)
7.8 6 1.3 1.8 6 1.4 4.8 6 1.1 83 6 22 18 (10–60)
7.4 6 1.4 1.8 6 1.4 4.5 6 1.0 83 6 19 42 (15–148)
.17 .93 .17 .96 .045
20 6 3 93 6 18 0.41 6 0.07
20 6 3 92 6 19 0.40 6 0.07
21 6 2 95 6 17 0.44 6 0.06
79 6 22 42 6 10 24 6 9 13 6 5 70 6 7 19.8 6 2.4
77 6 20 79 6 22 23 6 9 12 6 4 71 6 7 20.8 6 1.8
85 6 24 79 6 22 28 6 11 14 6 5 67 6 7 17.7 6 1.2
1.0 6 0.2 240 6 54 9.7 6 2.7 46 6 13
1.0 6 0.3 240 6 51 9.8 6 2.8 45 6 13
1.0 6 0.2 239 6 61 9.3 6 2.6 47 6 14
P*
.12 .48 .008 .08 .50
