clinical decision making
Delgado, V.
Citation
Delgado, V. (2010, November 11). Novel cardiac imaging technologies : implications in clinical decision making. Retrieved from
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Cardiac dysfunction is reversed upon successful treatment of Cushing’s syndrome
Eur J Endocrinol. 2010;162:331-40
Alberto M Pereira, Victoria Delgado, Johannes A Romijn, Johannes W. A. Smit, Jeroen J Bax, Richard A Feelders.
12
Chapter
Objective: In patients with active Cushing’s Syndrome (CS), cardiac structural and functional changes have been described in a limited number of patients. It is unknown whether these changes reverse after successful treatment. We therefore evaluated the changes in cardiac structure and dysfunction after successful treatment of CS, using more sensitive echocardio- graphic parameters (based on 2-dimensional strain imaging) to detect subtle changes in car- diac structure and function.
Methods: In a prospective study design, we studied 15 consecutive CS patients and 30 con- trols (matched for age, sex, body surface area, hypertension,and left ventricular [LV] systolic function). Multidirectional LV strain was evaluated by 2-dimensional speckle tracking strain imaging. Systolic (radial thickening and circumferential and longitudinal shortening) and diastolic (longitudinal strain rate at the isovolumic relaxation time [SRIVRT]) parameters were measured.
Results: At baseline, CS patients had similar LV diameters but significantly more LV hypertro- phy and impaired LV diastolic function, compared to controls. In addition, CS patients showed impaired LV shortening in the circumferential (-16.5±3.5% vs. -19.7±3.4%, p=0.013) and lon- gitudinal (-15.9±1.9% vs. -20.1 ±2.3%, p<0.001) directions and decreased SRIVRT (0.3±0.15 s-1 vs. 0.4±0.2 s-1, p=0.012) compared to controls. After normalization of corticosteroid excess, LV structural abnormalities reversed and LV circumferential and longitudinal shortening and SRIVRT normalized.
Conclusion: CS not only induces LV hypertrophy and diastolic dysfunction but also subclini- cal LV systolic dysfunction, that reverses upon normalization of corticosteroid excess.
INTRODUCTION
Cushing’s syndrome (CS) is a very rare disorder that results from endogenous hypercortisolism. CS is a fatal condition in the absenceof adequate treatment,1 but even many years after successful cure, the patients remain at increased risk for cardiovascular disease.2, 3
In patients with active CS, cardiac structural and functional changes have been described in a limited number of patients. These changes were characterized by left ventricular (LV) hypertrophy and concentric remodeling, and reduced midwall systolic performance with diastolic dysfunction.4 It is unknown whether these changes reverse after normalization of corticosteroid excess. Currently, 2-dimensional speckle tracking strain imaging constitutes a highly sensitive technique to detect subclinical LV systolic and diastolic dysfunction, which. in CS patients, may enable the detection of subclinical LV systolic dysfunction. In addition, subtle changes in LV structure and function after normalization of corticosteroid excess can be monitored. Therefore, the aim of the present study was first to evaluate cardiac structural and functional changes in CS patients with 2-dimensional speckle tracking strain imaging. Second, we also evaluated potential reversibility of these changes after normalization of corticosteroid levels using this novel imaging technique.
METHODS
Study design
In a prospective study design, patients with CS underwent echocardiography at baseline (during the untreated, active phase of the disease), at short-term follow-up after surgical treatment during a period of stable cortisol status, and at long-term follow-up after final remission. It was anticipated, that 1) successful surgery would result in a glucocorticoid withdrawal syndrome and hydrocortisone dependency, and 2) that not all patients would be in remission directly after surgery. Therefore, the timing of the post-surgical evaluations was as follows: the first post surgical evaluation up was planned at short term follow at least two weeks after surgery on a stable physiological hydrocor- tisone dose for those who were in remission, and between 2 and 6 weeks after surgery in those patients who were not in remission before additional therapy (i.e. radiotherapy) was instituted. The second post surgical evaluation was planned at least 1 year and max 18 months after documented remission. LV dimensions and function were evaluated with standard 2-dimensional echocardiogra- phy and, in addition, subclinical LV systolic and diastolic dysfunction was evaluated with 2-dimen- sional speckle tracking strain analysis. The time course for LV structural and functional changes was also studied to determine if changes occur at short- or long-term follow-up.
Patient population and evaluation of disease status
We evaluated 15 consecutive patients with CS. The diagnosis was made on clinicalgrounds together with biochemical confirmation of CS, based on the following tests: increased 24-h urinaryfree corti- sol (UFC) excretion (criterion > 220 nmol), failureof serum cortisol to suppress after low-dose dexa-
methasone (oneevening dose of 1 mg), and loss of diurnal rhythm. In case of ACTH dependent CS, we also evaluated the suppression of serumcortisol during a 7-h iv dexamethasone suppression test as describedby Biemond et al.,5 and the responseof serum cortisol and ACTH on iv CRH stimulation.6 Pituitaryimaging by magnetic resonance imagingwith iv contrast was performed in all patients with ACTH dependent hypercortisolism. In patients with ACTH independent CS, adrenal imaging was performed with computed tomography scanning.
The effect of treatment on biochemical control ofCS has been extensivelydescribed previously.7 After surgery, and if necessary after pituitary irradiation, patients were considered in remission ac- cording to normal 24-h urinary cortisolexcretion rates (< 80 µg/24 h or <220 nmol/24 h)and normal overnight suppression of serum cortisol (<1.8 µg/dl or < 50 nmol/liter) after 1 mg dexamethasone.
With these stringent criteria for cure, persistence of (subclinical)CS in these patients is unlikely. More- over,these tests were performed regularly during follow-up to detectpossible recurrence, which was notfound in the present series of patients. All patients were seen at least twice yearly by an endocrinologist,with adequate evaluation and treatment of possible deficitsof pituitary hormones.
In patients who were glucocorticoid-dependentafter surgery, recovery of thepituitary-adrenal axis was tested every three months. The hydrocortisonedose was on average 20 mg/d divided into three dosages.After withdrawal of hydrocortisone replacement for 24 h, a fastingmorning blood sample was taken for the measurement of serumcortisol concentration. Patients with a serum cortisol con- centration < 100 nmol/L were considered glucocorticoid dependent,and hydrocortisone treatment was restarted. Patients with aserum cortisol level between 100 and 500 nmol/L were testedby a ACTH stimulation test (250 µg). Normalizationof cortisol production was defined as a stimulated cortisolmore than 500 nmol/L.
In addition, 30 individuals frequency matched by age, sex, body surface area, LV ejection frac- tion and blood pressure were included as control group. These controls were recruited from an echocardiographic database, as previously described.8 We controlled for LV ejection fraction to avoid inclusion of patients with mitral regurgitation due to LV enlargement, with subsequent in- complete mitral leaflet closure. In addition, those controls who were referred for echocardiographic evaluation of known valvular disease, murmur, hypertrophic cardiomyopathy or heart failure were also excluded. Accordingly, the control group comprised individuals referred for atypical chest pain, palpitations or syncope without murmur and showed normal structural heart on echocardiography.
The study was approved by the local institutional ethicscommittee, and written informed consent was obtained from allsubjects.
Echocardiography
Patients were imaged in the left lateral decubitus position using a commercially available system equipped with a 3.5-MHz transducer (Vingmed Vivid-7, General Electric Vingmed, Horten, Norway).
Standard M-mode, 2-dimensional and color-Doppler data were acquired triggered to the QRS com- plex and saved in cine-loop format for off-line analysis (EchoPac 7.0.0, General Electric/Vingmed Ultrasound). The frame rate of the 2-dimensional grey-scale data ranged between 80-100 frames/s.
Left ventricular dimensions (end-diastolic and end-systolic diameters, end-diastolic interven-
tricular septum thickness and posterior wall thickness) were measured from M-mode recordings obtained at the parasternal long-axis views, according to the American Society of Echocardiography guidelines.9 Left ventricular mass was calculated by Devereux’s formula and indexed to body surface area.10 In addition, relative wall thickness was calculated as previously described to characterize LV geometry (a relative wall thickness >0.44 indicates LV concentric remodeling).11 End-diastolic and end-systolic LV volumes were calculated from the apical 2- and 4-chamber views, and LV ejection fraction was derived according to Simpson’s method.9
Diastolic function was evaluated by measuring the following parameters: E-wave, A-wave, E/A ratio, deceleration time of the E-wave and isovolumic relaxation time obtained from the pulsed- wave Doppler recordings.12 In addition, E’-velocity was measured at the septal and lateral mitral valve annulus from color-coded tissue Doppler imaging data and E/E’ ratio was derived, reflecting the LV filling pressures.13 Finally, left atrial volume was measured from the apical 2- and 4-chamber views as a morphologic marker of diastolic function. A left atrial volume indexed to body surface area >28 ml/m2 was considered abnormally dilated, according to current guidelines.9
Two-dimensional speckle tracking strain imaging
Multidirectional LV myocardial strain and strain rate were measured by 2-dimensional speckle track- ing strain imaging. This novel imaging tool enables the assessment of the LV mechanical properties by tracking frame-to-frame natural acoustic markers (so-called speckles), equally distributed within the myocardium and visible in the standard grey-scale 2-dimensional images.14, 15 Accordingly, LV deformation can be studied along the cardiac cycle in 3 orthogonal directions: radial, circumferen- tial and longitudinal.14, 15
From the LV mid-ventricular short-axis images, the thickening/thinning of the myocardial wall can be assessed with radial strain, whereas the myocardial shortening/lengthening along the curva- ture of the LV can be evaluated with circumferential strain. The mid-ventricular short-axis of the LV is divided in 6 segments and the global values of radial and circumferential strain are derived from the average of the 6 segmental peak systolic strain values (Figure 1, panels A and B).
From the apical 2-, 4-chamber and long-axis views, longitudinal strain evaluates the shorten- ing/lengthening of the myocardial wall, resulting from the movement of the mitral annulus plane upward/downward the LV apex. Each LV apical view is divided in 6 segments and the global longitu- dinal strain value is derived from the average of the 18 segmental peak systolic strain values (Figure 1, panel C).15
Finally, as a marker of global myocardial relaxation, global peak longitudinal strain rate at the isovolumic relaxation time (SRIVRT) is measured at the 3 apical views and averaged for final analysis (Figure 1, panel D), as previously described.16
Therefore, in the present study, LV mechanical properties were evaluated through 3 systolic param- eters (global radial, circumferential and longitudinal strains) and 1 diastolic parameter (SRIVRT), all of them derived with 2-dimensional speckle tracking strain imaging.
Intra- and inter-observer reproducibility for multidirectional strain measurements has been pre-
viously reported.17 The intraclass correlation coefficients for radial, circumferential and longitudinal strain measurements performed by the same observer were 0.97, 0.96 and 0.98, respectively, where- as the inter-observer intraclass correlation coefficients for radial, circumferential and longitudinal strain measurements performed by to independent observers were 0.81, 0.9 and 0.9, respectively.
Assays
Plasma cortisol was measured by RIA (GammaCoat; DiaSorin, Stillwater,MN). The detection limit of the assay was 25 nmol/L, andthe interassay variation ranged from 2 to 4%. Urinary free cortisol levels were measured by the same assay after purification overa C18 SPE-10 column (Baker, Phil- lipsbury, NJ).
Figure 1. Multidirectional LV strain assessment with 2-dimensional speckle tracking strain imaging.
At the mid-ventricular short axis view of the LV, radial (panel A) and circumferen- tial (panel B) strain are calculated, ob- taining the time-strain curves along the cardiac cycle for the 6 LV segments. Lon- gitudinal strain of the LV is calculated at the apical 4-chamber, 2-chamber and long-axis views (panel C). Global longi- tudinal strain value is obtained from the average of 18 segments and results are displayed in time-strain curves and po- lar map. Finally, SRIVRT (panel D) can be measured from the LV apical views, as a parameter of LV relaxation. The arrow points out the value of strain rate at the isovolumetric relaxation time.
Statistical analysis
Continuous variables are presented as mean ± standard deviation and categorical variables are pre- sented in number and frequencies. Comparisons between the group of CS patients at baseline and the control group were performed with the Mann-Whitney U-test for unpaired data. Comparisons within the group of CS patients along the follow-up were performed with Friedman’s test for re- peated measurements. LV dimensions and function were compared at 3 different stages: 1) baseline vs. short-term follow-up after surgery, 2) baseline vs. long-term follow-up after surgery, and 3) short- term vs. long-term follow-up after surgery. To adjust for inflation of the type I error with multiple tests, a posthoc analysis was applied; consequently, a p-value < 0.017 was considered significant (0.05 divided by 3 different stages). Finally, the independent determinants of multidirectional LV strain and strain rate were evaluated in univariable and multivariable linear regression analysis. All statistical analyses were performed with SPSS software (version 16.0, SPSS Inc., Chicago, Illinois). A p-value <0.05 was considered statistically significant.
RESULTS
Patient characteristics
Baseline clinical characteristics of CS patients and controls are summarized in Table 1A. Six patients were on anti-hypertensive agents (valsartan (n=2), enalapril (n=1), atenolol (n=1), metoprolol (n=1), and doxazosin (n=2). The underlying causes of CS were: ACTH dependent (n=12): ACTH producing pituitary adenoma (Cushing’s disease, 10 microadenomas and 2 macroadenomas), and ACTH inde- pendent (n=3): bilateral macronodular adrenal hyperplasia (n=1), bilateral micronodular hyperpla- sia, secondary to primary pigmented adrenocortical disease (PPNAD) (n=1), and adrenal adenoma (n=1). All patients were treated surgically: transsphenoidal adenomectomy (n=12), and unilateral (n=2) and bilateral (n=1) adrenalectomy. The patient with bilateral macronodular hyperplasia un- derwent bilateral adrenalectomy. The second patient with ACTH independent Cushing’s syndrome was diagnosed with bilateral micronodular hyperplasia, secondary to PPNAD, as part of the Carney Complex. Although PPNAD is bilateral, it is unknown whether both adrenal glands are equally af- fected with respect to autonomous cortisol production. Therefore, the patient underwent bilateral selective adrenal vein sampling, which documented much higher cortisol concentrations in the left adrenal vein. Consequently, a unilateral adrenalectomy of the presumably most affected adrenal was performed. After surgery, 24 h UFC excretion (4.2 times ULN before surgery), ACTH (suppressed before surgery), and the dexamethasone suppression test, all normalized. The third patient, with a unilateral adenoma, underwent unilateral adrenalectomy. Histological investigations confirmed the clinical diagnosis in all cases. Anti-hypertensive and anti-diabetic medication was used in 6, and 5 patients, respectively.
Changes in clinical status at short- and long-term follow-up after surgery
At short term follow up after surgery (median 1 month), at the time of the second echocardiography, 9/15 patients (60%) were in remission. Eight of these 9 patients were hydrocortisone dependent.
The 6 patients with Cushing’s disease and persistent disease were treated by pituitary irradiation (using a conventional linear accelerator (8 MeV) in a rotating field; total tumor dose: 40-45 Gy, frac- tionated in 20 sessions over a period of 4 weeks). During long-term follow-up (median 14 months), at the time of the third echocardiography, all patients were in biochemical remission. Six patients were still dependent on hydrocortisone.
After short-term follow-up after surgical treatment, systolic blood pressure decreased from 135±13 mmHg to 129±15 mmHg (p=0.168) and remained stable at long-term follow-up (127±12 mmHg, p=0.468 vs. short-term follow-up) (Table 1B). Similarly, diastolic pressure decreased progres- sively from 88 ± 12 mmHg to 85 ± 10 mmHg at short-term follow-up (p=0.347) and to 81 ± 7 mmHg at long-term follow-up (p=0.090 vs. short-term follow-up) (Table 1B). There were no significant changes in body mass index (Table 1B) or smoking status (n = 4, 27%).
Table 1
A) Baseline characteristics
Patients (N=15) Controls (N=30) p-value
Age (years) 41±12 44±11 0.329
Sex (male, %) 6 (40%) 13 (43%) 0.832
Body surface area (m2) 1.9±0.2 1.9±0.1 0.316
Body mass index (kg/m2) 28.6±4.9 24.5±4.0 0.038
Systolic blood pressure (mmHg) 135±13 134±17 0.635
Diastolic blood pressure (mmHg) 88±12 82±12 0.071
B) Changes in clinical status after surgical treatment (n=15) and after radiotherapy (n=6) Baseline Short-term
follow-up Long-term fol-
low-up p-value
Systolic blood pressure (mmHg) 135±13 129±15 127±12 0.057
Diastolic blood pressure (mmHg) 88±12 85±10 81±7 0.125
Median (IQR) 24 h UFC* (nmol)
880 (550, 3454)
586 (195, 940)
165†
(122, 220) 0.015
HbA1C (%) 5.7±1.1 5.7±0.8 5.9±1.1 0.502
Body mass index (kg/m2) 28.6 ± 4.9 28.7 ± 5.6 28.7 ± 5.6 0.905
Smoking status (n) 4 4 4
Patients on anti hypertensives (n) 6 6 4*
Patients on anti diabetics/insulin (n) 5 4 3
Patients on HC replacement (n) NA 8 6
Abbreviations: * 24 h UFC: 24 hour urinary free cortisol excretion; HC: hydrocortisone; IQR : interquartile range; NA: not applicable; † p = 0.002 vs. Baseline; *: reduction of dose in 1 patient vs. short term follow-up.
The number of patients using anti-hypertensive or anti-diabetic medication reduced from 6 to 4 and from 5 to 3 patients, respectively, after long-term follow-up. Before treatment, all 6 premenopausal female patients had secondary amenorrhea, and another 2 patients (both with pituitary macroad- enoma) had additional hormone pituitary insufficiency (both growth hormone deficiency and sec- ondary hypothyroidism). After surgery, a regular menstrual cycle was restored in all four women who obtained direct remission and in the remaining two patients after remission with additional radiotherapy (at the time of the third echo). Growth hormone deficiency and secondary hypogo- nadism persisted in the two patients after treatment. Other treatment induced deficiencies, besides hydrocortisone dependency, were not documented during the follow-up period.
Baseline echocardiography and 2-dimensional speckle tracking strain analysis: comparison between patients with active CS and controls
At baseline, there were no differences in LV diameters, volumes and ejection fraction between pa- tients with CS and controls (Table 2). However, patients with CS had significantly more LV hyper- trophy, with significantly higher values of interventricular septum and posterior wall thickness, LV mass index and relative wall thickness. In addition, patients with CS had impaired early LV relaxation, with significantly lower values of transmitral E-wave velocity, E/A ratio and significantly longer iso- Table 2. Baseline echocardiography
CS patients
(N=15) Controls
(N=30) p-value
LV dimensions and systolic function
LV end-diastolic diameter (cm) 5.0±0.6 4.9±0.4 0.981
LV end-systolic diameter (cm) 3.2±0.6 2.9±0.4 0.147
LV ejection fraction (%) 59±9 61±7 0.228
Interventricular septum thickness (cm) 1.3±0.2 1.0±0.2 0.001
Posterior wall thickness (cm) 1.2±0.2 1.0±0.2 0.008
LV mass index (g/m2) 126±37 97±20 0.008
Relative wall thickness 0.48±0.09 0.41±0.09 0.027
LV diastolic function
E-wave velocity (m/s) 0.58±0.13 0.79±0.14 <0.001
A-wave velocity (m/s) 0.65±0.22 0.61±0.15 0.718
E/A ratio 0.97±0.37 1.4±0.5 0.001
E-wave deceleration time (ms) 188±48 189±27 0.508
Isovolumic relaxation time (ms) 95±21 82±13 0.024
E’-velocity (m/s) 0.06±0.02 0.11±0.03 <0.0001
E/E’ ratio 10.9±3.8 7.3±2.3 0.002
Left atrial volume index (ml/m2) 45±14 43±14 0.480
Abbreviations: CS: Cushing’s syndrome; LV: left ventricular; SRIVRT: global peak longitudinal strain rate at the isovolumic relaxation time.
volumetricic relaxation time (Table 2). Mitral annular E’ velocity was also significantly reduced in CS patients, resulting in a significantly higher E/E’ ratio.
Two-dimensional speckle tracking strain imaging analysis demonstrated that LV shortening in the circumferential and longitudinal directions was significantly impaired in CS patients, with signifi- cantly less negative values of global circumferential strain and global longitudinal strain, compared to controls (Table 3). In contrast, there were no differences in LV global radial strain between both groups. Finally, SRIVRT was significantly lower in CS patients compared to controls, indicating im- paired global myocardial relaxation (Table 3).
Univariable and multivariable linear regression analysis were performed to evaluate the indepen- dent determinants of circumferential and longitudinal strain and SRIVRT. Cushing’s syndrome, body mass index, LV mass index were included as independent variables. As shown in Table 4, Cushing’s syndrome was the strongest independent determinant of circumferential and longitudinal strain and SRIVRT.
Table 3.
A) Baseline LV multidirectional strain assessed with 2-dimensional speckle tracking CS patients
(N=15) Controls
(N=30) p-value
Global radial strain (%) 33.8±12.8 42.1±17.1 0.144
Global circumferential strain (%) -16.5±3.5 -19.7±3.4 0.013
Global longitudinal strain (%) -15.4±1.9 -20.1±2.3 <0.001
SRIVRT (s-1) 0.3±0.1 0.4±0.2 0.012
Abbreviations: CS: Cushing’s syndrome; SRIVRT: global peak longitudinal strain rate at the isovolumic relaxation time.
B) Differences between patients with- and without complete remission at follow-up in longitudinal and circumferential shortening time course evolution.
Baseline Short-term
follow-up Long-term
follow-up p-value Global circumferential strain (%)
Remission -16.7±3.9 -18.3±4.3* -20.7±4.4† 0.011
No remission -14.4±1.9 -16.8±1.6 -19.2±2.3 0.097
Global longitudinal strain (%)
Remission -15.4±1.9 -17.1±1.3‡ -18.3±2.2§ 0.002
No remission -15.2±0.7 -15.7±2.4 -19.9±1.3 0.050
*p=0.011 vs. baseline; †p=0.017 vs. baseline and short-term follow-up; ‡p=0.008 vs. baseline; §p=0.012 vs. baseline
Changes in LV dimensions and function after surgery
After surgical treatment, there were no changes in LV internal dimensions, volumes or systolic func- tion. Importantly, there was a regression of LV hypertrophy, with a significant reduction in interven- tricular septum thickness, LV mass index and relative wall thickness (Table 5). In addition, LV diastolic function improved with significant increases in E-wave and E’ velocities and a significant reduction in indexed left atrial volume. Of note, all these significant changes were observed at long-term fol- low-up, whereas at short-term follow-up significant changes were not yet noted.
Changes in time in multidirectional LV strain after surgery
A gradual improvement in LV shortening in the circumferential and longitudinal directions was ob- served after surgical treatment, whereas no changes were noted in global radial strain (Figure 2).
Importantly, significant improvements in global circumferential and longitudinal strain were noted early at short-term follow-up after surgery and were sustained at long-term follow-up. These early improvements were observed only in patients who were in remission directly after surgery whereas in patients with persistent hypercortisolemia no significant changes were observed at short-term follow-up. Furthermore, these significant improvements in circumferential and longitudinal strains were observed at a similar extent in patients who remained under hydrocortisone therapy and in pa- tients who were not and no significant differences were observed between both groups of patients Table 4. Determinants of multidirectional left ventricular strain and strain rate.
Univariable Multivariable
Variable Beta p-value Beta p-value
Circumferential strain
Cushing’s syndrome 0.413 0.005 0.402 0.008
Body mass index 0.240 0.116 … …
LV mass index 0.358 0.018 … …
Longitudinal strain
Cushing’s syndrome 0.717 < 0.001 0.717 < 0.001
Body mass index 0.380 0.010 … …
LV mass index 0.379 0.011 … …
SRIVRT
Cushing’s syndrome -0.343 0.023 -0.338 0.027
Body mass index -0.293 0.054 … …
LV mass index -0.273 0.076 … …
Abbreviations: LV: left ventricular; SRIVRT: global peak longitudinal strain rate at the isovolumic relaxation time
at follow-up (∆Circumferential strain: 5.4±1.7 vs. 3.2±2.4, p=0.272; ∆Longitudinal strain: 3.1±2.5 vs.
3.8±2.2, p=0.639).
Similarly, global myocardial diastolic relaxation improved significantly with an increase in SRIVRT (Figure 2). However, this improvement was only noted at long-term follow-up.
DISCUSSION
This study has demonstrated for the first time that the abnormalities in LV structure and function in patients with CS are reversible upon normalization of corticosteroid excess. This has important implications for the treatment of patients exposed to persistent corticosteroid excess.
Two previous studies, involving a total of 82 patients, have evaluated cardiac function in CS.4, 18 These reports evaluated cardiac function only in the active phase of the disease and demonstrated that patients with CS commonly have abnormal LV geometry (with increased LV mass index and relative wall thickness) and LV diastolic dysfunction (impaired relaxation LV filling pattern), but pre- served LV ejection fraction.4, 18 The use of more sensitive echocardiographic parameters (such as mid-wall fractional shortening or strain imaging) may enable the detection of subtle LV systolic dys- Table 5. Changes in LV dimensions and function after surgical treatment
Baseline Short-term
follow-up Long-term
follow-up p-value LV dimensions and systolic function
LV end-diastolic diameter (cm) 5.0±0.6 5.0±0.6 5.0±0.5 0.643
LV end-systolic diameter (cm) 3.2±0.6 3.1±0.6 3.0±0.5 0.294
LV ejection fraction (%) 59±9 57±7 59±5 0.544
Interventricular septum thickness (cm) 1.3±0.2 1.3±0.2 1.0±0.2* <0.0001
Posterior wall thickness (cm) 1.2±0.2 1.0±0.2 1.0±0.2 0.218
LV mass index (g/m2) 126±37 105±19 98±31 0.013
Relative wall thickness 0.48±0.09 0.42±0.10 0.41±0.08† 0.039
LV diastolic function
E-wave velocity (m/s) 0.58±0.13 0.65±0.16 0.65±0.14 0.039
A-wave velocity (m/s) 0.65±0.22 0.63±0.20 0.65±0.23 0.385
E/A ratio 0.97±0.37 1.1±0.35 1.1±0.4 0.060
E-wave deceleration time (ms) 188±48 186±38 190±47 0.273
Isovolumic relaxation time (ms) 95±21 84±14 89±13 0.064
E’-velocity (m/s) 0.06±0.02 0.07±0.02 0.08±0.02 0.043
E/E’ ratio 10.9±3.8 9.8±4.7 9.5±3.7 0.236
Left atrial volume index (ml/m2) 45±14 40±9 39±9† 0.035
*p = 0.002 vs. Baseline; †p < 0.015 vs. Baseline Abbreviations: LV: left ventricular.
function, yielding important clinical implications for the risk stratification and clinical management of these patients.4, 19 In this regard, Muiesan et al. demonstrated the presence of subclinical LV sys- tolic dysfunction in patients with active CS by evaluating the LV mid-wall fractional shortening.4 Compared to controls, patients with CS showed more LV concentric remodeling and diastolic dys- function, whereas LV ejection fraction was preserved. In contrast, LV mid-wall fractional shortening was significantly reduced, indicating the presence of subclinical LV systolic dysfunction.4 However, Cushing’s syndrome per se and other related clinical conditions such as obesity or diabetes may in- duce ultrastructural changes that are not identified by conventional echocardiography. The miner- alocorticoid receptor and 11beta-HSD2, the enzyme that converts cortisol to the inactive cortisone, are co-expressed in human heart. Glucocorticoid excess impairs the conversion of cortisol leading to glucocorticoid-mediated mineralocorticoid effects, finally resulting in increased myocardial fi- brosis.20, 21 The presence of increased fibrosis and lipid content may induce metabolic and functional myocardial changes that can be detected with more sensitive and sophisticated imaging modalities (magnetic resonance spectroscopy and 2-dimensional speckle tracking imaging).22, 23
The present study extends these previous observations by providing full evaluation of LV di- astolic function and by studying, for the first time, myocardial deformation properties with 2-di- mensional speckle tracking strain imaging. Although the present cohort of patients had normal LV dimensions, LV mass index and relative wall thickness were increased. In addition, LV diastolic function was characterized by an impaired relaxation filling pattern in the majority of the patients, Figure 2. Changes in multidirectional LV strain at short- and long-term follow-up after surgical treat- ment for Cushing’s syndrome.
*p<0.010 vs. Baseline; †p≤0.005 vs. Short-term.
Abbreviations: SRIVRT = strain rate at the isovolumetric relaxation time.
with increased LV filling pressures, indicated by the relatively increased E/E’ ratio and enlarged left atrium. In accordance with the previous studies, LV ejection fraction was preserved. However, by applying 2-dimensional speckle tracking strain imaging, LV systolic dysfunction was detected, with deterioration in LV circumferential and longitudinal shortening. Furthermore, LV filling pressures were elevated, reflected by a decreased SRIVRT value. These findings add more insight into the cardiac pathophysiology of corticosteroid excess.
After surgical treatment for CS, the present study demonstrated, for the first time, that there is a significant reduction in LV mass and relative wall thickness together with a normalization of LV diastolic function. In addition, 2-dimensional speckle tracking strain imaging demonstrated subtle changes in LV mechanics, with a normalization of LV circumferential and longitudinal shortening and an improvement in SRIVRT indicating normalization of LV-filling pressures. Importantly, cardiac struc- tural and functional changes assessed with conventional 2-dimensional echocardiography were ob- served at long-term follow-up. In contrast, 2-dimensional speckle tracking strain imaging enabled an earlier detection of subtle changes in LV systolic performance, with a significant improvement in LV circumferential and longitudinal shortening after 1-month follow-up. Of note, these changes in myocardial mechanical properties were independent of changes in blood pressure. After normal- ization of corticosteroid levels, no significant changes in blood pressure were observed along the follow-up. Apparently, restoration of eucortisolemia can completely normalize cardiac dysfunction whereas cardiovascular risk factors, including hypertension or dyslipidemia, persisted in some pa- tients despite optimal medical treatment.2
However, we have to keep in mind that immediate surgical remission will not be obtained in a significant number (up to 40%) of the patients with Cushing’s syndrome.7 This was also the case in the present series. Radiation therapy is an effective treatment for patients with persistent disease, but normalisation of cortisol secretion only occurs after a prolonged period of time, usually after 1 to 3 years. In the mean time, the patient is exposed to persistent corticosteroid excess, and thus, to persistent alterations in LV mass and impairments in LV function.
Increased LV mass constitutes an independent risk factor for development of heart failure and concentric remodeling is related to adverse cardiovascular events and increased mortality despite preserved LV ejection fraction.24, 25 The presence of impaired LV circumferential and longitudinal shortening in patients with LV hypertrophy and preserved LV ejection fraction has been previously demonstrated using tagged magnetic resonance imaging.26 With an increasing degree of LV hyper- trophy and concentric remodeling, the subendocardial myocardial layer, responsible of the longitu- dinal and circumferential shortening, becomes more susceptible to ischemia, apoptotic and fibrosis phenomena, resulting in reduced LV longitudinal and circumferential shortening at an early stage of the disease. Instead, mid-wall myocardial layer, responsible of the radial thickening, is only affected at a late stage, when the cardiac afterload exceeds the compensatory LV hypertrophy.26 Therefore, unlike LV longitudinal and circumferential shortening, LV radial strain and ejection fraction will re- main preserved during a longer time. The onset of intensive therapies at this early stage reverses the structural cardiac abnormalities and restores the LV performance, as demonstrated by the current study.
However, in case of persistent hypercortisolism despite optimal treatment, we advocate addi- tional treatment with angiotensin-converting enzyme inhibitors in agreement with the treatment guidelines for patients with increased cardiovascular morbidity and mortality.27
Some limitations have to be acknowledged. The presence of hypertension or diabetes may in- fluence the results of the present study, since these cardiovascular risks may have a detrimental effect on LV performance. However, the inclusion of patients with CS and hypertension or diabetes strengthens the study since those patients represent a substantial part of the clinical spectrum of the disease and the daily clinical practice. In addition, the limited number of patients may have precluded us to observe significant changes in LV radial strain. Finally, the control group was not matched by body mass index, a potential confounder factor. However, the multivariable regression analyses demonstrated that Cushing’s syndrome was the strongest determinant of impaired multi- directional LV strain and strain rate.
In conclusion, patients with CS have abnormalities of LV structure and function that are revers- ible upon normalization of corticosteroid excess. These LV abnormalities reverse with an early im- provement in longitudinal and circumferential shortening and a late regression of LV hypertrophy.
Two-dimensional speckle tracking strain imaging is a valuable tool to detect subtle LV dysfunction in patients and to monitor the changes in LV performance after normalization of corticosteroid ex- cess. Considering the increased cardiovascular morbidity and mortality in Cushing syndrome, these findings have potentially important implications for all patients exposed to persistent corticosteroid excess.
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