Endocrine DOI 10.1007/s12020-014-0348-1
ORIGINAL ARTICLE
Atrial conduction times and left atrium mechanical functions in patients with active acromegaly A. Ilter • A. Kırıs¸ • S¸ . Kaplan • M. Kutlu • M. S¸ ahin • C. Erem • N. Civan • F. Kangu¨l
Received: 24 February 2014 / Accepted: 25 June 2014 Ó Springer Science+Business Media New York 2014
Abstract The aim of this study was to evaluate atrial electromechanical delay (EMD), P wave dispersion (Pwd), and left atrial (LA) mechanical functions in patients with active acromegaly. Twenty-three patients with active acromegaly and 27 age- and sex-matched controls were included in this study. All atrial electromechanical interval parameters (PA lateral, PA septum, PA tricuspid, interatrial EMD, intra-LA EMD, and intra-right atrial EMD) were measured from mitral lateral annulus, mitral septal annulus, and right ventricular tricuspid annulus by tissue Doppler imaging. LA volumes were measured by the disk method in the apical four-chamber view and were indexed to the body surface area. Mechanical function parameters of LA were calculated. Pwd was performed by 12-lead electrocardiograms. Atrial electromechanical intervals (PA lateral, PA septum, PA tricuspid, interatrial EMD, intra-LA EMD, and intra-right atrial EMD) and Pwd were similar between patients with acromegaly and control subjects (all p [ 0.05). LA volumes (maximum, minimum, and A. Ilter (&) Department of Cardiology, Kanuni Training and Research Hospital, Trabzon, Turkey e-mail: [email protected] A. Kırıs¸ S¸ . Kaplan M. Kutlu Department of Cardiology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey M. S¸ ahin Department of Cardiology, Ahi Evren Cardiovascular and Thoracic Surgery Training and Research Hospital, Trabzon, Turkey C. Erem N. Civan F. Kangu¨l Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
presystolic) and LA mechanical functions were not significantly different between the groups (all p [ 0.05). Additionally, serum levels of growth hormone and insulinlike growth factor-1 were not correlated with atrial electromechanical parameters and LA mechanical functions. Atrial electrical conduction times were not prolonged and LA mechanical functions were not impaired in patients with active acromegaly compared with controls. And the prevalence of supraventricular arrhythmia risk may not increase in this population. Keywords Active acromegaly Atrial electromechanical delay Left atrial functions Growth hormone Tissue Doppler imaging
Introduction Acromegaly is a rare disease leading to various cardiovascular disturbances, such as left ventricular (LV) hypertrophy [1–4], diastolic dysfunction [5], hypertension (HT) [6], cardiomyopathy [7, 8], and cardiac dysrhythmias [9]. Acromegaly is also associated with increased mortality and morbidity due to cardiovascular complications in large clinical series [10–12]. Several studies have focused on LV functions and structure in patients with acromegaly [1, 13, 14]. Impairment of LV synchronicity [15] and global function (assessment with Tei index) has also been reported in acromegalic patients [5]. To the best of our knowledge, however, left atrial (LA) functions and atrial conduction abnormalities have not previously been investigated in patients with acromegaly. LA volumes and mechanical functions have been identified as potential indicators of cardiac disease and arrhythmias in previous studies
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[16–18]. Non-homogeneous propagation of sinus impulses and inter- and intra-atrial conduction delays are well-documented electrophysiological alterations of the atria prone to atrial fibrillation (AF) [19]. In contrast to LA size, atrial conduction times reflect both electrical and structural remodeling of the atria [20–22]. The purpose of this study was to evaluate atrial conduction times and LA atrial mechanical functions in patients with active acromegaly.
valvular heart disease, pulmonary or neurological disease, pericarditis or myocarditis, familial hypertrophic cardiomyopathy, sleep apnea disorder, hypopituitarism, chronic obstructive pulmonary disease, hepatic or renal disease, heart failure, and poor echocardiographic imaging. The study was conducted in accordance with the guidelines set out in the declaration of Helsinki. Our university local Ethical Committee approved the study protocol. Laboratory analysis
Patients and methods Study population Twenty-three patients with active acromegaly (11 women, 12 men; mean age 45.5 ± 12.2 yrs) with normal sinus rhythm at electrocardiography (ECG) were included in this cross-sectional study. Twenty-seven healthy control subjects (19 women, 8 men; mean age 47.3 ± 9.1 yrs) were also enrolled as the control group. Active acromegaly was diagnosed by the presence of typical clinical signs and symptoms (soft tissue overgrowth, acral enlargement, headache, HT, hyperhidrosis, weight gain, and acanthosis nigricans), random growth hormone (GH) [1 ng/ml, nadir GH C0.4 ng/ml after 75 g oral glucose tolerance test (OGTT), and elevated insulin-like growth factor-1 (IGF-1) levels above the normal range for age and sex [23, 24]. Duration of disease was estimated by the onset of clinical symptoms, assessment of patient images, and findings of acromegaly. All patients were affected by active acromegaly at the time of the study. Duration of disease ranged from 1 to 30 yrs (mean 7.7 ± 7.2 yrs). In all patients, imaging of the pituitary was performed using magnetic resonance imaging (MRI) showing pituitary adenoma (14 and 9 microadenomas). All patients with acromegaly had pure GHsecreting adenomas. Pituitary adenomas were removed by selective transsphenoidal surgery, and immunohistochemistry confirmed the diagnosis in all patients. Adjuvant radiotherapy and/or medical therapy (11 patients received octreotide-LAR, six received cabergoline, and six patients received lanreotide) were administered to patients with elevated GH and IGF-1 levels after surgery. Mean duration of medical therapy with somatostatin analogs (SSA) in this study was 36.06 ± 25.2 months. Demographic characteristics, biochemical data, and ECGs were obtained for the entire study population. Exclusion criteria were previous coronary artery disease and myocardial infarction, acute coronary syndrome, uncontrolled HT (resting blood pressure C140/ 90 mmHg), atrial flutter or fibrillation, frequent ventricular pre-excitation and atrio-ventricular conduction abnormalities, medications known to alter cardiac conduction, alcohol abuse, cardiac pacing, prolonged QRS duration (C120 msn), reduced LV ejection fraction (LVEF \ 50 %), significant
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Blood was collected in the morning between 08:00 and 09:00 h after overnight fasting in order to avoid differences in diurnal variations of hormonal parameters. Serum GH and IGF-1 levels were measured using a chemiluminescent immunometric assay (Immulite 2000 DPC, Diagnostic Product Corporation, 5210 Pacific Concourse, LA). GH values were obtained via 75 g OGTT. Nadir GH values assessed during OGTT and random GH values were recorded. The normal ageadjusted reference values for IGF-1 levels were 21–25 yrs, 116–358 ng/ml; 26–30 yrs, 117–329 ng/ml; 31–35 yrs, 115–307 ng/ml; 36–40 yrs, 109–284 ng/ml; 41–45 yrs, 101–267 ng/ml; 46–50 yrs, 94–252 ng/ml; 51–55 yrs, 87–238 ng/ml; 56–60 yrs, 81–225 ng/ml; 61–65 yrs, 75–212 ng/ml; 66–70 yrs, 69–200 ng/ml; 71–75 yrs, 64–188 ng/ml; and 76–80 yrs, 59–177 ng/ml [25]. Assessment of P wave dispersion on 12-lead ECG Twelve-lead ECGs were obtained from all patients using a MAC1200 8T electrocardiograph (GE Healthcare, Freiburg, Germany) at a paper speed of 50 mm/s and 20 mm/ mV. All recordings were performed in the same quiet room through spontaneous breathing, followed by 20 min of adjustment in the supine position. P wave duration measurements were performed manually by two cardiologists using calipers and a magnifying lens for exact definition of the ECG deflection. The beginning of the P wave was defined as the point where the initial deflection of the P wave crossed the isoelectric line, and the end of the P wave was defined as the point where the final deflection of the P wave crossed the isoelectric line. ECG recordings with measurable P waves in fewer than ten leads were excluded from analysis. The difference between P wave maximum and P wave minimum durations was defined as Pwd [26]. Intra- and inter-observer variability was calculated as less than 5 % for PA maximum and PA minimum durations. Standard echocardiographic assessment All patients were evaluated by transthoracic M-mode, two dimensional (2D), pulsed wave (PW), continuous wave (CW), color flow, and tissue Doppler imaging (TDI). All
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examinations were performed using the GE-Vivid seven system (GE Vingmed Ultrasound AS, Horten, Norway) with a 2–4 MHz transducer at a depth of 16 cm. Continuous single-lead ECG recording was obtained during echocardiography. All patients were imaged in the left lateral decubitus position. 2D and conventional Doppler examinations were performed in the parasternal and apical views according to American Society of Echocardiography (ASE) guidelines [27]. LV diameters and wall thickness were measured using M-mode echocardiography. LV ejection fraction was calculated using the apical two- and four-chamber views by Simpson’s method, according to ASE guidelines [27]. The mitral valve inflow pattern and diastolic parameters (E-wave, A-wave, E’-wave, and E/A ratio) were measured using PW Doppler. LV mass index was calculated using the formula with the Devereux equation [28]. LA volumes were obtained echocardiographically from the apical four-chamber views using the biplane area length method [20, 29]. LA maximum volume (Vmax) at the end-systolic phase (onset of the mitral opening), LA minimum volume (Vmin) at the end-diastolic phase (onset of the mitral closure), and LA volume before atrial systole (Vp) were measured at the beginning of atrial systole (onset of P wave on ECG) and indexed to the body surface area. LA function parameters were calculated as LA active emptying volume = Vp-Vmin; LA active emptying fraction = [(Vp-Vmin)/Vp] 9 100 %; LA passive emptying volume = Vmax-Vp; and LA passive emptying fraction = [(Vmax-Vp)/Vmax] 9 100 % [26]. Tissue Doppler echocardiographic assessment Tissue Doppler imaging was performed using transducer frequencies of 3.5–4.0 MHz. The spectral pulsed Doppler signal filters were adjusted for a Nyquist limit of 15–20 cm/s. Myocardial TDI velocities including peak systolic (Sm), early diastolic (Em), and late diastolic velocities (Am) were measured via spectral pulsed Doppler as of the LV-free wall from the apical four-chamber view [27]. The ultrasound beam was positioned as parallel as possible to the myocardial segment in order to obtain an optimal imaging angle. The time interval from the P wave onset on the surface ECG to the beginning of the late diastolic wave (Am) was defined as atrial electromechanical coupling (PA interval) (Fig. 1). The PA interval is the interval from the P wave onset on the surface electrocardiogram to the beginning of the late diastolic A’-wave. This was obtained from lateral mitral annulus, septal mitral annulus, and right ventricular tricuspid annulus and referred to as PA lateral, PA septum, and PA tricuspid, respectively. The difference between PA lateral and PA tricuspid was defined as interatrial electromechanical delay (EMD), the difference between PA septum and PA tricuspid as intra-right atrial EMD, and the difference between PA lateral and PA septum
Fig. 1 Tissue Doppler imaging showing the atrial electromechanical delay from P wave onset on surface electrocardiography to the beginning of the late diastolic A wave
as intra-LA EMD [26, 27]. All measurements were repeated three times, and mean values were obtained for each of the atrial conduction delay times. All measurements were performed by two experienced investigators blind to the subject’s clinical status. Statistical analysis The SPSS software program (SPSS 13.0, Chicago, Illinois) was used for statistical analysis. Variable data were expressed as mean ± standard deviation or percentage. After determining normality of distribution using the Kolmogorov– Smirnov test for all continuous variables, appropriate parametric and nonparametric tests were performed. Relations between normally and non-normally distributed continuous variables were assessed using Pearson’s or Spearman’s correlation, respectively. All tests were two-sided. A value of p \ 0.05 was considered significant. Results Patient characteristics The clinical and laboratory characteristics of the two groups are shown in Table 1. Age, gender, body mass index (BMI), body surface area (BSA), smoking, heart rate, systolic and diastolic blood pressures, and diabetes mellitus (DM) were similar between patients with acromegaly and controls (Table 1). As expected, patients with acromegaly had significantly higher serum GH and IGF-1 levels compared with the controls (Table 1). Echocardiography M-mode and Doppler echocardiographic parameters in acromegalic patients and controls are shown in Table 2. No
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Endocrine Table 1 Baseline demographics and laboratory characteristics of the study population
Acromegaly (n = 23)
Control (n = 27)
P
Age (years)
45.5 ± 12.2
47.3 ± 9.1
Female gender, n (%)
11 (47.8 %)
19 (29.6 %)
0.560 0.149
Smoking, n (%)
5 (21.7 %)
3 (11.1 %)
0.444
Hypertension, n (%)
5 (21.7 %)
8 (29.6 %)
0.756
Diabetes mellitus, n (%)
3 (13 %)
0
0.090
BMI (kg/m2)
28.9 ± 5.0
30 ± 5.4
0.474
BSA (m2)
2 ± 0.2
1.91 ± 0.18
0.122
Heart rate (beats/min)
74.1 ± 11.1
74.07 ± 13.4
0.987
Systolic blood pressure (mm Hg)
120 ± 28.4
125.2 ± 12.12
0.393
Diastolic blood pressure (mm Hg)
74.5 ± 9.6
80.6 ± 8.9
0.055
Glucose (mg/dL)
106.7 ± 29.9
99.2 ± 28.5
0.405
Hemoglobin (g/dL)
12.91 ± 1.4
12.8 ± 1.5
0.899
Creatinine (mg/dL)
0.68 ± 0.18
0.7 ± 0.35
0.762
GH random (ng/ml))
7.75 ± 9.6
1.4 ± 0.9
0.002
GH nadir during OGTT (ng/ml) IGF-1 (ng/ml)
2.97 ± 3.5 632.8 ± 383.5
– 181.7 ± 64.7
Surgery ? medical, n (%)
22 (95.6 %)
–
Medical ? radiotherapy, n (%)
1 (4.4 %)
–
SSA, n (%)
17 (73.9 %)
–
DA, n (%)
6 (26.1 %)
–
\ 0.001
Treatment of acromegaly BMI, body mass index; BSA, body surface area GH, growth hormone; IGF-1, insulin-like growth factor-1; OGTT, oral glucose tolerance test; SSA, somatostatin analogs; DA, dopamine agonists
Medical, n (%)
Table 2 Comparison of conventional echocardiographic parameters of the study population Acromegaly (n = 23)
Control (n = 27)
P
LVESD (mm)
29.9 ± 4.4
31.7 ± 5.2
0.180
LVEDD (mm)
46.8 ± 3.9
47 ± 3.1
Ejection fraction (%)
65.6 ± 4.3
65.1 ± 3.3
IVS (mm)
11.2 ± 2
PW (mm) LVMI (g/m2)
Acromegaly (n = 23)
Control (n = 27)
Vmax (mL/m2)
22.7 ± 6.9
21.8 ± 5.5
0.615
0.829
Vmin (mL/m2)
7.2 ± 3.9
6.6 ± 4.8
0.549
0.172
Vp (mL/m2)
12.7 ± 5.4
12.8 ± 3.3
0.980
9.9 ± 4
9.2 ± 2.4
0.409
10.4 ± 1.4
0.111
LA passive emptying volume (mL/m2)
10.2 ± 1.5
9.5 ± 1.3
0.089
0.45 ± 0.13
0.43 ± 0.1
0.502
95.4 ± 28.9
88 ± 26.7
0.354
LA active emptying volume (mL/m2)
5.7 ± 2.9
6.2 ± 2.7
0.415
LA active emptying fraction (%)
0.45 ± 0.15
0.49 ± 0.11
0.314
LA (mm)
36.6 ± 5.5
34.7 ± 3.7
0.153
E (cm/s) A (cm/s)
69.9 ± 17.7 66.9 ± 16.3
72.3 ± 17.9 71.5 ± 15.9
0.640 0.324
E/Aratio
1.1 ± 0.4
1 ± 0.3
0.646
E/E’ ratio
6.6 ± 2.6
6.7 ± 2.5
0.865
LVESD, left ventricular end-systolic diameter; LVEDD, left ventricular end-diastolic diameter; IVS, interventricular septum; PW, posterior wall; LVMI, left ventricular mass index; LA, late diastolic mitral inflow velocity; E, early diastolic mitral inflow velocity
significant differences were determined between the two groups in terms of LV end-diastolic diameter, LV endsystolic diameter, LV mass index, LV ejection fraction, LA diameter, LV Em/Am and E/E’ ratio, septum thickness, and posterior wall thickness (Table 2).
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Table 3 Measurements of left atrial volumes and mechanical functions of the study population
LA passive emptying fraction (%)
P
Vmax, LA maximum volume; Vmin, LA minimum volume; Vp, LA volume before P wave; LA, left atrium
LA mechanical functions Left atrial volume measurements and mechanical functions are presented in Table 3. The groups were similar in terms of Vmax, Vmin, Vp, LA passive emptying volume/fraction, and LA active emptying volume/fraction (Table 3). Serum levels of GH and IGF-1 were not correlated with Vmax, Vmin, Vp, LA passive emptying volume/fraction,
Endocrine Table 4 P wave analysis and atrial electromechanical interval parameters of the study population Acromegaly (n = 23)
Control (n = 27)
P
0.810
PA lateral (ms)
58.8 ± 15.6
57.7 ± 17.5
PA septum (ms)
40.9 ± 12.6
41.2 ± 13.9
0.944
PA tricuspid (ms) PA lateral–PA tricuspid (ms)a
26.9 ± 12.9 31.9 ± 14.7
25.3 ± 12.8 32.4 ± 12.4
0.668 0.907
PA lateral–PA septum(ms)b
17.9 ± 10.8
16.5 ± 8.8
0.617
PA septum–PA tricuspid (ms)c Maximum P wave duration (ms)
14.0 ± 8.0
15.9 ± 9.5
0.469
93.6 ± 14.0
95.6 ± 12.8
0.477
Minimum P wave duration (ms)
47.8 ± 14.4
44.4 ± 11.5
0.406
P wave dispersion (ms)
46.0 ± 15.3
51.1 ± 16.0
0.215
PA, the interval measured by tissue doppler imaging from the onset of the P wave on the surface electrocardiogram to beginning of the late diastolic (Am) wave a
Interatrial electromechanical delay
b
Intra-left atrial electromechanical delay
c
Intra-right atrial electromechanical delay
or LA active emptying volume/fraction (not shown in the table; all p [ 0.05). Atrial conduction times P wave analysis and atrial electromechanical time intervals are presented in Table 4. PA lateral, PA septal, and PA tricuspid durations were similar between patients with acromegaly and control subjects. Intra-LA EMD, intraright atrial EMD, and interatrial EMD were not significantly different between the groups (Table 4). Analysis also revealed similar maximum P wave duration, minimum P wave duration, and Pwd between the groups (Table 4). Correlation analysis was performed among GH and IGF-1 levels and PA lateral, PA septal, PA tricuspid, Pwd, intraLA EMD, intra-right atrial EMD, and interatrial EMD and revealed non-significant differences (not shown in the table; all p [ 0.05).
Discussion This study demonstrates that atrial EMD is not prolonged and LA mechanical functions are not impaired in patients with active acromegaly compared with controls. To the best of our knowledge, this is the first investigation of atrial conduction times and LA mechanical functions in patients with acromegaly.
Increased mortality rates in patients with acromegaly primarily due to cardiovascular disease have been well documented [11, 24]. This is due to both the negative effects of excess GH/IGF-1 levels on the cardiovascular system and co-existing cardiovascular risk factors including HT, DM, cardiomyopathy, and sleep apnea disorder [8, 24]. Cannavo et al. also demonstrated an increased risk for coronary atherosclerosis based on Framingham and Agatston score [30]. Appropriate diagnosis and management of disease complications are, therefore, critical for favorable long-term outcomes and improved quality of life in patients with acromegaly [31]. LV structure and functions have particularly been investigated in patients with acromegaly. According to previous studies, GH and IGF-1 compromise cardiac structure and function through receptors expressed in cardiac myocytes [32]. Chronic excess of GH/IGF-1 that results in a specific ‘acromegalic cardiomyopathy’ is characterized by concentric biventricular hypertrophy, LV systolic/diastolic dysfunction, rhythm disturbances, and valve abnormalities [11]. Frequency of ventricular arrhythmia is also higher in patients with acromegaly compared with normal controls [9]. However, the relationships between excess GH and IGF-1 levels and atrial electromechanical functions in active acromegalics have not been investigated. Atrial electromechanical functions have also recently been the subject of interest. The relationship between prolonged atrial conduction times (intra-right atrial EMD, intra-LA EMD, and interatrial EMD) measured by TDI and a higher prevalence of new or recurrent AF is well documented in the literature [33, 34]. Prolonged Pwd has also been shown to increase the risk of AF [26]. Studies have suggested that prolonged atrial conduction times in patients with RA [19], type 1 DM [20], hyper and hypothyroid [35, 36], and systemic lupus erythematosus [22] may be associated with a higher risk of AF. Limited data are available concerning the prevalence of atrial arrhythmia in patients with acromegaly. One previous study reported no increase in frequency of supraventricular arrhythmia in acromegalics [37]. In contrast, Kahaly et al. reported frequent paroxysmal AF and supraventricular tachycardia in patients with acromegaly, mostly at peak exercise, compared with controls [9]. As with left ventricular diastolic dysfunction (LVDD), LA mechanical functions involving reservoir, passive emptying, and active emptying functions are necessary for adequate LV filling [18]. When LVDD develops, LA may preserve adequate cardiac output by regulation of its mechanical functions. Impairment of LV diastolic functions leads to an increase in LV filling pressure and LA wall tension. This situation is probably involved in both atrial electromechanical remodeling and a later increasing incidence of supraventricular arrhythmias. In our study, LVDD did not develop in acromegalic patients, and LV
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filling parameters were similar between the two groups. LA diameter was also within normal ranges in patients with acromegaly. Colao et al. reported a high prevalence of LV hypertrophy in acromegalic patients older than 50 yrs and stated that coexistence of cardiovascular risk factors (e.g., HT, DM, and hyperlipidemia) accelerates the onset of cardiac involvement in acromegalics [38]. In our study, however, the mean age of acromegalics was below 50 (45.5 ± 12.2 yrs), and the cardiovascular risk factors were similar between patients and the controls. The authors recently reported in a meta-analysis that sustained SSA treatment may have positive effects on structural and functional cardiac parameters in patients with acromegaly, including a reduction in left ventricular mass (LVM), LV hypertrophy, and heart rate, and an improvement in cardiac performance [32]. Lombardi et al. reported that just 6-months’ treatment with lanreotide significantly reduced both LVM, ventricular filling parameters, and ventricular arrhythmic profile [39]. Moreover, ventricular arrhythmic profile was correlated with LVM and disease duration but not with serum hormone levels [9]. In this study, 17 (73.9 %) out of 23 patients with acromegaly received SSA during the study protocol. In order to determine the effect of SSA treatment on atrial electromechanical functions, the relationships between the 17 patients with acromegaly receiving SSA and the six not receiving SSA, together with the 27 control subjects, were assessed. The relationships between duration of disease in the acromegalic patients with or without SSA were also evaluated. Analysis revealed that atrial conduction time parameters and LA mechanical functions did not differ significantly between the SSA, non-SSA, and control groups. However, estimated duration of disease was similar between acromegalics receiving SSA and those not receiving it. Differences between LV and atria, such as ultrastructural construction, electrophysiological features, and amount of GH/IGF-1 receptors, are probable reasons for this outcome. However, GH and IGF-1 are known to exert their effect on the heart via GH and IGF-1 receptors being expressed by cardiac myocytes [32]. Previous studies have demonstrated that the acromegalic heart is subjected to specific histological changes, such as interstitial fibrosis, inflammatory cell infiltration, and increased apoptosis [40, 41]. Myocardial fibrosis has been proposed as a probable cause of non-homogeneous action potentials and dysrhythmias in acromegalics [42]. We may hypothesize that atrial structure is less likely to involve fibrosis compared with the ventricle in the acromegalic heart. Relatively lower involvement of atrial fibrosis may be another explanation for the preserved atrial electromechanical functions in this population because interstitial fibrosis may impair electrical coupling in the myocardium [43].
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On the other hand, both co-existing cardiovascular factors (e.g., HT and DM) and associated treatment modalities may influence cardiovascular ultrastructure and functions in acromegaly. While the prevalence of HT and DM in our study was similar between the acromegalics and the controls, we evaluated the effect of HT and DM on atrial electromechanical functions. No significant difference was observed in electromechanical parameters between patients with or without HT and DM. Study limitations Potential limitations of our study are the relatively small number of patients and medical therapy in acromegalics receiving SSA. All patients were affected by active acromegaly and were receiving medical treatment during the study protocol. We cannot be sure whether medical treatment with SSA positively affected our results by reducing LVM and SSA-induced IGF-1 levels. The cross-sectional design is another important limitation. The study was designed to be cross-sectional from the outset, and no longterm data for progression and cure of acromegaly were available. Finally, we did not evaluate patients during physical exercise because increased paroxysmal AF and supraventricular tachycardia were documented, particularly at peak physical exercise, in a previous study [9]. Further large and prospective studies including newly diagnosed acromegalic patients who have not yet been prescribed any pharmacological treatment are now needed to evaluate the effect of active acromegaly on atrial electromechanical functions. Other parameters and/or methods (e.g., MRI and electrophysiological examination) may be needed to investigate atrial electromechanical functions in this population.
Conclusion Our study suggests that active acromegaly may not compromise atrial conduction times and LA mechanical functions compared with controls. Atrial electromechanical functions may, therefore, not be impaired, and there may be no increased risk of supraventricular arrhythmias in patients with acromegaly.
Conflict of interest
None
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ORIGINAL ARTICLE
Atrial conduction times and left atrium mechanical functions in patients with active acromegaly A. Ilter • A. Kırıs¸ • S¸ . Kaplan • M. Kutlu • M. S¸ ahin • C. Erem • N. Civan • F. Kangu¨l
Received: 24 February 2014 / Accepted: 25 June 2014 Ó Springer Science+Business Media New York 2014
Abstract The aim of this study was to evaluate atrial electromechanical delay (EMD), P wave dispersion (Pwd), and left atrial (LA) mechanical functions in patients with active acromegaly. Twenty-three patients with active acromegaly and 27 age- and sex-matched controls were included in this study. All atrial electromechanical interval parameters (PA lateral, PA septum, PA tricuspid, interatrial EMD, intra-LA EMD, and intra-right atrial EMD) were measured from mitral lateral annulus, mitral septal annulus, and right ventricular tricuspid annulus by tissue Doppler imaging. LA volumes were measured by the disk method in the apical four-chamber view and were indexed to the body surface area. Mechanical function parameters of LA were calculated. Pwd was performed by 12-lead electrocardiograms. Atrial electromechanical intervals (PA lateral, PA septum, PA tricuspid, interatrial EMD, intra-LA EMD, and intra-right atrial EMD) and Pwd were similar between patients with acromegaly and control subjects (all p [ 0.05). LA volumes (maximum, minimum, and A. Ilter (&) Department of Cardiology, Kanuni Training and Research Hospital, Trabzon, Turkey e-mail: [email protected] A. Kırıs¸ S¸ . Kaplan M. Kutlu Department of Cardiology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey M. S¸ ahin Department of Cardiology, Ahi Evren Cardiovascular and Thoracic Surgery Training and Research Hospital, Trabzon, Turkey C. Erem N. Civan F. Kangu¨l Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
presystolic) and LA mechanical functions were not significantly different between the groups (all p [ 0.05). Additionally, serum levels of growth hormone and insulinlike growth factor-1 were not correlated with atrial electromechanical parameters and LA mechanical functions. Atrial electrical conduction times were not prolonged and LA mechanical functions were not impaired in patients with active acromegaly compared with controls. And the prevalence of supraventricular arrhythmia risk may not increase in this population. Keywords Active acromegaly Atrial electromechanical delay Left atrial functions Growth hormone Tissue Doppler imaging
Introduction Acromegaly is a rare disease leading to various cardiovascular disturbances, such as left ventricular (LV) hypertrophy [1–4], diastolic dysfunction [5], hypertension (HT) [6], cardiomyopathy [7, 8], and cardiac dysrhythmias [9]. Acromegaly is also associated with increased mortality and morbidity due to cardiovascular complications in large clinical series [10–12]. Several studies have focused on LV functions and structure in patients with acromegaly [1, 13, 14]. Impairment of LV synchronicity [15] and global function (assessment with Tei index) has also been reported in acromegalic patients [5]. To the best of our knowledge, however, left atrial (LA) functions and atrial conduction abnormalities have not previously been investigated in patients with acromegaly. LA volumes and mechanical functions have been identified as potential indicators of cardiac disease and arrhythmias in previous studies
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[16–18]. Non-homogeneous propagation of sinus impulses and inter- and intra-atrial conduction delays are well-documented electrophysiological alterations of the atria prone to atrial fibrillation (AF) [19]. In contrast to LA size, atrial conduction times reflect both electrical and structural remodeling of the atria [20–22]. The purpose of this study was to evaluate atrial conduction times and LA atrial mechanical functions in patients with active acromegaly.
valvular heart disease, pulmonary or neurological disease, pericarditis or myocarditis, familial hypertrophic cardiomyopathy, sleep apnea disorder, hypopituitarism, chronic obstructive pulmonary disease, hepatic or renal disease, heart failure, and poor echocardiographic imaging. The study was conducted in accordance with the guidelines set out in the declaration of Helsinki. Our university local Ethical Committee approved the study protocol. Laboratory analysis
Patients and methods Study population Twenty-three patients with active acromegaly (11 women, 12 men; mean age 45.5 ± 12.2 yrs) with normal sinus rhythm at electrocardiography (ECG) were included in this cross-sectional study. Twenty-seven healthy control subjects (19 women, 8 men; mean age 47.3 ± 9.1 yrs) were also enrolled as the control group. Active acromegaly was diagnosed by the presence of typical clinical signs and symptoms (soft tissue overgrowth, acral enlargement, headache, HT, hyperhidrosis, weight gain, and acanthosis nigricans), random growth hormone (GH) [1 ng/ml, nadir GH C0.4 ng/ml after 75 g oral glucose tolerance test (OGTT), and elevated insulin-like growth factor-1 (IGF-1) levels above the normal range for age and sex [23, 24]. Duration of disease was estimated by the onset of clinical symptoms, assessment of patient images, and findings of acromegaly. All patients were affected by active acromegaly at the time of the study. Duration of disease ranged from 1 to 30 yrs (mean 7.7 ± 7.2 yrs). In all patients, imaging of the pituitary was performed using magnetic resonance imaging (MRI) showing pituitary adenoma (14 and 9 microadenomas). All patients with acromegaly had pure GHsecreting adenomas. Pituitary adenomas were removed by selective transsphenoidal surgery, and immunohistochemistry confirmed the diagnosis in all patients. Adjuvant radiotherapy and/or medical therapy (11 patients received octreotide-LAR, six received cabergoline, and six patients received lanreotide) were administered to patients with elevated GH and IGF-1 levels after surgery. Mean duration of medical therapy with somatostatin analogs (SSA) in this study was 36.06 ± 25.2 months. Demographic characteristics, biochemical data, and ECGs were obtained for the entire study population. Exclusion criteria were previous coronary artery disease and myocardial infarction, acute coronary syndrome, uncontrolled HT (resting blood pressure C140/ 90 mmHg), atrial flutter or fibrillation, frequent ventricular pre-excitation and atrio-ventricular conduction abnormalities, medications known to alter cardiac conduction, alcohol abuse, cardiac pacing, prolonged QRS duration (C120 msn), reduced LV ejection fraction (LVEF \ 50 %), significant
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Blood was collected in the morning between 08:00 and 09:00 h after overnight fasting in order to avoid differences in diurnal variations of hormonal parameters. Serum GH and IGF-1 levels were measured using a chemiluminescent immunometric assay (Immulite 2000 DPC, Diagnostic Product Corporation, 5210 Pacific Concourse, LA). GH values were obtained via 75 g OGTT. Nadir GH values assessed during OGTT and random GH values were recorded. The normal ageadjusted reference values for IGF-1 levels were 21–25 yrs, 116–358 ng/ml; 26–30 yrs, 117–329 ng/ml; 31–35 yrs, 115–307 ng/ml; 36–40 yrs, 109–284 ng/ml; 41–45 yrs, 101–267 ng/ml; 46–50 yrs, 94–252 ng/ml; 51–55 yrs, 87–238 ng/ml; 56–60 yrs, 81–225 ng/ml; 61–65 yrs, 75–212 ng/ml; 66–70 yrs, 69–200 ng/ml; 71–75 yrs, 64–188 ng/ml; and 76–80 yrs, 59–177 ng/ml [25]. Assessment of P wave dispersion on 12-lead ECG Twelve-lead ECGs were obtained from all patients using a MAC1200 8T electrocardiograph (GE Healthcare, Freiburg, Germany) at a paper speed of 50 mm/s and 20 mm/ mV. All recordings were performed in the same quiet room through spontaneous breathing, followed by 20 min of adjustment in the supine position. P wave duration measurements were performed manually by two cardiologists using calipers and a magnifying lens for exact definition of the ECG deflection. The beginning of the P wave was defined as the point where the initial deflection of the P wave crossed the isoelectric line, and the end of the P wave was defined as the point where the final deflection of the P wave crossed the isoelectric line. ECG recordings with measurable P waves in fewer than ten leads were excluded from analysis. The difference between P wave maximum and P wave minimum durations was defined as Pwd [26]. Intra- and inter-observer variability was calculated as less than 5 % for PA maximum and PA minimum durations. Standard echocardiographic assessment All patients were evaluated by transthoracic M-mode, two dimensional (2D), pulsed wave (PW), continuous wave (CW), color flow, and tissue Doppler imaging (TDI). All
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examinations were performed using the GE-Vivid seven system (GE Vingmed Ultrasound AS, Horten, Norway) with a 2–4 MHz transducer at a depth of 16 cm. Continuous single-lead ECG recording was obtained during echocardiography. All patients were imaged in the left lateral decubitus position. 2D and conventional Doppler examinations were performed in the parasternal and apical views according to American Society of Echocardiography (ASE) guidelines [27]. LV diameters and wall thickness were measured using M-mode echocardiography. LV ejection fraction was calculated using the apical two- and four-chamber views by Simpson’s method, according to ASE guidelines [27]. The mitral valve inflow pattern and diastolic parameters (E-wave, A-wave, E’-wave, and E/A ratio) were measured using PW Doppler. LV mass index was calculated using the formula with the Devereux equation [28]. LA volumes were obtained echocardiographically from the apical four-chamber views using the biplane area length method [20, 29]. LA maximum volume (Vmax) at the end-systolic phase (onset of the mitral opening), LA minimum volume (Vmin) at the end-diastolic phase (onset of the mitral closure), and LA volume before atrial systole (Vp) were measured at the beginning of atrial systole (onset of P wave on ECG) and indexed to the body surface area. LA function parameters were calculated as LA active emptying volume = Vp-Vmin; LA active emptying fraction = [(Vp-Vmin)/Vp] 9 100 %; LA passive emptying volume = Vmax-Vp; and LA passive emptying fraction = [(Vmax-Vp)/Vmax] 9 100 % [26]. Tissue Doppler echocardiographic assessment Tissue Doppler imaging was performed using transducer frequencies of 3.5–4.0 MHz. The spectral pulsed Doppler signal filters were adjusted for a Nyquist limit of 15–20 cm/s. Myocardial TDI velocities including peak systolic (Sm), early diastolic (Em), and late diastolic velocities (Am) were measured via spectral pulsed Doppler as of the LV-free wall from the apical four-chamber view [27]. The ultrasound beam was positioned as parallel as possible to the myocardial segment in order to obtain an optimal imaging angle. The time interval from the P wave onset on the surface ECG to the beginning of the late diastolic wave (Am) was defined as atrial electromechanical coupling (PA interval) (Fig. 1). The PA interval is the interval from the P wave onset on the surface electrocardiogram to the beginning of the late diastolic A’-wave. This was obtained from lateral mitral annulus, septal mitral annulus, and right ventricular tricuspid annulus and referred to as PA lateral, PA septum, and PA tricuspid, respectively. The difference between PA lateral and PA tricuspid was defined as interatrial electromechanical delay (EMD), the difference between PA septum and PA tricuspid as intra-right atrial EMD, and the difference between PA lateral and PA septum
Fig. 1 Tissue Doppler imaging showing the atrial electromechanical delay from P wave onset on surface electrocardiography to the beginning of the late diastolic A wave
as intra-LA EMD [26, 27]. All measurements were repeated three times, and mean values were obtained for each of the atrial conduction delay times. All measurements were performed by two experienced investigators blind to the subject’s clinical status. Statistical analysis The SPSS software program (SPSS 13.0, Chicago, Illinois) was used for statistical analysis. Variable data were expressed as mean ± standard deviation or percentage. After determining normality of distribution using the Kolmogorov– Smirnov test for all continuous variables, appropriate parametric and nonparametric tests were performed. Relations between normally and non-normally distributed continuous variables were assessed using Pearson’s or Spearman’s correlation, respectively. All tests were two-sided. A value of p \ 0.05 was considered significant. Results Patient characteristics The clinical and laboratory characteristics of the two groups are shown in Table 1. Age, gender, body mass index (BMI), body surface area (BSA), smoking, heart rate, systolic and diastolic blood pressures, and diabetes mellitus (DM) were similar between patients with acromegaly and controls (Table 1). As expected, patients with acromegaly had significantly higher serum GH and IGF-1 levels compared with the controls (Table 1). Echocardiography M-mode and Doppler echocardiographic parameters in acromegalic patients and controls are shown in Table 2. No
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Endocrine Table 1 Baseline demographics and laboratory characteristics of the study population
Acromegaly (n = 23)
Control (n = 27)
P
Age (years)
45.5 ± 12.2
47.3 ± 9.1
Female gender, n (%)
11 (47.8 %)
19 (29.6 %)
0.560 0.149
Smoking, n (%)
5 (21.7 %)
3 (11.1 %)
0.444
Hypertension, n (%)
5 (21.7 %)
8 (29.6 %)
0.756
Diabetes mellitus, n (%)
3 (13 %)
0
0.090
BMI (kg/m2)
28.9 ± 5.0
30 ± 5.4
0.474
BSA (m2)
2 ± 0.2
1.91 ± 0.18
0.122
Heart rate (beats/min)
74.1 ± 11.1
74.07 ± 13.4
0.987
Systolic blood pressure (mm Hg)
120 ± 28.4
125.2 ± 12.12
0.393
Diastolic blood pressure (mm Hg)
74.5 ± 9.6
80.6 ± 8.9
0.055
Glucose (mg/dL)
106.7 ± 29.9
99.2 ± 28.5
0.405
Hemoglobin (g/dL)
12.91 ± 1.4
12.8 ± 1.5
0.899
Creatinine (mg/dL)
0.68 ± 0.18
0.7 ± 0.35
0.762
GH random (ng/ml))
7.75 ± 9.6
1.4 ± 0.9
0.002
GH nadir during OGTT (ng/ml) IGF-1 (ng/ml)
2.97 ± 3.5 632.8 ± 383.5
– 181.7 ± 64.7
Surgery ? medical, n (%)
22 (95.6 %)
–
Medical ? radiotherapy, n (%)
1 (4.4 %)
–
SSA, n (%)
17 (73.9 %)
–
DA, n (%)
6 (26.1 %)
–
\ 0.001
Treatment of acromegaly BMI, body mass index; BSA, body surface area GH, growth hormone; IGF-1, insulin-like growth factor-1; OGTT, oral glucose tolerance test; SSA, somatostatin analogs; DA, dopamine agonists
Medical, n (%)
Table 2 Comparison of conventional echocardiographic parameters of the study population Acromegaly (n = 23)
Control (n = 27)
P
LVESD (mm)
29.9 ± 4.4
31.7 ± 5.2
0.180
LVEDD (mm)
46.8 ± 3.9
47 ± 3.1
Ejection fraction (%)
65.6 ± 4.3
65.1 ± 3.3
IVS (mm)
11.2 ± 2
PW (mm) LVMI (g/m2)
Acromegaly (n = 23)
Control (n = 27)
Vmax (mL/m2)
22.7 ± 6.9
21.8 ± 5.5
0.615
0.829
Vmin (mL/m2)
7.2 ± 3.9
6.6 ± 4.8
0.549
0.172
Vp (mL/m2)
12.7 ± 5.4
12.8 ± 3.3
0.980
9.9 ± 4
9.2 ± 2.4
0.409
10.4 ± 1.4
0.111
LA passive emptying volume (mL/m2)
10.2 ± 1.5
9.5 ± 1.3
0.089
0.45 ± 0.13
0.43 ± 0.1
0.502
95.4 ± 28.9
88 ± 26.7
0.354
LA active emptying volume (mL/m2)
5.7 ± 2.9
6.2 ± 2.7
0.415
LA active emptying fraction (%)
0.45 ± 0.15
0.49 ± 0.11
0.314
LA (mm)
36.6 ± 5.5
34.7 ± 3.7
0.153
E (cm/s) A (cm/s)
69.9 ± 17.7 66.9 ± 16.3
72.3 ± 17.9 71.5 ± 15.9
0.640 0.324
E/Aratio
1.1 ± 0.4
1 ± 0.3
0.646
E/E’ ratio
6.6 ± 2.6
6.7 ± 2.5
0.865
LVESD, left ventricular end-systolic diameter; LVEDD, left ventricular end-diastolic diameter; IVS, interventricular septum; PW, posterior wall; LVMI, left ventricular mass index; LA, late diastolic mitral inflow velocity; E, early diastolic mitral inflow velocity
significant differences were determined between the two groups in terms of LV end-diastolic diameter, LV endsystolic diameter, LV mass index, LV ejection fraction, LA diameter, LV Em/Am and E/E’ ratio, septum thickness, and posterior wall thickness (Table 2).
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Table 3 Measurements of left atrial volumes and mechanical functions of the study population
LA passive emptying fraction (%)
P
Vmax, LA maximum volume; Vmin, LA minimum volume; Vp, LA volume before P wave; LA, left atrium
LA mechanical functions Left atrial volume measurements and mechanical functions are presented in Table 3. The groups were similar in terms of Vmax, Vmin, Vp, LA passive emptying volume/fraction, and LA active emptying volume/fraction (Table 3). Serum levels of GH and IGF-1 were not correlated with Vmax, Vmin, Vp, LA passive emptying volume/fraction,
Endocrine Table 4 P wave analysis and atrial electromechanical interval parameters of the study population Acromegaly (n = 23)
Control (n = 27)
P
0.810
PA lateral (ms)
58.8 ± 15.6
57.7 ± 17.5
PA septum (ms)
40.9 ± 12.6
41.2 ± 13.9
0.944
PA tricuspid (ms) PA lateral–PA tricuspid (ms)a
26.9 ± 12.9 31.9 ± 14.7
25.3 ± 12.8 32.4 ± 12.4
0.668 0.907
PA lateral–PA septum(ms)b
17.9 ± 10.8
16.5 ± 8.8
0.617
PA septum–PA tricuspid (ms)c Maximum P wave duration (ms)
14.0 ± 8.0
15.9 ± 9.5
0.469
93.6 ± 14.0
95.6 ± 12.8
0.477
Minimum P wave duration (ms)
47.8 ± 14.4
44.4 ± 11.5
0.406
P wave dispersion (ms)
46.0 ± 15.3
51.1 ± 16.0
0.215
PA, the interval measured by tissue doppler imaging from the onset of the P wave on the surface electrocardiogram to beginning of the late diastolic (Am) wave a
Interatrial electromechanical delay
b
Intra-left atrial electromechanical delay
c
Intra-right atrial electromechanical delay
or LA active emptying volume/fraction (not shown in the table; all p [ 0.05). Atrial conduction times P wave analysis and atrial electromechanical time intervals are presented in Table 4. PA lateral, PA septal, and PA tricuspid durations were similar between patients with acromegaly and control subjects. Intra-LA EMD, intraright atrial EMD, and interatrial EMD were not significantly different between the groups (Table 4). Analysis also revealed similar maximum P wave duration, minimum P wave duration, and Pwd between the groups (Table 4). Correlation analysis was performed among GH and IGF-1 levels and PA lateral, PA septal, PA tricuspid, Pwd, intraLA EMD, intra-right atrial EMD, and interatrial EMD and revealed non-significant differences (not shown in the table; all p [ 0.05).
Discussion This study demonstrates that atrial EMD is not prolonged and LA mechanical functions are not impaired in patients with active acromegaly compared with controls. To the best of our knowledge, this is the first investigation of atrial conduction times and LA mechanical functions in patients with acromegaly.
Increased mortality rates in patients with acromegaly primarily due to cardiovascular disease have been well documented [11, 24]. This is due to both the negative effects of excess GH/IGF-1 levels on the cardiovascular system and co-existing cardiovascular risk factors including HT, DM, cardiomyopathy, and sleep apnea disorder [8, 24]. Cannavo et al. also demonstrated an increased risk for coronary atherosclerosis based on Framingham and Agatston score [30]. Appropriate diagnosis and management of disease complications are, therefore, critical for favorable long-term outcomes and improved quality of life in patients with acromegaly [31]. LV structure and functions have particularly been investigated in patients with acromegaly. According to previous studies, GH and IGF-1 compromise cardiac structure and function through receptors expressed in cardiac myocytes [32]. Chronic excess of GH/IGF-1 that results in a specific ‘acromegalic cardiomyopathy’ is characterized by concentric biventricular hypertrophy, LV systolic/diastolic dysfunction, rhythm disturbances, and valve abnormalities [11]. Frequency of ventricular arrhythmia is also higher in patients with acromegaly compared with normal controls [9]. However, the relationships between excess GH and IGF-1 levels and atrial electromechanical functions in active acromegalics have not been investigated. Atrial electromechanical functions have also recently been the subject of interest. The relationship between prolonged atrial conduction times (intra-right atrial EMD, intra-LA EMD, and interatrial EMD) measured by TDI and a higher prevalence of new or recurrent AF is well documented in the literature [33, 34]. Prolonged Pwd has also been shown to increase the risk of AF [26]. Studies have suggested that prolonged atrial conduction times in patients with RA [19], type 1 DM [20], hyper and hypothyroid [35, 36], and systemic lupus erythematosus [22] may be associated with a higher risk of AF. Limited data are available concerning the prevalence of atrial arrhythmia in patients with acromegaly. One previous study reported no increase in frequency of supraventricular arrhythmia in acromegalics [37]. In contrast, Kahaly et al. reported frequent paroxysmal AF and supraventricular tachycardia in patients with acromegaly, mostly at peak exercise, compared with controls [9]. As with left ventricular diastolic dysfunction (LVDD), LA mechanical functions involving reservoir, passive emptying, and active emptying functions are necessary for adequate LV filling [18]. When LVDD develops, LA may preserve adequate cardiac output by regulation of its mechanical functions. Impairment of LV diastolic functions leads to an increase in LV filling pressure and LA wall tension. This situation is probably involved in both atrial electromechanical remodeling and a later increasing incidence of supraventricular arrhythmias. In our study, LVDD did not develop in acromegalic patients, and LV
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filling parameters were similar between the two groups. LA diameter was also within normal ranges in patients with acromegaly. Colao et al. reported a high prevalence of LV hypertrophy in acromegalic patients older than 50 yrs and stated that coexistence of cardiovascular risk factors (e.g., HT, DM, and hyperlipidemia) accelerates the onset of cardiac involvement in acromegalics [38]. In our study, however, the mean age of acromegalics was below 50 (45.5 ± 12.2 yrs), and the cardiovascular risk factors were similar between patients and the controls. The authors recently reported in a meta-analysis that sustained SSA treatment may have positive effects on structural and functional cardiac parameters in patients with acromegaly, including a reduction in left ventricular mass (LVM), LV hypertrophy, and heart rate, and an improvement in cardiac performance [32]. Lombardi et al. reported that just 6-months’ treatment with lanreotide significantly reduced both LVM, ventricular filling parameters, and ventricular arrhythmic profile [39]. Moreover, ventricular arrhythmic profile was correlated with LVM and disease duration but not with serum hormone levels [9]. In this study, 17 (73.9 %) out of 23 patients with acromegaly received SSA during the study protocol. In order to determine the effect of SSA treatment on atrial electromechanical functions, the relationships between the 17 patients with acromegaly receiving SSA and the six not receiving SSA, together with the 27 control subjects, were assessed. The relationships between duration of disease in the acromegalic patients with or without SSA were also evaluated. Analysis revealed that atrial conduction time parameters and LA mechanical functions did not differ significantly between the SSA, non-SSA, and control groups. However, estimated duration of disease was similar between acromegalics receiving SSA and those not receiving it. Differences between LV and atria, such as ultrastructural construction, electrophysiological features, and amount of GH/IGF-1 receptors, are probable reasons for this outcome. However, GH and IGF-1 are known to exert their effect on the heart via GH and IGF-1 receptors being expressed by cardiac myocytes [32]. Previous studies have demonstrated that the acromegalic heart is subjected to specific histological changes, such as interstitial fibrosis, inflammatory cell infiltration, and increased apoptosis [40, 41]. Myocardial fibrosis has been proposed as a probable cause of non-homogeneous action potentials and dysrhythmias in acromegalics [42]. We may hypothesize that atrial structure is less likely to involve fibrosis compared with the ventricle in the acromegalic heart. Relatively lower involvement of atrial fibrosis may be another explanation for the preserved atrial electromechanical functions in this population because interstitial fibrosis may impair electrical coupling in the myocardium [43].
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On the other hand, both co-existing cardiovascular factors (e.g., HT and DM) and associated treatment modalities may influence cardiovascular ultrastructure and functions in acromegaly. While the prevalence of HT and DM in our study was similar between the acromegalics and the controls, we evaluated the effect of HT and DM on atrial electromechanical functions. No significant difference was observed in electromechanical parameters between patients with or without HT and DM. Study limitations Potential limitations of our study are the relatively small number of patients and medical therapy in acromegalics receiving SSA. All patients were affected by active acromegaly and were receiving medical treatment during the study protocol. We cannot be sure whether medical treatment with SSA positively affected our results by reducing LVM and SSA-induced IGF-1 levels. The cross-sectional design is another important limitation. The study was designed to be cross-sectional from the outset, and no longterm data for progression and cure of acromegaly were available. Finally, we did not evaluate patients during physical exercise because increased paroxysmal AF and supraventricular tachycardia were documented, particularly at peak physical exercise, in a previous study [9]. Further large and prospective studies including newly diagnosed acromegalic patients who have not yet been prescribed any pharmacological treatment are now needed to evaluate the effect of active acromegaly on atrial electromechanical functions. Other parameters and/or methods (e.g., MRI and electrophysiological examination) may be needed to investigate atrial electromechanical functions in this population.
Conclusion Our study suggests that active acromegaly may not compromise atrial conduction times and LA mechanical functions compared with controls. Atrial electromechanical functions may, therefore, not be impaired, and there may be no increased risk of supraventricular arrhythmias in patients with acromegaly.
Conflict of interest
None
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