Acromegaly is disease associated with a specific cardiomyopathy. Hitherto, it has been widely understood that acromegaly carries an increased risk of arrhythmia.
In this review we show that evidences are limited to a small number of case–control studies that reported increased rates of premature ventricular beats (PVB) but no more significant arrhythmia. In contrast, there are several studies that have reported impaired preclinical markers of arrhythmia, including reduced heart rate variability, increased late potentials, QT interval dispersion, impaired heart rate recovery after physical exercise and left ventricular dysynchrony. Whilst these markers are associated with an adverse cardiovascular prognosis in the general population, they do not have a high independent positive predictive accuracy for arrhythmia. In acromegaly, case reports have described sudden cardiac death, ventricular tachyarrhythmia and advanced atrio-ventricular block that required implantation of a cardio-defibrillator or permanent pacemaker. Treatment with somatostatin analogues can reduce cardiac dysrhythmia in some cases by reducing heart rate, PVBs and QT interval. Pegvisomant reduces mean heart rate. Pasireotide is associated with QT prolongation. In the absence of good quality data on risk of arrhythmia in acromegaly, the majority of position statements and guidelines suggest routine 12-lead electrocardiography (ECG) and transthoracic echocardiography (TTE) in every patient at diagnosis and then follow up dependent on initial findings.
Acromegaly is a rare disease caused by hypersecretion of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) mostly due to a pituitary adenoma. In the past, diagnosis of acromegaly was associated with increased cardio-respiratory morbidity and mortality [1, 2], although currently, GH excess seems not to reduce life expectancy compared to the general population [3, 4]. The latter has been attributed to improved therapy .
One of the major cardiovascular complications of acromegaly is a specific cardiomyopathy which is present in about 60% of patients at diagnosis. GH/IGF-1 excess is responsible for the pathogenesis of acromegaly cardiomyopathy through direct and indirect effects: directly, GH/IGF-1 stimulates cardiac hypertrophy, collagen deposition and possibly, interstitial fibrosis; indirectly, hormonal excess causes other cardiovascular complications, including hypertension, valvular heart disease, impaired endothelial function , microvascular dysfunction , and altered metabolic profile, all of which may contribute to secondary cardiac remodelling . Clinically, patients with active disease appear to develop cardiomyopathy in three stages: initially there is myocardial hypertrophy and hyperkinesis, progressing to diastolic dysfunction in the second phase, and ultimately to overt systolic and diastolic ventricular failure with dilated cardiomyopathy [3, 7]. In turn, these cardiovascular and metabolic co-morbidities of acromegaly patients (ACRO) are hypothesized to increase the risk of electrophysiological abnormalities and arrhythmia . The prevalence of arrhythmia in these patients can be as high as 40%  with an increased frequency in those with active disease .
The aims of the present review are to: (1) summarize the pathogenesis of arrhythmia associated to GH excess; (2) define the electrical conduction abnormalities in ACRO, including a review of pre-clinical markers of arrhythmia; (3) describe the effect of different medical treatments for acromegaly on arrhythmia; and (4) outline recommendations for detection of arrhythmia in ACRO.
Materials and methods
We conducted a systematic review of the literature searching the Medline/PubMed, ISI-Web of Knowledge and Google scholar databases from January 1st, 1970 to June 30st, 2019. The keywords “acromegaly”, “arrhythmias”, “cardiovascular”, “rhythm”, “cardiomyopathy”, “Holter”, “electrocardiogram”, “heart rate variability”, “late potentials”, “complications”, “prolonged QT”, “QT dispersion”, “heart rate recovery”, “tachyarrhythmia”, “bradyarrhythmia”, “sudden death”, “treatment”, “guidelines”, “consensus” were used in various combinations. The search was extended to reference lists of relevant reviews. We excluded duplicated studies. We included cross-sectional, prospective, review articles, meta-analysis, and basic studies meeting the following criteria: English language; relevant to the discussed matter. Studies were included regardless of their publication status or size. Studies not meeting these criteria were excluded.
Pathogenesis of arrhythmia in acromegaly
Cardiac arrhythmia is any abnormality in heart rate or rhythm. Under normal conditions, systolic contraction follows activation of the cardiac conduction system, which is made up of the sinoatrial node (heart pacemaker), atrioventricular node and His-Purkinje system. Activation of cardiac cells results from a transient depolarization known as the action potential. The action potentials of the His-Purkinje system and ventricular myocardium are divided into five phases: phase 0 the rapid depolarizing current, which is due to an influx of sodium and calcium (smaller and slower than sodium) into myocardial cells, phase 1 to 3 the repolarization phases due to outward flux of potassium and phase 4 that is the resting membrane potential. Previous studies have investigated the role of GH and IGF-1 on ionic currents in the action potential. Myocytes have two different Ca2+ channels, both of them contributing to excitation–contraction coupling. The first Ca2+ channel type (the L-Type) is present in myocytes and the conduction system and has a role in excitation–contraction coupling and pacemaker activity. The second type (the T-type), is most prevalent in the conduction system and facilitates the pacemaker role of the sinoatrial node, it also may be over-expressed in disease states such as hypertrophy and heart failure .
In general, it is thought there are three possible mechanisms involved in the pathogenesis of arrhythmia: (1) trigged activity (e.g. after earlier or delayed depolarizations that then initiate spontaneous multiple depolarizations), (2) enhanced or suppressed automaticity (e.g. as a result of myocardial ischemia, myocardial scarring, electrolyte disturbance, and/or pharmacotherapy), and (3) re-entry (e.g. via an accessory pathway). Except the third, there is evidence that the first and the second mechanisms may play a role in generation of arrhythmia in acromegaly. These features are summarized in Fig. 1.
In a study involving adult rats with acromegaly, Xu and Best found an increased density of T-type Ca2+ channels with enhanced current in atrial myocytes that preceded the development of cellular hypertrophy . Further work by the same group comparing female Wistar-Furth rats with GH secreting tumours to a normal cohort found an increase in duration of the action potential in tumour bearing rats, mainly due to a decrease in density of a transient outward current carried by K + and an increase duration influx of Ca2+ through the L-type Ca2+ channel . Conversely, Guo et al. studied K+ channel expression in cultured neonatal rat ventricular myocytes after IGF-1 administration and found an increased expression of K+ channel with increased current density; they also suggested that long term exposure to IGF-1 could regulate K+ channel expression, modulating myocardial cell excitability . K+ channels could have a key role in the development of cardiomyopathy in acromegaly as their expression and function are also closely linked to the development of myocyte hypertrophy.
Cittadini et al. studied the acute role of GH and IGF-1 administration on myocardial contractility in rat whole heart and ferret papillary muscles. Although the authors found no effect of GH, IGF-1 enhanced contractility due to increased myofilament Ca2+ sensitivity without increasing myocyte [Ca2+]I current . Furthermore, Stromer et al. studied the effect of chronic high dose treatment with GH and IGF-1 on isolated rat hearts and found increased cardiac inotropy with altered cardiac geometry, suggesting increased Ca2+ sensitivity and enhanced maximal response to Ca2+ . In isolated human myocytes from end-stage falling hearts, Von Lewinski et al. also found that IGF-1 had a dose-dependent, receptor-mediated positive inotropic effect with increase of the intracellular concentration of calcium, increasing calcium currents (L-type Ca2+), inhibiting Na+/H+ exchange and modifying the Na+-Ca2+ exchange . These data confirmed the study of Solem and Thomas that demonstrated an increase in dihydropyridine-sensitive Ca2+ channel activity in the heart in response to IGF-1 administration . Comparing the effect of GH and IGF-1 on both normal and failing human myocytes, Kinugawa et al. suggested that GH had no effect on contractility but IGF-1 acted as a positive inotrope by increasing availability of [Ca2+]I to the myofilaments . Finally, in a study of papillary myocytes from normal and short term streptozotocin- induced diabetic rats, Ren et al. found that the inotropic response to IGF-1 was depressed in diabetes, potentially related to changes in intracellular Ca2 + and NO production .
In acromegaly, there is evidence of interstitial fibrosis, myofibrillar derangement and cardiac hypertrophy that could promote arrhythmia [20, 21]. At post-mortem of a 54-year-old patient with acromegaly cardiomyopathy, VPB and left branch block, Maturri et al. found both sclerosis and fibrolipomatosis affecting multiple parts of the conduction system, which the authors thought had promoted electrical automaticity and contributed to the patient’s sudden cardiac death.. Other case reports have also reported an association between interstitial fibrosis on myocardial biopsy, heart failure and ventricular arrhythmia in acromegaly [23, 24]. Recently however, in a small study of 36 patients with acromegaly, no relationship was found between LVH (8%) or fibrosis (12%) using cardiac magnetic resonance imaging and the occurrence of arrhythmia (including atrial or ventricular ectopy, atrial flutter, tachycardia, or atrial fibrillation) .
Conduction abnormalities in acromegaly
There is a wide variation (7–40%) in the existing literature in the prevalence of conduction abnormalities on resting or exercise ECG in ACRO, which is likely to be due to a number of factors, including small study size, lack of appropriate control group, use of different monitoring techniques, short duration of monitoring, and variable definition of significant arrhythmia .
In a series of 256 ACRO patients, Hayward et al. reported the characteristics of 10 patients with heart disease for which no explanation other than acromegaly could be found. The 12-lead ECG was abnormal in 9 of these 10 patients, and arrhythmia was detected in 6 patients (paroxysmal atrial fibrillation –AF-, ventricular tachycardia –VT-, atrial premature beats –APBs- and ventricular premature beats –VPBs-). In 6 of the 10, ACRO was cured by transsphenoidal surgery but new episodes of arrhythmia developed in 4 patients despite successful treatment, leading the authors to speculate that irreversible cardiac alterations including fibrosis were responsible. Kahaly et al.  studied 32 ACRO compared to 50 controls without cardiac disease: on resting 12-lead ECG, all patients were in sinus rhythm (SR) but 3 ACRO had left anterior fascicular block (LAFB), 2 had first degree atrioventricular block, and 2 had ventricular premature beats (VPBs). On stress testing, 12 ACRO developed VPBs and SVPBs, and two patients were unable to complete a maximal test due to increased complex VPB (Lown grade III-IVb) during exercise. On 24 h-Holter monitoring, 4 patients had non-sustained VT, and the frequency and severity of VPBs (Lown classification III/IV- ) were significantly higher in ACRO. The prevalence of VPBs correlated with age (p = 0.076), duration of disease (p = 0.032), ventricular mass (p = 0.036) and a clinical activity score (p < 0.01) (a three-step questionnaire about acromegaly clinical activity which allowed patients’ classification based on clinical status), but not with hormone levels . This study was one of the few with a control group, and it is important to note that the study only found a higher prevalence of VPB but no more significant arrhythmia . Rodrigues et al.  analysed resting 12-lead ECG abnormalities in 34 ACRO, all of whom were in SR, 3 fulfilled the Romhilt-Estes criteria for LVH and 4 had conduction abnormalities, including left or right bundle branch block (RBBB/LBBB). On 24 h-Holter monitoring, abnormalities were detected in 14 patients, with VPBs the most common finding but 1 had prolonged asymptomatic episodes of ventricular bigeminism, 1 had runs of symptomatic VT, and 3 had sinus pauses (one of 4.4 s asymptomatic). There was no correlation with disease activity or disease duration.
These last two studies have been frequently cited in following literature [16, 21, 28, 29] as showing an increased risk of “ectopic beats, paroxysmal AF, paroxysmal supraventricular tachycardia, sick sinus syndrome, VT and bundle branch block”, especially during physical exercise. In contrast with these studies, Warszawsky et al. studied 36 ACRO using 24 h-Holter monitoring and cardiac MRI but found no major arrhythmia (defined as atrial flutter, atrial or ventricular fibrillation or any sustained arrhythmia) .
Fatal arrhythmia as cause of death
No prospective or cross-sectional study has ever reported an increased rate of life-threatening arrhythmia in ACRO, although there are case reports in many of which the patient first presented with syncope. Arias et al. reported a case of a 58-year-old man who presented with syncope due to non-exertional VT, despite having no evidence of coronary or structural heart disease. He was treated with beta-blocker and implantation of single-chamber defibrillator (ICD), although no further episodes occurred . Cardiac arrest due to ventricular fibrillation was described by Viani et al. in a 31-year-old pregnant acromegalic woman with a normal 12-lead ECG and echocardiogram: a cardioverter-defibrillator was implanted after resuscitation and 5 months later her child was born without complications . Tan et al. reported a 57-year-old man who presented with an episode of syncope due to third degree AV heart block early after ACRO diagnosis, eventually treated with permanent pacing . Maffei et al. also described an 82-year-old lady with controlled acromegaly, who required urgent pacing for third degree AV block, although in this case there were potential confounding factors, including recent consumption of codeine and mild hypothyroidism . An et al. also described the case of a 50-year-old man in whom the diagnosis of acromegaly was made after hospital admission for syncope due to monomorphic VT. LVH was present but invasive coronary angiography was normal . Likewise, there have been isolated case reports of sudden cardiac death in acromegaly [22, 24]. However, there have been no case–control or longitudinal studies that quantify lifetime risk of sudden cardiac death or arrhythmia in acromegaly, and none that identify specific electrophysiological changes predictive of outcome.
It should be pointed out that, while in the past the cardiovascular complications where considered the leading causes of death in patients with ACRO, recent evidences showed that they have a similar mortality rate to general population, with cancer as the main cause of death [3, 4].
Pre-clinical markers of arrhythmic risk
Although questions remain about the overall risk of arrhythmia in acromegaly, there are a number of studies that have documented significant changes in preclinical markers of arrhythmia, including reduced heart rate variability, late potentials, LV dyssynchrony, atrial conduction, QT dispersion and beat to beat QT variability. Each of these phenomena have been used in a broad range of more common cardiovascular diseases and associations with adverse prognosis and increased risk of arrhythmia was documented, for example following myocardial infarction. These have been measured in ACRO patients, although while differences have been found, studies have been limited by small sample size, lack of appropriate control group, use of different analysis techniques, short follow-up and variable definition of significant arrhythmia. We also must point out that each of these parameters has poor positive predictive value for predicting overall risk of arrhythmia in any single patient. All studies have been case–control but no large-scale prospective study has found high predictive value of any of these markers. Figure 2 summarize the following features.
Autonomic tone and heart rate variability
Risk of arrhythmia is increased in those with impaired autonomic tone but there are conflicting data about the relationship between activity of the sympathetic nervous system and acromegaly: for example, plasma noradrenaline levels are similar to those in the general population but there is impaired circadian rhythm of noradrenaline release [35,36,37,38]. Data from a transgenic mouse model of acromegaly secreting bovine GH suggested that there was a down regulation of alpha-adrenergic receptors on mesenteric resistance arteries and reduced autonomic modulation of heart rate . These authors also reported direct GH effects on autonomic tone, reducing sympathetic nervous system function via reduced noradrenaline stores . In humans, a non-invasive method to quantify cardiac autonomic function is to perform heart rate variability (HRV), which measures beat-to-beat variations of the R-R interval on surface ECG. In the general population, impaired sympathovagal balance measured by reduction in HRV was associated with increased risk of myocardial infarction, ventricular arrhythmia, heart failure and sudden cardiac death [40,41,42]. In acromegaly, results of HRV are conflicting. Comunello et al. found that several indices of cardiac autonomic function and HRV (SDNN -standard deviation of NN intervals- and SDANN—standard deviation of the mean NN intervals calculated over short periods) are impaired in acromegaly when compared to healthy controls. Although increased mean HR was also found, Comunello et al. did not find any increase in clinically significant arrhythmia . In contrast, Resmini et al. studied 22 ACRO non diabetic subjects without hypopituitarism in comparison with 21 normal controls, 20 patients affected by type 1 diabetes mellitus and 15 controls with type 2 diabetes mellitus, and found sympathovagal imbalance with increased vagal tone in the ACRO subjects . Chemla et al. considered HRV and OSA improvement in 16 naïve ACRO after successful treatment (surgical or surgical plus medical therapy –SSA or Pegvisomant-) with a mean follow-up of 10 ± 6 months. They observed a significant improvement of HRV parameters (normal-to-normal heart period (NN), SDNN, the root mean square of successive differences in NN and the percentage of NN differing from the previous NN by greater than 50 ms) after treatment (p < 0.05) . The authors did not find any significant relation between OSA and HRV, despite studies on general population documented that HRV can be impaired in obstructive sleep apnoea [45,46,47].
Cardiac autonomic response to physical exercise appears to be impaired in acromegaly . Sympathetic tone physiologically increases heart rate during physical exercise, while parasympathetic tone reduces heart rate in recovery. A decrease in heart rate recovery (HRR: a marker of parasympathetic activity after exercise) is due to parasympathetic impairment and is a predictor of mortality [49, 50]. Dural et al. compared the results of 24 h-Holter and stress test ECG tests in 20 newly diagnosed ACRO to gender matched healthy subjects. They found that indices of HRR were significant reduced in ACRO, as a marker of parasympathetic impairment . They also found that HRV and QT variability were significantly impaired in ACRO .
Late potentials (LPs)
Low amplitude and high frequency signals in the final part of the QRS complex that are recorded on a signal averaged ECG have been associated with an arrhythmogenic substratum and increased risk of sudden cardiac death in a number of cardiovascular conditions, both congenital (e.g. dilated, hypertrophic and arrhythmogenic right ventricular cardiomyopathies) and acquired (e.g. ischemic cardiomyopathy) [53,54,55,56]. LPs can be the electrocardiographic expression of an altered action potential conduction due to myocardial fibrosis . Hermann et al. found an increase in the rate of LPs in ACRO (23% vs 0%, p < 0.05) . This observation was confirmed by Maffei et al., who found a higher prevalence of LPs in 70 ACRO when compared to 70 control subjects (p = 0.001). In addition, VPBs were higher in ACRO with the presence of late potentials (p = 0.024), with a significant positive association (p < 0.05) between LPs and LVH on echocardiography .
LV dyssynchrony is impaired co-ordination of LV systolic contraction and is associated with an increased risk of arrhythmia in a number of cardiovascular diseases [58, 59]. In 30 ACRO compared to 30 controls, Kris et al. found evidence of dyssynchrony in ACRO by measuring differences in timing of systolic tissue velocities between the walls of the heart , with significant increases in Ts-12-SD, Ts-12, Ts-6-SD and Ts-6 in ACRO compared to controls (p < 0.005) .
There are conflicting data on atrial electromechanical function in acromegaly. Ilter et al. found no changes to atrial electromechanical function when measuring P wave dispersion, left atrial mechanical function on tissue Doppler and atrial volumes on 2D echocardiography in 23 ACRO compared to 27 controls . In contrast, Yayla et al. compared atrial electromechanical conduction in 34 ACRO (18 active/16 inactive) and 35 controls, finding both inter and intra atrial electromechanical delay in patients, consistent with structural remodelling .
QT dispersion and QT variability
QT dispersion (dQT) measures the heterogeneity of ventricular repolarization and is a predictor of ventricular arrhythmia and sudden cardiac death on 24 h-Holter monitoring in the general population . In 20 ACRO patients, Unubol et al. demonstrated that median dQTc (corrected dQT) was significantly higher than in 20 controls (p = 0.015); dQTc was not associated with LVH . Mohamed et al. found LP positivity more often in 17 ACRO compared to 17 matched controls on signal averaged ECG but also found greater dQT on standard 12-lead ECG (p < 0.005 and p < 0.05 respectively) . Some researchers have suggested that beat-to-beat QT variability may be a better predictor of malignant arrhythmia than dQT . In 30 ACRO compared to 30 controls, Osroz et al. found no significant differences in heart rate, PQ, QRS, QTc, and dQT but a significantly higher beat to beat QT variability (p < 0.0001) that could reflect a higher repolarization instability .
To summarize, preclinical markers of arrhythmias can be impaired in acromegaly. The independent predictive power of these variables in identifying those at greatest risk of arrhythmia, however, is unclear in clinical practice. Moreover, data are absent whether modification of any parameter or initiation of pharmacotherapy or device therapy in response to such changes may make any difference to risk of arrhythmia or alter prognosis.
Impact of treatment of acromegaly on arrhythmia (Table 1)
First generation somatostatin analogues (SSA)
There is evidence of an effect of SSAs on cardiac conduction tissue. Hou et al. studied the effect of somatostatin ex vivo on the action potential and contractile force of 54 human atrial preparations, finding that abnormal automaticity and triggered activity in human atrial fibres could be suppressed through a reduction in cellular calcium . The same year, Diez et al. demonstrated that somatostatin inhibited the Ca2+ current to inner myocytes in guinea-pig atrial fibres . Furthermore Wiley et al. found that SSAs stimulate the release of acetylcholine in canine cardiac cells  and Donald et al. demonstrated that somatostatin has negative chronotropic and inotropic effect on myocytes of snake Elaphe obsoleta . The effects of somatostatin were measured in vivo in 6 patients who underwent a complete electrophysiological study (before and after administration) for rhythm disturbances, including paroxysmal supraventricular tachycardia, sick sinus syndrome, Wolf-Parkinson White syndrome and ventricular tachycardia. The principal effects of somatostatin included prolongation of the atrioventricular nodal refractory time and reduction of heart rate. Atropine fully antagonized the effects of somatostatin .
SSAs may influence pre-clinical markers of arrhythmia in ACRO. Comunello et al. found a reduction in the HRV parameters SDNN and SDANN after SSA prescription in 28 ACRO patients. Fatti et al. reported the effect of first generation SSA treatment in 30 naive active ACRO, compared to 24 healthy controls. GH and IGF-1 significantly decreased after treatment, while QTc was significantly longer in ACRO before treatment compared to controls (438.6 ± 4.83 vs 407.5 ± 5.86 ms, p < 0.005) and shortened after treatment (438.6 ± 4.83 vs 421.0 ± 6.06 ms, p < 0.001); HR did not differ between ACRO and controls but significantly decreased in ACRO following treatment (70.0 ± 2.33 vs 63.6 ± 1.97 bpm, p < 0.05) .
Since the start of this millennium, there have been case reports on the efficacy of treatment with first generation SSAs in reducing VPBs [74, 75], followed by more data from new case–control studies. Lombardi et al. studied the impact of 6 months of treatment with Lanreotide in 19 naïve ACRO and found a significant reduction in both HR (66.5 ± 11 vs 71.5 ± 20 bpm, p < 0.05) and VPB count (16.5% vs 33.3%, p = not specified), although frequency of SVPB was not altered . Colao et al. studied 45 naïve ACRO patients before and after 5 years of SSA treatment with ECG or 24 h-Holter; at follow-up IGF-1 was controlled in 97.8% and the prevalence of ‘arrhythmia’ fell from 17.8% to 0%, p < 0.01, although the types of arrhythmia were not specified. Warszawsky et al. evaluated 28 ACRO after a year of octreotide LAR treatment: there was a reduction in mean HR (78 bpm to 73 bpm, p = 0.009), without other anatomical or electrophysiological changes noted . A meta-analysis of 18 studies of the effects of SSA on cardiac function in ACRO reported a consistent reduction in HR (14 studies, 199 patients, −5.8 ± 2.1 bpm; p < 0.001) and LVM (7 studies, 51 patients, −50.3 ± 13.3 g; p < 0.01), but no significant difference in LVM indexed to body surface area (14 studies, 143 patients). Similar results were obtained in separated analysis on octreotide and lanreotide . While these studies overall suggest a beneficial effect of somatostatin and SSAs on lowering heart rate, it is worth noting that the resulting bradycardia may have adverse consequences [78,79,80,81].
Second generation SSAs
Pasireotide, a new generation SSA that can bind to SSA receptor 1,2,3 and 5, is associated with QT prolongation and bradycardia, as warned by FDA . One study evaluated the effects of subcutaneous pasireotide on cardiac repolarization in healthy volunteers, and found a modest effect on QTc prolongation (13.2 ms (90% CI 11.4, 15.0)) and a maximum reduction in heart rate of −14.9 bpm (90% CI − 16.1, − 13.8) . One case report described second degree (type 1) atrioventricular block in a patient affected by Cushing’s disease after treatment with pasireotide . Petersenn et al. in a multicentre phase II trial involving 60 patients did not report any adverse arrhythmic effects , except for nine cases with at least one episode of sinus bradycardia who took part in an extension study of 30 ACRO participants . Due to the potential for QT prolongation, caution must be taken when using pasireotide .
Data from the Acrostudy and other registers have not found evidence of arrhythmia related to pegvisomant administration . Auriemma et al. reported the effects of short (6 months) and long (18 months) term treatment with pegvisomant on 13 ACRO patients. At baseline they found 15% patients with sinus tachycardia (the limit of HR to define sinus tachycardia was not specified by the authors) or “supraventricular episodes” (the term was left undefined by the authors). Although IGF-1 levels were normal in the majority and no differences were found on 24 h-Holter at 6 months, after 18 months follow-up average maximum, mean and minimum HR was reduced overall (− 4 bpm, p = 0.03; − 6 bpm, − p = 0.05; and − 7 bpm, p = 0.05 respectively) with rhythm abnormalities (sinus pauses, supraventricular episodes, and VPB) documented in 7.7% of patients (85% of ACRO had normal IGF-1 levels under pegvisomant treatment) .
Guidelines and consensus statements relating to arrhythmia management in acromegaly
There are more reviews on heart comorbidities than studies that analyze arrhythmic risk in acromegaly, but on close review of the primary research, it becomes apparent that the absolute risk is unclear. Further analysis of national registries does not provide additional information . Gadhela et al. in their review also pointed out that in many studies clinically significant arrhythmias were not detected . There are many guidelines and position statements about the management of cardiac and arrhythmic complications. Giustina et al. suggested ECG and echocardiography at diagnosis and suggested that 24 h-Holter may be warranted . Melmed et al. pointed out that “Arrhythmia is rarely a significant clinical challenge in acromegaly” but still recommended ECG and echocardiogram at diagnosis and annually thereafter . Katznelson et al., in the AACE (American Association of Clinical Endocrinologists) guidelines suggested cardiac assessment should include ECG and echocardiography if symptoms of cardiac involvement are present . The current guidelines of the Endocrine Society suggest that arrhythmias and conduction disorders are frequent and recommend complete cardiac assessment if there is clinical suspicion of involvement—but does not suggest specific tests  (Table 2).
Barnabeu et al. considered only the most recent guidelines in forming their recommendations: they suggested that an ECG should be performed at the diagnosis of acromegaly, and 24 h-Holter monitoring and echocardiography only if there is a clinical suspicion of either structural cardiac complications or arrhythmia. The authors pointed out that these recommendations were based on expert opinion alone and suggested that additional and subsequent cardiac investigations should be based on an individualized risk assessment . Recent consensus statements are similarly discordant in their recommendations: the statement of Melmed et al. on therapeutic outcomes, proposed “cardiac monitoring” as a strong recommendation , while Giustina et al. considered arrhythmias relatively uncommon and proposed ECG and echocardiography annually if abnormal . The latest guidelines by the Italian Association of Clinical Endocrinologists (AME) of 2020 are even more stringent (see Table 2) .
Based on our own experience, we suggest that low-cost, non-invasive investigations including a resting 12-lead ECG and 24 h-Holter are reasonable at diagnosis of acromegaly and annually during follow-up, especially in those patients with risk factors for arrhythmia  (Table 3). While this conservative approach may be pragmatic, unnecessary testing can delay initiation of therapy pending results, cause patient anxiety, and lead to further cardiological investigation that might not be needed. Current guidelines do not provide recommendations or suggestions about disease management in patients with arrhythmias. In our experience, we identify by medical history and physical/instrumental examination, ACRO patients with a highest probability to develop arrhythmias (i.e. patients with dilative cardiomyopathy/heart failure, valvular heart disease, history of syncope, medications that can prolong QT interval), in order to provide more strictly follow up or supplementary diagnostic exams. Upstream therapy with medications for acromegaly systemic complications, such as inhibitors of renin angiotensin system, statins, and polyunsaturated fatty acids, have shown anti-arrhythmic properties in the general population. What does seem clear is that further, large scale studies are needed before clear recommendations can be made on a solid evidence regarding onset, monitoring and treatment of arrhythmias in ACRO.
Although reviews and guidelines consider the higher risk of arrhythmia in acromegaly to be a fact, there is little good quality data to support this. Prevalence of arrhythmia remains a controversial issue in acromegaly. Despite the presence of multiple risk factors for arrhythmogenesis, data on the frequency of sudden cardiac death and major arrhythmia are limited to case reports and small case controls studies. This lack of data may reflect improved diagnosis and treatment of acromegaly but further research in larger populations are urgently needed.
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Parolin, M., Dassie, F., Vettor, R. et al. Electrophysiological features in acromegaly: re-thinking the arrhythmic risk?. J Endocrinol Invest 44, 209–221 (2021). https://doi.org/10.1007/s40618-020-01343-0