Growth hormone-releasing hormone (GHRH) from the hypothalamus signals the anterior pituitary to release growth hormone (GH) which in turn binds to its receptor in the liver and initiates the expression of insulin-like growth factor-1 (IGF-1). IGF-1 exerts its function through endocrine, paracrine, and autocrine signaling pathways [1, 2], and is responsible for DNA, RNA, and protein synthesis in the bone and muscle, cell growth, differentiation, and proliferation, and myriad other bodily functions (Fig. 1) [3]. An excess in circulating GH and IGF-1, most commonly due to a pituitary adenoma and rarely due to ectopic GH secretion or GHRH excess, leads to acromegaly [4]. Acromegaly is a chronic, multisystem disease with a wide range of manifestations, which may be due to a direct effect of the lesion or a long-term effect of excess GH and IGF-1 on organs and tissues [5]. Early manifestations may be subtle, and progression may be slow that patients and caregivers may not immediately recognize these changes as pathologic [6]. These factors contribute to the significant delay in diagnosing acromegaly, with a mean diagnostic delay of 5.5 years [7]. According to the ACRO-POLIS study by Caron et al. [6] in 2019, the most frequently reported symptoms 6–10 years prior to diagnosis are enlarged hands and feet, snoring, menstrual cycle changes, weight gain, and carpal and/or cubital tunnel syndrome. The diagnosis of acromegaly is typically confirmed with measurement of IGF-1 levels in patients with typical manifestations such as acral and facial features. However, recent guidelines recommend IGF-1 level measurement to also include those without typical manifestations but with several atypical signs such as sleep apnea, type 2 diabetes mellitus, debilitating arthritis, carpal tunnel syndrome, and hypertension [8]. Serum IGF-1 levels are preferred over GH levels as biomarker the in the diagnosis of acromegaly due to several factors: significantly longer half-life of approximately 15 hours compared to less than an hour for GH, the episodic nature of GH secretion, and a closer correlation of IGF-1 levels with the onset of clinical signs, wherein an elevated IGF-1 with normal GH reflects an earlier stage of the disease [9]. IGF-1 levels may be falsely increased in pregnancy and late adolescence, which reinforces the need for a standardized age and sex-matched IGF-1 levels specific for each of the assays used in measurement. On the other hand, falsely decreased levels may be seen in hepatic or renal failure, hypothyroidism, malnutrition, severe infections, poorly controlled diabetes, and in patients using combined oral contraceptive pills. If factors causing false variations of IGF-1 levels are present or if IGF-1 assays are not available, a GH suppression test with a 75 g oral glucose load can be performed as a confirmatory test [8].

Fig. 1.

Effects of GH/IGF-1 on different organs in the body.

Pituitary Magnetic Resonance Imaging (MRI) is recommended for all patients with acromegaly to determine the presence of any macro- or microadenomas [10]. In patients with biochemically confirmed acromegaly with a normal pituitary MRI, further testing with GHRH measurement, somatostatin receptor scintigraphy, and thoracic or abdominal imaging may be considered [8].

Cardiovascular diseases (CVD) is the leading cause of mortality in patients with acromegaly [10, 11, 12]. The most frequent cardiovascular complications in acromegaly are heart failure (HF), valvular disease, hypertension, arrhythmia and coronary artery disease (CAD) [13]. Risk factors for these cardiac abnormalities include longer duration of GH hypersecretion, increasing age and higher Body Mass Index (BMI) [13]. On top of the direct cardiovascular risk from prolonged GH hypersecretion, patients with acromegaly are further predisposed to develop other significant cardiovascular risk factors such as diabetes, dyslipidemia, obesity and sleep apnea [13]. The presence of any cardiovascular comorbidities at the time of acromegaly diagnosis is associated with significantly increased odds of hospitalization and risk of death [13]. Prolonged delay in diagnosis is also associated with significantly increased morbidity and mortality due to cardiovascular complications [7].

Globally, the prevalence rate of acromegaly is about 59 cases per 1,000,000 people, while the incidence is 3.8 cases per 1,000,000 people [13]. While different studies have shown some variability in sex distribution, the prevalence seems to be equal among men and women on average. Similarly, the prevalence in different countries may be affected by population size and geographical area. For instance, Lavrantaki et al. [14] based their study from the published data done in Europe and found the annual incidence to be between 2 to 11 cases per 1,000,000 people, while the prevalence was between 28 to 137 cases per 1,000,000 people. In Korea, on the other hand, the average 5-year incidence (2013–2017) was 4.2 cases per million, and the prevalence was 32 cases per million per year [15].

Patients are diagnosed at the fourth to fifth decade of life on average; however, there is a delay of 5 to 8 years before diagnosis is established [14, 16]. The most common manifestations of acromegaly are acral enlargement and coarse facial quality with 78.8–85.7% and 71.2–71.4% respectively [11]. Other signs and symptoms include macroglossia (46.2%), sweating (44.2–51.7%), skin thickening (38.5%), snoring (28.6%), arthralgias (28.6–50%), tiredness (14.3–38.5%), carpal tunnel syndrome (14.3%), and visual disturbances (34.6%) [14].

Patients may present with acute and/or chronic complications from acromegaly [17]. A study in New Zealand listed sweating, carpal tunnel, headache, visual field defect and sleep apnea as acute complications, while hypertension, diabetes, CVD and arthropathy were listed as chronic complications. The Liège Acromegaly Survey (LAS) Database in 2017 found that 28.8% of patients have hypertension; 27.5% with diabetes mellitus; 25.5% with sleep apnea; 15.5% with cardiac enlargement; and 5% with stroke, arrhythmias, ischemic heart disease, HF, and myocardial infarction. Other comorbidities that may be present in patients include thyroid nodule or goiter (34%), colonic polyps (13%), osteoporosis (12.3%), and cancer (breast, thyroid, and skin) (1%) [18]. The study showed that the prevalence of these complications decreased by 5–40% for acute complications and 10–20% for chronic complications after treatment when the final GH was 2 ug/L [16, 17]. Renehan & Brennan [19] emphasized the association of acromegaly with colon, rectal and thyroid cancers, with respective risk ratios of 2.46 (95% CI 1.79, 3.38), 1.41 (95% CI 0.54, 3.71), and 3.64 (95% CI 1.63, 8.11).

Acromegaly may be also associated with certain conditions including multiple endocrine neoplasia (MEN)-1, extrapituitary tumors (pancreas, lung, ovary), McCune-Albright Syndrome, Carney Syndrome, isolated familial somatotropinomas, and familial isolated pituitary adenoma (FIPA) [16]. Most patients have macroadenomas (66.7–88.9%) at the time of diagnosis, which could be likely due to the delay in diagnosis. Moreover, few cases (14.3–31.8%) were due to microadenomas. The different presenting sizes of adenomas may pose as a challenge for surgical interventions [14]. A significant increase in epicardial fat thickness (9.71 $\pm$ 1.54) in remission acromegaly (RA) and (10.08 $\pm$ 1.95 mm) in active acromegaly (AA) vs. controls (5.74 $\pm$ 0.92 mm, p 0001), significantly decreased aortic strain and aortic distensibility (3.81 $\pm$ 1.94) in RA and in AA (3.68 $\pm$ 1.99) vs. controls (8.19 $\pm$ 4.19%, p 0.0001), and increased aortic root diameter at the sino-tubular junction (30 $\pm$ 4 vs. 26 $\pm$ 3 mm, p = 0.0001) and the ascending aorta (33 $\pm$ 5 vs. 30 $\pm$ 4 mm, p = 0.006) warrant a more extensive cardiovascular evaluation (echocardiography, cardiac MRI) in the presence of these features [20, 19]. In a cohort study by Wu et al. [21] in 2020, 1195 patients displayed excessive risk of mortality (41% more) over a 17-year period, with higher risk in early-onset disease. Excessive circulating GH and IGF-1 in acromegalic patients induce comorbidities such as CVD (atherosclerosis, cardiomyopathy, arrythmias), diabetes, and cancers (digestive, respiratory, breast and lymphoma), which are direct contributors of higher mortality in acromegaly patients [21]. If left untreated, mortality occurs in almost 100% of patients within 15 years from CVD, and only 20% of patients with diabetes and acromegaly will survive 20 years [22]. For treated patients who survived more than 5 years in early and middle age onset groups, mortality rates were similar with the general population, emphasizing the importance of aggressive and early treatment which potentially neutralizes the associated mortality risk, especially with the advent of pituitary surgery and radiotherapy [21].

The effects of GH and IGF-I on the cardiovascular system have been studied in animal models and human myocardial tissue. The GH and IGF-I receptors are expressed at high levels in both myocardial tissue and blood vessels [23]. Animal studies have demonstrated that IGF-1 had a physiologic, antiapoptotic, and pro-survival effects on the heart and is associated with improved cardiac function, alleviation of high-fat diet-induced cardiac dysfunction, regeneration of the myocardium following infarction, and attenuation of endothelin receptor A (ETA)-mediated coronary contraction [2, 24, 25, 26, 27, 28]. Short term exposure of the normal heart to high GH and IGF-I concentrations can enhance myocardial contractility and relaxation [29]. Obradovic et al. [2] discussed the effects of IGF-1 on the cardiovascular system in a review article summarized in Fig. 2. Low IGF-1 or GH levels were associated with a twofold increased risk for ischemic heart disease due to its correlation with obesity and sedentary lifestyle [30]. IGF-1 has been shown to have atheroprotective effects in a study by Higashi et al. [31], where an inverse correlation of systemic IGF-1 levels and atherosclerosis was demonstrated by infusing IGF-1 in ApoE-null mice. The presence of IGF-1 was shown to induce phenotypic changes in plaques, represented by attenuated cytokine expression, decreased macrophage counts, decreased oxidative stress, and increased presence of collagen and smooth muscle cells (Fig. 3, Ref. [31]). In human myocardial tissue, activation of IGF-1 receptors demonstrated a concentration-dependent positive inotropic effect secondary to increased intracellular Ca${}^{2+}$, enhancement of L-type Ca${}^{2+}$ currents and Na${}^{+}$–H${}^{+}$ exchange. GH, in contrast, does not influence Ca${}^{2+}$ currents in acute settings; however, it has been shown to increase peak intracellular Ca${}^{2+}$ concentrations after long term exposure in vitro [32].

Fig. 2.

Effects of IGF-1 on the Cardiovascular System as seen in vivo studies.

Fig. 3.

IGF-1 effects on macrophage and smooth muscle cell decreasing atherosclerosis. Adapted from Higashi et al. [ 31 ] .

Excess IGF-1, however, can also have negative effects on the cardiovascular system. Increasing the presence of circulatory smooth muscle cells, as seen in animal models, can lead to restenosis, pulmonary hypertension, and vein graft failure [31]. Atherosclerosis in acromegaly is controversial since there is not much evidence on the effect of IGF-1 on forming atheromas [33]. In the work of Ito et al. [34], IGF-I was found to possibly induce hypertrophy in cultured neonatal rat cardiomyocytes. In a study done in 2017 by Cansu et al. [35], incidences of atherosclerosis, left ventricular hypertrophy (LVH), and diastolic dysfunction were more common in patients with acromegaly, both controlled and uncontrolled.

Pathologic abnormalities seen in an acromegalic heart include ventricular enlargement, interstitial fibrosis, cardiomyocyte degeneration, myofibrillar derangements, leukocyte infiltration and increased collagen deposition [22, 33]. Colao’s review article mentioned that aging and prolonged duration of excess GH/IGF-1 levels are determinants of cardiac derangement [36]. Cardiac hypertrophy was seen in patients who had acromegaly for an extended duration and was more common in patients aged $>$50 years. Because of this, it was suggested that cardiac hypertrophy may be an early manifestation of acromegaly, with a direct correlation between the severity of cardiac hypertrophy and duration of acromegaly [36]. These structural changes increase the risk of both right and left ventricular (LV) dysfunction leading to HF. Rhythm disturbances including atrial fibrillation are also more common in acromegaly patients compared to the general population, as IGF-1 can directly affect myocardial contractility by increasing intracellular Ca${}^{2+}$ levels [36]. Excessive GH/IGF-1 also contributes to diastolic and systolic dysfunction, which could lead to HF [37].

The sections below will individually discuss the different cardiovascular abnormalities which may be present in acromegaly patients.

Cardiovascular mortality in acromegalic patients depends on three main factors: GH levels, severity of arterial hypertension, and CVD. It has been shown that a reduction in serum GH concentrations to less than 1–2 $\mu$g/liter and normalization of serum IGF-I levels reduce mortality to a level similar to that of the general population [72]. Overall, normalization of GH/IGF levels either with pharmacotherapy or surgery improves cardiac mortality of acromegaly patients [72]. Well-controlled, middle-aged, acromegalic patients are more likely to have reversible cardiomyopathy than those with long-standing GH/IGF-1 elevation [50].

Studies suggest that the early initiation of somatostatin analogue (SSA) such as Octreotide LAR can potentially arrest or regress cardiac abnormalities and normalize GH/IGF-1 levels. In a case study, an acromegalic patient with chronic HF started on a daily dose of Octreotide showed an improved cardiac function including a decrease in LV wall thickness from 22.5 to 17.8 mm and an increase in systolic ejection fraction from 38 to 50% [73]. Its effect on arrhythmia has been particular on decreasing the frequency of premature ventricular complexes (PVC). In two separate case studies, Holter 24-hour electrocardiographic monitoring revealed improvement from 17,249 to 2882 beats a day and 24,277 to 2062 beats a day after Octreotide treatment. It has been hypothesized that Octreotide’s reduction of the hypertrophied cardiac tissue may have contributed to the improvement of PVCs [73, 74].

Pegvisomant (PEG) has also been shown to improve cardiac structure and function and reduce prevalence of arrhythmia and Framingham risk score. Combined therapy of SSA and PEG for 12 and 60 months showed significant improvement of cardiac structure and performance in terms of cardiac LV mass index and ventricular filling velocities, compared with long-term use of SSA alone. Its mechanism in acromegalic arrhythmias is still unclear; nonetheless, a study by Auriemma et al. [75] described that the effect may lie on the direct action of PEG on the pacemaker cells and on membrane calcium channels by working on the GH receptors in the conduction system. In this study, it was illustrated that PEG reduced the prevalence of arrhythmias by 50% (from 15 to 7.7%) and its complete disappearance was observed in one patient after an 18-month treatment. In conclusion, the study demonstrated that long-term treatment with PEG decreases a patient’s mean, minimum, and maximum heart rates and improves rhythm conduction abnormalities in acromegalic patients [75].

Cardiovascular effects of Cabergoline therapy on acromegalic patients remain to be unclear as it may be dose and duration dependent. In a study by Maione et al. [76], a median cumulative dose of 203 mg Cabergoline was used for a median of 35 months versus those who had never received Cabergoline. Results revealed a similar incidence of new valve regurgitation (40.0 and 45.8%, p-value: 0.68) and disease control [76].

Additionally, management of hypertension, dyslipidemia, diabetes, and other risk factors in acromegaly patients must be based on guidelines in the treatment of hypertension in the general population [66].

The current first-line treatment for acromegaly is transsphenoidal surgery (TSS), but remission is only seen in approximately half of patients, even in reference centers. Other available options include medical and radiotherapy. However, despite the multiple options for treatment, approximately 40% of patients remain uncontrolled [77]; and more importantly, regardless of biochemical control, health-related quality of life remains unimproved [78]. There is often a delay in treatment owing to delayed diagnosis as well, as symptom development in acromegaly can take years [79]. The current treatment for acromegaly is based on a “trial and error” approach, as no clear biomarkers or other treatment predictors are readily available to guide therapy with high accuracy. As such, studies are looking into innovations in treatment to a precision medicine which can direct treatment in a more individualized approach. Moreover, new drugs for acromegaly are being developed, with potential to further improve disease control [78]. Lastly, attempts at earlier diagnosis and treatment can decrease progression of disease and its associated comorbidities.

Cardiovascular complications of acromegaly can present as HF, arrhythmia, valvular disease, and hypertension. The severity of these complications is almost always correlated to the severity and duration of GH and IGF-1 excess. A thorough history and focused physical examination are not enough to determine the extent of the cardiac complications; hence, newer diagnostic modalities such as cardiac MRI and GLS are increasingly being used. Guideline-directed medical therapy as well as appropriate control of excess hormone levels can control and even reverse the cardiovascular complications in this population. Opportunities exist in developing a new drug to effectively balance GH/IGF-1 levels, as this will be of great benefit in the management of HF subjects with acromegaly. Further study is warranted to also assess the benefits of this strategy in acromegaly patients with other organ involvement, such as those with nonalcoholic steatohepatitis/nonalcoholic fatty liver disease (NASH/NAFLD).

FBR—Conceptualization, Data curation, Validation, Writing - original draft, Writing - review & editing; MKT and MFA—Validation, Writing - review and editing original draft; GFM, MLM, RHM, SP and PM—Data curation, Formal analysis, Methodology; SWC, JPA, MGY, MLC, EL and KV—Validation, Writing - review & editing. All authors have read and agreed to the published version of the manuscript.

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This research received no external funding.

The author declares no conflict of interest. Krishnaswami Vijayaraghavan is serving as one of the Editorial Board members and Guest editors of this journal. Peter A. McCullough is serving as one of the Guest editors of this journal. We declare that Krishnaswami Vijayaraghavan and Peter A. McCullough had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Jerome L. Fleg.