Cardiomyopathies of endocrine origin: A state-of-the-art review

Abstract

Endocrine disorders are increasingly recognized as potentially reversible causes of secondary cardiomyopathies, yet they often remain underdiagnosed in clinical practice. These conditions-including thyroid dysfunction, acromegaly, pheochromocytoma, diabetes mellitus, adrenal disorders, among others-can significantly alter cardiac structure and function through hormonal excess, metabolic remodeling, and neurohumoral activation. Hyperthyroidism may lead to high-output heart failure (HF) and atrial fibrillation, while hypothyroidism is associated with diastolic dysfunction, pericardial effusion, and accelerated atherosclerosis. Acromegaly promotes biventricular hypertrophy and myocardial fibrosis via insulin-like growth factor 1 overproduction. Pheochromocytoma triggers catecholamine-induced cardiomyopathy, resembling Takotsubo syndrome and carrying a high risk of mortality if left untreated. Diabetes induces a distinct phenotype of cardiomyopathy, affecting both systolic and diastolic function through microvascular injury and oxidative stress. Recognizing these endocrine etiologies is crucial, as targeted hormonal therapies-such as antithyroid agents, somatostatin analogs, or adrenalectomy-can reverse or significantly mitigate cardiac dysfunction. Comprehensive endocrine screening in patients with unexplained cardiomyopathy is therefore essential. This review synthesizes current knowledge on the pathophysiological mechanisms, clinical manifestations, and therapeutic strategies for endocrine cardiomyopathies and proposes a diagnostic algorithm for early recognition. Emerging biomarkers, such as galectin-3 in diabetic heart disease, may further enhance diagnostic accuracy and risk stratification. The interplay between endocrine and cardiovascular systems offers a unique opportunity for early intervention, potentially preventing progression to irreversible HF.

Key Words: Endocrine cardiomyopathy; Heart failure; Thyroid disease; Hormonal screening; Cardiac remodeling

Core Tip: Endocrine cardiomyopathies are an under-recognized but treatable group of heart diseases caused by hormonal imbalances. Timely diagnosis and targeted therapy can reverse cardiac dysfunction and prevent progression to heart failure. Systematic screening for endocrine causes in patients with unexplained cardiomyopathy is essential, and management significantly improves clinical outcomes.

INTRODUCTION

Nonischemic cardiomyopathies comprise a broad group of myocardial diseases that cause mechanical and electrical alterations, leading to inappropriate ventricular hypertrophy or dilation. These disorders are primarily classified according to morphological, functional, and genetic criteria[1] (Figure 1). While many of these conditions have idiopathic origins, several subtypes, particularly those induced by endocrine disorders, share common features such as metabolic remodeling, neurohumoral activation, and structural alterations. These shared pathophysiological mechanisms contribute to the development of cardiomyopathies in a variety of endocrine diseases.

Figure 1 Classification of primary cardiomyopathy. HCM: Hypertrophic cardiomyopathy; DCM: Dilated cardiomyopathy; LVNC: Left ventricular noncompaction cardiomyopathy.

Hypertrophic cardiomyopathy is defined by left ventricle (LV) hypertrophy and diastolic dysfunction, often due to mutations in sarcomeric proteins. Dilated cardiomyopathy (DCM) involves LV dilation and systolic impairment, which may be familial, toxin-induced, or secondary to endocrine and metabolic disorders. Restrictive cardiomyopathy is characterized by impaired ventricular filling with preserved systolic function and is frequently associated with systemic conditions such as amyloidosis[2-4].

Despite these established classifications, secondary cardiomyopathies-particularly those caused by endocrine disorders-receive insufficient attention. Endocrine conditions such as thyroid dysfunction, adrenal disease, and parathyroid disease can profoundly affect myocardial structure and function. For example, hyperthyroidism can lead to increased cardiac output (CO) and low systemic vascular resistance (SVR), which may result in heart failure (HF). Hypothyroidism is associated with myocardial fibrosis, prompting the American Heart Association (AHA) to recommend thyroid function tests for all patients presenting with DCM[5,6].

Other endocrine conditions such as primary hyperaldosteronism, Cushing's syndrome (CS), and pheochromocytoma can also induce myocardial remodeling through mechanisms including hypertrophy, myofibrillolysis, and direct catecholamine toxicity, as evidenced by endomyocardial biopsy findings[7]. In addition, primary hypoparathyroidism can lead to hypocalcemia-related cardiomyopathy, which is often reversible with appropriate treatment[8].

Recognizing and treating endocrine disorders as a cause of cardiomyopathies is critical, as it directly influences cardiac function and patient outcomes-a point emphasized by the AHA guidelines. This review aims to synthesize the pathophysiology and clinical implications of these conditions to improve the diagnostic approach, guide specific treatment, and ultimately enhance outcomes for affected patients.

METHODOLOGY

A narrative review was conducted to explore the pathophysiological mechanisms, clinical features, and management strategies of cardiomyopathies of endocrine origin. A comprehensive literature search was performed in PubMed, Scopus, Web of Science, EMBASE, and Scielo using search terms including (“cardiomyopathy” AND “endocrine diseases”) AND (“thyroid” OR “diabetes mellitus” OR “pheochromocytoma” OR “acromegaly” OR “Cushing syndrome” OR “hyperparathyroidism” OR “hypoparathyroidism” OR “Carcinoid”). Eligible articles included clinical trials, systematic reviews, meta-analyses, cohort studies, case-control studies, and relevant case reports published in English or Spanish. Conference abstracts and non-peer-reviewed materials were excluded. No publication date restrictions were imposed to ensure coverage of both classical and current evidence. The narrative design was chosen to integrate findings from basic science, cardiology, and endocrinology, aiming to provide a comprehensive synthesis. A total of 162 articles were included.

ETIOLOGY AND PATHOPHYSIOLOGICAL MECHANISMS OF ENDOCRINE CARDIOMYOPATHIES

Endocrine cardiomyopathies result from the complex interaction between hormones and the cardiovascular system. This interaction leads to structural and functional alterations of the heart. Some of the hormones involved include: T3/T4, aldosterone, catecholamines, cortisol, growth hormone (GH), insulin-like growth factor 1 (IGF-1), parathyroid hormone (PTH), androgens and estrogens.

General endocrine-cardiac interactions

Several key hormones directly influence cardiac function (Figure 2). Thyroid hormones, particularly triiodothyronine (T3), are essential for systolic contractions and diastolic relaxation, as well as for reducing SVR and promoting coronary arteriolar angiogenesis[9]. Insulin and IGF-1 are critical for myocardial metabolism and growth, activating signaling pathways such as PI3K/Akt that promote cardiomyocyte survival and hypertrophy[10]. Conversely, angiotensin II (Ang II) and endothelin-1 (ET-1) are potent vasoconstrictors that contribute to cardiac hypertrophy and myocardial fibrosis through the activation of pathways including MAPK and PKC[10].

Figure 2 Pathophysiological mechanisms. IGF-1: Insulin-like growth factor 1; Ang II: Angiotensin II; ET-1: Endothelin; VEGF: Vascular endothelial growth factor; CaMKII: Calcium/calmodulin-dependent protein kinase II; MEF2: Myocyte enhancer factor 2; AMPK: AMP-activated protein kinase.

Hormonal pathways affecting myocardial structure and function

Progression to HF, often preceded by cardiac hypertrophy, is driven by a spectrum of hormonal influences. Catecholamines, Ang II, and ET-1 are considered the primary pathogenic mediators. However, hormones such as thyroid hormones, insulin, IGF-1, and estrogens also play a significant physiological role in cardiac hypertrophy[10]. Thyroid hormones modulate myocardial performance by regulating myosin isoforms and calcium-handling proteins, thereby improving contraction and relaxation[11,12]. The renin-angiotensin-aldosterone system (RAAS), which regulates blood pressure and fluid homeostasis, can lead to myocardial hypertrophy and fibrosis when chronically activated[11]. Natriuretic peptides (ANP and BNP) counterbalance the RAAS effects by promoting vasodilation and natriuresis, thereby alleviating cardiac stress[9]. GH and IGF-1 promote cardiac cell growth and physiological ventricular remodeling[10], while catecholamines directly influence myocardial contractility and heart rate[12]. Disregulation in any of these systems can contribute to cardiovascular diseases[5,9-12].

Shared vs distinct mechanisms across different endocrine disorders

Cardiomyopathies and endocrine disorders have some pathophysiological mechanisms in common, but also have distinct features. Shared mechanisms in cardiomyopathies include alterations in calcium handling, myocardial fibrosis and energy metabolism[5,10,11]. In contrast, distinct mechanisms are specifically related to hormonal imbalances and their direct effects on cardiac tissue. For instance, thyroid-related cardiomyopathies function by modulating myosin isoforms and calcium-handling proteins[9], whereas adrenal disorders such as hyperaldosteronism and CS cause structural changes in cardiomyocytes due to hormonal excess[12].

Thyroid disorders

Hyperthyroidism: Hyperthyroidism induces high-output cardiomyopathy through both genomic and non-genomic actions of the thyroid hormone (Figure 3). T3 upregulates α-myosin heavy chain and sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a), while downregulating MHCβ and phospholamban, thereby enhancing myocardial contractility and diastolic relaxation[13-16]. Concurrently, T3 reduces SVR by 50%-70% via rapid activation of endothelial nitric oxide synthase, leading to vasodilation and increased preload and CO[15,16]. Chronic tachycardia and increased contractility raise myocardial oxygen demand, while shortened diastole compromises coronary perfusion, predisposing to ischemia and left ventricular hypertrophy[14,16]. Atrial fibrillation develops due to shortened atrial refractory periods, increased ectopic activity, and β-adrenergic hypersensitivity, with a prevalence of 10%-25% in thyrotoxicosis[15,17,18]. Ventricular arrhythmias may arise from QT interval shortening and decreased myocardial electrical stability[14] (Table 1).

Figure 3 Pathophysiology of cardiomyopathy in hyperthyroidism and hypothyroidism. T3: Triiodothyronine; T4: Thyroxine; a-MHC: Alpha-myosin heavy chain; SERCA2: Sarcoplasmic/endoplasmic reticulum calcium ATPase 2; LDL: Low-density lipoprotein; TSH: Thyroid-stimulating hormone.

Table 1 Cardiac manifestations and pathophysiological mechanisms of endocrine-related cardiomyopathies.

Endocrine disorder	Pathophysiological mechanisms	Cardiac manifestations	Distinctive features
Hyperthyroidism	Increased β-adrenergic receptor expression, oxidative stress, mitochondrial dysfunction, impaired calcium handling	High-output heart failure, tachyarrhythmias, systolic dysfunction	Often reversible; leads to tachycardia-induced cardiomyopathy
Hypothyroidism	Myocardial fibrosis, impaired mitochondrial function, altered lipid metabolism, decreased β-adrenergic receptor density	Bradycardia, diastolic dysfunction, pericardial effusion	Slowed myocardial relaxation; TFT recommended in DCM
Acromegaly	IGF-1-mediated myocyte hypertrophy, interstitial fibrosis, altered calcium signaling	Concentric LV hypertrophy, diastolic dysfunction, arrhythmias	May be subclinical for years; improvement with hormonal control
Diabetes mellitus	Activation of renin–angiotensin-aldosterone system (RAAS), increased oxidative stress, lipid accumulation, myocardial inflammation, and interstitial fibrosis	LV hypertrophy, diastolic dysfunction, interstitial fibrosis	Occurs independently of ischemic heart disease; linked to poor glycemic control
Cushing’s syndrome	Cortisol-induced insulin resistance, endothelial dysfunction, RAAS overactivation, myocardial remodeling	LV hypertrophy, diastolic dysfunction, arrhythmias	Cardiovascular risk may persist despite remission
Addison’s disease	Glucocorticoid and mineralocorticoid deficiency: ↓ vascular tone, electrolyte imbalance	Hypotension, arrhythmias, reduced cardiac output	May present with shock or cardiomyopathy; improves with hormone replacement
Primary hyperaldosteronism	Aldosterone-induced myocardial remodeling, oxidative stress, collagen deposition	LV hypertrophy, myocardial fibrosis, arrhythmias	Frequently associated with resistant hypertension; regression with mineralocorticoid receptor antagonists
Primary hyperparathyroidism	Oxidative stress, endothelial dysfunction, inflammatory cytokine release, vascular and myocardial smooth muscle proliferation, hypercalcemia leading to arterial calcification and atherosclerosis	Arrhythmias, vascular calcification, LV structural remodeling	Hypercalcemia and PTH excess cause vascular calcification and myocardial hypertrophy; frequently associated with metabolic comorbidities (e.g., hypertension, obesity, diabetes)
Hypoparathyroidism	Hypocalcemia leading to impaired excitation–contraction coupling and electrophysiological instability	Dilated cardiomyopathy, prolonged QT interval	Often reversible with calcium and vitamin D replacement
Carcinoid heart	Serotonin-induced fibrosis of endocardium and valves, elevated 5-HT and cytokines	Right-sided valvular disease (tricuspid, pulmonary), heart failure	Involves only right heart; associated with neuroendocrine tumors and elevated 5-HIAA
Pheochromocytoma	Catecholamine excess, calcium overload, myofibrillolysis, contraction band necrosis	Takotsubo-like cardiomyopathy, myocarditis, arrhythmias	Acute and reversible; EMB shows characteristic catecholamine toxicity

TFT: Thyroid function tests; DCM: Dilated cardiomyopathy; LV: Left ventricle; IGF-1: Insulin-like growth factor 1; PTH: Parathyroid hormone; 5-HT: 5-Hydroxytryptamine; 5-HIAA: 5-Hydroxyindoleacetic acid; EMB: Endomyocardial biopsy.

Hypothyroidism: Hypothyroidism leads to diastolic dysfunction primarily through decreased SERCA2a expression and increased phospholamban levels, delaying calcium reuptake and prolonging relaxation[13,19,20]. Echocardiographic findings include prolonged isovolumic relaxation time and reduced early mitral inflow velocity (E/A ratio)[13,19]. Increased SVR-up to 50%-due to endothelial dysfunction and diminished nitric oxide bioavailability contributes to diastolic hypertension[16,19,21]. Accelerated atherosclerosis is caused by dyslipidemia-elevated low-density lipoprotein (LDL) cholesterol secondary to reduced hepatic LDL receptor expression and cholesterol-α-monooxygenase activity-as well as hyperhomocysteinemia, elevated C-reactive protein, and carotid intima-media thickening[19,22-24]. Pericardial effusions, often protein-rich, result from increased capillary permeability and impaired lymphatic drainage, occurring in approximately 30% of overt cases[20,21].

Acromegaly

Chronic GH and IGF-1 excess in acromegaly drives a triphasic progression of cardiomyopathy through distinct molecular mechanisms (Figure 4). The initial hyperkinetic phase is characterized by GH-mediated calcium sensitization of cardiac myofilaments, which increases contractility and reduces peripheral vascular resistance[25,26]. Sustained hormonal exposure activates myocardial GH receptors, initiating JAK2/STAT5 signaling and inducing cardiomyocyte hypertrophy via sarcomere proliferation[27]. Simultaneously, IGF-1 activates PI3K/AKT and TGF-β1 pathways in cardiac fibroblasts, promoting collagen synthesis and extracellular matrix deposition[27,28]. This transitions to the intermediate hypertrophic phase, marked by biventricular concentric hypertrophy (septal thickness > 15 mm) with histological features such as myocyte disarray and lymphomonuclear infiltration[25-27]. In the fibrotic phase, TGF-β/Smad3-mediated collagen accumulation, matrix metalloproteinase dysregulation, and reactive oxygen species (ROS) accumulation result in interstitial stiffness and diastolic impairment[28,29]. Additionally, GH/IGF-1-induced activation of renal epithelial sodium channel exacerbates volume overload and increases ventricular wall stress[26,29].

Figure 4 Phases of acromegalic heart disease. GH: Growth hormone; IGF-1: Insulin-like growth factor 1; TGF-β1: Transforming growth factor beta 1; MMP: Matrix metalloproteinases; TIMP: Tissue inhibitors of metalloproteinases.

Diabetes mellitus

New-onset HF is a common complication of type 2 diabetes mellitus (T2DM), driven by combination of functional, structural and metabolic changes independent of ischemia or atherosclerotic disease. In type 1 diabetes mellitus (T1DM), development of DCM with reduced ejection fraction (HFrEF) has been linked to a dysregulated immune response. In contrast, patients with T2DM more frequently present with HF with preserved ejection fraction (HFpEF) phenotype, often associated with overweight or obesity[30]. Glycated hemoglobin (HbA1c) levels correlate with cardiac dysfunction severity; a 1% increase in HbA1c corresponds to a 30% increase in HF risk in T1DM and an 8% increase in T2DM[30-32]. Conversely, patients with HF also demonstrate a predisposition to developing new-onset diabetes, with risk correlating with HF severity[33-35].

Hyperglycemia, hyperinsulinemia, and insulin resistance promote cardiac stiffness, hypertrophy, and dysfunction via fibrogenic pathways, including increased ROS production, neurohumoral activation, growth factor signaling, pro-inflammatory cytokines, and advanced glycation end-product deposition[32,36,37]. In the setting of hyperglycemia and hyperlipidemia, limited glucose uptake shifts myocardial metabolism toward fatty acid oxidation, increasing ROS and apoptosis[33]. In T2DM with obesity or insulin resistance, these factors promote cardiomyocyte hypertrophy[38].

Endothelial dysfunction in diabetes increases vascular permeability, promotes vasoconstriction, and reduces vasodilation[34,36,37]. The myocardium overproduces endothelin, contributing to vascular hypertrophy and myocardial fibrosis. This is aggravated by upregulation of collagen types I and III, reduced nitric oxide availability, and oxidative stress[34-36,38]. Imbalance in macrophage polarization (pro- vs anti-inflammatory) sustains myocardial inflammation and injury[39]. In T1DM, autoimmune activation of fibroblasts contributes to fibrosis, hypertrophy, extracellular matrix remodeling, conduction abnormalities, and ultimately HF[33,37,39]. HbA1c is directly correlated with cardiomyopathy severity; a 1% increase is associated with a approximately 3.0 g increase in left ventricular mass, with fibrosis predominating over hypertrophy[33,38].

Adrenal disorders

CS: CS is associated with several comorbidities, including atherosclerosis, obesity, impaired glucose metabolism, hypercoagulability due to glucocorticoid excess, HF, and coronary artery disease[40-42]. Cardiovascular mortality risk is increased up to sevenfold during the active phase of CS[40,43,44]. Because the diagnostic process is often prolonged-frequently taking several years-23% of patients in one study required hospitalization for CS-related complications before receiving a definitive diagnosis[40]. The risk of complications appears lower in patients with adrenal CS and higher in cases of exogenous etiology[40].

Addison’s disease: Adrenal insufficiency, or Addison's disease (AD), is characterised by deficient production of glucocorticoids and mineralocorticoids. This condition is associated with cardiovascular involvement due to the regulatory role of adrenal hormones in hemodynamic and metabolic balance[45,46]. The most common metabolic disturbances in AD are hypoglycaemia, hyponatraemia, and hypercalcaemia. The latter is linked to an increased risk of arrhythmias and low-incidence heart block[45,47,48], with isolated reports of syncope or Stokes-Adams syndrome in patients with primary adrenal insufficiency[47].

Primary hyperaldosteronism

Excess aldosterone can be classified as either primary, due to increased secretion by the adrenal glands; or secondary, caused by increased activation of the RAAS system due to reduced intravascular volume[49,50].

Excess aldosterone may be primary, due to autonomous adrenal secretion, or secondary, due to RAAS activation in response to decreased intravascular volume[49,50]. Aldosterone regulates sodium and potassium balance and blood pressure via the RAAS[51,52]. Chronic overproduction and mineralocorticoid receptor (MR) activation promote hypertension and HF by inducing myocardial fibrosis and eccentric remodeling, with a dose-response relationship between aldosterone levels and structural changes[53,54]. RAAS blockade may mitigate fibrosis independently of blood pressure control[55].

Aldosterone excess also contributes to cardiac hypertrophy, perivascular inflammation, and electrophysiological disturbances, such as prolonged action potentials and impaired repolarization, predisposing to atrial fibrillation (Figure 5)[51,52]. It stimulates the release of pro-inflammatory mediators from coronary artery smooth muscle cells and promotes monocyte chemotaxis and differentiation into M1 macrophages. MR antagonists (MRAs) inhibit this process, favoring differentiation toward the anti-inflammatory M2 phenotype[49,55]. In animal models, aldosterone infusion increases renal interleukin-6 production, enhances fibroblast proliferation, and induces cardiomyocyte hypertrophy, elevating left ventricular diastolic pressure[56].

Figure 5 Pathological mechanisms of cardiomyopathy in primary hyperaldosteronism Created based on reference[49]. Image adapted from Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/Licenses/by/4.0/).

Parathyroid disorders

Primary hyperparathyroidism (PHPT), typically due to parathyroid adenomas or hyperplasia, leads to excessive PTH secretion and hypercalcemia. Elevated calcium levels accelerate arterial calcification and atherosclerosis, while PTH independently promotes oxidative stress, endothelial dysfunction, inflammatory cytokine release, and vascular and myocardial smooth muscle proliferation[57,58]. PTH also activates protein kinase C, contributing to myocardial hypertrophy and left ventricular remodeling[59]. PHPT is frequently associated with metabolic comorbidities-obesity, dyslipidemia, diabetes, and hypertension-that compound cardiovascular risk[57].

Conversely, hypoparathyroidism results from inadequate PTH secretion-most often post-surgical, autoimmune, or genetic in origin-and causes hypocalcemia. Calcium deficiency impairs cardiac contractility by disrupting calcium-dependent excitation-contraction coupling and actin-myosin crossbridge formation, potentially leading to left ventricular systolic dysfunction, arrhythmias (e.g., prolonged QTc), and DCM[60].

Carcinoid heart disease

Carcinoid heart disease (CHD) is a rare manifestation of carcinoid syndrome, which occurs in patients with metastatic neuroendocrine tumors (NETs), derived from enterochromaffin cells that secrete vasoactive substances. CHD typically involves the right-sided heart valves due to pulmonary degradation of circulating mediators before they reach the left heart. The disease is progressive and insidious, characterized by fibrous plaque deposition and valvular dysfunction, ultimately resulting in hemodynamic compromise and right-sided HF[61].

DIAGNOSTIC APPROACH: CLINICAL RED FLAGS AND ENDOCRINE EVALUATION IN CARDIOMYOPATHIES

Timely diagnosis and precise identification of the underlying endocrine disorder are pivotal for tailoring treatment strategies aimed at mitigating cardiac dysfunction. Early intervention in disorders like hyperthyroidism, diabetes, and acromegaly has shown substantial improvements in heart function. In the next section, we will discuss the therapeutic strategies that target these pathophysiological mechanisms to improve clinical outcomes

Focused hormonal panel for suspected cardiomyopathy of endocrine origin

Thyroid disorders: A persistently suppressed thyroid-stimulating hormone (TSH) (typically < 0.1 mIU/L) with elevated free thyroxine (T4) and/or T3 is diagnostic of hyperthyroidism, whereas an elevated TSH above the laboratory upper reference limit with low free T4 is indicative of hypothyroidism. Further evaluation commonly includes measurement of thyroperoxidase antibodies, TSH-receptor antibodies and thyroid imaging to determine etiology following biochemical confirmation[17,19]. Both hyperthyroidism (elevated T3/T4 Levels) and hypothyroidism (TSH > 10 mIU/L) are associated with potentially reversible cardiomyopathies. A study found that 20%-30% of hyperthyroid patients developed cardiac complications such as atrial fibrillation or high-output HF[62]. Low T3 Levels correlated with a decreased ejection fraction (r = 0.24, P < 0.001) and elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) (3866 vs 2310 pg/mL in euthyroid patients), underscoring the cardiovascular impact of thyroid dysfunction[62].

Adrenal disorders: The diagnosis of CS requires at least two of three key tests: Elevated late-night salivary cortisol (> 0.13 μg/dL), abnormal 24-hour urinary free cortisol, and failure to suppress serum cortisol below 1.8 μg/dL after a 1 mg dexamethasone suppression test. Confirmation typically demands concordant abnormalities in two tests due to the variable sensitivity. Once hypercortisolism is confirmed, adrenocorticotropic hormone (ACTH)-measurement, high-dose dexamethasone testing, and imaging help localize the source (pituitary, adrenal, or ectopic). AD is characterized by a marked reduction in basal cortisol (< 5 μg/dL) and elevated ACTH (> 50-100 pg/mL), due to the impaired negative feedback[45]. Hormonal studies and functional tests are valuable when suspecting adrenal dysfunction as the underlying cause of cardiomyopathy.

In patients with HF, cortisol levels showed an elevated circadian baseline of 12.02 μg/dL compared to 9.96 μg/dL in controls, along with higher minimum values (4.80 μg/dL vs 2.79 μg/dL) and reduced circadian variability, indicating sustained but dysregulated secretion. The acrophase (peak cortisol timing) showed no significant difference, while 77.8% of HF patients exhibited a non-dipping nocturnal blood pressure pattern. These findings reflect dysregulation of the hypothalamic-pituitary-adrenal axis, associated with endocrine-related cardiomyopathies, such as dilated or hypertensive forms[63].

Acromegaly: Diagnosis requires: (1) Clinical suspicion based on characteristic features or associated comorbidities; (2) Elevated age-adjusted IGF-1; (3) Lack of GH suppression during oral glucose tolerance test (OGTT); and (4) Pituitary magnetic resonance imaging (MRI). Elevated IGF-1 Levels > 97^th-98^th percentile (age- and sex-adjusted) are present in nearly 100% of cases. Up to 90% of patients develop acromegalic cardiomyopathy, often presenting with left ventricular hypertrophy (56.8%), diastolic dysfunction (51.4%), and hypertension (87.5%). IGF-1 measurement is thus essential in evaluating hormone-related cardiomyopathies[64].

Pheochromocytoma/paraganglioma: According to the Endocrine Society Clinical Practice Guidelines, the initial biochemical evaluation for pheochromocytoma/paraganglioma (PPGL) should include either plasma-fractionated or urinary-fractionated metanephrines (MN). Elevated plasma MNs [especially normetanephrine (NMN)] are more specific and sensitive than urinary assays and correlate with tumor size. NMN is the single most reliable marker of PPGL-related cardiomyopathies, with 97% sensitivity and 97% specificity. Combining MN + NMN (MN > 0.5 nmol/L or NMN > 0.9 nmol/L) yields the highest diagnostic accuracy. NMN levels > 2 nmol/L indicate high cardiovascular risk, particularly of catecholamine-induced cardiomyopathies like Takotsubo syndrome. Following biochemical confirmation, contrast-enhanced abdominal computed tomography (CT) is the preferred imaging modality for localization and preoperative planning[65].

Diabetes mellitus: HbA1c > 7% is associated with increased risk of diabetic cardiomyopathy in T2DM. Elevated HbA1c correlates with diffuse myocardial fibrosis detected by extracellular volume fraction (ECV) via cardiac MRI. Although direct correlation was not found, a 2.17% ECV increase was observed. HbA1c should prompt ECV assessment in diabetic patients with unexplained hypertrophy or diastolic dysfunction[66].

Parathyroid disorders: Intact PTH measurement is key in endocrine cardiomyopathy. In suspected PHPT, a focused panel includes serum calcium, PTH, vitamin D, high-density lipoprotein (HDL), and inflammatory markers. Postoperative PTH correlates negatively with vitamin D and positively with calcium and neutrophil-to-lymphocyte ratio (NLR)[57]. In hypoparathyroidism, diagnostic red flags include low or undetectable PTH levels (< 0.6 pmol/L), hypocalcemia, hyperphosphatemia, and electrocardiogram (ECG) findings such as prolonged QTc[60].

Imaging and biomarkers to confirm endocrine-related myocardial injury

Echocardiography: This remains a cornerstone tool for detecting left ventricular diastolic dysfunction (LVDD) in patients with subclinical hypothyroidism. In a cohort of 26289 adults, LVDD prevalence was significantly higher in those with TSH > 4.2 μIU/mL, and nearly doubled in patients with TSH ≥ 10 μIU/mL. Even low T3 Levels within the normal range were associated with increased LVDD risk[67].

Computer tomography: Cardiac CT is emerging as a valuable tool in the evaluation of cardiomyopathies, particularly for non-invasive phenotyping. This imaging modality provides a detailed morphological assessment of cardiac chambers, myocardium, and coronary arteries in a single acquisition. Its ability to accurately quantify ventricular volumes, myocardial mass, and ejection fraction, coupled with the detection of late enhancement indicative of fibrosis or amyloid deposits (via dual-energy CT), establishes it as a robust alternative, especially when cardiac magnetic resonance is unavailable or contraindicated. Furthermore, its high negative predictive value for excluding obstructive coronary artery disease is crucial for ruling out an ischemic etiology in patients with dilated or endocrine-induced Takotsubo cardiomyopathy[68].

Coronary angiography: Coronary angiography is essential in Takotsubo cardiomyopathy to confirm a catecholaminergic mechanism and exclude obstructive coronary artery disease. Angiographically normal coronaries, alongside transient wall-motion abnormalities-like apical ballooning (43.9%) or inverted variants (26.2%)-help differentiate these conditions from myocardial infarction. This allows for safe progression to surgical resection, typically laparoscopic adrenalectomy[69]. Moreover, identifying normal coronaries avoids unnecessary revascularization and guides optimized perioperative management, including α-blockade, volume repletion, and β-blockers, contributing to 96% favorable postoperative outcomes[69].

Galectin-3: Galectin-3, a β-galactoside-binding lectin involved in fibrosis and inflammation, is increasingly recognized as a biomarker of myocardial remodeling in endocrine cardiomyopathies. Its expression is stimulated by endocrine signals, particularly in diabetes, acromegaly, and CS. A review of 18 studies, elevated galectin-3 has been associated with HFpEF, diastolic dysfunction, adverse remodeling, and poor outcomes such as mortality and rehospitalization. Values > 17.8 ng/mL are considered clinically relevant. In some studies, galectin-3 showed greater diagnostic sensitivity than NT-proBNP, highlighting its emerging role in hormonal heart disease[70].

NT-proBNP: NT-proBNP is widely used to assess hemodynamic stress and cardiac dysfunction. In patients with hypertrophic obstructive cardiomyopathy and concurrent thyroid dysfunction, NT-proBNP levels were significantly elevated in those with atrial fibrillation (2476 ± 1808 mmol/mL vs 1814 ± 1712 mmol/mL; P = 0.002), reflecting increased volume and pressure overload. Although NT-proBNP levels vary by age and sex, values < 125 pg/mL are considered normal in healthy young adults. While it is a sensitive indicator of myocardial stress, its specific prognostic value in endocrine cardiomyopathies remains limited to small series and retrospective reports. Larger, prospective studies are needed to clarify its utility in risk stratification and management[71].

CARDIOVASCULAR MANIFESTATIONS OF ENDOCRINE DISEASES

Hyperthyroidism

Hyperthyroidism commonly presents with persistent sinus tachycardia (42%-73%), which may progress to atrial fibrillation (9%-23%) or atrial flutter[15,18]. Unexplained right HF should raise suspicion of thyrotoxicosis[16], which is characterized by exertional dyspnea, fatigue, widened pulse pressure, and pulmonary congestion. In these cases, CO may rise up to 300% above normal[72,73]. In rare instances, severe Graves' disease may present with a triad of HF, pancytopenia (< 1% of cases), and jaundice from congestive hepatopathy, as evidenced by ascites and cardiomegaly on imaging[72].

Hypothyroidism

Typical cardiovascular features include sinus bradycardia, often accompanied by chronotropic incompetence during exertion, diastolic hypertension with narrowed pulse pressure, and non-pitting edema[14,19,20]. Pericardial effusions, although frequently asymptomatic, may rarely lead to tamponade physiology; resolution generally follows thyroid hormone replacement[16,20]. Diastolic dysfunction results in fatigue and reduced exercise capacity, and echocardiography typically reveals impaired ventricular filling[19,74].

Acromegaly

Clinical suspicion of acromegalic cardiomyopathy should be based on cardiovascular symptoms correlating with disease stage: Exercise intolerance suggest signals hyperkinetic phase, exertional dyspnea indicates diastolic dysfunction, and orthopnea reflects late systolic failure in advanced stages[25,28]. Acral enlargement, frontal bossing, and mandibular prognathism should prompt cardiac screening even in the absence of symptoms[75,76]. Biochemical diagnosis requires elevated age-adjusted IGF-1 and lack of GH suppression on OGTT[77-79]. Echocardiography typically demonstrates left ventricular hypertrophy, abnormal relaxation (E/A < 1) and reduced ejection fraction[26,80,81]. Cardiac MRI with T1 mapping is superior in detecting diffuse fibrosis via and distinguishing active inflammation from irreversible remodeling[26,27,29].

Diabetes mellitus

Diabetic cardiomyopathy progresses in two stages: An early phase of asymptomatic diastolic dysfunction, with evidence of left ventricular hypertrophy, elevated atrial pressures, and myocardial stiffness, often maintaining preserved ejection fraction. In later stages, systolic dysfunction, fibrosis, and cardiac remodeling become evident (Figure 6)[30,31,33]. HFpEF is the predominant phenotype in early diabetic cardiomyopathy, while HFrEF emerges in advanced disease[31].

Figure 6 Phases of structural and functional changes in diabetic cardiomyopathy. Image adapted from Servier Medical Art (https://smart.servier.com/), licensed under CC BY 4.0 (https://creativecommons.org/Licenses/by/4.0/).

Diabetic cardiomyopathy diagnosis requires excluding coronary artery disease, valvular defects, and uncontrolled hypertension. High-risk patients—those with long-standing diabetes, poor glycemic control, microvascular complications, or inflammation-should be screened using ECG (QT prolongation, T wave abnormalities), echocardiography (LV global longitudinal strain), and natriuretic peptides. Speckle-tracking echocardiography can identify subclinical dysfunction even with preserved ejection fraction and is gaining recognition for early detection, though it is not yet standard for asymptomatic individuals[31].

CS

Hypokalemia is a hallmark of CS, exacerbating cardiovascular risk and increasing arrhythmic potential[40,42]. Theory suggests that cortisol-induced kaliuresis is more prevalent in ectopic CS (57%) compared to pituitary CS (10%)[43]. Hypertension affects up to 80% of endogenous cases and 20% of exogenous cases[41,43]. Echocardiographic evaluation often reveals left ventricular hypertrophy and remodeling related to chronic glucocorticoid exposure[41-44].

AD

The dominant electrolyte abnormality is hyponatremia, due to aldosterone deficiency leading to sodium loss, compounded by increased antidiuretic hormone secretion from cortisol deficiency[46-48]. ECG findings may include shortened QT interval, flattened T waves, and bradycardia in severe cases. Cardiac assessment may reveal LV hypertrophy, reduced ejection fraction, or volume-responsive diastolic dysfunction on echocardiography or myocardial fibrosis on cardiac MRI.

Pheochromocytoma and paraganglioma

Hypertensive crises (systolic blood pressure 180 mmHg) occur in 7%-17% of PPGL patients, often presenting with cyclic hemodynamic shifts and lactic acidosis > 6 mmol/L[82,83]. Key red flags include: Absence of chest pain with pulmonary rales (predicts 70.9% complication risk in Takotsubo), paradoxical hypertension during β-blockade, and unexplained hyperglycemia in lean patients[84,85]. The InterTAK Diagnostic Criteria explicitly recognize pheochromocytoma as a secondary cause of Takotsubo syndrome[56], requiring differentiation from primary stress-induced cases. Biochemical diagnosis prioritizes plasma-free MNs (sensitivity 96%-100%) over urinary metabolites during crises due to false positives from stress-induced catecholamine elevation[85,86]. Cardiac MRI reveals T1 mapping elevation (edema), late gadolinium enhancement (fibrosis), and atypical wall motion patterns[87].

Primary hyperaldosteronism

Hypokalemia, caused by renal potassium wasting, is the cardinal electrolyte disturbance. Metabolic alkalosis often coexists due to hydrogen ion loss. ECG changes include flattened T waves, prominent U waves, and QT prolongation, with ventricular arrhythmias in severe cases[51,52]. Imaging and echocardiography may reveal LV hypertrophy, fibrosis, diastolic dysfunction, and in some cases, systolic impairment[49].

CHD

CHD results from prolonged exposure to serotonin and other vasoactive substances produced by metastatic NETs. Although biomarkers exist for NETs and HF, few studies have validated their utility in CHD. Routine echocardiographic screening is essential, with annual monitoring recommended in patients with NETs. Advanced CHD shows thickened, retracted tricuspid valve leaflets with severe regurgitation. Additional imaging, including ECG-gated CT or cardiac MRI, may be needed during preoperative planning to assess the extent of myocardial and valvular involvement[61].

THERAPEUTIC STRATEGIES: HORMONAL CORRECTION AND DISEASE-SPECIFIC MANAGEMENT

Hyperthyroidism

The treatment of hyperthyroidism is aimed at hormonal correction and cardiac recovery[88]. Beta-blockers, such as propranolol 10-40 mg/6-8 hours or atenolol 25-100 mg/day, are often used to manage the cardiovascular symptoms of hyperthyroidism, particularly to control tachycardia and prevent arrhythmias like atrial fibrillation[89]. Antithyroid drugs, including methimazole or propylthiouracil, help reduce the production of thyroid hormones by inhibiting thyroid peroxidase, methimazole 10-20 mg/day does not inhibit peripheral conversion of T4 to T3, while propylthiouracil inhibits 5’-deiodinase, the enzyme responsible for peripheral conversion of T4 to the more active T3, this makes PTU 30-40 mg/day particularly useful in thyroid storm or acute severe hyperthyroidism[90]. In cases where medications are insufficient, radioactive iodine therapy can be used to ablate thyroid tissue, leading to a permanent reduction in thyroid hormone production. If these approaches are ineffective or contraindicated, surgical thyroidectomy may be considered to remove part or all of the thyroid gland[91,92]. These treatments not only aim to normalize thyroid hormone levels but also improve the cardiac function and recovery, particularly in reducing the risk of arrhythmias and managing the heart’s excessive workload in hyperthyroid states[93].

Hypothyroidism

Thyroid hormone replacement therapy with levothyroxine 1.6 mcg/kg/day (based on ideal body weight), has been shown to significantly improve cardiac symptoms in these patients, it helps restore normal thyroid hormone levels, reducing peripheral vascular resistance, improving left ventricular function, and normalizing lipid profiles[94]. This correction of thyroid hormone deficiency can lead to enhanced myocardial contractility and reduced risk of cardiovascular complications, including HF. Studies show that the CO, LVEF, and the ratio of peak E velocity/peak A velocity were all significantly increased after LT4 supplementation compared with the baseline level. Additionally, initiating levothyroxine therapy in hypothyroid patients with HF has demonstrated improved outcomes, as it addresses the underlying metabolic disturbances that contribute to impaired cardiac function. Proper titration of levothyroxine is essential, as overtreatment can result in a hyperthyroid state, which may exacerbate arrhythmias and other cardiovascular issues[95].

Acromegaly

The treatment of acromegaly focuses on addressing the underlying cause, with somatostatin analogs, pegvisomant, and pituitary surgery being the main therapeutic strategies[96,97]. Somatostatin analogs like octreotide 100 mcg/8 hours or lanreotide 90-120 mg/4 weeks inhibit GH secretion from the pituitary, reducing IGF-1 Levels, and achieving partial regression of hypertrophy and functional improvement in patients. Pegvisomant 40 mg loading dose and 10-30 mg /daily maintenance dose, a GH receptor antagonist, blocks peripheral GH action, normalizes IGF-1 and improves cardiac structure and function. Pituitary surgery also improves cardiac function if long-term hormonal control is achieved. However, 15%-25% of patients may retain residual damage due to irreversible fibrosis or late diagnosis. At present, surgical removal of tumors is still the preferred treatment for patients with acromegaly. Approximately 50% of patients are controlled by surgical treatment, total tumor resection can be easily achieved for microadenoma, and up to 85% of microadenoma is completely removed by surgery[98].

Diabetes mellitus

Sodium-glucose cotransporter type 2 (SGLT2) inhibitors and GLP-1 receptor agonists (GLP-1Ras) have emerged as preferred therapeutic agents due to their proven benefits in reducing cardiovascular mortality and improving overall outcomes. As a result, these drug classes are now considered first-line options in both several management guidelines. SGLT2 is expressed in the luminal membrane and in the early portion of the proximal tubule in kidney, where, under physiological conditions, approximately 80%-90% of the filtered glucose absorption occurs, SGLT2 inhibitors not only improve blood glucose control but also provide direct cardiovascular and renal benefits, including a reduction in blood pressure, HF hospitalizations and mortality. Similarly, GLP-1RAs have demonstrated favorable effects on both glycemic control and HF outcomes by promoting weight loss, reducing blood pressure, and improving myocardial function. Effects on mitochondria and oxidative stress, inflammation and atherosclerosis and vascular function. When combined with standard HF therapies, such as angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and aldosterone antagonists, these treatments can significantly improve both metabolic and cardiac health, enhancing the prognosis for patients with diabetes and HF[99-102].

CS

In cases where surgical management is indicated, tumor resection surgery achieves hormonal remission and cardiac improvement in 75%-85% of cases. Regarding pharmacological treatment, ketoconazole 200 mg/12 hours and titrated up slowly to 400-600 mg/day which inhibits CYP11A1 and CYP17A1 therefore normalizing cortisol levels. On the other hand, Metyrapone 250 mg/12 hours and titrated up slowly to 1000-1500 mg/day acts by reversibly inhibiting 11β-hydroxylase, an essential enzyme in cortisol synthesis[103-108]. Nevertheless, patients could retain persistent dysfunction due to myocardial fibrosis or late diagnosis promote hypertensive type cardiomyopathy with a concentric pattern, functionally restrictive or diastolic, which may progress to DCM. It has been estimated that untreated CS patients have a four- to five-fold higher mortality rate than the general population, with only 50% of patients surviving 5 years from diagnosis.3 The 5-year survival rate was improved to 86% after bilateral adrenalectomy[105].

AD

Hormonal replacement therapy with glucocorticoids (e.g., hydrocortisone 15-25 mg/day) and mineralocorticoids (e.g., fludrocortisone 0.05-0.2 mg/day) is essential for reversing the hemodynamic instability and improving myocardial function. Adequate cortisol replacement can normalize the low blood pressure, improve cardiac contractility, and prevent further progression of HF in these patients. Both conditions highlight the critical role of adrenal hormones in maintaining cardiovascular stability, with hormonal replacement therapy serving as a cornerstone in the management of these adrenal-related cardiovascular complications[102,104].

Pheochromocytoma

Early surgical resection of pheochromocytomas remains the cornerstone of treatment for localized disease, with significant improvements in myocardial function observed post-operatively and has been shown to improve these myocardial alterations. In addition to early surgical resection, the management of pheochromocytoma and paraganglioma involves the use of both alpha-blockers and beta-blockers to control the effects of excessive catecholamine release. Alpha-blockade is typically initiated first to control the vasoconstriction induced by catecholamines, followed by beta-blockade to prevent tachycardia and arrhythmias. This combination helps to stabilize the patient’s hemodynamic status before surgery. In cases of metastatic pheochromocytoma or paraganglioma, targeted therapies such as tyrosine kinase inhibitors (e.g., sunitinib) or radionuclide therapy with ¹³¹I-MIBG may be employed., particularly in terms of resolving catecholamine-induced cardiomyopathy and restoring normal cardiac function[109,110].

Primary hyperaldosteronism

Effective management hinges on both hormonal correction and targeting the underlying cause. MRAs, such as spironolactone 25-400 mg/day and eplerenone 50-100 mg/day, remain the cornerstone of medical therapy, mitigating aldosterone’s deleterious cardiovascular effects and improving cardiac structure and function. In cases where the disease stems from a unilateral adrenal adenoma or hyperplasia, adrenalectomy represents a curative approach, often leading to normalization of aldosterone levels, blood pressure control. Individualized treatment plans should consider biochemical profiles, lateralization studies, comorbidities, and the extent of cardiac involvement to optimize outcomes and prevent the progression of cardiomyopathy[111,112].

Parathyroid disorders

PHPT requires definitive surgical management through parathyroidectomy (PTX), ideally via minimally invasive techniques as per international guidelines, which rapidly normalizes serum calcium and PTH levels while elevating vitamin D and HDL within one month postoperatively[57,59]. For non-surgical candidates, pharmacotherapy with calcimimetics such as cinacalcet 60-90 mg/day modulates calcium-sensing receptors to mitigate cardiovascular risk[58]. This intervention reverses cardiac remodeling, reducing left ventricular mass index by 11.6 g/m² within six months and attenuating inflammatory markers like NLR and monocyte-to-HDL ratio, thereby improving myocardial hypertrophy and endothelial dysfunction[57,59].

Hypoparathyroidism demands urgent correction of acute hypocalcemia with intravenous calcium gluconate to prevent life-threatening arrhythmias and contractility impairment, followed by chronic management using oral calcium supplements combined with active vitamin D metabolites-specifically calcitriol or alfacalcidol-to sustain calcium homeostasis; strict adherence is essential to prevent relapse[60]. Timely normalization of serum calcium fully reverses DCM, restoring left ventricular dimensions and ejection fraction within three months while resolving systolic dysfunction and arrhythmia susceptibility[60].

CHD

The management of CHD is a multidimensional process integrating tumor control, hormonal activity inhibition, and HF management. The therapeutic approach for elevated serotonin levels entails a combination of somatostatin analogs and telotristat ethyl 250 mg/8 hours, a serotonin synthesis inhibitor. HF management is based on diuretics, ACE inhibitors, and aldosterone antagonists. In patients with advanced right-sided valvular disease and exhibiting symptoms of HF, surgical replacement of the tricuspid and pulmonary valves may be indicated, contingent upon the effective management of the underlying disease and a life expectancy exceeding one year. Transcatheter "valve-in-valve" procedures have emerged as an effective alternative, especially for frail patients who are not candidates for conventional surgery[61].

Role of cardio-endocrine teams

The importance of a multidisciplinary approach to managing endocrine-related cardiomyopathies cannot be overstated. Collaborative care involving cardiologists, endocrinologists, and other specialists is essential to ensure the comprehensive management of these complex conditions. Studies have shown that patients managed by cardio-endocrine teams experience better outcomes, particularly in cases where multiple endocrine imbalances contribute to HF[113,114]. A cardio-endocrine team can effectively coordinate hormonal therapies, disease-specific treatments, and cardiac interventions, ensuring a more personalized approach for each patient. Furthermore, early detection and proactive management of both endocrine and cardiovascular manifestations improve prognosis and quality of life in these patients[115,116]. This integrated care model is becoming an essential component in managing cardiomyopathies associated with endocrine dysfunction (Figure 7)[117-119].

Figure 7 Therapeutic strategies in cardiomyopathy of endocrine origin. GLP-1: Glucagon-like peptide-1; SGLT2: Sodium-glucose cotransporter-2.

PROGNOSIS AND IMPACT OF TIMELY ENDOCRINE INTERVENTION ON CARDIAC OUTCOMES

Hyperthyroidism

Cardiac dysfunction secondary to hyperthyroidism is highly reversible with early intervention. Restoration of euthyroidism leads to normalization of left ventricular systolic function, and sinus rhythm is restored in 60%-90% of patients with atrial fibrillation within months[14,15]. Even severe complications-including pancytopenia and congestive hepatopathy-resolve with timely β-blockade and antithyroid therapy[72]. Delayed intervention increases cardiovascular mortality (HR 1.2) and thromboembolic risks (arterial embolism HR 6.08)[18,120].

Hypothyroidism

Prognosis in hypothyroidism depends on timely levothyroxine initiation. Diastolic dysfunction and pericardial effusion typically resolve with early therapy, while delayed treatment may result in residual atherosclerotic changes[19,20]. In subclinical hypothyroidism treatment reduces cardiovascular risk by 50% in patients under 70 years of age[22,121].

Acromegaly

When treatment is initiated during the hyperkinetic or early hypertrophic phase (disease duration < 5 years), survival rates normalize (SMR 1.0) and left ventricular hypertrophy regresses in > 80% of cases[26,122-124]. In contrast, treatment during the fibrotic phase results in only partial improvement of diastolic dysfunction, with persistence of myocardial fibrosis and increased cardiovascular mortality (SMR 1.3)[28]. Poor prognostic markers include baseline septal thickness > 20 mm, disease duration > 10 years, and GH > 2.5 μg/L post-treatment[27,75,79]. Once systolic dysfunction is established, prognosis worsens significantly, with a 5-year mortality rate exceeding 50%, and limited response to pegvisomant in advanced disease[26,27,123].

Pheochromocytoma

Surgical resection within four years of symptom onset leads to complete recovery of cardiac function in 94% of patients, normalizing blood pressure and preventing fibrosis[125-127]. Delayed diagnosis is associated with persistent systolic dysfunction and increased mortality (22% vs 4% in post-resection cases) due to irreversible myocardial injury[125,128]. In metastatic PPGLs, 5-year survival ranges from 50%-81%, with better outcomes in bone metastases compared to liver or lung involvement[129,130]. The presence of fibrosis or elevated native T1 on cardiac MRI predicts poor recovery potential[85,88].

Diabetes mellitus

SGLT2 inhibitors significantly reduce cardiovascular events, hospitalizations for HF, and all-cause mortality, with greater benefit when introduced early[37,131,132]. Dapagliflozin monotherapy reverses remodeling, while empagliflozin improves cardiac function and reduces fibrosis[33,35,131,133].

GLP-1RAs offer cardioprotective effects, reducing cardiovascular mortality, myocardial infarction, and promoting weight loss and lipid profile improvement, with liraglutide showing superior outcomes[33,35,134].

Conversely, DPP-4 inhibitors have not demonstrated benefit in reducing LV hypertrophy, and saxagliptin has been associated with increased risk of HF hospitalization in patients with T2DM[31,33,135].

Emerging targets include microRNAs (miRNAs), which modulate oxidative stress, apoptosis, and inflammation in diabetic cardiomyopathy. Specific miRNAs profiles are being explored as early biomarkers and therapeutic targets[33,136-138].

CS

Despite successful treatment of hypercortisolism, up to 30% of patients develop persistent hypertension, which perpetuates LV hypertrophy and atrial fibrillation risk[41,43]. Structural abnormalities, such as LV concentric hypertrophy (42%) and remodeling (23%), are prevalent at diagnosis[41-44,91].

Although standard HF therapies can partially reverse these abnormalities, surgical correction of CS rarely restores normal cardiac structure or function once damage is established[41].

AD

While corticosteroid replacement is essential, adverse effects are rare but clinically relevant, including arrhythmias and bradycardia[139,140]. These have been linked to common glucocorticoids (e.g., prednisone, dexamethasone, hydrocortisone). Chronic corticosteroid exposure can result in electrolyte disturbances, vascular changes, and accelerated atherosclerosis, raising the risk of cardiovascular events[45].

Primary hyperaldosteronism

Patients treated with adrenalectomy or MRAs (e.g., spironolactone, eplerenone) demonstrate significant reduction in LV mass, lowering the risk of sudden cardiac death, HF, and cardiovascular mortality[54,56]. A relationship has been suggested between urinary sodium excretion levels and plasma aldosterone, implying that salt-insensitive aldosterone secretion may contribute to LV remodeling[53].

Parathyroid disorders

Timely PTX in PHPT results in rapid normalization of cardiovascular risk markers within one month, and regression of LV hypertrophy within six months[57-59]. Delayed treatment is associated with premature cardiovascular mortality. In hypoparathyroidism, prompt correction of hypocalcemia with calcium and vitamin D therapy leads to complete reversal of cardiomyopathy within three months. Prognosis depends critically on adherence to prevent recurrent hypocalcemia and cardiac complications[60].

CHD

Without appropriate management, CHD leads to progressive right HF with a 3-year survival rate of approximately 30%, which is often worse than the oncological prognosis of the underlying NETs. Surgical valve replacement, primarily of the tricuspid and pulmonary valves, has demonstrated improvement in 2-year survival rates and quality of life in patients with controlled systemic disease and > 1-year life expectancy. However, cardiac surgery entails high risks and requires a multidisciplinary approach. Reoperation may be needed due to early degeneration of bioprosthetic valves from persistent hormonal stimulation[61].

EMERGING CONCEPTS

Novel biomarkers

Recent advancements in biomarkers and imaging techniques have significantly enhanced the diagnosis and management of endocrine-related cardiomyopathies. Among the most promising emerging biomarkers, soluble suppression of tumorigenicity 2 and natriuretic peptides, such as NT-proBNP, have shown potential as prognostic indicators in HF. Additionally, miRNAs-small non-coding RNAs involved in the regulation of gene expression-are also gaining recognition for their ability to mirror underlying pathophysiological processes, offering new approaches for diagnosis, risk stratifications, and therapeutic monitoring in endocrine cardiac disorders[141-143].

Advanced imaging

Cutting-edge imaging modalities, such as myocardial strain imaging (MSI) and positron emission tomography (PET), have transformed the early detection and clinical management of fibrotic and inflammatory myocardial changes in endocrine-related cardiomyopathies[31,144]. MSI can detect subclinical alterations in myocardial mechanics that are often missed by conventional imaging, providing a crucial window for early intervention[145]. Meanwhile, PET imaging offers high-resolution metabolic mapping, enabling assessment of disease activity and treatment efficacy[146]. The integration of these imaging tools with emerging molecular biomarkers holds considerable promise in advancing personalized management strategies and improving outcomes in this patient population.

Genetic links

Genetic predisposition is increasingly recognized as a critical factor in the development of endocrine-related cardiomyopathies (Figure 8). Mutations associated with multiple endocrine neoplasia (MEN) syndromes-including MEN1 and MEN2-have been linked to pheochromocytoma, hyperparathyroidism, and adrenal dysfunction, all of which can precipitate cardiac remodeling. Notable genetic associations include SDHB/SDHD mutations in pheochromocytoma, PRKAR1A in CS, and HNF1A, HNF4A, and GCK in Maturity-Onset Diabetes of the Young. In acromegaly, GNAS mutations and GH receptor polymorphisms are implicated in cardiomyopathy pathogenesis[147-152].

Figure 8 Endocrinopathies and genes involved in cardiomyopathies. MEN1: Multiple endocrine neoplasia type 1; MEN2: Multiple endocrine neoplasia type 2; SDHB: Succinate dehydrogenase complex subunit B; SDHD: Succinate dehydrogenase complex subunit D; PRKAR1A: Protein kinase cAMP-dependent type I regulatory subunit alpha; GNAS: GNAS complex locus; THSR: Thyroid hormone receptor; HNF1A: Hepatocyte nuclear factor 1 alpha; HNF4A: Hepatocyte nuclear factor 4 alpha; MODY: Maturity-onset diabetes of the young; GH: Growth hormone; IGF-1: Insulin-like growth factor 1; TGF-β1: Transforming growth factor beta 1; sST2: Soluble suppression of tumorigenicity 2; microRNAs: Micro ribonucleic acids; PET: Positron emission tomography; CM: Cardiomyopathy.

Emerging data suggest that genetic screening for high-risk mutations could enable earlier diagnosis, prognostication, and tailored interventions, potentially altering the disease trajectory. As understanding of these molecular underpinnings expands, integration of genomics into clinical workflows may become a cornerstone of future cardiometabolic care.

Additionally, there is growing interest in the development of targeted therapies that can directly modulate the hormonal signaling pathways responsible for myocardial remodeling, potentially offering more effective and less invasive treatment options.

FUTURE DIRECTIONS: RESEARCH PRIORITIE S AND THE NEED FOR PROSPECTIVE STUDIES

Urgent need for large prospective clinical trials

Endocrinerelated cardiomyopathies remain understudied and poorly characterized, with most available data derived from retrospective analyses or isolated case reports. Critically, no prospective randomized trials have evaluated targeted therapies for Takotsubo syndrome or PPGL-associated cardiomyopathy, leaving current management to rely heavily on expert opinion[153,154]. Well-designed multicenter prospective studies are urgently needed to define evidence-based strategies for risk stratification, timing of adrenalectomy, pharmacologic optimization, and prevention of complications such as thromboembolism or HF recurrence. Addressing this gap is essential for improving both short- and long-term outcomes in affected patients.

Creation of global registries for endocrine cardiomyopathies

International registries would facilitate a comprehensive understanding of prevalence, phenotypic variability, and treatment outcomes, especially in rare presentations such as thyrotoxicosis-induced pancytopenia or carcinoid cardiomyopathy[16,72]. For instance, acromegaly-specific registries (e.g., the German Acromegaly Registry) can standardize cardiac phenotyping using MRI protocols (T1 mapping, extracellular volume quantification) and biomarker biobanking (e.g., PIIINP, galectin-3, FAP)[25,155,156].

In the case of pheochromocytoma and paraganglioma, registries integrating genetic profiles (SDHB, RET, VHL), cardiac outcomes, and surgical timelines would support risk-adapted management strategies[90,157]. These platforms will provide the necessary infrastructure for longitudinal surveillance, real-world evidence generation, and comparative effectiveness research.

Investigation of personalized therapies and genetic screening strategies

Personalized medicine holds promise in endocrine cardiomyopathy. For instance, thyroid hormone analogs, gene-informed levothyroxine dosing, and T3 supplementation in non-thyroidal illness syndrome represent potential novel therapies pending randomized validation[13,16,22,158,159]. In acromegaly, genetic stratification via GHR exon 3 deletions and SOCS2 polymorphisms may predict differential responses to pegvisomant or somatostatin analogs, while senolytic agents targeting GH-induced cellular senescence have shown preclinical efficacy in reducing fibrosis[28,29,160-162]. For PPGL, emerging targets include HIF-2α inhibitors (e.g., belzutifan) for SDHx-mutated tumors and the development of rapid SDHB testing in cases of unexplained Takotsubo syndrome[126,130]. These innovations demand rigorous clinical testing before routine integration into care pathways.

CONCLUSION

Cardiac involvement secondary to endocrine disorders is often underrecognized, despite its potential reversibility with timely diagnosis and intervention. Early identification of the hormonal etiology can lead to substantial improvement in cardiac function, reduction in morbidity, and enhanced survival. In patients with unexplained cardiomyopathy, a focused endocrine evaluation is imperative to enable prompt targeted, curative intervention. Advances in molecular diagnostics, imaging, and biomarker discovery are paving the way toward personalized care. Continued multidisciplinary collaboration, global data sharing, and investment in prospective research are essential to optimize clinical outcomes and develop robust, evidence-based guidelines for the management of endocrine-related cardiomyopathies.