Abstract Normal endocrine function is essential for cardiovascular health. Disorders of the endocrine system, consisting of hormone hyperfunction and hypofunction, have multiple effects on the cardiovascular system. In this review, we discuss the epidemiology, diagnosis, and management of disorders of the pituitary, thyroid, parathyroid, and adrenal glands, with respect to the impact of endocrine dysfunction on the cardiovascular system. We also review the cardiovascular benefits of restoring normal endocrine function.
Introduction Normal endocrine function is essential for cardiovascular health. Disorders of the endocrine system, consisting of hormone hyperfunction and hypofunction, have multiple effects on the cardiovascular system. The objective of this review is to explore the various cardiovascular changes that occur in endocrine dysfunction. We will also assess the cardiovascular benefits of correcting endocrine disorders. Diabetes is specifically excluded, as the well-known relationship between diabetes and cardiovascular risk is beyond the scope of this review.
The pituitary gland and the cardiovascular system Pituitary Overview The anterior pituitary gland contains five cell types that synthesize and secrete hormones (growth hormone [GH], prolactin, follicle stimulating hormone, luteinizing hormone, thyroid stimulating hormone [TSH], adrenocorticotropic hormone [ACTH]), that participate in hypothalamic- pituitary-target organ regulation. The posterior pituitary contains nerve terminals that secrete vasopressin (antidiuretic hormone) and oxytocin. Of the pituitary hormones secreted by the anterior pituitary, disorders of prolactin, GH, and ACTH may be associated with cardiac disease.
Prolactin Disorders and Cardiovascular Disease Prolactin is synthesized and secreted by lactotroph cells of the anterior pituitary gland, and stimulates lactation in the postpartum period. Prolactin is tonically inhibited by hypothalamic dopamine. Prolactin levels are physiologically elevated in pregnancy, the postpartum period, and in states of stress. Pathologic hyperprolactinemia may be caused by decreased dopaminergic inhibition, such as when the pituitary stalk is disrupted, or by prolactin secretion from prolactinomas (benign pituitary adenomas). The prevalence of hyperprolactinemia ranges from 0.4% in the general adult population to 9% in women with reproductive disorders.1 Although hyperprolactinemia itself does not have clear effects on the cardiovascular system, there is a possible association between long-term treatment with dopamine agonists and cardiac valve abnormalities.
Growth Hormone Overview GH is synthesized and secreted by somatotroph cells in the anterior pituitary gland. It acts directly on peripheral tissues via interaction with the GH receptor, and indirectly via stimulation of insulin-like growth factor type 1 (IGF-1) synthesis. In virtually all cell types, IGF-1 promotes glucose uptake and cellular protein synthesis. GH and IGF-1 regulate somatic growth, including cardiac development and function10 The prevalence of GH deficiency (GHD) in adults is approximately 1-2 per 10, The prevalence of acromegaly, or excess GH secretion, is approximately cases per million, with an estimated incidence of 3-4 per million annually.
Growth Hormone Deficiency Overview Adults with GHD can be grouped into three categories: those with childhood onset GHD, those with acquired GHD secondary to structural lesions or trauma, and those with idiopathic adult onset GHD. Diagnosis is confirmed by low serum IGF-1 levels and provocative testing using insulin- induced hypoglycemia, and the combination of arginine and GH-releasing hormone (GHRH), which are potent stimuli for GH secretion. A subnormal increase in serum GH concentration after insulin tolerance or GHRH-arginine tests confirms the diagnosis of GHD. Treatment of GHD consists of GH replacement.
Growth Hormone Deficiency and Cardiovascular Disease Cardiovascular Risk GHD is associated with increased body fat and central adiposity, dyslipidemia (low high density lipoprotein cholesterol [HDLc], high total cholesterol, and high low density lipoprotein cholesterol [LDLc]), endothelial dysfunction, and insulin resistance (Figure 1). Increased carotid arterial intima-media thickness (IMT), a marker of early atherosclerotic development, has also been described in GHD. GH replacement therapy can result in increased lean body mass and decreased visceral adipose tissue and may decrease total and LDLc levels, although effects on HDLc have been inconsistent. Endothelial dysfunction improves with GH replacement therapy, with increased flow-mediated dilatation and reduced arterial stiffness due to improved nitric oxide (NO) availability. Although GH replacement therapy has been shown to reduce IMT, effects on cardiovascular outcomes are uncertain.
Acromegaly and Cardiovascular Disease Cardiovascular Risk Hypertension occurs in 20%-50% of patients with acromegaly. Possible mechanisms include increased arterial stiffness due to hypertrophy and fibrosis of the arterial muscular tunica. Acromegaly is also associated with an increased prevalence of diabetes mellitus. Systolic and diastolic blood pressure and glycemic control improve with normalization of IGF-1 levels. Cardiac valve disease (aortic and mitral regurgitation) is frequent in acromegaly. GH/IGF-1 excess may lead to abnormal extracellular matrix regulation and thus to pathogenesis of myxomatous valvulopathy. The risk of valve disease increases significantly with the duration of GH excess. Aortic and mitral valve dysfunction often persist despite treatment of hormonal excess.
Electrocardiogram (ECG) and Holter studies have documented cardiac rhythm abnormalities in acromegaly. Resting ECG changes include left axis deviation, increased QT intervals, septal Q-waves, and ST-T wave depression. Additionally, up to 56% of patients with active acromegaly have late potentials on ECG that could predispose to arrhythmias. Rhythm disturbances, seen mainly during physical exercise, include atrial and ventricular ectopic beats, paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia, sick sinus syndrome, bundle branch block, and ventricular tachycardia. The frequency of ventricular premature complexes increases with the duration of acromegaly. The severity of ventricular arrhythmias correlates with increases in LV mass. Somatostatin analogs have been shown to reduce QT intervals, and to improve the arrhythmic profile in acromegalic patients.
Cushing's Syndrome and Cardiovascular Disease Cardiovascular Risk Hypercortisolism is associated with hypertension, central obesity, insulin resistance, dyslipidemia, and alterations in clotting and platelet function51 (Figure 2). Hypertension is present in about 80% of adult patients with endogenous Cushing's syndrome, and results from changes in regulation of plasma volume, systemic vascular resistance, and vasodilatation.53,54 Treatment of Cushing's syndrome usually results in improvement or resolution of hypertension, although hypertension may persist in patients with long-standing hypercortisolism and/or co-existing essential hypertension.55 Abnormal glucose metabolism in Cushing's syndrome results from stimulation of hepatic gluconeogenesis and glycogenolysis.
Patients with hypercortisolism may have impaired fasting glucose, impaired glucose tolerance, hyperinsulinemia, insulin resistance, and/or diabetes mellitus.56 Cushing's syndrome has been associated with increased lipoprotein (a), decreased HDLc, and increased triglycerides.54 The duration of cortisol excess correlates with the degree of dyslipidemia seen. Cortisol also increases the synthesis of several coagulation factors, stimulating endothelial production of von Willebrand factor and concomitantly increasing factor VIII.57 Hypercortisolism may also enhance platelet aggregation and reduce plasma fibrinolytic capacity.58,59
Hyperthyroidism and Cardiovascular Disease Hemodynamics Genomic and nongenomic actions of thyroid hormone result in cardiovascular hemodynamic changes in overt hyperthyroidism that include decreased systemic vascular resistance (SVR), increased heart rate, increased cardiac preload, and increased cardiac output. SVR is reduced in hyperthyroidism due to thyroid hormone- mediated relaxation of vascular smooth muscle cells and increased endothelial NO production.The decrease in SVR activates the renin- angiotensin-aldosterone system, leading to increased plasma volume and increased cardiac preload. Thyroid hormone also promotes an increase in blood volume via up-regulation of erythropoietin secretion, further enhancing cardiac preload.
The combination of increased preload and decreased SVR leads to increased cardiac output.72 Increases in contractility and in resting heart rate further contribute to the increase in cardiac output, which may be 50%-300% higher than normal in overtly hyperthyroid patients.73,74 Treatment of hyperthyroidism reverses these hemodynamic changes. Cardiovascular Risk Systolic hypertension may be seen in up to 30% of hyperthyroid patients.75 This elevation in systolic pressure may result from the combined effect of increased preload and cardiac output, and decreased arterial compliance.76
Rhythm Sinus tachycardia occurs in approximately 40% of cases of overt hyperthyroidism, and generally resolves after restoration of euthyroidism. Subclinical hyperthyroidism is also associated with an increased heart rate. Atrial fibrillation is the second most common arrhythmia in overt hyperthyroidism, and occurs in 10%-15% of patients, its prevalence increasing with age. Patients with subclinical hyperthyroidism also have an increased risk of atrial fibrillation.
In overtly hyperthyroid patients, factors independently predictive of atrial fibrillation include increasing age, history of cardiac failure, diabetes, elevated systolic or diastolic blood pressure, and LVH on ECG.Sinus rhythm can be restored in up to two thirds of patients with overt hyperthyroidism; however, increased age and duration of atrial fibrillation correspond with higher rates of persistent arrhythmia. There is limited evidence that treatment of subclinical hyperthyroidsm facilitates reversion of atrial fibrillation to normal sinus rhythm.
Hypothyroidism and Cardiovascular Disease Hemodynamics The hemodynamic changes in hypothyroidism are the opposite of those seen in hyperthyroidism. Overt hypothyroidism is associated with increased SVR, normal or decreased resting heart rate, decreased contractility, and decreased cardiac output. In addition, diastolic pressure is increased and pulse pressure is narrowed. Cardiac output may be reduced by up to 30%-40% as a result of decreased stroke volume and heart rate. The hemodynamic changes of hypothyroidism resolve with restoration of euthyroidism, with normalization of SVR and improved cardiac contractility, and with improved cardiac output.
Cardiovascular Risk Overt hypothyroidism is associated with accelerated atherosclerosis and coronary artery disease that may be attributable to diastolic hypertension, impaired endothelial function, and hypercholesterolemia. Significant diastolic hypertension may be seen in up to 20% of patients with overt hypothyroidism. This increase in diastolic pressure is the result of increased systemic vascular resistance and increased arterial stiffness, and resolves with T4 replacement therapy. Overt hypothyroidism has also been associated with hyperhomocysteinemia, increased C-reactive protein levels, and altered coagulation parameters. Subclinical hypothyroidism has been associated with elevated diastolic pressure and increased carotid artery IMT that may improve with T4 replacement.
Rhythm ECG changes in hypothyroidism include sinus bradycardia, low voltage complexes (small P waves or QRS complexes), prolonged PR and QT intervals, and flattened or inverted T waves. Cases of ventricular conduction abnormalities have been reported in association with hypothyroidism, and may be related to QT interval prolongation.
Parathyroid hormone and the cardiovascular system Parathyroid Hormone Overview Parathyroid hormone (PTH) plays a critical role in maintaining an adequate calcium–phosphorus homeostasis. PTH affects three principal target organs to maintain calcium balance: bone, intestinal mucosa, and kidney. The incidence of primary hyperparathyroidism (PHPT) is approximately 21.6 per 100,000 annually, with a higher incidence in females and in older adults, reaching a peak of 63.2 per 100,000 annually at ages years. Hypoparathyroidism is much less common.
Hyperparathyroidism and Cardiovascular Disease Cardiovascular Risk The cardiovascular risk associated with PHPT is attributable in large part to an increased prevalence of hypertension, obesity, glucose intolerance, and insulin resistance. Proposed mechanisms of hypertension in patients with PHPT include increased calcium deposition leading to arterial stiffness in long standing and/or severe disease, direct PTH-mediated stimulation of the renin-aldosterone system, and PTH-mediated endothelial dysfunction and increased sympathetic activity.
Surgical correction of hyperparathyroidism has not consistently demonstrated improvement in hypertension. Treatment of PHPT with surgery has been shown to improve insulin sensitivity in patients with more severe disease. Carotid IMT has been shown to be higher in patients with PHPT, and measures of carotid stiffness are associated with the degree of PTH elevation. This suggests that vessel stiffness may be related to the severity of hyperparathyroidism
Hypoparathyroidism and cardiovascular disease Cardiac Structure and Function There are case reports of decreased myocardial performance, dilated cardiomyopathy, and congestive heart failure in patients with acute and chronic hypocalcemia. The mechanism of the myocardial dysfunction is unclear, but may be related to impaired excitation-contraction coupling. Reversal of heart failure and correction of cardiomyopathy have been seen in select cases where correction of calcium deficiency was necessary for clinical and hemodynamic improvement.
Primary Aldosteronism and Cardiovascular Disease Cardiovascular Risk PA is associated with hypertension, endovascular dysfunction, and altered glucose metabolism. Mechanisms contributing to hyperaldosteronism-mediated hypertension include plasma volume expansion from sodium and fluid retention, and vasoconstriction from potassium depletion. Aldosterone has been shown to decrease NO bioavailability, inhibiting endothelium- dependent relaxation. Aldosterone-mediated perivascular fibrosis reduces vascular compliance.
Unilateral laparoscopic adrenalectomy in patients with aldosterone-producing adenoma or unilateral adrenal hyperplasia results in normalization of hypokalemia in all patients, improved blood pressure control in nearly all patients, and long-term hypertension cure rates of %. In PA due to bilateral adrenal disease, unilateral or bilateral adrenalectomy seldom corrects hypertension, necessitating continued mineralocorticoid receptor antagonist therapy. Impaired glucose tolerance and decreased insulin sensitivity have been reported in some patients with PA. Proposed mechanisms include direct effects of aldosterone on insulin receptor function, and effects of hypokalemia on insulin regulation.
Pheochromocytoma and Cardiovascular Disease Cardiovacular Risk Hypertension is present in over 50% of patients with pheochromocytoma, and may be sustained or paroxysmal. Higher variability of blood pressure has been demonstrated in pheochromocytoma compared to patients with essential hypertension, and is associated with a higher incidence of target organ damage. Resolution of hypertension has been reported in about 50% of patients after successful surgical treatment of pheochromocytoma.
Markers of endothelial dysfunction, such as increased carotid IMT, have been demonstrated in patients with pheochromocytoma. These changes have been attributed to the effects of excess catecholamines on vascular wall growth and thickening. Normalization of catecholamine levels after surgical removal of pheochromocytoma has been shown to improve carotid IMT, and reduce carotid wall fibrosis.
Conclusions Endocrine dysfunction may have a significant impact on the cardiovascular system. Restoration of normal endocrine function often results in reversal of adverse cardiovascular changes. Hormone-mediated cardiac changes should be considered when evaluating endocrine and cardiac patients.