Endocrine Disorders and Cardiovascular Disease

Growth Hormone

The somatotropic cells secrete human growth hormone (hGH). Excessive secretion of hGH and insulin-like growth factor type 1 (IGF-1) by benign pituitary adenomas leads to the clinical syndrome of gigantism in youth before fusion of the bony epiphysis and to acromegaly in adults after maturation of the long bones. hGH exerts its cellular effects through two major pathways. The first is by binding of the hormone to specific hGH receptors on target cells. Such receptors exist in the heart, skeletal muscle, fat, liver, and kidneys, as well as in many additional cell types throughout fetal development. The second growth-promoting effect of hGH results from stimulation of the synthesis of IGF-1. The liver produces the bulk of IGF-I, but other cell types can produce IGF-1 under the influence of hGH. Shortly after identification of the IGF family, this second messenger was thought to mediate most actions of hGH. The ability to promote glucose uptake and cellular protein synthesis gave rise to the term “insulin-like.” IGF-1 binds to its cognate IGF-1 receptor, which localizes on almost all cell types. Genetic experiments have demonstrated that the presence of IGF-1 receptors on cell types links closely to the ability of these cells to divide. Studies in which the IGF-1 receptor was overexpressed in cardiac myocytes reportedly produced an increase in myocyte number and mitotic rate and enhanced the replication of post-differentiated myocytes.

Infusion of hGH or IGF-1 acutely changes cardiac function and hemodynamics. The acute increases in cardiac contractility and cardiac output may result, at least in part, from a decrease in systemic vascular resistance and left ventricular afterload.

Cardiovascular Manifestations of Acromegaly

Acromegaly is a relatively uncommon condition with an annual incidence of 3 to 4 cases/million. Despite its rarity, this disorder is associated with markedly increased morbidity and mortality due to cardiovascular, respiratory, metabolic, and neoplastic complications, especially in undiagnosed and untreated patients. ^, The clinical disease activity of patients with an excess of hGH correlates better with serum levels of IGF-1 than with hGH concentrations.

About 60% of acromegalic patients develop cardiovascular disease. Hypertension, insulin resistance, diabetes mellitus, and hyperlipidemia represent the cardiovascular manifestations most frequently associated with acromegaly. ^, The Endocrine Society (ES) Clinical Practice Guidelines recommend that acromegalic patients undergo evaluation for associated comorbidities (hypertension, diabetes mellitus, cardiovascular disease, and sleep apnea).

The cardiovascular and hemodynamic effects of acromegaly vary considerably depending on the patient’s age and the disease’s severity and duration. A specific acromegalic cardiomyopathy develops in patients with persistently increased secretion of hGH and IGF-1; this condition is characterized by a concentric biventricular hypertrophy, diastolic dysfunction, and mitral and aortic valve disease, and can occur even in the absence of cardiovascular risk factors. The natural history of this specific cardiomyopathy has three phases. ^, The first phase typically develops in young patients with new onset acromegaly and involves a hyperkinetic syndrome with increased myocardial contractility and enhanced cardiac output. More evident hypertrophy usually develops during the second phase of cardiomyopathy which is associated with impaired diastolic filling and reduced cardiac performance during exercise. Impaired systolic function and low cardiac output progressively develop in the late phase of the disease in patients in whom acromegaly is undiagnosed or under-treated. Heart failure can complicate this late phase of the disease and portend a poor prognosis. Hypertension, type 2 diabetes, and hyperlipidemia may further contribute to the impaired contractile function. Hypertension occurs with a mean prevalence of 33% to 46%, although the mechanism remains poorly understood. Administration of hGH promotes sodium retention and volume expansion while IGF-1 has a potent antinatriuretic effect independent of any effect on aldosterone. Studies of the renin-angiotensin-aldosterone system have shown failure to inhibit release of renin optimally by volume expansion. Impaired glucose tolerance and diabetes mellitus are present in approximately 30% of acromegalic patients. Hyperlipidemia is principally characterized by hypertriglyceridemia and reduced high-density lipoprotein (HDL) cholesterol levels.

Acromegaly increases the prevalence of aortic and mitral valve disease. Patients with active acromegaly have a high prevalence of mitral and aortic abnormalities, which is higher in those with left ventricular hypertrophy. This condition can be considered one of the aspects of acromegalic cardiomyopathy because it is detectable even in young patients and in those with a short duration of the disease and can persist after treatment in cured patients. This persistence is likely to be correlated with the persistence of left ventricular hypertrophy and should be carefully monitored due to the risk of cardiac dysfunction. Progressive mitral regurgitation and increased left ventricular preload and afterload occur in patients with uncontrolled acromegaly. Patients with acromegaly can exhibit dilation of the aortic root, which is greater in men than in women. Left ventricular mass index is positively correlated with the diameter of the aorta, and patients with aortic ectasia usually have a greater left ventricular mass index than patients without this feature.

Although initial reports suggested that accelerated atherosclerosis impairs cardiac function in patients with longstanding acromegaly, a postmortem study revealed significant coronary artery disease in only 11% of patients dying of disease-related causes. Angiography showed normal or dilated coronary arteries in most cases. Fewer than 25% of the patients had positive nuclear stress tests, indicating that atherosclerosis and ischemic heart disease do not likely account for the marked degree of biventricular cardiac hypertrophy, cardiac failure, and cardiovascular mortality.

Abnormalities on the electrocardiogram (ECG), including left-axis deviation, septal Q waves, ST-T wave depression, abnormal QT dispersion, and conduction system defects, develop in up to 50% of patients with acromegaly. A variety of dysrhythmias can occur, including atrial and ventricular ectopic beats, sick sinus syndrome, and supraventricular and ventricular tachycardia. Monitoring shows a fourfold increase in complex ventricular arrhythmias. Signal-averaged ECGs reveal a parallel rise late potential, a finding related to ventricular arrhythmia. Patients with active acromegaly more commonly show these electrophysiologic abnormalities than do treated patients. Patients with newly diagnosed, untreated acromegaly also manifest derangements in cardiac autonomic function, as measured by heart rate recovery and variability.

Acromegalic patients have an increased mortality compared to age- and gender-matched controls. In uncontrolled acromegaly patients, the standardized mortality ratio (SMR) is significantly higher than the general population; however, mortality is strongly related to the disease control, which has normalized with the more frequent use of adjuvant therapy in the last decade. In a 20-year follow-up study, the causes of death shifted from predominantly cardiovascular deaths (about 44%) during the first decade to predominantly cancer-related deaths in the next two decades. Multiple studies have associated an increased risk of cancer of the gastrointestinal tract, colon, or lungs with this increased mortality.

Adrenocorticotropic Hormone and Cortisol

The adrenocorticotropic cells in the anterior pituitary synthesize a large protein (pro-opiomelanocortin), which is then processed within the corticotropic cell into a family of smaller proteins that include adrenocorticotrophic hormone (ACTH). The adrenal cortex zona glomerulosa produces aldosterone, and the zona fasciculata produces primarily cortisol and some androgenic steroids. The zona reticularis produces cortisol and androgens as well. ACTH regulates the synthesis of cortisol in both the zona fasciculata and reticularis.

Cushing Disease and Cushing Syndrome

Cushing syndrome results from prolonged and inappropriately high exposure of tissues to glucocorticoids. Excessive cortisol secretion and its attendant clinical disease state can arise from excessive release of ACTH by the pituitary (Cushing disease) or through the adenomatous or rarely malignant neoplastic process arising in the adrenal gland itself (Cushing syndrome). Well-characterized conditions of adrenal glucocorticoid and mineralocorticoid excess appear to result from the excessively high levels of (ectopic) ACTH produced by small cell carcinoma of the lung, carcinoid tumors, pancreatic islet cell tumors, medullary thyroid cancer, and other adenocarcinomas and hematologic malignancies. Clinical signs and symptoms of Cushing syndrome often develop in patients treated with exogenous steroids at doses equivalent to 20 mg of prednisone daily for more than 1 month. Cortisol, a member of the glucocorticoid family of steroid hormones, binds to receptors located within the cytoplasm of many cell types ( Fig. 96.1 ). After binding cortisol these receptors translocate to the nucleus and function as transcription factors. Several cardiac genes contain glucocorticoid response elements in their promoter regions that confer transcriptional-level glucocorticoid responsiveness. Such genes include those that encode voltage-gated potassium channels, as well as protein kinases, which serve to phosphorylate and regulate the voltage-gated sodium channels. In addition, there are more rapidly acting, nontranscriptional pathways by which cortisol may regulate the activity of voltage-gated potassium channels.

Patients with Cushing disease can exhibit a variety of electrocardiographic changes. The duration of the PR interval appears to correlate inversely with adrenal cortisol production rates. The mechanism underlying this correlation may be related to the expression or regulation of the voltage-gated sodium channel (SCN5A). Changes in the ECG, specifically in the PR and QT intervals, may also arise from the direct (nongenomic) effects of glucocorticoids on the voltage-gated potassium channel (Kv1.5) in excitable tissues.

The cardiac effects of Cushing syndrome arise from the effects of glucocorticoids on the heart, liver, skeletal muscle, and fat tissue. The interaction between high cortisol levels and active mineralocorticoid receptor (MR) in cardiomyocytes induces cardiac remodeling and fibrosis, ventricular remodeling, and an impairment of relaxation. It can also stimulate the expression of several pro-inflammatory and adhesion molecules, leading to increased myocardial stiffness and contractile dysfunction. Cortisol-mediated hypertension has multiple mechanisms in patients with Cushing ; cardiac structural and functional alterations are more severe in hypertensive patients, suggesting an interaction between the deleterious effects of hypertension and cortisol excess. Chronic cortisol hypersecretion can also cause central obesity, insulin resistance, dyslipidemia, a prothrombotic state, and metabolic syndrome. The prevalence of diabetes mellitus ranges between 18% and 30%.

A two- to fourfold increase in mortality has been reported in Cushing syndrome compared with the general population. This increased cardiovascular morbidity and mortality is largely due to cerebrovascular, peripheral vascular, and coronary artery disease, and CHF. The cardiovascular risk may persist even after restoration of eucortisolaemia. Recent evidence suggests an impaired cardiovascular profile even in patients with subclinical Cushing syndrome when compared with the general population; this condition is characterized by an incomplete post-dexamethasone cortisol suppression and adrenal incidentalomas.

Primary Hyperaldosteronism

Primary hyperaldosteronism (PA) (see also Chapter 26 ) refers to a group of disorders in which aldosterone production is inappropriately high, relatively autonomous from the major regulators of secretion (angiotensin II and plasma potassium concentration), and non-suppressible by sodium loading. ^, It is the most common cause of secondary hypertension, with a prevalence of 20% in patients with resistant hypertension and 10% in those with severe hypertension. ^, Hypokalemia in the setting of hypertension should induce a prompt consideration of PA, although most patients with PA are not hypokalemic. Common causes of PA include an adrenal adenoma, unilateral or bilateral adrenal hyperplasia, or, in rare cases, an adrenal carcinoma or an inherited condition: glucocorticoid-remediable aldosteronism (GRA).

Aldosterone’s mechanism of action on target tissues resembles that reported for glucocorticoids (see Fig. 96.1 ). Aldosterone enters cells and binds to the MR, which then translocates to the nucleus and promotes the expression of aldosterone-responsive genes. In addition to kidney cells, in which MRs control sodium transport, in vitro studies on rats have located these receptors in cardiac myocytes. MR is also expressed in vascular smooth muscle cells, endothelial cells, cells within brown adipose tissue, macrophages, and neurons in several brain regions.

In humans, primary aldosteronism causes cardiovascular damage; it can induce development of cardiac hypertrophy, myocardial fibrosis, diastolic dysfunction, and heart failure. ^, Stroke, nonfatal myocardial infarction, or atrial fibrillation are more frequent among patients with PA compared with patients with primary hypertension. Patients with PA also have an increased prevalence of metabolic syndrome and diabetes. Death resulting from cardiovascular causes is more common among patients with PA compared with matched control patients with primary hypertension. Fibrosis of the heart, adrenal glands, pancreas, and lungs has been found in autoptic studies in patients with PA.

In light of the cardiorenal and cerebrovascular implications stemming from an unrecognized and untreated PA, early diagnosis and screening are imperative. Primary aldosteronism should be investigated in patients with: (1) severe hypertension, systolic blood pressure ≥180, and diastolic blood pressure ≥110 mm Hg; (2) treatment-resistant hypertension (an office SBP/diastolic blood pressure ≥130/80 mm Hg and prescription of ≥3 antihypertensive medications at optimal doses, including a diuretic or an office SBP/diastolic blood pressure less than 130/80 mm Hg for a patient requiring ≥4 antihypertensive medications); (3) hypertension with spontaneous or diuretic-induced hypokalemia; (4) hypertension with incidentally discovered adrenal tumors; (5) hypertension and sleep apnea; (6) family history of early-onset hypertension or cerebrovascular accident at a young age (<40 years) ( Table 96.1 ). ^,

Addison Disease

Primary adrenal insufficiency occurs when the adrenal cortex cannot produce sufficient glucocorticoids and/or mineralocorticoids. Primary adrenal insufficiency arises most commonly from bilateral loss of adrenal function on an autoimmune basis; as a result of infection, hemorrhage, or metastatic malignancy; or in selected cases, from inborn errors of steroid hormone metabolism. Addison disease can manifest itself at any age; it may be associated with other autoimmune disorders (e.g., Hashimoto thyroiditis, type 1 diabetes mellitus, autoimmune gastritis/pernicious anemia, and vitiligo). In contrast, secondary adrenal insufficiency, which results from pituitary-dependent loss of ACTH secretion, leads to a fall in glucocorticoid production, whereas mineralocorticoid production, including aldosterone, remains at relatively normal levels.

The non-cardiac symptoms—including increased pigmentation, abdominal pain with nausea and vomiting, hypoglycemia, and weight loss can be chronic, but tachycardia, hypotension, hyponatremia, hyperkalemia, loss of autonomic tone, cardiovascular collapse, and crisis may develop especially in acutely ill or untreated patients with Addison disease. Delayed treatment of more severe symptoms is likely to increase morbidity and mortality.

Laboratory findings (hyponatremia and hyperkalemia) indicate loss of aldosterone production (high renin levels).

Hyperkalemia can alter findings on the ECG by producing low-amplitude P waves and peaked T waves. Blood pressure measurements uniformly show low diastolic pressure (<60 mm Hg) along with orthostatic changes that reflect loss of volume and acquired autonomic dysfunction. Patients with newly diagnosed, untreated Addison disease have reduced left ventricular end-systolic and end-diastolic dimensions in comparison to controls.

Diagnosis

Acute adrenal insufficiency characteristically occurs in the setting of acute stress, infection, or trauma in patients with chronic autoimmune adrenal insufficiency or in children with congenital abnormalities in cortisol metabolism. It can also develop as a result of bilateral adrenal hemorrhage in patients with severe systemic infection or diffuse intravascular coagulation. Secondary adrenal insufficiency can occur in the setting of hypopituitarism and is usually chronic, but acute changes caused by pituitary hemorrhage (apoplexy) or pituitary inflammation (lymphocytic hypophysitis) can also occur. Acute adrenal insufficiency can develop in patients treated with long-term suppressive doses of corticosteroids (>10 mg of prednisone for more than 1 month) if treatment is stopped precipitously or if an acute severe non–endocrine-related illness arises.

The diagnostic criteria include low cortisol levels (morning cortisol < 140 nmol/L [<5 μg/dL]) or when cortisol levels fail to rise above 500 nmol/L (20 μg /dL) 30 or 60 minutes after an intravenous injection of 250 μg of corticotropin. The simultaneous measurement of plasma renin and aldosterone can help determine mineralocorticoid deficiency.