Chapter 13 Cardiovascular Effects of Systemic Diseases

Francis W.K. Smith, Jr., Donald P. Schrope, Carl D. Sammarco

INTRODUCTION

Many systemic diseases are capable of profoundly affecting cardiovascular structure and function (Box 13-1). The veterinarian may detect cardiovascular abnormalities as the predominant clinical sign or systemic disease manifestations may overshadow cardiac abnormalities. Although cardiovascular manifestations may sometimes be of no clinical significance, at other times they may constitute the major medical concern. Detection of cardiovascular involvement may be based on clinical signs, radiographic changes, electrocardiographic (ECG) or echocardiographic abnormalities, or laboratory findings. Emphasis in this chapter is given to diseases having the greatest cardiovascular effects or incidence in practice. The focus of discussion is the cardiovascular effects and their treatment.

Box 13-1 Classification of Important Systemic Disorders That Affect the Heart

Endocrine

Thyroid gland

Hyperthyroidism

Hypothyroidism

Adrenal gland

Hyperadrenocorticism

Hypoadrenocorticism

Pheochromocytoma

Pituitary

Acromegaly (hypersomatotropism)

Pancreas

Diabetes mellitus (hyperglycemia)

Metabolic

Hypercalcemia

Hypocalcemia

Hyperkalemia

Hypokalemia

Hypoglycemia

Uremia

Anemia

Neoplastic and infiltrative heart diseases

Physical and chemical agents

Hyperpyrexia (heat stroke)

Hypothermia

Carbon monoxide

Toad poisoning

Oleander toxicity

Chocolate (theobromine) toxicity

Doxorubicin cardiotoxicity

Infectious/inflammatory myocardial diseases

Bacterial (Lyme disease)

Viral (parvovirus)

Mycotic

Protozoal (trypanosomiasis)

Miscellaneous

Systemic lupus erythematosus (SLE)

Neurologic disease

Gastric dilatation-volvulus (GDV)

Pancreatitis

Traumatic myocarditis

Endocrine Diseases

HYPERTHYROIDISM

• Hyperthyroidism is the most common systemic disturbance to affect cardiac function in cats and is rare in dogs. Hyperthyroid heart disease can be a severe problem, leading to heart failure in some animals.

• Hyperthyroidism is a disease of middle-aged to geriatric cats (range, 4 to 22 years; mean, 13 years) that is generally caused by a thyroid adenoma. Clinical evidence of thyrotoxic heart disease is unusual before the age of 6 years. Thyroid tumors in dogs are generally rare and nonfunctional adenocarcinomas that don’t cause hyperthyroidism. Iatrogenic hyperthyroidism can result from over supplementation of thyroxin in hypothyroid dogs.

Cardiac Pathophysiology

Direct Effects

• Positive inotropic effects (i.e., increased contractility) result from an increased sodium-potassium – exchanging adenosine triphosphatase (Na⁺, K⁺-ATPase) activity, increased mitochondrial protein synthesis, and increased synthesis and enhanced contractile properties of myosin. Thyroid hormone favors the production of the alpha heavy chain myosin isoenzyme, which has the fastest ATPase activity, but is less efficient at converting ATP to mechanical energy. Thyroid hormones increase the number of L-type calcium channels and expression of sodium calcium ATPase, which improves the recycling of calcium by the sarcoplasmic reticulum. Systolic and diastolic performances are both altered.

• Positive chronotropic effects (i.e., increased heart rate) result from an increased rate of sinoatrial firing, decreased threshold of atrial activation, and shortened refractory period of the conduction tissue. The effect on atrial activation may increase the risk for atrial arrhythmias.

Indirect Effects

• The effect of thyroid hormones on the adrenergic system is controversial. The number of myocardial beta-adrenergic receptors and their affinity are increased in hyperthyroid animals. However, this does not always explain or result in an increased responsiveness to catecholamines. Postreceptor effects of thyroid hormone are probably mediated by changes in intracellular G protein populations that result in an enhanced response to adrenergic agonists. Circulating catecholamine levels are normal.

• Hyperthyroidism results in an increased metabolic rate, and consequently an increased tissue oxygen demand. The need for increased tissue perfusion and oxygen delivery requires greater cardiac output. Peripheral vasodilation increases tissue perfusion and decreases afterload. As blood volume increases, increased venous return to the heart and increased preload result. The combination of increased preload, increased contractility, increased heart rate, and decreased afterload results in increased cardiac output. Chronic volume overload and high metabolic rate can result in heart failure even though the cardiac output is still greater than normal. This is referred to as high-output heart failure.

• Hypertension is a frequent although usually not severe sequela of hyperthyroidism in cats, with one study showing an incidence of mild to moderate hypertension in 73% of cases. This occurs in spite of peripheral vasodilation, and probably reflects the increased stroke volume and heart rate which increases cardiac output in these animals. Blood pressure is a function of cardiac output and systemic vascular resistance.

• The combination of volume and pressure overload alters myocardial protein synthesis and degradation, which results in myocardial hypertrophy and chamber dilation. These changes are most notable in the left heart. In rare cases, hyperthyroid cats with congestive heart failure develop a cardiomyopathy of overload that resembles dilated cardiomyopathy.

Key Point

The net effects of hyperthyroidism on the cardiovascular system are enhanced cardiac contractility, tachycardia, cardiomegaly, left ventricular hypertrophy, high cardiac output, systemic hypertension, and occasionally high-output heart failure.

Diagnosis

Therapy

Management of Hyperthyroidism

• Radioactive iodine is curative and does not require anesthesia or surgery. In most instances it is the safest and most effective treatment.

• Surgical treatment effectively cures the condition and eliminates the need for chronic medication. Medical management generally is instituted to stabilize the patient prior to surgery. The most frequent complication of surgery is transient postoperative hypocalcemia.

• Medical management generally involves administering methimazole (Tapazole) at 2.5 to 5 mg PO every 8 to 12 hours in cats. Start with a low dose and titrate up as needed and tolerated. A transdermal formulation in pleuronic lecithin organo gel can be used, but the rate of clinical improvement is slower than with oral administration. Carbimazole is an alternative to methimazole, available in Europe, and is dosed at 5 mg PO every 8 hours in cats. Propylthiouracil is no longer recommended because of a high incidence of side effects. These drugs inhibit the formation of thyroid hormones, but do not inhibit or block the release of already formed T₃ and T₄. Thus serum thyroid levels do not drop acutely.

• Inorganic iodine therapy is rarely used. Iodine blocks thyroid hormone synthesis and release, and thyroid levels rapidly drop. Rapid reduction of thyroid levels may benefit patients with severe congestive heart failure. Preoperative use may decrease the vascularity of the thyroid gland. Administer one dose of methimazole prior to the iodine, so that the iodine is not incorporated into new thyroid hormone. Administer one drop of saturated solution of potassium iodide orally once a day for 7 to 10 days.

• Sodium or calcium ipodate at 15 mg/kg PO every 12 hours blocks the conversion of T₄ to T₃. It is not effective in all cats and should be considered a treatment of last resort.

Management of Arrhythmias

• The expedient way to manage tachyarrhythmias is to start methimazole therapy. Even before euthyroidism is restored, many arrhythmias improve or are abolished. In this fashion, ancillary therapy is usually unnecessary.

• Severe tachyarrhythmias (i.e., atrial tachycardia, multiform VPCs, ventricular tachycardia) in patients without heart failure are best managed with beta blockers such as atenolol (3.125 to 6.25 mg PO every 12 hours) or propranolol (2.5 to 7.5 mg PO every 8 hours). Higher than normal doses of beta blockers may be needed because of an increased rate of metabolism and elimination. Supraventricular arrhythmias in asthmatic cats should be managed with diltiazem (7.5 mg PO every 8 hours).

• Supraventricular arrhythmias in patients with congestive heart failure can be managed with digoxin, beta blockers, or diltiazem. Exercise caution when using beta blockers in the presence of congestive heart failure, because these agents depress cardiac contractility and may exacerbate heart failure. Cats with hyperthyroidism almost always have increased contractility, so worsening of congestive heart failure with beta blockade is rare. Ideally, congestion should be treated and controlled with diuretics before prescribing a beta blocker. Diltiazem also depresses contractility, but less so than beta blockers. The vasodilating effects of diltiazem usually offset its negative inotropic effects.

Management of Hypertension

• Usually accomplished with control of the hyperthyroid state. The use of beta blockers, vasodilators (e.g., angiotensin-converting enzyme [ACE] inhibitors, amlodipine), and other agents is occasionally indicated.

Management of Congestive Heart Failure

• Diuretics are used to control pulmonary edema and pleural effusion.

• Nitroglycerin ointment can be used in patients with critical congestion or in those refractory to diuretics alone. Enalapril or benazepril also may be helpful in refractory cases.

• Treat arrhythmias as discussed previously.

• Digoxin may be useful in cases where chronic hyperthyroidism results in dilated cardiomyopathy.

Prognosis

• The prognosis for remission of sinus tachycardia, voltage changes, arrhythmias, and congestive heart failure is generally favorable when the hypermetabolic state is controlled through the medical or surgical techniques discussed.

• The prognosis is poor if dilated cardiomyopathy has developed secondary to chronic overload of the heart.

HYPOTHYROIDISM

• Hypothyroidism is a common endocrinopathy in dogs and is rarely encountered as a naturally occurring condition in cats. It is most commonly diagnosed in middle-aged dogs (22% are 2 to 3 years old; 32% are 4 to 6 years old; 22% are 7 to 9 years old). Many breeds are affected, and there appears to be a breed predilection in the golden retriever, Doberman pinscher, dachshund, Irish setter, miniature schnauzer, Great Dane, poodle, and boxer. There is no gender predilection. Hypothyroidism is rare in cats and generally limited to postoperative cases following surgical removal of unilateral or bilateral functional thyroid tumors.

• The cardiac effects of hypothyroidism are generally the opposite of those found in hyperthyroidism. The cardiac effects of hypothyroidism rarely have severe consequences. However, hypothyroidism can aggravate heart failure and complicate the management of cardiac patients.

Cardiac Pathophysiology

• Cardiac contractility is decreased as a result of decreased Na⁺,K⁺-ATPase activity, decreased mitochondrial protein synthesis, and decreased synthesis of contractile properties of myosin.

• Cardiac conduction is decreased as a result of a decreased rate of sinoatrial firing, increased threshold of atrial activation, and prolonged refractory period of the conducting tissue. Enhanced vagal tone in hypothyroidism also slows the heart rate and accentuates sinus arrhythmias.

Key Point

Evaluate the thyroid status in any dog in congestive heart failure with an inappropriately slow heart rate.

• Thyroid hormone plays an important role in lipid and cholesterol metabolism. Hypothyroidism predisposes animals to increased levels of cholesterol and, to a lesser extent, triglycerides. Although rare in dogs, hypercholesterolemia can result in atherosclerosis and myocardial infarction. Lipid abnormalities resolve with thyroid hormone supplementation.

• Hypothyroidism decreases the metabolic rate, thus lessening the required cardiac output. Correcting hypothyroidism increases the workload on the heart. This is important to remember when treating animals in congestive heart failure.

• Hypothyroidism decreases digoxin clearance, predisposing patients to digoxin toxicity.

Diagnosis

History and Physical Examination

• Historical findings in hypothyroid animals include alopecia and other dermatologic problems, lethargy, weakness, depression, infertility, and diarrhea.

• Cardiovascular abnormalities noted on physical examination can include muffled heart sounds, weak apex heart beat, weak pulses, and bradycardia.

• Noncardiac physical findings can include symmetric alopecia, seborrhea, myxedema, pyoderma, hypothermia, depression, and lameness.

Electrocardiography

• ECG changes in hypothyroidism reflect decreased automaticity of pacemaker tissue and depressed conduction. Changes that reflect decreased automaticity may include sinus bradycardia, pronounced sinus arrhythmia, and atrial and ventricular arrhythmias. Changes that reflect depressed conduction may include AV block, widened QRS complexes, and inverted T waves. The most common findings reported in dogs are sinus bradycardia and inverted T waves.

• Low-voltage QRS complexes are frequently seen in hypothyroid animals.

• Atrial fibrillation in giant-breed dogs occasionally accompanies hypothyroidism, usually in association with dilated cardiomyopathy. Supplementation with thyroid hormone rarely causes conversion to sinus rhythm.

• Radiographs are generally normal.

Echocardiography

• May reveal mild to marked decreases in indices of cardiac contractility and mild chamber enlargement. Decreased contractility is documented by increase in left ventricular interval diameter in systole, prolongation of the preejection period, decrease in left posterior wall thickness in systole and decrease in septal wall thickness in systole and diastole. There is a decrease in aortic root diameter, decrease in velocity of circumferential shortening and decrease fractional shortening.

• Always check thyroid status when depressed contractility is noted in an animal of a breed not predisposed to dilated cardiomyopathy.

Clinical Pathology

• The hemogram may reveal a low-grade nonregenerative anemia.

• The most common abnormality on the serum chemistry profile is hypercholesterolemia and, occasionally, hypertriglyceridemia.

• A normal serum T₄ value generally is sufficient to rule out hypothyroidism. Unfortunately, a low serum T₄ does not confirm the diagnosis. Concurrent systemic ailments and numerous drugs can cause depressed serum T₄ values in animals with normal thyroid function (euthyroid sick syndrome) (Box 13-2). To make a diagnosis in these cases requires integration of the history, physical findings, and other blood test results, or confirmation by specialized diagnostic tests.

• Serum T₃ values are less reliable than T₄ values at diagnosing hypothyroidism.

Box 13-2 Some Drugs and Diagnostic Agents that Can Alter Basal Serum Thyroid Hormone Concentrations in Humans and Possibly Dogs

From Feldman EC, Nelson RW: Canine and feline endocrinology and reproduction, 3rd ed. St Louis: WB Saunders, 2004.

Decrease T₄ and/or T₃	Increase T₄ and/or T₃
Amiodarone (T₃) Androgens Cholecystographic agents Diazepam Dopamine Flunixin Furosemide Glucocorticoids Heparin Imidazole Iodide Methimazole Mitotane Nitroprusside Penicillin Phenobarbital Phenothiazines Phenylbutazone Phenytoin Primidone Propranolol Propylthiouracil Radiopaque dyes (ipodate) (T₃) Salicylates Sulfonamides (sulfamethoxazole) Sulfonylureas	Amiodarone (T₄) Estrogens 5-Fluorouracil Halothane Insulin Narcotic analgesics Radiopaque dyes (ipodate) Thiazides

Specialized Diagnostic Tests

• The thyroid-stimulating hormone (TSH) response test has been the “gold standard” in veterinary medicine for diagnosing hypothyroidism. Animals with hypothyroidism have low baseline T₄ values and fail to increase their T₄ values above a predetermined level following administration of TSH. Animals with euthyroid sick syndrome will also have low baseline T₄ levels, but following TSH administration, their T₄ values will increase above an absolute cutoff value. Unfortunately, TSH is often difficult to obtain and expensive.

• Free T₄ by equilibrium dialysis as a diagnostic test of canine hypothyroidism has a sensitivity of 98% and specificity of 92%, versus a total T₄ sensitivity of 90% and specificity of 90%. The free T₄ by ED should be low in a hypothyroid animal.

• Canine TSH levels as a diagnostic test for canine hypothyroidism has a sensitivity of 75% and specificity of 90%. The TSH level should be high in a hypothyroid animal.

• When the endogenous TSH is high and the free T₄ by equilibrium dialysis is low, the diagnostic accuracy approaches 100%.

Therapy

• Treatment of hypothyroidism is simple and inexpensive. L-Thyroxin is administered at 20 μg/kg PO every 12 hours, or 0.5 mg/m² every 12 hours with a maximum dose of 0.8 mg/dose for a dog. After 6 to 8 weeks, evaluate a serum T₄ value 4 to 6 hours after a dose of L-thyroxin. If the post-pill T₄ value is normal and clinical signs have resolved, you can try decreasing the frequency to once a day. Ideally, a post-pill T₄ value should then be obtained in another month at 4 to 6 and 24 hours after a dose of thyroxin. This is important to make sure that there is an adequate duration of effect with once daily dosing.

• Treatment in patients with congestive heart failure is more complicated. Supplementation will increase the metabolic rate and demand on the heart. If the failing heart is unable to meet these demands, heart failure will worsen. Therefore, implement thyroid hormone supplementation gradually in patients with cardiac disease, especially if they are already in failure. Start with one fourth of the standard dose and increase it by one-fourth dose weekly. It should be emphasized that hypothyroidism rarely causes heart failure, but may significantly exacerbate cardiac function in an animal with underlying heart disease.

• The risk of digoxin toxicity is increased in hypothyroid states. Monitor hypothyroid animals closely for signs of digoxin toxicity, and consider assessing thyroid status in any animal with normal renal function that develops digoxin toxicity on reasonable doses of digoxin. Ideally the digoxin level on a sample obtained 8 hours postdose should be between 0.5 to 1 ng/dL.

Prognosis

• There are few complications in the treatment of hypothyroidism.

HYPOADRENOCORTICISM (ADDISON’S DISEASE)

• Hypoadrenocorticism is a potentially life-threatening endocrinopathy that is uncommon in dogs and rare in cats. The disease is more common in female dogs and usually occurs in young to middle-aged animals. Approximately 76% of cases occur before 7 years of age, with an age range of 5 weeks to 16 years.

• Primary hypoadrenocorticism (Addison’s disease) results from destruction of the zona glomerulosa and zona fasciculata of the adrenal gland. These areas of the adrenal gland produce aldosterone and cortisol, respectively. Destruction is generally immune mediated, but also can occur secondary to infection, neoplasia, infarction, and drugs such as o,p′-dichlorodiphenyldichloroethane (o,p′-DDD) (Lysodren, [mitotane]).

• Secondary hypoadrenocorticism results from decreased production or release of adrenocorticotropic hormone (ACTH) from the pituitary gland. Secondary adrenal insufficiency may occur following acute withdrawal of long-term, high-dose glucocorticoid therapy that has suppressed the hypothalamic-pituitary-adrenal axis. These patients have normal mineralocorticoid activity, so electrolyte values are normal. Cortisol values are depressed.

• Adrenal destruction occurs gradually, so basal hormone levels remain normal. It is only when the animal is stressed and the adrenal reserve is inadequate that signs develop. Eventually, the destruction proceeds to the point that basal hormone levels are depressed and clinical signs are present without stress.

Cardiac Pathophysiology

Cardiovascular Effects of Cortisol

• Cortisol is important in maintaining vascular integrity and responsiveness to catecholamines. Cortisol deficiency predisposes animals to hypotension.

• Cortisol has a positive inotropic effect on the heart.

• Cortisol affects the distribution and elimination of body water.

• Cortisol is important in helping the body deal with stress. This is why so many addisonian crises follow stress, and why glucocorticoid supplementation must be increased during periods of stress.

Cardiovascular Effects of Aldosterone

• Aldosterone acts on the distal renal convoluted tubule and collecting duct to enhance sodium retention and potassium elimination. Aldosterone deficiency results in hyponatremia and hyperkalemia.

• Hyponatremia decreases plasma osmotic pressure, causing fluid shifts out of the vascular compartment. This contributes to hypovolemia and hypotension.

• Hyperkalemia alters cardiac conduction, resulting in numerous arrhythmias. The cardiac effects of hyperkalemia are aggravated by low sodium, low calcium, and acidosis.

Key Point

Net cardiovascular effects of hypoadrenocorticism are hypovolemia, systemic hypotension, altered cardiac conduction, and depressed myocardial function. These changes can be fatal if not rapidly diagnosed and aggressively treated.

Diagnosis

History and Physical Examination

• A history of waxing and waning of clinical signs, with more severe signs during periods of stress, generally is present.

• Patients often present with history of anorexia, vomiting, diarrhea, depression, weakness, and cardiovascular collapse. Other signs include weight loss, polyuria, polydipsia, melena, and shivering.

• Transient improvement after intravenous fluid therapy or corticosteroid administration followed by subsequent relapse days or weeks later can occur.

• Findings on physical examination include depression, weakness, dehydration, hypothermia, slow capillary refill time, shaking, bradycardia, and weak femoral pulses.

Electrocardiography

• ECG changes vary with the magnitude of the hyperkalemia and are aggravated by hyponatremia, hypocalcemia, and acidosis. The following ECG findings are seen with experimentally induced hyperkalemia (Figure 13-1):

• Peaking of the T wave with a narrow base is the earliest ECG abnormality and may be observed when serum K⁺ exceeds 5.7 to 6.0 mEq/L.

• P wave morphology is altered, its amplitude reduced, intra-atrial conduction delayed, and PR interval prolonged when serum K⁺ exceeds 7.0 mEq/L.

• P waves become unrecognizable (atrial standstill) at plasma K⁺ levels greater than 8.5 mEq/L.

• The QRS widens uniformly at plasma K⁺ levels greater than 9 mEq/L.

• Sinoatrial exit block or junctional rhythms with and without escape complexes may be present.

• Ventricular fibrillation and ventricular asystole may occur at plasma K⁺ levels greater than 10 mEq/L.

• In clinical cases, ECG changes do not correlate as closely with potassium concentrations as they do in published experimental studies.

• The rhythm with atrial standstill secondary to hyperkalemia is generally slow and may be regular or irregular. It is a sinoventricular rhythm. The sinus node continues to fire, and impulses are transmitted to the AV node and ventricles by internodal pathways. P waves are absent because atrial myocytes are not activated.

Key Point

Hyperkalemia is the most common cause of atrial standstill. Atrial standstill also occurs with fibrous replacement of atrial muscle cells secondary to severe atrial distention (valve disease, cardiomyopathy) in dogs and cats, with cardiac arrest, and secondary to an atrial myopathy in dogs, a condition most commonly seen in English springer spaniels.

Figure 13-1 A, Hyperkalemia in a dog in cardiovascular collapse, consistent with an Addisonian crisis. P waves are absent (atrial standstill), and T waves are tall and peaked. Serum potassium was 8.4 mEq/L. B, After institution of therapy, P waves are present, and the T wave is of smaller amplitude. Serum potassium is now 4.8 mEq/L.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(From Tilley LP: Essentials of canine and feline electrocardiography: interpretation and treatment, ed 3, Malvern, Penn, 1992, Lea & Febiger.)