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Veterinary Medicine

Pathophysiology of heart failure

Heart failure, by definition, occurs when cardiac output is insufficient to provide the tissues with adequate blood flow and / or when the venous return to the heart is greater than the amount of blood that the heart can expel at normal filling pressure. Most animals with heart failure show signs of both forward and backward failure. Forward failure refers to the inability of the heart to pump sufficient blood forward and the inadequate tissue perfusion which ensues, backward failure occurs when the left and / or right ventricular end-diastolic pressure (preload) increases. This leads to increased venous pressure behind the affected chambers and the development of passive venous congestion of the lungs, liver and other tissues.

Numerous compensatory neurohumoral mechanisms become operative when cardiac output starts to fall. These compensatory changes are entirely appropriate for low output failure caused by circulatory shock, for example hypovolaemic shock, and are designed to maintain cardiac output at a level which is at least sufficient to ensure adequate tissue perfusion when the animal is at rest. If, however, a cardiac abnormality is responsible for the low output then, in the longer term, these compensatory responses become inappropriately regulated to a point that they are detrimental to the animal, further increasing the workload on the heart and setting up a self-perpetuating cycle of ventricular dysfunction. Sustained compensatory mechanisms trigger adaptive changes in the heart and blood vessels leading to further compromise in cardiac function and signs of passive venous congestion. Thus, clinically, signs of low output failure are usually associated with varying degrees of circulatory congestion. The cardiac function curves shown in site demonstrate these two situations of low output failure and congestive failure. Clinical cases can occur anywhere between these extremes and therefore may show a combination of low output and congestive signs depending on the level of activity attempted and the cardiac output required to maintain adequate tissue perfusion.

On a pathophysiological basis heart failure may be divided into four components; myocardial failure, volume overload, pressure overload and compliance failure.

Myocardial failure

Impaired myocardial contractility leads to systolic dysfunction which is characterized by a reduction in stroke volume and signs of low output (forward) failure. Myocardial failure may be primary (for example cardlomyopathy) or may occur secondary to prolonged volume overload. The myocardial failure which is a feature of dilated cardiomyopathy usually follows a more chronic course and numerous compensatory mechanisms come into operation to counteract the impaired myocardial function and decrease in cardiac output (see section on compensatory mechanisms).

Volume overload (increased preload)

Volume overload results in ventricular dilatation to a point where the ventricle decompensates, that is, myocardial contractility decreases and signs of both congestive heart failure and low output failure occur. Signs of congestive heart failure associated with the regurgitation of blood into the atria and volume overload may occur before myocardial decompensation and it has been shown that myocardial contractility is often normal or only mildly abnormal in dogs with congestive heart failure due to chronic mitral endocardiosis.

Causes of volume overload include the following.

  • Atrioventricular insufficiency. Incompetence of the atrioventricular valves leads to regurgilation of blood from the ventricles to the atria. This may be due to endocardiosis, endocarditis, dilation of the atrioventricular annuli as occurs with dilated cardiomyopathy, and ruptured chordae tendineae.
  • Left to right cardiovascular shunts which over-load the left side of the heart via the lungs. Examples include patent ductus artcriosus, ventricular septal defect and atrial septal defect.
  • Sodium and water retention (see section on compensatory mechanisms).

Pressure overload (increased atterload)

Conditions which cause increased vascular resistance and which impede the ejection of blood through the ventricular outflow tracts result in ventricular hypertrophy.

Causes of pressure overload include:

  • Aortic or pulmonic stenosis
  • Hypertrophic cardiomyopathy
  • Pulmonary hypertension (for example chronic obstructive pulmonary disease, dirofilariasis or pulmonary thrombosis).
  • Increase in systemic vascular resistance (for example systemic hypertension associated with chronic renal insufficiency).

Compliance failure

Compliance failure implies a loss of myocardial elasticity so that the ventricle is unable to relax and distend properly during diastolic filling. The haemodynamic abnormalities therefore reflect diastolic dysfunction rather than systolic dysfunction which occurs with myocardial failure. Compliance failure may be associated with ventricular hypertrophy, myocardial fibrosis and pericardial effusion (cardiac tamponade).

Extracardiac factors such as excitement, heat stress, overexertion, infection, trauma, anaemia, shock, obesity, pregnancy or any severe systemic or metabolic disease process can also contribute to cardiac decompensation in an animal with preexisting cardiac disease.

Circulatory disturbances can cause similar cardiac dysfunction either by reducing cardiac output or by creating high output states which overload the heart.

Low output states may be caused by:

1. Decreased preload, for example.

  • Overzealous use of diuretics and / or vasodilators to treat congestive heart failure
  • Hypovolaemia due to haemorrhage or hypoadrenocorticism
  • Reduced venous return (for example compression of the posterior vena cava by a large abdominal mass, ascites, gastric torsion)

2. Dysrhythmias (either tachy- or bradydys- rhythmias)

High output states which overload the heart may be associated with:

1. Chronic anaemia, arteriovenous fistulae (for example cardiovascular shunts) and hyper-thyroidism

2. Overzealous administration of intravenous fluids

Compensatory mechanisms in heart failure

Mechanisms which moderate these compensatory effects

If the compensatory mechanisms go unchecked their effects on cardiac function would be detrimental. A number of other mechanisms moderate their effects.

Increased atrial stretch by raised atrial filling pressures stimulates the release of atrial natriuretic peptide (ANP) and atrial stretch receptors elicit reflex responses. Both these hormonal and neural reflex responses to stretch tend to limit salt and water retention by the kidney and limit the high vascular resistance against which the heart has to pump. ANP itself inhibits release of noradrenaline from sympathetic nerve endings, reduces secretion of aldosterone and has direct vasodilatory and natriuretic effects. A trial natriuretic peptide (ANP) concentrations in dogs with congestive heart failure increase as much as sixfold. Neural reflexes also reduce traffic in sympathetic nerve fibres and stimulate the release of a non-peptide natriuretic factor from the hypothalamus.

Cardiac muscle hypertrophy occurs, increasing the thickness of the muscular ventricular wall. This tends to reduce wall stress (distributing it among an increased number of sarcomeres) and therefore the work required to raise the tension within the ventricular wall during the isovolumetric phase of systole.

These factors tend to create a delicate balance allowing the compensatory mechanisms to restore cardiac function back cowards normal while, at the same time, ensuring that the cost in terms of myocardiat energy consumption is minimal.

Adaptive consequences of sustained neurohormonal activation

Pathophysiology of heart failure related to the underlying cause

The above pathophysiological scenario is applicable to heart failure in patients regardless of the underlying cause. For example, in myocardial diseases such as dilated cardiomyopathy, the underlying problem is one of poor systolic function. During the chronic stages of this disease, the compensatory mechanisms and adaptive changes referred to above lead to volume overload and congestive signs which may hasten the deterioration of myocardial function.

Regurgitant valvular heart disease and congenital abnormalities causing left to right shunts also cause cardiac volume overload with the same mechanisms attempting to compensate for a reduction in cardiac output. Although cardiac muscle function may be normal in these diseases, prolonged activation of the compensatory mechanisms described above may eventually lead to detrimental effects on cardiac muscle function (cardiomyopathy of overload).

Diseases which affect diasiolic function to reduce cardiac output will also activate the same neurohortnonal mechanisms. Examples include hypertrophic cardiomyopathy and pericardial disease. In the former case, the problem is one of lack of ability of the cardiac muscle to relax and fill properly during diastole and it is characterized by concentric ventricular muscle hypertrophy. Here, expansion of the circulating volume and increased venous return fail to stretch the diseased muscle and circulatory congestion results. With pericardial disease, raised pericardial pressure opposes ventricular filling (particularly of the more compliant right ventricle)- Compensatory changes raising venous return and filling pressure are essential if cardiac output is to be maintained. Fortunately, congestion of the systemic circulation is less life-threatening in its effects than congestion and oedema of the lungs.

Valvular diseases which cause stenosis (aortic and pulmonic stenosis) lead to pressure overload of the respective ventricles. Concentric muscle hypertrophy results from the increased work load encountered in overcoming the obstruction to cardiac output. Such animals usually show signs of syncope on exercise and develop fatal arrhythmias before compensatory mechanisms for poor cardiac output lead to circulatory congestion.

In conclusion, the compensatory and adaptive changes which occur in cardiac failure are the same regardless of the underlying cause. Inappropriate regulation of these mechanisms in chronic heart failure contributes to the self-perpetuating cycle of events leading to cardiac decompensation and signs of both forward and backward failure. For this reason, medical management strategies are aimed at counteracting some of these compensatory and adaptive changes and knowledge of the underlying cause will assist in determining the most appropriate treatment regime.

Causes and clinical signs of congestive heart failure

Cardiac cachexia

Cardiac cachexia refers to the severe wasting that occurs in association with chronic congestive heart tail urc. The weight loss which can be rapidly progressive is usually accompanied by lethargy, generalized weakness, inappetence and poor hair coat. Affected animals generally show severe signs of congestive heart failure and are moderately hypoproteinaemic. Cardiac cachexia has been attributed to a combination of factors including poor tissue perfusion, cellular hypoxia, malabsorption and anorexia.

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Veterinary Medicine

Dilated cardiomyopathy in the cat

The aetiology of primary dilated cardiomyopathy in the cat is unknown. Recent work has indicated a close association between dietary taurine deficiency and dilated cardiomyopathy. In the cat, taurine is an essential amino acid which is required for the conjugation of bile acids. The premise that taurine deficiency is one of the causative factors in the pathogenesis of dilated cardiomyopathy is based on the fact that many cats on taurine-deficient diets develop myocardial failure which can be reversed with taurine supplementation.

However, not all cats on taurine-depleted diets develop dilated cardiomyopathy and some which do develop cardiomyopathy fail to respond to taurine supplementation. About 38% of cats with dilated cardiomyopathy in one study failed to respond to taurine supplementation and died within the first 30 days of treatment. Hypothermia and thromboembolism were found to increase the risk of early death.

It is also known that cats on apparently adequate diets can nevertheless become taurine deficient. The minimal concentration of taurine in the diet required to prevent signs of deficiency varies with the type of diet. For example, it has been shown that much higher concentrations (2000-2500 mg taurine / kg dry matter) of taurine are required in canned diets compared to dry cat foods since heating during the canning process produces products which increase the enterohepatic loss of taurine. Low plasma taurine levels have been reported in cats fed a taurine replete but potassium depleted diet containing 0.8% ammonium chloride as a urinary acidifier suggesting a possible association between taurine and potassium balance in cats. Dietary acidification exacerbates potassium depletion in cats by decreasing gastrointestinal absorption of potassium.

It has been suggested therefore that the aetiology of feline dilated cardiomyopathy, like that of dilated cardiomyopathy in dogs, is multifactorial. There is some evidence to show that genetic factors may play a role in feline dilated cardiomyopathy. Burmese, Siamese and Abyssinian cats appear predisposed. The incidence of dilated cardiomyopathy is higher in young to middle-aged cats; the evidence for a sex predilection is equivocal).

Pathophysiology

Impairment in myocardial contractility leads to systolic dysfunction and increased end-diastolic pressures. Progressive dilatation of the ventricles results in distortion of the atrioventricular valve apparatus and mitral regurgitation which, together with the reduction in myocardial contractility, contributes to the reduction in stroke volume and decreased cardiac output.

Clinical signs of Dilated cardiomyopathy

The clinical signs may be gradual in onset and are often rather vague (lethargy, reduced activity and decreased appetite). Many of the presenting signs are similar to those of hypertrophic cardiomyopathy making differentiation between the two diseases on a clinical basis difficult. Cats which are dyspnocic may be dehydrated and hypothermic with weak femoral pulses. There may be obvious pallor or cyanosis of the mucosae with a prolonged capillary refill time. Increased respiratory crackles in association with a gallop rhythm and systolic murmur are common findings; the presence of a large volume of pleural fluid may result in muffled heart sounds. Less frequently there is also evidence of right-sided failure (jugular distension, and hepatomegaly); ascites is a rare finding.

Electrocardiography

The electrocardiographic changes do not help differentiate dilated cardiomyopathy from the hypertrophic form of the disease. Some cats remain in a relatively slow sinus rhythm. Tall R waves and wide P waves and QRS complexes may be apparent in Lead II.

Arrhythmias, especially ventricular premature complexes, have been recorded in more than 50% of cases. The mean electrical axis is often within normal limits.

Radiographic findings

Thoracic radiographs typically show evidence of generalized cardiomegaly; enlargement of the-left atrium may be particularly marked. The cardiac silhouette is often obscured by the presence of a bilateral pleural effusion. Pulmonary venous congestion and oedema may be present but these changes are usually mild and are often masked by the presence of fluid in the pleural space. The caudal vena cava is often dilated and there may be evidence of hepatomegaly.

Echocardiography

Echocardiography offers the most reliable means of differentiating dilated cardiomyopathy from hypertrophic cardiomyopathy. The interventricular septum and left ventricular free wall appear thin and poorly contractile with a marked reduction in fractional shortening. Both ventricles and the left atrium appear dilated and left ventricular end-diastolic and end-systolic internal dimensions are increased.

Laboratory findings

Normal plasma taurine levels are greater than 60 nmol l-1 ; most cats with dilated cardiomyopathy have plasma taurine concentrations less than 20 nmol l-1 and often less than 10 nmol l-1. Taurine-defielent cats with thromboembolism may have slightly higher plasma taurine concentrations due to reperfusion hyperkalaemia. Whole blood taurine has been reported to be less sensitive to acute changes in taurine intake and provides a better indication of long-term taurine intake. Whole blood taurine concentrations greater than 280 nmol l-1 are considered adequate.

Prerenal azotaemia is a common finding in cats with dilated cardiomyopathy because of reduced renal perfusion. The pleural effusion which develops with feline dilated cardiomyopathy is typically a serosanguineous modified transudate; true chylous effusions have been reported in association with right heart failure.

Angiocardiography

Non-selective angiocardiography can be used to demonstrate dilatation of all cardiac chambers. The slow circulation time in cats with dilated cardiomyopathy increases the risk of thromboembolus formation during this procedure and decompensated cases should be stabilized beforehand.

Dilated cardiomyopathy: Treatment

Cats which are severely dyspnoeic should be given oxygen, kept warm and placed in a cage. Dyspnoeic animals, particularly those with suspected pleural effusion, should be handled with care and should not be placed in dorsal or lateral recumbency for radiography. A dorsoventral radiograph taken with the animal resting in sternal recumbency is usually sufficient to confirm the presence of pleural fluid. Thoracocentesis should be attempted before a more detailed radiographic examination is performed. Other therapeutic strategics are summarized below.

Digoxin improves myocardial contractility in some but not all cats with dilated cardiomyopathy and it has been suggested that the drug may act synergistically with taurine in this respect.The liquid form of the drug is unpalatable and is generally not well tolerated. There is considerable individual variation in the way in which cats respond to digoxin. The maintenance oral dose is 0.01 mg kg-1 every 48 h for an average 3-4 kg cat which is less than one quarter of a 62.5 μg tablet every other day. Cats with dilated cardiomyopathy are more susceptible to digoxin toxicity and tend to show toxic signs when the plasma concentration of digoxin is approximately 50% of the level which would be considered toxic in a normal healthy cat. Approximately 50% of cats given 0.01 mg kg-1 body weight every 48 h show signs of toxicity.

Other positive inotropic agents such as dopamine and dobutamine must be given by constant slow intravenous infusion and are, therefore, not used as extensively. Both drugs can be given at a rate of 1-5 μg kg-1 body weight min-1 ; with dobutamine, seizures have been reported with infusion rates as low as 5 μg kg-1 min-1 in cats.

Frusemide (initially 1.0 mg kg-1 body weight intravenously twice daily; for maintenance 1-2 mg kg-1 body weight per os once or twice daily)

Mixed arteriovenous vasodilators such as captopril (3.12-6.25 mg kg-1 body weight per os twice or three times daily; this dose equates to approximately one-eighth to one quarter of a 25 mg tablet) or venodilators such as 2% nitroglycerine ointment (1/8-1/4 inch applied three times daily to the inside of the pinna) can be given although the beneficial effects of these drugs have yet to be evaluated fully in cats with dilated cardiomyopathy. They should not be given to cats with cardiogenic shock since they may potentiate the fall in cardiac output especially if used in conjunction with diuretic agents.

Animals which are severely hydrated may require intravenous or subcutaneous fluid therapy, for example 0.45% saline with 2.5% dextrose solution may help combat the effects of circulatory failure. The recommended rate of infusion is 25-35 ml kg-1 body weight day-1 given in two or three divided doses. Care should be taken so that the rate of infusion optimizes cardiac output but minimizes the risk of exacerbating pulmonary oedema or a pleural effusion.

Aspirin (25 mg kg-1 body weight every 72 h).

Taurine supplementation (250-500 mg per os twice daily) may result in a dramatic clinical improvement within 1-2 weeks when dilated cardiomyopathy is associated with taurine deficiency although cehocardiographic evidence of improved cardiac performance is usually not evident until after at least three weeks of treatment.

Sodium restricted diet.

Prognosis

The prognosis for cats which fail to resond to taurine therapy is poor. About 93% of early deaths occur within the first two weeks; few survive longer than one month. Taurine supplementation can eventually be discontinued if adequate taurine intake is provided for in the food.

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Veterinary Medicine

Hypertrophic cardiomyopathy in the cat

The incidence of hypertrophic cardiomyopathy (HCM) is higher in the cat than it is in the dog. hypertrophic cardiomyopathy can be classified as primary or secondary. The aetiology of the primary or idiopathic form is unknown. A recent survey of 74 cases of hypertrophic cardiomyopathy showed no apparent breed predilection ; others have suggested that the Persian breed may be predisposed. The disease rarely occurs in the Siamese. Burmese and Abyssinian breeds in which there is a much higher incidence of dilated cardiomyopathy. Secondary hypertrophic cardiomyopathy most commonly occurs in association with hyperthyroidism.

Idiopathic hypertrophic cardiomyopathy typically occurs in young to middle-aged cats (mean age 6,5 years) and males are more commonly affected.

Pathophysiology

Hypertrophic cardiomyopathy is characterized by symmetrical hypertrophy of the interventricular septum and left ventricular free wall. Occasionally there may be evidence of left ventricular outflow obstruction especially if there is disproportionate hypertrophy of the septum. Partial aortic outflow obstruction may also be caused by anterior motion of the mitral valve during early systole but this appears to be a rare occurrence in feline hypertrophic cardiomyopathy. Indeed, echocardiographic studies have shown that most cats with hypertrophic cardiomyopathy do not have left ventricular outflow gradients and it appears therefore that obstructive hypertrophic cardiomyopathy, as occurs in dogs, is rare in cats.

Left ventricular hypertrophy results in decreased myocardial compliance, interference with normal diastolic filling due to impaired myocardial relaxation, and an increase in left ventricular end-diastolic pressure (despite a normal or often reduced end-diastolic volume). Decreased myocardial compliance may be aggravated by focal or diffuse endocardial fibrous tissue deposition. Pressure overload within the left ventricle may also be associated with mitral valve dysfunction and regurgitation leading to left atrial enlargement.

The decrease in stroke volume ultimately leads to a reduction in cardiac output and decreased coronary perfusion resulting in myocardial ischaemia. Abnormal myocardial handling of calcium may be a factor in the pathogenesis of hypertrophic cardiomyopathy (an increase in intracellular calcium inhibits complete myocardial relaxation which may explain why calcium blocking drugs have been shown to improve diastolic function significantly in affected cats.

More recently, excessive circulating levels of growth hormone has been implicated in the pathogenesis of hypertrophic cardiomyopathy. Cats with acromegaly due to functional pituitary tumours have hypertrophic cardiomyopathy (Q). It has also been shown that non-acromegalic cats with hypertrophic cardiomyopathy have significantly increased levels of growth hormone compared to normal cats and cats with other forms of cardiac disease but whether this is cause or effect is not clear.

Hypertrophic cardiomyopathy: Clinical signs

Recent studies have demonstrated the heterogeneity of feline hypertrophic cardiomyopathy with regard to the wide spectrum of clinical, electrocardiographic, radiographic and echocardiographic features of the disease. Some cases of hypertrophic cardiomyopathy remain asymptomatic until the cat is stressed. The clinical signs of hypertrophic cardiomyopathy are typically those of left-sided congestive heart failure. Bright and others showed that 61 % of cats with hypertrophic cardiomyopathy had a history of respiratory distress characterized by the acute onset of dyspnoea progressing to mouth breathing. Affected cats become lethargic, anorexic and may cough. Occasionally heart sounds may be muffled due to the presence of pleural or pericardial fluid, Clinical examination may reveal diffuse pulmonary crackles and the presence of a gallop rhythm and / or systolic murmur. Other more variable signs include prolonged capillary refill time and pallor or cyanosis of the tongue and mucous membranes- Animals showing severe signs of cardiac failure are often hypothermic with weak femoral pulses. The increased tendency towards thrombus formation may result in acute onset of hindlimb (less frequently forelimb) paralysis or lameness with cold limb extremities (see section on arterial thromboembolism).

Electrocardiography

Almost 70% of cases may be expected to have an abnormal ECG. Abnormalities reported include increased amplitude and width of P and R waves (P waves >0.04 s and >0,2 mV; QRS complexes >0.04 s and R waves >0.9 mV in lead II), arrhythmias (atrial or ventricular premature contractions) and conduction disturbances. Left anterior fascicular bundle branch block, with deep S waves in leads 1, 11 and 111 and left axis deviation, is particularly common.

Radiographic findings

Radiographic abnormalities consisting of mild to moderate left atrial and left ventricular enlargement or biventricular enlargement with evidence of pulmonary venous congestion and / or oedema are present in more than 80% of cases. Biventricular enlargement may lead to elevation of the trachea and increased sternal contact and, on the dorsoventral view, the enlarged atria may result in a ‘valentine-shaped’ heart. Occasionally there may also be radiographic signs of right heart failure (right ventricular enlargement, hepatomegaly and ascites.

Echocardiography

Hypertrophic cardiomyopathy is characterized by symmetric or less frequently asymmetric hypertrophy of the inter-ventricular septum and left ventricular free wall, and enlarged hypertrophied papillary muscles which contribute to a marked reduction in left ventricular internal dimensions. Most cases show evidence of a moderate degree of left atrial dilation and fractional shortening is usually normal or increased. Occasionally there is systolic anterior motion of the septal mitral valve leaflet and Doppler studies may show mitral regurgitation. Mild pericardial effusion may be evident.

Angiocardiography

With the increased use of ultrasound angiocardiography is rarely required. In the absence of ultrasound facilities, non-selective angiocardiography (injection of the contrast agent via the jugular vein) can be used to demonstrate the hypertrophied left ventricle and papillary muscles and regurgitation of contrast into the dilated left atrium. Circulation time is usually normal.

Prognosis of Hypertrophic cardiomyopathy

The prognosis for hypertrophic cardiomyopathy is guarded and other causes of left ventricular hypertrophy such as systemic hypertension, hyperthyroidism, acromegaly, chronic anaemia and congenital subaortic stenosis (rare in the cat) should be excluded. Plasma T3 and T4 concentrations should always be determined even when no thyroid nodules can be palpated in the neck.

Hypertrophic cardiomyopathy: Treatment

Cats presented with severe respiratory distress should be given oxygen and confined to a cage in the first instance. Initially frusemide may be given intravenously or intramuscularly (1-2 mg kg-1 body weight); thereafter it may be given orally at a dose rate of 1 mg kg-1 body weight two or three times daily. One of the main aims of therapy should be to reduce the heart rare to less than ISO beats per minute in order to improve cardiac filling.

Diltiazem not only decreases the heart rate in cats with hypertrophic cardiomyopathy but increases myocardial relaxation, decreases myocardial oxygen demand and dilates the coronary vasculature. It has minimal negative inotropic and peripheral vasodilating properties compared to other calcium blocking agents such as verapamil. A dose of 1.75-2.4 mg kg-1 body weight per os three times daily (mean effective dose 1.78 mg kg-1) has been shown to effectively reduce pulmonary congestion and improve left ventricular filling with no apparent side effects.

Recent work has shown that the survival times of cats with hypertrophic cardiomyopathy may be prolonged with the use of calcium Mocking agents such as diltiazem. About 94% of cats in one study receiving diltiazem survived longer than 6 months. Cats which show no clinical signs on initial presentation and those with heart rates less than 200 beats per minute survive significantly longer than do cats with emboli or congestive heart failure, 60% of which fail to survive 6 months.

Beta-blocking drugs such as propranolol (2,5-5,0 mg per os twice or three limes daily) slow the heart rate and improve diastolic filling. Propranolol is the antidysrhythmic drug of choice for cats but its effects on myocardial compliance in cases of feline hypertrophic cardiomyopathy have not been documented.

Although vasodilators are generally contra-indicated in cats with hypertrophic cardiomyopathy, captopril (3.12-6.20 mg twice or three times daily) may be useful In cases with severe mitral regurgitate on and signs of refractory congestive heart failure.

The administration of digoxin is contraindicated in cats with hypertrophic cardiomyopathy since myocardial contractility is often normal or increased. Aspirin (25 mg kg-1 body weight every 72 h) should be given to minimize the risk of throntboembolic disease although there is no evidence to date to suggest that aspirin, if given prophylactically, decreases the incidence of arterial thrombosis in cats with hypertrophic cardiomyopathy.

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Veterinary Medicine

Hypertension

The methods for measuring blood pressure and reported normal blood pressure measurements in small animals are extremely variable. Blood pressure should be measured with the animal unsedated, relaxed and minimally restrained. Heart rate should be within normal resting limits (an increased heart rate tends to increase the diastolic blood pressure measurement). Direct measurements can be performed by percutaneous puncture of the femoral artery connected to pressure sensing and recording equipment. Non-invasive indirect measurements can be obtained using Doppler ultrasound or, in dogs, oscillometric techniques. Normal direct and indirect measurements for dogs and cats are given in site.

In dogs, hypertension should be suspected if systolic and diastolic measurements greater than 180 mm Hg and 100 mm Hg respectively, are obtained using an indirect Doppler ultrasound technique. In cats, hypertension is defined as sustained systolic and diastolic pressures greater than 170 mm Hg and 100 mm Hg, respectively, using a Doppler technique (Morgan, 1986); systolic / diastolic pressures greater than 200 / 145 should certainly be regarded as abnormal.

Hypertension can be classified as primary (essential) or secondary. Most cases of hypertension in small animals are secondary to other diseases. Regulation of arterial blood pressure depends on the interaction of a number of neural, cardiac, renal and humoral factors which affect cardiac output, plasma volume and vascular tone. Deregulation of these pressor and volume homeostatic mechanisms may initiate a hypertensive state. Activation of the renin-angiotensin-aldosterone system, altered adrenergic activity, and the release of vasopressor substances by the kidney and antidiuretic hormone from the neurohypophysis (the latter in response to increased angiotensin II levels) act together to increase peripheral vascular resistance and retain sodium and water. Increased vascular ‘stiffness’ associated with atherosclerosis and arteriosclerosis may also play a role in creating a hypertensive state.

Primary (essential) hypertension

Spontaneous hypertension has been reported in dogs, including a colony of primary hypertensive dogs bred from two naturally occurring cases. Diagnosis of primary hypertension essentially involves ruling out secondary causes. Since spontaneous hypertension can result in secondary renal changes (glomeruloscterosis) and renal insufficiency, identification of the primary disease process is often extremely difficult. High sodium diets have been implicated in the pathogenesis of primary hypertension. A high sodium diet may be expected to accelerate the disease process if fed to an animal with pre-existing hypertension; it is not clear, however, if a high sodium load alone can result in hypertension.

Secondary hypertension

In the cat, renal disease and hyperthyroidism are both common causes of hypertension. Primary renal disease is the most common cause of hypertension in dogs. Hypertension may also be associated with hypothyroidism, hyperadrenocorticism, diabetes mellitus, phaeochromocytoma, primary hyperaldosteronism, hyperparathyroidism (resulting in hypercaleaemia), acromegaly and hyperoestrogenism. Other potential, but less well documented, causes include polycythaemia, anaemia, renin-producing tumours, coarctation of the aorta, obesity and ageing).

Clinical signs

Hypertension leads to glomerulosclerosis and a loss of functional nephrons. If renal function is already compromised hypertension may accelerate progression towards end-stage renal failure. Hypertension also results in concentric hypertrophy of the left ventricle which predisposes the myocardium to ischaemia and the development of arrhythmias. Hypertensive retinopathy is characterized by choroidal haemorrhage and focal retinal detachments. Some animals present with sudden onset blindness due to complete retinal detachment, papilloedema, intraocular haemorrhage or glaucoma. Neurological signs are usually attributed to cerebral haemorrhage; cerebral infarction associated with atherosclerosis of the cerebral arteries is occasionally seen in dogs with hypothyroidism.

Hypertension: Treatment

The main objective is to identify and treat appropriately the underlying disease (for example renal failure). When a specific disease cannot be identified and primary hypertension is suspected, therapy should be directed against the mechanism responsible for the hypertension, that is an attempt should be made to reduce the circulating blood volume, decrease sympathetic tone and / or inhibit the renin-angiotensin-aldosterone pathway. Suitable therapeutic strategies are summarized below.

Reduce sodium intake to 0.1-0.3% of the diet (10-40 mg kg-1 dry matter). Sodium restriction potentiates the action of antihypertensive drug therapy. Prescription diets are available which fulfil these requirements.

Diuretics. Frusemide has a natriuretic action and can be used in the face of renal failure. Spironolactone is a more appropriate drug for treating hyperaldosteronism.

Beta-adrenergic blocking drugs decrease cardiac output and decrease renin release by blocking the beta receptors on the juxtaglomerular apparatus. Their use is indicated in feline hyperthyroidism where hypertension is due to excessive adrenergic stimulation.

Alpha-adrenergic blocking drugs such as prazosin can be used as balanced vasodilators and can be used safely in animals with renal dysfunction.

Hydralazine is an arterial vasodilator. It lowers blood pressure but does not protect the kidney against glomerulosclerosis. Hydralazine may result in reflex sympathetic stimulation and renin release and therefore may have to be given with beta blockers.

Calcium channel blockers such as verapamil and diltiazem cause vasodilation. Verapamil is a renal vasodilator and may transiently increase glomerular filtration rate.

Angiotensin converting enzyme inhibitors are balanced vasodilators. The decreased production of aldosterone results in increased salt and water excretion. These drugs are nephrotoxic so care should be taken if there is evidence of renal dysfunction.

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Veterinary Medicine

Malformations of the atrioventricular valves

Mitral valve dysplasia

Congenital malformation of the mitral valve leaflets or associated chordae tendineae and papillary muscles is a relatively rare disorder in the dog but is probably the most common congenital cardiac defect reported in the cat. The affected valve cusps are often thickened and incomplete closure of the valve during systole results in regurgitation of blood into the left atrium. Clinical signs of left-sided congestive heart failure develop at an early age (in most cases before 6 months of age). German shepherds, great Danes, bulldogs, bull terriers and chihuahuas appear predisposed with a higher incidence in males.

The pathophysiology and clinical signs of mitral dysplasia are similar to those of severe decompensated acquired mitral insufficiency. A harsh holosystolic murmur is present over the left atrioventricular valve. Electrocardiography shows changes consistent with left atrial and left ventricular enlargement and arrhythmias are common. Radiographic abnormalities include generalized or left-sided cardiomegaly (the left atrium in particular is often markedly enlarged) and pulmonary venous congestion or oedema. Echocardiography may demonstrate thickened or fused mitral valve leaflets and wide excursions of the valve leaflets during systole and diastole. Initially, fractional shortening may increase as the preload increases but eventually chronic volume overload lends to dilation of the left ventricle and a progressive decrease in myocardial contractility.

The prognosis for mitral dysplasia is poor. Medical management of the congestive heart failure in the form of a low salt diet, cardiac glycosides (if myocardial contractility is impaired), diuretics and vasodilators may reduce the volume of the regurgitant fraction and temporarily alleviate the clinical signs. Mitral valve replacement with a biprosthetic valve is possible with cardiopulmonary bypass.

Mitral stenosis

Congenital mitral stenosis occurs infrequently in dogs often in association with subaortic stenosis; Newfoundlands and bull terriers appeared predisposed. A genetic basis may exist in bull terriers.

Mitral stenosis is usually caused by thickening and fusion of the mitral valve leaflets resulting in obstruction to the transmitral flow of blood. A diastolic pressure gradient is created across the mitral valve. Mean left atrial pressure increases resulting in left atrial enlargement and pulmonary venous congestion. Clinical signs include coughing, dyspnoea, exercise intolerance and syncope. Unlike humans where mitral stenosis is usually associated with a low-grade diastolic murmur, dogs with mitral stenosis often have a murmur typical of mitral regurgitation since most dogs develop concurrent mitral insufficiency. Radiographs show pronounced left atrial enlargement. Supraventricular arrhythmias are relatively common and echocardiography reveals abnormal diastolic motion of the mitral valve and thickened valve cusps with poor leaflet separation. Echocardiography may also detect diastolic doming of the septal mitral valve leaflet into the left ventricle in some dogs.

Dogs showing signs of congestive heart failure should be managed medically. Vasodilators and diuretics should be used cautiously since they may lead to hypotension.

Tricuspid valve dysplasia

Tricuspid dysplasia is less common than mitral dysplasia, the highest incidence occurring in male large breed dogs (great Danes. German shepherds. Labrador retrievers and weimaraners appear to be predisposed). In cats, tricuspid dysplasia is the second most common congenital defect next to mitral dysplasia. A harsh, regurgitant holosystolic murmur is present over the trucuspid valve region radiating across to the left side. Tricuspid regurgitation eventually leads to right ventricular volume overload and signs of right-sided congestive heart failure. A jugular pulse may be present in severe cases. An ECG may show changes consistent with right atrial and right ventricular enlargement. Radiographic evidence of tricuspid regurgitation (right-sided cardiomegaly and an enlarged caudal vena cava) is usually present. Echocardiography may show flattened or paradoxical septal motion and can be used to confirm right atrial and right ventricular dilation.

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Veterinary Medicine

Vasodilator drug therapy

The rationale behind using vasodilator drugs in the management of heart failure is to reduce the work load on the failing heart both by decreasing excessive cardiac filling pressures (by reducing preload; venodilation)and by reducing the resistance against which the heart has to work to pump the blood around the circulation (by reducing aftcrload; arterial vasodilation). The use of these drugs is an attempt to restore the balance between vasoconstrictor neurohormonal mechanisms activated by poor cardiac function and the natural vasodilator mechanisms which are reduced in chronic heart failure. The balance is delicate since excessive preload reduction may result in poor cardiac output once the cardiac filling pressure is reduced to the steep part of the cardiac function curve. Excessive afterload reduction may reduce arterial blood pressure to such a level that tissue perfusion is reduced and clinical signs of hypotension result. Vasodilator drugs are classified according to whether they act primarily on arterioles (arteriolar dilators), veins (venodilators) or on both sides of the circulation (balanced dilators).

Arteriolar dilators

Hydralazine has a spasmolytic effect on arteriolar vascular smooth muscle, the precise mechanism of action of which remains unknown. In veterinary medicine it has been most successfully used in the management of dogs with mitral regurgitation. By lowering systemic vascular resistance (arterial dilation) with hydralazine, the aim is to encourage blood to follow the normal pathway from the left ventricle rather than regurgitating through the mitral valve, thus increasing the forward (low through the aorta. Ideally, dogs given hydralazine should he hospitalized and monitored closely. Following oral administration, the onset of action of hydralazine is 30-60 min with peak effect at 3-5 h and duration of effect for 11—13 h. The dose of hydralazine required varies between individual dogs and a starting dose of 0.5 mg kg-1 every 12 h is recommended and this can be increased to effect up to 3 mg kg-1. Effective treatment will result in improvement of mucous membrane colour, capillary refill time and arterial pulse pressure in addition to resolving signs of circulatory congestion. The decrease in arterial blood pressure which occurs with effective treatment is subclinical but may cause reflex activation of the sympathetic nervous system and the renin-angiotensin-aldosterone systems. Combined use of hydralazine with diuretic therapy will prevent excessive sodium and water retention occurring in response to the small tails in arterial blood pressure which occur with effective doses of hydralazine. Weakness, lethargy and tachycardia indicate an excessive decrease in peripheral resistance resulting in clinical hypotension and these signs will occur with overdosage. Some 20-30% of dogs treated with hydralazine show signs of vomiting and anorexia which may be intractable, thus forcing withdrawal of the drug. These side effects may account for the unpopularity of this medication in veterinary medicine.

Venodilator drugs

Organic nitrates are routinely used in human medicine for the treatment of angina, where reduction of venous return and cardiac preload relieves angina attacks by reducing the work and therefore oxygen demand of the ischaemic myocardium. Glyceryl trinitrate (nitroglycerin) Is taken sublingually in human patients to avoid the excessive first pass hepatic metabolism which follows gastrointestinal absorption of the drug. Alternatively, the percutaneous route of administration can be used. This is the route recommended for use in dogs and cats where the drug is applied in ointment form to shaved or hairless areas of skin (gloves should be worn when administering the drug). Dosing is empirical at a rate of 0.5-5 cm every 6—8 h. No pharmacokinetic studies have been performed in dogs or cats to determine the bioavailability of glyceryl trinitrate following percutaneous administration and the efficiency of absorption across dog skin has been questioned. Little information is available concerning the use of the orally active organic nitrate, isosorbide dinitrate in the dog and cat. Continuous use of these drugs in humans results in tolerance.

Balanced vasodilators

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Veterinary Medicine

Potassium-losing diuretics

Frusemide

Frusemide is the only loop diuretic which is licensed for veterinary use. By inhibiting the co-transport of sodium, potassium and chloride ions in the loop of Henle, loop diuretics are the most efficacious diuretics available, being capable of stimulating the loss of up to 20% of the filtered load of sodium ions. Loop diuretics also promote loss of potassium, magnesium and calcium in the urine. Excessive loss of potassium and magnesium may have detrimental consequences for other drug therapies, for example cardiac glycosides and certain antidysrhythmic drugs. Frusemide can be administered orally or parenterally. In cases of severe pulmonary oedema due to left-sided heart failure, the intravenous administration of frusemide (up to 4 mg kg-1) is indicated. Frusemide is thought to have venodilator actions on the pulmonary vasculature which occur more rapidly than its natriuretic effects and these contribute to its therapeutic action in the management of cardio genie pulmonary oedema. Following intravenous administration, the onset of action of frusemide peaks at 30 min and returns to baseline within 2-3 h. When administered orally, the absorption of frusemide from the intestine can be variable in terms of rate and extent. This may be affected by the formulation of the preparation, the individual animal and the degree of congestion in the intestinal circulation. It is important to recognize that the dose required varies for each individual patient according to its physiological state and to the pharmacological effects of concurrent therapies (vasodilators, dietary salt restriction and other diuretics) which may be employed. In general, cats are more sensitive to frusemide than are dogs and unless lower dosages are used in the cat serious side effects may result.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic which works by interfering with sodium transport in the early distal tubule and is capable of causing excretion of up to 10% of the filtered load of sodium in the urine. Excessive loss of both potassium and magnesium in the urine will occur with thiazide diuretics but they reduce urinary loss of calcium. Hydrochlorothiazide can be administered by intramuscular injection or orally (2-4 mg kg-1). The absorption of orally administered drug will be affected by the state of the intestinal circulation and in cases of refractory right-sided heart failure, parenteral administration may be more successful The duration of action of hydrochlorothiazide is longer than frusemide with effects being evident for up to 12 hours after administration.

Adverse effects of potassium-losing diuretics

Overzealous use of diuretic drugs will lead to a fall in cardiac output and arterial blood pressure due to excessive reduction in cardiac filling pressure. This will lead to clinical signs of dehydration, weakness due to poor muscle perfusion, and azotaemia due to reduced renal blood flow and a consequent decrease in glomerular filtration rate. In addition, particularly in animals which are anorectic, excessive potassium loss in the urine can result in hypokalaemia. This may contribute to the state of muscle weakness, cause gastrointestinal and renal problems, predispose to the development of cardiac arrhythmias and enhance the toxicity of cardiac glycosides. Monitoring plasma potassium and urea concentrations in animals on diuretic therapy is good clinical practice as it allows early correction of hypokalaemia and prerenal azotaemia. Hypo-magnesaemia may contribute to the adverse effects of loop and thiazide diuretics although less information is available from veterinary patients. The animals most susceptible to these problems are cats which are often anorectic and azotaemic on presentation and become dehydrated very rapidly when challenged with potent diuretics (particularly frusemide). Provided appetite remains reasonably good, diuretic-induced hypokalaemia is less likely to be significant.

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Veterinary Medicine

Balanced vasodilators

Sodium nitroprusside

Sodium nitroprusside is a potent arteriolar and venodilator drug with a similar mechanism of action to the organic nitrates, h has a very short duration of action and is administered by continuous intravenous infusion starting at an initial infusion rate of 1-5 μg kg-1 min-1. It reduces pulmonary and systemic vascular resistance decreasing ventricular filling pressure and is most useful in the management of acute, life-threatening cardiogenic pulmonary oedema. The dose can be titrated upwards to effect whilst monitoring arterial blood pressure since excessive falls in arterial blood pressure are an indication of overdosage. The effects are reversed within 1-10 min of slowing the infusion rate allowing fine control of the drug’s effects. Since delivery of the drug requires accurate control at a low rate of fluid administration, an infusion pump should be used. In dogs with severe cardiac failure resulting from poor systolic function (dilated cardiomyopathy), a drug providing positive inotropic support (for example dobutamine) is required in addition to sodium nitroprusside, otherwise the reduction in preload caused by venodilation may result in a precipitous fall in cardiac output. Intravenous infusion of sodium nitroprusside should not exceed 48 h since toxic metabolites (thiocyanate) build up in the circulation. Infusions should be stopped gradually rather than abruptly to prevent rebound increases in vascular resistance and cardiac filling pressures.

Prazosin

Prazosin is a balanced vasodilator drug which can be given orally to dogs. It is an alpha1-selective adrenoceptor antagonist which blocks excessive sympathetic stimulation of vascular alpha1-adrenoceptors without affecting the autoinhibition of noradrenaline release by presynaptic alpha2-adrenoceptors. The recommended dosage is 1 mg tid for dogs weighing less than 15 kg and 2 mg tid for dogs weighing more than 15 kg. In humans and experimental animals, although prazosin is very effective initially, with repeated dosing its effects become attenuated, possibly as the renin-angiotensin system assumes greater importance in regulating vascular tone.

Angiotensin converting enzyme inhibitors

Given the effects of angiotensin II which are central to the pathophvsiology of chronic heart failure, the effects of drugs which inhibit the formation of angiotensin II by inhibition of anglotensin converting enzyme (ACE) are predictable. They are balanced vasodilators and will enhance the excretion of sodium and water by reducing circulating levels of aldosterone and ADH; thus they have a potassium-sparing diuretic effect. Angiotensin converting enzyme is also responsible for the breakdown of the natural vasodilator, bradykinin and some of the effects of ACE inhibitors can be attributed to potentiating bradykinin. Their effects on the vasculature are less profound and slower to take effect when compared to hydralazine and nitroprusside, hence these drugs are preferred to the ACE inhibitors when dealing with cases of life-threatening pulmonary oedema due to left-sided heart failure. Indeed, clinical signs may continue to improve for several weeks in human heart failure patients on ACE inhibitors and multicentre controlled clinical trials in veterinary medicine suggest that the same is true in veterinary medicine. Small but significant effects have been demonstrated on survival time of dogs with dilated cardiomyopathy and mitral valvular heart disease treated with enalapril.

Captopril was the first ACE inhibitor to be produced. It contains a sulphydryl group which causes certain side effects which are common to sulphydryl compounds, namely alterations in taste perception, proteinuria and drug-induced blood dyscrasias. The recommended dosage is 0.5-2.0 mg kgr-1 three times daily. Oral absorption is reduced by food. Exceeding the upper limit of this dose gives no further beneficial therapeutic effect but increases the drug’s toxiciry. Angiotensin II may maintain glomerular filtration pressures in the face of poor renal perfusion by constricting the efferent arteriole more than the afferent arteriole. Removal of this protective mechanism may precipitate acute renal failure in some patients with subclinical, pre-existing renal dysfunction. Hence blood plasma urea and creatinine should be determined in animals before and after they are put on ACE inhibitors. As with other vasodilator drugs, hypotension is a possible side effect, particularly if used in combination with high doses of diuretics. In humans. ACE inhibition has been associated with a drug-induced cough.

Enalapril is an ACE inhibitor with significant advantages over captopril. It does not possess a sulphydryl group and so lacks the associated side effects mentioned above. It is a pro-drug, the active form being a metabolite, enalaprilat, formed by the liver. The onset of action is slower than captopril and its duration of effect is longer (12-14 h). Recommended dosing in dogs is 0,5-1.0 mg kg-1 every 12-24 h and in cats is 0,25 mg kg-1 every 12 h. Side effects are those associated with ACE inhibition described above for captopril.

Benazepril is an ACE inhibitor recently licensed for veterinary use. It shares many properties with enalapril, lacking a sulphydryl group and being a pro-drug. In addition, the excretion of the active metabolite from the body occurs both in the bile and the urine. This contrasts with enalapril, which is eliminated in the urine only where dose adjustment may be necessary in animals with significant impairment of renal function. The recommended dose rate of benazepril for the dog is 0.25 to 0.5 mg kg-1 orally every 24 hours. Currently, there is no authorized dose rate for cats.

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Diseases

Canine Heartworm Disease: Complications And Specific Syndromes

Asymptomatic Heartworm Infection

Most dogs with heartworm infection are asymptomatic, even though many of these have heartworm disease (radiographic and pathologic lesions). Treatment is as described previously, using melarsomine in the split-dose regimen, along with a macrolide preventative.

Asymptomatic dogs may, however, become symptomatic af’er adulticidal therapy due to postadulticidal thromboembolization and lung injury (as “described elsewhere). The risk of postadulticidal thromboembolization can be imperfectly predicted by semiquantitation of the worm burden, using certain antigen tests, and by the severity of radiographic lesions. Clearly a dog with severe radiographic lesions will not tolerate thromboembolic complications well, but not all dogs with radiographic signs have heavy worm burdens. For example, a dog with moderate to severe radiographic lesions and high antigenemia may not be at high risk for postadulticidal PTE, because it is quite possible that the worms have died, explaining both the antigenemia (release from dead worms) and radio-graphic abnormalities (chronic HWD).This conclusion might also be valid in the dogs with severe radiographic lesions and negative or low antigenemia (assumes most or all worms have died, and antigen has been cleared). Alternatively, antigenic evidence of a heavy worm burden in a dog with minimal radiographic signs might still portend a severe reaction after melarsomine, because the findings suggest large worm numbers but without natural worm attrition (i.e., a relatively young infection with minimal disease). Of course, low worm burden and minimal radiographic lesions would suggest the least risk of an adverse reaction to adulticide.

It bears emphasis that with each scenario, guesswork is involved and precautions should be taken. When the risk is greatest, aspirin (5 to 7 mg/kg daily — begun 3 weeks prior to and continued until 3 weeks after adulticide) or even heparin may be used, and cage confinement is most important. The owners should be educated as to the risk, the suggestive signs, and the importance of prompt veterinary assistance in case of an adverse reaction.

Glomerulonephritis

The majority of dogs suffering from chronic HWI have glomerulonephritis, which can be severe. Therefore when a dog demonstrates glomerular disease, heartworm infection should be considered as a differential diagnosis. Although it is generally felt that the glomerular lesions produced by heartworm infection are unlikely to produce renal failure, a therapeutic dilemma results when one is found in a dog with proteinuria, azotemia, and HWI. Logic suggests that adulticidal therapy is indicated because heartworm infection contributes to glomerular disease, but it likewise carries risks. The approach embraced by this author is to hospitalize the patient and to administer intravenous fluids (lactated Ringer’s solution at 2 to 3 mL/kg/hr) for 48 hours (beginning 12 hours prior to the first melarsomine dose). The patient is then released, and a recheck appointment for blood urea nitrogen (BUN) and creatinine determination after 48 hours is advised. The second and third injections are tentatively scheduled for 1 to 3 months, with the treatment decision based on renal function and the overall response to initial adulticidal therapy.

Allergic Pneumonitis

Allergic pneumonitis, which is reported to affect 14% of dogs with HWD, is a relatively early development in the disease course. In fact, the pathogenesis probably involves immunologic reaction to dying microfilariae in the pulmonary capillaries. Clinical signs include cough and sometimes dyspnea and other typical signs of HWD, such as weight loss and exercise intolerance. Specific physical examination findings may be absent or may include dyspnea and audible crackles in more severe cases. Radiographic findings include those typical of heartworm disease but with an infiltrate, usually interstitial, but occasionally with an alveolar component, often worse in the caudal lung lobes. Eosinophils and basophils may be found in excess in peripheral blood and in airway samples. Corticosteroid therapy (prednisone or prednisolone at 1 to 2 mg/kg per day) results in rapid attenuation of clinical signs, with radiographic clearing in less than a week. The dose can then be stopped in 3 to 5 days if clinical signs subside. Although microfilaricidal therapy is typically not indicated because infections are often occult, macrolide prophylaxis is indicated to avoid further infection. Adulticidal therapy can be used after clinical improvement.

Eosinophilic Granulomatosis

A more serious, but rare, manifestation, pulmonary eosinophilic granulomatosis, responds less favorably. This syndrome is characterized by a more organized, nodular inflammatory process, associated with bronchial lymphadenopathy and, occasionally, pleural effusion. With pulmonary granulomatosis, cough, wheezes, and pulmonary crackles are often audible; when very severe, lung sounds may be muffled and associated with dyspnea and cyanosis. Treatment with prednisone at twice the dose for allergic pneumonitis is reported to induce partial or complete remission in 1 to 2 weeks. The prognosis remains guarded because recurrence within several weeks is common. Prednisone may be combined with cyclophosphamide or azathioprine in an effort to heighten the immunosuppressive effect. The latter combination appears to be the most effective Adulticide therapy should be delayed until remission is attained. As the prognosis for medical success is guarded; surgical excision of lobar lesions has been advocated.

Pulmonary Embolization

Spontaneous thrombosis or postadulticidal thromboembolization associated with dead and dying worms — the most important heartworm complication — may precipitate or worsen clinical signs, producing or aggravating PHT, right heart failure or, in rare instances, hemoptysis and pulmonary infarction. Acute fatalities may result from fulminant respiratory failure, exsanguination, DIC, or may be unexplained and sudden (arrhythmia or massive pulmonary embolism). The most common presentation, however, is a sudden onset of lethargy, anorexia, and cough 7 to 10 days after adulticidal therapy — often after failure to restrict exercise. Dyspnea, fever, mucous membrane pallor, and adventitial lung sounds (crackles) may be noted on physical examination. Thoracic radiographs reveal significant pulmonary infiltrates, most severe in the caudal lung lobes.

The degree of worsening, as compared with pretreatment radiographs, is typically dramatic. The infiltrate, typically alveolar, is most severe in the caudal lobes, and occasionally areas of consolidation are noted. Laboratory abnormalities vary with the severity of signs but may include leukocytosis, left shift, monocytosis, eosinophilia, and thrombocytopenia. The degree thrombocytopenia may provide prognostic information.

Medical management of thromboembolic lung disease is largely empiric and somewhat controversial. It is generally agreed that strict cage confinement, oxygen administration via oxygen cage or nasal insufflation (50 to 100 mL/kg), and prednisone (1 mg/kg/day for 3 to 7 days) are indicated in the most severe cases. KMW Some advocate careful fluid therapy (see recommendations for CS), measuring CVP to avoid precipitation of heart failure, to maximize tissue perfusion and combat dehydration. The use of heparin (75 IU/kg subcutaneously three times a day until platelet count has normalized [5 to 7 days]) and aspirin (5 to 7 mg/kg/day) has been advocated y some but remains controversial.

Other therapeutic strategies might include cough suppressants, antibiotics (if fever is unresponsive), and, although speculative at this time, vasodilators (amlodipine, hydralazine, diltiazem). If vasodilatory therapy is used, one must monitor blood pressure because hypotension is a potential side effect. Clinical improvement may be rapid and release from the hospital considered after several days’ treatment. For less severely affected dogs, careful confinement and prednisone at home are often adequate.

Congestive Heart Failure

Right heart failure results from increased right ventricular afterload (secondary to chronic pulmonary arterial disease and thromboemboli with resultant PHT). When severe and chronic, pulmonary hypertension may be complicated by secondary tricuspid regur-gitation and right heart failure. Congestive signs (ascites) are worsened in the face of hypoproteinemia. Calvert suggests that up to 50% of dogs with severe pulmonary vascular complication to heartworm disease will develop heart failure. Clinical signs variably include weight loss, exercise intolerance, ashen mucous membranes with prolonged capillary refill time, ascites, dyspnea, jugular venous distension and pulsation, arrhythmias with pulse deficits, and adventitial lung sounds (crackles and possibly wheezes). Dyspnea may be due to pulmonary infiltrates (PIE or PTE, but not cardiogenic pulmonary edema), abdominal distension, or pleural effusion.

Treatment aims include reduction of signs of congestion, reducing PHT, and increasing cardiac output. This involves dietary, pharmacologic, and procedural interventions. Moderate salt restriction is logical and probably useful in diminishing diuretic needs. This author chooses a diet designed for senior patients or early heart disease, because salt restriction should only be moderate. Diuretics may be useful in preventing recurrence of ascites but are typically not able to mobilize large fluid accumulations effectively. This then requires periodic abdominal or thoracic paracentesis (or both) when discomfort is apparent. Furosemide is typically used at 1 to 4 mg/kg daily, depending on severity and patient response Additional diuretics, which provide a supplemental effect by using differing parts of the nephron, include spironolactone (1 to 2 mg/kg orally twice a day) and chlorothiazide (2 mg/kg orally daily to every other day). The ACE-inhibitors (eg., enalapril, benazepril, lisino-pril, ramipril), by their effect on the renin-angiotensin-aldosterone system, may be of use as mixed vasodilators, in blunting pathologic cardiac remodeling, and in reducing fluid retention, particularly cases of refractory ascites. Adulticide therapy is delayed until clinical improvement is noted. No evidence indicates that digoxin improves survival in HWD. Because of the risk of toxicity and pulmonary vasoconstriction associated with its use, it is not routinely used by is author in the management of HWD-induced heart failure However, digoxin may be beneficial in the presence of supraventricular tachycardia or refractory heart failure Aspirin, theoretically useful because of its ability to ameliorate some pulmonary vascular lesions and vasoconstriction, may be used 5 mg/kg/day orally.

The arterial vasodilator, hydralazine, has been shown by Lombard to improve cardiac output in a small number of dogs with heartworm disease and heart failure. It has also been demonstrated to reduce pulmonary artery pressure and vascular resistance right ventricular work, and aortic pressure without changing cardiac output or heart rate in dogs with experimental heartworm disease (but without heart failure). Clinical experience has shown perceived improvement with the vasodilators diltiazem and amlodipine as well. Research and clinical experience suggest that hydralazine, amlodipine, and diltiazem might have a role in this setting, but further studies are necessary to define their role, if any. In heart failure the author uses hydralazine at 0.5 to 2 mg/kg orally twice a day, diltiazem at 0.5 to 1.5 mg/kg orally three times a day, or amlodipine at 0.1 to 0.25 mg/kg/day orally. The risk of hypotension with these therapies must be realized and blood pressure monitored.

Often heart failure follows adulticidal therapy, but if it is present prior to adulticidal therapy, the difficult question arises as when (or whether) to administer melarsomine. If clinical response to heart failure management is good, adulticidal therapy may be offered in 4 to 12 weeks, as conditions allow. Melarsomine is generally avoided if heart failure is refractory. Antiarrhythmic therapy is seldom necessary, although slowing the ventricular response to atrial fibrillation with digoxin, Diltiazem, or both () may be necessary in some cases.

Caval Syndrome

Heartworm CS is a relatively uncommon but severe variant or complication of HWD. Most studies have shown a marked sex predilection, with 75% to 90% of CS dogs being male. It is characterized by heavy worm burden (usually >60, with the majority of the worms residing in the right atrium and venae cavae) and a poor prognosis.

Studies performed in the author’s laboratory indicate that retrograde migration of adult heartworms to the cavae and right atrium, from 5 to 17 months after infection, produces partial inflow obstruction to the right heart and, by interfering with the valve apparatus, tricuspid insufficiency (with resultant systolic murmur, jugular pulse, and CVP increase). Affected dogs also exhibit pre-existent heartworm-induced PHT, which markedly increases the adverse hemodynamic effects of tricuspid regurgitation. These combined effects substantially reduce left ventricular preload and hence cardiac output. Cardiac arrhythmias may further compromise cardiac function.

This constellation of events precipitates a sudden onset of clinical signs, including hemolytic anemia caused by trauma to red blood cells (RBCs) as they pass through a sieve of heart-worms occupying the right atrium and venae cavae, as well as through fibrin strands in capillaries if disseminated intravascular coagulation has developed. Intravascular hemolysis, metabolic acidosis, and diminished hepatic function with impaired removal of circulating pro-coagulants contribute to the development of DIC. The effect of this traumatic insult to the erythron is magnified by increased RBC fragility, due to alterations in the RBC membrane in dogs with HWD. Hemoglobinemia, hemoglobinuria, and hepatic and renal dysfunction also are observed in many dogs. The cause of hepatorenal dysfunction is not clear, but it probably results from the combined effects of passive congestion, diminished perfusion, and the deleterious effects of the products of hemolysis. Without treatment, death frequently ensues within 24 to 72 hours due to cardiogenic shock, complicated by anemia, metabolic acidosis, and DIC.

A sudden onset of anorexia, depression, weakness, and occasionally coughing are accompanied in most dogs by dyspnea and hemoglobinuria. Hemoglobinuria has been considered pathognomonic for this syndrome. Physical examination reveals mucous membrane pallor, prolonged capillary refill time, weak pulses, jugular distension and pulsation, hepatosplenomegaly, and dyspnea. Thoracic auscultation may disclose adventitial lung sounds; a systolic heart murmur of tricuspid insufficiency (87% of cases); loud, split S2 (67%); and cardiac gallop (20%). Other reported findings include ascites (29%), jaundice (19%), and hemoptysis (6%). Body temperature varies from subnormal to mildly elevated.

Hemoglobinemia and microfilaremia are present in 85% of dogs suffering from CS. Moderate (mean PCV, 28%) regenerative anemia characterized by the presence of reticulocytes, nucleated RBC, and increased mean corpuscular volume (MCV) is seen in the majority of cases. This normochromic, macrocytic anemia has been associated with the presence of target cells, schistocytes, spur cells, and spherocytes. Leukocytosis (mean white blood cell (WBC] count, approximately 20,000 cells/cm) with neutrophilia, eosinophilia, and left shift has been described. Dogs affected with disseminated intravascular coagulation are characterized by the presence of thrombocytopenia and hypofibrinoginemia, as well as prolonged one stage prothrombin time (PT), partial thromboplastin time (PTT), activated coagulation time (ACT), and high fibrin degradation product concentrations. Serum chemistry analysis reveals increases in liver enzymes, bilirubin, and indices of renal function. Urine analysis reveals high bilirubin and protein concentrations in 50% of cases and more frequently, hemoglobinuria.

CVP is high in 80% to 90% of cases (mean, 11.4 cm H20). Electrocardiographic abnormalities include sinus tachycardia in 33% of cases and atrial and ventricular premature complexes in 28% and 6%, respectively. The mean electrical axis tends to rotate rightward (mean, +129 degrees), with an S1,2,3 pattern evident in 38% of cases. The S wave depth in CV6LU (V<) is the most reliable indicator of right ventricular enlargement (>0.8 mv) in 56% of cases. Thoracic radiography reveals signs of severe heartworm disease with cardiomegaly, main pulmonary arterial enlargement, increased pulmonary vascularity, and pulmonary arterial tortuousity recognized in descending order of frequency (). Massive worm inhabitation of the right atrium with movement into the right ventricle during diastole is evident echocardiographically. This finding on M-mode and two-dimensional echocardiograms is nearly pathognomonic for CS in the appropriate clinical setting. The right ventricular lumen is enlarged and the left diminished in size, suggesting pulmonary hypertension accompanied by reduced left ventricular loading. Paradoxical septal motion, caused by high right ventricular pressure, is commonly observed. No echocardiographic evidence of left ventricular dysfunction exists. Cardiac catheterization documents pulmonary, right atrial, and right ventricular hypertension and reduced cardiac output.

Prognosis is poor unless the cause of the crisis — the right atrial and caval heartworms — is removed. Even with this treatment, mortality can approximate 40%.

Fluid therapy is needed to improve cardiac output and tissue perfusion, to prevent or help to reverse DIC, to prevent hemoglobin nephropathy, and to aid in the correction of metabolic acidosis. Overexuberant fluid therapy, however, may worsen or precipitate signs of congestive heart failure. In the author’s clinic, a left jugular catheter is placed and intravenous fluid therapy instituted with 5% dextrose in water or one-half strength saline and 2.5% dextrose. The catheter should not enter the anterior vena cava because it will interfere with worm embolectomy. A cephalic catheter may be substituted for the somewhat inconvenient jugular catheter, but this does not allow monitoring of CVP. The intravenous infusion rate for fluids is dependent on the condition of the animal. A useful guideline is to infuse as rapidly as possible (up to 1 cardiovascular volume during the first hour) without raising the CVP or without raising it above 10 cm H20 if it was normal or near normal at the outset. Initial therapy should be aggressive (10 to 20 mL/kg/hr for the first hour) if shock is accompanied by a normal CVP (<5 cm HzO), and it should be curtailed to approximately 1 to 2 mL/kg/hr if CVP is 10 to 20 cm HzO. Whole blood transfusion is not indicated in most cases because anemia usually is not severe, and transfused coagulation factors may worsen DIG Sodium bicarbonate is not indicated unless metabolic acidosis is severe (pH, 7.15 to 7.20). Broad-spectrum antibiotics and aspirin (5 mg/kg daily) should be administered. Treatment for disseminated intravascular coagulation is described elsewhere in this text.

The technique for surgical removal of caval and atria] heartworms was developed by Jackson and colleagues. This procedure should be undertaken as early in the course of therapy as is practical. Often, sedation is unnecessary, and the procedure can be accomplished with only local anesthesia. The dog is restrained in left lateral recumbency after surgical clipping and preparation. The jugular vein is isolated distally. A ligature is placed loosely around the cranial aspect of the vein until it is incised, after which the ligature is tied. Alligator forceps (20 to 40 cm, preferably of small diameter) are guided gently down the vein while being held loosely between the thumb and forefinger. The jugular vein can be temporarily occluded with umbilical tape. If difficulty is encountered in passage of the forceps, gentle manipulation of the dog by assistants to further extend the neck will assist in passage of the forceps past the thoracic inlet; medial direction of the forceps may be necessary at the base of the heart. Once the forceps have been placed, the jaws are opened, the forceps are advanced slightly, the jaws are closed, and the worms are removed. One to four worms are usually removed with each pass. This process is repeated until five to six successive attempts are unsuccessful. An effort should be made to remove 35 to 50 worms. Care should be taken not to fracture heartworm during extraction. After worm removal, the jugular vein is ligated distally, and subcutaneous and skin sutures are placed routinely. Other catheters, such as urethral stone basket catheters, horsehair brushes, snares and flexible alligator forceps have also been used. Fluoroscopic guidance, when available, is useful in this procedure.

Successful worm retrieval is associated with a reduction in the intensity of the cardiac murmur and jugular pulsations, rapid clearing of hemoglobinemia and hemoglobinuria, and normalization of serum enzymatic aberrations. Immediate and latent improvement in cardiac function occurs over the next 24 hours. It is important to realize that removal of worms does nothing to reduce right ventricular afterload (PHT), and hence fluid therapy must be monitored carefully before and after surgery to avoid precipitation or worsening of right heart failure. Cage rest should be enforced for a period of time suitable for individual care.

Worm embolectomy through a jugular venotomy is frequently successful in stabilizing the animal, allowing adulticide therapy to be instituted to destroy remaining heartworms in a minimum of 1 month. Careful scrutiny of BUN and serum liver enzyme concentrations should precede the latter treatment. Aspirin therapy is continued for 3 to 4 weeks after adulticide therapy. Substantial improvement in anemia should not be expected for 2 to 4 weeks after worm embolectomy. Macrolide preventative therapy, as described previously, is administered at the time of release from the hospital.

Aberrant Migration

Although heartworms in the dog typically inhabit the pulmonary arteries of the caudal lung lobes, they may find their way to the right ventricle, and rarely (see Caval Syndrome) the right atria and venae cavae. Much less frequently, immature L5 may aberrantly migrate to other sites, including the brain, spinal cord, epidural space, anterior chamber of the eye, the vitreous, the subcutis, and the peritoneal cavity. In addition, the worms may inhabit the systemic circulation, producing systemic thromboembolic disease. Treatment of aberrantly migrating heartworms requires either nothing (e.g., peritoneal cavity), surgical excision of the offending parasite, adulticidal therapy, or symptomatic treatment (e.g., seizure control with brain migration). The method for surgical removal from internal iliac and femoral arteries has been described.

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Diseases

Management of Chronic Mitral Valve Insufficiency

Ideally, therapy of chronic mitral valve insufficiency would halt the progression of the valvular degeneration. Improvement of valvular function by surgical repair or valve replacement would likewise stop further deterioration. However, no therapy is currently known to inhibit or prevent the valvular degeneration, and surgery is usually not technically, economically, or ethically possible in canine and feline patients. The management of chronic mitral valve insufficiency is therefore concerned with improving quality of life, by ameliorating the clinical signs and improving survival. This usually means that therapy is tailored for the individual patient, owner, and practitioner and often involves concurrent treatment with two or more drugs once signs of heart failure are evident. Management of chronic mitral valve insufficiency will be discussed in five groups of patients: those without overt signs of heart failure (asymptomatic), those with left mainstem bronchial compression, those with syncope, those with mild to moderate heart failure, those with recurrent heart failure, and those with severe and fulminant heart failure. Possible complications are discussed separately. It is unusual to treat cases of isolated chronic mitral valve insufficiency in cats and details of drug dosages for cats are therefore not included in this section.

Asymptomatic Disease

The stage when a patient starts to show clinical signs of chronic mitral valve insufficiency (CMVI), that is, have developed decompensated heart failure, is the end of a process started much earlier with the onset of valve leakage. The valvular leakage was compensated through a variety of mechanisms but as the leakage increases the valves eventually became incapable of preventing pulmonary capillary pressures from exceeding the threshold for pulmonary edema, and of maintaining forward cardiac output. It is likely that minor signs of reduced activity and mobility are present even before overt signs of heart failure develop. However, it is very difficult to objectively evaluate the presence of slight to moderately reduced exercise capacity in most dogs with chronic mitral valve insufficiency (CMVI), as they are often old small companion dogs, which if obese, have little, if any, demand on their exercise capacity. Furthermore, other concurrent diseases in the locomotor system or elsewhere are common and restrict exercise. Thus vague clinical signs such as slightly reduced exercise capacity in a typical dog with progressed chronic mitral valve insufficiency may or may not be attributable to chronic mitral valve insufficiency (CMVI).

This dilemma leads to the questions of when to start therapy, and if therapy before the onset of decompensated heart failure is beneficial, ineffective, or harmful. ACE-inhibitors are frequently prescribed to dogs with chronic mitral valve insufficiency before the onset on heart failure. At present, however, there is no evidence that administration of any medication to a patient with asymptomatic chronic mitral valve insufficiency has a preventive effect on development and progression of clinical signs of heart failure or improves survival. Two large placebo-controlled multicenter trials, the SVEP and the VetProof trials, have been conducted to study the effect of monotherapy of the ACE-inhibitor enalapril on the progression of clinical signs in asymptomatic chronic mitral valve insufficiency in dogs. Both failed to show a significant difference between the placebo and the treatment groups in time from onset of therapy to confirmed congestive heart failure.H’ The two trials differ in the following features: the SVEP trial included

only dogs of one breed (Cavalier King Charles spaniels) whereas the VetProof trial included a variety of breeds. The dogs in the VetProof trial were more frequently progressed cases of chronic mitral valve insufficiency than the dogs in the SVEP trial, and the SVEP trial comprised more dogs than the VetProof trial (229 versus 139 dogs). Suggested reasons for the non-significant findings in these trials include lack of activation of circulating RAAS activity in asymptomatic animals, low concentration of angiotensin II receptors in the canine mitral valve, or lack of effect of ACE-inhibitors on myocardial remodeling and progressive ventricular dilatation in mitral regurgitation (MR).

Owners of dogs with progressed asymptomatic chronic mitral valve insufficiency should be instructed about signs of developing heart failure and, in case of breeding, about the fact that the disease is significantly influenced by genetic factors. The disease may be monitored at regular intervals of 3 to 12 months if significant cardiomegaly is present. Milder cases do not warrant frequent monitoring (see Significance and Progression). Frequently asked questions from owners of dogs with asymptomatic chronic mitral valve insufficiency are if exercise should be restricted and if dietary measures should be instituted. At present there is little evidence-based information concerning the effects of exercise or diet on the progression of chronic mitral valve insufficiency in dogs. Dogs with mild chronic mitral valve insufficiency do not need any dietary or exercise restriction. However, from the pathophysiologic standpoint, strenuous exercise or diets with high sodium content should be avoided in progressed chronic mitral valve insufficiency as this may promote pulmonary edema. Furthermore, it is the authors’ experience that dogs with advanced asymptomatic chronic mitral valve insufficiency usually tolerate comparably long walks at their own pace and do better if obesity is avoided.

Patients with Left Mainstem Bronchial Compression Without Pulmonary Congestion and Edema

Severe left artial enlargement may produce coughing even in the absence of pulmonary congestion and edema by compression of the left mainstem bronchi, which may be identified on the lateral radiograph. With significant coughing, therapy is aimed at suppression of the cough reflex or reduction of the influence of the underlying cause for the compression, the left atrial enlargement. Cough suppressants such as butorphanol (0.55 to 1.1 mg/kg q6-12h PO), hydrocodone bitartrate (0.22 mg/kg q4-8h PO), or dextromethorphan (0.5 to 2 mg/kg q6-8h PO) may alleviate the coughing in some cases. Dogs with evidence of concurrent tracheal instability or chronic small airway disease may improve with a bronchodilator, or a brief course of glucocorticoids. Different xanthine derivatives, such as aminophylline (8 to 11 mg/kg q6-8h) and theophylline (Theo-Dur (sustained duration) 20 mg/kg q12h PO, Detriphylline (Choledyl) (sustained action) 25 to 30 mg/kg q12h PO), are commonly used bronchodilators, although the efficacy of these drugs varies considerably between individuals. Beta 2-receptor agonists such as terbutaline and albuterol should be used with caution in chronic mitral valve insufficiency dogs, as these drugs may produce unwanted elevation in heart rate and contractility as a consequence of myocardial beta 2-receptor stimulation. A reduction of left atrial size may be obtained either by reduction of the regurgitation or by reduction of pulmonary venous pressure. Regurgitation can be decreased by reducing aortic impedance with an arterial dilator or by contracting blood volume with a diuretic.

ACE-inhibitors or a directly acting arterial vasodilator, such as hydralazine, may reduce systemic arterial resistance. The ACE-inhibitors are substantially weaker arterial vasodilators than hydralazine. Side effects of ACE-inhibitors are infrequent, but monitoring of renal function and serum electrolytes, particularly potassium, may be indicated.

Hydralazine has been widely used in patients with chronic mitral valve insufficiency at an initial dosage of 0.5 mg/kg every 12 hours PO. The dosage is increased at daily to weekly intervals to an appropriate maintenance dose of 1 to 2 mg/kg every 12 hours PO, or until hypotension develops, detected either by blood pressure measurements or by clinical signs. Clinical hypotension is defined as a mean arterial blood pressure of less than 50 to 60 mm Hg or a systolic blood pressure below 90 mm Hg. Reflex tachycardia may develop in response to hypotension, and gastrointestinal problems are sometimes observed. In tachycardia, digoxin may be considered in order to limit the resting heart rate. As a consequence of hypotension, hydralazine may induce fluid retention and thereby is needed in the form of a diuretic. Patients that receive hydralazine should routinely be monitored, including having the owner check the heart rate at home and having renal function assessed periodically. Diuretic mono-therapy may be considered to decrease the mitral regurgitation by contracting the blood volume and thereby the left ventricular size. However, diuretics activate the renin-angiotensin-aldosterone system (RAAS), and in the long term may cause electrolyte disturbances. Accordingly, these drugs are often reserved for patients with signs of pulmonary congestion and edema or patients in which cough suppressants, glucocortocoids, and vasodilators have failed to alleviate clinical signs.

Patients with Syncopes but Without Pulmonary Congestion and Edema

With advancing chronic mitral valve insufficiency it is not uncommon that episodes of syncope develop in otherwise asymptomatic dogs (see Clinical Signs). These episodes vary in frequency from isolated to multiple events every day. In dogs with chronic mitral valve insufficiency with syncope, it is important to ascertain that the patient is actually fainting and not suffering from neurologic or metabolic disease. Furthermore, it is important to rule out the presence of congestive heart failure or a bradyarrhythmia such as third degree AV-block or a tachyarrhythmia such as atrial fibrillation. Although ventricular tachyarrhythmias do occur in dogs with advanced chronic mitral valve insufficiency (CMVI), supraventricular tachyarrhythmia is far more common. Typically, the 24-hour (Holter) ECG shows episodes of a rapid supraventricular rhythm immediately followed by a bradycardia during which the dog faints. Management of these dogs often includes digoxin to control the supraventricular tachyarrhythmia. In fact, the frequency of syncopes may often be controlled at lower doses, such as 50%, of digoxin than the recommended dose (which is 0.22 mg/m2 q12h PO).The place for beta-blockers in controlling episodes of fainting in chronic mitral valve insufficiency dogs is not clear. Reports indicate positive results of carvedilol in some dogs. However, beta-blockers may reduce myocardial performance and some chronic mitral valve insufficiency dogs do not tolerate this type of therapy.

Patients Unth Pulmonary Edema Secondary To Chronic Mitral Valve Insufficiency

Considering the pathophysiology of chronic mitral valve insufficiency (CMVI), therapy should be directed toward (1) reduction of the venous pressures to alleviate edema and effusions, (2) maintainance of adequate cardiac output to prevent signs of weakness, lethargy and prerenal azotemia, (3) reduction of the cardiac workload and regurgitation, and (4) protection of the heart from negative long-term effects of neurohormones. Cases with mild pulmonary edema may be managed on an outpatient basis with regular re-examinations. Cases with moderate to severe pulmonary edema may need intensive care, including cage-rest and sometimes oxygen supplementation.

Mild to Moderate Heart Failure

Patients with mild to moderate heart failure usually present with cough, tachypnea, and dyspnea. It is not common for an untreated dog in congestive heart failure to present initially with isolated significant ascites. Signs of congestive heart failure are usually present on thoracic radiographs as pulmonary venous congestion and increased pulmonary opacity. In some cases, it may be difficult to appreciate mild edema owing to obesity, chest conformation, underinflated lungs, or presence of age-related changes. Radiographs from the patient obtained before the onset of clinical signs may be helpful for comparison. Dogs with mild to moderate heart failure should be treated. Treatment can often be managed on an outpatient basis and should include a diuretic, such as furosemide, and an ACE-inhibitor. The place of digoxin and other positive inotropes are more controversial for treating dogs with mild to moderate heart failure (see below). The dosage of furosemide should preferably be based on clinical signs rather than radiographic findings. A patient may breathe with ease even in the presence of radiologic signs of interstitial edema, or vice versa. The usual course of treatment of a case with mild to moderate heart failure is an initial intensive treatment with furosemide (2 to 4 mg/kg q8-12h) for 2 to 3 days, after which the dosage of the diuretic is decreased to a maintenance level, such as 1 to 2 mg/kg every 12 to 48 hours or lower. More severe cases of heart failure may require higher dosages. It is important to use an appropriate dosage of diuretic to relieve clinical signs but to avoid an unnecessarily high maintenance dosage. Overzealous use of diuretics may lead to weakness, hypotension, syncope, aggravation of prerenal azotemia, and acid-base and electrolyte imbalances. Often the owner can be instructed to vary the dosage, within a fixed dose range, according to the need of the dog.

The dosage of ACE-inhibitor (e.g., enalapril, benazepril, lisinopril, ramipril, and imidapril) is usually fixed and depends on the specific ACE-inhibitor used. ACE-inhibitors are indicated in advanced chronic mitral valve insufficiency with heart failure in combination with diuretics, because dogs in large placebo-controlled clinical trials receiving an ACE-inhibitor have been shown to have less severe clinical signs of disease, better exercise tolerance, and live longer than those not receiving an ACE-inhibitor. In the dose range that is recommended for use in dogs and cats, the vasodilating actions of the drugs are not prominent and side effects associated with hypotension, such as fainting and syncope, are rare. A reason for this may be that the short-term effects of ACE-inhibitors on the circulation are dependent on the activity of the RAAS prior to administration of the drug, the higher activity the more pronounced effect of the drug. In combination with diuretics, such as furosemide, the ACE-inhibitors have synergistic effect with the diuretic by counteracting the reflectory stimulation of RAAS that occurs in diuretic therapy. Thus they decrease the tendency for fluid retention and counteract a peripheral vaso-constriction and other negative effects on the heart.

Digoxin is controversial in treating dogs with chronic mitral valve insufficiency (CMVI). There is generally a lack of scientific evidence supporting the use of digoxin. Many cardiologists, however, initiate digoxin therapy when signs of heart failure first appear. Although digoxin is a comparably weak positive inotrope and myocardial failure may not be a prominent feature of chronic mitral valve insufficiency until progressed stages, digoxin has a place in heart failure therapy by reducing reflex tachycardia, by normalizing baroreceptor activity and by reducing central sympathetic activity. Thus digoxin may be useful to reduce the heart rate, such as when hydralazine is administered, or in supraventricular tachycardia such as atrial fibrillation, and to abolish or limit the frequency of syncope (see above).

The place for a positive inotrope in the management of chronic mitral valve insufficiency is controversial, since in small dogs signs of left-side heart failure usually precede overt myocardial failure. Nevertheless, the combined calcium sensitizer/PDE III inhibitor pimobendan is now approved for veterinary use in dogs with dilated cardiomyopathy and chronic mitral valve insufficiency in many European countries, Canada, and Australia at a dose of 0.25 mg/kg every 12 hours PO. Data from controlled clinical trials of pimobendan in veterinary patients is available, although its efficacy is less documented in chronic mitral valve insufficiency than in DCM. Recendy, two controlled clinical trials (the PITCH trial and a recendy completed study from UK) were presented (unpublished), The results indicate that dogs with chronic mitral valve insufficiency receiving pimobendan as adjunct therapy to diuretics show less severe signs of heart failure and are less likely to die or reach the treatment failure end-point than those receiving an ACE-inhibitor and diuretics. Many practitioners using pimobendan have experienced a dramatic improvement in overall clinical status in some CVMI dogs, even in dogs without overt myocardial failure. The reason for this may be that pimobendan, in addition to being a positive inotrope, has arterial vasodilating properties and differs from the pure phosphodiesterase III antagonists (such as milrinone) in that it increases myocardial contractility with minimal increase in myocardial energy consumption. Furthermore, positive inotropes may theoretically reduce the mitral regurgitation by decreasing the size of the left ventricle and the mitral valve annulus through a more complete emptying of the left ventricle. However, the increased contractility may also theoretically lead to an increased systolic pressure gradient across the mitral valve and thereby generate increased regur-gitation in some cases with high peripheral vascular resistance and increase the risk for chordal rupture in affected dogs. Therefore some cardiologists initiate pimobendan as adjunct therapy to other heart failure treatment in chronic mitral valve insufficiency dogs only when echocardiographic evidence of reduced myocardial performance (increased left ventricular end-systolic dimension) is evident. Whether or not this treatment strategy is the optimal use of calcium sensitizers has not been evaluated. Some cases of chronic mitral valve insufficiency with evidence of myocardial failure have evidence of disseminated myocardial micro-infarctions, most commonly as a consequence of widespread arteriosclerosis. Some of these patients might benefit from prophylactic antithrombotic and antiplatelelet therapy, although this has not been evaluated in veterinary medicine.

The way dogs with mild to moderate heart failure are managed after initiation of therapy varies. Typically, the dog is re-examined after 1 to 2 weeks of therapy, if the dog is managed on an outpatient basis, to monitor therapeutic outcome and to establish a suitable maintenance dosage of diuretic. Should the treatment response be satisfactory after this visit, dogs may often be managed by phone contacts and re-examinations every 3 to 6 months. More severe cases may require more frequent monitoring of the disease. In areas with a seasonal climate it may be valuable to re-examine the dog before the temperature increases and instruct the owner to avoid high ambient temperatures. The use of low-sodium diets as complementary therapy in heart failure is controversial. Currently, there are no clinical studies to support that they are beneficial in managing heart failure in dogs and cats. However, dogs with symptomatic chronic mitral valve insufficiency should avoid excessive intake of sodium. Dogs that are stable on their heart failure therapy usually tolerate walks at their own pace, but strenuous exercise should be avoided.

Recurrent Heart Failure

Once an appropriate maintenance dosage of furosemide has been set in a chronic mitral valve insufficiency patient with decompensated heart failure, the dosage has to be gradually increased, often over weeks or years. Reasons for increasing the dosage often include recurrent dyspnea caused by pulmonary edema or the development of ascites. Severe ascites, which compromises respiration, may require abdominocentesis. Many chronic mitral valve insufficiency cases with less severe ascites respond to an increased dose of diuretics. Even in case of abdominocentesis, the diuretic dosage should be increased as the ascites will re-occur without changed medication after evacuation. When the dosage of furosemide has reached a level of approximately 4 to 5 mg/kg every 8 to 12 hours, sequential blocking of the nephron should be considered by adding another diuretic. The drug of choice is spironolactone (1 to 3 mg q12-24h PO) which is an aldosterone antagonist and a potassium-sparing diuretic. A thiazide, such as hydrochlorothiazide (2 to 4 mg/kg q12h PO), or triamterene (1 to 2 mg/kg q12h PO) or amiloride (0.1 to 0.3 mg/kg q24h PO), may also be considered. The documentation of triamterene and amiloride in veterinary medicine is limited.

Because the furosemide treatment precedes and is used concomitantly with these drugs, the risk of hyperkalemia is low, even when they are added to a patient that is currently treated with an ACE-inhibitor. The risk of inducing prerenal azotemia, hypotension, and acid-base and electrolyte imbalances increases with the intensity of the diuretic treatment. However, the practitioner usually has to accept some degree of these disturbances when treating a patient with heart failure and, although common, they seldom result in clinical problems. A calcium senzitizer (pimobendan) is often introduced in cases with recurrent heart failure, as echocardiographic evidence of systolic dysfunction often has developed (see above).

Severe and Life-Threatening (Fulminant) Heart Failure

The causes of acute severe heart failure are often a ruptured major tendinous chord, development of atrial fibrillation, undertreatment of existing heart failure, or intense physical activity, such as chasing birds or cats, in the presence of significant chronic mitral valve insufficiency (CMVI). Patients with severe heart failure have radio-graphic evidence of severe interstitial or alveolar edema and have significant clinical signs of heart failure at rest. They are often severely dyspneic and tachypneic and have respiratory rates in the range of 40 to 90. They may cough white or pink froth, which is edema fluid. These dogs require immediate hospitalization and aggressive treatment. However, euthanasia should also be considered, if the dog is already on high doses of diuretics and other heart failure therapy, owing to the poor long-term prognosis. It is important not to stress dogs with severe or fulminant heart failure as stress may lead to death. Therefore thoracic radiographs and other diagnostic procedures may have to wait until the dog has been stabilized.

Dogs with significant dyspnea benefit from intravenous injections of furosemide at a relatively high dose (4 to 6 mg/kg q2-6h IV). The furosemide may be administered intramuscularly should placement of an intravenous catheter not be possible. Dogs with fulminant pulmonary edema may require Herculean furosemide doses at 6 to 8 mg/kg every 2 to 8 hours IV over the first 24 hours. The exact dosage of furosemide depends not only on severity of clinical signs but also on whether or not the dog is already on oral furosemide treatment. Oxygen therapy is always beneficial in hypoxemic patients and it can preferably be administered using an oxygen cage provided that the temperature can be controlled inside the cage. Nasal inflation or a facial mask may also be used provided that the animal accepts them without struggle. Once the dog has received furosemide and oxygen treatment, an arterial vasodilator and a positive inotrope may be considered to stabilize the patient.

Commonly used vasodilating agents are hydralazine per os or intravenous nitroprusside (2.0-10 mg/kg/min). Of these two vasodilators, hydralazine is most commonly used. Owing to the severity of heart failure, dogs without previous vasodilating therapy may receive an initial dose of hydralazine of 1 to 2 mg/kg PO. Titration of the hydralazine dosage as described above is indicated in dogs already on an ACE-inhibitor and blood pressure should be monitored to detect hypotension. Nitroprusside can only be administered as an intravenous infusion, which requires an intravenous catheter. This potent vasodilator has actions on both the venous and arterial circulation. However, it is not easy to control the effects of nitroprusside and the dosage has to be titrated under careful blood-pressure monitoring to avoid serious hypotension and to ensure efficacy. These disadvantages have prevented nitroprusside from being a commonly used arterial vasodilator.

A positive inotrope such as dobutamine, or more commonly the calcium-sensitizer pimobendan (0.25 mg/kg q12h PO), may be considered to stabilize the patient with fulminant heart failure. Pimobendan may be administered together with furosemide without any arterial vasodilator as the drug has vasodilating properties itself The dose of any concurrently administered arterial vasodilator has to be adjusted. Dobutamine is administered as a constant infusion usually in combination with nitroprusside. One problem with dobutamine that limits its use is that the patient needs to be weaned from IV to oral therapy within 1 to 2 days.

Patients with severe or fulminant heart failure need frequent initial monitoring of the respiratory rate because it reflects the clinical response to the furosemide treatment. Significandy decreased respiratory rate within the first hours indicates successful therapy, whereas absence of change indicate that furosemide is required at a higher dose or more frequently. Once the respiratory rate has decreased, the dose of furosemide may be reduced according to the status of the animal and clinical judgment. Abnormal laboratory findings such as pre-renal azotemia, electrolyte imbalances and dehydration are common after high doses of furosemide. Again, these abnormalities are seldom a clinical problem and the laboratory values often tend to shift towards normal with clinical improvement and as the dog starts to eat and drink. Dehydration is usually not severe even after intensive furosemide treatment and intravenous rehydration should be performed slowly and with caution in cases where it is needed, as the volume challenge may produce pulmonary edema.