|
Cardiology Matthew W. Miller, DVM, MS, DACVIM Professor of Cardiology Texas A & M University Feline Cardiomyopathy: Thick Hearts, Thin Hearts and Clots GENERAL INTRODUCTION Dilated Cardiomyopathy (DCM) - is characterized by left and right-sided dilatation, normal coronary arteries, normal (or minimally-diseased) atrioventricular valves, significantly decreased myocardial systolic function. Hypertrophic Cardiomyopathy (HCM) - is characterized by left ventricular and septal concentric hypertrophy with decreased ventricular compliance and dysfunction primarily during diastole; ejection fraction is normal. Systolic dysfunction also can develop when secondary mitral regurgiation (MR) develops. Hypertrophic Obstructive Cardiomyopathy (HOCM) - is characterized by myocardial concentric hypertrophy and obstruction to left ventricular outflow, causing a dynamic subvalvular stenosis. This is related to substantial ventricular septal hypertrophy coupled with abnormal mitral valve position secondary to papillary muscle hypertrophy. Some cats diagnosed with this form of cardiomyopathy may have primary mitral valve malformation (mitral valve dysplasia) rather than a primary myocardial abnormality. Restrictive/Intergrade Cardiomyopathy (RCM/ICM) - are increasingly being recognized and diagnosed in cats. These forms of , causes markedly decreased ventricular compliance caused by myocardial fibrosis. CLINICAL FINDINGS OF FELINE CARDIOMYOPATHY Signalment - Average age, 6 9 years, with a wide range of 6 months to 13 years. Males are affected more commonly with HCM. Cats with restrictive cardiomyopathy tend to be older with an average age at diagnosis of approximately 9-12 years. History - The cat may be asymptomatic or ill. Nonspecific signs of disease: Depression, reluctant to move. Anorexia, Relentless crying (secondary to pain from embolism). Dyspnea or tachypnea. Cough is somewhat unusual in cats with CM. Some cats vomit or retch. Thromboemboli inducing paralysis (usually to the rear limbs),vague neurologic signs, nondescript panful events (abdominal discomfort, muscle pain). Most owners do not notice significant premonitory signs of CHF owing to the fastidious nature of the cat. History of one diet (e.g. "off-brand") taurine deficiency DCM. Physical examination - Mucous membrane (MM) color and capillary refill time (CRT) are typically normal but marked disease especially complicated by pleural effusion, pulmonary edema and marked reductions in cardiac output may lead to abnormalities (cyanotic or pale MM, prolonged CRT). Jugular venous evaluation is commonly overlooked but abnormalities of the jugular veins (distension and/or pulsation provide strong evidence of signifcant cardiovascular disease. Abnormalities of precordial palpation may vary from a markedly increased precordial impulse associated with HCM to a diminshed apical impulse commonnly associated with DCM or pleural/pericardial effusion. It has been suggested that auscultatory abnormalities are present in greater than 80% of cats with clinically significant myocardial disease. Depending on the severity of disease the femoral pulses may range from normal to completely absent ( aortic thrombosis). The detection of pulse deficits suggests the presence of a hemodynamically significant arrhythmia and should prompt the clinician to perform an electrocardiogram. Radiography - There is some overlap between forms of CM, thus a definitive anatomic diagnosis cannot always be made from survey thoracic radiographs. With hypertrophic CM the heart is typically "valentine" in shape with shifting of the apex to the midline, widening across the left atrium, maintenance of the apex "point", and possible evidence of left heart failure (pulmonary venous dilation, pulmonary edema, small pleural effusion. ( Note:cats have a tendency towards more diffuse cardiogenic edema). Echocardiographic examination - Can usually determine the type of cardiomyopathy and give assessment of LA size and LV diameter, wall thickness and systolic and diastolic function (see text box). Echocardiographic Features of Feline Cardiomyopathy
Clinical Pathology: CBC, biochemical profile, urinalysis, pleural effusion analysis Differential Diagnosis: Rule out other causes of dyspnea; paresis, or other causes of cardiac signs (murmur, cardiomegaly, abnormal ECG). Dyspnea/Tachypnea - a common sign of feline CM may be caused by other common disorders: Airway obstruction - foreign body, neoplasm, laryngeal paresis/paralysis, upper respiratory infection (URI). Primary pulmonary disease: bronchial asthma, lungworms, pneumonia, neoplasia, aspiration, vascular disease (heartworms). Mediastinal masses - lymphosarcoma (LSA). Pleural effusions (pyothorax, hemothorax, FIP, lymphosarcoma associated effusions, chylothorax). Trauma: diaphragmatic hernia, pulmonary hemorrhage/edema,pneumothorax. The single most important laboratory test (following ausculation) for evaluation of dyspnea is a thoracic radiograph. One should be intimately familiar with the radiographic features of all of the previously mentioned diseases. If pleural fluid is strongly suspected based on physical examination, a thoracocentesis should be performed prior to obtaining radiographs. Cytologic examination of pleural fluid and ancillary tests (i.e. hemogram, FeLV test, etc.) will usually distinguish pleural effusions due to CM, FIP, LSA, chylothorax and pyothorax. The cat should be re-examined and the radiographs repeated following needle evacuation of the pleural fluid. THERAPY Asymptomatic but High Risk Cardiomyopathies Beta-adrenergic Blockers [propranolol, 2.5 to 5mg q8 - 12h PO; atenolol 6.25 - 12.5mg q12 to 24h PO]decrease mortality in people with acute MI and cardiac arrhythmias, and reduce long term mortality in chronic MI by antiarrhythmic effects and by preventing reinfarction. Sympathetic nervous system antagonists may indirectly improve ventricular compliance by reducing heart rate and myocardial ischemia. Angiotensin-Converting Enzyme (ACE) Inhibitors (Enalapril, 0.5 mg/kg q24h PO; benazepril (0.25-0.5mg/kg q 24h PO: avoid use with hypotension) have been advocated in human post myocardial infarction trials based upon their role in reducing cardiovascular remodeling, improving hemodynamics, reducing ischemic events, and increasing survival. Beta-adrenergic blockers (propranolol, 5 - 10 mg q8 to 12h PO; atenolol, 6.25 - 12.5 mg q12 - 24h PO) antagonize the sympathetic nervous system, and may be useful for treating serious ventricular or supraventriculr tachycardias. While digoxin (0.031 mg [ie, 1/4 of a 0.125 mg tablet] per 4.5 kg cat q 48h PO) or diltiazem may be administered for atrial tachyarrhythmias, heart rate control often requires the addition of a beta-blocker which is titrated to effect. Prognosis may be associated with severe LV hypertrophy in some cats (LVd free wall or interventricular septal thickness > 8 mm). Beta-blockers may be used with the following rationale: 1) heart rate control (negative chronotropism) and associated indirect improvement of diastolic filling; 2) reduction of dynamic LV outflow tract obstruction; 3) reduction in myocardial oxygen utilization; 4) antiarrhythmic effects; 5) ability to blunt sympathetic myocardial stimulation. Clinical reduction of resting heart rate to 120-160 beats/min is usually attainable with atenolol (6.25 - 12.5 mg q 12 - 24h PO) or propranolol (5 - 10 mg q 8 to12h PO) for an average size (4.5 kg) cat. Calcium Channel blockers are often advocated based upon their action to promote positive lusiotropy (ie, to directly improve ventricular diastolic relaxation and filling). Diltiazem may slightly slow the heart rate in some cats but not in others, and heart rate reduction is much weaker compared with beta-blocker therapy. Several preparations of diltiazem are available. Diltiazem hydrochloride comes in 30 mg tablets and is dosed at 7.5 mg q 8 -12h. Cardizem CD© capsules can be compounded and dosed at 10 mg/kg q24h; Dilacor XR is dosed initially at 30 mg/cat q12-24h; some cats may tolerate 60 mg q 12-24h though anorexia and vomiting may occur. (Note: each Dilacor XR 240 mg capsule contains four controlled-released 60 mg tablets which can be broken in half to create a 30 mg dose.) ACE inhibitors may blunt neuroendocrine activation and prevent deleterious cardiovascular remodeling. ACE inhibitors have been used safely, most commonly added to other therapies (Enalapril, 0.25 to 0.5mg/kg q 24h PO). Syncope Recurrent syncope is a risk factor for sudden death in humans with HCM. In cats, syncope can be associated with tachyarrhythmias, dynamic LV outflow obstruction (LVOTO), and ischemia (infarction). Symptoms can often be managed successfully with beta-blockers to reduce or abolish LVOTO. Myocardial Failure In some HCM cats LV contractility is mildly to moderately reduced (e.g., fractional shortening, 23-29%; LV end-systolic dimension, 12-15 mm). This can result from acute or chronic myocardial infarction, myocarditis, and other causes of LV remodeling. Oral taurine supplementation (250 mg q 12 - 24h) is initiated whenever myocardial failure is detected. ACE inhibitors may be added to counteract neurohormonal activation and reduce remodeling. Judicious beta-blocker therapy might be beneficial if myocardial infarction is suspected, or with tachyarrhythmia. Symptomatic Cats with Diastolic Heart Failure Acute Management of CHF Pulmonary edema is rapidly progressive and may become life threatening. Initially, furosemide is administered IV (1- 2 mg/kg) every 1 to 2 hrs until clinical evidence of respiratory embarrassment is substantially reduced. The administration frequency is then reduced, typically to every 8 to 12 hours IM or SC. Peak diuresis usually occurs within 30 minutes of IV administration. Resolution of edema may be enhanced in the first 24 to 36 hours of therapy by adding the preload reducer, 2% nitroglycerin ointment. Cutaneous application of ¼ to ½ inch every 6hours alternating 12 hours on and 12 hours off should provide substantial clinical benefit while reducing the likelihood of developing tolerance. Supplemental oxygen (40 to 60% FiO2) may provide added clinical benefit. Clinical parameters suggestive of improvement include: reduced respiratory rate and effort, reductions in pulmonary crackles and clearing of radiographic pulmonary parenchymal infiltrates. Radiographic evidence of improvement may lag behind clinical improvement sometimes requiring 24-36 hours to completely resolve. The end point of diuretic therapy is relief of clinical signs or progressive increase in BUN and creatinine. Dehydration and hypokalemia can result from overzealous diuresis. Chronic Management of CHF There are currently no data to indicate the most effective therapies, whether combined therapy is more advantageous than monotherapy, or whether therapy is significantly better than no therapy. Drugs are administered on an empirical basis, relying on clinical experiences, biases, and theoretical benefits. Chronic therapy is individualized to eliminate congestion; prevent arterial thromboembolism; halt, slow, or reverse myocardial dysfunction (theoretically); promote enhanced quality of life; and prolong survival. Identifiable co-morbid conditions (systemic hypertension, taurine deficiency, hyperthyroidism, anemia) must also be treated. Diuretics. Furosemide is gradually decreased to the lowest effective dosage, typically, 6.25-12.5 mg q 12 - 24h). Some cats remain stable on 1- 2 mg/kg PO given every other day while in others, diuretics may be used twice weekly or even discontinued. In contrast, upward titration is may be necessary with recurrent CHF. Because diuretic resistance may occur as heart failure progresses, cats with recurrent CHF are likely to benefit acutely from intravenous furosemide which has higher bioavailability, or to administration of two diuretics. (see Recurrent and Refractory Congestive Heart Failure, below). It is prudent to assess BUN, creatinine, electrolytes and blood pressure in anorectic cats. Beta-adrenergic Blockers. Prolonged activation of the sympathetic nervous system may lead to cardiovascular injury, disease progression, or arrhythmias. Since LV diastolic function is very sensitive to increases in sympathetic tone, by decreasing heart rate with beta-blockers, diastole is prolonged and passive ventricular filling and compliance may improve. Prolonged diastolic filling also allows more time for coronary blood flow and reduces myocardial ischemia. Beta-blockers decrease myocardial oxygen requirements by reducing cardiac sympathetic stimulation, heart rate, LV contractility, systolic myocardial wall stress, and systemic blood pressure. Dynamic LV outflow tract obstruction and related pressure gradient is often reduced or abolished with beta-blocker therapy. Propranolol (5 - 10 mg q8 - 12h PO) or atenolol (6.25-12.5 mg q12 - 24h PO) are commonly used agents. Clinically appropriate dosages are suggested by a heart rate in the clinic of 120-150 BPM. Adverse reactions are uncommon but include lethargy or hypotension. Beta-adrenergic blockers should never be administered to patients with overt signe of CHF or in patients with clinical signs consistent with acute thromboembolism. Calcium Channel Blockers. These agents are used to enhance diastolic performance, may reduce heart rate (verapamil much more so than diltiazem) and blood pressure; exert a mild negative inotropic effect (reducing myocardial oxygen consumption); and improve rapid diastolic ventricular filling. Diltiazem is generally ineffective to resolve dynamic LV outflow obstruction. For diltiazem hydrochloride (Cardizem, 1mg/kg tid PO), the reported half life (t1/2) is 113 ± 24 minutes; peak concentration following oral administration was achieved in 45 ± 36 minutes; and bioavailability 50 to 80%. Clinically, this drug is dosed at 7.5 mg tid PO. A long-acting diltiazem formulation is Cardizem CD, 10mg/kg PO q 24h (t1/2 411 ± 59 minutes; peak concentration following oral administration achieved in 340 ± 140 minutes; bioavailability 22 to 59%). Another diltiazem preparation, Dilacor XR, is available in an extended release formulation. Each 240 mg capsules contains four controlled-released 60 mg tablets. Starting dose for a 5kg cat is 30 mg q 24h and titration to 60 mg daily is tolerated in some patients, although vomiting is a side effect. Angiotensin Converting Enzyme (ACE) Inhibitors. Neurohormonal activation plays an important role in heart failure. Thus, disruption of neurohormonal activation represents therapeutic rationale for using ACE inhibitors. The RAAS plays a prominent role in human HCM patients by influencing or regulating the expression of myocardial hypertrophy. Inhibition of RAAS has a beneficial effect on extracellular remodeling in CHF, and ACE inhibitors reduce ventricular remodeling by blocking the tropic effects of angiotensin II on myocytes. There is also survival value provided by early use of ACE inhibitors in acute human myocardial infarction. Many clinicians combine an ACE inhibitor (usually enalapril) with furosemide, with or without a beta-blocker or diltiazem, particularly with recurrent heart failure. Enalapril (0.25-0.5 mg/kg q24h PO) and benazepril (0.25 - 0.5 mg/kg q24h PO) are clinically well tolerated. Optimal timing for ACE inhibitor therapy and the effects of these agents on morbidity and mortality in feline cardiomyopathy is undetermined. Negative inotropic drugs that reduce or eliminate LVOT obstruction have been widely used in humans with the obstructive form of HCM. In cats reduction of outflow gradient is usually best accomplished with beta-blocker therapy. Stimuli that provoke or intensify LV outflow tract gradients should theoretically be avoided including positive inotropes, reduction of LV volume, or decreased afterload. The clinical importance of decreasing obstruction, particularly in asymptomatic cats, has not been established. However, beta-blockers reduce or abolish syncope associated with dynamic LVOT obstruction. Recurrent and Refractory CHF When pulmonary edema or biventricular failure reoccurs, emergency treatment may be required (see above- Acute Pulmonary Edema). Therapy is then modified to either 1) increase the diuretic dose, 2) increase the "primary" drug dose (i.e., beta-blocker, calcium channel blocker, or ACE inhibitor), 3) change to a different class of primary drugs, or 4) add a second or even third primary agent. When CHF recurs in spite of these manipulations, particularly with severe, chronic effusions, further upward dose titration of furosemide (e.g., 2 - 4 mg/kg q 8 - 12h PO) may be required. Probably more effective is selective nephron blockade- the addition of a second diuretic agent which acts at a different site in the nephron (and thus, act synergistically with furosemide). Hydrochlorothiazide (1-2 mg/kg PO q12 - 24h PO) and hydrochlorothiazide-spironolactone (Aldactazide, 2.2 mg/kg/day PO) have proven to be useful as add-on diuretic agents but should not be used as a stand alone diuretic. Close monitoring for dehydration, azotemia, hyponatremia, and hypokalemia is advised. Digitalization may be prescribed for unresponsive right-sided CHF, atrial fibrillation or myocardial (systolic) failure (see below). For continued refractory CHF: 1) ascertain that prescribed drugs are being administered as directed, 2) recalculate drug doses based on current body weight, 3) generate and re-evaluate a new data base (e.g., ECG, radiographs, echocardiogram, clinical pathology) to rule out systemic and metabolic disease, heartworms, neoplasia, 4) assess serum T4 concentrations (cats > 6 years old), and 5) refer to a cardiologist. Systolic (Myocardial) Dysfunction Initial Therapy Initial therapy is directed at reducing to reduce or eliminate pulmonary and systemic venous congestion, promote increased forward cardiac output, control serious tachyarrhythmias or bradyarrhythmias, and improve myocardial contractility. General supportive measures such as thoracocentesis, external heating to combat hypothermia, oxygen administration, and minimization of stress are important and include the following considerations: Thoracocentesis If breathing is compromised by severe pleural effusion (muffled heart and lung sounds, dull thoracic percussion), thoracocentesis is advised, even before radiographs are taken. Acute Pulmonary Edema Life threatening pulmonary edema is uncommon with myocardial failure. When edema is severe, therapy is similar as was discussed above (see Diastolic Failure). Inotropic Support Synthetic sympathomimetic amines possess greater inotropic activity, provide quicker onset of action, and allow finer control than digoxin. Dobutamine (2-10 mg/kg/min constant rate infusion) is the preferred agent for hemodynamic support for severe myocardial failure. A common adverse side effect is seizures which are typically focal-facial, but occasionally become generalized. Often, they do not reoccur when the dose is reduced below 5 mg/kg/min. Taurine Supplementation Although taurine deficiency is now a rare cause of DCM, taurine is inexpensive and safe, and is empirically administered (250 to 500 mg q12h PO) for 8 weeks (re-evaluate by echocardiography). Chronic Maintenance Therapy When congestion is controlled, furosemide is tapered to the lowest effective dose. To manage chronic effusions, upward dose titration (2.2 to 4.2 mg/kg q8 - 12h PO) or sequential nephron blockade (additional diuretic agents such as hydrochlorothiazide and spironolactone) may be effective. Refractory cases may require periodic thoracocentesis. ACE Inhibitors may help blunt adverse neurohormonal alterations, limit progressive cardiac chamber remodeling (dilation), and prevent or delaying clinical deterioration. Enalapril monotherapy (0.5mg/kg PO daily) has been used to successfully manage some cases of mild idiopathic myocardial failure (%FS 23-29%; LVDs 12-14 mm). More severe systolic failure often require the addition of diuretics and digoxin. Thromboembolism Indications for aggressive therapy
The optimal therapy for prevention of initial or recurrent thromboembolic episodes is unknown. Aspirin administered at a dose of 5-25mg/kg PO Q3D has been the standard yet unproven recommendation. Therapy is directed toward 1) managing concomitant CHF or serious arrhythmias when present, 2) general patient support including nutritional supplementation, correction of hypothermia, and prevention of self mutilation, 3) adjunctive therapies to limit thrombus growth or formation, 4) close patient monitoring and 5) thrombus prevention. Limb and/or organ viability is enhanced by rapid resolution of arterial occlusion. Acutely affected cats are a high surgical/anesthesia risk. Various medical treatments have been proposed, although most are empirical and efficacy is unsubstantiated. Pain relief is most critical during the first 24-36 hours. It is also important to maintain hydration, electrolyte balance, and nutritional support. Placement of a nasoesophageal feeding tube is advocated for anorectic cats. Self mutilation is common following a saddle embolus and is characterized by excessive licking or chewing of the toes or lateral hock. Application of a loose-fitting bandage or stockinette is usually effective. Thrombolytic Therapy Streptokinase (loading dose [90,000 IU/cat over 20-30 minutes] followed by a constant rate infusion [45,000 IU/hr for 3 hours]) and urokinase generate the nonspecific proteolytic enzyme, plasmin, through conversion of the protien. Recombinant tissue-type plasminogen activator, t-pa (0.25 to 1.0 mg/kg/hr IV for a total dose of 1 to 10 mg/kg), has a lower affinity for circulating plasminogen and does not induce a systemic fibrinolytic state. It binds to fibrin within the thrombus and converts the entrapped plasminogen to plasmin. This initiates a local fibrinolysis with limited systemic proteolysis. Complications include bleeding and hyperkalemia (70%). Exposure of blood to subendothelial connective tissue leads to rapid platelet activation, formation of platelet plugs and subsequent thrombus. Pharmacologic measures are directed to modify platelet aggregation. Aspirin induces a functional defect in platelets by irreversibly inactivating (through acetylation) cyclo-oxygenase. This enzyme is critical for converting arachidonic acid to thromboxane A2, which in the vascular wall is responsible for converting arachidonic acid to prostacycline. Thromboxane A2 induces platelet activation (through release of platelet adenosine diphosphate) and vasoconstriction (as does serotonin), while prostacycline inhibits platelet aggregation and induces vasodilation. In cats aspirin (25 mg/kg, or 1/4 of a 5-grain tablet q48 - 72h PO) inhibits platelet function for 3 to 5 days and is relatively safe. The optimal dose to inhibit thromboxane A2 production but spare vascular endothelial prostacyclin synthesis is unknown for cats but may be as low as 5 mg/kg PO Q72 H. Valvular Heart Disease Introduction Chronic valve disease (CVD) is the most frequent cause of congestive heart failure in dogs. This condition has also been termed chronic degenerative valvular disease, myxomatous atrioventricular valvular degeneration, chronic valvular fibrosis and endocardiosis. The incidence is reported as being between 11% (clinical determination) and 42% (necropsy determination) depending on the method of examination. The incidence of CVD is increased further, to above 60%, in aged dogs. The mitral valve alone is affected in 60% of dogs with CVD, with the mitral and tricuspid valves both affected in 30% of cases and the tricuspid valve alone in 10% of dogs. The aortic and pulmonic valves may be affected but clinically important disease is uncommon. Signs of mitral valve disease and left-sided cardiac dysfunction predominate in most cases. Signalment The disease is most common in small to medium sized breeds of dogs. Cavalier King Charles Spaniels and Dachshunds are over-represented. CVD also occurs in large breed dogs (i.e., German Shepherd dog, Doberman pinscher), but dilated cardiomyopathy is much more common in these breeds than CVD. The incidence of CVD is increased in male dogs relative to females (1.5 to 1.0). This is a slowly progressive disease in which lesions may begin in the first half of life (e.g., 2 to 3 years), but clinical disease isunlikely before middle age. In the early stages, the only clinical sign may be a cardiac murmur detected on routine examination. Cardiac decompensation and congestive heart failure (CHF) typically occurs in later life (e.g., 6 to 10 years of age or older). Pathology Valve leaflets may be grossly thickened and shortened with curled, nodular margins. There is fibrosis of the valves with an accumulation of acid mucopolysaccharide ground substance. Valvular hemorrhage and calcification may be seen. Chordae tendineae are thickened and may rupture. The disease is primarily a non-inflammatory, myxomatous degeneration of the A-V valve that is commonly referred to as endocardiosis. Many dogs with chronic mitral regurgitation have histologic evidence of small foci of myocardial fibrosis and necrosis, as well as intramural coronary arteriosclerosis (referred to as microscopic intramural myocardial infarction or MIMI). The left ventricle is dilated and hypertrophied if there has been significant volume overload. The left atrium is dilated and, in severe cases, the endocardium may split and rupture creating cardiac tamponade. The onset of congestive heart failure is associated with chronic passive congestion of the lungs (left-sided CHF) or abdominal viscera (right-sided CHF). Pathophysiology Valvular regurgitation results in a volume overload of the associated ventricle. Classic compensatory mechanisms (sympathetic nervous system, renin-angiotensin system, etc.) are activated to restore blood pressure and tissue perfusion towards normal. In compensated mitral regurgitation, cardiac remodeling occurs with ventricular dilatation and left ventricular (LV) wall hypertrophy. The left atrium (LA) is dilated and, as long as the atrium remains compliant enough to accept the regurgitated blood, CHF does not develop. Eventually LA pressure rises and pulmonary edema develops. In the early to middle stages of the disease the LV wall thickness in increased and LV end- diastolic volume is greater than normal, yet the LV contracts down to a normal end-systolic volume (resulting in an increase in fractional shortening). Chronic mitral regurgitation eventually leads to myocardial dysfunction and myocardial failure, which can be manifest by increasing LV end systolic volume or decreasing fractional shortening. Chronic left heart failure leads to pulmonary hypertension, posing added strain to the right heart and contributing to signs of right-sided CHF in dogs with concurrent CVD of the tricuspid valve. There is reasonably good experimental evidence to indicate that dogs with significant mitral regurgitation have more compromise to myocardial systolic function than is evident from the "apparently" good systolic function seen on echocardiography. The leaking mitral valve allows a low pressure "pop-off" which permits a large volume of blood to be pumped into a low pressure chamber, allowing for a high fractional shortening on the echocardiogram despite significant myocardial dysfunction. Clinical Syndromes A wide range of clinical presentations are possible, depending on the degree and duration of valvular dysfunction. Many older dogs presented for routine examination or for other medical problems are identified to have the typical murmur of mitral (MR) or tricuspid (TR) regurgitation. Baseline testing (e.g., radiographs, echocardiography) is often helpful for comparison at subsequent examinations. In many dogs CHF is the cause for initial evaluation with cough, nocturnal dyspnea, altered sleep habits, abdominal distention or exercise intolerance as the presenting complaints. Congestive heart failure may be manifest as pulmonary edema, pleural effusion, or ascites. Acute, fulminant CHF result from rupture of a chorda tendineae or exacerbation of chronic CHF following a stressful or decompensating event (i.e., anesthesia/surgery, high sodium treats/diet, onset of rapid tachyarrhythmia, etc.). In dogs with advanced CVD and mitral regurgitation the LA may become large enough to put pressure on the large airways creating cough due to large airway compression. Tracheal and large airway collapse, concurrent bronchitis, and other respiratory diseases are common in small breed dogs and can contribute to cough, leading to confusion as to the most important cause of cough. Syncope can occur due to significant arrhythmias, cardiac output, or following a coughing spell (e.g., tussive syncope). In the author's experience, syncope occurring at the time of the initial presentation for heart failure usually resolves following resolution of pulmonary edema. Finally, endocardial splitting with left atrial rupture can result in acute collapse due to cardiac tamponade. In these cases, signs of reduced forward blood flow predominate; the lungs can be free of pulmonary edema. History Cough is the most common presenting complaint in dogs with clinical signs resulting from CVD. The cough is often described as a deep, resonant cough or a hacking cough. The cough may occur after exercise or excitement, or it may be more prominent at night. Additional historical complaints can include dyspnea, orthopnea, respiratory distress, reduced exercise tolerance, weight loss (cardiac cachexia), progressive abdominal distention due to right-sided CHF, and syncope. Physical Examination The classic auscultation finding is a systolic cardiac murmur in the typical mitral or tricuspid valve location. An extra systolic sound known as a mid-systolic "click" has been associated with early CVD and mitral valve prolapse. A mid-systolic click is likely the earliest auscultatory finding for CVD, but it can be easily missed or mistaken for a cardiac gallop. There is a tendency for the intensity of the murmur to be roughly correlated with the severity of cardiac dysfunction. The initial murmur of mitral regurgitation may not persist for the entire duration of systole and is localized to the 5th intercostal space at left apex. With increasing disease severity, the murmur becomes holosystolic and more intense, radiating cranially, dorsally, and to the right. When sufficiently intense, the murmur can radiate to the right midthorax, making it difficult to discern the presence of a second murmur due to tricuspid regurgitation. The murmur of tricuspid regurgitation is located on the right hemithorax, roughly midway between the cardiac apex and base. An S3 gallop is commonly heard in dogs with CHF or myocardial failure. Dogs with CHF may have tachypnea, hyperpnea, dyspnea, or orthopnea, and anxiety with a reluctance to lie down. A cough may be elicited by gentle tracheal palpation or may occur unprovoked. Paroxysms of cough may end in swallowing or the production of a white foam; in advanced cases, a blood tinged froth is produced. Mucous membranes are pink in early stages, but may progress to a muddy to somewhat cyanotic color with decompensation and severe left-sided CHF. Pulmonary auscultation may also reveal increased respiratory sounds which progress to crackles with the onset of alveolar edema. The latter may be particularly prominent over the hilar or caudal lung fields on inspiration. Hepatomegaly and ascites may be evident in dogs with right-sided CHF from advanced disease, and in these cases the jugular veins are typically distended and/or exhibit a prominent systolic "V" wave due to the ejection of blood into the RA. The femoral pulses are often easily palpated and prominent, but may exhibit a jerky "collapsing" character due to the abbreviation of LV ejection. Arterial pulses often become weak in animals with advanced CHF or myocardial failure. There may also be irregularities in pulse rate and strength resulting from cardiac arrhythmia. In animals with CHF, the heart rate is usually elevated or in the upper normal range and sinus arrhythmia is typically absent. The ventricular apex beat is hyperdynamic and is progressively shifted caudally from the 5th intercostal space with increasing disease severity. When present, a precordial thrill is also palpated in this region. Thoracic Radiology The earliest finding on thoracic radiographs is left atrial enlargement. On the lateral projection, the left atrium is visualized at the caudodorsal aspect of the cardiac silhouette. The left atrium enlarges progressively with advancing disease. Left atrial and left ventricular enlargement result in elevation of the trachea and carina, with a decrease in the angle made between the trachea and the thoracic spine. The left mainstem bronchus may become elevated (compressed) in cases of marked left atrial enlargement. There is straightening of the caudal cardiac border and loss of the caudal cardiac waist. Pulmonary venous dilation occurs and is often evaluated in the cranial lung fields in this view. Early pulmonary edema is seen as a diffuse increase in interstitial density in the hilar or caudal lung fields, progressing to fluffy densities and air bronchograms with the onset of alveolar edema. With tricuspid regurgitation and right-sided or biventricular CHF, the cranial aspect of the trachea may be elevated and the caudal vena cava will increase in size. Hepatomegaly and splenomegaly may be present. On the DV or VD radiographic projection, the earliest findings in CVD is enlargement of the left atrial appendage, located at the 2 to 3 o'clock position (using the clockface analogy). Left ventricular enlargement leads to rounding of the LV apex, which may be displaced to the left. With progressive enlargement of the left atrium there is an increase in the angle formed by the right and left main stem bronchi (resulting in the bow-legged cowboy sign). Right atrial and ventricular enlargement leads to rounding of the cardiac silhouette from the 6:00 to 11:00 position. Pulmonary veins (and arteries in severe cases) are distended in the caudal lung fields and the previously noted pulmonary parenchymal changes are evident when left-sided CHF develops. 
Electrocardiography ECG findings include evidence of left ventricular hypertrophy, left atrial enlargement (P mitrale; P > 0.04 sec), and infrequently P pulmonale (P > 0.4 mv). ST segment slurring is seen in some dogs with left ventricular hypertrophy, and ST depression may result from hypoxemia. Sinus rhythm or sinus tachycardia with a normal mean electrical axis are typical. Supraventricular arrhythmias occur commonly. Atrial fibrillation develops in some dogs with marked atrial enlargement, and ventricular arrhythmias are uncommon in dogs with compensated disease. Echocardiography Valvular thickening may be readily appreciated in most dogs with CVD. This valvular thickening and irregularity is most easily appreciated in the anterior mitral leaflet. With severe disease or with rupture of the chordae tendinae the valve motion takes on a vigorous, chaotic quality. The mitral valve leaflet can be noted to prolapse into the LA during systole. Left ventricular dilation is present to a variable degree depending upon disease severity. Progressive left atrial dilation occurs in most cases. Fractional shortening is increased with increasing regurgitant fraction, however fractional shortening can return toward "normal" or become diminished with disease progression and myocardial failure. End-systolic dimension or end-systolic volume index may be a better indication of myocardial function as these dimensions tend to increase with impending myocardial failure. As a crude indication of disease severity, the location and extent of the regurgitant jet can be estimated using color flow (CFD) Doppler echocardiography. While the degree of mitral or tricuspid regurgitation on color-flow Doppler may provide some qualitative information, the degree of disease progression is probably better characterized by left atrial size and measures of left ventricular function. Cavalier King Charles Spaniels are known to get CVD early in life. Absence of a cardiac murmur before 5 years of age in male dogs and before 6 years of age in female dogs has been proposed as a criterion for recommendations of populations for breeding. Most dogs will live three to four years after development of a cardiac murmur. Necropsy results of a small percentage of those CKCS examined revealed that mitral valve prolapse and ruptured chordae tendineae are major findings with CVD in this breed. More specifically, those tendineae associated with the medial aspect of the anterior mitral valve leaflet are most commonly ruptured, often in the absence of significant thickening due to endocardiosis. A study of enalapril use in this breed to prevent progression of the disease or delay the onset of CHF failed to identify a significant clinical benefit in asymptomatic dogs. Treatment The optimal treatment of dogs with CVD remains a topic of some discussion and debate. A variety of drugs and diets have been develop to manage the disease, however little research has been done to identify the cause of the valvular degeneration. If the cause of endocardiosis can be identified and treated then the disease could be slowed or reversed. Until that time, management of congestive heart failure (CHF) remains the cornerstone of therapy for CVD. Clinical trials of human heart failure patients have documented that use of certain therapies (e.g., Angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, spironolactone) leads to improved survival. The ACE inhibitors have been studied in dogs with CVD, however there is little information available regarding use of beta-blockers or spironolactone. Angiotensin-converting enzyme (ACE) inhibitors are commonly used in the management of CVD. One published study and data from another recently presented study failed to identify a clear benefit from early use of ACE inhibitors in dogs with CVD that have not yet developed clinical signs. However, once clinical evidence of heart failure is present, use of ACE inhibitors is appropriate and is also typically safe in the absence of significant pre-existing renal disease or excessive concurrent diuretic use. In general, ACE inhibitors should be used in all dogs with CVD that have developed CHF, assuming drug therapy is well tolerated. Diuretic therapy is indicated in any dog with evidence of congestion (e.g., pulmonary edema, pleural effusion, or ascites of cardiogenic origin). It can be quite difficult to define the exact dose of diuretic required by any individual dog. The dose required to clear significant edema accumulations and cause the animal to be minimally symptomatic (the desired dose) is often close to a dose that might result in electrolyte disturbance, dehydration and the development of pre-renal azotemia. The combined use of ACE inhibitors and diuretics compromises one of the kidneys' normal compensatory mechanisms (vasoconstriction of the efferent arteriole) and can lead to elevation of BUN and creatinine if an excessive diuretic dose is initiated. Diuretic dose should be reduced in dogs that are weak, lethargic, anorexic, or depressed, especially if congestive signs are well controlled. In most instances of mild CHF in dogs a furosemide dose of 2 mg/kg q 12-24 hours will control edema formation. When the furosemide dose of 2.2 mg/kg twice a day is exceeded during chronic therapy, diuretic resistance has been likely occurred and the author recommends addition of diuretics with differing mechanisms of action. Spironolactone has been documented to result in improved survival in a human CHF study, however information on the optimal dose and time of initiation of this drug is veterinary medicine is largely anecdotal. In cases of refractory CHF, a combination of hydrochlorothiazide with spironolactone is recommended. Serial electrolyte monitoring is advisable as spironolactone use can lead to mild hyperkalemia, and hydrochlorothiazide can result in hyponatremia and hypochloremia. Digitalis glycosides are also useful to control advanced CHF. The author most commonly uses digoxin as an add-on therapy to ACE inhibitors and diuretics for refractory CHF or in dogs with significant supraventricular arrhythmias. Beta blockade has gained favor recently as a therapeutic modality for treatment of CHF. Several studies on the use of beta-blockers have documented benefits that accrue from chronic treatment, although these effects are often not seen for several months. Reported benefits include up regulation of previously down regulated beta-receptors, improved cardiac performance (improved stroke volume), and improved survival. These clinical benefits appear to have sound theoretical basis, and are currently being evaluated in dogs with naturally occurring CHF. It is true that beta-blockers are negative inotropes, and this may be the most demonstrable effect when these drugs are used in animals with active CHF. The negative inotropic and negative chronotropic effects of the drugs will likely contribute to worsening of CHF in animals with active failure or those that are on the edge of compensation. Beta-blockers are best employed in animals that are minimally symptomatic with early/mild heart failure, or in animals in later stages of CHF that are already well controlled on a stable cardiac drug regimen. Sodium restricted diets and exercise restriction have long been a useful additions to the management of CHF in dogs. The optimal time to initiate a cardiac diet and the ideal sodium level relative to the severity of clinical disease are areas for debate and further research. A diet designed for early use in dogs with CVD has been recently developed (Waltham Early Cardiac Support Diet) and studies of this diet are ongoing. Exercise restriction with severe congestive heart failure is essential, however limited exercise in dogs with stable chronic heart failure is often well tolerated. Repetitive or strenuous activities like ball chasing and running should be restricted. Surgical procedures are being developed to repair or replace the mitral valve in dogs with CVD. Cardiopulmonary bypass is required for these surgeries, and successful cardiopulmonary bypass requires a dedicated team of surgeons, perfusionist, anesthesiologist, cardiologist, intensive care specialist, and strong veterinary technician support. The cost associated with surgery can be prohibitive, however cardiopulmonary bypass and mitral valve surgery have become routine in the human field. Once these techniques are mastered and refined for veterinary medicine it seems probable that surgery will become the preferred therapy for those that can afford the procedure. Re-evaluation with a physical examination and chemistry profile to check renal function and electrolytes 7 to 10 days after initiation or alteration of cardiac medications is prudent. Serum digoxin levels should be obtained if this drug is used, ideally 8 hours post-pill. Additional tests that might be appropriate at the time of the initial recheck examination include packed cell volume and total proteins to help assess hydration, blood pressure, follow-up thoracic radiographs in dogs with CHF, and follow-up electrocardiography in animals with arrhythmia. The next visit should be scheduled for 2 to 3 months and at that time a physical examination with chemistry profile should be performed. Pericardial Disease Diseases affecting primarily the pericardium account for approximately 1% of all patients with cardiovascular disease. Although primary pericardial disease represents a small percentage of the total number of cardiac diseases in small animals, it is an important cause of right heart failure in the dog. Pericardial disease of all types are uncommon in the cat. Several types of primary and secondary pericardial diseases occur, the most common of which are those resulting in the accumulation of pericardial effusion. CONGENITAL DISEASES There are several congenital diseases of the pericardium recognized in small animal species. While peritoneopericardial diaphragmatic hernias (PPDH) are the most common type of congenital abnormality encountered , sporadic reports of partial pericardial defects and intrapericardiac cysts 4have been published. Congenital complete absence of the pericardium is quite rare. Pericardial Defects Peritoneopericardial diaphragmatic hernias are commonly reported in dogs and cats. Peritoneopericardial diaphragmatic hernias have been reported in littermates, but there is no reported evidence that the lesion is hereditary. It has been suggested that Weimaraners are predisposed to PPDH.A large portion (48%) of dogs and cats with PPDH are diagnosed prior to one year of age and another 36% are diagnosed between one and four years of age. Clinical signs are most commonly gastrointestinal (anorexia, vomiting, discomfort following a meal) or respiratory (cough, dyspnea). Signs of cardiac compromise (abdominal distention and acute collapse) may occur, but are uncommon. Physical examination may reveal an apical impulse which is displaced or decreased in intensity. Cardiac murmurs may be detected if concurrent cardiac malformations are present. If the hernia is large and a significant amount of abdominal viscera has herniated, the abdomen may seem empty on palpation. Signs of CHF (ascites, jugular venous distension) may be present, but are uncommon. Concurrent defects (sternal malformations, cranial abdominal hernias) may be detected. Thoracic radiographs are extremely helpful in establishing a definitive diagnosis of PPDH. Radiographic abnormalities may include: overlap of the caudal cardiac silhouette and cranial diaphragm, variable radiographic densities within the cardiac silhouette, gas-filled bowel loops crossing the diaphragm, and sternal malformations. Oral administration of barium may help outline bowel loops present within the pericardial sac . Ultrasonography can readily identify the presence of abdominal viscera within the pericardial sac and help establish a definitive diagnosis Surgical correction of the hernia with replacement of viable herniated viscera is the recommended therapy. Consideration of the severity of concurrent congenital malformations should be made prior to surgical intervention. In uncomplicated (no concurrent malformations) cases, the prognosis following surgical repair is excellent. ACQUIRED PERICARDIAL DISEASES Pericardial Effusion Diseases causing pericardial effusion are the most common causes of clinically significant pericardial disease in the dog. Idiopathic intrapericardial hemorrhage (Golden retrievers are overrepresented) with or without pericardial reaction and neoplasia of the heart, heart base, or pericardium are the most common causes of hemorrhagic effusion in dogs. Clinically important tumor types in dogs include hemangiosarcoma of the right atrium (especially common in German Shepherds and Golden Retrievers). Aortic body tumors (chemodectoma, nonchromaffin paraganglioma) with invasion of the heart base is most commonly seen in aged brachycephalic breed dogs, ectopic (heart base) thyroid carcinoma, mesothelioma of the pericardium, and metastatic carcinoma. A well recognized but uncommon cause of intrapericardial hemorrhage in small breed dogs is left atrial tear secondary to severe chronic endocardiosis of the mitral valve. Diagnosis Special breed predilections have been noted previously. Most frequently, animals with pericardial disease are presented with vague signs. Clients will frequently describe lethargy, exercise intolerance, and anorexia. Occasionally, patients will be presented for signs of compromise of right heart function: abdominal distension, respiratory difficulty, or syncope. Signs of elevated right heart pressures are consistently present in patients with clinically significant pericardial disease. Jugular venous distention or a positive hepatojugular reflux are invariably present, but commonly overlooked. Heart sound intensity is frequently diminished. Lung sounds may be diminished if pleural effusion is present. Other auscultatory abnormalities (gallop rhythms, cardiac murmurs, arrhythmias) are uncommon. Dogs with left atrial tears secondary to chronic degenerative valvular disease will have a systolic murmur that may be decreased in intensity when compared to previous examinations. Hepatomegaly and free abdominal fluid are common findings. If the disease is chronic, significant weight loss may be observed. Thoracic radiography usually demonstrates abnormalities when there is significant accumulation of pericardial fluid. The cardiac silhouette loses its angles and waists and becomes globe-shaped (Figure 3). Most cases are not "classic" and require integration with the other data. Pulmonary vascularity is often reduced from low cardiac output in contrast to CHF from cardiomyopathy or valvular disease in which the pulmonary vascularity may be increased (especially the pulmonary veins). If CHF has developed, distension of the caudal vena cava hepatomegaly and pleural effusion are usually evident. Less commonly, distension of the pulmonary veins and increased pulmonary interstitial densities (edema) may be detected. Heart base tumors may deviate the trachea and produce a mass effect. Although there are no pathognomonic electrocardiographic findings for pericardial disease, there are several electrocardiographic abnormalities that are commonly seen. Electrical alternans is a beat-to-beat voltage variation of the QRS or ST-T complexes. It may be recorded in as many as 50% of patients with pericardial effusion. Elevation of the ST segment is commonly recorded in patients with pericardial disease. This represents an epicardial injury current. Reductions in QRS voltage (R < 1 mV in Lead II) are commonly recorded in dogs with pericardial effusion. Low electrocardiographic QRS voltage is considered a weak predictor of the presence of pericardial effusion. In the author's experience, arrhythmias other that sinus tachycardia are uncommon in primary pericardial disease. Echocardiography is the most sensitive and specific non-invasive method of detecting pericardial effusion currently available. The hemodynamic consequences of pericardial effusion depend not only on the amount of pericardial effusion present, but also on the rapidity with which the effusion has accumulated. A small or moderate amount of fluid accumulating rapidly (left atrial rupture) may produce significant hemodynamic compromise, while a large amount of effusion accumulating over months may have little hemodynamic effect. These principles should be remembered when assessing the significance of an echocardiographically-detected pericardial effusion. Echocardiography can detect as little as 15 ml of intrapericardial fluid. An anechoic space between the epicardium and pericardium is the classic echocardiographic finding in pericardial effusion. Cardiac motion is commonly abnormal often with dramatic side-to-side movement and diastolic compression. Overall cardiac chamber size is usually diminished due to impaired cardiac filling. Intrapericardiac or cardiac mass lesions may be visualized. THERAPY AND PROGNOSIS Pericardiocentesis Pericardiocentesis is the treatment of choice for initial stabilization of dogs and cats with pericardial effusion and cardiac tamponade. When performed properly, pericardiocentesis is associated with minimal complications. Prior to performing pericardiocentesis, it is necessary to shave and surgically prepare a large area of the right hemithorax (sternum to mid thorax, third to eighth rib). Local anesthesia is usually adequate; however, mild sedation is sometimes necessary. It is important to insure that the pleura has been infiltrated, as pleural penetration seems to cause significant discomfort. The patient is placed in sternal or lateral recumbency, depending on demeanor. Occasionally, pericardiocentesis can be accomplished in the standing animal, but adequate restraint is essential to prevent cardiac puncture or pulmonary laceration. Electrocardiographic monitoring during the procedure is helpful since epicardial contact often causes ventricular arrhythmias. The puncture site is usually determined based on the location of the heart on thoracic radiographs. This is most commonly between the fourth and sixth rib spaces at the costochondral junction. Ultrasound guidance is infrequently necessary unless the volume of effusion is very small or the effusion is compartmentalized. The size of the needle or catheter used is dependent on the size of the animal. In cats, a 19 to 21 gauge butterfly catheter may be adequate, while in large dogs, a 16 gauge over-the-needle catheter (usually with additional side holes) may be needed. The needle or catheter should be attached to a 3-way stopcock, extension tubing, and a syringe, to allow constant negative pressure to be applied during insertion and drainage. Care should be taken to avoid the large vessels that run along the caudal border of the ribs. Once the catheter has been inserted through the skin, negative pressure should be applied. If pleural effusion is present, it will be obtained immediately upon entering the thoracic cavity. It is most commonly a clear to pale yellow color. As the catheter is advanced and contacts the pericardium, a scratching sensation will be noticed. Minimal advancement will result in penetration of the pericardium. Most pericardial effusions are hemorrhagic and have a "port wine" appearance. Once effusion of this character is obtained, the catheter should be advanced over the needle, and the needle removed. The remainder of the drainage should be performed using the catheter. Advancing the needle too far will result in contact with the epicardium. This is often felt as a tapping or more intense scratching sensation and commonly results in ventricular arrhythmias. These arrhythmias are usually self-limiting following retraction of the needle or catheter. Pericardial effusion can be differentiated from peripheral blood in that it rarely clots unless it is from very recent hemorrhage and the PCV is significantly lower than that of peripheral blood. Every attempt should be made to drain the pericardial space as completely as possible. Drainage of the pericardium is often associated with an increase in the complex size on the ECG, a reduction in heart rate, and an improvement in arterial pulse quality. Potential complications include cardiac puncture (with resultant hemorrhage or arrhythmias), coronary artery laceration, lung puncture or laceration, and dissemination of infection or neoplasia throughout the thoracic cavity. Diagnostic evaluations of fluid obtained should include PCV and cytologic evaluation. Bacterial culture and sensitivity should be performed if indicated by cytologic evaluation. Caution should be exercised when evaluating the cellular component of pericardial effusion. Clinically important neoplasia of the heart and pericardium (hemangiosarcoma, chemodectoma) commonly do not exfoliate, resulting in frequent false negative evaluations. Reactive mesothelial cells within the pericardial sac are commonly over interpreted as being neoplastic, causing false positive results. The long-term prognosis for dogs with hemorrhagic effusion is dependent on the underlying etiology. With idiopathic hemorrhagic pericardial effusion, pericardiocentesis is curative in approximately 50% of the cases. In the remainder, repeat centesis is necessary to control clinical signs. Fluid may reaccumulate rapidly (within several days) or may not recur for months to years. In patients requiring more than 2 centeses, the author recommends subtotal pericardiectomy. Following the initial pericardial tap, administration of oral prednisolone (starting at a dose of 1 mg/kg orally every 12 hours, then gradually tapering off over a two to three week period) may be beneficial. Although antiinflammatory doses of prednisolone are commonly administered to dogs with idiopathic pericardial effusion, there are no controlled studies to confirm the efficacy of this therapy. Subtotal pericardiectomy is usually curative in dogs with idiopathic pericardial effusion. If cardiac or pericardial neoplasia is the cause of the pericardial effusion, the recommended therapy is subtotal pericardiectomy. The prognosis is again dependent on the nature of the underlying etiology. Aortic body tumors are commonly associated with slow growth and are late to metastasize. Subtotal pericardiectomy may afford palliation for up to three years. Hemangiosarcoma of the right atrium is associated with a poor long-term prognosis. Most mass lesions involving the right atrium or right ventricle are not amenable to surgical removal. The tumor has commonly spread to the lungs at the time of diagnosis and these patients may have neoplastic lesions in the spleen or liver as well. In those patients, subtotal pericardiectomy should be considered palliative. Recent reports have suggested that both thorascopic pericardiectomy and percutaneous pericardial balloon dilation may be reasonable alternatives to subtotal pericardiectomy in both neoplastic and benign effusions. These techniques allow the pericardial fluid to drain into the pleural space to be reabsorbed. This may provide significant palliation for patients with pericardial effusion and the resultant cardiac tamponade without necessitating a thoracotomy. These therapeutic modalities warrant further evaluation in canine patients. FELINE PERICARDIAL DISEASE Pericardial diseases appear to be quite uncommon in cats. Recent reports addressing the topic suggest that the most common single cause of pericardial disease in the cat is feline infectious peritonitis (FIP) FIP infection can cause massive accumulations of intrapericardial fluid and resultant cardiac compromise. Pericardial effusion is common secondary to cardiomyopathy. Echocardiography can readily detect pericardial effusion and determine the nature of concurrent myocardial disease. Peritoneopericardial diaphragmatic hernias may go undiagnosed for years in cats. Sternal abnormalities are commonly observed along with PPDH. Frequently, only falciform fat and liver will be present within the pericardial sac, making barium contrast studies less informative in cats than it is in dogs. Canine and Feline Heartworm Disease: Clinical Essentials INTRODUCTION Dirofilariasis or heartworm (HW) disease is an important and common parasitic disease of dogs and to a lesser degree the cat. Other species (such as ferrets and wild canines) also can be infected. Dirofilaria immitis is a large (12 - 30 cm), string-like parasite that resides within the pulmonary arteries but the parasite may be found in the right ventricle or right atrium as well. at necropsy. Adult heartworms can live up to 5 years in dogs but probably less than 3 years in cats. Males are up to 16 cm long with a "curly" end; females are longer, up to 30 cm. Young female worms are not only large, but the most resistant to adulticidal chemotherapy. Mature adults produce microscopic offspring that circulate in the blood (patent infection). Microfilaria can survive up to 2 years though circulating microfilaremia in infected cats is very brief and many dogs become amicrofilaremic. Should microfilaria be ingested by a mosquito, these can develop into infective larvae or L3 stage, provided the daily average ambient temperature is not too cold (above 57 degrees F, ideally more than 64 degrees). When an infected mosquito bites another animal, infective larvae are transmitted to the new host. Both dogs and cats can be infected experimentally by injection of infective larvae. Cats are a susceptible but resistant host. In natural settings, even in epidemic areas, where nearly 100% of unprotected dogs are positive for HW infection, only about 20% of unprotected cats may be positive. This demonstrates the relatively greater natural resistance of cats to this disease (as well as mosquito host preference); however, when infected with heartworms, the cat often manifests more severe clinical signs than in dogs. LIFE CYCLE The life cycle of the heartworm that takes approximately 200 days under optimal conditions. Domesticated and wild canine species constitute the definitive hosts. The cat is more resistant, and less frequently affected with heartworm infection. Mosquito and Pre-pulmonary Phases:
Viable L5 migrate and penetrate systemic veins where they are swept in the blood stream and to the peripheral pulmonary arteries. Here the parasite grows and matures. Pulmonary embolization of larvae occurs relative to the degree of pulmonary flow. Therefore, the caudal lobes are most severely affected by disease in most situations. Immature adults grow back towards the main pulmonary artery and right ventricular outflow tract.
Adult Infection:
There is no specific age or breed predilection, although dogs < 7 months cannot conceivably be diagnosed as having HW disease. It is possible for young dogs to be microfilaria positive owing to transplacental infection or a microfilaria positive blood transfusion but both are considered quite rare. Large breed, short-haired, male dogs are at greater epidemiologic risk. Environment is important since areas which abound with mosquitoes (beaches, lakes, and coastal states) will be endemic for HWD. Based on clinical serologic survey data and results of reported retrospective studies there is no age or breed predisposition to D. immitis infection or exposure in cats. Males have been shown to be more susceptible to infection in some clinical and experimental studies. This sex predisposition has not been supported by recent serologic surveys however these surveys report exposure and not mature infection. A recent necropsy study from Beaumont Texas reported that more males than females harbored adult heartworms but this difference was statistically insignificant Interestingly that same study reported that only 50% of the cats in which adult worms were found at necropsy were antibody positive. Cats that have outdoor exposure are at increased risk of infection with any exposure to the outdoors increasing the risk of exposure by a factor of two. It is important to emphasize that heartworm disease has been diagnosed in cats which the owners report as living strictly indoors. History Many dogs with dirofilariasis are asymptomatic (HW infection) and diagnosed on routine HW screening tests. The symptomatic patient (HW disease) may present for any or all of the following historical complaints:Weight loss, anorexia, poor condition
Physical examination may reveal a normal animal or any of the following clinical signs:
LABORATORY TESTS Routine diagnostic tests are often done in HWD. Some of these are very useful in staging the severity of disease, while others are of limited value. Radiography The history, clinical examination, and thoracic radiographs provide the most useful information about the status of a heartworm infection. Results of radiography may be normal. Abnormal thoracic radiographs may be found in either asymptomatic or ill patients. The following represent the salient radiographic features of moderate to severe HWD.
Echocardiography Routine echocardiography is not required in diagnosis or management of heartworm disease in dogs. Echocardiography is most useful for evaluating the patient with heart failure for diagnosing caval syndrome and eliminating the diagnosis of other common causes of right heart failure (pericardial disease and dilated cardiomyopathy). In severe disease the echocardiogram typically documents RV and right atrial enlargement, flattening of the ventricular septum, and dilated main and lobar pulmonary arteries. Adult parasites appear as parallel, linear, echodensities with a central hypoechoic zone. Ultrasound is more helpful in smaller animals as the parasites are located more centrally. In the caval syndrome, worms are evident in the tricuspid orifice and right atrium. In contrast to dogs, echocardiography is very helpful in the diagnosis in cats because laboratory tests can be negative in the setting of infection. Numerous reports and abstracts have documented the diagnostic utility of echocardiographic in cats with heartworm disease. Sensitivities ranging from 34-100% have been reported suggesting that in greater than 50% of cases worms can be visualized within the cardiac chambers or pulmonary arteries. It is imperative that adequate visualization of the entire right heart, bifurcation of the main pulmonary artery and the proximal portion of the right pulmonary artery be obtained. Most worms are seen in the pulmonary arteries and appear as parallel hyperechoic structures typically about 0.7-1.2 mm thick and separated by approximately 0.5-1.0 mm most commonly described as resembling a bright "equals (=) sign". The length, however is variable reflecting the angle at which the worms are aligned relative to the echocardiographic imaging plane. Determination of the exact number of worms is often quite difficult. Importantly, echocardiography is very helpful in establishing or refuting a diagnosis of primary cardiac disease. Electrocardiography The EKG is of limited value in this disease. The ECG is normal except in severe HWD when widening of P-waves, RVH pattern, and right axis deviation occur. If an arrhythmia is detected by auscultation, an ECG should be done as atrial and ventricular arrhythmias may be observed in advanced disease. In cats, although evidence of right ventricular enlargement is occasionally evident, the electrocardiogram is normal in most cats with heartworm disease. Significant axis shifts or dysrhythmias should increase the clinician's suspicion of primary cardiac disease. Complete Blood Count and Serum Biochemistries Abnormalities seen on the CBC in HW infection are can include eosinophilia but this is evident in less than 50% of cases; basophilia; and monocytosis. If thiss triad of findings is detected, always consider HW infection. It is emphasized, however, that the CBC are often normal. Mild normocytic, normochromic anemia, probably from chronic disease, is found in 30-35% of dogs. RBC fragments may be seen suggesting low grade disseminated intravascular coagulopathy. DIC occurs in severe cases (particularly in caval syndrome and with severe pulmonary vascular disease) Serum biochemical tests are normal except for protein changes and mild to moderate elevation of liver enzymes which are possibly related to congestion. Hyperglobulinnemia is also very common in cats with HW infection. In cats abnormalities detected on routine blood work are fairly nonspecific. Complete blood counts often show a mild non-regenerative anemia and occasionally increased numbers of nucleated red blood cells. Eosinophilia is an inconsistent finding, even on serial samples. Experimentally, peripheral eosinophilia most commonly occurs 4-7 months post-infection and intermittently thereafter. If peripheral basophilia is noted in conjunction with eosinophilia, the a diagnosis of heartworm disease should be pursued. Hyperglobulinemia is one of the few commonly observed biochemical abnormalities. Tests for Heartworm Infection Diagnosis of HW infection requires detection of circulating microfilaria or heartworm Antigens in the dog . Antigen tests are the method of choice as many dogs do not have circulateing microfilaria. A number of sensitive and specific antigen tests are available that detect the presence of heartworm antigens derived mainly from adult females. These tests vary in diagnostic methodology, but include simple single test kits and "batch" kits. The technology improves constantly, and some antigen tests can detect the presence of just one or two female adult parasites. Antigenemia is generally evident when worms are seven months of age; some tests may detect antigenemia in worms as young as 5 months of age. The competition among test kit manufacturers makes it difficult to identify a clearly superior test kit. Some kits are "semiquantitative" providing some information about relative worm burden. Careful attention to detail is important. Ambiguous test results are best followed up by sending the sample to an outside reference laboratory. It should be emphasized that regardless of test sensitivity and specificity, the positive predictive value of a test still depends on the prevalence of disease in the hospital population. Several testing methods are available for detection of amicrofilaremic infections in cats. The indirect fluorescent antibody test (IFA) detects host antibodies against microfilarial cuticular and somatic antigens. This test is commercially available only from Antec Labs (Farmingdale, New York; Irvine, California). Recent reports suggest that the IFA test is a highly specific and sensitive indicator of heartworm exposure detecting some infections as early as 1-2 months post infection. The ELISA test (Animal Diagnostics [BioClin] , St Louis, MO; Heska Corporation, Fort Collins, CO) which detects antibodies (Ab) to heartworm antigen is quite sensitive. The Ag against which the Ab is directed is present in large amounts in the L4 and L5 stages and to a lesser degree in the L3 stage. Recent studies using both tests to evaluate well characterized feline serum suggest they are quite specific even in the presence of heavy intestinal parasitism. A positive Ab test simply documents exposure while a negative test makes a diagnosis of feline heartworm disease less likely. There are however some cats with mature heartworm infection (positive ELISA Ag test or documented via necropsy or echocardiography) that have been Ab negative. This situation was thought to be quite uncommon however one study suggested this may occur in as many as 50% of adult infections. Antibody negative cats showing clinical signs typical of heartworm disease and in which other tests (radiography) support a diagnosis, deserve further evaluation. This additional evaluation might include and an echocardiogram, an ELISA Ag test, additional Ab tests (perhaps using an alternative laboratory) and in select cases nonselective angiography. Circulating Ab are typically detectable within 2-4 months of exposure and the ELISA tests may remain positive for 9-12 months, even if a mature infection is not established. An in house ELISA test marketed by Synbiotics Corporation (Assure®/FH) and an immunochromatography format test (SoloStep®) marketed by Heska Corporation have been approved by the FDA. The ELISA tests offered by Heska and Animal Diagnostic labs are considered quantitative with the intensity of the test correlating to some extent with the likelihood of mature infection. The results of Heska's test are reported in antibody units per milliliter (AbU/ml). Using these units a value less than 5 ABU would be considered a negative test, a value greater than 5 but less than 20 ABU/ml would be typical of exposure while a value greater than 20 ABU/ml would be common in cats with a mature infection. It is important to emphasize that these values are guidelines and do not represent definitive categories. The results of the Animal Diagnostics' test is reported as a titer (reported range is 1:70 to >1:5000) with a titer of 1:70 considered positive. The higher the titer the more likely it represents mature infection. In asymptomatic cats with a titer of < 1:120 only 1% had a positive Ag test. In symptomatic cats with titers <1:120 but greater than 1:70, 28% were Ag positive. In cats with titers greater than 1:3000, 78% were AG positive. Serial titers may be informative with increasing ABU concentrations or Ab titers suggesting sustained or ongoing infection. Due to the nature of the titering system a titer needs to change by a factor of four (4) to be considered significantly different. The ELISA and ICT tests which detect circulating adult heartworm antigen (HWAg) are the most specific tests currently available to detect mature infections. Although the tests were originally marketed for use in the dog, the methodology used allows the tests to be used in any species. The antigen detected is a series of related acidic proteoglycans derived primarily from the adult female worm. Low worm burdens (less than 3 worms), all male infections or immature infections may result in false negative test results. When evaluating the results of an ELISA or ICT (HWAg) test in a cat; a negative test result does not rule out dirofilariasis, but a positive test is very strong evidence of heartworm infestation. Several studies (echocardiographic, experimental and necropsy) suggest that approximately 40% of cats with adult worms are Ag positive. Table 1
Width and morphology are considered best for discriminating between the two parasites. Microfilaria tests There is still merit in detecting microfilaria when an antigen test is positive. The following summarizes the key morphologic features of concentration techniques or wet mount smears. The modified Knott's technique provides good differentiation between microfilaria of D. immitis and other nonpathogenic species. Microfilaria of D. immitis must be differentiated from microfilaria of the flea-transmitted, subcutaneous, nonpathogenic worm, Dipetalonema reconditum. In mixed infections, it is likely that D. reconditum will be missed since these usually constitute less than 1% of the microfilaria present Differentiation of larvae (microfilaria) can be made using a wet mount and Knott's test. In approximately 10 to 30% of dirofilarial-infected dogs (up to 50% in some areas), and in virtually all infected cats, microfilaria cannot be demonstrated; "occult" HWD. In some surveys up to 80% of cases of severe HWD are occult. Concentration techniques (Difil7, modified Knott's) can be performed in cats suspected of having heartworm disease but are often of little value as less than 20% of all infections are patent. Even in cats with circulating microfilaria, the low concentration and transient nature of the microfilaremia results in a large number of false negative test results. The sensitivity of the concentration tests may be improved by performing multiple tests and by using 5 ml of blood for each test rather than the standard 1 ml. Although the concentration tests have a very low sensitivity, a positive test establishes a definitive diagnosis (Table 1). PATIENT CLASSIFICATION and ADULTICIDE THERAPY in DOGS Melarsomine dihydrochloride (IMMITICIDER) emerged as a novel organic arsenical heartworm adulticide in the mid-nineties and is currently the only available drug approved for this purpose. It has inherent advantages over its predecessor, sodium caparsolate, being both safer and more efficacious. The drug is typically administered at 2.5 mg/kg IM twice, 24 hours apart, killing approximately 98% of immature and mature adult heartworms. Importantly, in more severe (Class 3; Table 2) heartworm disease (HWD), melarsomine may be administered in a "split dose". With this approach, an initial injection is followed in approximately 1 month by a series of 2 injections over a 24 hour period, thereby lowering the initial kill rate and, hence, the impact of dying worms on the pulmonary vasculature. Table 2
Figure 1 
Despite the enhanced safety of this product, adverse reactions are still noted . In fact, successful pharmacological adulticidal therapy, by definition, dictates that thromboembolic events will occur. The severity of this complication can be diminished by severely restricting exercise after melarsomine administration and by using the "split dose" regimen recommended for Class 3 heartworm disease. The author recommends 1 month of severe exercise restriction after adulticidal therapy. The method and degree of exercise restriction varies with the client needs and the pet's inherent activity level, but might include hospitalization, cage rest, sedation, housing in a restricted room of the house or garage and use of only gentle leash walks. Nevertheless, some owners do not or cannot restrict exercise, resulting in or worsening thromboembolic complications. Additionally, severe adverse reactions may be noted when dogs are incorrectly (or even correctly) categorized as Class 1 or Class 2 HWD severity and subsequently treated with the traditional 2-injection regimen. To minimize the chance of thromboembolic complication, the author has adapted an alternative approach, recommending the 3-injection ("split dose") method in all Class 1, 2, or 3 heartworm infection. Method At the time of diagnosis by a positive heartworm antigen test the author completes a minimum database, which includes a microfilariae test, chemistry panel, CBC, urinalysis, and thoracic radiographic evaluation. At this time, monthly macrolide preventative is prescribed (Figure 1). This approach is used to prevent further infection, to eliminate microfilariae (chronic therapy renders the dog of no further risk to infect itself or other dogs and cats), and to destroy developing L4, not yet susceptible to adulticidal therapy. In microfilaremic dogs, the first macrolide dosage is administered in the hospital or at home with observation so that an adverse reaction might be recognized and treated promptly. Corticosteroids with or without antihistamines (dexamethasone at 0.25 mg/kg IV and benadryl at 2 mg/kg IM OR 1 mg/kg of prednisolone PO 1 hour before +/- 6 hours after administration of the first dose of preventative) are commonly administered to reduce the potential for adverse reaction in highly microfilaremic patients. It is important to emphasize that adverse reactions are unusual with macrolides at preventative doses. Depending on the time of year, up to 2-3 months might be allowed to lapse before adulticidal therapy is administered. Monthly macrolide administration ensures that the dog does not receive further infection. The delay allows for larval maturation to adulthood, ensuring that the only stage of the life cycle present is the adult, which is vulnerable to melarsomine therapy. This delay is particularly important if the diagnosis is made during or at the end of a mosquito exposure season. If the diagnosis is made in the spring or late winter, when infective larvae have matured, adulticidal therapy may be immediately administered (Figure 1). Figure 2 
The first injection of Melarsomine is administered by deep IM injection (2.5 mg/kg) in the lumbar musculature as described in the package insert and the injection site recorded. The injection needle is changed before injection and care is taken to inject deep into the muscle and nowhere else. It is important to remember that the injection must be made into the center of the epaxial muscle (Figure 2). Patients are typically hospitalized for the day of the injections. The need for exercise restriction for 1 month is emphasized and sedation is provided, if necessary. Owners are also advised regarding potential adverse reactions (fever, lassitude, inappetence, cough, dyspnea, collapse) and to call if they have concerns. The owners are advised that they must return for a second series of 2 injections in approximately 1 month. Extending the time between the first injection and the subsequent two injectiosn injections has no adverse affects on adulticide efficacy. If serious systemic reaction results, the second stage of the adulticidal treatment is delayed or, occasionally, even cancelled. Typically, however, even with severe reactions, the entire treatment protocol is completed within 2-3 months (Figure 1). After a minimum of 1 month, the melarsomine injection procedure is repeated, again with recording of the injection site. If significant local reaction was noted after the first injection, dexamethasone or oral non-steroidal anti-inflammatory drugs to minimize pain at the injection site accompany subsequent injections. The following day (approximately, 24 hours after the first injection) the process is repeated with injection into the opposite lumbar area. Client instructions are similar to those previously given with reemphasis of the need for strict exercise restriction. Antigen testing is repeated 6 months following the second series of injections, with a positive test result indicating incomplete adulticidal efficacy. It is emphasized that, despite the proven efficacy of melarsomine, not all worms are killed in every patient. Worm burden is typically markedly reduced but if as few as 1-3 adult female worms remain, positive antigen tests are likely. Whether or not repeat adulticidal therapy is warranted, under these circumstances, is decided on a case by case basis with input from the owners. Justification This "split dose" or 3-injection method enhances both the efficacy and safety of melarsomine adulticidal therapy. Studies have shown that patients treated with the split dose regimen have a higher seroconversion to a negative antigen status (89.7%) rate than patients treated with either caparsolate (65.9%) or the standard melarsomine dosing regimen (76.2%). Additionally, in a study using experimental heartworm infection in dogs, more effective adulticide activity did not appear to increase the severity of clinically apparent pulmonary hypertension or thromboembolism. Perhaps more importantly, killing worms in 2 increments of approximately 50% each diminish the insult to the lung and pulmonary vasculature. After approximately 50% of the worms are destroyed, the lungs are allowed to heal for 1 month before the second insult. In addition, if there is a significant adverse reaction to the initial adulticidal injection, the 2nd and 3rd injections can be delayed (or even cancelled), until clinical signs have resolved and damaged tissue can heal - typically 2-3 months. Drawbacks Disadvantages to this approach include added cost of the 3rd injection. This may well be counteracted by reduction in adverse reactions, which often require hospitalization and intensive therapy. Secondly, the total arsenical dosage is increased. We have found the approach to be generally well tolerated but would advocate a 2-dose regimen and fluid therapy in dogs with significant renal disease who require heartworm adulticidal therapy. Lastly, exercise restriction is often a problem for owners and the "split dose" regimen requires approximately 2 months' exercise restriction (Figure 1). This may prove difficult or even impossible for some owners. Conclusions The author believes that this 3-injection approach of melarsomine administration in the management of virtually all heartworm infections is safer and probably more effective than the 2-dose regimen, justifying the increased cost. Even if owners cannot afford the minimum database for evaluation of general health and the presence and severity of heartworm disease, they may still benefit financially by use of the 3-dose regimen. In such instances, even though the attending clinician has more difficulty predicting an adverse reaction without thoracic radiographs, he or she can reduce the likelihood of adverse reaction (and attendant costs) by the approach described here. ANCILLARY THERAPY Corticosteroids are indicated in HWD in the face of pulmonary parenchymal complications (including PTE), to treat or prevent adverse reactions to microfilaricides, and possibly to minimize tissue reaction to melarsomine. Early studies demonstrated that corticosteroid therapy reduced pulmonary blood flow and worsened intimal disease in a model of HWI after adulticide. Subsequent studies however have suggested that corticosteroids actually decrease the severity of intimal disease and clinica signs of PTE. For allergic pneumonitis, prednisolone (1 mg/kg/day) is administered for 3-5 days and tapered as indicated.27 The response is generally favorable. Prednisolone has also been advocated for the management of PTE. Because of the potential for fluid retention, steroids should be used cautiously in the face of heart failure. Antithrombotic agents have received a good deal of attention in the management of HWD. Potential benefits include reduction in severity of vascular lesions of HWD, reduction in pulmonary arterial vasoconstriction and pulmonary hypertension, as well as minimization of post-adulticidal PTE. Aspirin has shown success in diminishing the vascular damage caused by segments of dead worms, reduced the extent and severity of myointimal proliferation caused by implanted living worms, and improved pulmonary parenchymal disease and intimal proliferation in dogs receiving thiacetarsemide after previous living HW implantation. More recent studies, however, have produced controversial results. Aspirin administered to dogs with implanted HW, receiving adulticide, showed no improvement in pulmonary angiographic lesions and had more severe vascular tortuousity than did controls and dogs receiving heparin. These authors emphasized that the ideal aspirin dosage would inhibit platelet function, but not PGI2 production. Dillon and associates demonstrated that the aspirin dosage required to decrease platelet reactivity by at least 50% was increased by nearly 70% with HWI (implantation model) and by nearly 200% with a model (dead worm implantation) of PTE. There were not significant differences in severity of pulmonary vascular lesions in aspirin-treated vs control dogs. For these reasons, the American Heartworm Society does not endorse antithrombotic therapy for routine treatment of HWD. Cage rest is an important aspect of the management of HWD after adulticidal therapy, after PTE, or during therapy of heart failure. This can often be best, or only, accomplished in the veterinary clinic. If financial constraints preclude this, crating at home and/or tranquilization are useful alternatives. ADULTICIDE THERAPY IN CATS It is the author's opinion that asymptomatic cats with heartworm infection should not receive any form of adulticide therapy. The fact that most cats infected with D. immitis are asymptomatic and the lifespan of D. immitis in the cat is so short, argues against the necessity for adulticide therapy. However, the pulmonary pathology associated with D. immitis infection and the possibility of acute death would seem to argue in favor of initiating adulticide therapy following definitive diagnosis. Although many published reports have stated that cats tolerate thiacetarsamide (Caparsolate®) therapy with minimal renal or hepatic toxicity these same reports are also quick to point out that cats seem to have severe thromboembolic complications. In an experimental study evaluating the pharmacokinetics of thiacetarsimide in normal cats, 3 of 14 cats developed an idiosyncratic acute respiratory distress syndrome resulting in pulmonary edema, respiratory failure and death within 1-3 hours of the second dose of thiacetarsamide. Subsequent investigations of a similar nature have been unable to reproduce this observation. Little data regarding the use of Immiticide in cats is available. An abstract reporting the use of Immiticide in cats with experimental (adult transplant) infection suggested that a single dose (2.5 mg/kg IM) reduced the worm burden by approximate 30% (statistically insignificant) without serious complications. Immiticide is not approved for use in cats. Cats presented for cough and/or dyspnea may initially respond to administration of corticosteroids and bronchodilators. The initial prednisolone dose is 1 mg/kg orally twice daily for 10-14 days then the dose is gradually reduced to the minimum dose that will eliminate clinical signs. Theophylline (TheoDurJ) 25 mg/kg orally once daily in the evening for the duration of the infection. If clinical signs are not relieved by symptomatic therapy, then adulticide therapy can be considered but is not recommended. It is generally accepted that cats have more severe post-therapy thromboembolic complications than dogs probably due in part to the large size of the worms relative to the cats pulmonary artery. The clinician should expect a 30% patient mortality rate associated with adulticide therapy and subsequent thromboembolic complications. This high mortality rate may reflect the fact that cats which do not respond to symptomatic therapy may have more severe disease or higher worm burdens and are therefore at more risk for significant complications. Interestingly a retrospective report which tried to assess the outcome in treated (adulticide) versus non-treated (only supportive care given ) reported no difference in longterm survival. Supportive care for thromboembolic complications includes corticosteroid administration, oxygen supplementation, and cautious fluid therapy. The thromboembolic complications seem to be most severe approximately 5-14 days following adulticide therapy. Although the use of aspirin has been advocated in the treatment of feline dirofilariasis, experimental evidence suggests that even at near toxic doses, aspirin has little effect on the arteriographic, hemodynamic and histopathologic abnormalities. Aspirin administration as an adjunctive therapy in heartworm disease is no longer advocated by the AHS. The dismal outcome associated with conventional therapy has prompted several investigators to pursue transthoracic and transvenous approaches for surgical removal of adult heartworms. Brown and colleages have removed adult worms from 5 cats using either a left or right thoracotomy. Cats with worms located primarily in the right atrium and cavae undergo a right lateral thoracotomy and right atriotomy while cats in which worms are seen only in the pulmonary artery undergo a left lateral throcatomy and pulmonary arterotomy. Using either a 2.5 mm diameter 2-3 pronged bronchoscopic grasping device or standard 10 cm length alligator forceps Thomas and colleagues have successfully removed adult worms from 3 of 4 cats. The forceps were manipulated using standard left sided echocardiographic imaging planes to adjust positioning. Venco et al report similar results using a flexible alligator forcep As techniques are refined surgical removal of adult heartworms may become the therapy of choice for symptomtic adult infections. Acute respiratory and cardiovascular failure have been reported during surgical heartworm retrieval typically following a worm being crushed or fragmented. Pretreatment with corticosteroids and/or antihistimes may reduce the severity of these types of reactions. MICROFILARICIDAL THERAPY Despite the fact that no available agent is FDA-approved for the elimination of microfilaria, microfilaricidal therapy is traditionally instituted 4-6 weeks after adulticide administration. Microfilaria are efficiently and rapidly cleared with ivermectin at 50 µg/kg (approximately 8 times the preventative dose) or with milbemycin at 500 µg/kg (the preventative dose), although each of these treatments represent extra-label uses of the drugs. Ivermectin can be diluted 1:9 in propylene glycol (IvomecR, MSD Agvet, Rahway, NJ) or in water (EqvalanR, MSD Agvet, Rahway, NJ) and administered orally at 1 ml/20 kg, although is practice is now strongly discouraged by the AHWS. Adverse reactions, the severity of which is likely related to microfilarial numbers, were observed in 10% (6% severe and 4% mild) of 126 dogs receiving ivermectin at the microfilaricidal dose. Signs included shock, depression, hypothermia, and vomiting. With fluid and corticosteroid (dexamethasone at 2-4 mg/kg IV) therapy, all dogs recovered within 12 hours. One fatality was observed 4 days after microfilaricidal therapy. Similar findings and frequency have been reported with milbemycin at the preventative dosage. Dogs so treated should be hospitalized and carefully observed for the day. Dogs <16 kg, harboring >10,000 microfilaria per ml blood are more apt to suffer adverse reactions. Benadryl (2 mg/kg IM) and dexamethasone (0.25 mg/kg IV) can be administered prophylactically to prevent adverse reactions to microfilaricidal doses of macrolides. A 90% microfilaricidal success rate can be expected with high dose ivermectin. Milbemycin, at 500 µg/kg, cleared 6/8 (75%) dogs which had received adulticide therapy and did not harbor male and female adults; microfilarial numbers were reduced by 99% on the day after treatment. A slower microfilarial kill rate can also be achieved with ivermectin, moxidectin, and selamectin at preventative doses. Microfilaricide therapy is infrequently necessary in cats as greater than 80% of all cases are occult. Dithiazanine iodide can be used at a dose of 6-10 mg/kg daily orally for 7 daysBoth ivermectin and milbemycin at the preventative dose are effective microfilariacides and should render cats microfilaria negative after 3-12 months of therapy. This author chooses an alternative approach beginning the administration of a macrolide preventative at the time of diagnosis, often days to weeks prior to adulticidal therapy. The advantage to this approach is that preventative is administered earlier. This allows immediate closure of the open theoretical window of HW exposure, while awaiting and 6 weeks beyond adulticide administration. With the "slow microfilaricides" (ivermectin, moxidectin, or selamectin), there is little chance of an adverse reaction, but the owner is warned and advised to administer the medication on a day when he/she will be at home. If milbemycin is used, it is administered in the hospital and/or preceded by administration of dexamethasone and benadryl, as described above. PREVENTION OF HEARTWORM INFECTION IN DOGS The introduction of the macrolide agents ivermectin (HeartgardR), milbemycin oxime (InterceptorR), moxidectin (ProHeartR and ProHeartR 6) and selamectin (RevolutionTM) has provided the veterinary profession with effective heartworm (HW) preventatives in a variety of formulations. Such agents, because they interrupt larval development during the first 2 months after infection, have a large window of efficacy and are administered monthly or less frequently. These agents are superior to diethylcarbamazine (DEC) in: convenience; producing less severe reactions when inadvertently given to microfilaremic dogs; allowing a grace period for inadvertent lapses in administration; efficacy with treatment lapses of up to 2-3 months when used continuously for the next 12 months; and lastly, having a dual role as microfilaricides. Ivermectin, a chemical derivative of avermectin B1 which is obtained from Streptomyces sp. is effective against a range of endo- and ectoparasites and is marketed as a once monthly heartworm preventative. It is marketed in a form with pyrantel pamoate to improve efficacy against intestinal parasites (Table 3). Macrolides offer a wide window of efficacy and provide some protection when treatment lapses (of up to two months) occur. This "reachback" effect is extended with continuous 12-month administration of ivermectin post-exposure to 3 months with 98% efficacy and to 4 months with 95% efficacy. As stated above, ivermectin is microfilaricidal at preventative doses (6-12 µg/kg/month), resulting in a gradual decline in microfilarial numbers. Despite this gradual microfilarial destruction, generally mild, adverse reactions (transient diarrhea) can occur if administered to microfilaremic dogs. Collies have been identified as a breed in which certain individuals are at increased risk of central nervous system signs and even death due to increased concentrations of ivermectin in the central nervous system. It is important to note that such adverse reactions have not been identified at preventative or even microfilaricidal doses of ivermectin. When used appropriately, ivermectin is virtually 100% effective in preventing HWI. Additionally, recent studies have shown ivermectin to have partial adulticidal properties when used continuously for 16-32 months. Milbemycin oxime is a member of a family of milbemycin macrolide antibiotics derived from a species of Streptomyces. At 500-999 µg/kg, it has efficacy against developing filarial larvae, arresting development in the first 6 weeks. It can therefore be given at monthly intervals with a "reachback effect" of 2 months when doses are inadvertently delayed. With 12 months' continuous treatment post-exposure, this "safety net" can be extended to 3 months with 97% efficacy, falling to 41% with lapses of 4 months. At the preventative dosage, milbemycin is a broad-spectrum parasiticide, also demonstrating effectiveness against certain hookworms, roundworms, and whipworms. Milbemycin is also safe for use in collies when prescribed at the preventative dose. With appropriate use, milbemycin is virtually 100% efficacious as a HW prophylactic. In microfilaremic dogs, milbemycin has greater potential for adverse reactions than do other macrolides, as it is a potent microfilaricide at preventative doses.2 Adverse reactions, similar to those observed with ivermectin at microfilaricidal doses (50 µg/kg) may be observed in microfilaremic dogs receiving preventative doses of milbemycin. Milbemycin has been used in an extra-label manner to eliminate microfilaria. As for microfilaricidal dosages of ivermectin, pretreatment with Benadryl® (2 mg/kg IM) and dexamethasone (0.25 mg/kg IV), prior to milbemycin treatment, may prevent adverse reactions, particularly in dogs with high microfilarial counts. Most recently, a semi-synthetic macrolide, selamectin, has been developed and marketed. It is unique in its spectrum and in the fact that is applied topically once monthly. Its efficacy is similar to that of other macrolides (virtually 100%, when used as directed). At 6-12 mg/kg topically, this preventative is effective at preventing heartworm infection and kills fleas and flea eggs, sarcoptic mange mites, ticks and ear mites. Bathing and swimming, as soon as 2 hours after application, did not affect efficacy. Safety has been shown at 10-fold topical doses, with oral consumption of single doses, and, in ivermectin-sensitive collies, at recommended dosages and five-fold overdoses for 3 months. Like other macrolides, selamectin has at least a 2 month "reachback effect" and with 12 months' continuous administration, is 99% protective after 3 month lapses in prophylaxis. Selamectin has microfilaricidal activity similar to other macrolides. In summary, the macrolides offer a convenient, effective and safe method of HW prophylaxis with varying spectra and methods of administration (Table 3). Prophylaxis should be commenced at 6-8 weeks of age in endemic areas, or as soon thereafter as climatic conditions dictate. Although safer than DEC in microfilaremic dogs, before first time administration, any dog over 6 months of age and at risk of infection, should be tested (antigen test, followed by a microfilaria test, if positive). Although protective for at least 8 weeks post-exposure, macrolides should be administered precisely as indicated by the manufacturer. If accidental lapses occur, the preventative should be reinstituted at recommended doses and maintained continuously for 12 months. If a lapse in preventative is prolonged (>2 months) and the risk for HWI deemed moderate or high, macrolides should be continued for a year without interruption. In addition, an antigen test should be performed approximately 6 months after the last chance for exposure to detect infection. Recent events have emphasized the importance of serial antigen testing when product switching is considered. If product switching is considered the author recommends obtaining a contemporary (at the time the switch is made), another test 4 months following the switch and then one at a year following the switch. This testing schedule will allow determination of the product involved in prevention failure if one were to occur. PREVENTION OF HEARTWORM INFECTION IN CATS Heartworm (HW) prevention should be discussed with every cat owner and considered for all cats cared for by veterinarians and students in this hospital. The estimated risk of heartworm infection among the population of chronically unprotected cats is about 20% of that in unprotected dogs in an area. Many people consider the low risk of feline HW disease to be so low that prevention is not important. However, feline HW disease is especially severe, and there is no available treatment. In many cases, the first sign is the only sign: sudden death. Other cats develop spontaneous worm death with life-threatening pulmonary inflammation/non-cardiogenic edema. Since the disease is very easy to prevent, and the products are both safe and effective, at a minimum the potential value of HW prevention in cats should be reasonably discussed with our clients. Although it is most likely safe to administer preventative medications to the vast majority of cats (even HW positive cats), the authors recommends obtaining at least and Ab titer prior to dispensing any product. This helps establish the exposure status of the individual patient and over time will help determine the exposure status of your practice population. Drugs Used for Prevention of Feline HW Disease
() = partially effective or incompletely studied. Ch = chewable, Tab = flavored tablet, T/I = tablet or injectable, Top = topical. *ivermectin/pyrantel pamoate, **milbemycin/lufenuron, ***injectable formulation Canine Myocardial Disease: Now We Are Talking Big Dogs Pathophysiology A "systolic dysfunction" syndrome (myocardial failure) with decreased LV ejection fraction and fractional shortening (FS%) similar to DCM in cats. There is significant decrease in myocardial inotropic state readily identified by echocardiography. Arrhythmias (especially atrial fibrillation) are common; tachycardia worsens the failure state by decreasing ventricular filling time. In atrial fibrillation, there is loss of the normal atrial "kick", which further decreases ventricular preload, especially at rapid ventricular heart rates.A-V anulus dilatation or papillary muscle atrophy often result in left or right A-V valve incompetency with MR/TR. Decreased cardiac output and renal and hormonal compensatory mechanisms lead to venous congestion causing left and/or right-sided heart failure.Acute ventricular arrhythmias may lead to syncope or sudden death and are very common in Doberman Pinscher dogs. Dilated Cardiomyopathy 
Dilated cardiomyopathy (DCM) is an idiopathic, genetic, or familial myocardial disease characterized by cardiac dilatation and reduced myocardial contractility. Histologic lesions include absence of inflammation, attenuated wavy fibers, loss of myocytes, and the presence of myocardial fibrosis. Coronary arteries are normal and the valves unremarkable, except in older dogs with concurrent mitral or tricuspid valve endocardiosis. Metabloic deficiencies (such as L-carnitine or taurine) are found in a minority of dogs, but the exact cause and effect relationship between these substrates and DCM is incompletely understood. Preclinical or occult DCM indicates an overtly healthy dog with echocardiographic evidence of systolic dysfunction by echocardiography. Most diagnoses are made when a breeder requests screening of an important dog or after a veterinary examination uncovers a murmur or arrhythmia. In most cases the suspicion of pre-clinical DCM is based on a minor axis measure of LV systolic function (the shortening fraction). Values less than 20-25% are considered suspicious in most laboratories. A grading scale for establishing a diagnosis of preclinical disease has been propsed but as yet has not been universally accepted., but there is no unanimity about one specific figure that indicates myocardial failure. This single linear approach can be questioned because larger dogs shorten relatively more in the apical to basilar direction and this motion is not assessed by the shortening fraction measure. Before rendering a diagnosis of occult DCM, the clinician should request more detailed echocardiographic measures of systolic function including LV short-axis shortening area, apical-to-basilar mitral annular motion, and volumetric estimates of LV ejection fraction using the method of discs or a prolate ellipsoid model. Serial examinations also can be helpful in establishing a downward trend in LV function. Holter ECG is a useful adjunct for establishing the diagnosis in breeds prone to DCM with cardiac arrhythmias. Most would consider >50 VPC/PVC's per day abnormal. When the diagnosis of occult DCM is certain, cardioprotection should be considered. This can be initiated with an angiotensin converting enzyme inhibitor (ACEI) such as enalapril, benazepril, ramapril (ramipril), or quinapril given once daily. If persistent arrhythmias are evident, a beta-blocker or sotalol should also be considered (see above for doses). Advanced cases of DCM are presented with exercise intolerance and clinical signs of CHF. There can be marked weight loss and cachexia. Clinical signs of left-sided CHF include tachypnea, respiratory distress, and coughing related to pulmonary edema. Right-sided CHF is characterized by jugular pulses and jugular venous distension, hepatomegaly, and ascites. Biventricular failure includes the above findings along with pleural effusion. Auscultation may reveal atrial and ventricular gallops, systolic murmurs, or arrhythmias. The arterial blood pressure usually is normal owing to vasoconstriction and neurohormonal activation, but will be decreased in profound DCM with cardiogenic shock 
Laboratory studies support the diagnosis in advanced cases of DCM. The EKG may demonstrate abnormalities typical of cardiomegaly (wide or tall P-waves; wide or increased amplitude QRS complexes) or myocardial disease (wide QRS, slurred R-wave descent, and ST-segment coving). One or more of the aforementioned cardiac arrhythmias may be evident, though a Holter examination (24 hour ambulatory) is needed to assess the frequency of ventricular ectopic rhythms. Thoracic radiography reveals cardiomegaly and may demonstrate typical radiographic features of heart failure. The echocardiogram shows ventricular dilation, reduced left ventricular shortening fraction, increased E-point to septal separation, decreased wall excursion, left atrial dilation and variably right-sided cardiomegaly. Doppler evidence of mitral regurgitation and tricuspid regurgitation, pulmonary hypertension, and diastolic ventricular dysfunction are common. Routine laboratory tests are usually normal or reflect intercurrent disease, consequences of CHF, or complications of CHF therapy. Specialized blood tests for L-carnitine or taurine may be performed in selected cases. Initial hospital therapy of CHF caused by DCM includes diuresis with furosemide (2-4 mg/kg IV, IM q6-8h), supplemental oxygen, nitroglycerin ointment (1-1.5 inches for a large breed dog q12h), and rest. Life-threatening pulmonary edema can be managed with furosemide and infusion of sodium nitroprusside (0.5-2.5 mcg/kg/min) with careful attention paid to arterial blood pressure (titrate the infusion to a systolic value of 85 to 90 mm Hg). Thoracocentesis is indicated for moderate to large pleural effusions. When there is CHF with systemic hypotension, the treatment should be furosemide, oxygen, and dobutamine (2.5 to 10 mcg/kg/min). Dobutamine can have relatively long-term benefits and is continued for at least two days, at which point the drug is tapered over a 6-12 hour period while assessing blood pressure. In the setting of hypotension, vasodilators are avoided until the pressure is stabilized by dobutamine for at least two hours after which therapy with either sodium nitroprusside or an ACEI can be initiated. In dogs with atrial fibrillation, digoxin (0.005 mg/kg PO q12h) or amioderone is prescribed to control the ventricular rate response. Home therapy for CHF caused by DCM includes furosemide, an ACE-inhibitor, digoxin, and sodium-restricted diet. Fluid retention is controlled with furosemide (2-4 mg/kg PO q8-12h) and sodium restriction if possible. Digoxin therapy is initiated unless there is a contraindication (moderate renal failure, complicated ventricular ectopics). An ACEI is prescribed for once daily use (with a typical dose of 0.5 mg/kg PO for enalapril or benazepril), and the dose increased to twice daily after one or two weeks of home care. Where available, pimobendan (a phosphodiesterase inhibitor-calcium sensitizing inotropic drug with vasodilating properties) should be considered based on limited but promising clinical studies. Spironolactone (12.5 to 25 mg PO q12h in a large dog) may be added to block the cardiotoxic effects of aldosterone and impede sodium retention in the distal nephron. A beta-blocker may be considered to blunt the cardiotoxic effects of the sympathetic nervous system; however, heart failure must be well controlled first. The beta-blocker of choice in human patients is carvedilol. This drug is both a beta-blocker and alpha-adrenergic blocker (which helps to reduce the afterload on the left ventricle). Carvedilol also had anti-oxidant properties that may benefit the myocardium. Unfortunately, the prescription drug (Coreg) is expensive. Dosing can be difficult even in large dogs that may not tolerate the negative inotropy of any beta-blocker. Thus, low initial dosages are mandatory (start with ¼ to ½ of a 3.125 mg carvedilol tablet q12h). While there are clear theoretical benefits of beta-blockers in canine DCM, one's practical ability to initiate and maintain treatment may be very limited and CHF can worsen (often with pleural effusion). Certainly, when AF complicates CHF, either a beta-blocker or diltiazem (0.25 to 1.0 mg/kg PO q8h) is prescribed to control ventricular rate. Clinical Syndrome Signalment "Giant" breeds and other large dogs (> 15 kg). Occasionally other breeds especially Springer and Cocker Spaniels. Males > Females. Age - usually 2 5 years. Client complaint and anamnesis Animals are usually presented for signs referable to heart disease or CHF: Respiratory: Hyperpnea - tachypnea - dyspnea - orthopnea - coughing Weight loss - often dramatic; it can occur within the 2 4 weeks prior to admission; this cardiac cachexia is severe in some dogs like Doberman Pinschers, Weakness Lethargy - anorexia Abdominal distension (ascites) Syncope Some dogs are asymptomatic Physical examination Weight loss is common, weakness, depression, possibly cardiogenic shock (obtunded, hypothermic, pale), pulse abnormalities: Hypokinetic from decreased output and arrhythmias, Erratic, with pulse deficits when atrial fibrillation or VPC/ventricular tachycardia is present, abnormal jugular pulses from TR, arrhythmias, or right-sided CHF, hyperpnea and dyspnea are common due to pulmonary edema or pleural effusion, pleural fluid may be evident on percussion or auscultation, muffled breath sounds are heard if there is pleural effusion; crackles if there is pulmonary edema. Abnormal heart sounds including reduced intensity S1 (myocardial failure) with S3 or summation gallops is common (the gallop is especially loud when the dog is in sinus rhythm), left or right apical systolic murmurs (due to MR or TR) are us |