UNISVET Itinerario di Cardiologia del cane e del gatto Weekend n.3 PULMONARY HYPERTENSION

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1 PULMONARY HYPERTENSION Introduction Pulmonary hypertension (PH) is characterised by an elevation of the arterial pressure and vascular resistance within the pulmonary circulation. Pulmonary hypertension is recognised as a complex and multidisciplinary disorder in people and this is even more so in small animals due to the paucity of appropriate studies. In veterinary medicine, PH has been described as echocardiographically-estimated pulmonary arterial systolic pressure (based on a peak systolic tricuspid regurgitation gradient) greater than 30 mmhg. In people, specific hemodynamic criteria include systolic pulmonary arterial pressure (PAP) >30 mmhg, diastolic PAP >20 mmhg, mean PAP >25 mmhg, pulmonary capillary wedge pressure <15 mmhg. Pre and Post capillary PH Pre-capillary PH should be distinguished from Post-capillary PH. Pre-capillary PH is characterised by an isolated elevation of PAP with normal pulmonary capillary pressure (PCP). Since in this setting, the pulmonary hypertensive state is limited to the arterial component of the pulmonary vasculature, pulmonary arterial hypertension (PAH) is distinguished from other forms of PH. In contrast, post-capillary PH is caused by diseases affecting the left side of the heart with secondary pulmonary venous congestion, which in turn leads to an elevation of PCP and PAP. The most important consequence of PH is chronic overload of the right heart (cor pulmonale) which ultimately leads to right heart failure and is thus responsible for the poor prognosis of patients with severe PH. Because of the complex pathophysiology, the importance of a proper diagnostic Dr Luca Ferasin ( 1

2 evaluation and to establish a precise diagnostic classification, and the dynamic development of therapeutic recommendations, patients with pulmonary hypertension should be assessed by experienced clinicians. Aetiology and Pathophysiology The ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension, defines PH as a syndrome resulting from restricted flow through the pulmonary arterial circulation and resulting in increased pulmonary vascular resistance (PVR) and ultimately in right-sided heart failure. The predominant cause of increased PVR is loss of vascular luminal cross section due to vascular remodelling produced by excessive cell proliferation, although excessive vasoconstriction plays a significant role in approximately 20% of human patients. Improved understanding of the disease pathways in PAH, even if a single primary cause remains elusive, has led to therapeutic strategies, including the administration of prostanoids, the antagonism of endothelin receptors, and inhibition of PDE-5 (which is currently the most used therapeutic intervention in veterinary medicine). Histologically, PAH is characterised by a variety of arterial abnormalities, including intimal hyperplasia, medial hypertrophy, adventitial proliferation, thrombosis in situ, varying degrees of inflammation. An individual patient may manifest all of these lesions, and the distribution of lesions may be diffuse or focal. The right ventricular (RV) function is a major determinant of functional capacity and prognosis in PAH. While RV hypertrophy and dilatation are initiated by increased afterload (i.e., elevated PVR), the adequacy of the RV s compensatory response (preservation of stroke volume) is quite variable amongst individuals and it is unclear why some patients compensate while others decompensate with clinical manifestations of right-sided heart failure. Dr Luca Ferasin ( 2

3 Table: Classification of pulmonary hypertension (adapted from Glaus T, BSAVA 2012) Group 1 Group 2 Group 3 Group 4 Group 5 Pulmonary arterial Pulmonary Pulmonary Pulmonary Miscellaneous hypertension (PAH) hypertension hypertension hypertension due associated with associated with to left heart respiratory disease thromboembolic disease and/or hypoxemia disease Idiopathic (formerly Left ventricular Interstitial lung Primary cardio- primary PH, PPH) or atrial disease disease, e.g. vascular lesion, pulmonary fibrosis e.g. D. immitis, A. vasorum Associated with congenital systemicto-pulmonic shunts Left-sided valvular disease Chronic upper airway obstruction Medical condition predisposing to pulmonary thromboembolism Persistent pulmonary hypertension of the Chronic exposure to high altitude newborn Associated with drugs, toxins, inflammation Clinical Signs Clinical presentation of dogs and cats with PVH are often nonspecific and are mainly characterised by exercise intolerance, respiratory distress, abdominal distension, occasional cough and syncopal episodes. However, it is almost impossible to establish whether the clinical signs are caused by the underlying disorder or the PH per se. If right-sided heart failure develops, signs may include jugular pulsation, abdominal enlargement (hepatomegaly and ascites), pleural effusion, arrhythmias. Diagnosis Thoracic radiography It can occasionally identify signs referable to PH as well as signs of potential underlying causes. The dorsoventral view is probably more helpful to identify right ventricular ( inverted D shape of the heart) and enlargement of the main pulmonary artery. Peripheral pulmonary vasculature may be Dr Luca Ferasin ( 3

4 tortuous and engorged. Left atrium is enlarged and pulmonary veins are congested with underlying left atrial, ventricular or mitral valve disease. Signs of underlying bronchial, interstitial or alveolar pulmonary disease may also be observed. Echocardiography It is necessary to confirm or rule out many causes of PH, including acquired left ventricular heart disease (mitral endocardiosis, dilated cardiomyopathy) and congenital cardiovascular shunts. It allows confirmation of PH qualitatively and quantitatively: Qualitative assessment: dilation of right ventricle and right atrium, thickening of right ventricular wall and papillary muscles, paradoxical septal motion, and decreased left ventricular chamber size. Quantitatively: in the absence of pulmonic stenosis, the Doppelr identification and quantification of tricuspid regurgitation will correlate to right ventricular systolic pressure (= systolic PAP) by using the modified Bernoulli equation (PAP = 4 x V 2 max, assuming that right atrial pressure approximates zero mmhg in systole). Therefore if TR Vmax is 2.8 m/s the PAP should be >30 mmhg indicating PH. Diastolic PAP is calculated with Doppler quantification of pulmonary valve insufficiency (PI); PH is considered to be present when end-diastolic PI-PG is >20 mmhg (Vmax >2.2 m/s). Finally, PH can be suspected on spectral Doppler interrogation of the pulmonic flow. A normal pulmonary artery velocity flow profile should have a dome-like profile with the peak velocity flow occurring in mid-systole with symmetric acceleration and deceleration phases. If the peak velocity flow is asymmetric occurring early in systole with a steep and rapid acceleration phase and slower deceleration or with a notch occurring in the deceleration phase, PH should be suspected. Values of AT: ET 0.31 for and an AT value of 58 ms are also predictive of PH (AT= acceleration time, ET= ejection time). Advanced or confirmatory testing Contrast ultrasound (bubble study) of the heart and descending aorta to rule out a cardiovascular right-to-left shunt. Shunting is also possible in congenital pulmonary arteriovenous fistulas or in acquired pulmonary arteriovenous shunting, such in A. vasorum infection. In this case, bubbles will take at least 3 cardiac cycles from their appearance in the right atrium till their appearance in the left atrium. Right-sided cardiac catheterisation for invasive measurement of pulmonary wedge pressure as an estimate of left atrial pressure, and systolic and diastolic pulmonary artery pressure. Pulmonary CT to identify/rule-out parenchymal disease and Angio-CT for PTE. Pulmonary ventilation-perfusion scintigraphy to rule out PTE Pulmonary histopathologic evaluation to confirm PAH Dr Luca Ferasin ( 4

5 Current therapeutic options for PH The therapeutic target remains the identification and removal of the primary cause of PH (e.g. removal of heartworms, thrombolysis in pulmonary thromboembolism, etc). Secondary target is to improve oxygenation (Oxygen, cage, nasal or mask) and reduce the vascular resistance (vasodilation). As far as I am aware, there are no controlled studies to prove the efficacy of any medical treatment in naturally occurring PH in dogs or cats, however, all the following treatments have been indicated as potentially beneficial for lowering PAP: Amlodipine (Istin, Norvasc) in moderate PH, starting at 0.05 mg/kg PO SID Sildenafil (Viagra) in severe PH, 2 3 mg/kg PO BID or TID. Pimobendan (Vetmedin, Cardisure), mg/kg BID. Further reading ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation (2009) 119: Glaus T. Pulmonary hypertension - pathophysiology, diagnosis and treatment. Proceedings BSAVA Annual Congress, Birmingham April 2012 Kellum HB and Stepien RL. Sildenafil citrate therapy in 22 dogs with pulmonary hypertension. J Vet Intern Med Nov-Dec;21(6): Rosenkranz S. Pulmonary hypertension: current diagnosis and treatment. Clin Res Cardiol (2007) 96: Schober KE and Baade H. Doppler echocardiographic prediction of pulmonary hypertension in West Highland white terriers with chronic pulmonary disease. J Vet Intern Med 2006;20: Dr Luca Ferasin ( 5

6 SYSTEMIC HYPERTENSION Introduction Systemic hypertension is a sustained increases in blood pressure (BP). In veterinary clinical settings this can be caused by artefacts (ie, stress-induced or white-coat hypertension) or be secondary clinical conditions that are accompanied by increased BP (secondary hypertension). Primary or idiopathic hypertension is also possible but this represents a rare condition in small animal medicine. White Coat Effect The artefactual increase in BP ( white-coat effect ) occurs as a consequence of the measurement process, generally due excitement or anxiety which evoke the sympathetic response of the autonomic nervous system. Since this condition represents a natural physiological response, the hypertension tends to resolve once the cause/artefact has been eliminated (eg, altering measurement conditions to reduce the animal s anxiety or measuring BP at the animal s home). Anxiety-induced increases in BP can lead to a false diagnosis of systemic hypertension. Unfortunately, the effects of anxiety on BP are not predictable, as some animals exhibit a dramatic increase in BP whereas others do not, and some animals may even exhibit a decrease in BP as a result of the measurement process. The latter effect presumably is due to parasympathetic nervous system over-activity. Secondary Hypertension This type of hypertension represents a secondary effect of another underlying clinical condition (eg renal disease, hyperadrenocorticism, diabetes, obesity, pheochromocytoma, hyperthyroidism), or could represent a side-effect of an hypertensive medication (eg glucocorticoids, mineralocorticoids, erythropoietin, sodium chloride, phenylpropanolamine, and nonsteroidal anti-inflammatory drugs). Dr Luca Ferasin ( 6

7 The presence of a condition known to cause secondary hypertension, even if effectively resolved by therapeutic intervention, should prompt serial follow-up evaluations. Primary (idiopathic) hypertension The term describes the presence of hypertension in the absence of any identifiable predisposing causes. It is rare in small animals, although it has been reported in dogs. However, it may also be caused by subclinical kidney disease, making diagnosis of primary hypertension exteremely challenging. Therefore, the term idiopathic is probably more accurate than primary in the veterinary clinical settings. A diagnosis of idiopathic hypertension is established when reliable BP measurements demonstrate a sustained increase in BP concurrent with normal CBC, serum biochemistry, and urinalysis, although hypertension may also induce polyuria ( pressure diuresis ). Other diagnostic tests may be indicated, such as renal and adrenal ultrasound examination, measurement of glomerular filtration rate, quantitative assessment of proteinuria, T4 determination, and adrenal function tests. Although secondary hypertension remains the most common category of high BP in dogs and cats, idiopathic hypertension is more common than previously recognised, accounting for approximately 18 20% of cases in cats. Isolated Systolic or Diastolic Hypertension These terms refer to the occurrence of an increase in systolic only or diastolic only pressure. Such a finding may be artefacts produced by under/over-estimation of the peak or trough of the blood pressure curve by an indirect device. The presence of this type of artefact should be considered whenever a very small (,20 mm Hg) or large (.60 mm Hg) pulse pressure is reported by an indirect device. Currently, in veterinary medicine, there is an emphasis on the diagnosis of systolic hypertension, primarily because the most common technique (Doppler) only provides systolic readings. Systolic BP is an important determinant of hypertensive tissue damage in small animals. However, isolated systolic and diastolic hypertension can and do occur in dogs and cats and, when properly diagnosed, warrant classification and management. Target Organ Damage (TOD) Sustained increases in BP cause injury to tissues and the rationale for treatment of hypertension is the prevention of such injury (end-organ or target-organ damage). In the kidney, for example, TOD is generally manifested as an enhanced rate of decrease in renal function, early renal death, and proteinuria or some combination of these findings. The severity of albuminuria has been directly Dr Luca Ferasin ( 7

8 related to the degree of increase in BP in an experimental study of chronic kidney disease (CKD) in cats. Proteinuria has also been directly related to the extent of increase in BP and to the rate of decrease in GFR in an experimental study in dogs. The magnitude of proteinuria is a negative prognostic factor in spontaneous feline CKD and reduction of proteinuria is perhaps the most reliable evidence of benefit in an animal treated with antihypertensive agents, particularly in cats. Ocular lesions, often accompanied by acute blindness, are observed in many cats with hypertension, and although prevalence rates for ocular injury vary, it has been reported to be as high as 100%! Encephalopathy has been reported in small animals as a consequence of cerebral oedema and haemorrhage. Observed clinical signs are typical of intracranial disease and include lethargy, seizures, acute onset of altered mentation, altered behaviour, disorientation, balance disturbances (eg, vestibular signs, head tilt and nystagmus), and focal neurologic defects due to stroke-associated ischemia. Cardiac changes in hypertensive animals are frequent and may include systolic murmur, gallop rhythm, and left ventricular concentric hypertrophy (LVH). Effective antihypertensive therapy may decrease the prevalence of LVH in affected dogs and cats. Epistaxis, presumably due to hypertension-induced vascular abnormalities, has been associated with systemic hypertension in people but it is rarely observed in small animals. Dr Luca Ferasin ( 8

9 Blood pressure measurement Measurement of arterial blood pressure allows an objective and definitive diagnosis of hypertension. Blood pressure measurements can be obtained either by direct or indirect measurements. Direct (invasive) technique requires the catheterisation of an artery and is mostly used for anaesthetic monitoring. Indirect (non invasive) procedures are more appropriate for use in the majority of clinical cases since they do not require sedation or anaesthesia and involve minimal stress to the patient. Two successful non-invasive methods are represented by Doppler and oscillometric techniques. On the contrary, the auscultatory technique commonly used in people, is unsuitable in small animal medicine, as the frequency of the sound associated with blood flow to a limb is too low to be audible just with a stethoscope. Blood pressure readings can be taken from the forelimb, the hindlimb and the tail. The author prefers to use the common digital artery on the forelimb. For blood pressure recording in this location, a cuff with a width approximately 40% of the circumference of the limb is placed around the forelimb between the elbow and the carpus. Doppler technique A small quantity of ultrasound gel is applied to the palmar surface of the forelimb between the carpal and metacarpal pads area to allow better detection of the Doppler signal. In some cases, the area in proximity of the artery needs to be clipped. The Doppler probe is gently placed onto the prepared area and moved until the pulse can be heard. Once a good signal has been obtained, the cuff is inflated using the hand-pump sphygmomanometer to a pressure of around 30 mmhg above the point at which the pulse can no longer be heard. The cuff is then slowly deflated and the pressure gauge observed. The reading at which the pulse is first heard to return is taken to be the systolic blood pressure (SBP). This procedure is repeated 5 times over 2-3 minutes and the SBP taken as an average of these readings. Oscillometric technique The oscillometric system is characterised by an automatically inflated and deflated cuff. During deflation, variations in cuff pressure are sensed by a transducer. This system is very easy to operate and also offers the advantage of giving diastolic as well as systolic blood pressure readings. On the other hand, errors can result if the patient moves or if significant arrhythmias are present. Dr Luca Ferasin ( 9

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11 Management of the hypertensive patient Underlying diseases that may be causing secondary hypertension should be identified and treated while continuing to monitor BP. With the exception of advanced cerebral hypertensive damage, antihypertensive therapy generally is not an emergency intervention. A decision to treat is made on the basis of categorization of TOD risk. As hypertension in dogs and cats is most often secondary, antihypertensive drug therapy by itself is often not sufficient and initial considerations should always include the identification and management of conditions likely to be causing secondary hypertension and the identification and treatment of TOD. Although frequently recommended as an initial step in the pharmacological management of high BP, dietary salt restriction is controversial and the available evidence suggests that substantial sodium restriction alone generally does not reduce BP. In fact, sodium restriction may activate the reninangiotensin-aldosterone axis (RAAS) and eventually increase BP ACEinhibitors (ACEI) and calcium channel blockers (CCB) are the most widely used antihypertensive agents in veterinary medicine. In dogs, ACEI are usually recommended as the initial agent of choice. Since ACEI preferentially dilate the efferent arteriole, they lower the intraglomerular pressure and frequently decrease the magnitude of proteinuria. However, ACEI should not be used in dehydrated patients in which the GFR might drop precipitously. These patients should be carefully rehydrated and then re-evaluated before instituting antihypertensive therapy. If primary causes of systemic hypertension have been ruled out, administration of amlodipine can be considered. Initial dose is mg/kg SID or BID. The dose can be titrated upwards weekly as required up to 0.4 mg/kg, monitoring blood pressure regularly. In cats, although the RAAS axis may play a role in the genesis or maintenance of systemic hypertension, CCB are often the first choice for antihypertensive therapy due to established efficacy (e.g. amlodipine mg/cat SID. The dose may be increased slowly or the frequency increased to BID if necessary). Blood pressure monitoring is essential. A mean decline in systolic BP of mm Hg is typically observed in cats with moderate-to-high risk of TOD. Despite significant antihypertensive efficacy, CCB have not been shown to increase survival time in treated cats and their use may activate the systemic or intrarenal RAAS. A key predictive factor is the effect on proteinuria. Dr Luca Ferasin ( 11

12 The co-administration of ACEI and CCB is another possibility. Although diuretics are frequently administered to hypertensive people, these agents are not firstchoice drugs for veterinary patients with CKD, in which dehydration and volume depletion may prove problematic. References Brown et al. Guidelines for the Identification, Evaluation, and Management of Systemic Hypertension in Dogs and Cats. J Vet Intern Med 2007;21: Dr Luca Ferasin ( 12

13 FELINE AORTIC THROMBOEMBOLISM Introduction Arterial thromboembolism (ATE) is characterised by the embolisation of a clot in an artery in the systemic circulation. The artery in which the clot will eventually lodge depends on the origin of the clot itself, its size and the diameter of the artery. In most cases, the initial blood clot forms inside the cavities of the left heart, particularly in the left auricle. The clot, or a fragment of it, can subsequently flow to an anatomical location in the systemic arterial circulation, normally represented by a saddle location at the aortic trifurcation, and subsequently compromising the blood flow in both external iliac arteries. Occasionally, emboli may travel into more distal arteries, compromising the blood flow to a single limb, including forelimbs. More rarely, ATE affects cerebral, renal, and mesenteric arteries. The majority of cats presenting with ATE have underlying heart disease, although neoplasia (hepatocellular carcinoma, pulmonary carcinoma, anaplastic carcinoma, vaccine-associated fibrosarcoma, and squamous cell carcinoma) and thyroid disease are also highly associated with ATE. Clinical presentation The classic clinical presentation is characterised by acute pain and paresis/paralysis of the affected limbs. The paws of the affected limb may appear pale or cyanotic depending on the severity of the local ischemia, and the limb extremity is generally colder than non-affected limbs. In most cases the saddle thrombus obstructs the external iliac arteries and consequently femoral pulses are weak or absent. However, if the thrombus lodges across the internal iliac arteries femoral pulses may still be palpable despite the presence of painl and hind limb paralysis/paresis. Dr Luca Ferasin ( 13

14 Conversely, the femoral pulsation may be difficult to be detected in cats with shock, therefore the use of a Doppler transducer may assist the clinician in the identification of the arterial pulsation in the affected limb. Diagnosis Diagnosis of ATE can be challenging and it is usually based on history and clinical signs. In cats spending most of their time outdoors, the patient can be found recumbent on the ground and the owner s initial thought is often towards a road traffic accident. Indeed, neurological disorders and musculo-skeletal injuries are important differential diagnoses. In these patients, marked elevations of AST and CK are highly suggestive of ischemic damage to the limb skeletal muscles. In cats, both AST and CK have short half-lives, and their values peak at 6-12 hours, returning to normal within hours after the acute ischemic event. Thoracic radiographs may reveal cardiomegaly and signs of CHF (pulmonary oedema and/or pleural effusion). Echocardiography allows identification of concomitant heart disease and, sometimes, confirms the presence of a thrombus or spontaneous echo-contrast (smoke) within the heart chambers. The localisation of the thrombus can be deduced from the affected limb and, in many cases with hindlimb paralysis/paresis, where available, colour Doppler ultrasound examination of the descending aorta can be used to visualise the point of obstruction. Clinical management There is little scientific evidence and no consensus amongst clinicians regarding the ideal treatment of cats affected by ATE. Surgical embolectomy would appear the most logical approach, but is difficult due to the size of the affected vessels and the anaesthetic risks encountered in cardiac patients. It is also an extremely unrewarding technique due to the high mortality associated with rapid reperfusion (reperfusion injury). This complex phenomenon occurs when a large ischemic area is acutely reperfused, accompanied by a violent inflammatory response within damaged tissues and leakage of cellular metabolic waste products into the circulation. Physical thrombolytic therapy may also appear as a rational intervention. This can be performed with pressurised saline jets to physically dissolve the thrombus (AngioJet Rheolytic Thrombectomy) with clinical outcome comparable with conventional therapies. Medical thrombolytic therapy (urokinase, streptokinase and tissue plasma activator -TPA) has shown mixed results, especially because of complications due to rapid reperfusion. In analogy with myocardial infarction in people, these expensive drugs are only effective if administered within hours of the occurrence of ischemia, which is rarely possible in veterinary patients. Dr Luca Ferasin ( 14

15 Conservative treatment is commonly recognised as an acceptable management for feline ATE cases, as long as pain is optimally controlled and patients undergoing treatment are properly selected. The rationale of conservative treatment is to support the patient until the development of collateral circulation to provide sufficient blood supply to the ischemic areas. The time necessary for a satisfactory clinical improvement depends on the severity of the insult and the underlying cause and may range from days to months. Euthanasia should be considered in cases of non-responsive patients (lack of clinical improvement after 2-3 days or unsatisfactory pain control) or for those exhibiting signs highly associated with a negative prognosis (severe hypothermia, multiple limbs affected with complete loss of motor function, concurrent CHF). The fact that feline ATE is a devastating clinical manifestation is undisputable. However, if euthanasia with no attempt to treat is excluded from survival analyses, the number of cats that can survive to discharge can increase up to 40-70%. Parameters that should be evaluated to select potential survivors are: rectal temperature above 37.2 C (98.9 F) presence of limb motor function as evidenced by voluntary movement of limbs or positive withdrawal reflex absence of radiographic signs of congestive heart failure (CHF) such as pulmonary oedema, pleural effusion single limb affected (rather than two or more) absence of tachycardia (i.e. HR < 180 bpm) absence of hyperkalaemia (i.e. potassium < 5 mmol/l) Of all the above parameters, rectal temperature is the strongest survival predictor, indicating that hypothermia is most likely a reflection of compromised systemic hemodynamic status rather than just local hypo-perfusion. Short-term, in-hospital, conservative management The goal of conservative treatment of ATE is to: guarantee adequate rest and pain relief reduce the risk of further thrombus formation improve systemic perfusion and preserve the function of the affected limbs control effusions in cases complicated by CHF provide additional support where needed The ideal analgesic for cats affected by ATE probably depends on different patient responses, individual clinician s experience and drug availability. However, a variety of successful analgesic drugs have been reported, including butorphanol, buprenorphine, morphine, and fentanyl. A Dr Luca Ferasin ( 15

16 common protocol adopted in veterinary practice is intravenous or sublingual buprenorphine administration followed by application of a fentanyl patch to allow consistent and prolonged analgesia. Intravenous or subcutaneous unfractionated heparin (UFH) can be considered during the acute phase (hospitalisation period) due to the rapid onset of its anticoagulation properties. Conversely, intramuscularly administration of heparin should be avoided due to the risk of injection-site haematomas. Low-molecular weight heparin (LMWH) does not offer any practical advantage over UFH for short-term treatment. Cats absorb and eliminate LMWH very rapidly and therefore require higher doses and more frequent injections of the LMWH to achieve the therapeutic effects observed in human patients. It is also considerably more expensive than UFH. Correcting systemic perfusion is a challenging task, especially in cats with signs of CHF who should never receive aggressive fluid therapy. However, if patients are not in CHF and appear dehydrated, cautious fluid therapy would certainly be indicated. Acepromazine (ACP) has been advocated for many years as a suitable drug to improve systemic perfusion in cats with ATE. However, it s hypotensive effect can also exacerbate the signs of shock and many clinicians consider the use of ACP inappropriate for cats with ATE. Similarly, external physical warming should only be performed very cautiously to avoid the risk of peripheral vasodilation and reduction of core perfusion. Little is known about the benefits of physiotherapy. Deep tissue massage of the affected areas and gentle forced movements of the affected limbs may be beneficial as long as the manoeuvre does not evoke pain or discomfort. Soft beds and gentle turning of the patient may also reduce pain and discomfort. Management of congestive heart failure is described in the previous chapter. Cats affected by ATE are usually inappetant and nutritional support can be easily achieved via nasooesophageal tubing in cats without respiratory distress. Long-term, at home, conservative management When the patient appears sufficiently comfortable and is regaining appetite, discharge can be discussed. The owner should be prepared to support the cat at home, including hand-feeding, grooming and toilet assistance. Cats with an underlying cardiac disease and CHF should receive appropriate chronic treatment. Similarly, appropriate treatment should be considered in cats affected by hyperthyroidism or neoplasia. Prophylactic anti-coagulation therapy has been debated for several years. However, at present, there is no sufficient scientific evidence to support a specific medication or protocol. Unfractionated heparin treatment requires frequent parenteral administrations to achieve consistent anticoagulation and is not generally suitable for home treatment. Oral aspirin is frequently Dr Luca Ferasin ( 16

17 prescribed at 75mg ( baby aspirin ) every 72h. However, a lower dose (5mg/cat/q72h) seems associated with fewer side effects and similar recurrence rate of ATE when compared to the traditional dose, although a compounding pharmacy is necessary to obtain accurate low dosing.. Nevertheless, very little is known about pharmacokinetics and clinical efficacy of aspirin in preventing ATE. Clopidogrel (Plavix, mg/cat PO q 24h) is another inhibitor of platelet aggregation that seems to have few adverse effects in cats. It is commonly used in veterinary practice as a daily medication to prevent recurrence of ATE often in association with aspirin. However, at present, the clinical efficacy of clopidogrel for ATE prevention has not yet been reported. Prognosis Long-term survival is negatively affected by the concomitant presence of CHF or neoplasia. Many survivors can experience a full recovery. However, a degree of neurologic or muscular dysfunction of affected limbs may persist in some patients. Recurrence rate of ATE is relatively low (approximately 30%), although these episodes are often fatal or require prompt euthanasia. Congestive heart failure represents the most common cause of death (or euthanasia) in cats surviving acute episodes of thromboembolism (median survival time of 77 days, compared to 223 days in cats with ATE without concurrent CHF). Further reading 1. Ferasin L. Cardiomyopathy and congestive heart failure. BSAVA Manual of Feline Practice: A Foundation Manual. 1st Edition Wiley Ed. 2. Smith SA, Tobias AH. Feline arterial thromboembolism: an update. Vet Clin North Am Small Anim Pract 2004;34: Borgeat K et al. Arterial thromboembolism in 250 cats in general practice: J Vet Intern Med :102-8 Dr Luca Ferasin ( 17

18 CARDIOVASCULAR PARASITES Introduction There are essentially caused by two parasites: Angiostrongylus vasorum or Dirofilaria immitis. Angiostrongylus vasorum metastrongyloid which causes a serious heart and lung condition in dogs. It is endemic in the dog population of Ireland, South-West of England and it is also present in Italy and France. Cycle the adult worms (2.5 cm) live in the pulmonary artery and right ventricle of dogs. viviparous: larvae are coughed up, swallowed, and passed in the faeces. the intermediate host of Angiostrongylus is one (or more) species of slug in which the larval worms live, and dogs may become infected either by eating the slugs themselves (and some dogs are known to do this) or by inadvertently ingesting slug faeces. once in the mammal host, the worms migrate to the right ventricle and pulmonary artery where they may cause pulmonary artery obstruction, endoarteritis, thrombosis, as well as parenchymal damage due to larval migration. Clinical signs congestive heart failure lower respiratory signs (cough, haemoptysis, dyspnoea) regional haemorrhage (including ocular, brain, dental, etc) DIC may occur in severely affected cases or after sudden death of parasites (parasitic embolism) after treatment Dr Luca Ferasin ( 18

19 Diagnosis history and clinical signs radiographs: mixed parenchymal changes (patchy alveolar density and/or diffuse interstitial pattern). Pulmonary congestion and right heart enlargement may be noted. echocardiography: severe cases may present with pulmonary hypertension, right ventricular dilation and hypertrophy. faecal parasitology (Baermann test) Larvae in BAL Angio Detect Test (pet-side antigen blood test that s specific for the detection of Angiostrongylus vasorum infection) Treatment fenbendazole (20 mg/kg daily for 21 days) imidacloprid/moxidectin (Advocate spot on) restricted exercise is recommended to reduce the risk of thromboembolism after treatment oxygen, blood transfusion, dexamethasone (in case of thromboembolism or DIC) Dirofilaria immitis It is a large, whitish worm. The females are approximately 30cm long, while the males are 23cm long with a spirally coiled tail. Cycle adults are primarily found in the right ventricle and pulmonary arteries of dogs (rarely cats). viviparous: the females produce small, vermiform embryos called microfilariae. they can cross the capillary beds and so are found throughout the vascular circulation circulating microfilariae are ingested by a female mosquito while taking a bloodmeal from an infected host (A). These prelarval stage develops in the mosquito into the 3rd stage (L3) larva (B). infective L3's migrate from the tubules to the lumen of the labial sheath in the vector's mouthparts. development in the mosquito is temperature dependent, requiring approximately two weeks of temperature at or above 27C (80F).Below a threshold temperature of 14C Dr Luca Ferasin ( 19

20 (57F),development cannot occur, and the cycle will be halted. As a result, transmission is limited to warm months, and duration of the transmission season varies geographically. during a later bloodmeal on an appropriate host (C), the L3 will exit the labium, enter the bite wound, and penetrate local connective tissues. moulting to the L4 ensues within seven days of infection (D). L4 stages undertake extensive migration through the subcutis, which continues for some days until the final moult to the immature adult (E). the juvenile worms migrate to the right heart within a few days of their final moult (F), presumably carried by the venous circulation. final maturation and mating occur in the pulmonary arteries, and the adult worms live in the right heart and pulmonary arteries, where they may survive for up to seven years. production of microfilariae by inseminated female worms begins approximately six and a half months (192days) after infection. Epidemiology the disease is endemic in many areas of USA, Asia, Australia, Africa and South of Europe. It is not endemically present in the UK. Pathophysiology narrowing and occlusion of the pulmonary arteries due to proliferation of intima (not direct blockage by the adult worms). distribution and severity of the lesions depends on both the number and location of adult worms (caudal lobar arteries are the most heavily infected) sometimes, worms may be found in the right atrium and ventricles, and the vena cavae pulmonary hypertension is the major consequence of intimal proliferation Dr Luca Ferasin ( 20

21 right ventricular dilation and hypertrophy, as well as ischemia and right ventricular failure, may also be observed disruption of the intima of the pulmonary arteries may cause attraction of platelets, and release of Platelet Derived Growth Factor (PDGF). PDGF triggers proliferation of medial smooth muscle cells and fibroblasts. Many filarial nematodes, including Dirofilaria immitis, harbour obligate, intracellular, gram-negative, endo-symbiotic bacteria belonging to the genus Wolbachia (Rickettsiales). Doxycycline reduces Wolbachia numbers in all stages of heartworms. Doxycycline administration during the first or second month following experimental heartworm infection was lethal to third- and fourth-stage heartworm larvae. In addition, in dogs with adult infections, doxycycline gradually suppressed microfilaremia. Microfilariae ingested by mosquitoes on dogs treated with doxycycline developed into third-stage larvae that appeared to be normal in appearance and motility, but these larvae were not able to develop into adult worms, thus reducing the risk of selecting for resistant subpopulations. Clinical signs can vary from no signs at all to signs of heart failure heart failure can be acute or gradual, and can lead to ascites, hydrothorax, and hydroperitoneum. exercise intolerance (increasing in severity with increasing resistance to pulmonary blood flow) chronic coughing, dyspnoea, hemoptysis, and syncope. pulmonary thromboembolism can occur, and is often a response to dying adult worms, whether the death of the worms be spontaneous or due to treatment with adulticidal drugs. thrombi form around a degenerating parasite, and a periarterial granuloma can develop in the lung parenchyma. Diagnosis tachypnoea and coughing with a history of exposure to mosquitoes in an enzootic area advanced stages: animals can show syncope, haemoptysis, and chronic weight loss with good appetite. A decreased exercise tolerance will also develop, and is more common than either the syncope or hemoptysis. ascites and hepatomegaly will be present in case of heart failure. Dr Luca Ferasin ( 21

22 Haematology: eosinophilia and basophilia in the early stage of infection. Radiography: enlarged right ventricle enlarged main pulmonary artery enlarged peripheral pulmonary arteries decreased peripheral pulmonary artery taper (i.e. truncation) tortuous peripheral pulmonary arteries interstitial/alveolar pulmonary pattern with a caudal lobar distribution Echocardiography: worms may be seen in the right heart and main pulmonary artery dilatation and thickening of the right ventricle Traditionally, the first line of diagnosis for heartworm infection has been a parasitological examination, looking for microfilariae in the peripheral blood. A direct examination of the blood in a wet mount with 1-2 drops is a quick, easy method of doing this. However, this type of test is relatively insensitive, and microfilariae cannot be examined morphologically. Knott technique and filtration methods (Difil-test) are quick, easy, sensitive and allow morphological examination. ELISA tests, utilises a monoclonal antibody to detect circulating worm antigens. Treatment Adulticidal Melarsomine dihydrochloride (Immiticide) given intramuscularly (lumbar muscles) AHS recommends use of doxycycline and a macrocyclic lactone prior to the three-dose regimen of melarsomine (one injection of 2.5 mg/kg body weight followed at least one month later by two injections of the same dose 24 hours apart) for treatment of heartworm disease in both symptomatic and asymptomatic dogs. Any method utilising only macrocyclic lactones as a slow-kill adulticide is not recommended. Microfilaricidal Ivermectin (not approved as a microfilaricide) not earlier than 3-4 weeks after adulticide treatment. It can be given subcutaneously or orally. CNS side effects are described in rough coated collies (and other pure breeds) with high doses of Ivermectin Milbemycin oxime ( mcg/kg) Selamectin (Stronghold) Dr Luca Ferasin ( 22

23 Careful observation is required after the initial dose (potential systemic side effects). Chemoprophylactic for any animal that could potentially become infected. Macrolide endectocides: ivermectin (Heartguard 6-12 mcg/kg) milbemycin oxime (Interceptor mcg/kg). selamectin (Stronghold) Further reading Willesen JL et al. Efficacy and safety of imidacloprid/ moxidectin spot-on solution and fenbendazole in the treatment of dogs naturally infected with Angiostrongylus vasorum. Veterinary Parasitology 147 (2007): S Ferasin L (2004) Disease risks for the travelling pet: heartworm disease. In Practice 26 (7) Veterinary Resources at Dr Luca Ferasin ( 23

24 PERICARDIAL DISEASE Introduction Pericardial disease is not common but its pathophysiology is unique and this demands a therapeutic approach that differs from that of more common forms of heart disease. Furthermore, unlike many more common cardiac disorders, pericardial disease is occasionally curable which emphasizes the importance of its recognition. The parietal pericardium consists of an outer fibrous layer and an inner serosal layer. The visceral pericardium, or epicardium, is a reflection of the serosal surface of the parietal pericardium. The pericardial cavity between the parietal and visceral pericardia is a potential space. In healthy individuals, it contains a small volume of serous transudate. The normal pericardium appears to fulfil only a minor role in cardiovascular function and its congenital absence is clinically silent. However, disease of the pericardium impairs cardiac filling and this can lead to marked cardiovascular compromise. Congenital abnormalities of the pericardium are relatively uncommon. Effusive pericardial disease is the most common pericardial condition observed in small animal practice; it is defined by the accumulation of an abnormally great volume of fluid within the pericardial space. Constrictive pericardial disease is less common but it can be occasionally seen in our patients. Pericardial constriction usually results from fibrosis of the parietal or visceral pericardium which limits ventricular expansion and therefore impairs ventricular filling. Pericardial disease is observed in both dogs and cats but is seldom the cause of clinical signs in the latter. In dogs, pericardial effusion (PE) usually is hemorrhagic; numerous causes have been reported but most commonly, canine PE is due to intrapericardial neoplasia or idiopathic pericarditis. The prevalence of neoplastic effusion is higher than the prevalence of idiopathic PE in the United States but there seems to be an inverted ratio in Europe. Right atrial haemangiosarcoma (HSA) and Dr Luca Ferasin ( 24

25 chemodectoma are the most common cardiac neoplasms but mesothelioma, ectopic thyroid carcinoma, rhabdomyosarcoma and metastatic neoplasms occasionally cause PE. Infective pericardial disease is rare and often associated with penetrating or migrating foreign bodies. Uraemia, anti-coagulants (i.e. warfarin), trauma, idiopathic myocarditis, etc represent rare causes of pericardial effusion. Pathophysiology of Cardiac Tamponade The consequences of pericardial effusion (PE) depend on the volume of pericardial fluid and on the rate at which it accumulates. Acutely, the pericardium is minimally distensible. Therefore, when PE accumulates rapidly, relatively small volumes cause intrapericardial pressures (IPP) to rise resulting in impaired ventricular filling and hemodynamic compromise. In contrast, the pericardium can stretch to accommodate an effusion that develops slowly and large volumes of fluid may accumulate before IPP impairs cardiac filling. The syndrome of cardiac compression that results from accumulation of pericardial fluid is known as cardiac tamponade. Right atrial and ventricular pressures normally are lower than corresponding pressures of the left atrium and ventricle; because of this, the right side of the heart is affected initially by tamponade. Progressive increases in intrapericardial pressure cause equalization of left and right ventricular filling pressures after which further increases in IPP cause ventricular filling pressures to rise in tandem. The increase in ventricular filling pressures causes venous pressures to increase, and when PE is chronic, signs of systemic congestion including ascites and pleural effusion are observed. Severe tamponade reduces stroke volume and results in systemic hypotension. When pericardial fluid accumulates rapidly, clinical signs of diminished peripheral perfusion usually dominate the clinical presentation. Signs of systemic congestion generally develop at venous pressures that are lower than those that cause pulmonary congestion. Most veterinary patients with PE are therefore presented for evaluation of signs such as ascites. Pulmonary oedema is uncommon in the setting of tamponade. Pericardial effusion and tamponade enhance ventricular interdependence potentially resulting in pulsus paradoxus. Pulsus paradoxus is an exaggeration of physiologic changes in cardiac loading that normally result from respiratory-associated variations in intrathoracic pressure. With respect to acute forces, the fibrous pericardium can be considered inelastic and therefore, the total volume of the pericardium does not vary in the short-term. During inspiration, intrathoracic pressure falls and this augments right ventricular filling. Because the total volume of the pericardium is fixed, the increase in right ventricular volume occurs at the expense of left ventricular filling and stroke volume. The result is a decrease in the strength of the arterial pulse during inspiration. Dr Luca Ferasin ( 25

26 Clinical Presentation PE develops most commonly in large-breed dogs including German shepherd dogs and retrievers. Often, PE develops relatively slowly and patients are presented for evaluation of signs of right-sided congestive heart failure. Abdominal distension due to ascites or dyspnea related to concurrent pleural effusion may be observed and occasionally peripheral oedema is evident. Signs of low cardiac output including weakness and syncope may also prompt veterinary evaluation and non-specific signs including inappetance, depression and lethargy are common. Patients that acutely develop severe tamponade are presented recumbent in circulatory collapse. The physical findings of cardiac tamponade are relatively distinctive. The heart sounds usually are muffled by the presence PE. Tachycardia is typically present and the arterial pulse may be weak. Pulsus paradoxus is occasionally detectable; this finding is virtually pathognomonic for the presence of cardiac tamponade. When tamponade is present, the jugular veins typically are distended and ascites is often present when PE is chronic. Radiography When large volumes of PE accumulate, the cardiac silhouette is enlarged and the contours of the cardiac silhouette are lost so that cardiac shadow has a globose appearance. Often, the pulmonary vessels are small. Pulmonary oedema is uncommon in the setting of tamponade. Electrocardiography Tachycardia is usually present when patients develop tamponade. Most often, the rhythm is sinus tachycardia; pathologic tachyarrhythmia such as ventricular premature complexes and ventricular tachycardia are relatively uncommon in tamponade. When the volume of PE is large, the amplitude of the QRS complexes may be markedly diminished. Occasionally, the QRS amplitude varies in a consistent alternating fashion known as electrical (or QRS) alternans. These electrocardiographic findings are not present in every case; however, when QRS alternans and small complexes accompany typical physical findings, they are highly suggestive of the diagnosis of PE. Echocardiography Echocardiography is invaluable in the diagnostic evaluation of patients with pericardial disease. It is the most sensitive and specific noninvasive means by which to detect PE. Of equal importance, echocardiography demonstrates the cause of effusion when intrapericardial masses are identified. Echocardiography is not essential for the diagnosis of PE and tamponade; however, Dr Luca Ferasin ( 26

27 echocardiography should be considered in all cases of suspected pericardial disease because it is the diagnostic test that is most likely to provide an etiologic diagnosis. Although two-dimensional echocardiography is a highly sensitive method for detection of PE, the sensitivity of 2DE for identification of cardiac masses has not been prospectively evaluated. Based on retrospective studies, the sensitivity of 2DE for detection of cardiac neoplasia is between 17 and 68%.When multiple imaging planes are evaluated using current echocardiographic technology, it is reasonable to suppose that the true figure is close to, or perhaps greater, than the upper limit of this range. Characteristics of the Effusion Most pericardial effusions in dogs result either from neoplasia or from idiopathic pericarditis. The prognosis associated with idiopathic pericarditis is better than that associated with neoplasia and therefore, antemortem distinction between the two disease processes is important. Ideally, the two causes could be distinguished by minimally invasive techniques but unfortunately a reliable means to do so is lacking. Cytologic evaluation of PE is rarely informative 2 probably because almost all PE in dogs are hemorrhagic and the tumours that are most commonly responsible exfoliate poorly. Effusions related to cardiac lymphosarcoma or infection are exceptions to this but these conditions are uncommon. It has been suggested that that idiopathic pericarditis results in an effusion that is relatively acidic. However, other evaluations of effusion ph have failed to demonstrate the diagnostic value of this measurement. Despite statistically significant differences between biochemical and hematologic variables measured in neoplastic and non-neoplastic effusions, neither haematocrit nor concentrations of analytes such as lactate, chloride and urea nitrogen usefully discriminate between the two basic disease processes. Recent evidence suggests that there might be a diagnostic role for determination of troponin-i; serum concentration of this biomarker is greater in dogs with cardiac HSA than in dogs with idiopathic pericarditis.15 Despite this encouraging finding, the non-invasive etiologic diagnosis of PE generally is made by echocardiography and clinical course. Therapy Pericardiocentesis is the appropriate initial therapy for patients with cardiac tamponade. The procedure is generally performed from the right hemithorax after aseptic preparation of the site. A 14 or 16 G over-the-needle catheter is introduced into the pericardial space, the needle is removed and fluid is withdrawn. A short pause after removal of the first 3-5 ml allows time to determine whether or not the fluid will clot. If the aspirated fluid clots, it is possible that the catheter is within the right ventricle. Dr Luca Ferasin ( 27

28 Monitoring of the electrocardiogram during the procedure is suggested. The procedure can be performed blindly although some prefer to puncture the pericardium using echocardiographic guidance. Complications are relatively uncommon and the risk:benefit ratio is decidedly in favour of performing the procedure when tamponade is present. It should be recognized that the vast majority of canine PE are hemorrhagic. Diuretic agents are unlikely to mobilize the effusion but are likely to decrease venous pressures and cardiac output. For this reason, diuretics are contraindicated in the setting of tamponade. If pericardiocentesis must be delayed, intravenous fluid infusion is the appropriate supportive treatment. Surgical exploration after pericardiocentesis can be considered when echocardiography demonstrates an intrapericardial mass. In cases in which a mass is detected, it is useful to consider the presumptive histological diagnosis. Masses that originate from the right atrium or right atrial appendage are usually HSA while chemodectomas generally arise from the proximal aorta. Surgical debulking and adjuvant chemotherapy may improve survival of patients with cardiac HAS.16 However, it should be recognized that this neoplasm is associated with a poor prognosis and survival after diagnosis is generally less than 8 months regardless of therapy. Patients with chemodectoma fare better and median survival of 730 days after pericardiectomy has been reported. Approximately 50 % of idiopathic PE resolves after a single centesis. Although it has been suggested that repeated centeses might carry a more favourable risk:benefit ratio, surgical exploration and pericardiectomy should be considered when apparently idiopathic PE recurs after two or three centeses. Surgical exploration provides a definitive diagnosis and when idiopathic pericarditis is confirmed, pericardiectomy is potentially curative. Subtotal pericardiectomy traditionally has been performed after a median sternotomy or lateral thoracotomy. More recently, minimally invasive techniques for pericardiectomy or pericardiotomy have been developed. Thoracoscopic subtotal pericardiectomy has been reported and this technique is apt to result in lower patient morbidity relative to thoracotomy. Balloon pericardiotomy is a minimally invasive technique in which a catheter of the type used for balloon dilation of outflow tract obstructions is used to create a rent in the pericardium and therefore prevent recurrence of tamponade. This procedure may have a favorable cost:benefit ratio particularly as a palliative procedure for patients with neoplastic effusion. Prognosis The prognosis associated with effusive pericardial disease is largely determined by the etiology of the effusion. In general, patients with cardiac HSA have a poor prognosis. The prognosis after pericardiectomy for patients with chemodectoma may be surprisingly good presumably because the tumours grow relatively slowly and are late to metastasize. Although prolonged survival has been Dr Luca Ferasin ( 28

29 documented, patients with pericardial mesothelioma generally fare poorly and have decreased survival relative to dogs with idiopathic PE. Patients with idiopathic pericardial effusion have a good or excellent prognosis. A few clinical findings provide prognostically useful information. Patients that have ascites when first presented for veterinary evaluation live longer than those that do not. Presumably this is because patients with aggressive, hemorrhagic tumours such as HSA are more apt to develop signs associated with circulatory collapse than signs of congestion. Independent of histological findings, the prognosis is generally poor for patients with an echocardiographically identified mass that originates from the right atrium. CONSTRICTIVE PERICARDITIS Constrictive pericarditis is an uncommon disease that impairs diastolic function.22 Ventricular filling is impeded due to pericardial constriction that is due to pericardial fibrosis. Clinical signs are generally related to systemic congestion and low cardiac output. The disease is a diagnostic challenge; cardiac catheterization studies are generally required. Surgical treatment consists of pericardial stripping. Further Reading Jonathan A. Abbott, Pericardial disease diagnosis and therapy, ACVIM forum proceedings, Louisville, Kentucky, 2006 Dr Luca Ferasin ( 29

30 SYNCOPE, FALLING, SEIZURES Introduction Episodic collapse, recurrent syncope, intermittent weakness and seizures are common complaints in canine and feline medicine. The term collapse derives from the Latin word collapsus, past participle of collabi, meaning to fall apart. In human medicine, the term collapse defines a state of extreme prostration and depression or a falling together of the walls of a structure or the failure of a physiologic system. The word collapse is not even mentioned in the Merck s manual of medicine. Therefore, for a pure semantic convention, we should probably reserve the word collapse to define conditions like tracheal collapse or profound hypotension and use the simple term fall to describe a loss of quadrupedal posture. Animals may fall as a consequence of: 1. cerebral hypoperfusion (syncope) 2. abnormal electrical activity of the brain (seizure) 3. weakness 4. cramps 5. pain Most cases of episodic fall occur during exercise, even in healthy young and fit individuals. Syncope Dr Luca Ferasin ( 30

31 The word syncope derives from ancient Greek synkopē, meaning cut off. It describes a sudden, unexpected, and unprovoked loss of consciousness. The affected subject loses postural control and remains unresponsive throughout the event. It is a transient condition which lasts for only a few seconds and it is always followed by spontaneous and complete recovery. This obviously differs from sudden death, which could be defined as an irreversible syncope. Therefore, the only difference between syncope and sudden death is that in one you wake up. The underlying mechanism is a transient global cerebral hypoperfusion4. Lipothymia (or pre-syncope) is a condition in which patients experience warning symptoms telling them they are about to pass out. This allows patients to "prepare" for collapse without bodily harm (laying on the sofa). In people, irrespective of the precise underlying cause of syncope, a sudden cessation of cerebral blood flow for 6 8 s and/or a decrease in systolic blood pressure to 60 mm Hg has been shown to be sufficient to cause complete loss of consciousness4. Critical physiological values that can induce syncope in dogs and cats are not available but it is not unrealistic to believe that they may be similar to those reported in people. Causes of syncope are primarily cardiovascular, although some noncardiovascular conditions need to be considered in the differential diagnosis. A summary of potential causes of syncope is reported in the table below. Dr Luca Ferasin ( 31

32 Cardiac Anatomical outflow obstruction (severe SAS o PS, heart base or intracardiac tumours) Cardiac tamponade (pericardial effusion) Obstructive HCM Myocardial ischemia Bradycardia (high degree AV block, Atrial standstill, sick sinus syndrome, asystole) Tachycardia (SVT, VT) Vascular Orthostatic hypotension (venous pooling = frequent in people) Pulmonary thromboembolism Pulmonary hypertension Neurocardiogenic (vasovagal) Hypovolaemia/ dehydration Situational (straining during coughing, defecation, micturition, swallowing) Non-Cardiovascular Neurological (seizure disorder, head trauma, hepatic encephalopathy, narcolepsy, Scottie cramp, episodic falling in CKCS, autonomic neuropathy) Metabolic (hypoglycaemia) Psychological (anxiety, panic, somatisation disorders) Iatrogenic (ACP, hydralazine, amlodipine, nitrates, etc) Miscellaneous (e.g. pacemaker failure) With the exception of the American opossums, which are renowned for "playing dead" when threatened, psychological syncope is not commonly described in veterinary medicine. Iatrogenic arterial dilation may occur after administration of drugs that induce vasodilation, such as nitroprusside, acepromazine, or amlodipine. All the abnormalities listed above can potentially induce cerebral hypoperfusion and ultimately loss of consciousness. However, some animals may fall, appear weak or present signs of pre-syncope when they experience milder events. Seizure The word seizure derives from the ancient German sezzen (to set) and indicates a temporary abnormal electrical activity of the brain, resulting in altered mental state and uncontrolled muscular activity (fit or convulsions). A seizure can last from a few seconds to a prolonged status epilepticus. The medical syndrome of recurrent, unprovoked seizures is termed epilepsy. However, seizures may Dr Luca Ferasin ( 32

33 also occur in patients that do not have epilepsy. Hepatic encephalopathy, narcolepsy, Scottie cramp, episodic falling in CKCS are some examples frequently observed in veterinary medicine5. Some cases of partial seizures can mimic syncope. Similarly, some cases of prolonged cerebral hypoperfusion can present with seizure-like activity. Weakness The word weak derives from the ancient Greek eikein (to give way). It is defined as a loss of muscular strength resulting in an animal becoming completely or partially recumbent or ataxic. Generalised muscle weakness is referred to as asthenia. Weakness during exercise can be physiological (exhaustion). However, it can also be caused by a variety of clinical abnormalities, such as muscular (myopathy), neuro-muscular (myasthenia), neurological, metabolic (electrolyte imbalance, hypoglycaemia), haematological (anaemia, polycytaemia), and cardiovascular (arrhythmias, forward heart failure, right-to-left PDA) conditions. Muscle Cramps The word cramp derives from ancient German krampf meaning squeezing, pressing, or pinching uncomfortably. It is a sudden, uncomfortable, contraction of a muscle, lasting seconds to minutes, often with a palpable hard knot in the affected muscle. Stretching the muscle or contraction of its antagonist muscle often relieves the cramp. On electromyogram (EMG), the involuntary muscle contraction is associated with repetitive firing of motor unit action potentials at high rates (up to 150 per second). In people, the significance of cramps ranges from a benign, infrequent muscle pain to one of the symptoms heralding a devastating neurological disease such as amyotrophic lateral sclerosis (ALS). Muscle cramps have also been described in athletic dogs8 and in dogs with hypoadrenocorticism or hypothyroidism. However, cramps are rarely reported as a complaint in small animal practice. Pain Muscle pain (myalgia) or pain originating from the spinal or appendicular musculo-skeletal system can cause fall, especially during exercise. A sudden, intermittent and painful recumbency in cats can be the result of a partial arterial occlusion caused by arterial thromboembolism (ATE). Clinical investigation of episodic falls The transitory nature of episodes and spontaneous resolution of clinical signs represent a real diagnostic challenge. In people, when there are not abnormalities detected on history or clinical Dr Luca Ferasin ( 33

34 examination, diagnosis may not be achieved in approximately 50% of cases. Similar figures are reported in small animal practice. An excellent understanding of the efficacy and utility of the investigational tools for syncope is therefore required in order to institute promptly and efficiently an appropriate management. In fact, a wrong choice of sequential tests may result in poor diagnostic yield and unnecessary costs. Finally, a delayed diagnosis may result in sudden death. History and physical examination A thorough and consistent history, followed by a full physical examination, is the most important component of the evaluation of a patient with episodic fall. Every effort should be made to differentiate between true syncope with loss of consciousness from apparent syncope, although an overlap between the two may exist. In the history interview, we should always evaluate: 1. History of cardiac disease or medications that may induce arrhythmias or hypotension 2. Number and frequency of the episodes in full details 3. Identifying precipitating factors, including detailed description of physical activity, time of the day, environmental conditions, degree of excitement, etc. 4. Quantifying type and duration of the event, including prodromal and recovery period. 5. Obtain information about colour of mucous membranes and heart beat during phases 6. Obtain careful accounts of witnesses who may have been present and, when possible, acquire a video recording of the event Clinical history of arrhythmia (both brady- and tachy-arrhythmias) are similar. In both cases syncope occurs after approximately 5 seconds of warning, lasts for a few seconds and recovery is very rapid and uneventful. Arrhythmia should always be suspected in case of predisposed breeds like Boxers (ARVC), Dobermans (occult DCM) and German shepherd puppies (GSD inherited VT). Disorientation and behavioural changes following the event, absence of pale or cyanotic mucous membranes, frothing at the mouth, aching muscles, lethargy after the event, and unconsciousness lasting for more than a few minutes would suggest seizure rather than syncope. Although urination and/or defecation can occur during syncope, this is more commonly associated with a seizure. Gran mal seizures are commonly associated with tonic-clonic movements, while syncope is often characterised by a flaccid paralysis of the limbs. However, syncope caused by cerebral ischemia can result in decorticate rigidity, with clonic movements of the limbs. Akinetic or petit mal seizures are often characterised by lack of responsiveness in the absence of a loss of postural tone. Dr Luca Ferasin ( 34

35 Physical examination should be conducted in a thorough and consistent manner. Particular attention should be paid at the examination of the cardiovascular system (including blood pressure measurement), level of hydration, and presence of significant neurological or musculoskeletal abnormalities. Pre-organized questionnaires and checklists will tremendously assist the clinician in obtaining valid information in an efficient and standardised manner. In human patients with recurrent falls, blood tests (basic haematology and serum biochemistry) have a low diagnostic value and the tilt-table represent the first line test. However, orthostatic syncope in small animals is unlikely and tilt-table testing is inapplicable. Echocardiography should be considered in case of abnormal findings during physical exam (i.e. heart murmur, arrhythmia, etc) or in case of familial history/predisposition of cardiac disease. Resting ECG may identify the reason of fall in a small percentage of patients. However, the diagnostic power of ECG increases dramatically if it is recorded during exercise via radio-telemetry, especially in cases of exercise-induced falls. Twenty-four hour (Holter) ECG recording has a very low diagnostic value, especially when the falling episodes occur sporadically. The only exception for justifying Holter analysis in these cases is for the breed-related predispositions mentioned above. Conversely, event recorders can provide a diagnostic yield in approximately 25% of the patients and the figure increases dramatically (47%) if an implantable recorder (ILR) is used. Recently, the reliability and accuracy of an implantable loop recorder has been reported in the veterinary literature with excellent results described both in dogs and cats. These studies show that in dogs and cats with unexplained syncopal episodes, the manually activated ILR can provide invaluable diagnostic and prognostic information in almost all patients, by either confirming or disproving the association between syncope and arrhythmias. Other investigations (e.g radiology, abdominal US, CT scan, MRI, EM, EEG, etc.) might be recommended in case all the tests listed above result inconclusive. In the last few years, I have tried to design a diagnostic algorithm in an attempt to increase the diagnostic ratio in cases of episodic fall. This algorithm is continuously revised following the availability of new diagnostic tests and the increasing personal experience in this field. However, case reports and discussion with colleagues are strongly encouraged in order to achieve a more successful and cost/time-efficient diagnostic approach to these extremely challenging cases. Dr Luca Ferasin ( 35

36 EXERCISE INDUCED COLLAPSE (EIC) IN LABRADOR RETRIEVERS Introduction Exercise induced collapse (EIC) is a term that describes a form of exercise intolerance seen in young Labrador retrievers after strenuous exercise. Although the first report of EIC dates back to 1993, the first citation in the veterinary literature is very recent (2008). According to the authors, affected dogs sometimes develop an abnormal gait or collapse when subjected to strenuous exercise, but the underlying cause has not been well established. Affected dogs usually tolerate mild-moderate exercise but occasionally become ataxic and collapse after 5 to 15 minutes of intense exercise, especially when accompanied by excessive excitement or stress. The pattern of the clinical signs (described by the aforementioned authors as collapse ) is poorly characterised, as demonstrated in a survey carried out by 225 owners of dogs with a history of EIC (table 1) Table 1 Owner description of clinical signs 17 Description % of dogs Rear limbs floppy/dragged 78 Wobbly, uncoordinated 60 Falling to side/ balance problem 1 episode 68 Rear limbs only affected 82 All four limbs affected 1 episode 18 Forelimb rigidity 1 episode 18 Dazed/disoriented 1 episode 23 Loud/excessive panting 1 episode 19 Generalised seizure during 1 episode 3 The physical activity that appears to trigger the event is also poorly defined and includes retrieving toys (46%), retrieval training on land (43%), upland hunting (25%), excitement during play with other dogs (22%), retrieval training in water (12%) and waterfowl hunting (2%). Some factors seem to contribute to the onset and development of clinical signs, including excitement (83%), heat and humidity (31%), use of live birds in training or hunting (25%), stress during training (13%) and competition with other dogs (9%). Dr Luca Ferasin ( 36

37 In the examination of the pedigree of 326 dogs, 169 individuals appeared to be affected, with nine of these appearing to have an affected parent. Males and females were equally represented, excluding an X-linked mode of inheritance. Six of the nine affected parents had full phenotypic information. One affected parent mated with another affected parent producing two affected and two unaffected offspring. In three families, an affected dog produced multiple affected second and third generation offspring. The pedigree analysis was most consistent with an autosomal recessive mode of inheritance, although a dominant disorder with partial penetrance or a polygenic disorder could not be excluded. Median age of dogs when they presented the first episode of collapse was 12 months. 10% of dogs had experienced more than 25 episodes of collapse and seven had died during a collapsing episode. Three of these individuals had generalised seizure just before death. However, the authors do not report whether or not these dogs underwent a cardio-vascular investigation to rule out, for example, episodic arrhythmias or a right-to-left shunting persistent ductus arteriosus (reversed PDA). Although the authors failed to report in their first paper that most EIC dogs will experience spontaneous resolution of the clinical signs and will not show any further collapsing episodes during adult life, in a most recent publication they state: Five years have passed since the 14 dogs with EIC were evaluated. One dog was euthanized immediately following evaluation. Six dogs were adopted out to pet homes where they no longer participate in the trigger activities associated with the collapse, and five dogs have not collapsed since relocation. Three dogs remained with their owners and episodes of collapse reportedly occur if they are allowed to engage in trigger activities. One dog has not had activity limited, but episodes of collapse have become very infrequent. Three dogs were lost on follow-up. No dogs have developed progressive systemic or neurological disorders and all are considered by their owners to be healthy aside from the EIC. The mechanism of EIC has not been determined yet, although a mutation in dynamin 1 gene (DNM1) was recently suggested as the causal mutation of EIC in Labrador retrievers. A genetic test for the mutation is now available through the Veterinary Diagnostic Laboratory at the University of Minnesota. Regrettably, the conflict of interest was not disclosed in the above manuscript despite the fact that authors share royalties for the test. Dr Luca Ferasin ( 37

38 The DNM1 mutation has been described in an elegant study published in 2008 by the same research group.19 In this study, the authors used a genome-wide scanning technique on six pedigrees of Labrador retrievers in which EIC was segregating and they identified a locus at the 60.4 Mb position of canine chromosome 9 (CFA9) with significant linkage. They subsequently analysed SNP markers from the region for association with EIC using 310 Labrador retrievers and found multiple associated markers. After further stratification of the population, they identified three significantly associated SNPs in a 355-kb region ( Mb). The most common haplotype in EIC dogs extended nearly the entire 4.5-Mb segment for which SNPs were analysed and homozygosity was observed for a minimum of 929 kb in 89% of these dogs. Homozygosity in 10% of the affected dogs was, however, limited to two short haplotype blocks: a 137-kb block and an 87-kb block, separated by a 184-kb gap (Fig. 2a). These two haplotype blocks were also observed in the unaffected dogs, as would be expected from their unavoidably close relationships to the affected dogs. The major criticism about the above discoveries is about the arbitrary stratification operated by the authors to achieve a significant association. Dogs were divided into six groups (presumed EIC, recurrent collapse, single collapse, atypical collapse, alternative collapse, and no collapse). Further arbitrary selection is observed in the alternative collapse group where other potential causes of repeated collapse were listed, such as cardiac arrhythmia, laryngeal paralysis, lactic acidaemia, and metabolic myopathy. Moreover, 9% of dogs without a history of collapse resulted homozygous for the mutation, which was explained by the owners as insufficient exercise or excitement to trigger collapse. Finally, if the cause of collapse was really induced by insufficient vesicles for sustained synaptic transmission and subsequent reversible loss of motor function, why do clinical signs not present at all times? What is the real threshold or cut-off limit? Have the authors proved the lack of synaptic transmission? The major problem in the study of this condition originates from the lack of objective parameters to assess the physical condition of these dogs. It is well known that exercise causes significant acute alterations in rectal temperature (BT), pulse rate (HR), blood lactate (BL) and other physiological parameters in healthy dogs However, until recently, there were no available data originating from standardised studies where test retest reliability has been assessed. In our recent publication, Dr Marcora and I assessed the reproducibility of a non-invasive exercise test in healthy Labrador retrievers and evaluated BL, HR and BT responses that occur during and after incremental exercise in this breed. In this study, we demonstrated that differences between Dr Luca Ferasin ( 38

39 tests may exist even under the strictest controlled conditions, such as environmental temperature, humidity, intensity of exercise, diet, time of the day, etc. Therefore, the standardised field tests conducted by other groups present several limitations, with little scientific accuracy and clinical utility. Another important finding in our study was a prolonged recumbency and temporary inability to regain the quadrupedal posture in most dogs during the recovery period. This resembled the typical features of exercise-induced collapse described by Taylor et al. We interpreted these signs as an extreme physiological condition (exertional fatigue or exhaustion). This could be attributed to a variety of reasons. Exercise-induced changes in muscle action potential, extracellular and intracellular ions, and intracellular metabolites reduce the ability to produce force (peripheral fatigue). Changes at spinal and supraspinal level due to alterations in brain metabolism and neurotransmitters, or inhibitory afferent feedback from type III and IV muscle afferents can also reduce the ability of the CNS to activate the locomotor muscles (central fatigue). It is also possible that, in these dogs, the increased pulmonary blood flow and capillary pressure during intense exercise induced the activation of pulmonary C fibers (or J receptors). This activation can evoke a somatomotor reflex (the J reflex) that provides potent inhibition of limb muscles in animals but not humans. In contrast with what has been observed in people, incremental exercise did not appear to induce abrupt increases in BL concentration in Labrador retrievers, although significant variation was observed between test stages. Moreover, in humans, BL concentrations would be expected to decrease during recovery after intense exercise. However, in our study, BL values remained stable after a 20-min recovery period in all dogs. Blood lactate concentration during exercise is the result of lactate production by the contracting muscle, lactate transport from the muscle to the vascular bed, as well as intracellular and hepatic clearance. Assuming that lactate clearance would continue during recovery and that lactate production in the muscle would cease after termination of the exercise, it can be speculated that the modest increase of lactate values observed in Labradors depends on a slow transport of this compound from muscle to blood. This could be caused by a low muscular density of proteins involved in lactate transport (i.e., monocarboxylate transporter or MCT) and/or intracellular lactate clearance. According to the EIC test patent owners, breeders need to be selective in their breeding, avoiding the production of dogs that actually have EIC. They advise that all breeding dogs should be tested, and if carrier dogs are bred they should only be bred to dogs that are genetically clear of EIC so that Dr Luca Ferasin ( 39

40 affected puppies will not be produced. They also advocate avoidance of intensive exercise and, in some cases, the use of phenobarbital to decrease the dog s level of excitement or anxiety. I kindly (and strongly) disagree with the above approach. I have now managed to successfully treat dozens of Labrador (and non Labrador) dogs with a history of EIC. First of all, it is necessary to rule out an underlying cardiac abnormality with a full cardiac work-up, including full echo-colour Doppler and 24h Holter ECG monitoring. Afterwards, the exercise capacity should be assessed on a validated treadmill test to obtain baseline values of BL, HR and BT. A field test would offer limited value due to its poor repeatability. Finally, a well-designed exercise prescription, primarily based on interval training, is normally sufficient to improve the physical ability of the dog to undergo intense training. The exercise prescription can be designed based on the results of the exercise test. It is mandatory to maintain a good communication with the dog s owners and make sure that the prescribed exercise is recorded on a diary. Finally, owners expectations need to be carefully evaluated. Sometimes, owners force their dogs to undergo exhausting exercise even several times a day. Under these circumstances, young excitable dogs are at higher risk of collapse because they tend to exercise above their physical capacity. Further reading Stedman TL. Stedman's medical dictionary, 28th ed. ed. Philadelphia, Pa. ; London: Lippincott Williams & Wilkins; 2006;1 v. (various pagings). Beers MH. The Merck manual of medical information, 2nd home ed. ed. Whitehouse Station, N.J.: Merck Research Laboratories; 2003;xxxviii, 1907 p. Engel GL. Psychologic stress, vasodepressor (vasovagal) syncope, and sudden death. Ann Intern Med 1978;89: Brignole M. Distinguishing syncopal from non-syncopal causes of fall in older people. Age Ageing 2006;35 Suppl 2:ii46-ii50. Martin MWS, Corcoran BM, Martin MWSCdotd, et al. Notes on cardiorespiratory diseases of the dog and cat, 2nd ed. ed. Oxford: Blackwell Publishing; 2006;x, 205 p. Zaidi A, Clough P, Cooper P, et al. Misdiagnosis of epilepsy: many seizure-like attacks have a cardiovascular cause. J Am Coll Cardiol 2000;36: Miller TM, Layzer RB. Muscle cramps. Muscle Nerve 2005;32: Shadan S. Genetics: run, whippet, run. Nature 2007;447:275. Saito M, Olby NJ, Obledo L, et al. Muscle cramps in two standard poodles with hypoadrenocorticism. J Am Anim Hosp Assoc 2002;38: Dr Luca Ferasin ( 40

41 Shelton GD. Muscle pain, cramps and hypertonicity. Vet Clin North Am Small Anim Pract 2004;34: Gould PA, Krahn AD, Klein GJ, et al. Investigating syncope: a review. Curr Opin Cardiol 2006;21: Willis R, McLeod K, Cusack J, et al. Use of an implantable loop recorder to investigate syncope in a cat. J Small Anim Pract 2003;44: Libby P, Braunwald E. Braunwald's heart disease : a textbook of cardiovascular medicine, 8th ed. ed. Philadelphia, Pa. ; Edinburgh: Elsevier Saunders; 2008;1 v. (various pagings). Ferasin L. Recurrent syncope associated with paroxysmal supraventricular tachycardia in a Devon Rex cat diagnosed by implantable loop recorder. J Feline Med Surg 2009;11: James R, Summerfield N, Loureiro J, et al. Implantable loop recorders: a viable diagnostic tool in veterinary medicine. J Small Anim Pract 2008;49: Santilli RA, Ferasin L, Voghera SG, et al. Evaluation of the diagnostic value of an implantable loop recorder in dogs with unexplained syncope. J Am Vet Med Assoc 2010;236: Taylor SM, Shmon CL, Shelton GD, et al. Exercise-induced collapse of Labrador retrievers: survey results and preliminary investigation of heritability. J Am Anim Hosp Assoc 2008;44: Taylor SM, Shmon CL, Adams VJ, et al. Evaluations of labrador retrievers with exercise-induced collapse, including response to a standardized strenuous exercise protocol. J Am Anim Hosp Assoc 2009;45:3-13. Patterson EE, Minor KM, Tchernatynskaia AV, et al. A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse. Nat Genet 2008;40: Hinchcliff KW, Olson J, Crusberg C, et al. Serum biochemical changes in dogs competing in a longdistance sled race. J Am Vet Med Assoc 1993;202: Ilkiw JE, Davis PE, Church DB. Hematologic, biochemical, blood-gas, and acid-base values in greyhounds before and after exercise. Am J Vet Res 1989;50: Matwichuk CL, Taylor S, Shmon CL, et al. Changes in rectal temperature and hematologic, biochemical, blood gas, and acid-base values in healthy Labrador Retrievers before and after strenuous exercise. Am J Vet Res 1999;60: Steiss J, Ahmad HA, Cooper P, et al. Physiologic responses in healthy Labrador Retrievers during field trial training and competition. J Vet Intern Med 2004;18: Ferasin L, Marcora S. Reliability of an incremental exercise test to evaluate acute blood lactate, heart rate and body temperature responses in Labrador retrievers. J Comp Physiol B 2009;179: Matwichuk CL, Taylor S, Shmon CL, et al. Changes in rectal temperature and hematologic, biochemical, blood gas, and acid-base values in healthy Labrador Retrievers before and after strenuous exercise. Am J Vet Res 1999;60: Dr Luca Ferasin ( 41

42 Steiss J, Ahmad HA, Cooper P, et al. Physiologic responses in healthy Labrador Retrievers during field trial training and competition. J Vet Intern Med 2004;18: Ferasin L, Marcora S. Reliability of an incremental exercise test to evaluate acute blood lactate, heart rate and body temperature responses in Labrador retrievers. J Comp Physiol B 2009;179: Dr Luca Ferasin ( 42

43 CONGENITAL HEART DISEASE PATENT DUCTUS ARTERIOSUS (PDA) Introduction The PDA is the Ductus Arteriosus that fails to close after birth and remains Patent (PDA). This abnormality will lead to pulmonary over-circulation due to the shunting of blood from the high pressure aorta to the low pressure pulmonary artery. Secondary left heart volume overload will develop as a consequence of this pulmonary over-circulation. Finally the pathology will degenerate in left congestive heart failure associated or not with pulmonary hypertension and Eisenmergher physiology (pulmonary resistance to systemic resistance ratio equal to or greater than one). Anatomical and functional considerations Structurally the DA originates from the left 6 th aortic arch and allows a direct communication between the descending aorta and the pulmonary artery. In foetal development DA allows shunting of blood from the pulmonary to the systemic circulation since the oxygenation of blood occurs in the placenta and not in the lungs. The direction of shunt from pulmonary to systemic circulation is a consequence of the fact that the lungs are collapsed resulting in high pulmonary vascular resistance. Following parturition there is a decrease in pulmonary pressure as the lung begins to ventilate. This leads to an increase in oxygen saturation that combined with the lower prostaglandin levels causes functional closure of the ductus, followed by anatomic obliteration during the ensuing weeks of life. Failure of ductal closure is due to the lack of normal ductal musculature. The ductal wall in healthy dogs is constituted predominantly (about 98%) by uniformly distributed smooth muscle throughout the wall, mainly circumferential and contracted. The remainder tissue is made up of scattered subadventitial elastic fibres intermingled with loose collagen in the adventitia. Dr Luca Ferasin ( 43

44 Histopathology in a line of dogs derived from Miniature Poodles with hereditary PDA, consistently identified abnormalities in the wall of the ductus arteriosus that explained failure of the ductus closure after birth. The two main histological features observed in these cases were hypoplastic and asymmetric ductus smooth muscle and the presence of non-contracting aorta-like elastic tissue (segments of the ductus wall that should be muscular had instead a non-contracting, aorta-like elastic wall). The muscular portion was always situated near the pulmonary artery and the thinner elastic portion (aorta-like tissue) always was adjacent to the aorta. Serial-section histology of foetuses predisposed to PDA identified 6 grades of abnormality characterized by asymmetrically reduced smooth muscle and increased aorta-like elastic tissue that correlated with increased PDA gene concentration in breeding experiments. Grade 1-2 Lack of enough muscle to close the aortic end of the duct but presence of enough muscle to close the pulmonary artery end resulting in a non PDA. This leaves a ductal aneurysm, a blind diverticulum (non-patent forme fruste). This mild defect is the occult form that it can be diagnosed only by necropsy and angiography Grade 3-5 Lesions result from small, medium, and large sizes ductus respectively based on the muscle quantity that remains at the pulmonary end. The ductal musculature is absent at the aortic end of the duct and mostly present at the pulmonary end, with some muscle remaining along the duct. This distribuition result in a partial closure. The less muscle remaining at the pulmonary end the greater will be the pulmonary end opening so the greater will be the ductus. This distribution of muscle results in the characteristic funnel shape of the typical left-toright shunting PDA Grade 6 Is the most severe but the least frequent form. The ductus remains as it was in fetal life (large shunt) because of completely no ductal constriction. This type of ductus results in a large left-to-right shunt that may determine perinatal death as well as will develop pulmonary hypertension early in life (Eisenmenger s syndrome, see in the pathophysiology section) creating a bi-directional or right-to-left shunt. The ductus is widest at the aortic end and smaller at the pulmonary end being the pulmonary end the smallest orifice in the PDA, also called PDA ostium. PDA ostium provides resistance to blood flow and determines a pressure gradient between the aorta and pulmonary artery that can be measured non-invasively by Doppler echocardiography. Dr Luca Ferasin ( 44

45 Genetics and Breeds Increased prevalence of this condition has been observed in certain breeds of dogs indicating that genetic factors were involved in the pathogenesis of PDA, and a mixed-breed Poodle line of dogs with hereditary PDA was developed. It has been observed also that the heritability does not follow a simple Mendelian genetics. PDA is one of the most common congenital heart disease. There is a breed and sex predisposition (affecting more females than males in a ratio 2:1 or 3:1): German Shepherd American cocker spaniel Collie Pomeranian Shetland sheepdog Maltese English Springer spaniel Keeshond Yorkshire terrier Rottweiler Pathophysiology After birth, as a consequence of the higher systemic pressures compared to pulmonary pressures, the blood shunts through the ductus from left to right during both systole and diastole. The blood that flows from the aorta to the low pressure pulmonary circulation through the PDA, traverses the lungs and returns to the left heart. To accommodate this increased blood return, the left ventricle grows to a larger size. The result is an increased left ventricle end-diastolic volume, termed volume overload, that compensates blood shunted through PDA from systemic to pulmonary circulation. The increased end-diastolic volume of the left ventricle will determine an increased end-diastolic LV wall stress which will determine an eccentric hypertrophy of the left ventricle as a compensatory mechanism. The amount of shunting blood is dependent on the size of the smallest PDA diameter and the relative resistances of the systemic and pulmonary circulations. The quantity of smooth muscle will determinate the size of the ductus. Small ductus may not result in serious hemodynamic sequelae because compensatory mechanisms may be able to accommodate mild overload. However, in the long term, even small ductus may lead to congestive left heart failure (CHF). Large Dr Luca Ferasin ( 45

46 ductus usually overwhelms the ability of the left heart to compensate by volume overload hypertrophy, resulting in increased left ventricular end-diastolic pressure, which frequently leads to CHF. Depending also on the ductus size, enlargement of the proximal aorta, main pulmonary artery and over-circulation of the pulmonary vascular bed may be seen. The right atrium and right ventricle remain usually normal because shunting happens at the level of the great vessels. These structures are never overloaded unless pulmonary artery pressure increases. Bi-directional or complete reversed shunting direction (right to left) may also be found in a small number of cases. In these cases, the lumen of PDA remains wide open after birth being the same size as aorta and pulmonary artery, not offering resistance to blood flow. Blood flows between the aorta and pulmonary artery without resistance and the aortic pressure is transmitted to the pulmonary circulation and therefore, both aortic and pulmonary pressures become balanced. These patients are not presented with left heart failure after birth probably because pulmonary vascular resistance do not decrease to normal but remain partially elevated to prevent massive shunting. The increase in pulmonary artery pressure combined with the increase in pulmonary blood flow causes pathologic responses in the pulmonary arteries over time. The histological changes observed in these pulmonary arteries include hypertrophy of the media and thickening of the intima in the medium and small pulmonary arteries. This will determine a reduction of the lumen dimensions leading to the pulmonary hypertension (Eisenmenger s syndrome physiology). The exact mechanism for this process in unknown but probably involves injury to the endothelial cells that activates growth factors. These lesions are considered irreversible. Blood flow from the aorta to the pulmonary artery through the ductus starts to decrease due to increase in pulmonary vascular resistance. Consequently, the blood flow velocity decreases. When pulmonary vascular resistance is greater than systemic vascular resistance, blood shunts from right to left and it is called reversed PDA. A large amount of deoxygenated blood shunts from the pulmonary artery into descending aorta producing a differential cyanosis. Exercise result in a decrease in systemic vascular resistance producing an increase in right-to-left shunt and exacerbation of cyanosis occur. This mechanism, together with the increased muscular O 2 demand, explain why some of these patients present episodic rear limb weakness during exercise. The renal oxygenation is decreased leading to an increase of erythropoietin production secondary to activation of oxygen receptors. Compensatory polycythaemia occurs and may become harmful if the haematocrit reaches 70-75% causing increased blood viscosity and resistance to blood flow. This compromises systemic blood flow and decreases tissue oxygen delivery. In the pulmonary Dr Luca Ferasin ( 46

47 circulation, systemic hypoxemia produces pulmonary vasoconstriction. Pulmonary vasoconstriction combined with the increased viscosity worsen pulmonary hypertension. Although it is a rare scenario, a dog with a common moderate-severe left-to-right shunting can develop pulmonary hypertension and gradual reversion may occur with age. This type of pulmonary hypertension may be due to chronic pulmonary venous congestion but the exact mechanism for this is not completely known. Diagnosis: Clinical presentation Although severely affected pups and kittens may appear stunted, thin or tachypnoeic from left heart failure, most are reported to be asymptomatic and developing normally at the time the condition is discovered. Clinical signs are rarely recognized within the first few weeks of life, and most dogs are not diagnosed until the initial examination at 6 to 8 weeks of age. Some dogs that the condition has not been recognized during the first months of life may develop congestive heart failure having a history of coughing, dyspnoea and tachypnoea. The hallmark of a PDA is a continuous murmur over the left 3rd intercostal space. The PMI is in the left axillary area which means that we have to stress the auscultation (sometimes pulling forward the arm of the dog) in order to interrogate this cranial region properly otherwise is very easy to miss this murmur. This usually occurs if the veterinarian auscultates only over the left heart apex and base. In some cases there is a different intensity of the murmur through the cardiac cycle increasing the intensity throughout systole and decreasing throughout diastole but usually the murmur is truly continuous. The murmur may be of any intensity but is often loud (grade 4-6/6) and may radiate cranially (to the sternum) and to the right cranial thorax. A palpable thrill can be felt in the cranial thorax, especially in those cases with a large PDA. When the PDA is very small, the murmur may be very localized and a thrill may not be palpable. Neonatal or older dogs with a very large left to right shunt and equalizing diastolic pressures (low systemic or elevated pulmonary artery pressure) have only a systolic rather than a continuous murmur. Dogs with large shunts may also have mitral regurgitation secondary to annular dilatation with a consequent systolic murmur at the left apex. The murmur may be difficult to be auscultated in dogs in heart failure as pulmonary crackles are predominant. The femoral artery pulse is often increased and it is often described as a bounding or water-hammer pulse. Dr Luca Ferasin ( 47

48 Dogs with pulmonary hypertension and bi-directional shunt or right-to-left PDA are easily missed on physical examination because they usually have a mild systolic or no murmur at all. They may have a split second heart sound but this is not always detectable. Occasionally they have a faint diastolic murmur caused by pulmonic valve regurgitation. Radiography Radiographic abnormalities reflect the degree of cardiac volume overload, congestive heart failure and pulmonary over-circulation. These changes depend on the size of the PDA, presence of concomitant cardiac abnormalities and pulmonary hypertension. In mild cases it is possible to observe only the over-circulation pattern characterized by an increased pulmonary vascular size. However the variation in pulmonary vascular size in normal dogs sometimes makes this finding difficult. Dogs with a relatively large left to right shunt commonly have an enlargement of the left ventricle, left atrium and a dilated aortic arch, giving the appearance of generalized cardiomegaly with pulmonary over-circulation, and venous prominence often evident. An increase in pulmonary vascular size usually correlates with a significantly increased shunt volume. An aneurysmal bulge in the descending aorta in the region of the ductus may be seen on the dorsoventral or ventrodorsal radiograph. In cases with increased main pulmonary artery, it may be observed as a buldge at the 2- o clock position on the dorsoventral or ventrodorsal radiograph. Pulmonary venous enlargement and pulmonary oedema may be visible in dogs with left heart failure. Dogs with right to left shunting may present right ventricle enlargement and enlarged main pulmonary artery with normal or diminished peripheral pulmonary vasculature. Electrocardiography The most common abnormality on the electrocardiogram is an increase in R wave amplitude in lead II as a result in left ventricular enlargement. This finding is present in approximately 50% of cases with left ventricular enlargement. Deep S waves can occur in patients with right heart hypertrophy in patients with pulmonary hypertension. Supraventricular and venticular arrhythmias may be present. In a recent preliminary study we have observed an increased risk for sudden death in patients who presented ventricular arrhythmias suggesting to be a negative survival prognostic factor. Further studies are necessary to support these preliminary results. Clinical PDA Classification Dr Luca Ferasin ( 48

49 Patient history and clinical features of PDA depend upon the size and duration of the shunt. Based on the patient history, clinical signs, plain radiography and electrocardiography it is possible to do a clinical PDA classification based in 4 types as an anatomical and functional diagnosis without resorting to angiocardiography or echocardiography. Type 1 (small PDA): - Asymptomatic left to right shunt. - High frequency continuous murmur only at the left heart base. - Pre cordial thrill is faint or not present at the left heart base. - Heart rate and pulse quality are normal. - Radiographs and ECG are normal even at 1-2 years of age. - Surgery is not urgent but is recommended for normal life span. Type 2 (medium size PDA): - Asymptomatic left to right shunt. - Coarse continuous murmur at the left heart base and slightly audible at the left apex. - Palpable continuous thrill at left heart base - Pulses normal or slightly bounding. - Mild to moderate left heart enlargement before one year of age. - Small to medium size ductus aneurysm may be present - Borderline increase in pulmonary vascular markings. - ECG Lead II R waves usually exceed 3 millivolts indicating left ventricular hypertrophy. - Surgery is recommended but it can still wait a few weeks. Type 3a (large PDA prior to congestive heart failure) - Usually reduced exercise capacity. - Coarse continuous murmur and thrill over most of the left thorax. - Systolic murmur of mitral regurgitation often present at the left apex. - Medium to large ductus aneurysm usually present. - Marked left heart enlargement before 6 months of age. - Significant increase in pulmonary vascular markings - Pulses bounding due to wide pulse pressure - ECG Lead II R waves may exceed 5 mv. - Surgery recommended without delay. Dr Luca Ferasin ( 49

50 Type 3b (large PDA plus congestive heart failure) - All 3a features plus dyspnoea due to pulmonary oedema. - Usually poor body condition (cachexia). - Atrial fibrillation occasionally seen in ECG. - Pulmonary oedema must be cleared as much as possible with cage rest, oxygen, digitalization and diuresis before surgery. Type 4 (large PDA plus pulmonary hypertension) - Right-to-left or balanced shunt - Two weeks to 12 years old. - Hind leg weakness or collapse with exercise. - Cyanosis usually limited to caudal part of body. - Pulses normal or weak. - Polycythaemia (packed cell volume as high as 80%). - Usually no murmur or precordial thrill after 1 month old. - Split and/or prominent second heart sound often detectable. - Right side apex beat stronger than left. - Right axis deviation in electrocardiogram due to right ventricular hypertrophy. - Large right heart and main pulmonary art e ry in radiographs. - Peripheral pulmonary artery size can appear normal or decreased and show slight tortuosity. - Surgery is contraindicated because of severe pulmonary vascular disease - Treat polycythemia by periodic phlebotomy or chemotherapy. Echocardiography Transthoracic echocardiography (TTE) provides a non invasive examination that permits definitive diagnosis of PDA by visualizing the shunt as well as evaluation of the hemodynamic consequences. In a left-to-right shunting PDA, the left ventricular end-diastolic diameter is increased and generally corresponds to the size of the PDA. Left ventricular end-systolic diameter tends to be normal in young dogs and increased in older dogs. Fractional shortening is usually in the normal range but in severe cases may be reduced. Evidence of systolic dysfunction (elevated left ventricular internal diameter in systole, reduced fractional shortening) may be seen in dogs with large volumetric shunts and typically persist or appears worse following successful ligation or occlusion. The left atrium is usually enlarged to a similar degree as the left ventricle. Identifying continuous turbulent flow with spectral and colour flow Doppler in the main pulmonary artery is characteristic of a PDA. The PDA Dr Luca Ferasin ( 50

51 itself can be visualized from the right parasternal short axis view and from the left parasternal cranial view and it presents as a hypoechoic space between the pulmonary arterial trunk and the aorta. Usually the left cranial short axis view provides the optimal image. Spectral Doppler allows the evaluation of the Qp/Qs which gives the information of the shunt fraction. Qp/Qs 2 means that the dimension of the ductus is from moderate to large. Peak velocity through the ductus, when there is no increase resistance in the pulmonary artery, is between 4 and 6m/sec. Peak aortic velocity is frequently increased due to the volume overload and low pulmonary resistance. Trans-aortic flow velocity may be as high as 3.75m/s with large shunts. This may lead to an erroneous diagnosis of concurrent SAS. Therefore caution should be used when interpreting aortic flows in patients with large shunts. Although the ductus can be viewed by using transthoracic echocardiography, this technique is postulated to be unsuited for achieving sufficient evaluation of PDA morphology in dogs. In order to get complete information about PDA morphology is necessary to integrate the measurement of the minimal PDA diameter and the ampulla diameter together with the ampulla length. TTE showed limitations to properly measure PDA ampulla diameter. Furthermore PDA s ampulla length is not possible to be measured using transthoracic echocardiography because of the position of the PDA and the descending aorta, being generally difficult or impossible to see the confluence of the 2 vessels. PDA ampulla diameter and length can be visualized and measured properly by angiography as well as by transesophageal echocardiography (TEE). TEE uses a two-dimensional transducer at the end of a flexible endoscope placed in the oesophagus capable of providing higher quality images in result of a closer proximity to the heart, allowing a better visualization of the PDA. This contributes to the understanding of the anatomical structure as has been demonstrated by angiography and post-mortem examination. We have observed that TEE provides accurate anatomic information regarding PDA morphology and in some cases may be superior to angiography. We have to consider that optimal positioning of the patient for angiographic viewing of the ductus does not always occur and overlying structures interfere with the clarity. Also angiography is a radiologic method in which we are evaluating a shadow of the heart and sometimes it may be very difficult to determine the real size and shape of the ductus. Therefore, TEE may be an important echocardiographic tool to overcome these angiographic limitations. Right to left shunting PDA may be documented with echocardiography by injecting in the cephalic vein micro bubbles contrast preparation (saline mixed with colloid solution). In the right to left shunt we see the micro bubbles in the abdominal aorta which normally should not be seen because Dr Luca Ferasin ( 51

52 of the pulmonary entrapment. If we see micro bubbles in the abdominal aorta means that the bubbles had to bypassed the lungs through a reversed ductus. Treatment Uncorrected PDA often results in left-sided congestive heart failure with a mortality rate reported to be greater than 60% within the first year. In some dogs, clinical signs are not apparent until they are mature, but signs are present before the dog is 3 years old. In dogs older than 24 months almost 50% presented clinical signs such as cough, collapse, exercise intolerance, lethargy and dyspnoea. So, the closure of PDA is always recommended. Pharmacological In human medicine the use of aspirin or indomethacin is described to induce closure of ductus in the neonatal period. To be effective, this technique requires normal ductal muscle morphology. In dogs, the patency is related to ductus muscle abnormality therefore this treatment is not effective. As consequence, the approach to wait until it closes is equally ineffective. All patients with PDA should undergo curative closure. Since the path physiology of the shunt leads to pulmonary vasculature and cardiac damage a delay in the procedure is also contraindicated. Medical treatment of a left-to right shunting PDA is aimed at treating heart failure. Medical management of a right-toleft shunting PDA is aimed at reducing the haematocrit. Surgical While surgical ligation has historically been the most utilized correction technique, interventional or minimally invasive catheter-based procedures have become common over the past decade. Since then, several devices has been used and published in veterinary medicine such as coils, Amplatzer duct occluder (ADO), Amplatzer vascular plug and Amplatz canine duct occluder (ACDO). The Amplatz canine duct occluder (ACDO) is a novel device for PDA occlusion in the dog and has rapidly gained popularity since becoming commercially available. ACDO is a nitinol mesh device with a short waist separating a flat distal disc from a cupped proximal disc. Specifically designed for this purpose, this self-expandable device renders possible the treatment of PDA of varying sizes and morphologies, in a wide range of dog weights and somatotypes. Its deployment is straightforward and followed by rare complications if the size of the device is selected carefully according to the size and shape of the ductus. Briefly, device size selection, and hence patient edibility, depends mainly on the minimum ductal diameter (MD) and ductal morphology. Given the currently available ACDO sizes, it should be possible to use this device to close PDA with a MD from 2 to 9 mm, considering Dr Luca Ferasin ( 52

53 that an over sizing factor (OF) of 1.5 to 2 between device waist diameter and MD is advised. Ductal morphology is another very important aspect to consider when assessing the feasibility of this technique. Successful ACDO deployment has been described for PDA of types IIA, IIB and III according to Miller s classification. Experience with type III PDA is however scarce and caution is advised. Its tubular conformation and probable lack of support for the device may lead to instability and embolisation. From the discussion above, one can easily understand that an accurate study of PDA anatomical characteristics is of extreme importance when considering percutaneous treatment with ACDO. Inaccurate device size selection may result in adverse events including systemic or pulmonary embolisation, incomplete ductal closure, and haemolysis. Angiography has been traditionally the recommended method for correct evaluation of PDA characteristics and ACDO size selection, but TEE may contribute as well to this purpose. In a recent study we showed that TEE may be used as a valid alternative to angiography in the evaluation of PDA dimensions in dogs, providing correct ACDO size selection. The use of TEE during the ACDO procedure facilitates the placement of the device trough the ductus ostium and permit improved assessment of ACDO stability. The decrease in ductal flow associated with clot formation can be viewed in real-time with a final assessment of the amount of reduced ductal flow possible and quantifiable. TEE may be advantageous during these procedures by providing superior anatomical information regarding PDA morphology, dimensions, ACDO deployment, and ductal closure. Similar results have been observed by other authors during PDA coil embolisation. So, TEE is an important tool for an easier ACDO deployment and confirmation of intraoperative ductal closure. Furthermore, use of TEE reduces the number of contrast injections required and decrease fluoroscopy and anaesthesia time, leading to a reduction in radiation exposure and cost. Dr Luca Ferasin ( 53

54 PULMONIC STENOSIS (PS) Introduction Pulmonic stenosis is one of the most common congenital heart defects in dogs. Pulmonic stenosis can be classified in 3 types, according to the localization of the lesion along the right ventricular outflow tract (RVOT), as subvalvular, valvular and supravalvular. The most common type is valvular pulmonic stenosis which also can be subdivided in two different types: type A and type B; both types of stenosis may coexist in some patients determining a mixed type pulmonic stenosis. Type A pulmonic stenosis is the most frequent type observed in veterinary clinics. Anatomical and functional considerations Pulmonic stenosis, in contrast to subaortic stenosis, usually presents with its definite grade of severity early in the life of the affected puppy. We have to consider, though, that pressure gradients may increase during the growing period so mild pulmonic stenosis in a 4 months old dog usually progresses to a moderate or severe stenosis at 1 st year of age based on pressure gradients. In humans, valvular stenosis is subdivided into dysplastic valve leaflets with annular hypoplasia and no post stenotic dilatation, and cases with non-dysplastic valves and fused leaflets. In veterinary medicine, have been published similar criteria of subdivision differentiating PS into 2 main types: Type A The annular size is normal. Various degrees of leaflet thickening with incomplete separation of the commissures to almost complete fusion. It causes a systolic doming of the valve ( windsock type image) with most often eccentric valvular opening with various degrees of reduced crosssectional area. Poststenotic dilatation of the pulmonary trunk is present with various degrees of severity. Type B The pulmonary ostium is hypoplastic, with various degrees of valvular leaflet thickening and immobility, but little commissural fusion. The main pulmonary trunk is also often hypoplastic, and rarely has a poststenotic dilatation. Type A pulmonic stenosis is the most common type of valvular PS observed. Primary subvalvular obstructions by an infundibular fibrous ring, analogous to SAS, appear to be rare in dogs. Secondary stenosis of the infundibulum with various degrees of fibromuscular infundibular hypertrophy, as a result of pressure-induced hypertrophy, due to pulmonic stenosis is well described Dr Luca Ferasin ( 54

55 and is the more common form of subvalvular PS; likely, it has a dynamic component and leads to worsening of the stenosis with exercise or stress. Primary infundibular stenosis has been sporadically reported in humans, dogs, and cats. This rare form of stenosis divides the right ventricle into a proximal high pressure chamber and a distal low pressure chamber and has been attributed to (1) anomalous muscle bundles; referred to as double chambered right ventricle (DCRV) and (2) a fibrous diaphragm or fibromuscular band of tissue obstructing the infundibulum; referred to as infundibular pulmonic stenosis in humans. In some breeds, especially the English bulldog and Boxers, an anomalous R2A-type left coronary artery encircles and constricts the right ventricular outflow tract. This anomaly represents an exclusion criteria for any valvuloplasty procedure, as a dilation of the infundibulum would lead to severe coronary ischemia and the patient s demise. Isolated supravalvular PS appears to be extremely rare. Attention should be taken during the ecocardiographic examination of the systolic doming of the valve in type A PS cases because supravalvular PS could be easily misdiagnosed. Combination of SAS and PS occurs in a considerable number of boxers. In one retrospective study of 500 Boxers a combination of the SAS and PS occurred in 24% of dogs with cardiac disease. In a recent study it has been observed associated congenital cardiac defects in 32% of dogs with pulmonic stenosis. The most common associated congenital anomalies were subaortic stenosis followed by ventricular septal defect and patent ductus arteriosus. Genetics and Breeds A heritable basis for pulmonic stenosis has been shown in Beagles and Keeshonds based on breeding studies. Other breeds at increased risk for pulmonic stenosis include: English Bulldog Fox Terrier Miniature Schnauzer Chihuahua Beagle Samoyed Boxer Bull Mastiff American Cocker Spaniel West Highland White Terrier Dr Luca Ferasin ( 55

56 Boykin Spaniel In Oliveira s study (2011), the most commonly affected breed is the Boxer with 38% of PS cases followed by English Bulldog (9%), Mixed breed (7%), French Bulldog (6%) and Beagle (4%). The other multiple breeds were 3% of dogs. Although it is considered that both sexes are affected equally a male predominance has been reported for the English Bulldogs and Bull Mastiff. Pathophysiology Irrespective of the obstruction s location the main hemodynamic consequence of pulmonic stenosis is an increased right ventricular systolic pressure and wall stress leading to right ventricular hypertrophy. Leftward septal deviation or flattening, and an increased systolic pressure gradient across the pulmonary valve are observed. The magnitude of the resultant pressure gradient is directly related to both the quantity and rate of blood flow across the obstruction and to the crosssectional area of the stenotic region. The pressure gradient is commonly used as an index of the lesion severity. Distal to the obstruction, blood flow velocity increases and becomes turbulent determining in some cases a main pulmonary artery enlargement also called pos-stenotic dilation. The right ventricular hypertrophy try to normalize the increased wall stress, following Laplace s law, as well as try to normalize right ventricular systolic function trying to maintain the right ventricular stroke volume within the normal range. This right ventricular hypertrophy will also determine a reduced ability of the ventricle to fill properly determining also a diastolic dysfunction. With the progression of the disease, a right side congestive heart failure develops due to an increased right atria dimensions and right ventricular systolic dysfunction. Progressive right atria enlargement results from various factors including elevated right ventricular diastolic pressure, secondary tricuspid regurgitation caused by high systolic pressure and geometric changes within the right ventricle, right ventricular hypokinesia (right ventricle loses the force of contraction in a similar way as does left ventricle in advanced cases of aortic stenosis) and decreased cardiac output with compensatory retention of sodium and water. When elevated peak velocities are found in the RVOT, the values are then transformed into an estimated pressure gradient with the simplified Bernoulli equation (ΔP=4v 2 ): Mild stenosis Moderate stenosis Severe stenosis Gradient under 50 mmhg Gradient between mmhg Gradient over 80 mmhg Dr Luca Ferasin ( 56

57 Natural history depends on lesion severity. Dogs affected by mild and even moderate PS may live normally. Animals with moderate-to-severe stenosis may develop complications, including exertional syncope, cardiac arrhythmias, secondary tricuspid regurgitation, atrial fibrillation, right congestive heart failure and sudden death. Systolic pressure gradients are not always predictive of clinical outcome but a general correlation can be observed between pressure gradient and survival. Diagnosis Clinical presentation: Usually dogs are asymptomatic showing only a left basilar ejection murmur over the pulmonic valve that radiates to the left craniodorsal cardiac base and in some cases it can also radiate to the right craniodorsal base. In general the intensity of the murmur increases with the severity of obstruction. The murmur is a classic ejection-harsh sound with crescendo-decrescendo quality. Rarely a diastolic murmur of pulmonic insufficiency can also be heard. It is not uncommon to auscultate a holosystolic murmur of tricuspid regurgitation over the right hemi thorax. Some cases present with ascites, exercise intolerance and syncope related to right-sided congestive heart failure and low cardiac output. Arrhythmias and reflex-mediated syncope are other causes for collapse. Sudden death without premonitory signs is rare but may occur. Clinical signs are more likely to occur in dogs older than 1 year of age. Symptoms may develop earlier in dogs with severe stenosis or with the presence of other congenital cardiac abnormalities such as SAS, ventricular septal defects and PDA. Radiography Thoracic radiographs provide little information regarding the severity of the stenosis since they are usually normal in mild to moderate affected animals although right-sided cardiomegaly may be present. In moderate to severely affected patients a prominent right heart enlargement may be observed and dogs with Type A pulmonic stenosis a post-stenotic dilation of the main pulmonary artery can be seen. Pulmonary underperfusion may also be observed depending on the severity of the stenosis. Electrocardiography Electrocardiography may be completely normal or may show a pattern of right-sided enlargement especially in severe cases with marked right ventricular hypertrophy; ventricular arrhythmias and supraventricular arrhythmias may also be present. In some cases Holter monitoring may be useful. Dr Luca Ferasin ( 57

58 Echocardiography Echocardiographic examination is the most important diagnostic tool in order to identify the presence of this congenital heart defect as well as permits to classify the different types and severity of PS. The right ventricular outflow tract has to be optimized in its entire length with a perfect long axis view although it may be difficult in many cases due to its curved course. Initially an oblique, somewhat tangential section of the RVOT, obtained from a right parasternal short axis view, can be generated in all dogs which permit to measure appropriately the pulmonary annulus. Then, this projection may be optimized by moving the probe towards the sternum, maintaining the same angle section, trying to visualize the maximum length of the RVOT, pulmonary annulus and main pulmonary artery; this last view permits the best alignment to perform spectral and colour flow Doppler recordings. In patients with subvalvular PS, these views are sufficient to image subvalvular narrowing caused by muscular infundibular hypertrophy, fibrous diaphragm or fibromuscular band, as well as to observe the presence of a dynamic stenosis, which is not uncommon. Dynamic stenosis is well observed with the spectral Doppler characterized by a knife shaped flow pattern. A differential diagnosis of DCRV and an anomalous R2A-type left coronary artery has to be done in all patients with subvalvular PS. Usually cases with valvular PS can be studied properly using this right side view, observing also a thickened and hypertrophic right septum and RV free-wall with some hyperechoic areas relative to endomyocardial fibrosis, especially in severe cases. Left side views are mandatory in order to complete the echocardiograhic examination. Left cranial parasternal short axis view is obtained doing a steep dorsal and slightly more cranial angulation after obtaining a long axis view of the aortic root; this view shows the RVOT with the main pulmonary artery in most of its length and also the pulmonary bifurcation. This view displays valvular abnormalities. Another suggestive finding of pulmonic stenosis that may be observed is the presence of post-stenotic dilatations, although this feature is not present in type B phenotype. Echocardiography also allows determination of the severity of right ventricle hypertrophy or altered kinetics as in the presence of paradoxical motion or flattening of the septum. These findings are also strongly suggestive of increased RV pressure. However, a non-invasive estimation of increased pressure can only be obtained by measuring pulmonary peak velocity with the continuous wave Doppler beam in parallel alignment with the direction of flow. This usually is accomplished from either the right or left cranial parasternal windows. The values obtained are then transformed into an estimated pressure gradient with the simplified Bernoulli equation. Tricuspid annulus dilatation is also an important aspect to evaluate as well as the high velocity tricuspid regurgitation. Colour Doppler may also identify associated Dr Luca Ferasin ( 58

59 congenital defects such as ventricular muscular defects, or dynamic obstruction in the left ventricular outlet related to altered ventricular geometry. In some cases transesophageal echocardiography (TEE) may be a complementary tool to study the subvalvular, valvular or supravalvular anatomy especially in those cases with deficient echocardiographic window or structural thoracic abnormalities. Treatment: Special consideration Patients with resting gradients of over 80 mmhg are at risk of sudden death and balloon valvuloplasty is recommended whether the patient is symptomatic or not. Patients presenting intermediate resting gradients (50-80 mmhg) often live normal lives although long term prognosis is uncertain. In these patients, therapeutic decision is determined by the clinical presentation (presence of clinical signs), degree of RV hypertrophy and the nature of the progression. Patients presenting low resting gradients (under mmhg) usually live normal lives and therapy is unnecessary. Pharmacological The decision to treat pulmonic stenosis is based on the severity of clinical signs, the magnitude of the pressure gradient across the pulmonic valve and degree of RV hypertrophy. The pressure gradient for which a medical treatment should be recommended cannot be stated with certainty. Usually with a pressure gradient greater than 50-60mmHg a medical treatment based on betablocking agent could be started. This drug reduce myocardial oxygen demand and increase coronary perfusion by decreasing heart rate and contractility; these effects may help in preventing or at least reducing the incidence of the late stage characterized by a right ventricular myocardial insufficiency. Also this drug reduces the dynamic stenosis at the RVOT as it reduces the heart rate and contractility as well as reduces ventricular arrhythmias, syncopal events and may prevent sudden death. The reduction of the dynamic stenosis and arrhythmias is very important in those cases where a pulmonary balloon valvuloplasty will be performed. Atenolol is used with a starting dose of 0,2mg/Kg SID or BID and progressively increased (weekly increments) up to 0,5-1 mg/kg SID or BID always with blood pressure and ECG monitoring. Surgical Pulmonary balloon valvuloplasty (BVP) is the first line of treatment for PS. Valvuloplasty should be performed in any symptomatic patient and in any patient with severe pressure gradient with RV Dr Luca Ferasin ( 59

60 hypertrophy (even if they are asymptomatic) as soon as PS is diagnosed. Delay in the treatment can lead to progression of RV and infundibular hypertrophy, not only making the procedure technically more difficult but also diminishing the immediate response to therapy. In one retrospective study in which BVP was performed in 95 dogs we documented a significant reduction of pressure gradient after the procedure at 24h and at 1 year either for type A and type B pulmonic stenosis. The mean pressure gradient after the procedure at 24h and at 1 year between group A and B resulted to be lower in type A, suggesting better results. The PBV was considered successful (more than 50% reduction in pressure gradient from baseline) in 65 dogs with type A (90%) and in 7 dogs with type B (54%). The PBV was performed without significant complications in 93% of dogs. Based on these data we could say that PBV is effective in type A and B PS, being even more effective in type A. In human literature similar results are reported. The PBV of patient with dysplastic valve was less effective (61, 11%) when compared with those with typical PS (80, 59%). Despite the success rate was lower in the dysplastic group, PBV is still considered the first treatment option in both types of PS in humans. Furthermore PBV in type B (or dysplastic) may avoid or delay the need of surgery and provides a good long outcome in dogs as it occurs in humans. In a study involving 120 pulmonary BVPs in dogs (Oriol Domenech, personal data), the major complications observed were: right ventricle perforation, ventricular tachycardia, ventricular fibrillation and severe bradycardia with asystole. The major complication rate during PBV were around 4.8% and death rate about 2.4%. Right ventricle perforation with a consequent pericardial effusion and presence of the contrast in pericardial space, is the most spectacular complication we have seen but it did not determine pericardial tamponade nor death. S-T segment depression, as a sign of myocardial ischemia, is of great importance because is related to an increased risk of severe ventricular tachycardia. Mortality during BVP was mainly due to life threatening ventricular arrhythmias. Ventricular tachycardia usually responded very well to lidocaine infusion unless there is a severe myocardial ischemia. These complications are related to material, procedure technique, size of patient, patient stability before the procedure, RV hypertrophy degree with presence of fibrosis, type of the stenosis and experience of the operator. We also have observed that patients pre-treated with beta-blocking agents presented much less incidence of malignant arrhythmias as well as less worsening of the dynamic pulmonic stenosis. In some patients with significant infundibular hypertrophy is possible to observe a worsening of the dynamic pulmonic stenosis after the valve dilation due to the decreased resistance of the RVOT that determines an exaggerated systolic motion of the infundibular area of the RVOT. This is a very important feature because it may Dr Luca Ferasin ( 60

61 evoke to a suicide infundibulum and patient death. This is one of the reasons why we pre-treat with a beta-blocking agent (atenolol) all patients that will be performed a BVP. We can also find errors of the catheterisation that can complicate or not all the procedure, being the most frequent: contrast tattoo, air bubble, inappropriate localization of the catheter during contrast injection and guide wire loop formation in the right atrium or right ventricle. It is already well known that anomalous left main coronary artery (originating from a single right coronary artery) which encircles the stenotic RVOT, is present in some affected dogs, especially in English Bulldogs and Boxers, so coronary anatomy examination with echocardiography or a selective coronario-angiography is imperative. Balloon dilation in these patients has been reported to cause rupture of the artery and sudden death of the patient. Recheck evaluations are typically performed 3, 6 and 12 months after the procedure and then annually. Gradients may continue to decrease in the first 3 to 6 months, if we compared with 24h post-procedure gradient, probably due to resolution of the valve oedema following balloon dilation and regression of RV/infundibular hypertrophy. So determination whether BVP has been successful should not be judged until several months following the procedure. We usually continue with beta blockers in dogs with residual pressure gradient 60-80mmHg, RV hypertrophy and residual dynamic RV outflow obstruction. AORTIC STENOSIS (AS) Introduction Aortic stenosis can be classified in 3 types, according to the localization of the lesion along the left ventricular outflow tract (LVOT), as subvalvular, valvular and supravalvular. The most common form is subvalvular, commonly referred to as subaortic stenosis (SAS), and can be subdivided into three different types: type 1, type 2 and type 3. Canine subaortic stenosis is the second most frequent congenital heart defect in some studies. The incidence has been estimated to be between 22 and 34 percent of the reported canine congenital heart disease although geographic variation in prevalence is an important factor. Anatomical and functional considerations The subvalvular lesion may be present at birth or may develop during the first weeks / months of life. In pathology studies of SAS in the Newfoundland, subvalvular lesions were detected only in pups that were older than 3 weeks. Based on this finding, SAS is not strictly congenital but rather develops early in life. This observation has also been reported in humans. It has been speculated that the Dr Luca Ferasin ( 61

62 lesion arises due to morphological abnormalities in the LVOT that increase shear stress and induce proliferation of cells in the LVOT. This proliferation may be derived from persistent embryonic endocardial tissue that retains its proliferative capacity. In dogs, the obstruction may progress for the first 12 months of life. This progression is important in order to correctly identify pups of breeds known to be at risk for this disease and it is probably inappropriate to clear dogs for subaortic stenosis before they are full grown. A full certification of phenotipically normal dogs can only be issued after 12 months of age.additionally, pressure gradients may also increase in affected dogs during the growing period so that a mild aortic stenosis at the age of 4 months usually progresses to a severe aortic stenosis at in the first year. So, whenever mild-to-moderate SAS has been documented in a young dog, no prognosis should be given, because the obstruction may, and often becomes, more severe. Three different types of subaortic stenosis have been described based on necropsy findings and with increasing severity of the disease from type 1 to 3: The ventricular surfaces of the aortic valve leaflet may also be thickened and this may induce sometimes a misdiagnosis of valvular aortic stenosis, therefore it is very important to carefully evaluate the LVOT. The most frequent forms observed, are type 1 and 2 representing 85% of all SAS cases. Apart from the fixed subaortic lesion, a dynamic (labile) component may also affect the behaviour of the SAS. In the fixed stenotic lesion the severity of the stenosis does not change from beat to beat or Dr Luca Ferasin ( 62