Update on mitral valve disease in 2018

Transcription

1 Update on mitral valve disease in 2018 Rebecca L. Stepien DVM, MS, DACVIM (Cardiology) University of Wisconsin School of Veterinary Medicine Madison, WI USA 1. What is this disease? (endocardiosis, acquired degenerative valvular disease, chronic valvular disease, CVD) a) VERY COMMON: accounts for 75% of cardiovascular disease in dogs b) most commonly seen in dogs (occasionally in cats, most aspects same as dogs) c) small breed dogs > large breed dogs > cats d) murmur detected: usually > 5 years, onset of clinical signs: variable or never e) exception: Cavalier King Charles Spaniel, onset as early as 4 years 2. Pathology: a) etiology unknown (no proven relationship to dental disease) b) thickened valve leaflets with curled edges and opaque appearance c) smooth surface (differentiate from rough-surfaced endocarditis lesions) d) mitral valve more frequently affected (60%), tricuspid only (10%), both (30%) e) associated lesions i) chordae tendineae lesions ii) thickened, nodular and/or elongated chordal structures iii) ruptured chordae (leads to mitral valve prolapse) iv) atrial enlargement (severity related to severity of valve abnormality) w/ jet lesions v) ventricular dilation/mild thickening (variable with stage of disease) 3. Physiology: a) easier to push blood backward (through leaky valve) than forward b) decreased forward stroke volume leads to hypotension and activation of SNS and reninangiotensin-aldosterone system c) regurgitant flow leads to atrial enlargement and increased atrial pressure (leading to pulmonary congestion or ascites) RLStepien

2 4. Clinical findings: a) Physical Exam (if no heart failure is present): i) murmur: systolic, loudest over left or right cardiac apex, radiates dorsocranially ii) mitral insufficiency: cough iii) severe tricuspid insufficiency: jugular pulsation, hepatomegaly iv) pulse strength: normal to hyperkinetic (short ticking pulse) b) Physical Exam (if heart failure is present): i) mitral: tachypnea, cough, increased breath sounds or crackles, tachycardia ii) tricuspid: ascites, distended jugular veins, muffled heart sounds if pleural effusion, tachycardia iii) either/both valves: weak peripheral pulses, cold feet/ears c) Echocardiography i) CONFIRM the diagnosis ii) RULE OUT vegetative lesions iii) ASSESS the severity of the lesions based on remodeling of heart (1) size of jet by color Doppler mapping may be misleading (2) LA size is best assessment of severity of insufficiency (3) LV and LA dilation are often accompanied by globoid appearance of chambers iv) Pulmonary hypertension may be diagnosed by 2-D/Doppler examination (1) May result from SEVERE LA hypertension (high LA pressure from chronic MR) (2) Main pulmonary artery enlargement (3) Tricuspid or pulmonary insufficiency jets allow assessment of pulmonary arterial pressure 5. Natural history of chronic valvular disease a) Long presymptomatic period is typical b) Myocardial function remains normal until after chronic volume loading c) Therapeutic period is often long (months to years after 1st clinical signs) d) Timeline: i) Most breeds develop CVD in early middle to middle age (~6-8 years) ii) Some breeds and dogs may develop detectable murmurs as early as 2-4 years iii) Clinical signs typically occur 1-3 years after murmur detected RLStepien

3 6. Congestive heart failure and the chronic valvular disease patient a) Staging of heart failure allows understanding of progression AND helps direct therapy b) Most therapies begin in Stage C, when clinical signs are present American College of Cardiology/American Heart Assoc (ACC/AHA) Classification System At risk for heart failure STAGE A No structural disease, but high risk for developing heart disease STAGE B1 Asymptomatic disease, minimal remodeling (enlargement) STAGE B2 Asymptomatic disease, significant remodeling (enlargement) Heart failure STAGE C STAGE D Past or current signs/symptoms of CHF End stage CHF, signs refractory to Rx c) ACEI and beta blockers are sometimes used in Stage B1 and especially B2 d) NEW: pimobendan in later Stage B2 dogs (meeting enlargement criteria, see below) 7. How do we do the staging? a) History: is the owner reporting clinical signs? i) Cough ii) Fatigue iii) Dyspnea/tachypnea/shortness of breath, recent increases in resting respiratory rate b) Physical exam findings: is the patient exhibiting clinical signs? i) Auscultatory evidence of valve disease PLUS ii) Spontaneous cough iii) Weakness iv) Dyspnea/tachypnea/increased RRR v) Abnormal pulmonary auscultation (increased breath sounds, crackles) c) Radiology i) Stage A and B1: no radiographic abnormalities ii) Stage B2: compensated valvular disease (1) Cardiomegaly by vertebral heart scale measurement RLStepien

4 (2) Tracheal elevation compatible with left heart enlargement (3) LA enlargement, may impinge on left mainstem bronchus iii) Stage C: decompensated valvular disease (congestive heart failure) (1) Findings of Stage B2 PLUS (2) Distended pulmonary veins (3) Interstitial to alveolar infiltrates d) Echocardiography i) Full diagnosis of disease: valve prolapse, chordal rupture? ii) iii) Complications: pulmonary hypertension Check for B2 criteria for pimobendan use (see EPIC Trial, below) iv) Some easy to measure markers are correlated to survival (Sargent et al. 2015) (1) LA:Ao > 1.6: indicator of LA enlargement (2) LVIDdias: Ao >2.87: indicator of LV dilation (3) Markers of severe valvular damage: leaflet prolapse or flail (4) Markers of increased regurgitant volume: increased diastolic E wave > 1.4 m/s e) What about biomarkers? i) Cardiac troponin I reflects myocardial necrosis-not helpful here ii) NT-proBNP shows promise as reflector of ventricular stress (1) Can be used to diagnose CHF vs. other causes of dyspnea (2) Can be used to differentiate heart disease from heart failure (3) Recent changes to the assay mean diagnostic numbers will change (watch the literature!) 8. Therapy: Valvular Heart Disease a) Stage A and B1: i) Diagnostic testing to identify extent of disease (PE, rads, ECG, +/- bloodwork) ii) Educate owners on signs to watch for (e.g. cough, exercise intolerance) b) Stage B2 (no clinical signs) i) ACEI therapy often prescribed if LA enlargement is severe ii) Pimobendan prolongs time to congestive heart failure (Boswood et al. 2016) for dogs meeting criteria for late Stage B2. RLStepien

5 EPIC Clinical Trial Results: Use of pimobendan to treat preclinical MMVD: Boswood et al small breed dogs with late B2 valve disease (severe enlargement) Criteria: >/= 3/6 systolic murmur L apex left atrial-to-aortic ratio 1.6 normalized left ventricular internal diameter in diastole (LVIDDN) 1.7 vertebral heart sum > Randomized Pimobendan: n=178 (~0.3 mg/kg q 12 hr) Placebo: n=176 (equivalent tablet) Primary endpoint: time to CHF, cardiac euthanasia, or cardiac death RESULTS: Median time extended by 462 days (~15 months) RLStepien

6 Conclusions: For B2 dogs meeting EPIC criteria: Pimobendan is indicated Side data: Dogs that went into heart failure tended to live longer and spend a smaller proportion of their remaining lifetime in heart failure Recommended summary: How has this changed what we do? Echocardiography and thoracic radiographs together are used to determine whether preclinical use of pimobendan is warranted. Now, dogs in LATE Stage B2 will be treated with pimobendan in hopes of prolonging preclinical time before CHF occurs. Late Stage B2 dogs often receive pimobendan and ACEI together, prior to the onset of overt clinical signs. What if the patient has Stage B2 disease that does not meet enlargement criteria? Consider scheduling a recheck in 6 months to re-evaluate thoracic radiographs If VHS now exceeds approximately 11.5, consider pimobendan therapy ( What about cough? Cough is not heart failure: A dry hacking cough is often a sign of cardiomegaly, rather than of congestive heart failure. RLStepien

7 When cough is due to congestive heart failure, it is usually associated with increased respiratory rate and/or dyspnea and is usually productive, with expectoration of blood-tinged foam. When cough is dry and hacking (non-productive) and associated with normal respiratory rate and effort, it is likely due to cardiomegaly (or respiratory causes) Stage B2 Vasodilators (e.g. ACEI) may ease forward flow by decreasing afterload and lessen regurgitant volume. Patients with cough due to cardiomegaly may respond to pimobendan +/- ACEI. If the patient has evidence of bronchial compression due to airway disease (tracheal +/- bronchial collapse), cough suppressants may be helpful. Drug doses: Review: QUEST study: Use of pimobendan in CHF due to valvular disease: Häggström et al small breed dogs Stage C MR due to valvular disease (CHF) Randomized (furosemide+/-digoxin) Pimobendan n=124 Benazepril n=128 Outcome: Time from randomization to withdrawal because of death or euthanasia owing to cardiac causes or treatment failure. Pimobendan: 267 days Benazepril: 140 days Median benefit: 127 days, ~4 months Conclusions: Survival benefit of pimobendan in Stage C mitral valve disease dogs How has this changed what we do? Pimobendan therapy has become a mainstay of treatment of MMVD in small breed dogs when CHF has occurred, and survival times have been extended by about 4-6 months on average. RLStepien

8 c) Stage C: Heart failure is present i) Left heart failure: pulmonary edema: (1) triple therapy begins here + spironolactone (a) Furosemide: relief of fluid retention (2-4 mg/kg q 8-12 hrs) (b) ACEI: vasodilation, neurohormonal blockade (0.5 mg/kg q 12 hrs) (c) pimobendan: inodilator (0.3 mg/kg q 12 hrs) (d) spironolactone MAY begin here (1-2 mg/kg q 12 hrs) (e) (digoxin may be used, especially if supraventricular arrhythmias present) ii) SV arrhythmias (atrial premature complexes, atrial tachycardia, atrial fibrillation [AF]) (1) treat heart failure (2) add digoxin (3) may need to add diltiazem to slow atrial fibrillation (1-3 mg/kg PO q 8 hrs) iii) Right heart failure: ascites or pleural effusion (1) check for pulmonary hypertension (echocardiography) (2) abdominocentesis to level of comfort (3) furosemide (moderate doses) (4) ACEI and spironolactone to combat hyperaldosteronism (5) If right heart failure is due to pulmonary hypertension, consider sildenafil (pulmonary arterial vasodilator) d) Stage D: Refractory or recurrent heart failure is present i) Definition: normal doses of quadruple therapy (pimobendan/furosemide/ ACEI/spironolactone) no longer control congestive heart failure signs ii) Therapy is based on manifestations of disease. (1) If pulmonary edema recurs or persists: (a) Check for drug administration compliance (b) Check for arrhythmias (especially new AF) (c) Increase drug doses: furosemide up to 2 mg/kg q 8 hrs, pimobendan up to 0.3 mg/kg q 8 hrs (d) Beyond these doses: consult a cardiologist for help (2) If new arrhythmia is present: diagnose and treat (3) If new right heart failure is present: screen for pulmonary hypertension RLStepien

9 9. What about dental disease and valvular disease? a) Bacteremia is a clear issue with severe dental/periodontal disease and procedures b) Bacteremia puts ALL small vessels at risk c) Recent papers claim an epidemiologic association between periodontal disease and risk of CV disease methodology problems make study invalid d) Few well-documented cases despite prevalence of dental disease and valvular disease in the same population e) WORRY ABOUT BACTEREMIA S EFFECT ON ALL ORGANS, especially kidneys 1. Boswood A, Häggström J, Gordon SG, et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: The EPIC study-a randomized clinical trial. J Vet Intern Med. 2016;30(6): doi: /jvim Häggström J, Boswood A, O'Grady M, et al. Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: The QUEST study. J Vet Intern Med. 2008;22(5): doi: /j x. 3. Cardiaceducationgroup.org 4. Sargent J, Muzzi R, Mukherjee R, et al. Echocardiographic predictors of survival in dogs with myxomatous mitral valve disease. J Vet Cardiol. 2015;17(1):1-12. RLStepien

10 Pulmonary hypertension in dogs: Common & treatable Rebecca L. Stepien DVM, MS, DACVIM (Cardiology) University of Wisconsin School of Veterinary Medicine Madison, WI USA In many canine cardiac conditions, the diagnosis of the presence of cardiac disease, if not the exact cause, is evident based on history, physical examination, and a few well-chosen diagnostic tests. In contrast, some important and life-limiting or life-threatening conditions are not obvious on cursory exam, and must be thought of before they can be diagnosed. Pulmonary hypertension, an abnormal elevation in the pulmonary arterial blood pressure, is such a condition. Pulmonary hypertension (PH) is a clinical condition that may complicate left-sided cardiac disease in dogs or may be the cause of clinical signs of collapse or right-sided heart failure. Pulmonary hypertension, defined as an abnormal elevation in the pressure in the pulmonary arterial tree, may be secondary to a chronic pulmonary problem (chronic pulmonary diseases, diseases of the pulmonary vasculature, including heartworm infestation), occur acutely with pulmonary thromboembolism (PTE) or occur secondary to increased flow (due to left to right shunts like patent ductus arteriosus), or increased left atrial pressure (most often due to mitral valve disease in dogs). The key to diagnosing pulmonary hypertension is to suspect its presence when signs of diseases commonly associated with pulmonary hypertension are present. PHYSIOLOGY Mechanisms of development of PH vary with the cause of syndrome. In some cases, medial hypertrophy and intimal hyperplasia of the pulmonary arteries develops in response to a physical insult (e.g. the presence of heartworms or a large shunt). In other cases, pulmonary artery pressure increases due to vasoconstriction, either acute (e.g. high altitude) or chronic (secondary to left-sided pressure increases). Physical obstruction, with a thrombus or heartworms, can lead to acute PH. Although the mechanism matters in terms of response to therapy and prognosis, it is the final common pathway, increased pulmonary arterial pressure, that leads to a large portion of the clinical signs by causing right-sided congestive heart failure, with the familiar clinical findings of ascites, jugular distension and exercise intolerance. A clinical sign that occurs in many dogs with PH is exertional collapse; the patient exerts him- or herself and collapses, usually while remaining conscious. This clinical sign is thought to occur when the demand for cardiac output exceeds the right ventricle s ability to overcome the increased afterload of PH. In rare cases, non-cardiogenic pulmonary edema may be an acute sign of severe PH 1. HISTORY/PHYSICAL FINDINGS Dogs with pulmonary hypertension may have cough, tachypnea and a history of exertional collapse, or may show only signs of their causative condition (left-sided congestive heart failure, chronic pulmonary disease). The clinical signs of moderate PH are similar to those of the respiratory and cardiac conditions that underlie its development: exercise intolerance, cough and increased respiratory effort and cyanosis, especially with exercise. More severe PH will lead to exercise-related RLStepien

11 collapse or syncope, or development of signs of right-sided CHF (ascites, jugular distension). When patients predisposed to thromboembolic disease (e.g. patients with hyperadrenocorticism or proteinuria) develop signs of PH acutely, pulmonary thromboembolism is suspected. When patients with dirofilariasis, left-sided heart disease or chronic pulmonary disease develop these clinical signs, secondary PH should be suspected. Development of PH secondary to left-sided heart disease is the underlying cause of the commonly observed clinical syndrome of right-sided failure secondary to left-sided failure. Physical examination findings specifically suggestive of PH include: Murmur of tricuspid regurgitation (TR) Jugular pulsation related to TR, or jugular distension if right-sided CHF is present Loud second heart sound (S2) at the left heart base Pulmonary crackles if chronic pulmonary fibrosis is present Cyanosis of tongue and oral mucous membranes Significant polycythemia (PCV 70-80%) may be present if reversed congenital shunt is present DIAGNOSIS OF PH Routine thoracic radiographs may be suggestive of PH (see Radiographic Findings, below). Once suspected base on history, PE and radiographs, the definitive diagnosis of pulmonary hypertension can be made via invasive measurements of pulmonary blood pressure (via cardiac catheterization). This procedure is invasive and requires advanced equipment and technical skills, so the diagnosis and staging of PH most often occurs in clinical patients using specific assessments that can be made during routine 2-D and Doppler echocardiographic examination. When these findings are considered as a group, the severity and clinical importance of PH may be determined in a given patient. ECG Findings: HR is often normal, may be bradycardic due to high vagal tone Right axis deviation (negative complexes in Leads 1, 2 and avf) due to RV hypertrophy Arrhythmias variable Radiographic Findings: Right-sided cardiomegaly (right atrial and right ventricular enlargement) Main pulmonary artery enlargement Branch and peripheral pulmonary arteries are enlarged, and wider than pulmonary veins Caudal vena cava enlargement Acutely dyspneic cases: above findings with diffuse alveolar infiltrates of non-cardiogenic pulmonary edema Signs of causative disease: left sided heart enlargement in patients with left-sided heart disease, areas of wedge-shaped atelectasis due to PTE, etc.) RLStepien

12 Echocardiographic Findings: 2-D echocardiographic changes consistent with PH include: Enlargement of the right atrium and right ventricle Thickening of RV free wall (hypertrophy) Enlargement of the main pulmonary artery the diameter of MPA should be approximately the same diameter as the aorta in the short axis view Septal flattening: the interventricular septum is flattened toward the LV cavity in systole; degree of flattening is roughly correlated to degree of PH Right atrial and ventricular enlargement (normal and abnormal): Septal flattening (normal and abnormal) Doppler findings consistent with PH: Color-flow mapping: evidence of tricuspid regurgitation and/or pulmonic regurgitation Spectral or continuous wave imaging: Increased tricuspid regurgitation velocity (> ~3 m/s) Increased pulmonary regurgitation velocity (> ~2.5 m/s) RLStepien

13 Tricuspid systolic velocity trace Pulmonic diastolic velocity trace Tissue Doppler imaging: Abnormal TAPSE (tricuspid annular plane systolic excursion) Evidence of RV diastolic dysfunction Evidence of concurrent or causal diseases Intra- or extracardiac shunts (reversed ASD, reversed VSD, reversed PDA) Visible intracardiac (RA or RV) or pulmonary arterial heartworms Visible thrombus in branch pulmonary artery(ies) Evidence of increased left atrial pressure (left atrial dilation) The severity of PH can be roughly estimated based on the tricuspid regurgitant jet velocity. Tricuspid regurgitant velocity Normal Mild PH Moderate PH Severe PH < 2.8 m/s 2.8 to <3.5 m/s m/s > 4.3 m/s TR systolic gradient <31 mmhg 31.4 to <50 mmhg mmhg >75 mmhg Although echocardiography is essential in the diagnosis of PH in clinical canine patients, it is not precise enough to rely upon as monitoring device. In many patients, numerical changes in Doppler values do not correlate to observed improvements in clinical condition. NT-proBNP in PH: The cardiac biomarker NT-proBNP has been investigated in patients with PH. Its diagnostic utility for this purpose is limited in many canine patients due to the frequent presence of concurrent, and sometimes unrelated, cardiac disease. In these circumstances, it is difficult to differentiate the exact cause of the NT-proBNP concentration elevation. Severe PH has been shown to produce marked elevations in NT-proBNP that are roughly related to the severity of the PH, but it remains unclear if NT-proBNP can be used in monitoring of therapy of PH. RLStepien

14 Therapy of PH in dogs: The underlying disease associated with the development of PH should be addressed primarily, if possible. Effective therapy for dirofilariasis may decrease the severity of PH, even though damage to the pulmonary arterial tree may persist after eradication of the worms. Left-sided heart failure should be addressed with triple therapy (furosemide, pimobendan and ACEI) in order to reduce the left atrial pressure. Chronic pulmonary diseases, especially pulmonary fibrosis, often cannot be effectively treated directly, but symptomatic control of cough and use of bronchodilators, when appropriate, may improve the patient s quality of life. Pulmonary thromboembolism may be treated supportively while addressing the underlying cause. When syncope or right-sided CHF are present in a patient with PH, the PH is considered a primary therapeutic target. In both cases, a full cardiac assessment, including thoracic radiographs, an ECG to rule out arrhythmias as a cause of syncope, blood pressure assessment and the diagnostic echocardiogram are part of the diagnostic evaluation. When severe PH is confirmed, and clinical signs persist after optimal therapy of underlying disease conditions, therapy with the phosphodiesterase-5 inhibitor sildenafil (Viagra ; Revatio ; generic forms available) has been shown to effectively improve clinical signs. Sildenafil, dosed at 1 mg/kg PO q 8 hrs, has been shown to improve quality of life and prolong survival of dogs with PH, compared to historical controls. In one study, dogs receiving sildenafil had a 95% probability of survival at 3 months, an 84% probability of survival at 6 months, and a 73% probability of survival at 1 year (2). References and recommended readings: 1. Kellihan HB, Waller KR, Pinkos A, Steinberg H, Bates ML. Acute resolution of pulmonary alveolar infiltrates in 10 dogs with pulmonary hypertension treated with sildenafil citrate: J Vet Cardiol. 2015;17(3): Kellum HB, Stepien RL. Sildenafil citrate therapy in 22 dogs with pulmonary hypertension. J Vet Intern Med. 2007;21: Kellihan HB, Stepien RL. Pulmonary hypertension in canine degenerative mitral valve disease. J Vet Cardiol Mar;14(1): Kellihan HB, MacKie BA, Stepien RL. NT-proBNP, NT-proANP and ctni concentrations in dogs with pre-capillary pulmonary hypertension. J Vet Cardiol. 2011;13(3): Stepien RL. Pulmonary arterial hypertension secondary to chronic left-sided cardiac dysfunction in dogs. Journal of Small Animal Practice. 2009;50(s1): Johnson L, Boon J, Orton EC. Clinical characteristics of 53 dogs with Doppler-derived evidence of pulmonary hypertension: J Vet Intern Med Sep-Oct;13(5): Borgarelli M, Abbott J, Braz-Ruivo L, et al. Prevalence and prognostic importance of pulmonary hypertension in dogs with myxomatous mitral valve disease. J Vet Intern Med. 2015;29(2): RLStepien

15 Atrial fibrillation: Common and treatable Rebecca L. Stepien DVM, MS, DACVIM (Cardiology) University of Wisconsin School of Veterinary Medicine Madison WI USA Atrial fibrillation (AF) is a common complication of heart disease in dogs and cats. All components necessary to create AF are present in typical severe cases of mitral regurgitation due to severe MV disease or cardiomyopathy (canine DCM or any feline cardiomyopathy). Although lone AF (atrial fibrillation without structural heart disease) is occasionally seen in dogs, most AF is associated with severe structural heart disease and often, congestive heart failure (CHF). 1. Necessary components for development of AF during structural heart disease a. Intact and functional AV node, in which physiologic AV block prevents consecutive transmission of high rates of atrial depolarization (normal AV node function prevents conduction of HR greater than approximately 250 bpm in dog). b. Severe atrial myocardial damage; this damage is usually due to stretch/fibrosis of the atrial myocardium that is usually associated with SEVERE atrial enlargement. Islands of nondepolarizing tissue in atrium cause micro-obstructions to coordinated forward movement of atrial depolarization waves and the previously solid wavefront breaks into small islands of re-entry, leading to atrial depolarization waves bombarding the AV node at up to depolarizations per minute. The underlying rhythm is sinus rhythm, but cannot be seen on surface ECG, and small fibrillation waves ( f waves) replace the P waves on the ECG. c. Development of re-entry circuits (1) Wave of depolarization hits an island of non-conducting tissue (2) Wavelet of depolarization goes around the non-conducting tissue, sending off wavelets in every direction along the way (3) The initial wave front circles the non-conducting tissue and, finding the initial portion ready to be depolarized again, begins the loop again (4) Each wavelet hits the AV node randomly (up to 500 x/minute), and the AV node transmits as many signals as it can. Smaller ( weaker ) wavelets may not be transmitted, leading to an irregular ventricular response rate (a) Typical ventricular response rate in dogs ~ bpm (b) Typical ventricular response rate in cats ~ bpm RLStepien

16 Normal Atrial Fibrillation SIZE MATTERS! The larger the atria are, the easier it is to go into AF and to maintain AF. Dogs develop AF with moderate to severe atrial enlargement, cats must have very severe LA atrial enlargement and rats almost never get atrial fibrillation, no matter how big their atria are. 2. The uncontrolled tachycardia of AF is detrimental for cardiac patients. RLStepien

17 a. Disadvantages of ANY tachycardia: i. Diastolic filling time is shortened in any tachycardia (~85% of stroke volume). ii. Atrial contraction (~15% of stroke volume) is diminished, or completely lost in AF iii. Myocardial perfusion takes place in diastole: tachycardia myocardial hypoxia b. Cardiovascular effects of prolonged tachycardia (AF or other) i. Decreased rapid ventricular filling decreased stroke volume ii. Decreased atrial emptying increased pulmonary venous pressure ( edema) iii. Limited myocardial perfusion increased myocardial ischemia ( decreased function) These effects of any tachyarrhythmia make AF and CHF closely related in dogs and cats. Animals with CHF often develop atrial fibrillation due to cardiac dilation AND animals with AF commonly develop CHF due to the effects of the tachycardia. 3. Atrial fibrillation in DOGS: Disease associations: dilated cardiomyopathy, severe mitral or tricuspid regurgitation, MV or TV dysplasia, PDA Clinical presentation: Exercise intolerance: onset may be noticeably sudden, especially hunting dogs Sudden onset cough in previously stable patient New onset of CHF Recurrence of CHF in previously stable patient Refractory CHF: AF prevents resolution of CHF signs Physical examination: Rapid, irregular heart rhythm ( tennis shoes in dryer ) ~50% femoral pulse deficits CHF Slow atrial fibrillation: AF with ventricular rate <140 bpm without medications May indicate concurrent 2 AV block (not every atrial depolarization is conducted) May be seen in giant breed dogs suspect occult (preclinical) DCM 4. Atrial fibrillation in CATS: Disease associations: cardiomyopathies of any type (HCM, DCM, unclassified CM, RV cardiomyopathy) Clinical presentation: CHF almost always present at time of diagnosis Intracardiac echogenic smoke or discrete thrombus AF greatly increases risk of peripheral thromboembolism Physical examination: Rapid, irregular heart rhythm irregularity may be difficult to detect at high HR ~50% femoral pulse deficits CHF RLStepien

18 5. Rapid, confident diagnosis of atrial fibrillation a. Suspect AF based on physical examination b. ECG IS REQUIRED! (ventricular tachycardia can be confused with AF by auscultation) c. Any rhythm strip is useful (patient can be in any position except standing) d. Diagnostic hallmarks of AF on ECG: i. Tachycardia (> ~140 bpm in dogs, > ~200 bpm in cats) ii. Rhythm is irregular (may be subtle in cats) iii. QRS complexes are (typically) narrow (not wide and bizarre) iv. No consistent P waves are identified 6. Therapy of atrial fibrillation: a. AF is the result of severe damage to the myocardium - damage that is seldom reversible in dogs or cats with severe heart disease. b. The goal of medical therapy is to slow transmission of atrial impulses to the ventricle, and thereby bring ventricular contraction rate to within reasonable range this involves giving medications that cause (controlled) AV block. i. Diltiazem (calcium channel blocker); can combine with digoxin ii. Digoxin; can combine with diltiazem or beta blocker) iii. Beta blockers (e.g. sotalol): used less frequently due to negative inotropic effects; can combine with digoxin, do NOT combine with diltiazem c. Dogs: target HR is usually < 140 bpm, with optimal rate = bpm. d. Cats: target HR is usually < 180 bpm, with optimal rate = bpm. e. In dogs: Holter monitor-recorded average 24-hour heart rate appears to be the best way to monitor efficacy in the patient at home; smartphone app (AliveCor) measurement of sleeping HR at home may be helpful. 7. Triage of AF patients: a. Who needs aggressive therapy? i. AF rate is > 240 bpm ii. CHF is present iii. Patient is weak/hypotensive/collapsed/hypothermic (cats) b. What is aggressive therapy? i. IV diltiazem (dogs): rapid, dose-related response 1. IV bolus (dog): mg/kg IV over 5 minutes; can repeat to cumulative dose of 0.3 mg/ kg (then reassess or begin oral therapy) 2. Continuous rate infusion (to follow IV bolus): 2-6 micrograms/kg/min ( mg/kg/min) RLStepien

19 ii. IV Nexterone (injectable amiodarone, Baxter Healthcare) (dogs) mg/kg IV infused over 30 to 60 minutes with careful BP and rhythm monitoring 2. Consultation with cardiologist recommended! iii. Anesthesia with synchronized defibrillation (consultation with cardiologist recommended!) 8. Chronic oral therapy (both dogs and cats): a. Diltiazem (regular): Onset 2 hours, peak activity by 4 hours post-dose) i. Dogs: 2-8 mg/kg PO q 8 hrs, begin at low end of dosing range and titrate up as needed to get HR< 125 bpm at home, < ~140 bpm in clinic. ii. Cats: 1-3 mg/kg PO q 8 hrs (~7.5 mg per dose for average cat) b. Diltiazem (long acting preparations): calculate total dose for patient per day, divide into 2 doses. For example: a dog receiving 30 mg of regular diltiazem every 8 hours receives a daily dose of 90 mg. If long-acting diltiazem is used, the total dose of 90 mg is divided into 45 mg PO q 12 hrs. c. Amiodarone can be used orally in dogs and cats consultation with a cardiologist is recommended. d. Digoxin: time-honored therapy for AF in dogs i. Often added to diltiazem therapy, especially in DCM dogs ii. Dose: mg/kg PO q 12 hrs (round dose DOWN) iii. 8-hour post-pill concentrations can be checked in 5-7 days; target concentration is ng/ml iv. Avoid digoxin in cats Gelzer ARM, Kraus MS, Rishniw M, et al. Combination therapy with digoxin and diltiazem controls ventricular rate in chronic atrial fibrillation in dogs better than digoxin or diltiazem monotherapy: a randomized crossover study in 18 dogs. J Small Anim Pract. 2009;23(3): Sugimoto T, Sagawa K, Guyton AC. Effect of tachycardia on cardiac output during normal and increased venous return. Am J Physiol. 1966;211(2): Janus I, Noszczk-Nowak A, Nowak M et al. A comparison of the histopathologic pattern of the left atrium in canine dilated cardiomyopathy and chronic mitral valve disease. BMC Veterinary Research 2016;12:3-7. Jung SW, Sun W, Griffiths LG et al. Atrial fibrillation as a prognostic indicator in medium to large-sized dogs with myxomatous mitral valvular degeneration and congestive heart failure. J Vet Intern Med 2016;30:51 57 RLStepien

20 What is feline NT-proBNP and how can I use it in my practice? Rebecca L. Stepien DVM, DACVIM (Cardiology) University of Wisconsin School of Veterinary Medicine Madison, WI USA 1. NT-proBNP as a clinical test for cardiac stretch/stress B-type natriuretic peptide (BNP) is a hormone that causes renal sodium and water loss, as well as vasodilation. Secreted into the blood by the muscle cells of the heart Secretion occurs continuously, but increases in response to excessive stretching of heart muscle cells. Excessive stretching of heart muscle cells is common in many forms of heart disease and in the setting of heart failure. 2. Tests for NT-proBNP in cats NT-proBNP is a cleaved end of the BNP pro-hormone that is secreted in amounts correlating to the severity of the cardiac stress (or stretch). NT-proBNP is stable and has a long half-life, so its concentration is a good reflection of the concentration of circulating BNP. A commercial assay for feline NT-proBNP (Cardiopet probnp) as well as a cageside, semi-quantitative ELISA (SNAP Feline probnp) is available, and best clinical use of each of these types of test differs. Numerical and SNAP tests for NT-proBNP available NT-proBNP ELISA Quantitative Testing NT-proBNP attaches to antibody in well Detection antibody connects to NT-proBNP in plasma sample Marker attaches to anti-probnp antibody QUANTITATIVE results SNAP Feline probnp Semi-quantitative (normal vs. abnormal vs. more abnormal) Answers yes or no question for presence of cardiac stress SNAP assay reads positive up to 150 pmol/l SNAP positive typically indicates moderate to severe changes 3. Other causes of increased NT-proBNP in cats Besides increasing in the presence of cardiac stretch due to primary cardiac disease, NT-proBNP may be increased in other situations. Knowledge of these situations becomes important if NT-proBNP concentrations are increased in a patient that has a normal echocardiogram. Because NT-proBNP is excreted through the kidneys, concentrations may be increased in cats with true renal insufficiency or pre-renal azotemia due to dehydration, although the effect of renal disease on NT-proBNP concentration in cats appears to be smaller than that in people or dogs. Other diseases may affect RLStepien

21 blood volume or cardiac work-related stress, and thereby increase NT-proBNP. Feline diseases known to affect NT-proBNP concentrations include systemic hypertension and hyperthyroidism. 4. Uses of NT-proBNP assessment in cats NT-proBNP assessment in cats provides valuable information regarding the presence primary heart disease (Fox et al. 2011), the presence of heart failure as a cause for dyspnea (Fox et al. 2009, Connolly et al. 2008), may be used to confirm systemic hypertension in cases without ocular changes. Situations that increase (feline) NT-proBNP Congestive heart failure Heart disease without heart failure Systemic hypertension (Lalor et al. 2009) Hyperthyroidism (renal disease: Cr > 2.3 mg/dl) Greater values more severe abnormality HD with CHF vs. without CHF Primary HD vs. secondary HD HD vs. renal-related elevations NT-proBNP assessment can help Is this murmur indicating true cardiac abnormality? Does this cat have heart disease or heart failure? Are the respiratory signs in this cat due to heart failure? Is this white coat hypertension? RLStepien

22 NT-proBNP assessment does NOT. Specify which type of heart disease is present Differentiate between primary heart disease and secondary cardiac remodeling (hypertension, hyperthyroid) Detect genetic disease in preclinical state Provide an indication for therapy Quantitative NT-proBNP to detect occult CM (Fox et al. 2011) > 46 pmol/l: Sensitivity best at this cut point. Se 86% to rule out occult CM (a high sensitivity test is one in which a negative test result means you can be nearly certain that they DON T have disease) Sp 91% to diagnose occult CM (a high specificity test is one in which a positive result means you can be nearly certain that they DO have disease) >99 pmol/l: Specificity improved at this cut point. Se 71% Sp 100% Quantitative NT-proBNP in dyspneic cats (Fox et al. 2009) Cut off: 265 pmol/l Se: 90% Sp: 88% PPV: 92% NPV: 85% CHF cats Median: 754 pmol/l (90%: > 300 pmol/l) Higher = more diagnostic certainty for CHF When to SNAP? You need an answer right now (dyspneic patient) You think the answer is NO Low risk patients with murmur Normal radiographs Dyspneic with history of respiratory disease When to submit quantitative NT-proBNP? You re worried the answer might be YES You want a number to follow over time You suspect the patient may have heart disease AND another cause for dyspnea Whenever the question is how high is it? (this may be as a follow-up for an abnormal SNAP result) What do I do with (+) quantitative or SNAP results? Compare results to other clinical test results History of signs suggestive of heart failure? Physical examination supportive? Auscultatory abnormalities in normal cat Signs of CHF: arrhythmia, dyspnea, hypothermia etc. Radiographs suggestive of HD or CHF? RLStepien

23 Treat if indicated by clinical signs (CHF) When does the heart disease cat need an echo? The client wants to know There is a breeding or pedigree issue The patient needs or may need anesthesia or fluid therapy without NT-proBNP info with + results You KNOW the patient has heart disease but don t know if it s the cause of current clinical signs (CHF as a cause of dyspnea) You have the chance to identify an intracardiac thrombus 5. Cases: 1. Mo: 2.5 yrs MN DSH History: Normal this am, respiratory distress noted around 5 pm ER clinic: RR 52, HR 160 bpm, lungs sound moist 12.5 mg furosemide PO, seemed more comfortable 45 min later Transfer to UW Veterinary Care Physical exam: Depressed, tachypneic, expiratory push HR 200 bpm, RR 80, T=102º F 2/6 right parasternal heart murmur RLStepien

24 No pulmonary crackles Radiographs: VHS: Pulmonary infiltrates: Purpose of NT-proBNP in this patient?: Quantitative NT-proBNP or SNAP?: Results: Outcome: 2. Alan: MN DSH, unknown age History Presented for evaluation for dentistry No history of any problems 2/6 systolic murmur L caudal sternum heard for first time today (owner is DVM) Alan is otherwise without complaint Client Question What is needed to anesthetize Alan safely? Typical decision points: What abnormality does his murmur represent? Does he have a problem that will change anesthesia choices? What is his heart failure status? Assessing Alan s Risk No history of medical problems Hyperthyroidism, DM, ± significant renal disease etc.? Screen for anesthesia-related organ function RBCs, systemic disease, lungs ± heart PCV/TP: 44%, 8.5 g/dl Chem/T4 normal Low risk or high risk patient?: Quantitative NT-proBNP or SNAP?: Results: Outcome: RLStepien

25 3. Coco: 5 yrs FS DSH History Was diagnosed with CHF at young age elsewhere In the two years since 1st referral, Coco s original echo findings (HCM) are no longer documented (?) No respiratory complaint except one episode of shortness of breath one month ago. Echo today unchanged, walls and diameter normal. Owners are moving need a way to follow up Radiograph results: VHS: Pulmonary infiltrates: Low risk or high risk patient?: Purpose of NT-proBNP in this patient?: Quantitative NT-proBNP or SNAP?: Results: Outcome: 4. Kitten Pants: 11 yrs FS domestic short-haired cat History: Presented for evaluation of chronic vomiting, hard swallowing and nasal discharge Grade 3/6 left parasternal systolic murmur PCV 34% Question: Safe for anesthesia for nasal work-up? Assess the patient: Moderate murmur (3/6), no gallop Age risk factor Normal PCV What other tests might you request? Low risk or high risk patient?: Quantitative NT-proBNP or SNAP?: Results: RLStepien

26 Why was NT-proBNP negative in each of these cases? NT-proBNP testing is most helpful in. Cases where a no avoids more costly evaluation and is likely. Cases that are truly on the fence How/when might NT-proBNP mislead? NT-proBNP is more sensitive than echocardiography May identify abnormalities that the echocardiographer doesn t identify May increase earlier than echo changes are manifest: Stress on muscle compensatory dilation/thickening Small increases may be due to concurrent diseases (hypert4, hypertension, severe azotemia, Sangster et al. 2014, Lalor et al. 2009). Patient variability in NT-proBNP (Harris et al. J Fel Med Surg 2017) Day to day CV: 13% Week to week CV: 21% When the quantitative value is close to the cut point for abnormality (Harris et al. JVIM 2017) Summary: Feline NT-proBNP Helpful addition to diagnostic testing list Adds information in selective cases Presence/absence of disease Add weight to echo recommendations Especially helpful to RULE OUT heart disease References: Connolly DJ, Magalhaes R, Fuentes VL, et al. Assessment of the diagnostic accuracy of circulating natriuretic peptide concentrations to distinguish between cats with cardiac and non-cardiac causes of respiratory distress. J Vet Cardiol. 2009;(11):S41-S50. Fox PR, Oyama MA, Reynolds C, Rush JE, DeFrancesco TC. Utility of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) to distinguish between congestive heart failure and non-cardiac causes of acute dyspnea in cats. J Vet Intern Med. 2009;11:S51-S61. Fox PR, Rush JE, Reynolds CA, et al. Multicenter evaluation of plasma N-terminal probrain natriuretic peptide (NT-pro BNP) as a biochemical screening test for asymptomatic (occult) cardiomyopathy in cats. J Vet Intern Med. 2011;25(5): Harris AN, Beatty SS, Estrada AH, et al. Investigation of an N-terminal prohormone of brain natriuretic peptide point-of-care ELISA in clinically normal cats and cats with cardiac disease. J Small Anim Pract. 2017;31(4): Harris AN, Estrada AH, Gallagher AE, et al. Biologic variability of N-terminal pro-brain natriuretic peptide in adult healthy cats. J Fel Med Surg. 2017;19(2): Lalor SM, Connolly DJ, Elliott J, Syme HM. Plasma concentrations of natriuretic peptides in normal cats and normotensive and hypertensive cats with chronic kidney disease. J Vet Intern Med. 2009;11:S71-S79. Sangster JK, Panciera DL, Abbott JA, Zimmerman KC, Lantis AC. Cardiac biomarkers in hyperthyroid cats. J Vet Intern Med. 2014;28(2): RLStepien

27 Common and uncommon uses of pimobendan in 2018 Rebecca L. Stepien DVM, DACVIM (Cardiology) University of Wisconsin School of Veterinary Medicine Madison WI USA Pimobendan, first available in the United States in the early to mid-2000s, has quickly risen to be a standard of care therapy for congestive heart failure (CHF) in dogs. Although FDA approval and labeling is for chronic therapy of congestive heart failure due to valvular disease in dogs and canine DCM and in some cases, therapy prior to CHF in these patients, this medication has proven to be beneficial in other circumstances. 1. Pimobendan as a medication for cardiovascular disease Clinical effects of pimobendan Acute and chronic support of cardiac contractile function (positive inotrope) Acute and chronic support of diastolic function (positive lusitrope) Acute and chronic arterial and vasodilation Mechanism: inodilation Positive inotropic effects: sensitizes myocardial proteins to existing intracellular calcium such that there is more calcium binding with the amount of calcium already in the cell (no additional, possibly toxic increases in intracellular Ca) and better re-uptake of Ca into the sarcoplasmic reticulum. Vasodilation effects: phosphodiesterase III and V inhibition causes vasodilation End result: increased contractile function, better diastolic function and peripheral vasodilation (decreases the load on the working heart) Relevant pharmacology Rapid absorption: mean peak plasma levels achieved hour after administration of a single oral dose High degree of protein-binding Pimobendan is oxidatively demethylated to an active metabolite with the same pharmacodynamic profile as pimobendan so the effect of the drug is longer than the actual half-life would indicate Half-life of pimobendan: 0.5 hours, half-life of metabolite: 2.0 hours Prolonged pharmacodynamic effect (>8h) Routes of excretion: 95% gastrointestinal (normal renal function not required) Dose: mg/kg total dose per day, divided into 2 (not necessarily equal) doses per day RLStepien

28 Toxicity Short term: minimal side effects, occasional GI signs (diarrhea) Acute toxicosis (overdose): severe tachycardia, mild hypotension or hypertension, and identification of a new (transient) heart murmur (Reinker et al. 2012) Long term: some data supports long term high doses may worsen the valvular changes associated with chronic valvular disease. It is unclear whether this occurs in standard clinical doses. One clinical paper describing two dogs with apparent myocardial dysfunction after 5 months and 10 months of standard doses of pimobendan has been published (Tissier R et al. 2005), but the cause of such changes was unclear. In any case, anecdotal use of pimobendan in the US and Europe over a period of up to five years seems to indicate that occurrence of this type of side effect is rare in routine clinical use. 2. Current Uses of Pimobendan Currently, pimobendan is labeled as Vetmedin TM for use in dogs Indications: o CHF due to valvular heart disease o CHF due to dilated cardiomyopathy (DCM) o For concurrent use with other CHF medications, as needed (e.g. furosemide) o Preclinical use in Doberman pinschers with occult DCM and selected small breed dogs with preclinical valvular disease Contraindications: HCM, aortic stenosis, any disease in which an increase in cardiac output is contraindicated Use in Dogs with CHF: Valvular disease: The QUEST Trial (Haggstrom et al. 2008; Haggstrom et al. 2013) Compared (pimobendan + furosemide) to (benazepril + furosemide) for therapy of CHF due to valvular disease in 252 dogs Pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD compared with benazepril plus conventional therapy. Pimobendan versus benazepril resulted in similar quality of life during the study, but conferred increased time before intensification of CHF treatment. Dilated Cardiomyopathy: Tested in Doberman pinschers (Fuentes et al. 2002, O Grady et al. 2008) Luis Fuentes: 10 Doberman pinschers o Compared pimobendan vs. placebo with background Rx (digoxin, furosemide, enalapril) o Median survival in CHF: pimobendan 329d, placebo 50d (diff: 279d) O Grady: 16 Doberman pinschers o Compared pimobendan vs. placebo with background Rx (benazepril, furosemide) RLStepien

29 o Median survival pimobendan: 130d, placebo 14d (diff 116d) Use in Preclinical Dogs (no past or current CHF): Valvular Heart Disease: The EPIC Trial (Boswood et al. 2016) Theory Combined preload and afterload reduction with inotropic support may result in a reduction in cardiac size and filling pressures in dogs with significant remodeling secondary to myxomatous mitral valve disease These effects are considered to be cardioprotective and may delay the onset of pulmonary edema and clinical signs in dogs with preclinical myxomatous mitral valve disease Caution: reports of pimobendan worsening pathology of myxomatous valves in one report (Tissier et al. 2005; Chetboul et al. 2007) Study 354 dogs with Stage B2 mitral valve disease (moderate to severe cardiac enlargement is present based on radiography and echo, no history of/current CHF), received pimobendan OR placebo, no other drugs, followed until CHF occurred. Conclusions: Dogs that receive pimobendan when they meet the entry criteria will remain asymptomatic for ~15 months longer on average (MST pimobendan 1228 d vs. 766d on placebo) and live for ~5 months longer on average than dogs that did not receive pimobendan. Applicability to practice (please see cardiaceducationgroup.org for full discussion) o If a left apical systolic murmur >/= 3/6 is present AND o You document cardiac enlargement (radiographs/echo) o Begin pimobendan (0.3 mg/kg q 12 hrs) if VHS is <10.5, reevaluation is advised in 12 months if the VHS is between 10.5 and 11.5 and an echocardiogram is not performed or does not exceed enlargement criteria, reevaluation in 6 months. o If an echocardiogram is not available and only thoracic radiographs are performed, start pimobendan in dogs with heart murmurs of grade 3/6 or louder ONLY WHEN: the VHS exceeds 11.5 vertebral bodies an incremental increase of greater than 0.5 vertebral bodies per 6 months has occurred Pimobendan NOT recommended: o Dogs with left apical systolic murmurs < grade 3/6 o Dogs without any imaging-supported cardiomegaly Dilated Cardiomyopathy: The PROTECT Trial (Summerfield et al. 2012) Compared placebo vs. pimobendan in 76 Doberman pinschers with occult (preclinical) DCM The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. New recommendations: Begin pimobendan in Doberman pinschers as soon as they are diagnosed with DCM, whether clinical signs are present or not. RLStepien

30 Controversial: other breeds? 3. Newer Applications for Pimobendan Acute therapy of pulmonary edema in the emergency situation Rapid absorption of pimobendan after oral administration: often useful in emergency situations (DCM with acute pulmonary edema, valvular disease with acute pulmonary edema) In many cases, replaces dobutamine as an emergency medication in acute heart failure, but can be used WITH dobutamine CRI in severe or non-responsive cases Use with other acute CHF medications as usual (oxygen, furosemide, acute vasodilators) Dosing (UW Veterinary Care): Consider 0.3 mg/kg PO q 8 hrs on first day, the 0.3 mg/kg PO q 12 hrs thereafter Major concern: extremely dyspneic animals may have trouble with swallowing pills; may need to delay until after several doses of furosemide/o2 Therapy of pulmonary hypertension (PH) in dogs Pathophysiology Clinical signs of PH may be respiratory (dyspnea/cough), reflect myocardial failure (ascites) or be manifest as exercise or excitement-related collapse Severe elevations in left atrial pressure (most often due to mitral regurgitation) require increased pulmonary arterial pressures in order to maintain forward flow Concurrent increases in pulmonary vascular resistance, due to pulmonary arteriolar vasoconstriction and/or concurrent pulmonary disease, may have an additive effect, increasing PA pressure in excess of that needed to overcome LA pressure Therapy Sildenafil remains the medication of choice for direct pulmonary artery vasodilation Pimobendan may have helpful additive effects o Effectively treats left-sided heart disease/chf o May increase RV systolic function in dogs with PH not related to LCHF o Single study in 10 dogs with CHF and PH (due to mitral regurgitation) rendered results that showed benefit but were difficult to interpret in terms of mechanism of benefit (Atkinson et al. 2009). Recommendations o Pimobendan therapy is indicated in dogs with right-sided heart failure (typically ascites) secondary to PH associated with elevated LA pressures o Pimobendan MAY be helpful in patients with other forms of PH if right heart failure signs (e.g. ascites) are present, or if the patient is showing exercise intolerance/collapse or signs of RV systolic dysfunction on echocardiography. In these patients, CONCURRENT THERAPY with sildenafil to treat the PH primarily is strongly recommended. RLStepien

31 Therapy of CHF in Cats Rationale for use of pimobendan in cats The majority of CHF-inducing abnormalities in cats are due to cardiomyopathies, and the predominant cardiomyopathy in cat is hypertrophic cardiomyopathy, with (HOCM) or without (HCM) left ventricular outflow obstruction. Since pimobendan has primarily been discussed as an inotropic medication with vasodilating properties, concern has been expressed as to whether it is indicated for use in HCM, a disease that appears to be primarily of disordered diastolic function. The possibility of causing adverse effects by providing increased contractile function to a patient with a dynamic outflow obstruction (as is the case with HOCM) has limited some veterinary cardiologists to consider its use only in cats with diseases associated with systolic dysfunction and avoid its use in cats with known left ventricular outflow tract obstruction. BUT Cats with systolic, diastolic or mixed ventricular dysfunction may benefit from pimobendan therapy. The positive inotropic and vasodilatory action of pimobendan are result of calcium sensitization of the cardiomyocytes and phosphodiesterase-3 inhibition, respectively. Positive inotropic effects, vasodilation, anti-platelet properties and improved diastolic function in response to pimobendan have been documented in dogs, and these properties could be considered potentially beneficial in a variety of cardiac conditions in cats. Current Evidence Not much has been published in available literature regarding the pharmacodynamics of this medication in cats, but a single report a study of 10 normal cats (Hanzlicek et al. 2012) indicated that after a typical clinical dose (~2.8 mg/kg orally), the mean plasma elimination half-life (T1/2) was 1.3 ± 0.2 hrs, almost three times as long as that reported in dogs and the maximum plasma concentration (Cmax) was 34.5 ± 6.59 n/ml, more than 10 times greater than that reported in dogs. Time to peak concentration was short; animals were dosed on an empty stomach. Two cats showed evidence of mild gastrointestinal upset. A second study (Yata et al. 2016) showed more variability in T1/2, and, as is the case in dogs, the presence of an active metabolite (Odesmethylpimobendan), although there was less conversion to this metabolite than in dogs. No prospective clinical trials regarding use of pimobendan in cats with naturally-occurring cardiac disease have been published to date, but several retrospective studies of this type of patient have been published. Taking three non-controlled retrospective studies into account, pimobendan was administered to 213 cats with a diverse set of diagnosed cardiac disease (DCM: n=47, HCM: n=69, UCM: n=90, miscellaneous cardiac conditions: n=15) based on the presence of CHF or advanced heart disease poorly responsive to conventional therapies. In these retrospective studies, the dose of medication was similar (approximately 0.24 mg/kg PO q 12 hours). In a study including 32 cats with non-taurine deficient dilated cardiomyopathy (Hambrook et al. 2012), median survival time (MST) in cats treated for CHF without pimobendan was short (MST 12 RLStepien

32 days [1-244], n=16) but longer overall survival was associated with the addition of pimobendan to standard CHF therapies (MST 49 days [1-502], n=16). The other two non-controlled retrospective studies looked at a more diverse population of cats (MacGregor et al. 2011, Gordon et al. 2012). Taken together, these last two studies encompass 197 cats, 191 of which were in CHF at the time pimobendan was initiated. Although cats in all studies were generally treated with similar background therapies (e.g. furosemide, angiotensin-converting enzyme inhibitors, clopidogrel), some cats received antiarrhythmic medications including beta-blockers, additional diuretics and additional anti-coagulant medications, making it difficult to distinguish the effect of pimobendan from the effects of the other medications, or to identify whether certain concurrent medications are needed to provide any beneficial effect of pimobendan. A subsequent case-control study (Reina-Doreste et al. 2014) both provided information in comparison with a control group of cats with HCM or HOCM and CHF who received standard therapy but no pimobendan, and attempted to address the question whether dynamic left ventricular outflow tract obstruction is a contraindication for use of pimobendan in cats with normal systolic function. o 27 cats, 5 of which had dynamic LVOTO, were matched to control cats by age, sex, weight and manifestation of CHF (pulmonary edema vs. body cavity effusion). o The small number of cats with LVOTO did not exhibit any adverse reactions to pimobendan therapy, and no adverse events were reported overall. o Survival time of HCM or HOCM cats with CHF treated with pimobendan in addition to standard therapy was significantly prolonged (pimobendan: 626 days vs. control: 103 days, p = 0.024). Pimobendan therapy, in association with current standard CHF medications, appears to be safe in cats with a variety of cardiac diseases. There is no evidence from retrospective studies that pimobendan is associated with major adverse effects, despite the current lack of knowledge regarding appropriate dosing. It appears that addition of pimobendan to standard therapy in cats with CHF may confer a survival benefit. Thus far, based on a very small number of cats, the presence of LVOTO does not appear to negatively affect outcome in cats treated with pimobendan. Recommendations for use **Echo diagnosis strongly recommended except for acute emergencies** Cats with CHF due to dilated CM or diseases with systolic dysfunction Cats with CHF due to HCM if dynamic left ventricular outflow tract is not present and cat has no history of syncope Use WITH typical therapies for CHF, including furosemide, angiotensin-converting enzyme inhibitors and dobutamine in acute situations NO indication for use in cats without CHF (preclinical heart disease) Dose: mg PO q 12 hrs per cat RLStepien

33 References: Atkinson KJ, Fine DM, Thombs LA, Gorelick JJ, Durham HE. Evaluation of pimobendan and n-terminal probrain natriuretic peptide in the treatment of pulmonary hypertension secondary to degenerative mitral valve disease in dogs. J Vet Intern Med. 2009;23(6): Boswood A, Häggström J, Gordon SG, et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: The EPIC study-a randomized clinical trial. J Vet Intern Med. 2016;30(6): Cardiac Education Group Website: cardiaceducationgroup.org Fuentes VL, Corcoran B, French A, Schober KE, Kleemann R, Justus C. A double-blind, randomized, placebo-controlled study of pimobendan in dogs with dilated cardiomyopathy. J Small Anim Pract. 2002;16(3): Gordon SG, Saunders AB, Roland RM, et al. Effect of oral administration of pimobendan in cats with heart failure. J Vet Intern Med. 2012;241(1): Häggström J, Boswood A, O'Grady M, et al. Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: The QUEST Study. J Vet Intern Med. 2008;22(5): Häggström J, Boswood A, O'Grady M, et al. Longitudinal analysis of quality of life, clinical, radiographic, echocardiographic, and laboratory variables in dogs with myxomatous mitral valve disease receiving pimobendan or benazepril: The QUEST Study. J Vet Intern Med. 2013;27(6): Hambrook LE, Bennett PF. Effect of pimobendan on the clinical outcome and survival of cats with non-taurine responsive dilated cardiomyopathy. Journal of Feline Medicine & Surgery. 2012;14(4): Hanzlicek AS, Gehring R, Kukanich B, et al. Pharmacokinetics of oral pimobendan in healthy cats. J Vet Cardiol. 2012;14(4): MacGregor JM, Rush JE, Laste NJ, et al. Use of pimobendan in 170 cats ( ). J Vet Cardiol. 2011;13(4): O'Grady MR, Minors SL, O'Sullivan ML, Horne R. Effect of pimobendan on case fatality rate in Doberman Pinschers with congestive heart failure caused by dilated cardiomyopathy. J Small Anim Pract. 2008;22(4): Payne J, Luis Fuentes V, Boswood A, Connolly D, Koffas H, Brodbelt D. Population characteristics and survival in 127 referred cats with hypertrophic cardiomyopathy (1997 to 2005). J Small Anim Pract. 2010;51(10): Reina-Doreste Y, Stern JA, Keene BW, et al. Case-control study of the effects of pimobendan on survival time in cats with hypertrophic cardiomyopathy and congestive heart failure. J Vet Intern Med. 2014;245(5): Reinker LN, Lee JA, Hovda LR, Rishniw M. Clinical signs of cardiovascular effects secondary to suspected pimobendan toxicosis in five dogs. J Am Anim Hosp Assoc. 2012;48(4): Summerfield NJ, Boswood A, O'Grady MR, et al. Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman pinschers with preclinical dilated cardiomyopathy (The PROTECT Study). J Vet Intern Med. 2012;26(6): Tissier R, Chetboul V, Moraillon R, et al. Increased mitral valve regurgitation and myocardial hypertrophy in two dogs with long-term pimobendan therapy. Cardiovasc Toxicol. 2005;5(1): Yata M, McLachlan AJ, Foster DJR, Hanzlicek AS, Beijerink NJ. Single-dose pharmacokinetics and cardiovascular effects of oral pimobendan in healthy cats. J Vet Cardiol. 2016;18(4): RLStepien

34 Top 10 mistakes in clinical care of cardiovascular patients Rebecca L. Stepien DVM, MS, DACVIM (Cardiology) University of Wisconsin School of Veterinary Medicine Madison, WI USA The dictionary describes a mistake as An error or fault resulting from defective judgment, deficient knowledge, or carelessness. In clinical medicine, most cases are complicated enough that many pieces of information must be integrated and coordinated, and when large numbers of diagnoses, medications and concurrent problems are involved, it is almost impossible to proceed without some misunderstandings and misconceptions that may lead to making inappropriate or less than optimal decisions. In cardiovascular medicine, some mistakes are inadvertent, perhaps because the misunderstanding of the topic is widespread, the situation in cats/dogs differs from conventional wisdom for the other species or human patients, or because the facts are counter-intuitive. The following mistakes are common, widespread, and can negatively affect patient care and the clinical success of therapy. 1. Treating a coughing cat with furosemide As a species, cats usually do not display cough as a symptom of congestive heart failure (CHF). The most common cause for cough in cats is respiratory disease, including feline bronchial disease (i.e. asthma), infectious diseases resulting in bacterial or parasitic pneumonia, or inflammatory pleural effusions, including chylothorax and pyothorax. Identification of a cough as a significant historical in a patient is an important moment that can lead the clinician AWAY from CHF as the problem, or as the ONLY problem. Some cats with chronic bronchial disease will eventually develop heart disease, so may have chronic coughing as the presenting complaint, yet have a heart murmur or gallop that leads the clinician to consider heart disease. In these patients, it s important to recognize that the clinical question is: One disease or two diseases?, and if two diseases, which one is causing today s clinical signs? This decision is aided by careful physical examination (cough and crackles together in an otherwise healthy animal = likely bronchial disease, while cough and dull heart sounds may indicate the presence of an inflammatory pleural effusion). Further testing may include NT-proBNP, thoracic radiographs, echocardiographic imaging, or some combination of these. 2. Not looking at the jugular veins of a dyspneic cat Dyspneic cats that are NOT coughing are CHF suspects, and the physical findings of CHF in cats may include findings of pulmonary edema (pulmonary crackles) or findings consistent with pleural effusion (dull heart sounds). Preliminary physical examination may reveal heart murmurs or gallop rhythms that indicate heart disease is present, but some cardiac diseases may cause CHF without detectable auscultated abnormalities. Because severe pleural effusions are rapidly fatal and life-saving treatment can occur rapidly, a dyspneic cat, regardless of whether abnormalities are detected by auscultation, should be suspected of having pleural effusion until proven otherwise. Immediate RLStepien

35 thoracic imaging with ultrasound can identify fluid rapidly, but even faster and less expensive is an examination of the jugular vein, looking for jugular distension. A dyspneic cat with identifiable jugular distension almost always has CHF-related pleural effusion as the cause of dyspnea, and exploratory thoracocentesis should take place immediately to remove as much fluid as possible. Jugular examination is easier and quicker if the fur is rapidly clipped over the vein. A small amount of alcohol can be swabbed onto the skin to aid identification of the jugular vein. 3. Being timid when performing a therapeutic challenge In emergency situations with dyspneic dogs or cats, it is sometimes necessary to administer what may be life-saving medications without a clear diagnosis, either because thoracic radiographs may not be available or tolerated by critically dyspneic patients, or because the radiographic results are ambiguous or difficult to interpret. The life-saving medications may be furosemide in the case of severe pulmonary edema or corticosteroids in the case of acute asthma signs. After pleural effusion has been ruled out as the cause of dyspnea, the purpose of a therapeutic trial is to let the action of medication show you that the medication is successfully treating the problem. When acute CHF is a possible diagnosis, the least ambiguous results are obtained by giving the FULL dose of furosemide (2 mg/kg furosemide IM or IV in an emergency dyspnea case). After dosing, the goal is to have the animal urinate within an hour, and have the respiratory rate decline progressively over the first several hours. A full dose of furosemide causes visible and undeniable improvement in respiratory rate when pulmonary edema due to CHF is present, but partial doses may cause mild improvement in any respiratory disease, so are less helpful as a diagnostic tool. 4. Giving an angiotensin-converting enzyme inhibitor to a dehydrated animal Animals rely on the local control of vasoconstriction/vasodilation in the kidneys to support GFR when they are dehydrated. These changes typically involve angiotensin II-mediated vasoconstriction in the efferent glomerular arteriole, and vasodilation in the afferent arteriole. Angiotensin-converting enzyme inhibitors block formation of ATII, and lead to release of efferent arteriolar vasoconstriction and a decrease in GFR. Decreases in GFR can contribute to development of prerenal azotemia (and occasionally hyperkalemia) in patients that are dehydrated. A good rule of thumb is to avoid use of ACEI in dehydrated patients until they are rehydrated, and to avoid giving ACEI to patients that are not eating (who can be assumed to be somewhat dehydrated). In the case of chronic CHF patients, ACEI may be temporarily discontinued in hospitalized acute CHF patients, but can be restarted as soon the patient is eating again. 5. Letting a single baseline undulation talk you out of an AF diagnosis in a dog with heart disease Atrial fibrillation (AF) is an extremely common arrhythmia in dogs with heart disease, whether or not CHF is present. The ECG findings of untreated AF are: tachycardia (rates usually > 180 bpm), an irregular rhythm, supraventricular-appearing complexes (narrow) and a lack of P waves. The undulating baseline of atrial fibrillation can often appear to have waves that seem like P waves but are not. If you are examining an ECG and suspect AF is present but are noticing P wave-like baseline movement, the following tests can be applied. If the wave in question IS a P wave, it should be within sec of the following QRS, and every QRS complex of similar appearance should RLStepien

36 have the SAME P wave at the SAME distance in front of it. If additional consistent P waves in consistent relation to similar QRS complexes are not identified, the first questionable wave is likely NOT a P wave. In addition, AF is so common in canine heart disease patients that if a dog with known heart disease seems like he has AF, he probably does. Lead II, 25 mm/sec, 1 cm: mv 6. Letting a Doberman with a history of syncope and an irregular tachycardia out of your office without screening ± therapy for ventricular arrhythmias Doberman pinschers are well-known for their propensity for developing dilated cardiomyopathy and the common complication of severe ventricular arrhythmias. In many cases, Dobermans can develop extremely rapid and electrically unstable ventricular tachycardias that display the R on T morphology, wherein the T wave of the previous ventricular ectopic leads directly into the R wave of the next complex without a visible isoelectric shelf. These arrhythmias can rapidly degenerate to ventricular flutter and ventricular fibrillation, resulting in sudden death. A history of syncope in a Doberman should be considered an indication of impending sudden death and be treated as a diagnostic emergency. Dobermans with no history of syncope but with rapid, irregular heart rhythms in the exam room should have a diagnostic ECG recorded immediately. Physical exercise may provoke sudden death in Dobermans with ventricular arrhythmias, and use of a gurney or wagon to move the patient within the hospital is recommended. Lead II, 50 mm/sec, 1 cm:mv 7. Missing the chance to let an acute NT-proBNP assessment in a feline patient help your client and patient The SNAP NT-proBNP test (Idexx Laboratories) provides rapid heart disease is likely or unlikely diagnostic capabilities and has been recommended for use in differentiation of the causes of feline dyspnea (abnormal SNAP = heart disease is likely, normal SNAP = heart disease is unlikely). The RLStepien