New perspectives on diagnosis and treatment of canine congestive heart failure (Proceedings)

Congestive heart failure (CHF) is a common sequela to severe cardiac disease. Myxomatous mitral valve disease and dilated cardiomyopathy (DCM) are the most common heart diseases in dogs to result in CHF. CHF develops when the left ventricular diastolic filling pressures are substantially increased, leading to elevated left atrial and pulmonary capillary wedge pressure. Pulmonary venous distension may be seen on thoracic radiographs prior to overt pulmonary edema. When the left atrial pressure increases above 20 mmHg, pulmonary edema forms. Initially, there is interstitial pulmonary edema, and alveolar edema occurs with progressive increase in pulmonary capillary wedge pressure. Right sided CHF occurs when right ventricular diastolic pressure, right atrial pressure, and central venous pressures increase over 15 mmHg. Right sided CHF is evidenced by jugular venous distension, hepatomegaly and ascites, and possibly pleural effusion and peripheral edema. When stroke volume is decreased, there is decreased renal blood flow and decreased sodium delivery to the macula densa of the kidney, which activates the renin-angiotensin-aldosterone system (RAAS) to increase intravascular volume by increasing sodium and water retention. The net effect of RAAS activation is maintenance of systemic organ perfusion by increased systemic vascular resistance, increased blood volume through sodium and water retention, increased sympathetic tone by increasing norepinephrine, vasopressin and endothelin-I, and counter-regulate nitric oxide, natriuretic peptides, and prostaglandins to further increase systemic vascular resistance. Except for the generation of renin by the kidney, all components of RAAS are present at the myocardial level (as well as in many other organs), and are capable of generating high levels of angiotensin II (ATII) and aldosterone locally, which induce myocardial hypertrophy and fibrosis. Aside from cardiac ACE, other pathways including chymase, ACE-2, cathepsins, and tonin convert ATI to ATII. In fact, in dogs, cats, and humans, chymase is responsible for 90% of myocardial ATII formation.

Diagnosis of CHF

Clinical signs of coughing, tachypnea, dyspnea, orthopnea may be seen in animals with heart failure. Other nonspecific history may include exercise intolerance, lethargy, anorexia, or weight loss. Syncope may be seen in dogs with heart failure. The main diagnostic tool for diagnosis of CHF is thoracic radiographs. Vertebral heart score may be useful to quantify heart size. The length of the long axis of the heart is measured from the level of the carina to the left ventricular apex. A perpendicular line is drawn at the widest part of the short axis of the heart. The long axis and short axis lengths are then converted to the length of vertebrae, starting at the cranial aspect of T4, and then added together for total vertebral heart scale. Normal VHS in cats is 6.9- 8.1, and normal VHS in dogs is 9.7 ± 0.5.1 VHS of 10.7 vertebrae or larger accurately (78% accuracy) discriminates dogs with cardiomegaly and heart disease from normal dogs.2 In dogs, identification of perihilar to caudodorsal interstitial to alveolar pulmonary infiltrates, along with cardiomegaly and in particular left atrial dilation are the main criteria for diagnosis of CHF, and pulmonary venous distension is also often seen. An echocardiogram is necessary to identify the etiology of the heart disease, and is also helpful to confirm whether there is significant enough heart disease present to cause dyspnea in patients with pulmonary infiltrates.

Measurement of circulating biomarkers such as brain natriuretic peptide (BNP) is useful to help distinguish whether dyspnea is due to CHF or primary respiratory disease in dogs and cats. NT-proBNP, the precursor of the biologically active BNP, has a longer circulating half-life and data suggests that it is a very promising cardiac biomarker of disease and failure. A commercially available test (Cardiocare®, IDEXX laboratory) has been evaluated for differentiation of CHF from primary respiratory disease in dyspnic dogs, and a cutoff of >1725 pmol/L is highly sensitive (88%) and specific (77%) for diagnosis of CHF.3 Likewise, a cutoff of >445 pmol/L is moderate to highly sensitive (83%) and specific (90%) for distinguishing dogs with asymptomatic heart disease from normal control dogs. The company is currently working to refine cut-off values for diagnosis of heart disease and for diagnosis of heart failure, as there seems to be a fair amount of overlap between normal dogs and dogs with heart disease in recent testing.

Treatment of congestive heart failure

ACE inhibitors have been the standard choice for RAAS antagonism, and are indicated for treatment of CHF in people, dogs, and cats. Dogs and people benefit from improved quality of life as well as survival. The IMPROVE trial showed that enalapril resulted in very modest acute reductions of pulmonary capillary wedge pressure and arterial blood pressure in dogs, but greater long term clinical improvement was seen only in the DCM group and not the mitral regurgitation group. Other clinical trials found improved symptoms and survival in both DCM and mitral regurgitation groups. There is a lack of evidence showing beneficial effects of early ACE inhibitor treatment in asymptomatic dogs with mitral regurgitation in the absence of CHF. Two large-scale, blinded, randomized, placebo controlled clinical studies (SVEP and VETPROOF) of dogs with mitral regurgitation without CHF failed to show an improvement in survival or increased time until development of CHF when treated early with enalapril. ACE and aldosterone escape is a problem in some people and animals (dogs and cats) treated with ACE inhibitors, and is characterized by progressive increases in ATII and aldosterone over time despite low ACE activity. Aldosterone antagonists or angiotensin receptor blockers may be added in conjunction with ACE inhibition for more complete RAAS inhibition.

The standard therapy for CHF of all causes includes furosemide (1-4 mg/kg PO BID-TID for stable patients), an angiotensin converting enzyme (ACE) inhibitor, and pimobendan. The dose and route of administration of furosemide varies depending on the severity of the CHF and the stability of the patient. Dogs with mild heart failure may be managed with lower furosemide doses (1-2 mg/kg PO q24 hr – BID), while dogs with severe or refractory heart failure require the highest oral dose of 4 mg/kg PO TID. Furosemide is within the most powerful class of diuretics, the loop diuretics, which inhibit the Na+/K+/2Cl- cotransporter in the thick ascending loop of henle, leading to urinary loss of water, sodium, chloride, potassium, calcium, and magnesium. It is highly protein bound (86-91%), which traps the diuretic in the vascular space to deliver it to the proximal renal tubule, where 55% is excreted in the urine, and 45% is eliminated by the liver.(1) Therefore, there must be adequate blood flow to deliver the furosemide to the kidney (a problem with low output heart failure), and adequate renal function to excrete the drug. Renal insufficiency prolongs the plasma half life of furosemide since the excretion is slower. Non-steroidal anti-inflammatory drugs also reduce the diuretic response to furosemide by increasing the solute reabsorption at the thick ascending LOH. Oral bioavailability is only ~50% with marked individual variability. When administered intravenously, the diuretic effect is seen 5 minutes post-IV injection, with a peak diuretic effect 30 minutes post IV injection, and duration of diuresis 2- 3 hrs. Venodilation is seen 5-15 minutes after IV injection. When given orally, the diuretic effect seen by 1 hr, with a peak effect at 1-2 hrs, and duration of diuresis 6 hrs.

In patients with myocardial failure (i.e. DCM), positive inotropic therapy with digoxin is indicated. Large dogs with severe mitral regurgitation also often develop myocardial failure, although not to the degree of dogs with DCM, and they may benefit from digoxin. Small dogs with chronic refractory severe mitral regurgitation may possibly have symptomatic improvements when given digoxin. In refractory cases of severe CHF that have maximized the oral lasix dose, addition of a second diuretic such as a thiazide may be necessary to control fluid accumulation. Spironolactone is a much weaker diuretic than both thiazides and loop diuretics, and may not add enough additional diuresis for adequate fluid control, but may have attractive ancillary properties as a neurohormonal antagonist. In dogs with refractory CHF due to mitral regurgitation, another option is afterload reduction with an arteriolar vasodilator. Amlodipine and hydralazine are effective in reducing systemic arterial pressure (10-40 mmHg) and reducing the mitral regurgitant fraction by approximately 15%. Low salt diets are indicated in refractory CHF patients receiving the previously mentioned pharmacologic treatments. Low salt diets (0.15- 0.2 g sodium/1000kcal) will help limit sodium and water retention. Dogs with mitral regurgitation and CHF fed low salt diets along with standard background therapy had smaller left atrial and left ventricular diastolic and systolic dimensions than when they were fed a moderate sodium diet.

Pimobendan is an exciting drug used for treatment of dogs with CHF secondary to DCM or mitral regurgitation. Pimobendan is a phosphodiesterase III (PDEIII) inhibitor and a calcium sensitizer, which exerts powerful positive inotropic and vasodilatory effects. Inhibition of PDEIII results in decreased degradation of cAMP, resulting in increased phosphorylation of protein kinases and positive inotropic and lusitropic (relaxation) effects. Pimobendan also sensitizes the myofilaments (troponin C) to calcium to enable increased contraction. PDE III inhibition in the vasculature leads to vasodilation of the systemic arterioles and pulmonary vasculature. The combination of a positive inotrope and vasodilation leads to increased cardiac efficiency without increasing the myocardial oxygen consumption. In normal dogs, pimobendan produces moderate reductions in systemic and pulmonary vascular resistance, a decrease in left ventricular filling pressure, a moderate increase in heart rate, and a moderate increase in cardiac output. It also increases myocardial blood flow and improves diastolic function. Pimobendan reduced the mitral regurgitant fraction in dogs with experimentally created mitral regurgitation. In an open label study, pimobendan reduced heart failure score in dogs with CHF compared to digoxin. Pimobendan improved survival in 15 Dobermans with DCM (mean survival 128 days versus 63 days for placebo group) and had greater time before treatment failure.4 Similarly, another small scale blinded, placebo controlled study in 16 Dobermans with CHF showed a marked improvement in survival in dogs treated with pimobendan as well as background therapy of benazepril, spironolactone, and furosemide compared to placebo and background therapy (median survival time 130 days vs. 14 days respectively).5 The QUEST trial (QUality of life and survival trial) has recently been completed, and compared pimobendan versus the positive placebo benazepril on survival in dogs with heart failure secondary to myxomatous valve degeneration.6 It was a placebo controlled, blinded, prospective, randomized trial with independent data analysis. 260 small breed dogs with current or recent pulmonary edema and cardiomegaly, with current or recently resolved dyspnea were included in the study. Dogs given pimobendan lived longer (median survival time 267 days versus 140 days in dogs given benazepril, with a 91% extension of median survival time. There was a maximal absolute risk reduction of 25% in dogs given pimobendan, and greater than 20% reduction in risk over a prolonged period of time (120- 329 days). There was no difference in number of dogs reaching the end-point, but they lived longer and reached the clinical end-points later than dogs treated with benazepril. Another placebo controlled, blinded, prospective, randomized trial (VETSCOPE) compared the effects of pimobendan versus benazepril in 76 dogs with mitral regurgitation and moderate CHF.7 Dogs treated with pimobendan had greater improvement in heart failure score, vertebral heart score, and increased overall efficacy compared to the benazepril group. There was a dramatic improvement in survival in the pimobendan group (430 days versus 228 days in the benazepril group). Improvement in survival appeared to occur relatively early in the course of treatment. The dose is 0.25 mg/kg PO BID.

Aldosterone receptor antagonists (i.e. spironolactone and eplerenone) have gained great attention in the veterinary community following the announcement of improved survival in people treated with spironolactone in the RALES clinical trial. Caution should be exerted before extrapolating positive effects seen in people who mostly had ischemic heart disease to dogs with other cardiac diseases. The mortality benefit was due to a decrease in sudden death, and was mostly seen in people with higher baseline circulating collagen markers of myocardial fibrosis. Recently, the only large scale clinical trial has been completed evaluating the effect of spironolactone in dogs with Class II- IV heart failure. This study has not been published, but information is available in the technical dossier from Ceva Sante Animale. This was a placebo controlled, blinded, randomized study, and included 221 dogs with mild to severe heart failure, with a majority of cases due to myxomatous valve degeneration (90%). Most dogs with myxomatous valve degeneration had mild heart failure (92% Class II, 8% Class III). Dogs treated with spironolactone had improved dyspnea and syncope compared to placebo at 3 months, and improved dyspnea, mobility, less deterioration in cough and syncope after 12 months compared to placebo. Dogs treated with spironolactone lived longer than placebo (P= 0.024, median survival times not given) over the 12 month study. Prilactone® reduced the risk of death or deterioration by 53% at 15 months, and by 46% over 3 years. A small number of dogs (n=43) had myxomatous valve degeneration and mild clinical signs without pulmonary edema (early class II). Dogs in this group treated with pimobendan had reduced morbidity-mortality over 3 years (P= 0.033) compared to dogs treated with placebo. There are no other clinical trials in dogs with spontaneously developing CHF, and more studies are needed to evaluate whether these seemingly strong benefits are reproducible.

References

Buchanan JW, Bucheler J. Vertebral scale system to measure canine heart size in radiographs. J Am Vet Med Assoc 1995; 206:194-199.

Lamb CR, Tyler M, Boswood A, Skelly BJ, Cain M. Assessment of the value of the vertebral heart scale in the radiographic diagnosis of cardiac disease in dogs. Vet Rec 2000 Jun 10;146 (24 ):687 -90 2000; 146:687-690.

Oyama MA, Fox PR, Rush JE, Rozanski EA, Lesser M. Clinical utility of serum N-terminal pro-B-type natriuretic peptide concentration for identifying cardiac disease in dogs and assessing disease severity. J Am Vet Med Assoc 2008 May 15 ;232 (10):1496 -503 2008; 232:1496-1503.

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 Vet Intern Med 2002 May -Jun ;16 (3):255 -61 2002; 16:255-261.

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 Vet Intern Med 2008 Jul -Aug ;22 (4):897 -904 2008; 22:897-904.

Haggstrom J, Boswood A, O'Grady M, Jons O, Smith S, Swift S 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 Jul 11 2008.

Lombard CW, Jons O, Bussadori CM. Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs. J Am Anim Hosp Assoc 2006 Jul -Aug ;42 (4):249 -61 2006; 42:249-261.