A wholehearted approach to treating the cardiac patient

We all want best medicine for our patients, but must balance that need with ensuring the cure isn’t worse than the disease

Activation of RAAS in the MMVD patient leads to chronic vasoconstriction, retention of sodium and water, and cardiac remodeling. Even with the use of angiotensin-converting enzyme inhibitors, aldosterone is present both as a function of stimulation from sources other than angiotensin II (e.g. chymase and endothelin) and in some patients, aldosterone breakthrough. Images courtesy Susanne Heartsill
Figure 1: Activation of RAAS in the MMVD patient leads to chronic vasoconstriction, retention of sodium and water, and cardiac remodeling. Even with the use of angiotensin-converting enzyme inhibitors, aldosterone is present both as a function of stimulation from sources other than angiotensin II (e.g. chymase and endothelin) and in some patients, aldosterone breakthrough.
Images courtesy Susanne Heartsill

Cardiology can seem intimidating, but as our knowledge and treatment recommendations advance, so do the benefits for our patients. Marry that evolution with resources such as the 2019 American College of Veterinary Internal Medicine (ACVIM) consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease (MMVD) in dogs and you essentially have a cardiac disease guidebook that helps make managing these dogs a little easier.1

To understand the updates to the 2019 guidelines, it’s prudent to dust off the physiology books and review the renin-angiotensin-aldosterone system (RAAS) and the concept of aldosterone breakthrough (ABT). RAAS and ABT are important fundamentals to understanding the management of MMVD and congestive heart failure (CHF).

Clinically, knowing what to do and when to do it is 75 percent of the battle. The other 25 percent is recognizing the patient.

Who is your cardiac patient?

The cardiac patient can present in many different ways, but will usually be a male, small breed, older dog. Asymptomatic (pre-congestive heart failure) mitral valve disease patients present normally. Your only clue that danger lurks beneath is a left apical murmur.

The symptomatic cardiac patient is often seen as a “persistent kennel cough” appointment. Frequently, these dogs present for a history of lethargy or panting at rest. This history in a predisposed breed (Table 1) should prompt one to immediately think of cardiac disease.

Communication with the owner can be especially challenging in these cases. A client often believes his or her dog has a “mild cold” or some other benign cause for coughing. They suspect nothing as nefarious as a failing heart.

Suggesting expensive, though necessary, diagnostic testing for something the owner can’t see
or hear can be difficult, as well. The communication barriers created during the pandemic have only made these conversations more difficult.

Change occurs at lightning speed and even if you’re comfortable with the client conversation, the recommendations for treating mitral valve disease have progressed.

Understanding MMVD

Also known as endocardiosis and degenerative or chronic valvular heart disease, MMVD is the most common cardiac condition in dogs.

Approximately:

  • 10 percent of dogs present to primary care veterinary hospitals with heart disease
  • 75 percent of them (more than 4.5 million dogs) have MMVD1
  • 30 percent of mitral valve disease dogs eventually succumb to CHF3
  • 30 percent of MMVD cases include disease of the tricuspid valve as well2,4,5

Disease progression is typically slow. However, certain breeds are predisposed to rapid progression and a worse prognosis, the poster child for this being the Cavalier King Charles spaniel.

Running diagnostics

Besides a thorough physical examination, radiographs should be the first diagnostic step in suspected MMVD cases. As these dogs often have concurrent tracheobronchial disease, baseline radiographs are ideal to differentiate future cardiac from noncardiac etiologies of coughing.

Additionally, pulmonary edema associated with CHF is a radiographic diagnosis. Measuring vertebral heart scores (Table 2) or the more recently described vertebral left atrial size (VLAS) is also beneficial, following increasing heart size as disease progresses and remodeling of the cardiac muscle occurs.1

Baseline and serial blood pressure measurements are also recommended to monitor for concurrent hypertension. While this condition is not typically associated with MMVD, it is associated with many of the comorbidities (e.g. hyperadrenocorticism and renal disease) seen in the older, small dog. If present, systemic hypertension increases ventricular afterload. This worsens the severity of mitral regurgitation and elevation of left atrial pressure in dogs with MMVD.

Echocardiography performed by an experienced ultrasonographer is useful to measure chamber sizes and identify other cardiac abnormalities such as pulmonary hypertension. This test also provides definitive diagnosis of the etiology of cardiac disease, differentiating MMVD from dilated cardiomyopathy from infective endocarditis.

Because impaired renal function is an important comorbidity, baseline laboratory tests should be obtained. At a minimum, these should include packed cell volume (PCV) with serum total protein, creatinine, urea nitrogen, electrolyte concentrations, and urine specific gravity.

For the pet owner, monitoring the at-risk dog’s resting (or sleeping) respiratory rate routinely is often the best defense against failing to notice the dog tipping over from compensated MMVD to CHF. A resting respiratory rate of 30 breaths or fewer per minute is normal. When the rate starts trending above 30 breaths per minute in a dog, concern exists the patient may be decompensating and CHF is imminent.

The role of RAAS

One consequence of MMVD is activation of the renin-angiotensin-aldosterone system, which is a primal, lifesaving mechanism meant to detect and adjust for changes in body homeostasis. For instance, where blood loss or dehydration occurs, the kidneys detect decreased perfusion and release renin.

This begins the cascade that causes vasoconstriction and retention of sodium and water. These functions work to expand blood volume and maintain organ perfusion. When the bleeding is stopped or dehydration is corrected, the cascade is deactivated.

Short-term, RAAS activation is a good thing, particularly if you’re a caveman who just had his arm bitten off by a saber-toothed tiger. This is not the case if you’re a dog with MMVD.

Decreased cardiac output leads to long-term, chronic, unchecked activation of the RAAS, resulting in negative consequences, such as:

  • Chronic vasoconstriction, which raises arterial pressures
  • Increased afterload, which further depresses systolic function and decreases cardiac output
  • Limited perfusion at smaller arterioles
  • Worsening of mitral regurgitation—mitral regurgitant fraction rises, as it is harder to eject blood forward in the systemic arteries, which increases left atrial pressure and preload

In addition to sodium and water retention, cardiac remodeling is associated with chronic RAAS activation.

How the body compensates

To fully understand the whys and hows of therapeutic management of MMVD, it’s important to remember how this compensatory system works.

Due to decreased cardiac output, renin is released from the kidneys. Renin cleaves a piece off angiotensinogen to create angiotensin I (AT1). Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II (AT2). Angiotensin II causes the adrenal glands to release aldosterone, norepinephrine, and epinephrine. It also binds with AT1 and AT2 receptors in the vessel walls and (along with norepinephrine and epinephrine) causes vasoconstriction.

Aldosterone causes retention of sodium and water at the nephron, which acts to further expand blood volume. While this can be lifesaving in cases of acute blood loss, it contributes to pulmonary congestion in the MMVD patient.

Aldosterone and angiotensin II excess contributes to cardiac muscle remodeling or fibrosis, which causes stiffening and dysfunction of the heart muscle, contributing to further decreased cardiac output and arrhythmias.

For these reasons, RAAS suppression is a key strategy in the management of canine cardiovascular disease. Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), direct renin inhibitors, and mineralocorticoid receptor antagonists (MRAs) are all used in varying combinations to suppress the effects of RAAS.

Furosemide triggers RAAS cascade

Because furosemide—both when administered alone and in combination with pimobendan—has been shown to activate the RAAS, its use as a sole agent or with pimobendan alone is not appropriate.6 When loop diuretics are used for CHF treatment, mitigation of the RAAS cascade with ACEIs and MRAs is necessary.

Aldosterone breakthrough… Why ACEIs alone are not enough

Now well accepted as a human, feline, and canine phenomenon, the concept of aldosterone breakthrough (ABT) was first described in human medicine by Bertram Pitt in 1995.7

ABT is the condition in which ACEIs and/or ARBs fail to fully suppress the activity of the RAAS. Current thinking shows the need for a more complete way to address the RAAS cascade. Ideally, ACEIs inhibit ACE from converting angiotensin I to angiotensin II. Decreased angiotensin II reduces the release of aldosterone from the adrenal glands. ARBs inhibit the action of type 1 angiotensin II receptors, which also ultimately reduces aldosterone levels.

One theory behind ABT is that since angiotensin II inhibits renin release via a negative feedback loop, a large increase in plasma renin activity occurs with the administration of ACEIs and ARBs. Even with ACEIs on board, angiotensin I can be converted to angiotensin II via non-ACE-dependent pathways (chymase).

Human studies have shown plasma aldosterone returning to pretreatment levels in up to 30 to 40 percent of patients just a few weeks after ACEI or ARB therapy.8 In one canine study, ABT occurred in approximately 30 percent of dogs (32 percent in CHF and 30 percent not in CHF) despite ACEI administration.9,10

This phenomenon is the reason spironolactone, a mineralocorticoid receptor antagonist (MRA), is recommended to augment the traditional triple-therapy approach to CHF management in dogs and more fully block the RAAS pathway.

ACVIM classification of MMVD in dogs.
Figure 2: ACVIM classification of MMVD in dogs.

A closer look at ACVIM’s MMVD guidelines

In 2019, ACVIM revised its consensus guidelines for the diagnosis and treatment of MMVD in dogs.1 The document contains updates to the diagnostics, medical, surgical, and dietary treatment recommendations that were last published in 2009. The ACVIM classification of mitral valve disease in dogs is pictorially summarized in Figure 2.

Updates of particular interest to the practitioner are the recommendations to use a positive inotrope in Stage B2 and the addition of spironolactone to CHF management in Stages C and D. This update changes the traditional use of triple-therapy (diuretics, ACEI, pimobendan) for the CHF patient to a quad-therapy approach (diuretics, ACEI, pimobendan, and spironolactone).

Treatment of the asymptomatic, the acute, and the post-acute CHF dog

Asymptomatic (ACVIM Classification B2):

The term “asymptomatic MMVD” refers to a patient with cardiac remodeling and changes associated with an abnormal mitral valve, but one who has not yet gone into congestive heart failure. They may not be clinically symptomatic; however, subclinical changes are occurring. ACVIM consensus is that dogs in Stage B2 benefit from pimobendan. While mild sodium restriction is recommended for MMVD, excessive sodium restriction triggers the RAAS cascade and should be avoided.

Acute (ACVIM Classification C1/D1):

The term “acute MMVD” refers to a patient currently experiencing pulmonary edema and in congestive heart failure. These dogs require intensive hospitalization for oxygen and diuretic therapy.

While there are other adjunct medications (dobutamine, sodium nitroprusside, etc.) to consider in some CHF cases, traditional management of an acute CHF crisis includes oxygen and furosemide as the heart of therapy.

 

Post-acute (ACVIM Classification C2/D2):

The “post-acute” MMVD patient has survived the acute CHF, hospitalized event, and is considered stable. ACVIM recommends a quad-therapy approach for these dogs.

The compliance quandary

How important is compliance to your treatment recommendations for the MMVD patient? How important should it be? With a polypharmacy approach to CHF management in dogs now being recommended by ACVIM, compliance becomes a more significant consideration for these patients. The CHF patient is also often hyporexic and cachexic, making drug administration even more challenging. Compounding has traditionally been touted as an option, but both extra-label drug use legalities and product stability concerns make this a risky choice.

The role of compliance in post-acute CHF treatment

Do we really think enough about the patient and owner experience when we send the CHF dog home after hospitalization? The post-acute CHF patient has a dedicated owner…both financially and emotionally. We send home a bag of pill vials and pages of instructions, but do we really consider their situation? Flavored, chewable medications have made strides in improving compliance in all areas of veterinary medicine.

In the cardiology realm, pimobendan has been the only easy option. A new, once daily, chewable combination of spironolactone and benazepril was approved by the U.S. Food and Drug Administration (FDA) last July. Once officially launched and accessible, it will be another step toward improved compliance for these patients.

Future availability of diuretics in chewable form would make the entire quad-therapy, CHF regime for dogs easier to comply with, which would provide an improvement in both quality and quantity of life.

You know your patient and her owner

Making clinical decisions for the welfare of your patients and their owners is not just based on best medicine, but also includes considerations such as the pet’s temperament, appetite, comorbidities, and most importantly, quality of life. We all want best medicine for our patients, but must balance that need with ensuring the cure isn’t worse than the disease.

Considerations for patient comfort and quality of life go a long way toward enhancing that bond.

Who’s your patient? The CHF dog is looking to you for progress. There is no reason to avoid the head or the heart.

Susanne Heartsill, DVM, is veterinary services manager at Ceva Animal Health. She is a passionate advocate of the human-animal bond, and the mother of two (human) daughters and numerous four-legged children. Dr. Heartsill’s areas of interest include parasites, zoonotic diseases, and minimizing their impact on the human-animal bond. In 2018, she joined Ceva where she hopes to make a global difference for companion animals and their humans.

References

  1. Keene, BW, Atkins, CE, Bonagura, JD, et al. ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. J Vet Intern Med. 2019; 33: 1127– 1140, https://doi.org/10.1111/jvim.15488
  2. Buchanan JW. Chronic valvular disease (endocardiosis) in dogs. Adv Vet Sci Comp Med. 1977;21:75-106.
  3. Parker HG, Kilroy-Glynn P. Myxomatous mitral valve disease in dogs: does size matter? J Vet Cardiol. 2012;14(1):19-29. doi:10.1016/j.jvc.2012.01.006
  4. Borgarelli M, Häggström J. Canine degenerative myxomatous mitral valve disease: natural history, clinical presentation and therapy. Vet Clin North Am Small Anim Pract. 2010; 40:651-663.
  5. Häggström J, Höglund K, Borgarelli M. An update on treatment and prognostic indicators in canine myxomatous mitral valve disease. J Small Anim Pract. 2009; 5:25-33.
  6. Lantis A, Atkins C, Defrancesco T, Keen B, Weere S. Effects of furosemide and the combination of furosemide and the labeled dosage of pimobendane on the circulating renin-angiotensin-aldosterone system in clinically normal dogs. Am J of Vet Research 2011; 72. 1646-51. 10.2460/ajvr.72.12.1646.
  7. Pitt B. “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther. 1995;9(1):145-149. doi:10.1007/BF00877755
  8. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol. 2007;3(9):486-492. doi:10.1038/ncpneph0575
  9. Ames MK, Atkins CE, Eriksson A, Hess AM. Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease. J Vet Cardiol. 2017;19(3):218-227. doi:10.1016/j.jvc.2017.03.001
  10. Ames MK, Atkins CE, Pitt B. The renin-angiotensin-aldosterone system and its suppression [published correction appears in J Vet Intern Med. 2019 Sep;33(5):2551]. J Vet Intern Med. 2019;33(2):363-382. doi:10.1111/jvim.15454
  11. Sayer, M., Atkins, C., Fujii, Y., Adams, A., DeFrancesco, T. and Keene, B. (2009), Acute Effect of Pimobendan and Furosemide on the Circulating Renin‐Angiotensin‐Aldosterone System in Healthy Dogs. J Vet Intern Med. 23: 1003-1006. doi:10.1111/j.1939-1676.2009.0367.x
  12. Freedom of Information Summary, NADA #141-538 (July 27, 2020)
  13. Textbook of Veterinary Internal Medicine Expert Consult, 8e (2Volumes) 8th Edition by Stephen J. Ettinger DVM DACVIM (Author), Edward C. Feldman DVM DACVIM (Author), Etienne Cote DVM DACVIM(Cardiology and Small Animal Internal Medicine) (Author) page 1171.
  14. VIN Veterinary Drug Handbook
  15. Kittleson MD, Kienle RD. Small animal cardiovascular medicine. 2nd ed. 2005. Available at: https://beta.vin.com/members/cms/project/defaultadv1.aspx?pId=5928. Accessed May 4, 2016.
  16. Elanco Europe Ltd. Fortekor tablet [summary of product characteristics]. Basingstoke, Hampshire, UK; 2016:7. Available at: http://www.vmd.defra.gov.uk/ProductInformationDatabase/SPC_Documents/SPC_130807.DOC. Accessed May 5, 2016.
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