19 Apr 2022
Image: © Dmytro Titov / Adobe Stock
When considering treatment for patients in congestive heart failure due to myxomatous mitral valve disease (MMVD), many drugs are available.
Treatment typically involves a combination of several medications, some of which provide haemodynamic benefits (for example, diuretics, positive inotropes, vasodilators), and others that aim to tip neurohormonal activation in the right direction (for example, angiotensin-converting enzyme [ACE] inhibitors [ACEIs], beta-blockers or mineralocorticoid blockers).
Whichever drugs are chosen, the aim should be to alleviate clinical signs associated with the disease and/or to prolong survival time of the patient, or the time to onset of clinical signs, by slowing the progression of the disease.
Currently, medication for mitral valve disease does not address the degenerative process in the valve itself, but alleviates the consequences of progressively more severe mitral regurgitation.
When choosing any cardiac drug, the veterinary practitioner should consider:
In recent years, significant advances have been made in veterinary cardiology research with large, multicentre studies being published1-4. However, there are still areas where evidence-based medicine is not available or is of limited value and, therefore, opinions based on experience and the rationale behind a drug’s effects rather than evidence from clinical trials, can influence a clinician’s decision. In 2009, a panel of experts in veterinary cardiology meeting to form a consensus statement at the American College of Veterinary Internal Medicine congress, adopted a staging system which divided MMVD into stages A to D5. The panel defined the standard therapeutic guidelines for dogs affected by MMVD with the aim of guiding therapeutic choices using guidelines based on evidence-based medicine where possible.
This consensus statement was reviewed and updated in 20196.
The aim of this article is to outline the evidence-based medicine supporting the use of spironolactone.
Heart failure (HF) is the pathophysiological state that results from the inability of the heart to deliver enough blood to the peripheral tissues to meet metabolic demands.
Typically, this is slowly progressive so the body has time to compensate for the disease, but in other cases it can be acute in onset.
In many cases, HF progresses to become congestive heart failure (CHF) when the heart function is sufficient to prevent fluid build-up within the lungs (pulmonary oedema due to left-sided CHF) or effusions within body cavities (right-sided CHF).
In some cases, HF and CHF are due to low output (most often due to myocardial failure, stenotic congenital lesions, arrhythmias, or pericardial effusion with tamponade), but in other cases output is sufficient, but increased venous pressure due to raised atrial pressure causes congestion (most often acquired or congenital mitral valve disease, myocardial changes leading to diastolic failure, tricuspid valve disease and left-to-right congenital shunts).
The reduced blood pressure activates compensatory mechanisms, including the sympathetic nervous system and the renin angiotensin aldosterone system (RAAS).
The aim of these compensatory mechanisms is to restore the cardiac output by increasing heart rate, contractile force and to redistribute perfusion due to regional vasoconstriction.
The RAAS system is triggered in the kidneys in response to a reduction in renal perfusion. Renin is an enzyme released from the kidneys that converts angiotensinogen, which is released from the liver into angiotensin I (AGI), further converted by ACE to angiotensin II (AGII) mainly in the lungs, but to a much lesser extent locally in the kidneys.
AGII may restore blood pressure by vasoconstriction and stimulating release of aldosterone from the adrenal gland.
Aldosterone increases the excretion of potassium and reabsorption of sodium, and, therefore, water and chloride from the distal tubule of the kidney, thus helping to increase volume and restore cardiac output and blood pressure.
Initially, these mechanisms are adaptive and benefit the patient by maintaining cardiac output, blood pressure and, therefore, tissue perfusion, despite the decline in cardiac function.
However, these mechanisms can be detrimental when chronically activated and contribute to the progression of cardiac failure, resulting in a cycle that further decreases cardiac performance and ultimately results in venous congestion and pulmonary oedema, weakness, fatigue, and weight loss. These maladaptive changes can also have pro-arrhythmogenic effects, and trigger or worsen myocardial fibrosis, vascular remodelling and endothelial dysfunction.
As the heart failure progresses, compensatory mechanisms cannot maintain blood pressure, congestion can progress and ultimately death occurs.
Spironolactone is a potent mineralocorticoid receptor antagonist. It is a non-specific receptor blocker for aldosterone – different papers may use the terms mineralocorticoid or aldosterone blocker interchangeably (although the receptors are also sensitive to glucocorticoids).
Spironolactone also has moderate anti-androgenic activity (the targets of androgens like testosterone) and weak steroidogenesis inhibition (inhibits the enzymes involved in steroid hormone production).
It is usually listed as a diuretic and, while this can be useful, the diuretic action is relatively weak and its use is principally for its mineralocorticoid blocking action. It should never be regarded as a replacement for loop diuretics such as furosemide or torasemide.
Aldosterone is the principal mineralocorticoid hormone and is synthesised in the zona glomerulosa of the adrenal glands.
It is released into the circulation in response to hyperkalaemia and AGII, and binds to mineralocorticoid receptors located in the kidneys, heart and blood vessels.
Aldosterone’s main function is maintaining sodium and potassium balance, and controlling blood pressure. In the kidneys, it results in an increase in water resorption and potassium secretion, which increases the extracellular fluid and cardiac preload, which helps to maintain cardiac output.
Mineralocorticoid receptor antagonists counteract retention of sodium and water, and reduce the aldosterone-induced potassium loss. This has led to the classification of spironolactone as a potassium sparing diuretic.
In human medicine, this classification has been described by some authorities as obsolete based on the findings that typical daily doses of spironolactone have had no apparent diuretic effect7. Little published data exists on the efficacy of spironolactone as a diuretic in animals with congestive heart failure.
The explanation for spironolactone being a weak diuretic is that it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed.However, in healthy dogs, doses up to 8mg/kg have not been shown to have any effect on water or sodium diuresis; therefore, it is thought to have its diuretic effects in patients only with CHF8. Despite this weak diuretic effect, in clinical trials in humans with severe CHF spironolactone has been shown to have a beneficial effect on morbidity and mortality. Those receiving the medication had fewer symptoms of heart failure and were hospitalised less frequently9. Therefore, a conclusion was made that it was the aldosterone blockade that resulted in the reduction in morbidity.
Aldosterone has been shown to induce myocardial and perivascular fibrosis in rats10–12 and humans13, 14.
Evidence also exists that it alters the endothelial function of vessels15,16.
Aldosterone antagonists have been shown to have an antifibrotic effect in intracoronary microembolisation and rapid ventricular pacing canine models of CHF with spironolactone17, and eplerenone, another aldosterone antagonist18.
Studies have demonstrated that a proportion of dogs with naturally occurring MMVD had intramyocardial arterial changes associated with areas of fibrosis in the myocardium19.
Therefore, the beneficial effect of spironolactone on survival time could be related to a counteractive effect of spironolactone on the arterial changes and replacement fibrosis.
Aldosterone is involved in retention of sodium and loss of potassium and magnesium, which predisposes to arrhythmias, and in humans it has been shown to increase ACE expression locally (up-regulates receptors for ACE)20.
Studies performed in human patients with CHF showed that these pro-arrhythmic effects are counteracted by aldosterone antagonists21. Aldosterone is also known to be involved in myocardial hypertrophy/remodelling and fibrosis, sympathetic activation, vagal inhibition and decreasing in baroreceptor activity22, which can lead to ischaemia, tachycardia and arrhythmias, promoting perivascular and interstitial myocardial fibrosis via mineralocorticoid receptors in the heart16, and also contribute to endothelial dysfunction23.
The cellular mechanisms are complex, but evidence exists that blocking aldosterone makes ventricular arrhythmias24 and atrial arrhythmias, such as atrial fibrillation, less likely to occur18, 25.
When ACEIs were first introduced, it was thought ACEI therapy alone would suppress aldosterone production.
However, it is now known that the level of aldosterone can rise after the initial drop following ACE inhibition and in some levels can rise back to baseline26.
The same has been noted in patients treated with both an ACEI and AGI receptor blocker.
This inability of ACEI or angiotensin receptor blockers to reliably suppress aldosterone release is known as “aldosterone escape” (also called “refractory hyperaldosteronism” and “aldosterone breakthrough”).
The mechanism by which aldosterone levels rise is unclear. Levels of AGII are known to increase with time in patients receiving ACEI.
However, AGII levels rise independently from increases in aldosterone27 and weak correlation exists between the two hormones in patients receiving an ACEI. The presence of factors other than failure of ACEI is likely and may involve:
The benefit of interrupting RAAS through ACEI has been shown in MMVD and dilated cardiomyopathy (BENCH study group; COVE study group).
However, in dogs, recent work has shown aldosterone breakthrough in approximately one-third of dogs receiving furosemide and an ACEI28.
Aldosterone escape is not prevented by higher doses of ACEI29. Therefore, a sound theoretical basis exists to adding spironolactone to ACEI in dogs with an activated RAAS, such as those in CHF and those receiving furosemide.
