Dilated cardiomyopathy-born under a bad sign (Proceedings)
Dilated cardiomyopathy (DCM) is a cardiac disease due to an inherent abnormality in the myocardium that results in a decrease in myocardial contractility (i.e., myocardial failure) and is not secondary to another primary disease.
Dilated cardiomyopathy (DCM) is a cardiac disease due to an inherent abnormality in the myocardium that results in a decrease in myocardial contractility (i.e., myocardial failure) and is not secondary to another primary disease. It is generally classified as a disease of the left and right ventricles although atrial myocardium is almost certainly affected also. In the majority of dogs and cats the diseased left ventricle predominates the clinical picture. If the cause of the myocardial failure is known, then a different name is often given to the disease, which describes the inciting feature of the disease (e.g., adriamycin cardiotoxicity or cardiomyopathy). In other instances, even though the cause is known the disease is still commonly called DCM (e.g., DCM due to taurine deficiency in a cat or a dog). Because there are other causes of myocardial failure, the diagnosis of DCM may be a diagnosis of exclusion although an increase in end-systolic diameter with a shortening fraction below normal in a breed of dog known to be predisposed to DCM is DCM until proven otherwise.
DCM is usually characterized with echocardiography as a primary increase in left ventricular end-systolic diameter and volume (because of the decrease in myocardial contractility) and usually (but not always) by a compensatory increase in left ventricular end-diastolic diameter and volume. An initial increase in end-diastolic diameter has also been described but this is rare. Because end-diastolic diameter and volume do not have to increase as much as the end-systolic diameter and volume increase to maintain a normal stroke volume, shortening fraction (the amount of wall motion) decreases. The increase in chamber size is usually a compensatory, not a primary, mechanism and does not usually define the disease. Left ventricular wall thickness is normal to decreased
Dilated cardiomyopathy, literally translated, means "a heart muscle disease in which the heart is dilated." Although the ventricular chambers are increased in size in this disease, the ventricles themselves have undergone volume overload (eccentric) hypertrophy; therefore the term dilated is a misnomer since dilated means a structure that is stretched and thinned. In addition, the term dilated describes a common secondary feature of the disease, the chamber dilation, rather than the primary abnormality, the myocardial disease leading to the decrease in myocardial contractility. Consequently, the presenter would prefer the name "idiopathic primary myocardial failure" for this disease.
In dogs, DCM is primarily a disease of large and giant purebred dogs. In the United States the American cocker spaniel and the Portuguese water dog would be exceptions. Because of the breed predilection, DCM is almost certainly genetic in origin in most dogs although a specific mutation in most breeds has yet to be identified. Numerous genetic causes of DCM have been identified in humans. Examples include missense mutations in the cardiac actin, desmin, metavinculin, and lamin A/C genes as well as missense mutations in genes that have already been shown to cause HCM, including the β-myosin heavy chain, myosin binding protein C, titin, and cardiac troponin T genes.
In dogs, an autosomal dominant pattern of inheritance has been reported or suspected in Irish wolfhounds, Doberman pinschers, Boxers and Newfoundlands. Recently a mutation in the pyruvate dehydrogenase gene in mitochondria has been identified in Doberman pinschers with DCM, which should result in decreased ATP production in cardiac myocytes. This is consistent with a previous study (from 1992) that showed that the mitochondria of Doberman pinschers with DCM do not function normally. This study showed that electron transport is decreased, energy (ATP) production is decreased, and lactate concentration is increased in affected Dobermans. Although there is a genetic test to identify Doberman pinschers with this mutation, very little is known regarding prevalence, penetrance etc. at this time.
Most Boxer dogs get a form of cardiomyopathy called arrhythmogenic right ventricular cardiomyopathy (ARVC). This disease is most commonly manifested as ventricular tachyarrhythmias (i.e., PVCs and ventricular tachycardia) that originate from the right ventricle and leads to syncope and sudden death. Myocardial function in these dogs is normal. However, some Boxers also get DCM as part of this disease. So in addition to the ventricular tachyarrhythmias these dogs have severe myocardial failure. Recently a mutation in the gene that encodes for a desmosomal protein called striatin was identified in Boxers with ARVC. It appears that not all Boxers with ARVC have the striatin mutation but preliminary evidence suggests that Boxers with DCM due to ARVC are homozygous for the striatin mutation.
Portuguese water dogs get a particularly malignant form of DCM where they exhibit clinical signs of heart failure at a very early age (1-6 months) and often die within a week. The disease is inherited as an autosomal recessive trait. Affected dogs have an increased desmin density on immunohistochemical staining and myofibrillar atrophy most prominent near the intercalated disks. Many also have a low plasma taurine concentration and some have a modest response to taurine supplementation.
Dilated cardiomyopathy is more frequently diagnosed in male dogs. In one study, 79% of the dogs were male. Because most of the diagnoses are made in symptomatic dogs, this male predilection may be for the disease or may be for developing more severe disease. In other words factors in male dogs may be present that influence the disease process to produce a more malignant phenotype. Since females are involved the disease is obviously not X-linked.
The prevalence of DCM in most breeds increases with age. In Doberman pinschers, the disease is most commonly identified between 7 and 10 years of age. A significant number, however, are diagnosed with the disease between 4 and 7 years of age and after 10 years of age. In great Danes, most of the disease is identified in 4-to-10-year-old dogs. Because the natural life span of great Danes is commonly less than 10 years, few cases are seen in dogs more than 10 years of age.
Briefly, the pathophysiology of DCM starts with the myocardial disease of unknown etiology that results in a progressive decrease in myocardial contractility. This starts as a mild decrease and may progress over months but more likely years to a severe decrease in contractility. The decrease in contractility results in an increase in end-systolic diameter and end-systolic volume, which results in a decrease in stroke volume. Chronically the heart compensates for this decreased function by growing larger ventricular chambers through eccentric (volume overload) hypertrophy. This growth occurs secondary to many factors. One primary factor is renal sodium and water retention, leading to an increase in blood volume that leads to an increase in venous return and intracardiac volumes. This places stretch on the myocardium that stimulates sarcomere replication in series and so the myocytes and chambers to grow longer and larger. This results in an increase in end-diastolic diameter and end-diastolic volume. The increased chamber size allows the stroke volume to return to normal when the disease is mild to moderate. At some stage the myocardial failure becomes so severe that the ability of the cardiovascular system to compensate for the disease is overwhelmed and the ventricular chambers can grow no larger. At this stage, left ventricular end-diastolic pressure increases, which results in pulmonary edema (congestive heart failure). If the right heart is also severely involved, right ventricular end-diastolic pressure increases, which most commonly results in ascites. Stroke volume is reduced at this stage. Increased sympathetic tone increases the heart rate, which helps compensate for the decrease in stroke volume. However, cardiac output ultimately decreases also (low-output heart failure). In the terminal stages of the disease, cardiac output may decrease to the point that, even with a marked increase in peripheral vascular resistance, systemic arterial blood pressure decreases severely(cardiogenic shock).
Other abnormalities may also contribute to the production of heart failure. Myocardial diseases not only result in systolic dysfunction but also in diastolic dysfunction. The primary abnormality that results in clinically significant impairment of diastolic function is altered ventricular compliance due to increased collagen deposition. A stiffer or less compliant left ventricle results in a higher diastolic pressure for any given diastolic volume, and therefore more pulmonary edema for any degree of volume overload. Secondary or functional mitral regurgitation is also commonly present in dogs with DCM. In DCM, two changes can occur that result in atrioventricular valve regurgitation. First, the atrioventricular annulus dilates as the left ventricle enlarges. Second, the papillary muscles are displaced laterally and apically as the ventricular chamber enlarges. Both result in the leaflets failing to close completely during systole (incomplete valve closure). This manifests as the coaptation point (the point where the valve leaflets come together) being displaced apically.
Natural history and prognosis
The natural history of DCM in most breeds of dogs has not been studied in detail. It has been better studied in Doberman pinschers. Doberman pinschers have a subclinical period, usually between 2 and 4 years, during which they have echocardiographically detectable myocardial failure but no clinical signs. Female Doberman pinschers tend to be older (median age = 9.5 years) than male dogs (median age = 7.5 years) at the time their myocardial failure becomes severe enough for them to go into heart failure. Although it appears that males and females are equally affected, more males develop heart failure and die of their disease than do females. In one study, of 66 Doberman pinschers that either died from heart failure or died suddenly, 55 (83%) were males.
Doberman pinschers, like cats, often appear to develop heart failure acutely. The presentation is often so acute that an owner thinks that someone has poisoned the dog. Instead, dogs hide their clinical signs well until heart failure is severe and only show obvious clinical signs when heart failure is severe. Doberman pinschers may be diagnosed with DCM at almost any age and most commonly present in heart failure between 2 and 14 years of age. The time course of the disease appears to be accelerated in Doberman pinschers that develop echocardiographic evidence of the disease at less than 2 years of age and more prolonged when it develops after 6 to 7 years of age. Approximately 75% are between 5 and 10 years of age at the time they die.
Ventricular arrhythmias are an extremely common finding in affected Doberman pinschers with one study reporting their presence in 92% of affected dogs. They most commonly originate from the LV. The number and the complexity of the ventricular arrhythmias increase as the disease progresses. One investigator reported a study of 129 Doberman pinschers with no clinical signs of disease. Of these, 87 (57%) had a shortening fraction between 30% and 34% and had no or fewer than 50 ventricular premature depolarizations on a 24-hour ECG recording (Holter monitor). All of these dogs were alive and healthy 3 years later. Thirty-four dogs had a shortening fraction less than 25% and had more than 100 ventricular premature depolarizations per 24 hours. Eight had a shortening fraction between 25% and 29% and 50 to 100 ventricular premature depolarizations per 24 hours. Of these 42 dogs, 21% died suddenly (n = 9) and 62% died of heart failure (n = 26) within 3 years.
The presence of more than 50 ventricular premature depolarizations within a 24-hour period on a Holter monitor recording is indicative of DCM in Doberman pinschers. The type of arrhythmia appears to be important. All of the dogs with complex ventricular arrhythmias (pairs of ventricular premature depolarizations, runs of ventricular premature depolarizations, and periods of nonsustained ventricular tachycardia) in one study died suddenly, presumably from the ventricular tachyarrhythmia degenerating into ventricular fibrillation. Large numbers of single ventricular premature depolarizations did not appear to predict sudden death. However, in a more recent report by the same author, even complexity of a ventricular arrhythmia did not predict sudden death, because both many dogs that died suddenly and many dogs that went on to develop heart failure had complex ventricular arrhythmias. Only the presence of sustained (greater than 30 seconds) ventricular tachycardia predicted which dogs would die suddenly in this report. Approximately 30% of Doberman pinschers are in atrial fibrillation at the time they are diagnosed with heart failure.
When the shortening fraction decreases to less than 15%, dogs with DCM can go into heart failure. It is extremely unusual for a dog with DCM in heart failure to have a shortening fraction greater than 15%, and they are commonly less than 10%. Consequently, the diagnosis of DCM should always be questioned in a dog that is in heart failure and has an accurately measured shortening fraction greater than 15%. Although dogs can theoretically have both DCM and primary mitral regurgitation (usually myxomatous mitral valve disease), this appears to be uncommon. More often, large-breed dogs with primary mitral regurgitation develop secondary myocardial failure and present in heart failure with a shortening fraction between 20% and 30%.
Once they are in heart failure, dogs with DCM have both a poor short-term and long-term prognosis despite adequate medical therapy. They commonly present in fulminant heart failure that can be difficult to manage. Consequently, they may die shortly after presentation. These dogs are also commonly euthanized once the owners are made aware of the poor long-term prognosis. Prior to the introduction of pimobendan, most symptomatic Doberman pinschers died within the first 3 months after diagnosis. Somewhere between 30% and 40% died suddenly during this stage, while the remainder died of CHF. The median and mean survival times were between 10 and 6 weeks. Approximately 25% were dead within 2 weeks of presenting in heart failure, 40% were dead within 4 weeks, and 65% were dead within 8 weeks. Survival of Doberman pinschers with DCM placed on pimobendan is significantly better but comparable data are not available on a large population of these dogs for comparison. Doberman pinschers that present in both left and right heart failure and that have atrial fibrillation have a worse prognosis.
Other breeds with DCM do somewhat better In one study, 50% of the dogs with heart failure resulting from DCM died within the first 3 months and 75% were dead within the first 6 months after diagnosis. About 10% of the dogs lived for 1 year and 5% for 2 years. Dogs with severe heart failure fared somewhat worse than dogs with mild-to-moderate heart failure. Approximately 50% of the dogs with severe heart failure were dead within 2 months and 75% were dead within 4 months, whereas 50% of the dogs with mild-to-moderate heart failure died within 4 months and 75% died within 7.5 months. About 20% of the dogs with mild-to-moderate heart failure lived for 1 year, and 10% lived for 2 years. Another study has examined survival time in 37 symptomatic and asymptomatic dogs with DCM. Approximately 50% of these dogs also died within the first 3 months after diagnosis. This can be compared to survival in humans with DCM, of which approximately 50% die within 36 months and 75% die within 72 months. In a retrospective study of 189 dogs of various breeds with DCM and heart failure the mean and median survival times were 175 and 27 days (range = 0 to 1640 days). In another study of all breeds, including Doberman pinschers, mean survival time was 184 days and median was 59 days. Out of multiple variables, end-systolic diameter, shortening fraction, not using an ACE inhibitor, and atrial fibrillation at presentation were all associated with reduced survival.
Treatment of DCM is aimed at reducing the clinical signs due to heart failure, improving survival time, and delaying or abolishing sudden death. Success at achieving any of these goals is generally poor in most dogs with DCM. Taurine and L-carnitine supplementation improves ventricular function in most American cocker spaniels to the point that they can be removed from drug therapy.
In the United States treatment of chronic heart failure is generally attempted using a combination of a diuretic, an ACE inhibitor, and pimobendan. The primary clinical signs in dogs with DCM are usually referable to pulmonary edema. Consequently, drug therapy aimed at reducing pulmonary edema usually results in the most clinical benefit. All three drug types mentioned have the potential of reducing edema formation. They differ markedly in their ability to achieve this endpoint, however. Diuretics reduce blood volume, ventricular diastolic volumes, and therefore ventricular diastolic pressures. Diuretics are by far the most efficacious of the three drug classes, with furosemide being very efficacious and the most commonly used diuretic.
ACE inhibitors produce venodilation and reduce renal sodium and water retention by decreasing aldosterone secretion. In so doing, they reduce ventricular diastolic volumes, and therefore ventricular diastolic pressures. They are also efficacious drugs in this disease and should be used routinely to treat DCM. Their efficacy is much less than that of furosemide, however. The fact that moderate-to-severe pulmonary edema can usually be controlled with just furosemide and never controlled with just an ACE inhibitor is a primary reason for this judgment. ACE inhibitors also produce systemic arteriolar dilation, which helps increase cardiac output.
Pimobendan is an inodilator (i.e., positive inotrope and arteriovenous dilator). It produces its positive inotropic effects through inhibition of phosphodiesterase (PDE) III and sensitization of cardiac contractile proteins (primarily troponin C) to intracellular calcium. Its positive inotropic effect is thought not to increase myocardial oxygen consumption and so increases the efficiency of contraction. Its effects on arrhythmogenesis are not well known. PDE III is also found in vascular smooth muscle. Inhibitors of PDE III, such as pimobendan, lead to vasodilation and reduction of both preload and afterload.
In one study of the effects of pimobendan in dogs with naturally occurring DCM, 10 English cocker spaniels and 10 Doberman pinschers were studied with regard to change in heart failure severity and survival time after pimobendan administration. The study was randomized, blinded, and placebo-controlled. Eight of the 10 dogs on pimobendan improved clinically while only one dog on placebo did so. In the Doberman pinschers median survival time for dogs on placebo was 50 days and on pimobendan was 329 days (95% confidence interval for hazards ratio = 1.4-39.8). There was no significant difference for the English cocker spaniels but this is most likely due to the fact that when this breed contracts DCM it lives for a relatively long time in comparison to other breeds.
In some dogs, clinical signs of low-output heart failure predominate. These dogs may be weak and usually have cold extremities and ears. Often these dogs are clinically dehydrated. The dehydration, coupled with the decreased myocardial contractility, is often the primary cause of the severe decrease in cardiac output in these patients. The dehydration is most commonly due to anorexia, with or without concomitant diuretic administration. If dehydration is severe, cautious intravenous fluid administration is warranted. Complete rehydration will commonly result in edema formation. Diuretic administration must be discontinued in this type of case. Prerenal azotemia is commonly present in these dogs.