Hypertrophic cardiomyopathy

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Hypertrophic cardiomyopathy
Classifications and external resources

ICD-10	I42.1-I42.2
ICD-9	425.4
DiseasesDB	6373
MedlinePlus	000192
eMedicine	med/290  ped/1102 radio/129

Hypertrophic cardiomyopathy, or HCM, is a disease of the myocardium (the muscle of the heart) in which a portion of the myocardium is hypertrophied (thickened) without any obvious cause ^{[1] [2] [3] [4] [5] [6]}. Though perhaps most famous as a leading cause of sudden cardiac death in young athletes ^[7] HCM's more important significance is as a cause of sudden unexpected cardiac death in any age group and as a cause of disabling cardiac symptoms.

A cardiomyopathy is any disease that primarily affects the muscle of the heart. In HCM, the normal alignment of muscle cells is disrupted, a phenomenon known as myocardial disarray. HCM also causes disruptions of the electrical functions of the heart. HCM is believed to be due to a mutation in one of many genes that results in a mutated myosin heavy chain, one of the components of the myocyte (the muscle cell of the heart). Depending on the degree of obstruction of the outflow of blood from the left ventricle of the heart, HCM can be defined as obstructive or non-obstructive.

HCM is also known as idiopathic hypertrophic subaortic stenosis (IHSS) and hypertrophic obstructive cardiomyopathy (HOCM). A non-obstructive variant of HCM is apical hypertrophic cardiomyopathy ^[8], which is also known as nonobstructive hypertrophic cardiomyopathy and Japanese variant hypertrophic cardiomyopathy (since the first cases described were all in individuals of Japanese descent).

While most literature so far focuses on European, American, and Japanese populations, HCM appears in all racial groups. The incidence of HCM is about 0.2% to 0.5% of the general population.

Contents 1 Genetics 2 Anatomic characteristics 2.1 Dynamic outflow obstruction 3 Associated symptoms 4 Physical examination 5 Diagnostic testing 5.1 Cardiac catheterization 6 Treatment 7 Related disorders 8 References 9 External links

[edit] Genetics

Hypertrophic cardiomyopathy is attributed to mutation in one of a number of genes that encode for one of the sarcomere proteins (usually effecting either the α or β myosin heavy chain on chromosome 14 q11.2-3). While the severity of the disease process is dependent on the particular gene mutation, about 80% of cases are inherited in an autosomal dominant pattern. Other gene mutations that are associated with HCM include mutations in α-tropomyosin (on chromosome 15), troponin T (on chromosome 1), Troponin I (on chromosome 14), and myosin-binding protein C (on chromosome 11). The prognosis is variable, based on the gene mutation.

The MYH7 gene (encoding the Β-myosin heavy chain) was the first specific gene identified in familial hypertrophic cardiomyopathy. About 50 percent of all familial cases involve mutation in the MYH7 gene. In individuals without a family history of HCM, the most common cause of the disease is also mutations of the gene that produces the β-myosin heavy chain. Many different mutations in this gene have been identified, and the prognosis is dependent on the particular mutation.

An insertion/deletion polymorphism in the gene encoding for angiotensin converting enzyme (ACE) has been associated with some cases of HCM. The D/D (deletion/deletion) genotype of ACE is associated with more marked hypertrophy of the left ventricle and may be associated with higher risk of adverse outcomes ^{[9] [10]}.

[edit] Anatomic characteristics

Individuals with HCM have some degree of left ventricular hypertrophy. Usually this is an asymmetric hypertrophy, involving the inter-ventricular septum, and is known as asymmetric septal hypertrophy (ASH). This is in contrast to the concentric hypertrophy seen in aortic stenosis or hypertension. About two-thirds of individuals with HCM have asymmetric septal hypertrophy.

Many individuals with HCM demonstrate an obstruction to the outflow of blood from the left ventricle. This is known as dynamic outflow obstruction, because the degree of obstruction is variable and is dependent on the amount of blood in the ventricle immediately before ventricle systole (contraction).

[edit] Dynamic outflow obstruction

Dynamic outflow obstruction (when present in HCM) is usually due to systolic anterior motion (SAM) of the anterior leaflet of the mitral valve. Systolic anterior motion of the mitral valve (SAM) was initially thought to be due to the septal subaortic bulge, narrowing the outflow tract, causing high velocity flow and a Venturi effect — a local underpressure in the outflow tract. Low pressure was thought to suck the mitral valve anteriorly into the septum. But SAM onset is observed to be a low velocity phenomenon: SAM begins at velocities no different from those measured in normals ^{[11] [12]}. Hence, the magnitude and importance of Venturi forces in the outflow tract are much less than previously thought, and Venturi forces cannot be the main force that initiates SAM.

Recent echocardiographic evidence indicates that drag, the pushing force of flow is the dominant hydrodynamic force on the mitral leaflets ^{[11] [12] [13] [14] [15] [16]}. In obstructive HCM the mitral leaflets are often large ^[17] and are anteriorly positioned in the LV cavity ^{[11] [18]} due to anteriorly positioned papillary muscles^[11] that at surgery are often "agglutinated" onto the LV anterior wall by abnormal attachments ^{[15] [16]}.

The mid-septal bulge aggravates the malposition of the valve and redirects outflow so that it comes from a lateral and posterior direction^[13]. The abnormally directed outflow may be visualized behind and lateral to the enlarged mitral valve, where it catches it, and pushes it into the septum ^{[11] [12] [13] [14]}. There is a crucial overlap between the inflow and outflow portions of the left ventricle ^[19]. As SAM progresses in early systole the angle between outflow and the protruding mitral leaflet increases. A greater surface area of the leaflets is now exposed to drag which amplifies the force on the leaflets – drag increases with increasing angle relative to flow^[13]. An analogy is an open door in a drafty corridor: the door starts by moving slowly and then accelerates as it presents a greater surface area to the wind and finally it slams shut. The necessary conditions that predispose to SAM are: anterior position of the mitral valve in the LV, altered LV geometry that allows flow to strike the mitral valve from behind, and chordal slack ^{[11] [12] [13] [14]}. SAM may considered anteriorly directed mitral prolapse ^{[12] [13] [14]}. In both conditions the mitral valve is enlarged and is displaced in systole by the pushing force of flow resulting in mitral regurgitation.

Because the mitral valve leaflet doesn't get pulled into the LVOT until after the aortic valve opens, the initial upstroke of the arterial pulse will be normal. When the mitral valve leaflet gets pushed into the LVOT, the arterial pulse will momentarily collapse and be followed by a second rise, as the left ventricular pressure overcomes the increased obstruction that SAM of the mitral valve causes. This can be seen on the physical examination as a double tap upon palpation of the apical impulse and as a double pulsation upon palpation of the carotid pulse, known as pulsus bisferiens.

[edit] Associated symptoms

The clinical course of HCM is variable. Many patients are asymptomatic or mildly symptomatic. The symptoms of HCM include shortness of breath, chest pain (sometimes known as angina), uncomfortable awareness of the heart beat (palpitations), lightheadedness, fatigue, fainting (called syncope) and sudden cardiac death. Dyspnea is largely due to increased stiffness of the left ventricle, which impairs filling of the ventricles and leads to elevated pressure in the left ventricle and left atrium. Symptoms are not closely related to the presence or severity of an outflow tract gradient ^[20].

Risk factors for sudden death in individuals with HCM include a young age at first diagnosis (age < 30 years), an episode of aborted sudden death, a family history of HCM with sudden death of relatives, specific mutations in the genes encoding for troponin T and myosin, sustained supraventricular or ventricular tachycardia, recurrent syncope, ventricular septal wall thickness over 3cm, hypotensive response to exercise, syncope (especially in children), and bradyarrhythmias (slow rhythms of the heart)^[21]

[edit] Physical examination

Differentiating hypertrophic cardiomyopathy and valvular aortic stenosis

	Aortic stenosis	Hypertrophic cardiomyopathy
Echocardiography
Aortic valve calcification	Common	No
Dilated ascending aorta	Common	Rare
Ventricular hypertrophy	Concentric LVH	Asymmetric, often involving the septum
Physical examination
Murmur of AI	Common	No
Pulse pressure after PVC	Increased	Decreased
Valsalva maneuver	Decreased intensity of murmur	Increased intensity of murmur
Carotid pulsation	Normal or tardus et parvus	Brisk, jerky

The physical findings of HCM are associated with the dynamic outflow obstruction that is often present with this disease.

Upon auscultation, the cardiac murmur will sound similar to the murmur of aortic stenosis. However, this murmur will increase in intensity with any maneuver that decreases the volume of blood in the left ventricle (such as standing or the strain phase of a Valsalva maneuver).

If dynamic outflow obstruction exists, physical examination findings that can be elicited include the pulsus bisferiens and the double apical impulse with each ventricular contraction. These findings, when present, can help differentiate HCM from aortic stenosis. In addition, if the individual has premature ventricular contractions (PVCs), the change in the carotid pulse intensity in the beat after the PVC can help differentiate HCM from aortic stenosis. In individuals with HCM, the pulse pressure will decrease in the beat after the PVC, while in aortic stenosis, the pulse pressure will increase.

[edit] Diagnostic testing

A diagnosis of hypertrophic cardiomyopathy is based upon a number of features of the disease process. While there is use of echocardiography, cardiac catheterization, or cardiac MRI in the diagnosis of the disease, other important factors include ECG findings and if there is any family history of HCM or unexplained sudden death in otherwise healty individuals.

[edit] Cardiac catheterization

Upon cardiac catheterization, catheters can be placed in the left ventricle and the ascending aorta, to measure the pressure difference between these structures. In normal individuals, during ventricular systole, the pressure in the ascending aorta and the left ventricle will equalize, and the aortic valve is open. In individuals with aortic stenosis or with HCM with an outflow tract gradient, there will be a pressure gradient (difference) between the left ventricle and the aorta, with the left ventricular pressure higher than the aortic pressure. This gradient represents the degree of obstruction that has to be overcome in order to eject blood from the left ventricle.

The Brockenbrough–Braunwald–Morrow sign is observed in individuals with HCM with outflow tract gradient. This sign can be used to differentiate HCM from aortic stenosis. In individuals with aortic stenosis, after a premature ventricular contraction (PVC), the following ventricular contraction will be more forceful, and the pressure generated in the left ventricle will be higher. Because of the fixed obstruction that the stenotic aortic valve represents, the post-PVC ascending aortic pressure will increase as well. In individuals with HCM, however, the degree of obstruction will increase more than the force of contraction will increase in the post-PVC beat. The result of this is that the left ventricular pressure increases and the ascending aortic pressure decreases, with an increase in the LVOT gradient.

While the Brockenbrough–Braunwald–Morrow sign is most dramatically demonstrated using simultaneous intra-cardiac and intra-aortic catheters, it can be seen on routine physical examination as a decrease in the pulse pressure in the post-PVC beat in individuals with HCM.

[edit] Treatment

In all patients with hypertrophic cardiomyopathy risk stratification is essential to attempt to ascertain which patients are at risk for sudden cardiac death ^{[2] [5]}. In those patients deemed to be at high risk the benefits and infrequent complications of defibrillator therapy are discussed; devices have been implanted in as many as 15% of patients at HCM centers. Treatment symptoms of obstructive HCM is directed towards decreasing the left ventricular outflow tract gradient and symptoms of dyspnea, chest pain and syncope. Medical therapy is successful in the majority of patients. The first medication that is routinely used is beta-blockade (metoprolol, atenolol, bisoprolol, propranolol)^[2]. If symptoms and gradient persist disopyramide may be added to the beta-blocker ^[22]. Alternately verapamil may be substituted for beta-blockade. It should be stressed that most patient's symptoms may be managed medically without needing to resort to inteventions such as surgical septal myectomy, alcohol septal ablation or pacing. Severe symptoms in non-obstructive HCM may actually be more difficult to treat because there is no obvious target (obstruction) to treat. Medical therapy with verapamil, beta-blockade and diuretics may improve symptoms.

Surgical septal myectomy is the gold standard for relief of symptoms for patients who do not experience relief of symptoms from medications ^{[2] [3] [5] [6] [22] [23]}. It has been performed successfully for more than 25 years. Surgical septal myectomy uniformly decreases left ventricular outflow tract obstruction and improves symptoms, and in experienced centers has a surgical mortality of 1%. It involves a midline thoracotomy (general anesthesia, opening the chest, and cardiopulmonary bypass) and removing a portion of the interventricular septum^[2]. Surgical myectomy resection focused just on the subaortic septum, to increase the size of the outflow tract to reduce Venturi forces may be inadequate to abolish systolic anterior motion (SAM) of the anterior leaflet of the mitral valve. With this limited sort of resection the residual mid-septal bulge still redirects flow posteriorly: SAM persists because flow still gets behind the mitral valve. It is only when the deeper portion of the septal bulge is resected that flow is redirected anteriorly away from the mitral valve, abolishing SAM ^{[3] [24]}. With this in mind, a modification of the Morrow myectomy termed extended myectomy, mobilization and partial excision of the papillary muscles has become the excision of choice ^{[3] [15] [16] [25]}. In selected patients with particularly large redundant mitral valves, anterior leaflet plication may be added to complete separation of the mitral valve and outflow ^{[25] [26]}.

Alcohol septal ablation — introduced by Sigwart in 1994 — is a percutaneous technique that involves injection of alcohol into the first septal perferator of the left anterior descending artery. This is a technique with results similar to the surgical septal myectomy procedure but is less invasive, since it does not involve general anaesthesia and opening of the chest wall and pericardium (which are done in a septal myomectomy). In a select population with symptoms secondary to a high outflow tract gradient, alcohol septal ablation can reduce the symptoms of HCM ^{[2] [5] [27]}.

The use of a pacemaker has been advocated in a subset of individuals, in order to cause asynchronous contraction of the left ventricle. Since the pacemaker activates the interventricular septum before the left ventricular free wall, the gradient across the left ventricular outflow tract may decrease. This form of treatment has been shown to provide less relief of symptoms and less of a reduction in the left ventricular outflow tract gradient when compared to surgical myectomy ^[28].

In cases that are refractory to all other forms of treatment, cardiac transplantation is an option.

[edit] Related disorders

Feline hypertrophic cardiomyopathy is the most common heart disease in cats; the disease process and genetics are believed to be similar to the disease in humans ^[29]. The first feline marker has been discovered ^[30] in 2005. It has been shown to be both heterozygous and homozygous present in about one third (total) of the breed, where a lot of cats seem to be a-sympthomatic. It has also been shown that about half the Maine Coon cats with clinical HCM test negative for this mutation, proving that a second mutation exists in the breed. This mutation has not been found in cats with HCM in other breeds yet.

[edit] References

[edit] External links

• Hypertrophic Cardiomyopathy Association
• Cardiomyopathy Association
• Information from the Stanford Hypertrophic Cardiomyopathy Center
• Hypertrophic Cardiomyopathy Research Foundation
• Physician's Guide to Treating HCM at the Mayo Clinic website
• MedPix