Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy 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. It is perhaps most well known as a leading cause of sudden cardiac death in young athletes. The occurrence of hypertrophic cardiomyopathy is a significant cause of sudden unexpected cardiac death in any age group and as a cause of disabling cardiac symptoms. Younger people are likely to have a more severe form of hypertrophic cardiomyopathy

HCM is frequently asymptomatic until sudden cardiac death, and for this reason some suggest routinely screening certain populations for this disease.

A cardiomyopathy is a primary disease that affects the muscle of the heart. With hypertrophic cardiomyopathy (HCM), the sarcomeres (contractile elements) in the heart replicate causing heart muscle cells to increase in size, which results in the thickening of the heart muscle. In addition, 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 most commonly due to a mutation in one of 9 sarcomeric genes that results in a mutated protein in the sarcomere, the primary component of the myocyte (the muscle cell of the heart).

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

Myosin heavy chain mutations are associated with development of familial hypertrophic cardiomyopathy.

Obstructive and non-obstructive
Depending on whether the distortion of normal heart anatomy causes an obstruction of the outflow of blood from the left ventricle of the heart, HCM can be defined as obstructive or non-obstructive.


 * The obstructive variant of HCM, Hypertrophic obstructive cardiomyopathy (HOCM) has also historically been known as idiopathic hypertrophic subaortic stenosis (IHSS) and asymmetric septal hypertrophy (ASH).


 * Another, non-obstructive variant of HCM is apical hypertrophic cardiomyopathy, also called Yamaguchi Syndrome or Yamaguchi Hypertrophy, first described in individuals of Japanese descent.

Genetics
Hypertrophic cardiomyopathy is inherited as an autosomal dominant trait and is attributed to mutations in one of a number of genes that encode for one of the sarcomere proteins including:

About 50-60% of patients with a high index of clinical suspicion for HCM will have a mutation identified in at least 1 of 9 sarcomeric genes. Approximately 45% of these mutations occur in the β myosin heavy chain gene on chromosome 14 q11.2-3, while approximately 35% involve the cardiac myosin binding protein C gene. Since HCM is typically an autosomal dominant trait, children of an HCM parent have 50% chance of inheriting the disease-causing mutation. Whenever a mutation is identified through genetic testing, family-specific genetic testing can be used to identify relatives at-risk for the disease (HCM Genetic Testing Overview). In individuals without a family history of HCM, the most common cause of the disease is a de novo mutation of the gene that produces the β-myosin heavy chain.

An insertion/deletion polymorphism in the gene encoding for angiotensin converting enzyme (ACE) alters the clinical phenotype of the disease. 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 .

Children and cardiomyopathy
While much has been written about adults with HCM, information regarding children and cardiomyopathy is limited. At this point, it is estimated 30,000 children are affected by cardiomyopathy of all types (dilated, hypertrophic, restricted, etc.) are considered.

Once HCM has been identified in a family, immediate testing of all family members will help to identify those at risk. Children often do not show signs of HCM; the first sign many children display is sudden cardiac arrest. Both invasive and non-invasive techniques exist to detect thickening of the left ventricle and other abnormalities associated with HCM. The most common non-invasive diagnostic test for detecting HCM is electrocardiography, though the most sensitive test for diagnosing HCM is genetic testing.

Beta blockers are often prescribed as the first medical treatment for HCM in children. Many options exist, so it is important to remember to inform one's doctor if undesirable side-effects occur so a switch can be made. Stopping a beta blocker treatment without the consent of your doctor is never advised.

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.

About 25% of individuals with HCM demonstrate an obstruction to the outflow of blood from the left ventricle during rest. In other individuals obstruction only occurs under certain conditions. 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).

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 . 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 . In obstructive HCM the mitral leaflets are often large and are anteriorly positioned in the LV cavity due to anteriorly positioned papillary muscles that at surgery are often "agglutinated" onto the LV anterior wall by abnormal attachments .

The mid-septal bulge aggravates the malposition of the valve and redirects outflow so that it comes from a lateral and posterior direction. 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 . There is a crucial overlap between the inflow and outflow portions of the left ventricle . 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. 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 . SAM may considered anteriorly directed mitral prolapse . 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 left ventricular outflow tract (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.

Associated symptoms
The clinical course of HCM is variable. Many patients are asymptomatic or mildly symptomatic. The symptoms of HCM include dyspnea (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. Often, symptoms mimic those of congestive heart failure (esp. activity intolerance & dyspnea), but treatment is very different. To treat with diuretics (a mainstay of CHF treatment) will exacerbate symptoms in hypertrophic cardiomyopathy by decreasing ventricular volume and increasing outflow resistance.

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, ventricular septal wall thickness over 3 cm, hypotensive response to exercise, recurrent syncope (especially in children), and bradyarrhythmias (slow rhythms of the heart).

Physical examination
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, a murmur due to HCM 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). Classically, the murmur is also loudest at the left parasternal edge, 4th intercostal space, rather than in the aortic area.

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. However, the murmur intensity increases with both Aortic Stenosis and HCM post-PVC.

Screening
HCM is frequently asymptomatic until sudden cardiac death, and is the leading cause of sudden cardiac death in young athletes. HCM can be detected with an echocardiogram with 80%+ accuracy, which can be preceded by screening with an electrocardiogram (ECG) to test for heart abnormalities. History and physical examination alone are ineffective, giving warning of heart abnormalities in only 3% of patients before sudden cardiac death. One study found that the incidence of sudden cardiovascular death in young competitive athletes declined in the Veneto region of Italy by 89% since introduction of routine Hypertrophic Cardiomyopathy Screening of athletes.

United States
There are several potential challenges associated with routine screening for HCM in the United States. First, the U.S. athlete population of 15 million is almost twice as large as Italy's estimated athlete population. Second, these events are extremely rare in the U.S., with less than 100 deaths due to HCM in competitive athletes per year, or about 1 death per 220,000 athletes.

In the United States such screening is not routine and the American Heart Association has "consistently opposed" routine screening.

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 and genetic test findings and if there is any family history of HCM or unexplained sudden death in otherwise healthy individuals.

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.

Treatment
In all patients with hypertrophic cardiomyopathy, risk stratification is essential to attempt to ascertain which patients are at risk for sudden cardiac death. In those patients deemed to be at high risk, the benefits and infrequent complications of implantable cardioverter defibrillator (ICD) therapy are discussed; devices have been implanted in as many as 15% of patients at HCM centers. The ICD is the most effective and reliable treatment option available, harboring the potential for absolute protection and altering the natural history of this disease in some patients. Treatment of 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 a beta-blocker (metoprolol, atenolol, bisoprolol, propranolol). If symptoms and gradient persist, disopyramide may be added to the beta-blocker. Alternately a calcium channel blocker such as verapamil may be substituted for a beta blocker. It should be stressed that most patients' symptoms may be managed medically without needing to resort to interventions 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 and beta-blockade may improve symptoms. Diuretics should be avoided, as they reduce the intravascular volume of blood, decreasing the amount of blood available to distend the left ventricular outflow tract, leading to an increase in the obstruction to the outflow of blood in the left ventricle.

Surgical myectomy
Surgical septal myectomy is an open heart operation done to relieve symptoms in patients who remain severely symptomatic despite medical therapy. 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 less than 1%. It involves a median sternotomy (general anesthesia, opening the chest, and cardiopulmonary bypass) and removing a portion of the interventricular septum. 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. 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. In selected patients with particularly large redundant mitral valves, anterior leaflet plication may be added to complete separation of the mitral valve and outflow.

Alcohol septal ablation
Alcohol septal ablation, introduced by Ulrich Sigwart in 1994, is a percutaneous technique that involves injection of alcohol into one or more septal branches 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. In addition, older individuals and those with other medical problems, for whom surgical myectomy would pose increased procedural risk, would likely benefit from the lesser invasive septal ablation procedure.

When performed properly, an alcohol septal ablation induces a controlled heart attack, in which the portion of the interventricular septum that involves the left ventricular outflow tract is infarcted and will contract into a scar. Which patients are best served by surgical myectomy, alcohol septal ablation, or medical therapy is an important topic and one which is intensely debated in medical scientific circles.

Ventricular pacing
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.

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

Related disorders


Feline hypertrophic cardiomyopathy (HCM) is the most common heart disease in cats; the disease process and genetics are believed to be similar to the disease in humans. In Maine Coon and American Shorthair cat breeds, HCM has been confirmed as an autosomal dominant inherited trait. The first genetic mutation (in cardiac myosin binding protein C) responsible for feline hypertrophic cardiomyopathy was discovered in 2005 in Maine Coon cats. A test for this mutation is available. About one third of Maine Coon cats tested for the mutation have been shown to be either heterozygous or homozygous for the mutation, although many of these cats have no clinical signs of the disease. Some Maine Coon cats with clinical evidence of hypertrophic cardiomyopathy test negative for this mutation, strongly suggesting that a second mutation exists in the breed. The cardiac myosin binding protein C mutation identified in Maine Coon cats has not been found in any other breed of cat with HCM but more recently another myosin binding protein C mutation has been identified in Ragdoll cats with HCM.

Turkish Angoras also may be susceptible to HCM because of this gene. The CatScan study performed at the Royal Veterinary College, London, is looking at the prevalence of the disease within a normal population of apparently healthy domestic cats (non-pedigree). This study has just begun (October 2009) and the results of should be available in early 2012.

While there is no cure for HCM, early detection and regular echocardiograms are key to trying to ward off life-threatening problems. Early signs may include a murmur or even heart failure. Unfortunately, death may occur without any other signs present, making the disease a difficult and often deadly one. While medication is commonly given to cats with HCM that have no clinical signs, no medication has been shown to be helpful at this stage and it has been shown that an ACE inhibitor is not beneficial until heart failure is present (at which time a diuretic is most beneficial). Diltiazem generally produces no demonstrable benefit. Atenolol is commonly administered when systolic anterior motion of the mitral valve is present.

Thromboembolic disease (TED) is relatively common sequelae of Feline HCM. The aetiology remains a little uncertain, but it is thought that ischemic damage to the hypertrophied left ventricular myocardium facilitates thrombus formation and subsequent embolism. Classically the embolus lodges at the iliac bifurcation of the aorta, occluding either one or both of the common iliac arteries. Clinically this presents as a cat with complete loss of function in one or both hindlimbs. The hindlimbs are cold, and the cat is in considerable pain. This pain derives from the exaggerated inflammatory response to the embolus at the point of impact, and the inflammatory mediators released generally have a vasoconstrictor effect further exacerbating the problem. Emboli may, rarely, lodge in other locations, typically the renal or ovarian/testicular arteries as they exit the abdominal aorta.

Treatment of TED is variable - typically very low doses of aspirin may be prescribed (aspirin however is extremely toxic to cats and should only be prescribed and administered by a veterinary surgeon). Plavix is also another widely used drug that may or may not prevent clot formation in HCM cats. The FATCAT study at Purdue University is addressing the efficacy of aspirin vs. Plavix for the prevention of a second clot in cats that have already experienced a clot. Thrombolytic agents (e.g., tissue plasminogen activators) have been used successfully, but their cost is usually prohibitively high in veterinary medicine. Despite the relative efficacy of treatment, the prognosis for cats with TED is poor as they are likely to have significant HCM already, and a recurrent bout of TED is very likely. For this reason euthanasia is often considered in TED cats.

Notable people
After the death of Marc-Vivien Foé of Cameroon during a 2003 FIFA Confederations Cup match, his autopsy revealed hypertrophic cardiomyopathy. Miklós "Miki" Fehér, a Hungarian football player who died during a match on January 25, 2004, also suffered from HCM.

Other noted athletes believed or suspected to have died from HCM include NFL players Thomas Herrion, Mitch Frerotte, Damien Nash, Gaines Adams, and Derrick Faison; NBA players Reggie Lewis, Jason Collier, and Kevin Duckworth; NHL player Sergei Zholtok; baseball pitcher Joe Kennedy; long distance runner Ryan Shay; Loyola Marymount basketball star Hank Gathers; Loyola Marymount soccer player David Kucera; NFL Defensive End Kansas State football player Anthony Bates; OHL Windsor Spitfires captain Mickey Renaud; and Russian ice hockey star Alexei Cherepanov. Jesse Marunde, an American strongman, died of HCM in 2007 after a workout at his gym.

On December 10, 2008, NBA player Cuttino Mobley announced his retirement due to worsening HCM. The disease also ended the career of former Wake Forest star Robert O'Kelley, after a mandatory EKG in Brazil discovered his condition in 2006.

British comedy actor Leonard Rossiter died from hypertrophic cardiomyopathy in 1984 while waiting to go onstage at the Lyric Theatre, London. The autopsy of actor Corey Haim identified HCM as one of the contributing causes (along with pneumonia and coronary arteriosclerosis) for his death in 2010. American pornographic actress Aurora Jolie also has HCM.

Fictional characters
In the CW television show One Tree Hill, characters Dan and Lucas Scott have HCM.

In the Fox series Beverly Hills 90210, Joe Bradley, a quarterback for California University and boyfriend of Donna Martin for much of season 6, is diagnosed with HCM by Donna's father, Dr. John Martin.

Vivian Johnson on Without a Trace also has HCM.

Willie Cager in Glory Road was benched with HCM.

The main character of the 1997 film The Sixth Man, Antoine Taylor, played by actor Kadeem Hardison, died from HCM.

In the Australian TV series Love My Way, Frankie and Charlie's daughter, Lou, dies suddenly from HCM.

In an episode of Eli Stone (10/21/2008) the character Grace Fuller played by Katie Holmes has HCM.

The lead girl in the Korean Movie A Millionaire's First Love played by Lee Yeon Hee died from HCM.