Hypertrophic cardiomyopathy overview

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Hypertrophic Cardiomyopathy Microchapters
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Overview
Historical Perspective
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Pathophysiology
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Epidemiology and Demographics
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Natural History, Complications and Prognosis
Diagnosis
Diagnostic Study of Choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
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Echocardiography and Ultrasound
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MRI
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Soroush Seifirad, M.D.[2]

Overview

Hypertrophic cardiomyopathy, or HCM, is a disease of the myocardium in which a portion of the myocardium is hypertrophied without any alternate known cause such as hypertension, amyloid or aortic stenosis. Although HCM has gained notoriety as a leading cause of sudden cardiac death in young athletes, it should be noted that HCM is a cause of sudden cardiac death in any age group and may be associated with cardiac morbidity and disabling cardiac symptoms as well. There are two variants of hypertrophic cardiomyopathy: an obstructive variant, and a non-obstructive variant. A non-obstructive variant of HCM is known as apical hypertrophic cardiomyopathy ,which is also known as nonobstructive hypertrophic cardiomyopathy and Japanese variant hypertrophic cardiomyopathy or the Yamaguchi variant (since the first cases described were all in individuals of Japanese descent). In hypertrophic cardiomyopathy (HCM), the sarcomeres 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. Myosin heavy chain mutations are associated with the development of familial hypertrophic cardiomyopathy. HCM also causes disruptions of the electrical functions of the heart. Hypertrophic cardiomyopathy is most commonly due to a mutation in one of 14 sarcomeric genes that results in a mutated protein in the sarcomere, the primary component of the myocyte. 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. HCM is frequently asymptomatic until sudden cardiac death, and that is why some experts suggest routinely screening certain populations for this disease. Echocardiographuc surveys in general population showed HCM in approximately 1 in every 500 people (0.2% of the general population). Only 15% of HCM patients have been diagnosed, which means the majority of patients with HCM are undiagnosed. The symptoms associated with hypertrophic cardiomyopathy are quite variable and range from no symptoms, to the development of heart failure, or sudden cardiac death. The symptoms may vary tremendously from individual even within a family (different penetrance). The timing of symptom onset is quite variable as well and may range from infancy to adulthood. Symptoms may include chest pain, dizziness, fainting, especially during exercise, heart failure (in some patients), hypertension, dizziness during activity or when standing up suddenly, sensation of feeling the heart beat (palpitations), shortness of breath, fatigue, reduced activity tolerance, and shortness of breath when lying down (orthopnea). The medical management of the patient with hypertrophic cardiomyopathy involves minimizing diastolic dysfunction, reducing left ventricular outflow tract obstruction, optimizing heart failure management, maintaining normal sinus rhythm, rate control and anticoagulation in the presence of atrial fibrillation, and implantation of an automatic implantable cardiac defibrillator in selected patients such as those who survive sudden cardiac death.

Historical Perspective

The first case of hypertrophic cardiomyopathy (HCM) was described by in 1869 Henri Liouville in the Gazette Medecine Paris. In 1907 Dr. A. Schmincke, a German pathologist, described two hearts with left ventricular hypertrophy; both came from women in their mid-fifties. Levy and von Glahn in 1944, from Colombia University in New York, published a series of cases which resembles HCM. In 1949, William Evans, a London cardiologist, described familial occurrence of cardiac hypertrophy in a series of patients which were similar to those described in the paper by Levy and von Glahn. In 1961 Paré et al. reported thirty members of five generations of a French Canadian family in Quebec in whom the condition was inherited in an autosomal dominant manner. In 1958 Teare, an English pathologist, described eight cases of asymmetric cardiac muscle hypertrophy, he thought that they might be benign cardiac tumors. Seven of these caused sudden death in young adults. Teare named the condition “Asymmetrical Hypertrophy of the Heart.” In 1959 Sir Russell Brock described a young man with angina and a subaortic stenosis and a subaortic intraventricular pressure gradient. Morrow and Braunwald published their first report in the same year, followed by several other reports. The sudden cardiac deaths of 387 young American athletes (under age 35) were analyzed in a 2003 medical review, and HCM was the leading cause of sudden cardiac death in athletes. In 1961, Morrow described a surgical procedure to relieve the obstruction, which is still the most widely used method of surgical treatment. In 1962, with respect to the observed intensification of obstruction in HCM with the beta-adrenergic agonists, Braunwald suggested the use of newly developed beta-blockers. In 1964, Braunwald reported beta-blockers beneficial hemodynamic effects. 1967, the clinical benefits of treatment with beta blockers in patients with HCM has been proved to the scientific society.

Classification

There are two variants of hypertrophic cardiomyopathy: an obstructive variant, and a non-obstructive variant. About 25% of individuals with hypertrophic cardiomyopathy (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. If left ventricular outflow obstruction is present, then this syndrome has been known as wide variety of terms including: hypertrophic cardiomyopathy or HCM, asymmetric septal hypertrophy or ASH, hypertrophic obstructive cardiomyopathy, HOCM, idiopathic hypertrophic subaortic stenosis or IHSS.

A non-obstructive variant of HCM is known as apical hypertrophic cardiomyopathy, which is also known as nonobstructive hypertrophic cardiomyopathy and Japanese variant hypertrophic cardiomyopathy or the Yamaguchi variant (since the first cases described were all in individuals of Japanese descent), also known as apical hypertrophic cardiomyopathy (ApHCM) or Yamaguchi syndrome.

Pathophysiology

The progression to hypertrophic cardiomyopathy usually involves the mutations in contractile sarcomeric proteins of myocardium, which describe the presence of left ventricular hypertrophy (LVH) in the absence of an increased external load (unexplained LVH). Additionally, HCM hypertrophy is generally asymmetric.

HCM is the most common genetically transmitted cardiovascular disease. 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. Penetrance of HCM is incomplete, variable and time or age-related. The disease may be sporadic but affected family members are discovered in 13% of cases. More than 200 mutations involving at least 10 chromosomes encoding structural proteins of the myocyte have been discovered. These mutations have varying degrees of penetrance and even the same mutation may have variable expression, implying the superimposed effects of other genes or environmental influences. Children of a patient with HCM have a 50% chance of inheriting the trait.

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. 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).

Although there may be structural or functional obstruction of the left ventricular outflow tract, symptoms may arise more often from diastolic dysfunction.There is extensive periarteriolar fibrosis that results in microvascular dysfunction and impairment in coronary flow reserve in patients with hypertrophic obstructive cardiomyopathy. Individuals with HCM have some degree of left ventricular hypertrophy. In approximately 2/3rds of cases this is asymmetric hypertrophy, involving the interventricular septum, and is known as asymmetric septal hypertrophy (ASH). This is in contrast to the symmetric and concentric hypertrophy seen in aortic stenosis or hypertension. On histopathologic examination, hypertrophic cardiomyopathy is characterized by both myocardial disarrays and by periarteriolar fibrosis. Myocardial disarray can be associated with aberrant impulse conduction and arrhythmias, and periarteriolar fibrosis can be associated with myocardial ischemia.

Causes

Hypertrophic cardiomyopathy is a condition that is most often passed down through families (inherited). It is thought to result from gene mutations that control heart muscle growth. Genes involved in the pathogenesis of hypertrophic cardiomyopathy include MYH7, TNNT2, TPM1. Nevertheless, number of chronic medical conditions might be contributed to hypertrophic cardiomyopathy development, among them are thyroid disease, diabetes, and obesity, and hypertension.

Differentiating Hypertrophic Cardiomyopathy from Other Diseases

Cardiomyopathy must be differentiated from athlete heart (which is often confused with HCM on echocardiography), hypertrophy due to hypertension or aortic stenosis; as these have common clinical features, including thickened myocardium on imaging and high QRS voltage on EKGs. On the basis increased LV to aortic gradient, hypertrophic cardiomyopathy must be differentiated from sever volume depletion, subaortic stenosis, and valvular aortic stenosis.

Epidemiology and Demographics

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease. Prevalence rates have been reported between 1:500 (0.2%) and 1:3,000 (0.03%) because of variations in study designs and cohort characteristics including different age groups and ethnicity. According to the CARDIA (Coronary Artery Risk Development in Young Adults) cohort study that used standard echocardiography in 4,111 unrelated people 23 to 35 years of age, HCM prevalence is reported as 1 in 500 persons (0.2%). Nevertheless, lower prevalence has been reported in some European countries such as Germany (0.07%). Patients of all age groups may develop hypertrophic cardiomyopathy. Prevalence increased with advancing age and showed a constant yearly rise but sudden death is more prevalent in young patients, particularly athletes. The case-fatality rate is 6 per 10,000 per year in young people without symptoms of hypertrophic cardiomyopathy but in syptomatic patients a case-fatality rate is 420 and 110 deaths per 10,000 per year in tertiary referral centers and general hospital clinics respectively. Hypertrophic cardiomyopathy affects men and women equally. However, despite more frequent outflow obstruction, women with HCM are underrecognized and referred to centers later than men, often with more advanced heart failure. Greater awareness of HCM in women should lead to earlier diagnosis and treatment, with implications for improved quality of life. HCM is less prevalent in African Americans, but they are more pron to early presentation, developing heart failure, and sudden death is more prevalent due to less awareness and screening in this population.

Risk Factors

Obstructive hypertrophic cardiomyopathy (HCOM) is known as a familial genetic disorder. The most potent risk factor in the development of hypertrophic cardiomyopathy are genetic mutations in Beta-myosin heavy chain, Myosin binding protein C, and Cardiac troponin T. Genes involved in the pathogenesis of hypertrophic cardiomyopathy include but not limited to MYH7, TNNT2, TPM1. However, hypertension, thyroid disease, diabetes, and obesity also play a role in non obstructive forms of hypertrophic cardiomyopathy. This is in response to chronic effects of abnormal pressure and volumes on the heart muscle and is different from apical hypertrophy (Yamaguchi syndrome).

Screening

Genetic testing is the diagnostic study of choice to definitively diagnose hypertrophic cardiomyopathy. While definitive, these techniques can be expensive and can be difficult to access. If the mutation has already been identified in other family members, it is fairly efficient to test for that isolated mutation. Once HCM has been identified in a family, immediate testing of all family members will help to identify those at risk.

Natural History, Complications, and Prognosis

The natural history of hypertrophic cardiomyopathy is quite variable. Signs and symptoms range from none, to atrial fibrillation, to heart failure, to embolic stroke, to sudden cardiac death. Signs and symptoms are quite variable from individual to individual but are also quite variable within a given family (all of whom carry the same mutation). The disease is quite variable in the timing of its appearance and may appear anywhere from infancy to late in adult life. About 25% of HCM patients achieve normal longevity. The myosin binding proteins C genetic variant carries a good prognosis. The presence of VT / VF carries the poorest prognosis. The severity of the outflow gradient is also related to prognosis. Athletes should be screened for HOCM based upon a family history of sudden cardiac death and a murmur on physical examination. Electrocardiograms and echocardiograms are not cost effective screening tools in this population with a low pre-test probability of disease.

Diagnosis

Diagnostic Study of Choice

There is no single study of choice in the diagnosis and management of patients with HCM. Hypertrophic cardiomyopathy can be diagnosed based on clinical examination, imaging, ECG, and genetic testing. In fact, a series of studies are indicated the time of diagnosing HCM among them are Echocardiography and ECG. Echocardiography is the imaging study of choice for the diagnosis of hypertrophic cardiomyopathy. However, MRI might detect HCM sooner, and as mentioned above genetic tests are also helpful.

History and Symptoms

A large number of the patients with hypertrophic cardiomyopathy are asymptomatic or complain of mild nonspecific symptoms, Patients are often diagnosed by family screening, incidental murmur auscultation during routine examination or screening for school athletic events, or via an abnormal ECG. Nevertheless, in symptomatic patients, left ventricular outflow tract gradients and result in symptoms of dyspnea, fatigue, chest pain, and syncope are the most common presentations. The symptoms associated with hypertrophic cardiomyopathy are quite variable and range from no symptoms, to the development of heart failure, to the occurrence of sudden cardiac death. The symptoms may vary tremendously from individual even within a family. The timing of symptom onset is quite variable as well and may range from infancy to adulthood.

Physical Examination

There are numerous teachers on physical examination that allow one to distinguish hypertrophic cardiomyopathy from other conditions such as aortic stenosis. On physical examination, (as shown in the table below) maneuvers that decrease left ventricular filling augment the murmur and maneuvers that increase afterload or filling decrease the murmur.

Laboratory Findings

Genetic studies may be used in the diagnosis and screening of patients and families with known hypertrophic cardiomyopathy (HCOM). Laboratory findings consistent with the diagnosis of hypertrophic cardiomyopathy may include but not limited to mutations in the genes involved in Beta-myosin heavy chain, Myosin binding protein C, and cardiac troponin T. Genes involved in the pathogenesis of hypertrophic cardiomyopathy include MYH7, TNNT2, and TPM1.

Electrocardiogram

A 12 lead EKG is strongly recommended at the time of the initial diagnosis of hypertrophic cardiomyopathy. Common findings on an EKG in these patients include tall R waves, deep Q waves, inverted T waves, ST segment abnormalities and 'strain pattern' in the chest leads. The deep Q waves indicate septal hypertrophy and similarly deeply inverted T waves indicate apical hypertrophy.

X-ray

There are no x-ray findings associated with hypertrophic cardiomyopathy.

Echocardiography and Ultrasound

Echocardiography is the imaging modality of choice in the diagnosis of hypertrophic cardiomyopathy. Classically there is a small left ventricular cavity with hypertrophy out of proportion to any underlying condition that would cause LVH. The hypertrophy is often asymmetric.

CT scan

There are no CT scan findings associated with hypertrophic cardiomyopathy. However, a CT angiography may be helpful in the diagnosis of concomitant CAD in patients with hypertrophic cardiomyopathy.

MRI

Late myocardial enhancement has been associated with myocardial fibrosis and may allow for earlier detection of hypertrophic cardiomyopathy (HCM) than is currently available with echocardiography and ECG. MRI is helpful in visualizing the asymmetric thickening of the interventricular septum in patients with HCM. However, it may be more helpful than other forms of imaging to differentiate the variant types of hypertrophic cardiomyopathy. MRIcan be helpful in evaluating the extent of systolic anterior motion of the mitral valve. MRI can help visualize turbulence in the left ventricular outflow tract created by an obstruction in patients with obstructive hypertrophic cardiomyopathy.

Other Imaging Findings

Positron Emission Tomography (PET) may be helpful in the diagnosis of ischemia in patients with hypertrophic cardiomyopathy. PET studies have demonstrated that coronary flow reserve is reduced in patients with HCM. Those patients who subsequently died had a greater reduction in coronary flow reserve at baseline. It has been hypothesized that this ischemia may mediate in part the higher risk in sudden cardiac death.

Other Diagnostic Studies

Left heart catheterization can be a useful diagnostic study to ascertain the severity of the dynamic outflow obstruction and its location. Among patients who have chest discomfort or an anginal equivalent, coronary angiography carries a class I recommendation to evaluate for the presence of obstructive coronary artery disease.The prognostic value of electrophysiologic testing of patients with HOCM in the absence of spontaneous, sustained ventricular tachycardia is limited, and in fact, the study itself may be dangerous. Paced electrogram fractionation in hypertrophic cardiomyopathy may helpful in determining which patients are at risk for ventricular fibrillation.

Treatment

Medical Therapy

The medical management of the patient with hypertrophic cardiomyopathy involves minimizing diastolic dysfunction, reducing left ventricular outflow tract obstruction, optimizing heart failure management, maintaining normal sinus rhythm, rate control and anticoagulation in the presence of atrial fibrillation, and implantation of an automatic implantable cardiac defibrillator in those patients who survive sudden cardiac death.

One of the fundamental goals of treatment is to relieve disabling dyspnea and improve exercise tolerance. It should be noted that the majority of patients do not have outflow tract obstruction, and therefore would not benefit from surgery. Medical therapy is, therefore, a mainstay of treatment. Given the limited number of patients with the condition, there are few randomized trials comparing strategies/agents in the management of HCM.

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 defibrillator therapy are discussed; devices have been implanted in as many as 15% of patients at HOCM centers. Treatment symptoms of obstructive HOCM is directed towards decreasing the left ventricular outflow tract gradient and symptoms of dyspnea, chest pain and syncope.

Interventions

Alcohol septal ablation, ventricular pacing, automatic implantable cardiac defibrillator placement are among interventions used to manage patients with hypertrophic cardiomyopathy.

Surgery

Septal myectomy is a surgical treatment for hypertrophic cardiomyopathy (HCM). Septal myectomies have been successfully performed for more than 25 years.

Cardiac transplantation can be performed in patients with HOCM and has been associated with better post-operative survival than those patients transplanted for ischemic cardiomyopathy.

Primary Prevention

There is no primary prevention for hypertrophic cardiomyopathy. This is a genetic familial disorder. But there are important approaches to decrease and prevent development of sudden death and heart attack in known cases of HCM (tertiary prevention). Any activity, drug or circumstance that increases left ventricular outflow obstruction, reduced left ventricular filling, or increases left ventricular afterload should be avoided.

Secondary Prevention

Effective measures for the secondary prevention of hypertrophic cardiomyopathy include screening. Once HCM has been identified in a family, immediate testing of all family members will help to identify those at risk. Both imaging and genetic testing might be helpful. Athletes and military commanders (this in danger group barely discussed in the literature) are particularly in danger and it is recommended to undergo screening for HCM.

Management During Pregnancy

Women with hypertrophic cardiomyopathy should be managed by a skilled cardiovascular specialist and a high-risk obstetrician during pregnancy. Among HCM patients who chronically have mild symptoms, pregnancy is generally well tolerated . Although pregnancy causes vasodilation which should exacerbate the outflow gradient, pregnancy also causes fluid retention and an increase in plasma volume which increases preload and offsets the reduction in afterload. In a series of 100 HCM patients, only one of 28 asymptomatic patients developed NYHA Class III or IV heart failure.

Epidural Anesthesia Should Be Avoided due to the potential for venous pooling. Bleeding should be minimized. Blood should be crossed and typed in case a transfusion is needed for bleeding, which can exacerbate outflow obstruction. Although both beta blockers and verapamil may improve symptoms in the mother, the dosing should be limited to minimize the risk of fetal bradycardia, growth retardation and hypoglycemia. There is more experience with the use beta blockers during pregnancy. Home delivery without IV access is not preferred. Vaginal delivery is usually successful.

References