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SCH3227 Biology of human disease

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SCHWARTZKOPFF TRISTAN

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10330671

NAME OF LECTURER Associate Professor Peter Roberts DUE DATE

Topic of assignment Hypertrophic Cardiomyopathy: Literature Review

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1

Hypertrophic Cardiomyopathy: Literature Review

Tristan Schwartzkopff

10330671

Edith Cowan University

SCH3227: Biology of human disease

Associate Professor Peter Roberts

4/5/2015

2

Table of contents

Introduction 4

Disease overview 4

Description 5

Cause 6

Disease Physiology 7

Diagnosis 8

Treatments 10

Beta Blockers 10

Amiodarone 11

Alcohol Septal Ablation 11

Myectomy 12

Conclusion 13

References 14

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Introduction

Hypertrophic cardiomyopathy is a genetic condition of the heart. It affects 1 in 500

(Popjes & Martin, 2003) and is the leading cause of sudden death in athletes aged 15 to

35 (Day, 2009). The purpose of this literature review is to compare and contrast the

current literature regarding hypertrophic cardiomyopathy. The review will begin with a brief

summary of how the understanding of the disease has developed, followed by examining

the cause, physiology and diagnosis of the condition. The review will then review current

treatments including; beta blockers, amiodarone, alcohol septal ablation and myectomy.

Disease overview

Initial reports of the disease during the 1950’s and 1960’s highlighted symptoms

such as heart a murmur, increased left ventricle pressure gradient, asymmetrical

hypertrophy of the left ventricle (Elliot & McKenna, 2004), and sudden unexpected death in

young individuals (Criley & Siegel, 1986). These symptoms lead to the conclusion that the

condition was caused by an obstruction, most likely a muscular sphincter or contraction

ring in the left ventricle (Criley & Siegel, 1986; Elliot & McKenna, 2004; Said, Dearani,

Ommen, & Schaff, 2013). Due to this theory, early treatments were based on the belief

that the sudden death associated with the disease was caused by this obstruction,

therefore common early treatments involved either a transaortic septal myotomy-

myectomy or a mitral valve replacement (Criley & Siegel, 1986). Further research lead to a

more thorough understanding, allowing for the development of improved treatments.

These treatment options will be discussed in later sections of this review.

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Description

The current definition of hypertrophic cardiomyopathy is provided by Elliot &

McKenna, who defines it as “left ventricle hypertrophy in the absence of a detectable

cause” (2004). This definition is supported by Popjes & Martin (2003) and Cambronero et

al. (2009), with Cambronero et al. (2009) adding that increased myocyte disarray, fibrosis

and abnormal intramyocardial vessels are also present. Further changes to normal

physiology may also include inflammation, endothelial dysfunction, platelet activation and

degradation of the extracellular matrix (Cambronero et al., 2009).

Initial descriptions of the condition included the sudden and unexplained death of

young individuals, particularly athletes (Corrado, Basso, Schiavon, & Thiene, 1998). As the

understanding of the condition improved, it was discovered that the majority of patients

with hypertrophic cardiomyopathy were asymptomatic (Cambronero et al., 2009; Elliot &

McKenna, 2004), however as explained by Day (2009), symptoms can often be induced in

affected individuals by high intensity exercise and extreme weather conditions. This is

supported by Elliot & McKenna (2004) and Popjes & Martin (2003) who report exercise

intolerance along with angina, palpitations and syncope as common HCM symptoms.

The asymptomatic nature of this condition in a rested state is particularly dangerous

for athletes, as complications may only occur when stimulated by intense exercise as

experienced during training or competition (Day, 2009). This has led to increased death

rates in athletes attributed to HCM, with HCM reported as the number one cause of death

in athletes 35 or younger (Maron & Maron, 2013). Day (2009) agrees, adding that 36% of

sudden deaths of young US athletes can be attributed to hypertrophic cardiomyopathy with

athlete death rates estimated between 1 in 50000-200000. Further Italian studies also

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conclude that athletes are 2.5 times more likely to die from the condition compared to non-

athletes (Day, 2009).

The overall prevalence of the condition is 1 in 500 (Popjes & Martin, 2003) with an

annual mortality rate of between 1% and 2% (Elliot & McKenna, 2004; Popjes & Martin,

2003). 70% of patients present with obstructive HCM, with 30% presenting with non-

obstructive HCM (Geske, Klarich, Ommen, Schaff, & Nishimura, 2014; Maron & Maron,

2013). These figures are disputed by Masry & Breall (2008) who reports as few as 25-30%

of cases present with an obstruction, while Brown & Schaff (2008) attempts to explain this

discrepancy, stating that 37% appear to suffer from obstruction at rest, while a further 33%

show an obstruction after exercise testing. Of symptomatic obstructive cases, 10% will

progress to the dilated phase where the left ventricular wall thins, leading to cavity

enlargement and systolic dysfunction (Cambronero et al., 2009).

Cause

HCM is caused by gene mutations, with several sources agreeing that there are 11

known gene mutations which contribute to the condition (Cambronero et al., 2009; Maron

& Maron, 2013; Popjes & Martin, 2003). Varma & Neema (2014) disagree, reporting 14

gene mutations, while Frey, Luedde, & Katus (2011) states as many as 23 gene mutations

contribute to the condition. Debate also remains over the total number of protein mutations

caused by these gene mutations. Maron & Maron (2013) and Varma & Neema (2014)

reports a total of 1400 mutations of contractile myofilaments contribute to the condition,

while Cambronero et al. (2009) states 400 known protein mutations and Popjes & Martin

(2003) reports as few as 150.

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Whatever the total number of protein mutations, the result appears to be impaired

cardiac myocyte function (Cambronero et al., 2009). These genetic mutations and

impaired myocyte function result in left ventricle hypertrophy (Cambronero et al., 2009;

Elliot & McKenna, 2004 ;Popjes & Martin, 2003). Hypertrophy of the left ventricle leads to a

reduced left ventricular cavity and possible obstruction (Frey et al., 2011). The result is a

reduced ability for left ventricular contraction and therefore reduced blood flow from the

heart (Varma & Neema, 2014). When stressed from increased exertion, heart rate

increases in an attempt to increase blood flow, If the heart fails to keep up, heart failure

and sudden death may result (Frey et al., 2011). These genetic mutations appear to be

hereditary with a 50% chance of the offspring of an individual with HCM inheriting the

disease (Maron & Maron, 2013). Genetic testing is available and can be used to identify at

risk individuals (Popjes & Martin, 2003).

Disease physiology

As stated by Cambronero et al. (2009) the pathophysiology of HCM is still being

developed. While it is well established that gene errors lead to protein mutations and

impaired cardiac myocyte function (Cambronero et al., 2009), debate remains as to how

this causes hypertrophy of the left ventricle. There are currently two theories being

investigated. Cambronero et al. (2009) reports that although the two theories are different,

both theories are based on the idea that protein mutations cause reduced filament activity,

leading to reduced power production by the sarcomere. This results in reduced ATPase

activity, altered calcium sensitivity and promotes myocyte atrophy (Cambronero et al.,

2009).

The first of these theories states that HCM protein mutations affect myocyte

contractility, leading to impaired diastolic and systolic function, which increases the stress

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on the wall of the left ventricle (Cambronero et al., 2009). This activates stress factors

which stimulates the enlargement of the septum, causing an obstruction and increased

pressure gradient along with myocyte disarray (Cambronero et al., 2009). The main issue

with this theory as reported by Cambronero et al., (2009) is that in some cases of HCM,

mutations appear to increase the contraction force of thin filaments.

The second theory is the energy compromise theory (Cambronero et al., 2009).

This theory is well supported by both Cambronero et al. (2009) and Elliot & McKenna

(2004) which states that a reduced ratio of phosphocreatine to ATP as seen in HCM

sufferers, indicates inefficient utilisation of ATP by cardiac muscle. Thus the increased

demand for ATP by cardiac muscle draws ATP away from the calcium pump of the

sarcoplasmic reticulum. As the calcium pump requires ATP to function, the decreased

availability of ATP leads to reduced function of the calcium pump, allowing a build-up of

calcium in the cytosol (Cambronero et al., 2009; Elliot & McKenna, 2004). Cambronero et

al. (2009) reports that this increase in calcium concentration of the cytosol leads to

increased left ventricular hypertrophy and fibrosis. Thus increased size of the left ventricle

with impaired function.

Diagnosis

There are several ways to test for and diagnose HCM, the most common

techniques include genetic testing, ECG, echocardiography, MRI testing and exercise

testing. As previously discussed genetic testing can be used to test for a phenotype which

identifies an individual at risk of the disease (Popjes & Martin, 2003). This test is often the

first test completed, as once an individual is identified as having a positive genotype,

further testing is completed to monitor the condition (Popjes & Martin, 2003). This

diagnostic technique has seen a reduction in athlete death rates in Italy, with professional

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soccer players in certain leagues required to undergo phenotype testing before being

cleared to compete (Corrado et al., 1998). For players who test positive, regular ECG, MRI

and exercise stress tests are required for the athlete to continue to play in the league

(Corrado et al., 1998).

The second test is the electrocardiogram (ECG) test on the electric activity of the

heart. In individuals with HCM the ECG will show an altered Q wave, with some patients

also presenting a giant negative T wave or a slurred QRS upstroke (Elliot & McKenna,

2004). These results indicate left atrial enlargement such as seen in HCM (Elliot &

McKenna, 2004).

Further testing may also involve the use of an echocardiography to view the size

and shape of the heart (Day, 2009; Elliot & McKenna, 2004). Patients suffering from HCM

will have the wall of the left ventricle thicker than 15mm and often a thickened

interventricular septum (Elliot & McKenna, 2004). Echocardiographs of HCM patients may

also indicate contact between the inerventricular septum and the mitral valve leaflet (Elliot

& McKenna, 2004), this is an example of obstructive HCM and is a symptom in 25% of

patients (Elliot & McKenna, 2004). These results may be further confirmed by the use of

MRI or magnetic resonance imaging (Elliot & McKenna, 2004).

The final technique for HCM testing is an exercise stress test involving open circuit

calorimetry (Elliot & McKenna, 2004). The test involves the patient exercising while hooked

up to an oxygen mask to measure total oxygen consumption. Patients with HCM often

show reduced peak oxygen consumption with 25% also showing abnormal blood pressure

(Elliot & McKenna, 2004).

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Treatments

General guidelines for patients include avoiding high intensity exercise such as

progressive training or heavy weightlifting (Day, 2009; Popjes & Martin, 2003), with Day

(2009) also suggesting to avoid exercise in extreme extreme heat or cold. This is not to

say that exercise in general should be avoided, with recent studies suggesting that

moderate intensity exercise programs may reduce the risk of sudden death (Day, 2009).

These findings were supported by Popjes & Martin (2003) who agrees that light aerobic

exercise is beneficial to HCM sufferers. There are several treatment techniques for HCM

with drug interventions such as the use of beta blockers and amiodarone being the

preferred starting point, while myectomy and alcohol ablation treatments may be required

when drug interventions are unsuccessful (Brown & Schaff, 2008).

Beta blockers

Beta blockers are often the first choice drug prescribed to sufferers of HCM (Popjes

& Martin, 2003). These drugs are commonly prescribed for the treatment of angina (Shin &

Johnson, 2007) and have been shown to reduce blood pressure and lower heart rate, thus

reducing the oxygen requirements of cardiac muscle (Brown & Schaff, 2008; Shin &

Johnson, 2007). Beta blockers are often used simultaneously with calcium channel

blockers and diuretics (Popjes & Martin, 2003).

Calcium channel blockers such as verapamil have been shown to be affective when

the patients response to beta blockers is inadequate (Geske et al., 2014; Masry & Breall,

2008), while diuretics are used to decrease blood volume, decrease stroke volume and

cardiac output (Popjes & Martin, 2003). Although beta blockers are the most common

medication prescribed to HCM sufferers, Maron & Maron (2013) disputes their use citing a

lack of supporting research into their benefits for the treatment of HCM, instead believing

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that implantable defibrillators are a better option for avoiding sudden death caused by

tachyarrhythmia’s.

Amiodarone

Amiodarone has also been used due to its benefits as an anti-arrhythmic drug

however it is not well supported by evidence (Prasad & Frenneaux, 1998). Hudzik &

Zubelewicz-Szkodzinska (2014) reports that it is well tolerated by patients with left

ventricular systolic dysfunction, and states that benefits include coronary vasodilation to

reduce obstruction, and acts as a weak beta blocker and calcium channel blocker.

However, Maron & Maron (2013) highlights the toxic properties associated with long term

use as making it far from ideal as a treatment option. This is supported by Prasad &

Frenneaux (1998) who states that chronic use has been shown to alter thyroid function,

which may aggravate symptoms in individuals with pre-existing thyroid conditions.

Alcohol septal ablation

Alcohol septal ablation (ASA) is a relatively new technique developed to treat HCM.

ASA involves the injection of absolute alcohol into the myocardium to induce an infarction

in the obstructing tissue (Geske et al., 2014). The resultant infarction acts to thin the basal

septum, thus reducing the obstruction (Geske et al., 2014), improving oxygen consumption

of cardiac tissue (Masry & Breall, 2008), improving the pressure gradient and relieving

symptoms of heart failure (Said et al. 2013). This procedure has typically only been

recommended for patients who have failed to respond to medical therapies such as beta

blockers and calcium channel blockers.

However; Masry & Breall (2008) states that several specialists have started

recommending ASA as a first choice treatment. The main benefit of this treatment over a

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myectomy is that this is not a surgical procedure, making it ideal for patients who may not

be physically fit enough to endure surgery (Said et al. 2013). The overall benefit of the

treatment compared to surgical interventions is in dispute by several sources. Both Said et

al. (2013) and Popjes & Martin (2003) report higher success rates and better long term

symptomatic relief from surgery, while ASA patients also have an increased risk of

complications such as reduced left ventricular function, pulmonary embolism, septal

defects and most notably heart blockage (Popjes & Martin, 2003). This if further enforced

by Brown & Schaff (2008) who states that 53% of ASA patients suffer an AV block, 46% a

right bundle branch block and 10% suffer a complete heart blockage requiring a

permanent pacemaker.

Myectomy

Myectomy, historically known as the morrow procedure, is a surgical intervention

and is commonly considered the gold standard for treating obstructions brought on by

HCM (Brown & Schaff, 2008). While medication is typically recommended as the first

treatment option, for patients who don’t show improvement from medication, myectomy is

the preferred option (Brown & Schaff, 2008; Gao et al., 2012).

The procedure involves surgically removing the part of the septum which is causing

the obstruction, leading to a reduction of the pressure gradient (Brown & Schaff, 2008;

Gao et al., 2012). Geske et al. (2014) agrees also stating that the gradient reduction is

often greater than from treatment by ASA, while the risks involved are considered less.

Like ASA there still remains the risk of an atrial ventricular block requiring an implantable

defibrillator, however the risk is considered lower (Yunhu, 2014).

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Conclusion

Hypertrophic cardiomyopathy is genetic condition which affects 1 in 500 and

is described as left ventricle hypertrophy in the absence of a detectable cause. It is

brought on by mutations to genes which manifest as protein mutations in the contractile

myofilaments of the left ventricle. Debate remains as to the pathophysiology, however,

mutations appear to lead to myocyte disarray, fibrosis, and altered function leading to

hypertrophy and possible obstruction.

The condition is commonly asymptomatic with stress testing often required to

provoke symptoms. Once provoked symptoms typically consist of angina, palpitations,

syncope, altered Q waves from ECG scans, reduced oxygen consumption and reduced

exercise tolerance. Mortality rates are between 1% and 2% for affected individuals, while

death rates in athletes are between 1 in 50000 and 1 in 200000, with Hypertrophic

cardiomyopathy rated as the number one cause of sudden death in young athletes.

For affected individuals, medical treatment should be the first option with beta

blockers and amiodarone being the most popular. If patients fail to respond to medical

intervention, surgical intervention in the form of a myectomy is considered the gold

standard, however an increasing number of medical practitioners are recommending

alcohol septal ablation, despite the increased risks.

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References

Brown, M. L., & Schaff, H. Z. (2008). Surgical management of obstructive hypertrophic cardiomyopathy the gold standard. Expert Reviews: Cardiovascular therapy, 6(5), 715-722.

Cambronero, F., Marin, F., Roldan, V., Hernandez-Romero, D., Valdes, M., & Lip, G. Y. (2009). Biomarkers of pathophysiology in hypertrophic cardiomyopathy: implications for clinical management and prognosis. European Heart Journal, 30(2), 139-151.

Corrado, D., Basso, C., Schiavon, M., & Thiene, G. (1998). Screening for Hypertrophic Cardiomyopathy in Young Athletes. New England Journal of Medicine, 339(6), 364-369.

Criley, J. M., & Siegel, R. J. (1986). Obstruction is unimportant in the pathophysiology of hypertrophic cardiomyopathy. Postgraduate Medical Journal, 62(728), 515-529.

Day, S. M. (2009). Exercise in Hypertrophic Cardiomyopathy. Journal of Cardiovascular Translational Research, 2(4), 407-414.

Elliot, P., & McKenna, W. J. (2004). Hypertrophic cardiomyopathy. Lancet, 363(9424), 1881-1891.

Frey, N., Luedde, M., & Katus, H. A. (2011). Mechanisms of disease: hypertrophic cardiomyopathy. Nature Reviews Cardiology, 9(2), 91.

Gao, C. Q., Ren, C. L., Xiao, C. S., Wu, Y., Wang, G., Liu, G. P., & Wang, Y. (2012). Surgical treatment with modified Morrow procedure in hypertrophic obstructive cardiomyopathy. Chinese Journal of Surgery, 50(5), 434-437.

Geske, J. B., Klarich, K. W., Ommen, S. R., Schaff, H. V., & Nishimura, R. A. (2014). Septal reduction therapies in hypertrophic cardiomyopathy: comparison of surgical septal myectomy and alcohol septal ablasion. interventional cardiology, 6(2), 199-215.

Hudzik, B., & Zubelewicz-Szkodzinska, B. (2014). Amiodarone-related thyroid dysfunction. internal and emergency medicine, 9(8), 829-839.

Maron, B. J., & Maron, M. S. (2013). Hypertrophic cardiomyopathy. Lancet, 350(9071), 127-133.

Masry, H., & Breall, J. (2008). Alcohol Septal Ablation for Hypertrophic Obstructive Cardiomyopathy. current cardiology reviews, 4(3), 193-197.

Popjes, E. D., & Martin, J. S. (2003). Hypertrophic cardiomyopathy: pathophysiology, diagnosis, and treatment. Geriatrics, 58(3), 41.

Prasad, K., & Frenneaux, M. P. (1998). Hypertrophic cardiomyopathy: is there a role for amiodarone? Heart, 79(4), 317-318.

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Said, S. M., Dearani, J. A., Ommen, S. R., & Schaff, H. V. (2013). Surgical treatment of hypertrophic cardiomyopathy. Expert review of cardiovascular therapy, 11(5), 617-627.

Shin, J., & Johnson, J. A. (2007). Pharmacogenetics of Beta-Blockers. pharmacotherapy, 27(6), 874.

Varma, P., & Neema, P. (2014). Hypertrophic cardiomyopathy Part 1 - Introduction, pathology and pathophysiology. Annals of Cardiac Anaesthesia, 17(2), 118.

Yunhu, S. (2014). Outcome of patients with hypertrophic obstructive cardiomyopathy after modified Morrow procedure: A single center experience in China. Journal of the American College of Cardiology, 64(16), 196.

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