Hypertrophic cardiomyopathy pathophysiology
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Hypertrophic Cardiomyopathy Microchapters |
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Differentiating Hypertrophic Cardiomyopathy from other Diseases |
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Hypertrophic cardiomyopathy pathophysiology On the Web |
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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] Lakshmi Gopalakrishnan, M.B.B.S. [3]
Overview
The exact pathogenesis of Hypertrophic cardiomyopathy is not fully understood.
OR
It is thought that Hypertrophic cardiomyopathy is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
OR
[Pathogen name] is usually transmitted via the [transmission route] route to the human host.
OR
Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
OR
[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
OR
The progression to Hypertrophic cardiomyopathy usually involves the [molecular pathway].
OR
The pathophysiology of [disease/malignancy] depends on the histological subtype.
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 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).
Pathophysiology
Physiology
The normal physiology of [name of process] can be understood as follows:
Pathogenesis
- The exact pathogenesis of Hypertrophic cardiomyopathy is not completely understood.
OR
- It is understood that Hypertrophic cardiomyopathy is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
- [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
- Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
- [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
- The progression to Hypertrophic cardiomyopathy usually involves the [molecular pathway].
- The pathophysiology of [disease/malignancy] depends on the histological subtype.
Genetics
Hypertrophic cardiomyopathy is transmitted in an autosomal dominant pattern. Genes involved in the pathogenesis of Hypertrophic cardiomyopathy include:
- [Gene1]
- [Gene2]
- [Gene3]
The development of Hypertrophic cardiomyopathy is the result of multiple genetic mutations such as:
- [Mutation 1]
- [Mutation 2]
- [Mutation 3]
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 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. 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 superimposed effects of other genes or environmental influences. Children of a patient with HCM have a 50% chance of inheriting the trait.
Mutations
Common Mutations
Mutations in three regions affect more than half the patients with HCM:
- Beta-myosin heavy chain
- Myosin binding protein C
- Cardiac troponin T
Complete List of Mutations
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 beta-cardiac myosin heavy chain (the first gene identified), cardiac actin, cardiac troponin T, alpha-tropomyosin, cardiac troponin I, cardiac myosin-binding protein C, and the myosin light chains. Specific gene mutations that have been identified include the following:
| Gene | Locus | Type |
|---|---|---|
| MYH7 | 14q12 | CMH1 |
| TNNT2 | 1q32 | CMH2 |
| TPM1 | 15q22.1 | CMH3 (115196) |
| MYBPC3 | 11p11.2 | CMH4 (115197) |
| ? | ? | CMH5 |
| PRKAG2 | 7q36 | CMH6 (600858) |
| TNNI3 | 19q13.4 | CMH7 |
| MYL3 | 3p | CMH8 (608751) |
| TTN | 2q24.3 | CMH9 |
| MYL2 | 12q23-q24 | CMH10 |
| ACTC1 | 15q14 | CMH11 (612098) |
| CSRP3 | 11p15.1 | CMH12 (612124) |
While the above table represents the most common genetic mutations, there are also about 200 intergenic (within a gene) mutations. These include missense and single amino acid residue substitutions. There are different genetic mutations in different families. The environment may also play a role because affected individuals in the same family may have a different phenotypic expression (i.e different degrees of left ventricular hypertrophy). The goal of modifier genes in regulating phenotypic expression is not clear.
While genes, gene modifiers, and environment may play a role in the phenotypic expression of left ventricular hypertrophy, genes may also play a role in the risk of arrhythmias. 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.
Specific Chromosomal Abnormalities
β Myosin Heavy Chain-Chromosome 14 q11.2-3
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. This chromosomal abnormality accounts for approximately 35%-45% of HCM cases. Significant LVH (left ventricular hypertrophy) is usually present. The Arg403Gln mutation is associated with an extremely poor prognosis with an average age of death at 33 years, while the Val606Met mutation is associated with a better prognosis.
Cardiac Troponin T-Chromosome 11
Accounts for approximately 15% of cases. Substantially less hypertrophy is noted but histology demonstrates the characteristic myocyte disarray of HCM. Most mutations of this gene are associated with markedly reduced survival.
Cardiac Myosin Binding Protein-C-Chromosome 11
This chromosomal abnormality accounts for 15% to 35% of patients, but given the reduced penetrance associated with this abnormality, the true incidence may actually be greater. Patients generally present later in life and in general, have a better prognosis than beta myosin heavy chain or cardiac troponin T mutations. Up to 60% of patients at age 50 years have no evidence of LVH. LVH may appear later in life in these patients. Because of this, a normal EKG and a normal ECHO at age 18 does not exclude the presence of HCM.
Arg663 His mutation
The beta-myosin heavy chain Arg663 His mutation is associated with a higher risk of atrial fibrillation [16].
PRKAG2 Mutation
There is no myocyte disarray, but the conduction block is present. This variant is more akin to a storage disease[17].
Mutations that Alter the Phenotypic Expression of the Disease
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 [18] [19].
Genetic Testing
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.
Outflow Obstruction
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).
Location Of The Left Ventricular Outflow Obstruction
The left ventricular obstruction can be either
- Mid-cavitary: the middle of the ventricle or
- Sub-aortic: just below the aortic valve
Classification of the Valve Gradient in Hypertrophic Cardiomyopathy
The valve gradient in HCM can be classified into three categories:
- A gradient greater than 30 mm Mercury under basal conditions
- A gradient that is greater than 30 mm Mercury with provocation
- A gradient that is less than 30 mm Mercury at rest and with provocation
Maneuvers that Increase the Outflow Gradient
- Amyl nitrite inhalation
- Valsalva maneuver
- Premature ventricular contractions (PVCs)
- Isoproterenol infusion
- Dobutamine infusion; but this is not recommended as a diagnostic tool[20][21]
- Treadmill or exercise stress testing
Causes of Left Ventricular Outflow Obstruction: Systolic Anterior Motion of the Mitral Valve (SAM)
If dynamic outflow obstruction is present in a patient with HCM, it is usually due to systolic anterior motion (SAM) of the anterior leaflet of the mitral valve. The systolic anterior motion of the mitral valve (SAM) may be due to a subaortic bulge of the septum along with narrowing the left ventricular outflow tract, which taken together cause high-velocity flow. This, in turn, is associated with the Venturi effect which is a local low-pressure zone in the left ventricular outflow tract. This low-pressure zone was thought to suck the mitral valve anteriorly into the septum. More recently, however, SAM onset has been observed to be instead a low-velocity phenomenon. [22] [23]. The role of Venturi forces in the left ventricular outflow tract may be less important than previously thought. While the Venturi effect was thought to cause the abnormality in prior studies, more recent echocardiographic studies indicates that drag, which is more of a pushing force rather than a sucking force like the Venturi effect, maybe the dominant hydrodynamic force acting on the mitral leaflets [22][23][24][25][26] [27].
The videos below show examples of systolic anterior motion of the mitral valve:
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Impact of Systolic Anterior Motion of the Mitral Valve: The Spike and Dome Pattern to the Carotid Pulse
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 pressure will be normal. When the mitral valve leaflet gets pushed into the LVOT, the arterial pulse will momentarily collapse and will later be followed by a second rise in the pulse pressure, as the left ventricular pressure overcomes the increased obstruction caused by the SAM of the mitral valve. 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 or a "spike and dome pattern" to the carotid pulse.
Accompanying Mitral Regurgitation
As a result of the drag effect or the Venturi effect, there may be mild to moderate mitral regurgitation in association with hypertrophic cardiomyopathy. Most often the mitral regurgitation jet is directed posteriorly. If the jet is not directed posteriorly then other diagnoses should be considered which include myxomatous degeneration or other anomalies of the mitral valve.
Pathophysiologic Consequences of Outflow Obstruction
Chronic outflow obstruction and result in the following abnormalities[28][29]:
- Increased left ventricular wall stress
- Myocardial ischemia
- Myocardial necrosis
- Replacement fibrosis
Prognostic Significance of Outflow Obstruction
The presence of outflow obstruction is associated with a twofold increased risk of death and a 4.4 fold increase in the risk of progression to New York Heart Association class III or IV heart failure [30][31]. Above a gradient of 30 mm Hg, there was no further increase in the risk of sudden cardiac death or progression of congestive heart failure symptoms[32].
Associated Conditions
Conditions associated with Hypertrophic cardiomyopathy include:
- [Condition 1]
- [Condition 2]
- [Condition 3]
Gross Pathology
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of Hypertrophic cardiomyopathy.
Microscopic Pathology
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of Hypertrophic cardiomyopathy.
References
- ↑ Maron BJ, Moller JH, Seidman CE et al. Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases. Hypertrophic cardiomyopathy, long-QT syndrome, and Marfan syndrome. [A statement for healthcare professionals from the Councils on Clinical Cardiology, Cardiovascular Disease in the Young, and Basic Science, American Heart Association]. Circulation 1998;98:1460–71.
- ↑ Schwartz K, Carrier L, Guicheney P, Komajda M. Molecular basis of familial cardiomyopathies. Circulation 1995;91:532–40.
- ↑ Niimura H, Bachinski LL, Sangwatanaroj S et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 1998;338:1248–57.
- ↑ Thierfelder L, Watkins H, MacRae C et al. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy. A disease of the sarcomere. Cell 1994;77:701–12.
- ↑ Watkins H, McKenna WJ, Thierfelder L et al. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy. N Engl J Med 1995;332:1058–64.
- ↑ Charron P, Dubourg O, Desnos M et al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin-binding protein C gene. Circulation 1998;97: 2230–6.
- ↑ Maron BJ, Niimura H, Casey SA et al. Development of left ventricular hypertrophy in adults in hypertrophic cardiomyopathy caused by cardiac myosin-binding protein C gene mutations. J Am Coll Cardiol 2001;38:315–21.
- ↑ Anan R, Greve G, Thierfelder L et al. Prognostic implications of novel beta cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J Clin Invest 1994;93:280–5.
- ↑ Coviello DA, Maron BJ, Spirito P et al. Clinical features of hypertrophic cardiomyopathy caused by mutation of a “hot spot” in the alpha-tropomyosin gene. J Am Coll Cardiol 1997;29:635–40.
- ↑ Blair E, Redwood C, Ashrafian H et al. Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy. Evidence for the central role of energy compromise in disease pathogenesis. Hum Mol Genet 2001;10:1215–20.
- ↑ Erdmann J, Raible J, Maki-Abadi J et al. Spectrum of clinical phenotypes and gene variants in cardiac myosin-binding protein C mutation carriers with hypertrophic cardiomyopathy. J Am Coll Cardiol 2001;38:322–30.
- ↑ Gruver EJ, Fatkin D, Dodds GA et al. Familial hypertrophic cardiomyopathy and atrial fibrillation caused by Arg663His beta-cardiac myosin heavy chain mutation. Am J Cardiol 1999;83:13H–8H.
- ↑ Kimura A, Harada H, Park JE et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet 1997;16:379–82.
- ↑ Marian AJ, Roberts R. Recent advances in the molecular genetics of hypertrophic cardiomyopathy. Circulation 1995;92:1336–47.
- ↑ Niimura H, Patton KK, McKenna WJ et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation 2002;105:446–51.
- ↑ Seidman JG, Seidman CE. The genetic basis for cardiomyopathy. From mutation identification to mechanistic paradigms. Cell 2001; 104:557–67.
- ↑ Arad M, Benson DW, Perez-Atayde AR et al. Constitutively active AMP kinase mutations cause glycogen storage disease mimicking hypertrophic cardiomyopathy. J Clin Invest 2002;109:357–62.
- ↑ Doolan G, Nguyen L, Chung J, Ingles J, Semsarian C. Progression of left ventricular hypertrophy and the angiotensin-converting enzyme gene polymorphism in hypertrophic cardiomyopathy. Int J Cardiol. 2004 Aug; 96(2):157–63. (Medline abstract)
- ↑ Marian AJ, Yu QT, Workman R, Greve G, Roberts R. Angiotensin-converting enzyme polymorphism in hypertrophic cardiomyopathy and sudden cardiac death. Lancet. 1993 Oct 30; 342(8879):1085–6. (Medline abstract)
- ↑ Pellikka PA, Oh JK, Bailey KR, Nichols BA, Monahan KH, Tajik AJ. Dynamic intraventricular obstruction during dobutamine stress echocardiography. A new observation. Circulation 1992;86:1429–32.
- ↑ Okeie K, Shimizu M, Yoshio H et al. Left ventricular systolic dysfunction during exercise and dobutamine stress in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2000;36:856–63.
- ↑ 22.0 22.1 Jiang L, Levine RA, King ME, Weyman AE. An integrated mechanism for the systolic anterior motion of the mitral valve in hypertrophic cardiomyopathy based on echocardiographic observations. Am Heart J 1987; 113:633–44
- ↑ 23.0 23.1 Sherrid MV, Gunsburg DZ, Moldenhauer S, Pearle G. Systolic anterior motion begins at low left ventricular outflow tract velocity in obstructive hypertrophic cardiomyopathy. J Am Coll Cardiol 2000; 36:1344–54
- ↑ Sherrid MV, Chu Ck, DeLia E, Mogtader A, Dwyer Jr. EM, An echocardiographic study of the fluid mechanics of obstruction in hypertrophic cardiomyopathy. J Am Coll Cardiol 1993; 22:816–25
- ↑ Levine RA, Vlahakes GJ, Lefebvre X, et al. Papillary muscle displacement causes systolic anterior motion of the mitral valve. Circulation 1995; 91:1189–95
- ↑ Messmer BJ. Extended myectomy for hypertrophic obstructive cardiomyopathy. Ann Thorac Surg 1994; 58:575–7
- ↑ Schoendube FA, Klues HG, Reith S, Flachskampf FA, Hanrath P, Messmer BJ. Long-term clinical and echocardiographic follow-up after surgical correction of hypertrophic obstructive cardiomyopathy with extended myectomy and reconstruction of the subvalvular mitral apparatus. Circulation 1995; 92:II-122–7
- ↑ Maron MS, Olivotto I, Betocchi S et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003;348:295–303.
- ↑ Choudhury L, Mahrholdt H, Wagner A et al. Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol 2002;40:2156–64.
- ↑ Maron MS, Olivotto I, Betocchi S et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003;348:295–303.
- ↑ Kofflard MJ, Ten Cate FJ, van der Lee C, van Domburg RT. Hypertrophic cardiomyopathy in a large community-based population. Clinical outcome and identification of risk factors for sudden cardiac death and clinical deterioration. J Am Coll Cardiol 2003;41:987–93.
- ↑ Maron MS, Olivotto I, Betocchi S et al. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med 2003;348:295–303.