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==Overview==
==Overview==
[[Cardiomyopathy|Cardiomyopathies]] are defined as a heterogeneous group of diseases of the heart associated with a mechanical and/or electrical dysfunction that usually (but not always) exhibit inappropropriate [[ventricular hypertrophy]] or [[dilation]] and are due to a variety of causes that frequently are [[genetic]]. Phenotypic characteristics typically include [[ventricular chamber enlargement]] and [[systolic dysfunction]] with normal [[wall thickness]]. Patients with dilated cardiomyopathy may experience a progressive decline in left ventricular [[contractile function]], ventricular and supraventricular [[arrhythmias]], [[conduction system]] problems, [[thromboembolism]], [[sudden cardiac death]] and/or [[heart failure]].<ref name="pmid16567565">{{cite journal| author=Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D et al.| title=Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. | journal=Circulation | year= 2006 | volume= 113 | issue= 14 | pages= 1807-16 | pmid=16567565 | doi=10.1161/CIRCULATIONAHA.106.174287 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16567565 }} </ref> Dilated cardiomyopathy is the third most common cause of [[heart failure]].
[[Cardiomyopathy|Cardiomyopathies]] are defined as a heterogeneous group of diseases of the heart associated with a mechanical and/or electrical dysfunction that usually (but not always) exhibit inappropropriate [[ventricular hypertrophy]] or [[dilation]] and are due to a variety of causes that frequently are [[genetic]]. Phenotypic characteristics typically include [[ventricular chamber enlargement]] and [[systolic dysfunction]] with normal [[wall thickness]]. Patients with dilated cardiomyopathy may experience a progressive decline in left ventricular [[contractile function]], ventricular and supraventricular [[arrhythmias]], [[conduction system]] problems, [[thromboembolism]], [[sudden cardiac death]] and/or [[heart failure]]. Dilated cardiomyopathy is the third most common cause of [[heart failure]].


==Pathophysiology==
==Pathophysiology==

Revision as of 12:10, 30 December 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sachin Shah, M.D., Jennifer Hall Abdelrahman Ibrahim Abushouk, MD[2]

Overview

Cardiomyopathies are defined as a heterogeneous group of diseases of the heart associated with a mechanical and/or electrical dysfunction that usually (but not always) exhibit inappropropriate ventricular hypertrophy or dilation and are due to a variety of causes that frequently are genetic. Phenotypic characteristics typically include ventricular chamber enlargement and systolic dysfunction with normal wall thickness. Patients with dilated cardiomyopathy may experience a progressive decline in left ventricular contractile function, ventricular and supraventricular arrhythmias, conduction system problems, thromboembolism, sudden cardiac death and/or heart failure. Dilated cardiomyopathy is the third most common cause of heart failure.

Pathophysiology

Physiology

The normal physiology of myocardium can be understood as follows:

  • The myocardium is composed of specialized cardiac muscle cells with an ability not possessed by muscle tissue elsewhere in the body. Cardiac muscle, like other muscles, can contract, but it can also carry an action potential (i.e. conduct electricity), like the neurones that constitute nerves.
  • The cardiac myocyte is a specialized muscle cell, which is composed of bundles of myofibrils that contain myofilaments. The myofibrils have distinct micro-anatomical units, called "sarcomeres", which are considered as the basic contractile units of the cardiac cell. The sarcomere is defined as the region of myofilament structures between two Z-lines. The distance between Z-lines ranges between 1.6 and 2.2 μ. The sarcomere is composed of thick (myosin) and thin (actin) filaments. The chemical and physical interactions between the actin and myosin shortens the sarcomere length and the myocyte to contract during the process of excitation-contraction coupling, which is known as the "sliding filament theory of muscle contraction".[1]
Figure. Sarcomere, pictured with component proteins actin, myosin, titin, etc.

Pathogenesis

Dilated cardiomyopathy usually results from a failed physiological response to myocyte injury. Mocyte injury can generally end in one of three outcomes: Immediate myocyte cell death, delayed myocyte cell death (apoptosis), or pathological compensatory response.[2] The third outcome usually results in a cycle that occurs as follows:

  • Myocyte injury
  • Hypertrophy of the remaining myocytes to increased wall stress
  • Hyperadrenergic response
  • Dynamic remodeling of the interstitial myocardial skeleton (e.g. fibrosis).
  • Reduced diastolic function and increased ventricular dilatation.
  • Distortion of valvular apparatus
  • Increased ventricular afterload
  • Initiating the process of heart failure that causes more myocyte injury.[3]

Genetics

Our understanding of the role of genetics in dilated cardiomyopathy continues to grow. Inherited familial dilated cardiomyopathy has been associated with 50 mutations in genes encoding cytoskeletal, nucleoskeletal, mitochondrial and calcium handling proteins.[4] These mutations are listed below.

Genes Encoding Plasma Membrane Proteins

Gene Abbreviation
Laminin alpha 4 LAMA4[5]
Sarcoglycan delta SGCD[6][7]

Genes Encoding Cytoskeletal Proteins

Gene Abbreviation
Actin, alpha, cardiac muscle 1 ACTC1[8]
Actinin, alpha 2 ACTN2[9]
Ankyrin repeat domain 1 ANKRD1[10]
BCL2-associated athanogene 3 BAG3[11]
Cardiotropin CTF1[12]
Cysteine and glycine-rich protein 3 CSRP3[9]
Desmin DES[13] [14]
Desmoplakin DSP[15][16][17]
DNAJ (Hsp40) homology, subfamily C, member 19 DNAJC19[18]
Dystrophin DMD[19][20][21][22][23][24][25]
Eyes absent homology 4 EYA4[26]

[27]

Four and a half LIM domains 2 FHL2[28]
Fukutin FKTN[29]
Lysosomal-associated membrane protein 2 LAMP2[30]
LIM domain binding 3 LDB3[31][32][33][34]
Myosin binding protein C, cardiac MYBPC3[35]
Myosin, heavy chain 6, cardiac muscle, alpha MYH6[36]
Myosin, heavy chain 7, cardiac muscle, alpha MYH7[37]|

[38]

Nexilin (F actin binding protein) NEXN[39]
Presenilin 1 PSEN1[40]
Presenilin 2 PSEN2[40]
RNA binding motif protein 20 RBM20[41][42]
Sarcoglycan alpha SGCD[6][7]
Sodium channel, volatage-gated, type V, alpha subunit SCN5A[34][43][44][45][46][47]
Tafazzin TAZ[48][49]
Thymopoietin TMPO[50]
Troponin C type 1 (slow) TNNC1[51]
Troponin I type 3 (cardiac) TNNI3[52][53]
Troponin T type 2 (cardiac) TNNT2[38][54][51][55][56][57][58]
Tropomyosin 1 (alpha) TPM1[59][60]
Titin TTN[61][62][63]
Vinculin VCL[64][65]

Genes Encoding Calcium Handling Proteins

Gene Abbreviation
Phospholamban PLN[66][67][68][69][70][71][72][73]

Genes Encoding Mitochondrial Proteins

Gene Abbreviation
Succinate dehydrogenase complex, subunit A, flavoprotein SDHA[74]

Genes Encoding Nuclear Proteins

Gene Abbreviation
ATP-binding cassette, sub-family C, member 9 ABCC9[75]
Lamin A/C LMNA[76][77][78][79][80][81][82][83]
Spectrin repeat containing, nuclear envelope 2 SYNE2[84]

The increase in whole exome and whole genome sequencing has significantly increased the number of rare variants that are associated with dilated cardiomyopathy [4]. A challenge in the field today is that many individuals without disease carry rare variants in their genome. Thus the task at hand is not in the sequencing but rather in the translation to define if the rare variants discovered are in fact pathophysiologic in nature. Secondly, evidence is accumulating that many patients with dilated cardiomyopathy may have many different mutations that contribute to or modify disease. [85]

Associated Conditions

A review of systems is also helpful in regards to connective tissue disease associated dilated cardiomyopathy. Some of the disease that can be associated with dilated cardiomyopathy are:

Gross Pathology

On gross pathological examination, the heart may show

  • Globular heart (markedly dilated ventricles > 4 cm at the level of papillary muscles)
  • Patchy fibrosis in the epicardium
  • Endocardial thickening (Cardiac fibroelastosis)
  • Ballooning of valve leaflets into the atria
  • Few patients show left ventricular non-compaction or minimally dilated ventricles.

Images shown below are Courtesy of Professor Peter Anderson DVM PhD and published with permission. © PEIR, University of Alabama at Birmingham, Department of Pathology

Microscopic Pathology

On microscopic pathological examination, the heart may show

  • Variations in myocyte size
  • Interstitial fibrosis
  • Myofiber disarray
  • Transmural scars may be present.
  • Further, microscopic examination can verify the underlying cause as inflammation, amyloid, iron, and granulomas

References

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