Coxsackievirus-induced cardiomyopathy

Last updated
Coxsackievirus-induced cardiomyopathy
Specialty Cardiology

Coxsackieviruses-induced cardiomyopathy are positive-stranded RNA viruses in picornavirus family and the genus enterovirus, acute enterovirus infections such as Coxsackievirus B3 have been identified as the cause of virally induced acute myocarditis, resulting in dilated cardiomyopathy. [1] Dilated cardiomyopathy in humans can be caused by multiple factors including hereditary defects in the cytoskeletal protein dystrophin in Duchenne muscular dystrophy (DMD) patients). A heart that undergoes dilated cardiomyopathy shows unique enlargement of ventricles, and thinning of the ventricular wall that may lead to heart failure. In addition to the genetic defects in dystrophin or other cytoskeletal proteins, a subset of dilated cardiomyopathy is linked to enteroviral infection in the heart, especially coxsackievirus B. Enterovirus infections are responsible for about 30% of the cases of acquired dilated cardiomyopathy in humans. [2]

Contents

Cause

Coxsackievirus shows a cardiac tropism partly due to the high expression of coxsackievirus and adenovirus receptors (CAR) in cardiomyocytes. [3] Coxsackievirus B genome is approximately 7.4 Kb and translated as a polycistronic polyprotein. Upon translation, the polyprotein is cleaved by two essential viral proteases, 2A and 3C. The viral protease 2A cleaves the proteins in a sequence specific manner. These viral proteases can also act on host proteins exerting negative effects on the residing cell. Enteroviral protease 2A can cleave the cytoskeletal dystrophin protein in cardiomyocytes disrupting the dystrophin glycoprotein (DCG) complex. The cleavage site of dystrophin by protease 2A occurs in the hinge 3 region of the protein resulting a disruption of DCG complex and loss of sarcolemma integrity and increasing myocyte permeability. This eventually results in similar cardiac deformities observed in dilated cardiomyopathy caused by hereditary defects in dystrophin in DMD patients. Additionally, dystrophin deficiency has been shown to increase the severity in dilated cardiomyopathy in a mouse model for DMD. The increased susceptibility of dystrophin deficient heart to coxsackievirus-induced dilated cardiomyopathy is attributed to more efficient release of the virus from infected cells resulting an increase in viral-mediated cytopathic effects. [4]

Viral-induced dilated cardiomyopathy can be characterized using different methods. A 2011 study showed in coxsackievirus infected heart proteome, increased levels of fibrotic extracellular matrix proteins and reduced amounts of energy-producing enzymes can be observed suggesting they could be characteristic in enteroviral cardiomyopathy. [5]

There are notable differences between the hereditary dilated cardiomyopathy in DMD and acute coxsackieviral-mediated cardiomyopathy. [6]

  1. The amount of virally infected cardiomyocytes varies in different stages of the disease. In a mouse model, at the acute stage (7 days after infection with coxsackievirus B3) approximately 10% of the myocytes are infected and could affect overall cardiac function. In chronic murine infection, the percentage of infected cardiomyocytes are much lower.
  2. Unlike in the DMD, in coxsackievirus induced cardiomyopathy, acute cleavage of dystrophin in cardiomyocytes is unlikely to induce any prompt compensatory mechanism since host cell translation mechanism is defective in the infected cells.

Treatment

A wide variety of treatment modalities are currently recommended including Immunosuppressive agents, intravenous immunoglobulins (IVIG), and antiviral agents although the effectiveness of these treatments are not well established and no specific treatment is available. [7]

Related Research Articles

<span class="mw-page-title-main">Coxsackie A virus</span> Virus that causes digestive upset and sometimes heart damage

Coxsackie A virus (CAV) is a cytolytic Coxsackievirus of the Picornaviridae family, an enterovirus.

Coxsackie B4 virus are enteroviruses that belong to the Picornaviridae family. These viruses can be found worldwide. They are positive-sense, single-stranded, non-enveloped RNA viruses with icosahedral geometry. Coxsackieviruses have two groups, A and B, each associated with different diseases. Coxsackievirus group A is known for causing hand-foot-and-mouth diseases while Group B, which contains six serotypes, can cause a varying range of symptoms like gastrointestinal distress myocarditis. Coxsackievirus B4 has a cell tropism for natural killer cells and pancreatic islet cells. Infection can lead to beta cell apoptosis which increases the risk of insulitis.

<span class="mw-page-title-main">Coxsackievirus</span> Virus that causes digestive upset and sometimes heart damage

Coxsackieviruses are a few related enteroviruses that belong to the Picornaviridae family of nonenveloped, linear, positive-sense single-stranded RNA viruses, as well as its genus Enterovirus, which also includes poliovirus and echovirus. Enteroviruses are among the most common and important human pathogens, and ordinarily its members are transmitted by the fecal–oral route. Coxsackieviruses share many characteristics with poliovirus. With control of poliovirus infections in much of the world, more attention has been focused on understanding the nonpolio enteroviruses such as coxsackievirus.

<span class="mw-page-title-main">Coxsackie B virus</span> Virus that causes digestive upset and sometimes heart damage

Coxsackie B is a group of six serotypes of coxsackievirus (CVB1-CVB6), a pathogenic enterovirus, that trigger illness ranging from gastrointestinal distress to full-fledged pericarditis and myocarditis.

<span class="mw-page-title-main">Cardiac muscle</span> Muscular tissue of heart in vertebrates

Cardiac muscle is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall of the heart. The cardiac muscle (myocardium) forms a thick middle layer between the outer layer of the heart wall and the inner layer, with blood supplied via the coronary circulation. It is composed of individual cardiac muscle cells joined by intercalated discs, and encased by collagen fibers and other substances that form the extracellular matrix.

<span class="mw-page-title-main">Dilated cardiomyopathy</span> Medical condition

Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Complications can include heart failure, heart valve disease, or an irregular heartbeat.

<i>Enterovirus</i> Genus of viruses

Enterovirus is a genus of positive-sense single-stranded RNA viruses associated with several human and mammalian diseases. Enteroviruses are named by their transmission-route through the intestine.

The genome and proteins of HIV (human immunodeficiency virus) have been the subject of extensive research since the discovery of the virus in 1983. "In the search for the causative agent, it was initially believed that the virus was a form of the Human T-cell leukemia virus (HTLV), which was known at the time to affect the human immune system and cause certain leukemias. However, researchers at the Pasteur Institute in Paris isolated a previously unknown and genetically distinct retrovirus in patients with AIDS which was later named HIV." Each virion comprises a viral envelope and associated matrix enclosing a capsid, which itself encloses two copies of the single-stranded RNA genome and several enzymes. The discovery of the virus itself occurred two years following the report of the first major cases of AIDS-associated illnesses.

<i>Pestivirus</i> Genus of viruses

Pestivirus is a genus of viruses, in the family Flaviviridae. Viruses in the genus Pestivirus infect mammals, including members of the family Bovidae and the family Suidae. There are 11 species in this genus. Diseases associated with this genus include: hemorrhagic syndromes, abortion, and fatal mucosal disease.

<span class="mw-page-title-main">Costamere</span>

The costamere is a structural-functional component of striated muscle cells which connects the sarcomere of the muscle to the cell membrane.

Group-specific antigen, or gag, is the polyprotein that contains the core structural proteins of an Ortervirus. It was named as such because scientists used to believe it was antigenic. Now it is known that it makes up the inner shell, not the envelope exposed outside. It makes up all the structural units of viral conformation and provides supportive framework for mature virion.

Visna-maedi virus from the genus Lentivirus and subfamily Orthoretrovirinae, is a retrovirus that causes encephalitis and chronic pneumonitis in sheep. It is known as visna when found in the brain, and maedi when infecting the lungs. Lifelong, persistent infections in sheep occur in the lungs, lymph nodes, spleen, joints, central nervous system, and mammary glands; The condition is sometimes known as ovine progressive pneumonia (OPP), particularly in the United States, or Montana sheep disease. White blood cells of the monocyte/macrophage lineage are the main target of the virus.

<span class="mw-page-title-main">Coxsackievirus and adenovirus receptor</span> Protein-coding gene in the species Homo sapiens

Coxsackievirus and adenovirus receptor (CAR) is a protein that in humans is encoded by the CXADR gene. The protein encoded by this gene is a type I membrane receptor for group B coxsackie viruses and subgroup C adenoviruses. CAR protein is expressed in several tissues, including heart, brain, and, more generally, epithelial and endothelial cells. In cardiac muscle, CAR is localized to intercalated disc structures, which electrically and mechanically couple adjacent cardiomyocytes. CAR plays an important role in the pathogenesis of myocarditis, dilated cardiomyopathy, and in arrhythmia susceptibility following myocardial infarction or myocardial ischemia. In addition, an isoform of CAR (CAR-SIV) has been recently identified in the cytoplasm of pancreatic beta cells. It's been suggested that CAR-SIV resides in the insulin secreting granules and might be involved in the virus infection of these cells.

<span class="mw-page-title-main">Delta-sarcoglycan</span> Mammalian protein found in Homo sapiens

Delta-sarcoglycan is a protein that in humans is encoded by the SGCD gene.

Mayaro virus disease is a mosquito-borne zoonotic pathogen endemic to certain humid forests of tropical South America. Infection with Mayaro virus causes an acute, self-limited dengue-like illness of 3–5 days' duration. The causative virus, abbreviated MAYV, is in the family Togaviridae, and genus Alphavirus. It is closely related to other alphaviruses that produce a dengue-like illness accompanied by long-lasting arthralgia. It is only known to circulate in tropical South America.

sCAR-Fc is an experimental prophylactic treatment against coxsackievirus B3 (CVB) infections. Coxsackievirus B3 can cause cardiac damage, eventually resulting in a weakened and enlarged heart that is termed dilated cardiomyopathy. While many other treatments inhibit viral proliferation in myocytes, sCAR-Fc prevents the virus entering the cell by competitively binding to coxsackie virus and adenovirus receptors (CAR) on the membrane of myocytes.

<span class="mw-page-title-main">Picornain 3C</span>

Picornain 3C is a protease found in picornaviruses, which cleaves peptide bonds of non-terminal sequences. Picornain 3C’s endopeptidase activity is primarily responsible for the catalytic process of selectively cleaving Gln-Gly bonds in the polyprotein of poliovirus and with substitution of Glu for Gln, and Ser or Thr for Gly in other picornaviruses. Picornain 3C are cysteine proteases related by amino acid sequence to trypsin-like serine proteases. Picornain 3C is encoded by enteroviruses, rhinoviruses, aphtoviruses and cardioviruses. These genera of picoviruses cause a wide range of infections in humans and mammals.

Viral cardiomyopathy occurs when viral infections cause myocarditis with a resulting thickening of the myocardium and dilation of the ventricles. These viruses include Coxsackie B and adenovirus, echoviruses, influenza H1N1, Epstein–Barr virus, rubella, varicella, mumps, measles, parvoviruses, yellow fever, dengue fever, polio, rabies and the viruses that cause hepatitis A and C, as well as COVID-19, which has been seen to cause this in persons otherwise thought to have a "low risk" of the virus's effects.

Heart problems are more common in people with HIV/AIDS. Those with left ventricular dysfunction have a median survival of 101 days as compared to 472 days in people with AIDS with healthy hearts. HIV is a major cause of cardiomyopathy. The most common type of HIV induced cardiomyopathy is dilated cardiomyopathy also known as eccentric ventricular hypertrophy which leads to impaired contraction of the ventricles due to volume overload. The annual incidence of HIV associated dilated cardiomyopathy was 15.9/1000 before the introduction of highly active antiretroviral therapy (HAART). However, in 2014, a study found that 17.6% of HIV patients have dilated cardiomyopathy (176/1000) meaning the incidence has greatly increased.

Dystrophinopathy refers to a spectrum of diseases due to mutations in the DMD gene, which encodes for the dystrophin protein found in muscle. The severe end of the spectrum includes Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and DMD-associated dilated cardiomyopathy. The mild end of the spectrum includes asymptomatic increases in serum creatine kinase and muscle cramps with myoglobinuria. Because dystrophin is located on the X chromosome, dystrophinopathy mainly affects males, whereas females range from being carriers, to having delayed-onset and mild disease, to having severe DMD.

References

  1. ↑ Badorff, C; Lee, G. H.; Knowlton, K. U. (2000). "Enteroviral cardiomyopathy: bad news for the dystrophin-glycoprotein complex". Herz. 25 (3): 227–32. doi:10.1007/s000590050011. PMID   10904843. S2CID   25973717.
  2. ↑ Badorff, C; Lee, G. H.; Lamphear, B. J.; Martone, M. E.; Campbell, K. P.; Rhoads, R. E.; Knowlton, K. U. (1999). "Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy". Nature Medicine. 5 (3): 320–6. doi:10.1038/6543. PMID   10086389. S2CID   9309488.
  3. ↑ Knowlton, KU (2008). "CVB infection and mechanisms of viral cardiomyopathy". Curr Top Microbiol Immunol. Current Topics in Microbiology and Immunology. 323: 315–35. doi:10.1007/978-3-540-75546-3_15. ISBN   978-3-540-75545-6. PMID   18357777.
  4. ↑ Xiong, D; Lee, G.-H.; Badorff, C.; Dorner, A.; Lee, S.; Wolf, P.; Knowlton, K. U. (2002). "Dystrophin deficiency markedly increases enterovirus-induced cardiomyopathy: a genetic predisposition to viral heart disease". Nature Medicine. 8 (8): 872–7. doi:10.1038/nm737. PMID   12118246. S2CID   5832584.
  5. ↑ Nishtala, K; Phong, T. Q.; Steil, L.; Sauter, M.; Salazar, M. G.; Kandolf, R.; Kroemer, H. K.; Felix, S. B.; Völker, U.; Klingel, K.; Hammer, E. (2011). "Virus-induced dilated cardiomyopathy is characterized by increased levels of fibrotic extracellular matrix proteins and reduced amounts of energy-producing enzymes". Proteomics. 11 (22): 4310–4320. doi:10.1002/pmic.201100229. PMID   21954127. S2CID   5339376.
  6. ↑ Badorff, C; Lee, G. H.; Knowlton, K. U. (2000). "Enteroviral cardiomyopathy: bad news for the dystrophin-glycoprotein complex". Herz. 25 (3): 227–32. doi:10.1007/s000590050011. PMID   10904843. S2CID   25973717.
  7. ↑ Brunetti, L; Desantis, E. R. H (2008). "Treatment of viral myocarditis caused by coxsackievirus B". American Journal of Health-System Pharmacy. 65 (2): 132–137. doi:10.2146/ajhp060586. PMID   18192257.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.