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Heart damage from hcv treatment?
I am posting this for two reasons. First, I am interested in this topic and secondly, I noticed that a web address I posted yesterday was disallowed by medhelp. So I am trying to see if this is a new "thing" or what.
http://circres.ahajournals.org/cgi/content/short/96/2/144
Cardiomyopathies may present as idiopathic dilated, hypertrophic, or restrictive disease, arrhythmogenic right ventricular cardiomyopathy (ARVC), and various other distinct disorders of the heart muscle.1 They constitute a heterogeneous group of myocardial diseases of multifactorial etiologies, including genetic anomalies and acquired immune factors, such as viral infections. The myocardium may be infected by a wide variety of viruses, although most commonly by enteroviruses, coxsackievirus B in particular. However, in many cases, when myocarditis has been diagnosed on the basis of clinical manifestations, a viral origin cannot be confirmed, despite extensive laboratory investigations.
The clinical presentation of viral myocarditis is variable. When myocardial necrosis is diffuse, congestive heart failure develops, and growing evidence now links viral myocarditis with dilated cardiomyopathy.2,3 Localized myocardial lesions may result in thinning or aneurysms of the ventricular wall which, in the case of ARVC, are complicated by arrhythmias.4 When myocardial necrosis is limited to the subendocardium, restrictive cardiomyopathy may develop. Finally, although it has not been established that hypertrophic cardiomyopathy is a complication of viral myocarditis, asymmetrical septal hypertrophy has been observed in some patients with myocarditis.5
A high prevalence of hepatitis C virus (HCV) infection has recently been noted in patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, and myocarditis (Figure 1).6–15 In this issue of Circulation Research, Omura et al16 report that mice transgenic for the HCV-core gene develop ventricular dilatation, cardiac dysfunction, and myocardial fibrosis at 12 months, similar to the pathological manifestations observed in human dilated cardiomyopathy. Although HCV infection may be the cause of several phenotypically different cardiomyopathies, mild inflammation with mononuclear cell infiltration has also been observed with HCV infection in humans.6,7,9 However, no lymphocytic infiltration was observed in these HCV-core transgenic mice. Furthermore, cardiomyocyte hypertrophy and disarray of the myofibers are typical characteristics of human hypertrophic cardiomyopathy, but the wall thickness of the HCV-core mice was not increased. Therefore, although the HCV-core mice did not have all the phenotypical manifestations of human cardiomyopathies, the observations made by Omura et al are nevertheless relevant, because they show that the expression of the HCV-core is associated with the long-term development of myocardial disease. They also found that the expression of atrial and brain natriuretic polypeptides was enhanced, and that activator protein-1 (AP-1) was activated in the heart. However, nuclear factor-B (NF-B) was not activated. The authors state that the activation of myocardial AP-1 by HCV-core is an important pathway toward cardiomyopathic changes, although it has not been shown that blocking this pathway changes the disease phenotype. Whereas AP-1 is activated in transgenic mice of HCV core protein,17 the latter interferes with the activation of AP-1 in human macrophages.18 Furthermore, HCV core protein inhibits AP-1,19 and activates extracellular signal-regulated kinase (ERK), C-jun N-terminal kinase (JNK), and p38 mitogen-activated protein (MAP) kinase.20 Although, HCV core protein is known to activate NF-B,21 the authors found no changes in NF-B. Therefore, further studies will be necessary to clarify the molecular pathogenetic changes observed in HCV-core transgenic mice.
http://circres.ahajournals.org/cgi/content/short/96/2/144
Cardiomyopathies may present as idiopathic dilated, hypertrophic, or restrictive disease, arrhythmogenic right ventricular cardiomyopathy (ARVC), and various other distinct disorders of the heart muscle.1 They constitute a heterogeneous group of myocardial diseases of multifactorial etiologies, including genetic anomalies and acquired immune factors, such as viral infections. The myocardium may be infected by a wide variety of viruses, although most commonly by enteroviruses, coxsackievirus B in particular. However, in many cases, when myocarditis has been diagnosed on the basis of clinical manifestations, a viral origin cannot be confirmed, despite extensive laboratory investigations.
The clinical presentation of viral myocarditis is variable. When myocardial necrosis is diffuse, congestive heart failure develops, and growing evidence now links viral myocarditis with dilated cardiomyopathy.2,3 Localized myocardial lesions may result in thinning or aneurysms of the ventricular wall which, in the case of ARVC, are complicated by arrhythmias.4 When myocardial necrosis is limited to the subendocardium, restrictive cardiomyopathy may develop. Finally, although it has not been established that hypertrophic cardiomyopathy is a complication of viral myocarditis, asymmetrical septal hypertrophy has been observed in some patients with myocarditis.5
A high prevalence of hepatitis C virus (HCV) infection has recently been noted in patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, and myocarditis (Figure 1).6–15 In this issue of Circulation Research, Omura et al16 report that mice transgenic for the HCV-core gene develop ventricular dilatation, cardiac dysfunction, and myocardial fibrosis at 12 months, similar to the pathological manifestations observed in human dilated cardiomyopathy. Although HCV infection may be the cause of several phenotypically different cardiomyopathies, mild inflammation with mononuclear cell infiltration has also been observed with HCV infection in humans.6,7,9 However, no lymphocytic infiltration was observed in these HCV-core transgenic mice. Furthermore, cardiomyocyte hypertrophy and disarray of the myofibers are typical characteristics of human hypertrophic cardiomyopathy, but the wall thickness of the HCV-core mice was not increased. Therefore, although the HCV-core mice did not have all the phenotypical manifestations of human cardiomyopathies, the observations made by Omura et al are nevertheless relevant, because they show that the expression of the HCV-core is associated with the long-term development of myocardial disease. They also found that the expression of atrial and brain natriuretic polypeptides was enhanced, and that activator protein-1 (AP-1) was activated in the heart. However, nuclear factor-B (NF-B) was not activated. The authors state that the activation of myocardial AP-1 by HCV-core is an important pathway toward cardiomyopathic changes, although it has not been shown that blocking this pathway changes the disease phenotype. Whereas AP-1 is activated in transgenic mice of HCV core protein,17 the latter interferes with the activation of AP-1 in human macrophages.18 Furthermore, HCV core protein inhibits AP-1,19 and activates extracellular signal-regulated kinase (ERK), C-jun N-terminal kinase (JNK), and p38 mitogen-activated protein (MAP) kinase.20 Although, HCV core protein is known to activate NF-B,21 the authors found no changes in NF-B. Therefore, further studies will be necessary to clarify the molecular pathogenetic changes observed in HCV-core transgenic mice.
Yeah, they NOTED it because they don't agree it should be the case in people with genetic predispositions.
And I "get" the entire gist of the article. Its saying what you seem to have trouble with. That heart disease can be caused long before extensive liver damage. Much of the damage in extrahepatic situations IS caused by the body's immune response, including inflammatory arthritis, which is frequently misdiagnosed as rheumatoid arthritis.
The article is clearing bucking for the restrictions on some people who have heretofore been thought not to be good candidates for treatment to be listed.
The only dots you connect are the ones in your head most of the time.
And I "get" the entire gist of the article. Its saying what you seem to have trouble with. That heart disease can be caused long before extensive liver damage. Much of the damage in extrahepatic situations IS caused by the body's immune response, including inflammatory arthritis, which is frequently misdiagnosed as rheumatoid arthritis.
The article is clearing bucking for the restrictions on some people who have heretofore been thought not to be good candidates for treatment to be listed.
The only dots you connect are the ones in your head most of the time.
"This observation suggests that the
CD+4 Th1 cell response was strong enough to keep the
HCV “under control” in the liver; however, in the myocardium,
a strong CD+4 Th1 cell response would have led to
a local increase in infl ammatory cytokines, including TNF
alpha. A TNF alpha rich microenviroment would be detrimental
to the myocardium, as already stated. "
This is detailing the etiology of cardiomyopathy as mediated by the immune system. The immune system is actually attacking the myocardium tissues, creating inflammation (myocarditis), and eventually cell death. As you know INF stimulates our own immune system to produce stronger immune responses. It does so by attempting to increase the production of the very cytokines (Th1, Th2, IFN gamma,etc) that the study states is responsible for one pathway (immune-mediated) of damage to the myocardium.
this from the study also: "It is worth noting that patients with HCV infection and cardiomyopathy sometimes are excluded from treatment with interferon due to the side effects of this drug."
CD+4 Th1 cell response was strong enough to keep the
HCV “under control” in the liver; however, in the myocardium,
a strong CD+4 Th1 cell response would have led to
a local increase in infl ammatory cytokines, including TNF
alpha. A TNF alpha rich microenviroment would be detrimental
to the myocardium, as already stated. "
This is detailing the etiology of cardiomyopathy as mediated by the immune system. The immune system is actually attacking the myocardium tissues, creating inflammation (myocarditis), and eventually cell death. As you know INF stimulates our own immune system to produce stronger immune responses. It does so by attempting to increase the production of the very cytokines (Th1, Th2, IFN gamma,etc) that the study states is responsible for one pathway (immune-mediated) of damage to the myocardium.
this from the study also: "It is worth noting that patients with HCV infection and cardiomyopathy sometimes are excluded from treatment with interferon due to the side effects of this drug."
Thank you for finding the entire article for me, as what I had before was the abstract only. I am pleased to now have the entire article.
I do have a pretty bad headache today, still, I think I am assessing this correctly. What this article, and the above portion you copied over, is stating is that the hcv virus, not hcv treatment, can cause cardiac dysfunction in genetically susceptible individuals. This is due to "inflammatory cytokines" TNF alpha among them, produced by the CD+4 Th1 cell response (which generates natural interferon in the body, which is intstrumental in the generation of TNF alpha).
I can't find anything in the study that argues against treatment. Rather, it seems to be suggesting that genetically predisposed folks would benefit from early tx.
Here is the article's conclusion:
CONCLUSIONS
Evidence suggests that the HCV is a cardiotropic virus. The mechanism by which the HCV may cause dilated cardiomyopathy may be multifactorial, including direct damage to the myocardium by HCV, autoimmunity, and programmed cell death in genetically susceptible patients. The replication of the HCV may result in myocarditis, which
progresses to cardiomyopathy in subjects with genetic susceptibility. The HCV associated myocarditis would progress to chronic persistent myocarditis via the direct (viral) effect, and via the indirect (immune) effect, which would lead to the activation of the apoptotic pathways via internal and external signals causing apoptotic cell death of
the myocardium producing myocardial dysfunction, which translates into dilated cardiomyopathy. As suggested by the outcome of the patient described in this report, early treatment of HCV in patients with non-ischemic cardiomyopathy may lead to clearance of the virus and to recovery of myocardial function. It is worth noting that patients with HCV infection and cardiomyopathy sometimes are excluded from treatment with interferon due to the side effects of this drug. However, the risks of no intervention in this specifi c group of patients seem to outweigh the benefits. Patients with cardiomyopathy and heart failure have an increased cardiovascular mortality and total mortality [85] and chronic hepatitis C can lead to cirrhosis and its complications,
which are associated with a high disease burden worldwide [86]. Therefore, these patients should be considered for early intervention. The clinical relevance and scientific opportunities that HCV-associated cardiomyopathy provides concern many disciplines. International epidemiological studies to assess the prevalence of chronic hepatitis C in patients with nonischemic cardiomyopathy need to be conducted. Clinical studies of the treatment of patients with chronic hepatitis C and non-ischemic cardiomyopathy should be carried out. This type of studies may include comparisons between the effect of antiviral therapy alone or in combination with medications used to treat heart failure and/or immunosuppressant drugs. In addition, measurements of cardiac antibodies, serum levels of TNF alpha, and indices of programmed cell death during the course of treatment can be included to determine the effect of therapy on these markers.
One line of investigation that will prove fruitful in discerning the mechanisms by which the HCV mediates dilated cardiomyopathy is the study of TNF alpha dynamics in
patients who carry haplotypes associated with susceptibility to dilated cardiomyopathy.
I do have a pretty bad headache today, still, I think I am assessing this correctly. What this article, and the above portion you copied over, is stating is that the hcv virus, not hcv treatment, can cause cardiac dysfunction in genetically susceptible individuals. This is due to "inflammatory cytokines" TNF alpha among them, produced by the CD+4 Th1 cell response (which generates natural interferon in the body, which is intstrumental in the generation of TNF alpha).
I can't find anything in the study that argues against treatment. Rather, it seems to be suggesting that genetically predisposed folks would benefit from early tx.
Here is the article's conclusion:
CONCLUSIONS
Evidence suggests that the HCV is a cardiotropic virus. The mechanism by which the HCV may cause dilated cardiomyopathy may be multifactorial, including direct damage to the myocardium by HCV, autoimmunity, and programmed cell death in genetically susceptible patients. The replication of the HCV may result in myocarditis, which
progresses to cardiomyopathy in subjects with genetic susceptibility. The HCV associated myocarditis would progress to chronic persistent myocarditis via the direct (viral) effect, and via the indirect (immune) effect, which would lead to the activation of the apoptotic pathways via internal and external signals causing apoptotic cell death of
the myocardium producing myocardial dysfunction, which translates into dilated cardiomyopathy. As suggested by the outcome of the patient described in this report, early treatment of HCV in patients with non-ischemic cardiomyopathy may lead to clearance of the virus and to recovery of myocardial function. It is worth noting that patients with HCV infection and cardiomyopathy sometimes are excluded from treatment with interferon due to the side effects of this drug. However, the risks of no intervention in this specifi c group of patients seem to outweigh the benefits. Patients with cardiomyopathy and heart failure have an increased cardiovascular mortality and total mortality [85] and chronic hepatitis C can lead to cirrhosis and its complications,
which are associated with a high disease burden worldwide [86]. Therefore, these patients should be considered for early intervention. The clinical relevance and scientific opportunities that HCV-associated cardiomyopathy provides concern many disciplines. International epidemiological studies to assess the prevalence of chronic hepatitis C in patients with nonischemic cardiomyopathy need to be conducted. Clinical studies of the treatment of patients with chronic hepatitis C and non-ischemic cardiomyopathy should be carried out. This type of studies may include comparisons between the effect of antiviral therapy alone or in combination with medications used to treat heart failure and/or immunosuppressant drugs. In addition, measurements of cardiac antibodies, serum levels of TNF alpha, and indices of programmed cell death during the course of treatment can be included to determine the effect of therapy on these markers.
One line of investigation that will prove fruitful in discerning the mechanisms by which the HCV mediates dilated cardiomyopathy is the study of TNF alpha dynamics in
patients who carry haplotypes associated with susceptibility to dilated cardiomyopathy.
Interesting. I wonder if the studies take into account the % of HCV patients who were also exposed to bacterial endocarditis at the time of their viral infection.
http://www.medscimonit.com/fulltxt.php?ICID=855742
According to this recent study, treatment can induce cardiomyopathy especially in those who are thought to be genetically inclined. Tx creates an immune response which is heavily implicated in myocarditis and eventually cardiomyopathy. Excerpt: " A TNF alpha rich microenviroment would be detrimental
to the myocardium, as already stated."
HEPATITIS C VIRUS MEDIATED MYOCARDIAL DYSFUNCTION
When the HCV enters the body an immune response is produced
to eliminate the virus. A strong HCV specific CD+4
Th1 cell response is associated with HCV suppression and
sometimes clearance. This immunologic response has to be
maintained to control the HCV; the loss of this response is
followed by relapse [67–69]. Among the cytokines produced
by CD4+ Th1 cells upon activation is interferon (IFN) gamma,
which leads to macrophage activation, one of the cells
responsible for the production of TNF alpha. The stronger
the activation of CD4+ Th1 cells, the greater the activation
of macrophages, and hence the greater the production of
the TNF alpha. With respect to the liver, this leads to an effective
immune response and control or “clearance” of the
HCV. The liver has the capacity to regenerate; therefore,
an effective immune response plus its regenerative properties
would lead to minimal liver damage. In the patients
who developed myocarditis associated with HCV infection
the serum aminotransferases activity remained within normal
range until the terminal stage of heart failure, when
the liver panel became abnormal as a reflection of congestive
hepatopathy [41]. This observation suggests that the
CD+4 Th1 cell response was strong enough to keep the
HCV “under control” in the liver; however, in the myocardium,
a strong CD+4 Th1 cell response would have led to
a local increase in infl ammatory cytokines, including TNF
alpha. A TNF alpha rich microenviroment would be detrimental
to the myocardium, as already stated.
If you were anemic from the treatment when you had the heart murmur, anemia can be the culprit. Also, 6% of all females have mitral valve prolapse.
It has long been my contention that the fallacy behind the watch and wait manner of handling things is that hcv is damaging more than just your liver while you are waiting.
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I agree.
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I agree.
My point is that there is now more than one study showing that hcv (not the treatment of hcv, but hcv itself) CAUSES heart damage. There is another study that shows that people with hcv die from heart disease more often than people without (not to mention other issues).
It has long been my contention that the fallacy behind the watch and wait manner of handling things is that hcv is damaging more than just your liver while you are waiting. Hey - not that this isn't someone's choice. Just sayin'
It has long been my contention that the fallacy behind the watch and wait manner of handling things is that hcv is damaging more than just your liver while you are waiting. Hey - not that this isn't someone's choice. Just sayin'
Like NYGirl, some of that is over my head as well. But, I do know that on the last clinical trial that I was in last June/July, I had a total of 5 EKG's for it. All of them were normal, but obviously, it is something that is a some level, at issue, either before or after treatment. But, then again, most of us are in the middle age to older bracket by the time we are diagnosed and the normal aging process could be at play here. You know like for people who don't even have HCV, who have high cholesterol, obesity, high blood pressure, etc., etc., as extra factors involved. I was told that a hugh percentage of people have a murmur. I had never been told that I had a murmur, until I went to one doctor, who for some reason, heard a murmur. He had me get a whole slew of tests and they all came back normal, except one that said that I had a mild mitral valve prolapse. Since then, different doctors, have heard no murmur and all of my tests-normal. So, I don't know what would make that happen? Could it be that the Riba that I was on at the time had caused it? I have no idea. For awhile, they were having me take antibiotics prior to dentist appts. and now, the new recommendations for mitral valve patients is no antibiotics prior to dentist appts...., who knows?
Susan400
Susan400
I have a pretty good heart murmur and had the whatever it's called electric test before treatment.
After treatment I just got an echocardiagram just to check what was what and it's fine. That doesn't really mean anything to your questions and post (which of course is so over my head I only glanced at it) but - for someone who already has a heart situation it gave me peace of mind and I thought it might help you too (you've had enough issues already time for some PEACE!)
As for medhelp disappearing text or links - back in the olden days we weren't allowed to copy and paste here we were ONLy allowed to do links.......just something I remember from the stone ages!
After treatment I just got an echocardiagram just to check what was what and it's fine. That doesn't really mean anything to your questions and post (which of course is so over my head I only glanced at it) but - for someone who already has a heart situation it gave me peace of mind and I thought it might help you too (you've had enough issues already time for some PEACE!)
As for medhelp disappearing text or links - back in the olden days we weren't allowed to copy and paste here we were ONLy allowed to do links.......just something I remember from the stone ages!
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