HER2 Support Group Forums - View Single Post - Blood test "promising" in predicting herceptin induced cardiotoxicity

R.B. · 05-21-2006, 09:18 AM

Fascinating.

IF the heart is not taking up Herceptin, and yet there are cardiac problems, what is causing them.

Would it not be a logical deduction that herceptin is intervening in another process that would impact on cardiac health.

Herceptin is reported as restricting FAS in cells overexpressing HER2. The relationship between FAS and HER2 is reported as bidirectional. EPA and DHA are products of FAS. Western diets are reported as being containing low levels of DHA and high levels of n6.

HER2 from very limited reading figures highly in heart function (see abstract below "ErbB receptors, expressed in cardiomyocytes and noncardiomyocytes, are downregulated in failing myocardium").

Using the term "DHA cardiac" into the NCBI search engine produces 300 odd results including this which suggest DHA is important in cardiac health. It is recognised in a Medscape PQE module, and on the Mayo clinic site that omega threes are at the least important to heart health. ( My reading is that the n3 and n6 derivatives are fundamental to vascular health but I am not organised enought at the moment to argue it)

Could the combination of Herceptin blocking FAS in cells expressing HER2 (which includes cardiac cells if I understand correctly) at cellular level, thereby reducing available supplies of DHA and EPA key regulators in vascular health, added to the lack of dietary intake and excess of omega six (both in fat stores and in ongoing dietary intake) account for the cardiac side effects of Herceptin?

RB

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum

1: Int J Cardiol. 2006 Mar 8;107(3):299-302. Related Articles, Links
Click here to read
Effects of n-3 polyunsaturated fatty acid on upper limit of vulnerability shocks.

Chattipakorn N, Shinlapawittayatorn K, Sungnoon R, Chattipakorn SC.

Cardiac Electrophysiology Unit, and Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. nchattip@mail.med.cmu.ac.th

BACKGROUND: Ventricular fibrillation (VF) can be induced when a strong shock is delivered during the vulnerable period of a cardiac cycle. VF, however, cannot be induced if the shock strength is increased to the "upper limit of vulnerability" (ULV) level. Docosahexaenoic acid (DHA) has been shown to prevent the occurrence of VF after coronary occlusion. However, its effects on the ULV have not been verified. We tested the hypothesis that ULV shock strength is decreased after DHA administration. METHODS: In 10 pigs, 10 S1s (square, 5-ms) were delivered from the RV apex electrode at 300 ms cycle length. Shocks (S2, biphasic) were delivered from the RV-SVC electrodes after the last S1. The ULV was determined using an up/down protocol. In group 1 (n = 5), after the control ULV was determined at the beginning of the study, a solution containing 1.0 gm of DHA was infused intravenously within 90 min. The ULV (DHA-ULV) was determined again after the end of infusion. In group 2 (n = 5), the vehicle for DHA was infused instead of DHA to confirm that the vehicle did not have an effect on the ULV. RESULTS: DHA-ULV (412 +/- 58 V, 12 +/- 3 J) was significantly decreased (P < 0.04) compared to the control ULV (478 +/- 32 V, 16 +/- 3 J). The ULV before (483 +/- 28 V, 16 +/- 1 J) and after (463 +/- 28 V, 15 +/- 2 J) the vehicle infusion was not different (P = 0.4). There was no change in the systolic blood pressure as well as heart rate in both groups. CONCLUSION: DHA significantly decreases the ULV (13% by voltage and 25% by energy), suggesting that DHA can help to prevent VF induced by a strong stimulus delivered during the vulnerable period.

PMID: 16503251 [PubMed - in process]

http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_DocSum

1: Basic Res Cardiol. 2005 May;100(3):240-9. Epub 2005 Feb 3. Related Articles, Links
Click here to read
Neuregulin receptors erbB2 and erbB4 in failing human myocardium -- depressed expression and attenuated activation.

Rohrbach S, Niemann B, Silber RE, Holtz J.

Institute of Pathophysiology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06097 Halle, Germany. susanne.rohrbach@medizin.uni-halle.de

Membrane-bound and secreted neuregulin isoforms induce growth, survival and differentiation by activating erbB tyrosine kinase receptors. In cultured cardiomyocytes, erbB2 and erbB4 receptors regulate apoptosis by controlling bcl-x splicing, and conditional elimination of erbB2 induces dilative cardiomyopathy in vivo. Therefore, we analyzed expression and activation of erbB receptors in left ventricular myocardium from 32 heart failure patients, from 10 organ donors, and from 15 heart failure patients prior to and following unloading by ventricular assist devices. ErbB receptors, expressed in cardiomyocytes and noncardiomyocytes, are downregulated in failing myocardium as mRNA (which is renormalized by hemodynamic unloading) and as protein (erbB2: -25%; erbB4: -70%), their phosphorylation is reduced and bcl-x splicing is shifted towards 6.7-fold augmentation of proapoptotic Bcl-xS, compatible with attenuated erbB signaling. However, secreted and membrane-anchored neuregulin-1 isoforms, preferentially expressed in microvascular endothelium, are induced and not lowered with heart failure, while expression of erbB-inhibitory neuregulin isoforms or of autoinhibitory soluble erbB isoforms could not be demonstrated as potential causes of erbB receptor inhibition. We conclude that erbB receptor inactivation by unknown mechanisms results in altered splicing of bcl-x towards enhanced formation of proapoptotic Bcl-xS, thereby contributing to enhanced apoptotic susceptibility of failing human myocardium.

PMID: 15685397 [PubMed - indexed for MEDLINE]

05-21-2006, 09:18 AM	#2
R.B. Senior Member Join Date: Mar 2006 Posts: 1,843	Fascinating. IF the heart is not taking up Herceptin, and yet there are cardiac problems, what is causing them. Would it not be a logical deduction that herceptin is intervening in another process that would impact on cardiac health. Herceptin is reported as restricting FAS in cells overexpressing HER2. The relationship between FAS and HER2 is reported as bidirectional. EPA and DHA are products of FAS. Western diets are reported as being containing low levels of DHA and high levels of n6. HER2 from very limited reading figures highly in heart function (see abstract below "ErbB receptors, expressed in cardiomyocytes and noncardiomyocytes, are downregulated in failing myocardium"). Using the term "DHA cardiac" into the NCBI search engine produces 300 odd results including this which suggest DHA is important in cardiac health. It is recognised in a Medscape PQE module, and on the Mayo clinic site that omega threes are at the least important to heart health. ( My reading is that the n3 and n6 derivatives are fundamental to vascular health but I am not organised enought at the moment to argue it) Could the combination of Herceptin blocking FAS in cells expressing HER2 (which includes cardiac cells if I understand correctly) at cellular level, thereby reducing available supplies of DHA and EPA key regulators in vascular health, added to the lack of dietary intake and excess of omega six (both in fat stores and in ongoing dietary intake) account for the cardiac side effects of Herceptin? RB http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_docsum 1: Int J Cardiol. 2006 Mar 8;107(3):299-302. Related Articles, Links Click here to read Effects of n-3 polyunsaturated fatty acid on upper limit of vulnerability shocks. Chattipakorn N, Shinlapawittayatorn K, Sungnoon R, Chattipakorn SC. Cardiac Electrophysiology Unit, and Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. nchattip@mail.med.cmu.ac.th BACKGROUND: Ventricular fibrillation (VF) can be induced when a strong shock is delivered during the vulnerable period of a cardiac cycle. VF, however, cannot be induced if the shock strength is increased to the "upper limit of vulnerability" (ULV) level. Docosahexaenoic acid (DHA) has been shown to prevent the occurrence of VF after coronary occlusion. However, its effects on the ULV have not been verified. We tested the hypothesis that ULV shock strength is decreased after DHA administration. METHODS: In 10 pigs, 10 S1s (square, 5-ms) were delivered from the RV apex electrode at 300 ms cycle length. Shocks (S2, biphasic) were delivered from the RV-SVC electrodes after the last S1. The ULV was determined using an up/down protocol. In group 1 (n = 5), after the control ULV was determined at the beginning of the study, a solution containing 1.0 gm of DHA was infused intravenously within 90 min. The ULV (DHA-ULV) was determined again after the end of infusion. In group 2 (n = 5), the vehicle for DHA was infused instead of DHA to confirm that the vehicle did not have an effect on the ULV. RESULTS: DHA-ULV (412 +/- 58 V, 12 +/- 3 J) was significantly decreased (P < 0.04) compared to the control ULV (478 +/- 32 V, 16 +/- 3 J). The ULV before (483 +/- 28 V, 16 +/- 1 J) and after (463 +/- 28 V, 15 +/- 2 J) the vehicle infusion was not different (P = 0.4). There was no change in the systolic blood pressure as well as heart rate in both groups. CONCLUSION: DHA significantly decreases the ULV (13% by voltage and 25% by energy), suggesting that DHA can help to prevent VF induced by a strong stimulus delivered during the vulnerable period. PMID: 16503251 [PubMed - in process] http://www.ncbi.nlm.nih.gov/entrez/q...=pubmed_DocSum 1: Basic Res Cardiol. 2005 May;100(3):240-9. Epub 2005 Feb 3. Related Articles, Links Click here to read Neuregulin receptors erbB2 and erbB4 in failing human myocardium -- depressed expression and attenuated activation. Rohrbach S, Niemann B, Silber RE, Holtz J. Institute of Pathophysiology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Str. 40, 06097 Halle, Germany. susanne.rohrbach@medizin.uni-halle.de Membrane-bound and secreted neuregulin isoforms induce growth, survival and differentiation by activating erbB tyrosine kinase receptors. In cultured cardiomyocytes, erbB2 and erbB4 receptors regulate apoptosis by controlling bcl-x splicing, and conditional elimination of erbB2 induces dilative cardiomyopathy in vivo. Therefore, we analyzed expression and activation of erbB receptors in left ventricular myocardium from 32 heart failure patients, from 10 organ donors, and from 15 heart failure patients prior to and following unloading by ventricular assist devices. ErbB receptors, expressed in cardiomyocytes and noncardiomyocytes, are downregulated in failing myocardium as mRNA (which is renormalized by hemodynamic unloading) and as protein (erbB2: -25%; erbB4: -70%), their phosphorylation is reduced and bcl-x splicing is shifted towards 6.7-fold augmentation of proapoptotic Bcl-xS, compatible with attenuated erbB signaling. However, secreted and membrane-anchored neuregulin-1 isoforms, preferentially expressed in microvascular endothelium, are induced and not lowered with heart failure, while expression of erbB-inhibitory neuregulin isoforms or of autoinhibitory soluble erbB isoforms could not be demonstrated as potential causes of erbB receptor inhibition. We conclude that erbB receptor inactivation by unknown mechanisms results in altered splicing of bcl-x towards enhanced formation of proapoptotic Bcl-xS, thereby contributing to enhanced apoptotic susceptibility of failing human myocardium. PMID: 15685397 [PubMed - indexed for MEDLINE]