What is new (to us) for Cu(I) in cardiovascular disease
We at CopperOne have been obsessed with Covid. In the process of honoring our late colleague George Brewer, we are reexamining the Cu(I) literature. In 1973 Leslie Klevay was perhaps first to sound the alarm that a high ratio of zinc to copper in the drinking of rats fed egg white protein, sucrose, and vegetable oil could raise cholesterol and contribute to heart disease.  Eight years later Klevay and Viestenze published a report that rats on a copper deficient diet had abnormal electrocardiograms as well as a 39% increase in blood cholesterol.  It’s been close to 50 years since Dr Klevay’s first report. What have we learned? What we are learning is that maybe the copper dependent collagen cofactor enzyme lysyl oxidase may be an important player that is being overlooked. Lay readers might want to skip to the end for a cartoon summary of our journey through the literature.
Three reviews, back up of animal data
We have posted much on copper handling proteins on this website. What do experts in heart disease say in their reviews on copper? More importantly, what do the latest animals studies say on copper deficiency and heart disease?
Who authored these reviews?
-  James J DiNicolantonio is part of the Mid America Heart Institute and author of The Salt Fix. Dennis Mangan is a sales and scientific communication guy. James H O’Keefe is a scientist at CardioTabs, a dietary supplement company, and on the staff at the Mid America Heart Institute.
-  Tohru Fukai and Musuko Ushio-Fukai are affiliated with the Vascular Biology Center at the Medical College of Georgia in Augusta. Jack Kaplan is in the Department of Biochemistry and Medical Genetics at the University of Illinois, Chicago
-  Yun Liu is part of Guangzhou Medical University in China. Ji Miao is now at Boston Childrens. Dr Miao studies copper deficiency in a number of rodent models of human diseases.
back up Cu deficient animal studies
- Roberto Olivares is a professor at the Universidad de Buenos Aires. Cattle were made Cu deficient with a diet supplemented with sodium molybdate (11 mg of Mo/kg). The other group received 9 mg/kg copper sulfate. Each group and nine bovine that were followed for close to a year.  After almost a year Cu deficiency had no significant influence on weight but halved the serum Cu and decreased the heapatic Cu to less than 5% of the control. 
- Ahmed Mandour of Suez Canal University and other authors from Egypt and Japan compared cardiovascular measurements of copper adequate and deficient goats.  Male Shiba goats were fed a diet of alfalfa hay cubes supplemented with 11 mg of Cu+2/kg dry matter. Molybdate sulfate was used to induce Cu deficiency.  These animals were followed for seven months with electrocardiograms, echocardiograms, and routine blood work. 
The DiNicolantonio review did notCtr1.  The Fukai gave a good discussion of structural components in transporting Cu+ . The Liu/Miao review alsocovered the need for prior reduction of Cu2+ to Cu+, perhaps by STEAP, for transport by Ctr1 [4,5] The Liu/Miao review also discussed the consequence of Ctr1 down down in rodent heart disease models. 
We’ve discussed this image on our own Ctr1 post. Personal communications with Ji Miao reiterate our conviction that Cu+ is most natural and least toxic way to absorb copper.
The Fukai review mentioned the anti oxidant protein 1 (Atox1) being both a chaperone ferry from the Ctr1 to the nucleus as a transcription factor  The Liu/Miao review discussed the interplay between Atox1, angiotensin II, and expression of Cu/Zn SOD3.  We’ve discussed this in another post on Atox1 in Covid… of course.
Atox1 in Covid post went into more details into the cardiovascular function of angiotensin II in increasing blood pressure and how Cu/Zn SOD3 mitigates this response.
We have covered copper chaperones in another post. The DiNicolantonio review had very little to say about chaperones, but much to say about SOD.  Not yet covered on this site is the production of peroxy nitrite when NO reacts with nitric oxide. NO. is needed to relax blood vessels. The Liu/Miao review makes brief mention of SCO1-2, the cytochrome C oxidase assembly protein, and mutations that can cause heart disease . The Fukai review mentioned SCO and went into more detail about CCS, the chaperone for Cu/Zn SOD. 
GSH chaperone of Cu+ was covered in another post. The affinity of GSH complexes for Cu may not be as it was pictured in the Hatorie review covered on the copper chaperones post. We have largely ignored PAM, peptidylglycine alpha-amidating monooxygenase. Dopamine beta hyroxylase (DBH) is also largely off the radar in terms of cardiovascular disease reviews. What are the important copper cofactor enzymes in heart disease?
All reviews agree that the ability of Cu/Zn superoxide dismutase to scavenge superoxide is important. [3-5] In the bovine study, cardiac Cu/Zn SOD activity decreased from 23.8 ± 7.2 to 16 ± 5.4 U per gram tissue in the Cu adequate versus deficient animals.  Thiobarbituric acid reactive substances (TBARS) are formed as a byproduct of lipid peroxidation. These were increased from 76.9 ± 27.2 to 154.3 ± 37.4 moles per gram heart in the Cu adequate versus deficient bovines. 
By the seventh month, the copper deficient goats had a notable decrease in SOD activity and ceruloplasmin ferrioxidase activity. Cardiac troponin I is a heart protein that only appears in the blood when the heart has been damaged. Ceruloplasmin, Cp, is also a carrier for iron. Dr Mondour and coauthors made a argument that the cardiac problems seen in the goats could have resulted from iron deficient anemia.  Creatine kinase is found in heart, skeletal muscle, and brain; finding it in the blood is a sign of damage.
lox, lysyl oxidase
Lysyl oxidase is a copper cofactor enzyme that cross-links collagen fibrils. DiNicolantonio and coauthors presented a compelling argument that this cross-linking contributes to the mechanical properties of the heart.  This group also thinks that advanced glycation endproducts are a problem in Cu deficiency.  The Fukai group discussed lox from the standpoint of vascular wound and the consequences of lacking the caperone Atox1 and the transporter ATP7A.  Liu and Miao also focused on collagen cross linking and mechanical properties of the heart. 
The GMS stain reacts with carbohydrates. If lysyl oxidase is under active, the aldehyde form of glucose could react with the side chains of lysine that have not undergone the oxidation to the allyl lysine form (above).
cytochrome C oxidase..ATP to power the heart beat
Or not. Copper deficiency may be linked decreased Cox activity and ultimately cardiac hypertrophy. [3,5] Cardiac Cox was not significantly different between the adequate and deficient bovines. 
ATP and the action potential
Cytochrome C oxidase is a component of the mitochondria that makes ATP. ATP is an absolute requirement for the action potential That signals a post synaptic neuron to
Action potentials, in neurons and muscles require the ATP fueled Na Pump to return to the resting membrane potential. Muscle contraction requires to other ATP intensive processes. The action potential in muscle travels to the DHP Ca2+ channel that signals the Ryanodine (& caffeine) receptor to release even more Ca2+ from the sarcoplasmic reticulum. Ca2+ binds to TnC of the troponin complex that moves tropomyosin aside so that myosin heads may move about on actin. This of course requires ATP! Getting Ca2+ back into the SR requires ATP!
The makers of CopperOne have a tendency to want to make everything about ATP and the mitochondria. Let us continue this journey that leads to Cu/Zn SOD and lysyl oxidase.
Mandour et al ECG and echo data
This is an extremely nice study by a group of physiologists.
Electrocardiogram (ECG) is a recording of the heart’s electrical activity during the cardiac cycle. The ECG is a graph of electrical potential difference detected by electrodes placed on strategic places on the skin … as a function of time.
Only specific intervals of the cardiac cycle were prolonged in the Cu deficient goats.
In the ECG data the P wave duration and the time between the QRS and T wave were the most influence by copper. Note that there was no change in heart rate as a result of copper deficiency. Changes in the ST segment are usually associated with ischemia. Indeed, a significant negative correlation was observed for the ST interval as a function of serum copper, see table 4 edited for only significant values. Graphs on the right hand side illustrate hypothetical correlations. The more copper, the longer the T segment duration.
Echo cardio data
Table 3 from Mandour 2021 has been edited to show only the significant results. Some images of the cardiac cycle have been added for the non cardiologists. The cardiac output and stroke volumes have increased, the end volumes and diameters have also increased. It’s as if blood is moving through
Correlating heat data with serum copper content…
Dr Mandour and colleagues attributed the prolongation of the ECG parameters in the
Cu deficient group at five and seven months to ventricular enlargement via hypertrophy or dilation.  They proposed that the reduced ECG T-wave duration may be due to cardiac damage as based up by increases in systolic volume, cardiac output, left atrium area, and so on in Table 3. Increased preload and cardiac dilatation were cited as possible explanations.  The preload is the extent of which the sarcomers are stretched before the heart contracts. Mandour and coauthors favored cardiac remodeling in response to anemia as the explanation.  Anemia results in decreased systemic peripheral resistance and thus a decreased afterload. Interestingly. anemia may arise from decreased plasma and cardiac Fe2+ secondary to the decrease in Cu.  In spite of these alterations, the copper deficient goats did not develop severe cardiomyopathy or heart failure. these are some images of goat hearts in the Mandour 2021 study. 
We’ve known from early studies of Leslie Klevay that Cu deficiency is associated with heart disease. [1,2] What we have posted about copper in regards to Covid-19 is more or less consistent with what experts in the heart have written about Cu deficiency and heart disease. [3-5] Olivares and coauthors found increased extracellular matrix and decreased serum and hepatic Cu in Cu deficient bovines.  Much of the Olivares report focused on mitochondrial defects.  Mandour and coauthors conducted and extensive cardiology study on Cu deficient goats. A concluding suggestion that secondary iron deficiency anemia might be cause of decreased after load and accompanying cardiac changes.  We could just as easily argue that a decrease in Cu/Zn SOD could allow super oxide to react with the blood vessel relaxing small molecule nitric oxide. We could also argue that changes in lysyl oxidase cross linking of collagen in blood vessels is important. The cartoon of Hatori and coauthors says it all. CCO might get first dibs when Cu is deficient. Lysyl oxidase being further down in the Cu “lunch line” may create long term problems.
This is the CopperOne summary_cartoon. Thank you for reading.
- Klevay LM. (1973) Hypercholesterolemia in rats produced by an increase in the ratio of zinc to copper ingested. Am J Clin Nutr. 1973 Oct;26(10):1060-8.
- Klevay LM, Viestenz KE. Abnormal electrocardiograms in rats deficient in copper. Am J Physiol. 1981 Feb;240(2):H185-9. doi: 10.1152/ajpheart.1981.240.2.H185. PMID: 7468813.
- DiNicolantonio JJ, Mangan D, O’Keefe JH. Copper deficiency may be a leading cause of ischaemic heart disease. Open Heart. 2018 Oct 8;5(2):e000784. PMC free article
- Fukai, T., Ushio-Fukai, M., & Kaplan, J. H. (2018). Copper transporters and copper chaperones: roles in cardiovascular physiology and disease. American journal of physiology. Cell physiology, 315(2), C186–C201. PMC free article
- Liu, Y., & Miao, J. (2022). An Emerging Role of Defective Copper Metabolism in Heart Disease. Nutrients, 14(3), 700. PMC free article
- Olivares RWI, Postma GC, Schapira A, Iglesias DE, Valdez LB, Breininger E, Gazzaneo PD, Minatel L. (2019) Biochemical and Morphological Alterations in Hearts of Copper-Deficient Bovines. Biol Trace Elem Res. 2019 Jun;189(2):447-455. free article
- Mandour AS, Elsayed RF, Ali AO, Mahmoud AE, Samir H, Dessouki AA, Matsuura K, Watanabe I, Sasaki K, Al-Rejaie S, Yoshida T, Shimada K, Tanaka R, Watanabe G. The utility of electrocardiography and echocardiography in copper deficiency-induced cardiac damage in goats. Environ Sci Pollut Res Int. 2021 Feb;28(7):7815-7827. free article
- Hatori Y, Inouye S, Akagi R. Thiol-based copper handling by the copper chaperone Atox1. IUBMB Life. 2017 Apr;69(4):246-254. free article
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