During our cardiac lectures, we discussed coronary artery
bypass graft and angioplasty as ways to restore proper coronary circulation and
heart function. Coronary artery bypass graft, known as a heart bypass, is a
surgical procedure that uses a section of a healthy blood vessel to bypass a
blocked coronary artery (1). An angioplasty, also known as percutaneous
coronary intervention or percutaneous transluminal coronary angioplasty, uses a
small balloon-like device that is inserted into the femoral artery and navigated
to the coronary artery, where the balloon is inflated at the site of a clot or
narrowed artery. The inflation of the balloon breaks up the clot and allows for
a cleared vessel (1). To keep the vessel open, often times a stent, a small
metal cylinder, is inserted into the site (2). This stent should in theory keep
the vessel open and allow for proper blood flow.
Sometimes the trauma of inserting a stent induces
inflammation along with growth factors and cytokines, causing the smooth muscle,
tunica media, to thicken (3). This muscular thickening then narrows the vessel,
completely reversing the effects of the angioplasty. A risk for scar tissue is
also a major problem as well. To prevent scar tissue development, drug-eluting
stents are often used, because they slowly release a drug that prevents the
formation of scar tissue within the artery. However, the drug coating used may
cause a defect in endothelial re-growth, thus increasing the risk of thrombosis
(3). This problem is the focus of research today to find an alternative for the
drugs currently used.
To prevent the smooth muscle proliferation induced upon
stent insertion, Tang et al. examined the role of the metabolic enzyme CTP
synthase (CTPS) in stent-induced inflammation (3). The researchers found that
the endothelial and smooth muscle cells use different CTPS pathways to
proliferate. It was also found that CTPS1, a key molecule in DNA synthesis
during cellular proliferation, was induced by the growth factors produced
during cardiovascular intervention. With these findings, the researchers decided
to block CTPS1 function and found that smooth muscle cells reduced
proliferation and therefore endothelial growth inhibiting paracrine factors,
leading to increased proliferation of endothelial cells (3). A therapeutic drug
that inhibits CTPS1 would allow for smooth muscle cell proliferation inhibition
and improved vascular endothelial repair for patients with stents. Further
research on a CTPS1 inhibitor as a therapeutic option for stent insertion
following angioplasty could potentially eliminate thrombosis due to stent
insertion and improve the recovery rate for stent patients.
References:
1. Campisi J.
Cardiovascular system: organization & hemodynamics. Biomedical Physiology
Notes, 2013.
2. Harvard Health
Publications.
Building a better stent. Harvard Health Letter 23(8): 3, 2013.
3. Tang R, Cui XB, Wang JN,
Chen SY. CTP
synthase 1, a smooth muscle-sensitive therapeutic target for effective vascular
repair. Arterioscler Thromb Vasc Biol 33(10): 2336-44, 2013.
Jamie,
ReplyDeleteExcellent post, it is very well written. I think that the drug-eluting stents are amazing so I went and searched a little more about them. In addition to having these stents in your body that are constantly secreting life saving drugs, researchers are now incorporating biocompatible and biodegradeable stents (Palmerini et al 2013). Basically, the biocompatible polymers cover the metal stent and act as a median between the foreign metal and your vascular tissue. This greatly reduces the damage caused by having a metal tube shoved in your artery and doctors are seeing better patient outcomes (Freitas de Suza et al 2013).
Freitas de Souza C, Mohamed El Mouallem A, Sandoli de Brito Junior F, Cunha Abizaid B, Goncalves A, Cunha Nascimento TCD, Perin MA and Caizeta A. Sep 2013. Saftey and efficacy of biolimus-eluting stent with biodegradable polymer: insights from Einstein Registry. Einstein. 11(3): 350-356
Palmerini T, Biondi-Zoccai G, Della Riva D, Mariani A, Genereux P, Branzi A and Stone GW. Nov 2013. Stent thrombosis with drug eluting stents: Is the paradigm shifting? Journal of American College of Cardiology. 62(21):1915-1921
Jamie,
ReplyDeleteI thought your post was very eloquent as well. I did some research on endothelial cell regeneration and found that like everything else in the body, it's complicated. One article I did find examined the role of the enzyme dimethylarginine dimethylaminohydrolase (DDAH) on endothelial cell cycle. DDAH normally functions to clear asymmetric dimethylarginine (ADMA), a substrate naturally produced by the body, from circulation (1). ADMA functions to inhibit endothelial cell proliferation by causing the cells to arrest in G1 or G2 of the cell cycle. Anyways, people with a genetic predisposition to coronary heart disease had decreased levels of DDAH and, thus an increased ADMA blood concentration (1). If stents were able to deliver a drug that inhibited CTPS1 and another drug that promoted DDAH production, then endothelial cell proliferation would be doubly promoted.
Reference:
1. Zhang P, Xu X, Hu X, Wang H, Fassett J, Huo Y, Chen Y, Bache RJ. DDAH1 Deficiency Attenuates Endothelial Cell Cycle Progression and Angiogenesis. PLoS One 8: e79444, 2013.
Thank you Ian. There is definitely some awesome research on biodegradable and drug-eluting stents right now. Some of the polymer “concoctions” used are incredible. To think that the human body is able to accept such a foreign substance! In addition to the drug-eluting stents, I think it is also important to add that antiplatelet therapy is used for up to 12 months after implantation of a drug-eluting stent (1). The combination of a drug-eluting stent and antiplatelet therapy greatly reduces the risk of thrombosis and an MI. However, often times the patients end therapy early, because they do not see symptom relief. The other problem with the antiplatelet therapies is the risk for bleeding. Newer, stronger drugs are being tested, thus increasing the risk of bleeding (1). As with all medicine, there are many factors that must be taken into consideration. The biggest problem I see, however, is patient education. Increased patient education, I think, would lead to better therapeutic outcomes and patient adherence.
ReplyDelete1. Rossini R, Baroni M, Musumeci G, Gavazzi A. Oral antiplatelet therapy after drug-eluting stent implantation: adherence and side effects. Journal of Cardiovascular Medicine. 14(2): 81-90, 2013.
Joel,
ReplyDeleteThank you as well. Tackling endothelial cell proliferation from two different angles would definitely be a great option for therapy. However, I question whether this could cause too much endothelial growth, and narrow the artery instead? The other possibility is that it would work great, and the treatment would only have to be very short-term, thus reducing cost and increasing patient compliance. What do you think about this?
Jamie,
ReplyDeleteThe study I found simulated the endothelial damage associated with implanting a carotid artery stent. They used a DDAH deficient mouse model, and observed impaired endothelial repair. I feel like a more patient specific treatment could be implemented with the different drugs associated with the stents. If a patient is not DDAH deficient, then they could receive a stent with only a CCTPS1 inhibitor or only a DDAH promoter to have only one factor of endothelial cell proliferation. If a patient is DDAH deficient, then they could receive a stent with both drugs essentially getting a two-fold promotion of endothelial cell growth.
I don't think the two drugs have been studied together for adverse interactions. Thorough testing in animal models would have to be conducted to find the tipping point where the combination of drugs resulted in too much endothelial growth or if their combination resulted in any cell growth at all. I feel like either of the two scenarios you proposed are very possible because every patient responds differently to pharmaceuticals.
Wow, DES's are cool! Great post Jamie!
ReplyDeleteAfter reading all the excellent comments I did some of my own research. Most of the drugs mentioned earlier seemed were either immunosuppressants or NOS inhibitors. Since you discussed that one of the problems post stent placement is increased smooth muscle proliferation, I was curious if a anti vascular endothelial growth factor (anti-VEGF) drug such as Avastin may help because it would not affect the existing tissue, but it would reduce new tissue growth. Sadly, my research on this topic did not turn up anyone with published results on this, but maybe someone is out there working on it. The nice thing about anti-VEGF treatments is that since they are a mulch-clonal antibody treatment, they could be combined with the other treatments such as NOS inhibitors for a possibly synergistic effect.
Ref:
Tan A, Farhatnia Y, de Mel A, Rajadas J, Alavijeh MS, Seifalian AM. Inception to actualization: next generation coronary stent coatings incorporating nanotechnology. Journal of biotechnology 164: 151–70, 2013.
Thanks Brad! Since you mentioned VEGF, I did some research and found that is a pro-angiogenic growth factor needed for vascular endothelial cells. Specifically in the cardiovascular system, it is suggested that VEGF allows tissue remodeling at a site of necrosis. This being said, I would think an anti-VEGF therapy would not be beneficial, since endothelial proliferation is vital for vascular repair after a stent insertion. A therapy to block smooth muscle proliferation specifically would have the most beneficial outcome, since it would not interfere with endothelial cell proliferation.
ReplyDeleteReference:
Duffy AM, Bouchier-Hayes DJ, Harmey JH. Vascular endothelial growth factor (VEGF) and its role in non-endothelial cells: autocrine signaling by VEGF. In: Madam Curie Bioscience Database. Austin, TX: Landes Bioscience, 2000.