Open artery hypothesis
The open artery hypothesis was first postulated by Eugene Braunwald in 1993 (Ref 1). He suggested that restoring blood flow in an occluded coronary artery, has time independent benefits. beyond the acute phase of myocardial infarction. The proposal was, it could improve left ventricular function, reduce remodeling, and potentially decrease mortality by mechanisms beyond myocardial salvage, such as reduced ventricular arrhythmias and improved healing and also potential channels of future collaterals.It was a great concept and sounded very logical and got world wide attention.
Is it really valid now as a therapeutic concept in CCS ? If so, why we struggle to show benefits in asymptomatic CTOs ?
The fact that, opening a CTO is not bringing the expected benefits is one of the most intellectual questions in coronary physiology. Most of us are not keen to go deep into this question.
Could Opening a CTO Confer More Risk Than Leaving It Closed?
Now get ready for some nasty truths. There are plausible mechanisms by which opening a CTO might increase the risk of recurrent events compared to a stable, closed artery.
1.Procedural Risks:
CTO-PCI is technically complex, with risks including periprocedural myocardial infarction ,coronary perforation, stent thrombosis, restenosis, and contrast-induced nephropathy. In this context , it is worth noting the DECISION-CTO trial reported a 2-3% rate of major procedural complications, which could of offset benefits of PCI in asymptomatic patients.
2.Restored Flow and Plaque Instability:
Opening a CTO restores blood flow to a previously ischemic territory, but the downstream vessel may have unstable or vulnerable plaques that were previously “protected” by the occlusion. Sudden reperfusion could trigger microembolization, increasing the risk of acute coronary syndromes (ACS).
3 .Stent-Related Issues:
CTO-PCI often requires not only long procedure times, it often requires long stents , or multiple stents, increasing the risk of stent thrombosis compared to a naturally occluded artery that has adapted with collaterals. Dual antiplatelet therapy (DAPT) post-PCI introduces bleeding risks, which may outweigh benefits in asymptomatic patients.
4.Collateral Regression:
CTOs often develop robust collateral circulation, which may provide adequate perfusion to the myocardium. After successful PCI, collaterals may regress, leaving the myocardium dependent on the newly opened vessel. If restenosis or reocclusion occurs, this could lead to ischemia or infarction, potentially worse than the pre-PCI state fed by the caring collaterals.
5. Inflammatory Response:
PCI also induces an inflammatory response in the vessel wall, which may promote neointimal hyperplasia or accelerate atherosclerosis in the treated segment, increasing the risk of future events. All these, bring a curious and serious assumption close to reality. (That is, opening a CTO could, in some cases, disrupt a stable, quiescent milieu into, potentially un-predictable terrain and lead to more events than leaving the artery closed.)
Why CTO-PCI May Not Outperform Medical Therapy in Asymptomatic Patients
The lack of clear benefit from CTO-PCI in asymptomatic patients, as seen in trials like the Occluded Artery Trial (OAT) and DECISION-CTO, may partly stem from these risks. Key reasons include:
- Stable Collaterals: In asymptomatic CTOs, well-developed collaterals may provide sufficient perfusion, reducing ischemia-driven events. Opening the artery may not add significant benefit but introduces procedural and stent-related risks.
- Optimal Medical Therapy (OMT): Advances in OMT (e.g., statins, beta-blockers, SGLT2 inhibitors) have significantly reduced event rates in stable coronary artery disease (CAD), making it harder for PCI to show incremental benefit.
- Lack of Ischemia or Viability: Most importantly ,In asymptomatic patients, the absence of significant ischemia or already viable myocardium. reduces the potential for PCI to improve outcomes.
Squeezing the landmark studies on CTOs for some data
While no study has explicitly tested whether closed arteries are better than open ones , several trials and analyses have explored whether CTO-PCI increases event rates compared to leaving the artery closed.
Occluded Artery Trial (OAT)
- Design: Note : It randomized 2,166 patients with an occluded infarct-related artery (post-MI, >24 hours) to PCI or OMT. OAT is not a strict CTO study.
- Findings: At 4 years, there was no significant difference in major adverse cardiac events (MACE: death, MI, or heart failure) between PCI (17.2%) and OMT (15.6%) However, there was a trend toward more nonfatal MIs in the PCI group (7.0% vs. 5.3%, ) suggesting a potential for increased events post-PCI, possibly due to procedural complications or restenosis.
- Implication: This supports the idea that opening an occluded artery may not always be beneficial and could introduce risks.
DECISION-CTO Trial
- Design: Randomized 834 patients with CTOs to PCI + OMT vs. OMT alone.
- Findings: At 3 years, there was no difference in MACE (death, MI, stroke, or revascularization) between groups. However, periprocedural complications (e.g., perforation, tamponade) occurred in the PCI arm, and there was a non-significant trend toward higher restenosis-related events.
- Implication: The trial suggests that PCI does not consistently outperform OMT and may introduce risks that offset benefits in asymptomatic patients.
EXPLORE Trial
- Design: Randomized 304 patients with STEMI and a CTO in a non-infarct-related artery to CTO-PCI or no PCI.
- Findings: No significant difference in left ventricular ejection fraction (LVEF) or MACE at 4 months. A subset analysis showed a trend toward more revascularization events in the PCI group, possibly due to restenosis or reocclusion.
- Implication: Opening a CTO did not improve outcomes and may have increased event rates in some cases.
A provocative proposal
Thanks to the absolute democracy in science , I can propose a concept, however crazy it may appear. Yes, it is the Closed artery hypothesis . It can be defined as follows: In asymptomatic patients with chronic total occlusions and well-developed collaterals, leaving the occluded artery closed may result in fewer recurrent cardiovascular events than opening it via PCI, due to the stability of the collateralized system and the risks associated with intervention.
The closed artery hypothesis could turn out to be a compelling concept that merits further investigation
Reference
Postamble
What makes coronary blood flow dynamics so fascinating ?
A cardiologist’s primary job is to open the artery when it is closed in an emergency . This rule goes topsy-turvy when it happens in a chronic fashion**. Think about the two contrasting behavior of the same myocardium. In Stemi, it bounces back to life with emergent opening of the artery, while in the other, myocardium simply doesn’t bother about total shut down and possibly enjoys* the protection conferred by a closed artery.
*Objection my Lord. The word enjoys is brutal .Are you aware CTOs can be responsible for Stemi too ? ** But, Is it not Intriguing to note, OAT study included primarily ACS population and it looks so true , even acutely occluded coronary artery need some rest from reperfusion Injury.
Dr.S.Venkatesan MD 