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Repeated stunning precedes myocardial hibernation in progressive multiple coronary artery obstruction
B Shivalkar1, W Flameng, M Szilard
1Department of Cardiology and Cardiac Surgery, Katholieke Universiteit Leuven, Belgium. bharati.shivalkar@skynet.be
Insights
This study in dogs shows that collateral-dependent heart muscle dysfunction initially presents episodically, then persistently, with normal resting flow and later subendocardial hypoperfusion. Beta-adrenergic receptor density was downregulated in dysfunctional areas.
Area of Science:
- Cardiovascular Physiology
- Myocardial Perfusion Imaging
- Coronary Artery Disease Models
Background:
- Understanding the relationship between blood flow and heart muscle function is crucial in coronary artery disease.
- Collateral-dependent myocardium, often viable but dysfunctional, presents unique challenges in diagnosis and treatment.
- Characterizing the progression of dysfunction in this tissue is essential for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the regional myocardial flow-function relationship in collateral-dependent myocardium.
- To characterize the temporal progression of dysfunction and its correlation with coronary flow reserve.
- To explore potential underlying molecular changes, such as beta-adrenergic receptor density.
Main Methods:
- A canine model was created with multiple coronary artery obstructions (Right Coronary and Circumflex arteries occluded, Left Anterior Descending artery stenosed).
- Regional myocardial function was assessed using echocardiography (wall thickening, fractional shortening).
- Resting flow and coronary reserve were measured using colored microspheres before and after dipyridamole administration.
Main Results:
- Persistent regional dysfunction (reduced wall thickening and fractional shortening) was observed in collateral-dependent areas.
- Initially, resting flow was normal, but coronary reserve was reduced.
- Later, subendocardial hypoperfusion was detected in dysfunctional regions, alongside downregulated beta-adrenergic receptor density.
Conclusions:
- The canine model demonstrated viable, collateral-dependent myocardium with initially reversible, then persistent, dysfunction.
- Dysfunction progressed from normal resting flow to subendocardial hypoperfusion.
- Downregulation of beta-adrenergic receptors may contribute to the observed myocardial dysfunction.
Objective:
The aim of this study was to characterize a regional myocardial flow-function relationship in collateral dependent myocardium produced by multiple coronary artery obstruction.
Methods:
Ameroid constrictors were placed around the proximal right (RC) and circumflex (CX) coronary arteries and a silicon tubing cuff around the proximal LAD (left anterior descending artery) (luminal stenosis +/- 77%) in 18 dogs. Weekly two-dimensional echocardiography was performed for regional function (anterior [A], inferoposterior [IP], wall thickening [WT]), and fractional shortening (FS). Colored microspheres injected at baseline and before sacrifice, before and after dipyridamole (0.5 mg/kg) injection, determined resting flow (RF) and coronary reserve (CR), respectively.
Results:
Coronary angiography performed at four weeks after surgery confirmed occlusion of RC and CX with collateralization and a tight stenosis of LAD. Initially, an episodic reduction in A and IP WT was observed which became persistent later (AWT: 16 +/- 3%; IPWT: 16 +/- 4%, FS: 20 +/- 4%, p < 0.005 vs. baseline [BS]). With dobutamine a biphasic response (improvement in A and IP WT between 5-15 and dysfunction between 20-30 microg/kg/min) was observed. Seven dogs were sacrificed at eight weeks and showed normal RF but reduced transmural CR (A: 75 +/- 18%; IP: 46 +/- 22% of control). Seven dogs underwent PTCA of the LAD at eight weeks and showed gradual improvement in AWT with normalization at 12 weeks (AWT: 30 +/- 5%, p < 0.001 vs. eight weeks). At sacrifice RF and CR in the A wall were normal but there was reduced subendocardial RF in the IP region (64% of BS). Further, biopsy samples showed normal histological findings and high energy phosphate content in all dogs. Radioligand binding assays using 125I-iodocyanopindolol showed downregulation of beta-adrenergic receptor density in the dysfunctional regions compared with control.
Conclusions:
In this canine model of viable, collateral dependent and reversibly dysfunctional myocardium, there was early episodic dysfunction followed by persistent dysfunction which was initially associated with normal RF and later with subendocardial hypoperfusion.