|Sabbah HN et al.|
Remodeling of the cardiac interstitium in the progression of heart failure
Journal of Clinical and Basic Cardiology 1999; 2 (1): 113-116
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Keywords: Apoptose, Kapillardichte, kongestive Herzinsuffizienz, Tiermodell, Ventrikelfunktion, animal models, apoptosis, capillary density, congestive heart failure, ventricular function
A characteristic feature of heart failure is the progressive deterioration of left ventricular (LV) function that occurs in the absence of clinically apparent intercurrent adverse events. The mechanism or mechanisms responsible for this haemodynamic deterioration are not known but may be related to progressive intrinsic contractile dysfunction of cardiomyocytes and/or to ongoing degeneration and loss of viable cardiomyocytes. We examined the concept that progressive LV dysfunction in heart failure is associated with remodeling of the cardiac interstitium manifested by progressive accumulation of interstitial collagen (reactive interstitial fibrosis) that can potentially lead to chronic hypoxia of the collagen encircled cardiomyocytes, the latter a trigger of cardiomyocyte apoptosis. Studies were performed in dogs with progressive LV dysfunction and failure produced by multiple sequential intracoronary microembolizations. In all dogs, embolizations were discontinued when left ventricular ejection fraction was 30 % to 40 %. Subsequently, dogs were randomly selected to sacrifice at 2 weeks and 4 months after the last embolization and left ventricular tissue was obtained for histologic examination. Ejection fraction decreased significantly between 2 weeks and 4 months (33 ± 3 vs. 20 ± 2 %, p < 0.05). This was associated with increased volume fraction of interstitial fibrosis (8.7 ± 0.8 vs. 12.2 ± 0.7 %, p < 0.05), reduced capillary density (capillary per fiber ratio 0.93 ± 0.01 vs. 0.98 ± 0.01, p < 0.05) and increased oxygen diffusion distance (14.6 ± 0.32 vs. 12.2 ± 0.09 μm, p < 0.05). The observations suggest that in heart failure, progressive LV dysfunction is accompanied by remodeling of the interstitial compartment manifested as progressive accumulation of collagen in the cardiac interstitium that is associated with decreased capillary density and increased oxygen diffusion distance. All of these maladaptations can lead to hypoxia of the collagen encircled cardiomyocyte, a potential trigger of ongoing cardiomyocyte apoptosis or programmed cell death. The latter may contribute to ongoing loss of functional cardiac units and consequently progressive global LV dysfunction. J Clin Basic Cardiol 1999; 2: 113-6.