Remodeling of the chronic severely failing ischemic sheep heart after coronary microembolization: functional, energetic, structural, and cellular responses

Abstract

The mandatory use of pharmacotherapy in human heart failure (HF) impedes further study of natural history and remodeling mechanisms. We created a sheep model of chronic, severe, ischemic HF [left ventricular (LV) ejection fraction (LVEF) <35% stable over 4 wk] by selective coronary microembolization under general anesthesia and followed hemodynamic, energetic, neurohumoral, structural, and cellular responses over 6 mo. Thirty-eight sheep were induced into HF (58% success), with 23 sheep followed for 6 mo (21 sheep with sufficient data for analysis) after the LVEF stabilized (median of 3 embolizations). Early doubling of LV end-diastolic pressure persisted, as did increases in LV end-diastolic volume, LV wall stress, and LV wall thinning. Contractile impairment (LV end-systolic elastance, LV preload recruitable stroke work, and dobutamine-responsive contractile reserve) and diastolic dysfunction also remained stable. Cardiac mechanical energy efficiency did not recover. Plasma atrial natriuretic peptide levels remained elevated, but rises in plasma aldosterone and renin activity were transient. Collagen content increased 170%, the type I-to-III phenotype ratio doubled in the LV, but right ventricular collagen remained unaltered. Fas ligand cytokine levels correlated with expression of both caspase-3 and -2, suggesting a link in the apoptotic "death cascade." Caspase-3 activity also bore a close relationship to LV meridional wall stress calculated from echocardiographic and intraventricular pressure measurements. We concluded that the stability of chronic untreated severe ischemic HF depends on the recruitment of myocardial remodeling mechanisms that involve an interaction among hemodynamic load, contractile efficiency/energetics, neurohumoral activation, response of the extracellular matrix, wall stress, and the myocyte apoptotic pathway.

β 3 Adrenergic Stimulation of the Cardiac Na + -K + Pump by Reversal of an Inhibitory Oxidative Modification

“…19 The effects of BRL37344 (BRL) on standard hemodynamic variables and LV end-systolic pressurevolume relationships (ESPVRs) of continuous LV pressure-volume loops were determined at baseline and after induction of heart failure. Because ESPVR is relatively load independent, it was chosen a priori as the primary index of cardiac contractility.…”

“…19 Expression of the ␤ 3 AR in sheep heart was ascertained by immunoblotting. Myocardium from wild-type and ␤ 3 AR Ϫ/Ϫ mouse as positive and negative controls ( Figure 7A).…”

The effect of a myocardial infarction on the normalized time-varying elastance curve

“…However, subsequent studies revealed limitations to this simplified theory, such as ESPVR curvilinearity, afterload dependence under certain conditions, and that V o may change during contraction (18,26,29). Furthermore, the ESPVR has been reported to be influenced by regional ischemia in acute and chronic animal models of heart failure (13,21) and augmented in spontaneously hypertensive rats (5).…”

Novel Porcine Models of Myocardial Ischemia/Infarction – Technical Progress, Modified Electrocardiograms Validating, and Future Application

“…In addition, the trauma may render successful recovery from anesthesia in models of myocardial infarction more difficult, compared with closed chest procedures. Besides, to date, there are various myocardial ischemic animal models, such as ligating the coronary artery (Takahashi et al, 2005), placing constrictors on the coronary artery (Laham et al, 2000), putting microembolus into the coronary artery (Huang et al, 2004), or injecting ferric chloride via the vein (Dogne et al, 2005). However, operations in these methods lead to much damage in animals, and channelization can not be restored in the obstructed coronary artery.…”