title: 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.
authors.affiliation: Cardiac Technology Centre, Dept. of Cardiology, Block 4, Level 3, Royal North Shore Hospital, Sydney, New South Wales 2065, Australia.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Huang
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Hunyor
authors.forename: Lele
authors.initials: L
authors.lastname: Jiang
authors.forename: Osamu
authors.initials: O
authors.lastname: Kawaguchi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shirota
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yuasa
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Gallagher
authors.forename: Biao
authors.initials: B
authors.lastname: Zeng
authors.forename: Xing
authors.initials: X
authors.lastname: Zheng
mesh_terms: D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D003331:Coronary Vessels / Q000503:physiopathology; D004617:Embolism / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005109:Extracellular Matrix / Q000473:pathology; D053222:Fas Ligand Protein; D005260:Female; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008833:Microcirculation; D008863:Microspheres; D009200:Myocardial Contraction; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D012756:Sheep; D013318:Stroke Volume; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D000804:Angiotensin II; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D003094:Collagen; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases