title: Increased stiffness is the major early abnormality in a pig model of severe aortic stenosis and predisposes to congestive heart failure in the absence of systolic dysfunction.
abstract: BACKGROUND
  It remains unclear whether abnormal systolic function and relaxation are essential for developing heart failure in pathophysiology of severe aortic stenosis.
  
  
  RESULTS
  Yorkshire pigs underwent surgical banding of the ascending aorta. The animals were followed for up to 5 months after surgery, and cardiac function was assessed comprehensively by invasive pressure-volume measurements, 3-dimensional echocardiography, echocardiographic speckle-tracking strain, and postmortem molecular and histological analyses. Pigs with aortic banding (n=6) exhibited significant left ventricular hypertrophy with increased stiffness compared with the control pigs (n=7) (end-diastolic pressure-volume relationship β: 0.053±0.017 versus 0.028±0.009 mm Hg/mL, P=0.007); however, all other parameters corresponding to systolic function, including ejection fraction, end-systolic pressure-volume relationship, preload recruitable stroke work, echocardiographic circumferential strain, and longitudinal strain, were not impaired in pigs with aortic banding. Relaxation parameters were also similar between groups. Sarcoplasmic reticulum calcium (Ca(2+)) ATPase protein levels in the left ventricle were similar. There were significant increases in 3-dimensional echocardiographic left atrial volumes, suggesting the usefulness of these indexes to detect increased stiffness. Right atrial pacing with a heart rate of 120 beats per minute induced increased end-diastolic pressure in pigs with aortic banding in contrast to decreased end-diastolic pressure in the control pigs. Histological evaluation revealed that increased stiffness was accompanied by cardiomyocyte hypertrophy and increased perimysial and perivascular fibrosis.
  
  
  CONCLUSIONS
  Increased stiffness is the major early pathological process that predisposes to congestive heart failure without abnormalities in systolic function and relaxation in a clinically relevant animal model of aortic stenosis.
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., J.A., J.G.O., N.H., L.F., L.L., B.P., C.G.S.G., K.F., R.J.H.).
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., J.A., J.G.O., N.H., L.F., L.L., B.P., C.G.S.G., K.F., R.J.H.).
authors.forename: Jaume
authors.initials: J
authors.lastname: Aguero
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., J.A., J.G.O., N.H., L.F., L.L., B.P., C.G.S.G., K.F., R.J.H.).
authors.forename: Jae Gyun
authors.initials: JG
authors.lastname: Oh
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., J.A., J.G.O., N.H., L.F., L.L., B.P., C.G.S.G., K.F., R.J.H.).
authors.forename: Nadjib
authors.initials: N
authors.lastname: Hammoudi
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., J.A., J.G.O., N.H., L.F., L.L., B.P., C.G.S.G., K.F., R.J.H.).
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Fish
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., J.A., J.G.O., N.H., L.F., L.L., B.P., C.G.S.G., K.F., R.J.H.).
authors.forename: Lauren
authors.initials: L
authors.lastname: Leonardson
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., J.A., J.G.O., N.H., L.F., L.L., B.P., C.G.S.G., K.F., R.J.H.).
authors.forename: Belén
authors.initials: B
authors.lastname: Picatoste
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., J.A., J.G.O., N.H., L.F., L.L., B.P., C.G.S.G., K.F., R.J.H.).
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Santos-Gallego
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., J.A., J.G.O., N.H., L.F., L.L., B.P., C.G.S.G., K.F., R.J.H.).
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Fish
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY (K.I., J.A., J.G.O., N.H., L.F., L.L., B.P., C.G.S.G., K.F., R.J.H.).
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000150:complications* / Q000000981:diagnostic imaging / Q000473:pathology; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D015984:Causality; D004195:Disease Models, Animal; D004452:Echocardiography; D006325:Heart Atria / Q000000981:diagnostic imaging; D006333:Heart Failure / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000201:enzymology / Q000473:pathology; D006339:Heart Rate; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000473:pathology*; D006984:Hypertrophy / Q000473:pathology; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D013318:Stroke Volume / Q000502:physiology; D013552:Swine; D013599:Systole / Q000502:physiology; D059289:Vascular Stiffness; D016277:Ventricular Function, Left / Q000502:physiology*
chemical_list: D000252:Calcium-Transporting ATPases
keywords: diastolic dysfunction; fibrosis; hypertrophy; stiffness; systolic dysfunction