title: Distinct Endothelial Cell Responses in the Heart and Kidney Microvasculature Characterize the Progression of Heart Failure With Preserved Ejection Fraction in the Obese ZSF1 Rat With Cardiorenal Metabolic Syndrome.
abstract: BACKGROUND
  The combination of cardiac and renal disease driven by metabolic risk factors, referred to as cardiorenal metabolic syndrome (CRMS), is increasingly recognized as a critical pathological entity. The contribution of (micro)vascular injury to CRMS is considered to be substantial. However, mechanistic studies are hampered by lack of in vivo models that mimic the natural onset of the disease. Here, we evaluated the coronary and renal microvasculature during CRMS development in obese diabetic Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats.
  
  
  RESULTS
  Echocardiographic, urine, and blood evaluations were conducted in 3 groups (Wistar-Kyoto, lean ZSF1, and obese ZSF1) at 20 and 25 weeks of age. Immunohistological evaluation of renal and cardiac tissues was conducted at both time points. At 20 and 25 weeks, obese ZSF1 rats showed higher body weight, significant left ventricular hypertrophy, and impaired diastolic function compared with all other groups. Indices of systolic function did not differ between groups. Obese ZSF1 rats developed hyperproliferative vascular foci in the subendocardium, which lacked microvascular organization and were predilection sites of inflammation and fibrosis. In the kidney, obese ZSF1 animals showed regression of the peritubular and glomerular microvasculature, accompanied by tubulointerstitial damage, glomerulosclerosis, and proteinuria.
  
  
  CONCLUSIONS
  The obese ZSF1 rat strain is a suitable in vivo model for CRMS, sharing characteristics with the human syndrome during the earliest onset of disease. In these rats, CRMS induces microvascular fibrotic responses in heart and kidneys, associated with functional impairment of both organs.
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Christian G M
authors.initials: CG
authors.lastname: van Dijk
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Nynke R
authors.initials: NR
authors.lastname: Oosterhuis
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Yan Juan
authors.initials: YJ
authors.lastname: Xu
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Maarten
authors.initials: M
authors.lastname: Brandt
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Paulus
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Loek
authors.initials: L
authors.lastname: van Heerebeek
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Duncker
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Verhaar
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Dulce
authors.initials: D
authors.lastname: Fontoura
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: André P
authors.initials: AP
authors.lastname: Lourenço
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Adelino F
authors.initials: AF
authors.lastname: Leite-Moreira
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Falcão-Pires
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal.
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Joles
authors.affiliation: From the Division of Internal Medicine and Dermatology, Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands (C.G.M.v.D., N.R.O., Y.J.X., M.C.V., J.A.J., C.C.); Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (W.J.P., L.v.H.); Experimental Cardiology, Department of Cardiology, Thoraxcenter Erasmus University Medical Center, Rotterdam, The Netherlands (M.B., D.J.D., C.C.); Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal (D.F., A.P.L., A.F.L.-M., I.F.-P.); Departments of Anesthesiology (A.P.L.) and Cardiothoracic Surgery (A.F.L.-M.), Hospital São João, Porto, Portugal. K.L.Cheng-2@umcutrecht.nl.
authors.forename: Caroline
authors.initials: C
authors.lastname: Cheng
mesh_terms: D000818:Animals; D059347:Cardio-Renal Syndrome / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D005921:Glomerulonephritis / Q000209:etiology / Q000503:physiopathology; D006333:Heart Failure / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000503:physiopathology; D007668:Kidney / Q000098:blood supply*; D008297:Male; D024821:Metabolic Syndrome / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology; D055806:Microvessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D011507:Proteinuria / Q000209:etiology / Q000503:physiopathology; D011921:Rats, Inbred WKY; D011924:Rats, Zucker; D013318:Stroke Volume; D013997:Time Factors; D066253:Vascular Remodeling; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
keywords: animal model; cardiorenal syndrome; endothelial cell; heart failure; mortality