Uremic Cardiomyopathy with a focus on the role of α-klotho and FGF23

Transcription

1 Uremic Cardiomyopathy with a focus on the role of α-klotho and FGF23 Marc G Vervloet, MD, PhD, FERA VU university medical center Amsterdam, The Netherlands

2 Disclosures Scientific support AbbVie, Amgen, Dutch Kidney Foundation, FMC, Pfizer, Sanofi, Shire, Consultant, lecture fees, other AbbVie, Alexion, Amgen, Astellas, FMC (See DOI at

3 Content Introduction Phenotypes of uremic cardiomyopathy Geometry The role of α-klotho and FGF23 Microbiome and klotho Treatment perspective of novel insights?

4 What is uremic cardiomyopathy Hypertrophy? Fibrosis? Propensity of arrythmia? HFpEF? Remodeling? Does it include valvular disease?

5 Not all that glitters is gold

6 Bodyak, PNAS 2007 Paricalcitol and LVH (DSS rat)

7 PRIMO trial on Left Ventricular Hypertrophy Placebo 227 diabetics, moderate LVH egfr Age: 65 Paricalcitol 2 mg Thadhani, JAMA 2012 Randomized, Double-blind follow-up: 48 weeks

8 PRIMO trial on Left Ventricular Hypertrophy Placebo 0.07 g/m 2 P=0.06 Paricalcitol 2 mg 0.34 g/m 2 Thadhani, JAMA 2012

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10 Dialysis outcome (Netherlands, complete data) Patients on renal replacement therapy Annual mortality Renine 2016

11 Progress in treatment requires: Novel interventions on known pathways Develop interventions on novel pathways

12 Mechanical Volume overload Hypertension Arterial stiffness Valvular disease High output (shunt) Asynchronicity Non-Mechanical/Metabolic FGF23 excess α-klotho deficiency Uremic retention molecules RAAS activation Autonomous nervous system Inflammation

13 Phenotypes and outcome Concentric remodeling Concentric hypertrophy Normal Absent Eccentric hypertrophy Present Left Ventricular Hypertrophy Rodriguez,J Am Coll Card 2010

14 Geometry and outcome Concentric hypertrophy Eccentric hypertrophy Concentric remodeling Normal Paoletti, Clin J Am Soc Nephrol 2015

15 Increased risk for cardiovascular events among CKD patients Go, A. et al. N Engl J Med 2004 U.S. Renal Data System, USRDS 2014 Annual Data Report

16 Cardiorenal connections Disturbed volume homeostasis Sodium retention Sympathetic activity RAAS activation Inflammation and oxidant stress Novel insights: FGF-23 too high, Klotho too low

17 Fibroblast Growth Factor 23 a bone derived phosphate lowering hormone Phosphaturia FGF23 Vitamin D metabolites Hyperphosphatemia

18 FGF23 receptor: klotho comes in CYP27B1 Pi transport PTH inhibition } } Renal effects Parathyroid effects Urakawa. Nature 2006 Vervloet, Larsson Kidney Int Suppl 2011

19 Isakova, JAMA 2011 FGF23 in CKD stage II-IV

20 Faul 2011 J Clin Invest Causality for FGF23?

21 Faul, J Clin Invest 2011 The role of FGF23

22 Sham 5/6 Nephrectomy 5/6 Nephrectomy + FGFR blocker Sham 5/6 Nx 5/6 Nx + FGFR blocker Faul 2011 JCI

23 FGF23 studies in mice: Cardiovascular endpoints Control CKD Control + FGF23 CKD - FGF23 Verkaik, Vervloet ERA-EDTA 2016

24 Myocardial perfusion in mice LV lumen Myocardium Long axis view of LV in end-systole Verkaik, Vervloet ERA-EDTA 2016

25 Control FGF23 CKD - FGF23 CKD induces endothelial dysfunction in the myocardium Sham Reduced Flow reserve M ic ro v a s c u la r b lo o d v o lu m e (a rb. u n its ) B a s e lin e # $ A c h 5 g /k g /m in SShamh a m 55/6 NNx x 5/6Nx Acetylcholine Verkaik, Vervloet ERA-EDTA 2016 Data are Mean±SEM, # p<0.05 vs. Baseline; $ p<0.05 vs. Sham.

26 Control FGF23 CKD - FGF23 FGF23 and myocardial flow reserve Acetylcholine Microvascular blood volume Video intensity (arb. unit) Baseline Ach 5 g/kg/min Ach 7,5 g/kg/min PBS i.p. injections FGF23 i.p. injections Verkaik, Vervloet ERA-EDTA 2016

27 Assessment of cardiomyocyte contraction and relaxation Shenoy, Nature 2011

28 A r b i t r a r y u n i t s ( % ) A r b i t r a r y u n i t s ( % ) A r b i t r a r y u n i t s ( % ) Control FGF23 CKD - FGF23 FGF23 causes calcium flux disturbances (Isolated cardiomyocytes) A r b i t r a r y u n i t s ( % ) Diastolic D i a s t o l i c Sarcomere S a r c o m e r e l elength n g t h Diastolic Calcium Fura340/380 ratio ** Sham surgery 5/6 Nx surgery PBS i.p. injections FGF23 i.p. injections A r b i t r a r y u n i t s ( % ) Calcium influx velocity C a l c i u m i n f l u x v e l o c i t y * * * * Systolic Sarcomere Length S y s t o l i c S a r c o m e r e L e n g t h Systolic Calcium S y s t o l i c C a l c i u m Calcium efflux velocity C a l c i u m e f f l u x v e l o c i t y * * * * * * * * * * * * Working on the molecular mechanism Verkaik, Vervloet ERA-EDTA 2016

29 Cardiac MRI in mice RV LV RV LV LV (average HR mouse during MRI: ~ 500BPM) No effect in short term experiment Cine FLASH MRI Field of view: 3x3 cm 2 TR 7 ms, TE 1.8 ms, acq time: 2 min per slice 50 frames/cardiac cycle ECG prospectively triggered and respiratory gated Verkaik, Vervloet ERA-EDTA 2016 Collaboration with Eindhoven University of Technology (TU/e): D. Abdurrachim and Dr. J.J. Prompers

30 Shalhoub, J Clin Invest 2012 Blocking FGF23?

31 Hope from FGF23 research Specific FGFR4 function Grabner, Cell Metab 2015

32 Hagel, Cancer Discovery 2015

33 FGF23 and Klotho Modern summary of nephrology

34 Serum αklotho (pm) α-klotho declines in progressive human CKD Immunoprecipitation-Immunoblotting Healthy Dialysis Barker, Nephrol Dial Transplant 2015

35 Klotho deficiency causes LVH and fibrosis (in CKD) Xie, J Am Soc Nephrol 2015

36 Xie, Nature comm 2012 sklotho protection via TRPC6

37 Hope for specific targeting TRPC6 Urban, Mol Pharmacol 2016

38 Indoxyl sulphate and sklotho Yang, J Am Soc Nephrol 2015

39 CKD and α-klotho-expression P-Cresyl sulphate Indoxyl sulphate Young, Kidney Int 2012 Sun, Kidney Int 2012

40 CKD microbiome and LVH Urea Ammonia CKD microbiome Preventing toxin production: Low protein diet Probiotic, prebiotic, synbiotic treatment Oral sorbent? GI permeability Toxin removal: Dialysis Transplantation Inflammation Lekawanvijit, Circ J 2015

41 Conclusions FGF23 induces heart disease α-klotho protects from heart disease Besides lowering FGF23 or increasing sklotho, specific interventions (for instance at FGFR4; blocking TRPC6) hold promise Modulating microbiome: promising

42 Thank you!