Diastolic Heart Failure: A Matter of Renal Dysfunction?

1. Diastolic Heart Failure: A Matter of Renal Dysfunction? Maria Rosa Costanzo, M.D., F.A.C.C., F.A.H.A Medical Director, Midwest Heart Specialists Heart Failure and Pulmonary Arterial Hypertension Programs Medical Director, Edward Hospital Center for Advanced Heart Failure Naperville, Illinois U.S.A.

2. Renal Function Influences Outcomes of Patients with Heart Failure Regardless of Ejection Fraction Hillege, H. L. et al. Circulation 2006;113:671-678

3. ROC Curves for CVP and CI on Admission for the Development of WRF Mullens, W. et al. J Am Coll Cardiol 2009;53:589-96

4. Prevalence of Worsening Renal Function During Hospitalization According to Categories of Admission CVP, CI, SBP, and PCWP Mullens, W. et al. J Am Coll Cardiol 2009;53:589-596

5. Impact of Venous Congestion on Glomerular Net Filtration Pressure Jessup M and Costanzo MR. J Am Coll Cardiol 2009; 53:597-9

6. Relationship Between CVP and eGFR According to Different Cardiac Index Values CI >3.2 l/min/m2 CI <2.5 l/min/m2 CI 2.5 to 3.2 l/min/m2 p = 0.0217 for interaction between CI and CVP on the relationship with eGFR. Damman, K. et al. J Am Coll Cardiol 2009;53:582-588

7. Changes in Renal Function with Age SrCr .9±.1 .9±.1 1±.2 1.1±.2 • % With Nl. GFR • Young NT = 100% • Elderly NT = 66% • Elderly HT = 64% • Elderly HF = 29% • % With Nl. ERPF • Young NT = 100% • Elderly NT = 45% • Elderly HT = 24% • Elderly HF = 21% Fliser D et al. Kidney Int. 1997; 51: 1196-204

8. Differential Decline in Renal Function with Age in Men and Women • Estrogen • Increased NO production • Antigrowth effect on glomerular mesangial cells • Inhibition of mesangial extracellular matrix accumulation • Stimulation of endothelial NO • Inhibition of AII effects EPRF/BSA GFR/BSA Filtration Fraction Berg UB Nephrol Dial Transplant 2006; 21: 2577-82

9. Estimated Distribution of Calibrated SrCr Levels in the U.S. Population (NHNES III) Men At the same SrCr, a greater % of women have more reduced GFR • Multiple factors contribute • to SCr concentration • Renal function • Cr production • in muscles • Cr secretion from • renal tubules • The majority of elderly • adults have at least mild • reductions in GFR • (< 90 ml/min/ 1.73 m2) • ¼ of individuals >70 y: • GFR < 60 ml/min/1.73 m2 Women Coresh et al. Am Kidney Dis 2003; 41: 1-12

10. The Hallmarks of the Aging Kidney Intimal Thickening of Interlobular Artery Reduplication of Internal Elastica Lamina Hyaline Atherosclerosis Hypertrophic Glomerulus, Compensating for Obsolete Ones Glomerulosclerosis, Tubular Atrophy, Vascular Changes

11. Genetic Influences Androgen production Loss of one allele of glial cell-derived neurotrophic factor 30% fewer glomeruli HTN Glomerular Hypertrophy Hyperfiltration Reduced expression of the gene for the senescence marker protein 30 (SMP30) Senescence of proximal tubules: Lipofuscin accumulation Enlargement of lisosomes Accumulationof electron-dense material Downregulation of klotho gene by AII Altered Calcium and Phosphorus omeostasis AA heritage Increased susceptibility for hypertensive nephrosclerosis Cellular Changes Subcellular structural changes Brush border abnormalities Mitochondrial changes Lipofuscin acc. Somatic and Mitochondrial DNA mutations Telomere Shortening Oxidative damage Imbalance between free radicals from aerobic metabolism and endogenous scavengers (superoxide dismutase, Vit. C & E, selenium) leading to carbonylation and nitrotyrosination Accumulation of AGEs Direct toxicity Interaction with RAGEs leading to inflammatory molecule expression Increased apoptosis Single gene expression changes Hypoxia Fibrosis Inflammation Renal Aging

12. Functional changes GFR 7.5-8.0 ml/min per decade Accelerated by HTN and other acute and chronic illnesses Proteinuria Tubular changes Loss of concentration ability Loss of dilution ability Loss of ability to excrete Na+ and H2O Blunted renin responses Vascular Changes RBF Actual (10%/decade from age 40) In relation to CO Renal arterioles Altered responsiveness Autoregulation Sensitivity to a number of agents Intrarenal arterial changes Renal Aging Hyaline Atherosclerosis Fibrointimal Hyperplasia • Outer Cortical Glomerulosclerosis • Local Tubular Hypertrophy • Interstitial Fibrosis Protein-Rich Diet Hypertrophy of Medullary Glomeruli Hyperfiltration Injury Segmental and Global Glomerulosclerosis

13. Interstitial Changes Tubules Thickening of basement membrane Luminal dilatation Epithelial flattening Accumulation of eosinophilic hylaline cast material Number Volume (PTV from 0.076 mm3 at 20-39 y to 0.059 mm3 at 80-101 y) Length Diverticula Interstitial fibrosis Fibronectin and TGF-β MMP Upregulation of hypoxia-induced genes (HIF, VEGF, GLUT1) Advanced glycation end-products (AGEs) Binding to mesangial cells RAGEs>oxidant stress-dependent NF-kB> inflammatory cytokines, TGF- β, CTGF Glomerular Changes Number 600,000-1,200,000 until age 40 Progressive 30%-50% thereafter Percent of glomeruli with sclerosis 10% by age 40 Up to 36% after age 50 Subcapsular > juxtamedullary Filtration area of the glomerular basement membrane/permeability> GFR Mesangial matrix volume & material Due to imbalance between formation and breakdown of extracellular matrix Renal Aging

14. Determinants of Hypertensive Renal Damage • Systemic BP “Load” • Degree to which BP Load Is Transmitted to Renal Vascular Bed • Local Tissue Susceptibility to Barotrauma Spectrum of Pressure/Flow Relationships in the Renal Vascular Bed in HTN Relationship between BP and Renal Damage Complete Loss of RBF Autoregulation Impaired RBF Autoregulation Nl. Renal Autoregulation Ambient Renal Vasodil. & Preserved Autoregulation after Uninephrectomy Bidani AK and Griffin KA Hypertension 2004; 44: 595-601

15. ODDS RATIO FOR CHANGES IN SERUM CREATININE >/= 0.3 MG/dL 1.66 1.8 1.52 1.6 1.31 1.4 1.16 1.12 1.12 1.2 0.87 1 Odds Ratios 0.8 0.6 0.4 0.2 0 Female Gender Weight ↑ 10 lbs Baseline SrCr SBP ↑ 10 N. Cigarettes ↑ Carotid Intimal Age ↑ 5Y ↑ 1 mg/dl mmHg 5/day Thickness ↑ 0.1 mm Tobacco, HTN, and Vascular Disease: Risk Factors for Renal Functional Decline in an Older Population P= 0.53 P= 0.0005 P= 0.0001 P= 0.0003 P= 0.0011 P= 0.011 P= 0.0001 Bleyer AJ et al. Kidney Int 2000; 57:202-9

16. Atherosclerotic Burden Accelerates Renal Function Decline in the Elderly: The Italian Longitudinal Study on Ageing (ILSA) P= 0.050 P < 0.001 P=0.017 P=0.006 P=0.050 Baggio B et al. Nephrol Dial Transplant 2005; 20: 114-23

17. The Kidney, Hypertension and Obesity Obesity Leptin/POMC Renal Medullary Compression SNS Activity RAS Activity Glucose Intolerance Tubular Na+Cl- Reabsorption Renal Vasodilatation + Volume Expansion Lipids Arterial Hypertension Glomerular Hypertension Glucose Glomerulosclerosis Hall JE Hypertension 2003; 41: 625-33

18. The Dietary Na+Cl- -BP Plot “Stiffens” ↑Na+Cl- Intake ↑AII ↑AT1R Signaling Brain Kidney CV Tissues Ouabain-Like Substance ↑NADPH Oxidase ↑Asymmetric Dimethylarginine Adrenal Cortex Peroxinitrite Inhibition of NOS Release of Sodium Pump Ligands (Marinobufagenin) Oxidative Damage of Arterial Wall ↓NO Production Inhibition of Na+K+ Pump in Vascular Cells Inhibition of Na+K+ Pump in the Kidney Growth Factors, Fibronectin, MMP II ↓NO Bioavailability Vasoconstriction Na+ andH2O Reabsorption Altered Endothelial Cells Function Altered Vascular Cells Function Arterial Wall Hypertrophy and Structural Remodeling ↑ Arterial Stiffening and ↓ Compliance ↑Intravascular Volume Bagrov Y et al. Hypertension 2004; 44: 22-4

19. Long Term Dietary Sodium Reduction Independently Improves CV Outcomes! Incidence of CVD Decreased by 25% Total Mortality Decreased by 19% Cook NR et al. BMJ 2007; 334: 885-93

23. Cardiorenal Syndrome Type 4

24. Cardiorenal Syndrome Type 5

25. Conclusions • HFNEF and coexisting renal dysfunction have the underlying common denominator of Vascular Stiffness. • The cardiac and renal changes which accompany advancing age are, at least in part, adaptive, occurring to some extent in response to the arterial changes that occur with aging. • These age-related adaptive changes may vary by gender • Age associated changes of heart and kidneys are amplified by risk factors for cardiovascular disease, including hypertension, dyslipidemia, smoking, obesity, and DM. • Salt intake plays a pivotal role in the development and progression of vascular stiffness. • Regardless of whether damage occurs first in the heart or in the kidney, the impairment of each organ eventually worsens the structure and function of the other.