Diastolic Heart Failure: Diastolic Heart Failure: A Matter of A Matter of

Renal Dysfunction?Renal Dysfunction?

Maria Rosa Costanzo, M.D., F.A.C.C., F.A.H.AMaria Rosa Costanzo, M.D., F.A.C.C., F.A.H.AMedical Director, Midwest Heart Specialists Heart Failure and Pulmonary Medical Director, Midwest Heart Specialists Heart Failure and Pulmonary

Arterial Hypertension ProgramsArterial Hypertension ProgramsMedical Director, Edward Hospital Center for Advanced Heart FailureMedical Director, Edward Hospital Center for Advanced Heart Failure

Naperville, IllinoisNaperville, IllinoisU.S.A.U.S.A.

Hillege, H. L. et al. Circulation 2006;113:671-678

Renal Function Influences Outcomes of Patients with Heart Failure Regardless of Ejection Fraction

Mullens, W. et al. J Am Coll Cardiol 2009;53:589-96

ROC Curves for CVP and CI on Admission for the Development of WRF

Mullens, W. et al. J Am Coll Cardiol 2009;53:589-596

Prevalence of Worsening Renal Function During Hospitalization According to Categories of Admission CVP, CI, SBP, and PCWP

Impact of Venous Congestion Impact of Venous Congestion on Glomerular Net Filtration on Glomerular Net Filtration

PressurePressure

Jessup M and Costanzo MR. J Am Coll Cardiol 2009; 53:597-9

Damman, K. et al. J Am Coll Cardiol 2009;53:582-588

Relationship Between CVP and eGFR According to Different Cardiac Index Values

p = 0.0217 for interaction between CI and CVP on the relationship with eGFR.

CI <2.5 l/min/m2

CI 2.5 to 3.2 l/min/m2

CI >3.2 l/min/m2

Changes in Renal Function with Changes in Renal Function with AgeAge

Fliser D et al. Kidney Int. 1997; 51: 1196-204

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%

Differential Decline in Renal Differential Decline in Renal Function with Age in Men and Function with Age in Men and

WomenWomen

EstrogenEstrogen– Increased NO productionIncreased NO production– Antigrowth effect on glomerular Antigrowth effect on glomerular

mesangial cellsmesangial cells– Inhibition of mesangial Inhibition of mesangial

extracellular matrix accumulationextracellular matrix accumulation– Stimulation of endothelial NOStimulation of endothelial NO– Inhibition of AII effectsInhibition of AII effects

GFR/BSA EPRF/BSA

Filtration Fraction

Berg UB Nephrol Dial Transplant 2006; 21: 2577-82

Estimated Distribution of Calibrated SrCr LevelsEstimated Distribution of Calibrated SrCr Levels in the U.S. Population in the U.S. Population

(NHNES III) (NHNES III)

Coresh et al. Am Kidney Dis 2003; 41: 1-12

Men

Women

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

The Hallmarks of the Aging KidneyThe Hallmarks of the Aging KidneyIntimal Thickening

of Interlobular ArteryHyaline Atherosclerosis Reduplication of

Internal Elastica Lamina

Glomerulosclerosis, Tubular Atrophy, Vascular Changes

Hypertrophic Glomerulus, Compensating for Obsolete

Ones

Renal AgingRenal Aging

Genetic InfluencesGenetic Influences– Androgen productionAndrogen production– Loss of one allele of glial cell-derived Loss of one allele of glial cell-derived

neurotrophic factorneurotrophic factor 30% fewer glomeruli30% fewer glomeruli HTNHTN Glomerular HypertrophyGlomerular Hypertrophy HyperfiltrationHyperfiltration

– Reduced expression of the gene for the Reduced expression of the gene for the senescence marker protein 30 (SMP30)senescence marker protein 30 (SMP30)

Senescence of proximal tubules:Senescence of proximal tubules:– Lipofuscin accumulationLipofuscin accumulation– Enlargement of lisosomesEnlargement of lisosomes– AccumulationAccumulation of electron-dense materialof electron-dense material

– Downregulation of Downregulation of klothoklotho gene by AII gene by AII Altered Calcium and Phosphorus Altered Calcium and Phosphorus

omeostasisomeostasis– AA heritageAA heritage

Increased susceptibility for hypertensive Increased susceptibility for hypertensive nephrosclerosisnephrosclerosis

Cellular ChangesCellular Changes– Subcellular structural changesSubcellular structural changes

Brush border abnormalitiesBrush border abnormalities Mitochondrial changesMitochondrial changes Lipofuscin acc.Lipofuscin acc.

– Somatic and Mitochondrial DNA Somatic and Mitochondrial DNA mutationsmutations

– Telomere ShorteningTelomere Shortening– Oxidative damageOxidative damage

Imbalance between free radicals from Imbalance between free radicals from aerobic metabolism and endogenous aerobic metabolism and endogenous scavengers (superoxide dismutase, scavengers (superoxide dismutase, Vit. C & E, selenium) leading to Vit. C & E, selenium) leading to carbonylation and nitrotyrosinationcarbonylation and nitrotyrosination

– Accumulation of AGEsAccumulation of AGEs Direct toxicityDirect toxicity Interaction with RAGEs leading to Interaction with RAGEs leading to

inflammatory molecule inflammatory molecule expressionexpression

– Increased apoptosisIncreased apoptosis– Single gene expression changesSingle gene expression changes

HypoxiaHypoxia FibrosisFibrosis InflammationInflammation

Renal AgingRenal Aging Functional changesFunctional changes

– GFRGFR 7.5-8.0 ml/min per decade7.5-8.0 ml/min per decade Accelerated by HTN and Accelerated by HTN and

other acute and chronic other acute and chronic illnessesillnesses

ProteinuriaProteinuria

– Tubular changesTubular changes Loss of concentration abilityLoss of concentration ability Loss of dilution abilityLoss of dilution ability Loss of ability to excrete NaLoss of ability to excrete Na++

and Hand H22OO

– Blunted renin responsesBlunted renin responses

Vascular ChangesVascular Changes– RBFRBF

Actual Actual (10%/decade from age 40)(10%/decade from age 40)

In relation to COIn relation to CO

– Renal arteriolesRenal arterioles Altered responsivenessAltered responsiveness Autoregulation Autoregulation Sensitivity to a number of Sensitivity to a number of

agentsagents

– Intrarenal arterial changesIntrarenal arterial changes

Hyaline Atherosclerosis

Fibrointimal

Hyperplasia

•Outer Cortical Glomerulosclerosis•Local Tubular Hypertrophy•Interstitial Fibrosis

Hypertrophy of Medullary Glomeruli

Hyperfiltration Injury

Segmental and Global Glomerulosclerosis

Protein-Rich Diet

Renal AgingRenal Aging Interstitial ChangesInterstitial Changes

– TubulesTubules Thickening of basement membraneThickening of basement membrane Luminal dilatationLuminal dilatation Epithelial flatteningEpithelial flattening Accumulation of eosinophilic hylaline Accumulation of eosinophilic hylaline

cast materialcast material NumberNumber Volume Volume (PTV from 0.076 mm(PTV from 0.076 mm33 at 20- at 20-

39 y to 0.059 mm39 y to 0.059 mm33 at 80-101 y) at 80-101 y) Length Length DiverticulaDiverticula

– Interstitial fibrosisInterstitial fibrosis Fibronectin and TGF-Fibronectin and TGF-ββ MMPMMP Upregulation of hypoxia-induced Upregulation of hypoxia-induced

genes (HIF, VEGF, GLUT1)genes (HIF, VEGF, GLUT1) Advanced glycation end-products Advanced glycation end-products

(AGEs)(AGEs)– Binding to mesangial cells RAGEs>oxidant stress-Binding to mesangial cells RAGEs>oxidant stress-

dependent NF-kB> inflammatory cytokines, TGF- dependent NF-kB> inflammatory cytokines, TGF- ββ, , CTGFCTGF

Glomerular ChangesGlomerular Changes– NumberNumber

600,000-1,200,000 until age 40600,000-1,200,000 until age 40 Progressive 30%-50% thereafterProgressive 30%-50% thereafter

– Percent of glomeruli with Percent of glomeruli with sclerosissclerosis

10% by age 4010% by age 40 Up to 36% after age 50Up to 36% after age 50 Subcapsular > juxtamedullarySubcapsular > juxtamedullary Filtration area of the glomerular Filtration area of the glomerular

basement membrane/permeability> basement membrane/permeability> GFRGFR

– Mesangial matrix volume & Mesangial matrix volume & materialmaterial

Due to imbalance between formation Due to imbalance between formation and breakdown of extracellular matrixand breakdown of extracellular matrix

Determinants of Hypertensive Renal Determinants of Hypertensive Renal DamageDamage

Relationship between BP and Renal Damage

Spectrum of Pressure/Flow Relationships in the Renal Vascular

Bed in HTN

Nl. Renal Autoregulation

Ambient Renal Vasodil. & Preserved Autoregulation after

Uninephrectomy

Impaired RBF Autoregulation

Complete Loss of RBF

Autoregulation

1. Systemic BP “Load”

2. Degree to which BP Load Is Transmitted to Renal Vascular Bed

3. Local Tissue Susceptibility to Barotrauma

Bidani AK and Griffin KA Hypertension 2004; 44: 595-601

0.87

1.12 1.12 1.161.31

1.521.66

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Od

ds

Rat

ios

Female Gender Weight ↑ 10 lbs Baseline SrCr↑ 1 mg/dl

SBP ↑ 10mmHg

N. Cigarettes ↑5/day

Carotid IntimalThickness ↑

0.1 mm

Age ↑ 5Y

ODDS RATIO FOR CHANGES IN SERUM CREATININE >/= 0.3 MG/dL

Tobacco, HTN, and Vascular Disease: Risk Factors Tobacco, HTN, and Vascular Disease: Risk Factors for Renal Functional Decline in an Older Populationfor 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

2.29 2.26

1.771.68

1.6

0

0.5

1

1.5

2

2.5

Od

ds

Rat

io

Current Smokers> 20 Cig./day

Fibrinogen > 3.5g/L

DM Age > 75 Y Isolated SystolicHTN

RISK FACTORS FOR PATHOLOGICAL RENAL DECLINE (SCr Increase > 26.5 mmol/L)

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

The Kidney, Hypertension and The Kidney, Hypertension and ObesityObesityObesity

Tubular Na+Cl-

Reabsorption

ArterialHypertension

Glomerulosclerosis

Renal Medullary

CompressionRAS

Activity

Leptin/POMC

SNS Activity

Volume ExpansionRenal

Vasodilatation

Glomerular Hypertension

+

Lipids

GlucoseIntolerance

Glucose

Hall JE Hypertension 2003; 41: 625-33

The Dietary NaThe Dietary Na++ClCl- - -BP Plot -BP Plot “S“Stiffenstiffens””↑↑Na+Cl- IntakeNa+Cl- Intake

↑AII

↑AT1R Signaling

Brain CV TissuesKidney

Ouabain-Like Substance

Adrenal Cortex

Release of Sodium Pump Ligands(Marinobufagenin)

Growth Factors, Fibronectin,

MMP II

Inhibition of Na+K+ Pump in the Kidney

Inhibition of Na+K+ Pump

in Vascular Cells

Vasoconstriction Na+ and H2O Reabsorption

↑NADPH Oxidase ↑Asymmetric Dimethylarginine

Peroxinitrite

Oxidative Damage of Arterial Wall

Inhibition of NOS

↓NO Production

↓NO Bioavailability

Altered Endothelial Cells FunctionAltered Vascular Cells Function

Arterial Wall Hypertrophy and Structural Remodeling↑ Arterial Stiffening and ↓ Compliance

↑Intravascular Volume

Bagrov Y et al. Hypertension 2004; 44: 22-4

TOHP I(n=744)

Active Na+ Intervention(n= 327)

Ususal Care(n= 417)

TOPH II(n=2382)

Active Na+ Intervention(n= 1191)

Na+ Control(n= 1191)

Combined Intervention

(n= 597)

Na+ Only Intervention

(n+594)

Wt. Loss Intervention

(n=595)

Usual Care(n= 596)

Incidence of CVD

Decreased by 25%

Total Mortality Decreased

by 19%

Cook NR et al. BMJ 2007; 334: 885-93

Long Term Dietary Sodium

Reduction Independently

Improves CV Outcomes!

Cardiorenal Syndrome Type 4

Cardiorenal Syndrome Type 5

ConclusionsConclusions HFNEF HFNEF and coexisting renal dysfunction have the

underlying common denominatorcommon denominator of of Vascular Vascular Stiffness.Stiffness.

The cardiac and renal changes which accompany The cardiac and renal changes which accompany advancing age are, at least in part, advancing age are, at least in part, adaptiveadaptive, , occurring to some extent in response to the occurring to some extent in response to the arterial changes that occur with aging.arterial changes that occur with aging.

These age-related adaptive changes may vary by These age-related adaptive changes may vary by gendergender

Age associated changes of heart and kidneys are Age associated changes of heart and kidneys are amplifiedamplified by risk factors for cardiovascular by risk factors for cardiovascular disease, including hypertension, dyslipidemia, disease, including hypertension, dyslipidemia, smoking, obesity, and DM. smoking, obesity, and DM.

Salt intakeSalt intake plays a pivotal role in the plays a pivotal role in the development and progression of vascular development and progression of vascular stiffness.stiffness.

Regardless of whether damage occurs first in the Regardless of whether damage occurs first in the heart or in the kidney, heart or in the kidney, the impairment of each the impairment of each organ eventually worsens the structure and organ eventually worsens the structure and function of the other.function of the other.