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.