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Cardiovascular problems on hemodialysis – current deficits and potential improvements. Eberhard Ritz Heidelberg (Germany). Epidemiological facts Underlying cardiac disease coronary heart disease cardiomyopathy New therapeutic targets - salt and salt mediated hormones

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slide1

Cardiovascular problems on hemodialysis –

current deficits and potential improvements

Eberhard Ritz

Heidelberg (Germany)

slide2

Epidemiological facts

Underlying cardiac disease

  • coronary heart disease
  • cardiomyopathy

New therapeutic targets

- salt and salt mediated hormones

- sympathetic activity

Neglected cardiovascular risks

- depression

- sleep apnea

  • disrupted biorhythm

Attractive areas for future investigation

- micro-RNA – arrhythmia/cardiac fibrosis

  • salt and marinobufagenin
  • sympathetic overactivity and beta blockers
  • oxydative stress
slide3

Only observational evidence, but …

Ultrafiltration rate andtreatment time –

impact on mortality

(DOPPS study)

ultrafiltration rate

treatment time

odds ratio

intradialytic hypotension

1.3 (p=0.045)

Saran, Kidn.Internat.(2006) 69:1222

slide4

Diureticuse

(DOPPS study)

rel.risk

diureticvsnodiuretic

all cause mortality 0.93 p=0.12

cardiac mortality 0.86 p<0.03

interdialytic weight gain > 5.7% 0.51 p<0.0001

hypotensive episodes 0.55 p<0.006

Bragg-Gresham, Am.J.Kidn.Dis.(2007) 49:426

slide5

In the case of dialysis patients, a low normal level of ECV is maintained

by the powerful tool of ultrafiltration,

which if properly used along with

moderate dietary sodium restriction and

maintenance of natriuresis by diuretics,

are the only proven method of

controlling blood pressure in the hemodialysis population.

Scribner, Trans. Am. Soc. Artif. Intern. Organs (1960) 6:114

slide6

Epidemiological facts

Underlying cardiac disease

  • coronary heart disease vs.
  • cardiomyopathy

New therapeutic targets

- salt and salt mediated hormones

- sympathetic activity

Neglected cardiovascular risks

- depression

- sleep apnea

- disrupted biorhythm

Attractive areas for future investigation

- micro-RNA – arhythmia/cardiac fibrosis

- salt and marinobufagenin

- sympathetic overactivity and beta blockers

- oxydative stress

causes of death in dialysis patients
Causes of death in dialysis patients

USRDS

4D study

coronary heart disease 9 % 6 %

other cardiac causes 35 % 33 %

(sudden death 26%; heart failure 6%; other cardiac 3%)

stroke 6 % 10 %

non-cardiovascular 50 % 51%

Wanner, New Engl J Med (2005) 353:238

slide8
Higher mortality in CKD patients with diastolic (EF>45%) vs systolic heart failure(Digitalis Investigation Group Trial)

systolicmalfunction

diastolicmalfunction

Ahmed, Am.J.Cardiol.(2007) 99: 393

myocardial changes in patients with renal failure
Myocardial changes in patients with renal failure

normal morphology

morphology of the myocardium of a patient with chronic renal failure

consequences of cardiac fibrosis on heart function
Consequences of cardiac fibrosis on heart function
  • reduced LV compliance
  • arrhythmia

fibrous tissue encircling cardiomyocytes has high

electrical resistance

local delay of the spreading front of action potential

favours “reentry” type atrial and ventricular arrhythmias

slide11

Cardiac fibrosis –

most powerful predictor of survival in HD patients

(endomyocardial biopsies)

dilated

cardiomyopathy

idiopathic

< 30%

fibrosis

area

hemodialysis

> 30%

Aoki, Kidn.Internat.(2005) 67:333

cardiovascular risk in chronic kidney disease
Cardiovascular risk in chronic kidney disease

vascular disease

cardiomyopathy

  • atherosclerosis

(plaques)

  • arteriosclerosis

(arterial stiffening)

  • inappropriate (LV)

hypertrophy

  • interstitial fibrosis
  • microvessel

disease

(wall thickening of postcoronary

arteries,

capillary deficit)

systolic dysfunction, diastolic dysfunction,electrical instability

slide13

Epidemiological facts

Underlying cardiac disease

Novel pathogenetic pathways and therapeutic targets

- salt and salt mediated hormones

- (phosphate

- vitamin D)

- sympathetic activity

Neglected cardiovascular risks

- depression

- sleep apnea

- disrupted biorhythm

Attractive areas for future investigation

- micro-RNA – arhythmia/cardiac fibrosis

- salt and marinobufagenin

- sympathetic overactivity and beta blockers

- oxydative stress

slide14

Adverse effects of high salt

  • not only high blood pressure and hypervolemia, but also
  • blood pressure independent target organ damage

(cardiovascular damage, progression of CKD)

Frohlich, Hypertension (2007) 50:161

Matavelli, Journal of Physiology (Heart Circulation Physiol.) (2007) 292:h814

Sanders, Hypertension (2004)143:142

slide15

Marinobufagenin

cardiotonic steroid

inhibitor of Na+ K+ ATP’ase

- concentration correlated to cardiomyopathy

in subtotally nephrectomised rats

  • cardiomyopathy reproduced by

administration of marinobufagenin

  • cardiomyopathy prevented by

neutralizing antibodies to marinobufagenin

- deserves investigation in dialsysis patients

Kennedy, Hypertension (2006) 47:488

Federova, American Journal Physiology (Renal Physiology) (2009) e-pub

slide16

Correlationbetweenouabain (OLF) andleft

ventricularabnormalities in dialysispatients

Stella, J.Intern.Med.(2008) 263:274

Antagonist: Rostafuroxin ?

slide17

Therapeutic targets and potential future approaches

# reduction of salt intake (recommended by Scribner, but sadly forgotten today)

Ritz, Blood Purification (2006) 24:63

# lowering of serum Na concentration (physicochemical activity)

by adjusting dialysate Na concentration ?

even minor increases of sodium concentration in serum or cerebrospinal fluid

stimulate pressor-mechanisms and increases the release of cardiotonic steroids

Huang, Hypertension (2007) 49:1315

slide18

Newlydiagnosed essential hypertension :

diastolicbloodpressureand

plasmasodium

in different quartilesofouabain

Manunta, J.Hypertens.(2007) 26:914

slide19
Plasma sodium concentration stiffens human vascular endothelium in vitro –in the presence of aldosterone,abrogated by eplerenone

Oberleithner, Proc.Natl.Acad Sci USA (2007) 104:16281

slide20
In presence of activated mineralocorticoid receptor NO production by endothelial cells loweredby sodium

Wildling, Pflügers Arch. (2008)e-pub Sept 3rd

slide21

Therapeutic targets and potential future approaches

# reduction of salt intake

Ritz, Blood Purification (2006) 24:63

# lowering of serum Na concentration

by adjusting dialysate Na concentration ?

Huang, Hypertension (2007) 49:1315

# ouabain antagonistRostafuroxin

Ferrari, American Journal of Physiology (Regul. Integr. Comp. Physiol.) (2006) 290:r529

# aldosterone antagonist Spironolactone

Bomback, Nat.Clin.Pract.Nephrol.(2009) 5:74

lowering of blood pressure by 50 mg spironolactone in anuric hemodialysis patients no change in s k
Lowering of blood pressure by 50 mg Spironolactone in anurichemodialysis patients – no change in S-K+

Blood pressure : Spironolactone 142→131 mmHg

Placebo 146→142 mmHg

Gross, Am.J.Kidn.Dis (2005) 46:94

slide23

Quartiles of plasma aldosterone concentrations within the normal range –

progressively higher hazard ratio for CV death in 3153 coronary patients

LURIC study

Tomatschik, submitted

slide25

Sympathetic overactivity(well investigated, few practical consequences)documented in earliest stage of CKD Klein, J.Am.Soc.Nephrol. (2001) 12:2427pronounced in endstage kidney diseaseConverse, New Engl.J.Med. (1992) 327:1912caused by increased afferent signals emanating from the kidneyYe, Kidney International (1997) 51:722

slide26

in dialysis patients: beta blockers 22.9% in USA, 29.5% worldwide (DOPPS I and II)

Kidney International (2006) 70: 1905

like the prophet in the desert

slide27

Phagocytic cells produce catecholamines

amplifying inflammatory reactions

Flierl, Nature (2007) 449:721

PLoS ONE (2009) 4:e4414

benefit beyond blood pressure and antiarrhythmic activity?

slide28

LPS stimulates production of noradrenaline

by macrophages and neutrophils

Flierl, Nature (2007) 449:721

renalase normally detected in blood or urine but absent if renal function is lost
Renalase –normally detected in blood or urine but absent if renal function is lost

Li, Circulation (2008) 117:1277

slide30

Epidemiological facts

Underlying cardiac disease

New therapeutic targets

- salt and salt mediated hormones

- phosphate

- vitamin D

- sympathetic activity

Neglected cardiovascular risks

- depression

- sleep apnea

- disrupted biorhythm

Attractive areas for future investigation

- micro-RNA – arhythmia/cardiac fibrosis

- salt and marinobufagenin

- sympathetic overactivity and beta blockers

- oxydative stress

slide31
Science’s greatest advances occur on

the frontiers, at the interface between

ignorance and knowledge, where the

most profound questions are posed

Science (2005) 309: 76

depression and adverse outcomes on hd dopps study
Depression and adverse outcomes on HD(DOPPS study)

prevalence of depression ~ 20 %

adjusted rel.risk

death hospitalisation

physician diagnosed 1.23 1.11

patient diagnosed !! 1.48 1.15

(“so down in the dumps”)

Lopes, Kidn.Intern. (2002) 62:199

slide33

Depression and mortality

DOPPS

How often have you felt :

“So down in the dump“

“Downhearted and blue“

Lopes, Kidn.Intern. (2002) 62:199

depressive syndromes predict later appearance of cardiovascular disease
Depressive syndromes –predict later appearance of cardiovascular disease

risk higher by factor 1.7 – 4.5

(e.g. NHANES and INTERHEART studies)

depression independent factor predicting higher

cardiovascular mortality

Ferketich, Arch Int Med (2000) 160:1261

Pratt Circulation (1996) 94:3123

Yusuf, Lancet (2004) 364:953

Frasure-Smith, Circulation (1995) 91:999

Glassman Am J Psychiatr (1998) 155:4

slide35

Melancholie

Albrecht Dürer

1471-1528

in patients with cardiovascular disease
In patients with cardiovascular disease

16 – 23 % major depression requiring intervention (DSM-III-R or DSM IV)

Musselman, Arch Gen Psychiatr (1998) 55:580

depression and cardiovascular risk linked to
Depression and cardiovascular risklinked to:
  • autonomic imbalance
  • hypercorticism
  • insulin resistance
  • microinflammation

Everson-Rose, Diabetes Care (2004) 27:2856

slide38

Etanercept in psoriasis

improved clinical outcomes and less depression

(Double-blind placebo controlled randomized phase III trial)

Türing, Lancet (2006) 307:29

Depression provoked by interferon-α therapy in patients

with malignancy

successfully treated with the antidepressant paroxetine

Musselman, New Engl.J.Med. (2001) 344:961

slide39

Less depression – the explanation ?

for the positive effect of :

# spirituality

Finkelstein, Nephrol.Dial.Transpl.(2007) 22:2432

# and support provided by care givers

Tong, Nephrol.Dial.Transplant. (2008) 23:3060

► on quality of life of patients on renal

replacement therapy?

slide40

Sleep quality score correlated to mortality

(DOPPS study)

Elder, Nephrol.Dial.Transplant.(2008) 23:998

sleep apnea in hd patients
Sleep apnea in HD patients

in symptomatic HD patients(restless sleep, morning

headaches, daytime sleepiness, personality changes)

→ frequency 73 %

estimated overall prevalence in HD patients

→ 21 - 47%

prevalence in general population

→ 2 - 4%

Kimmel,Am.J.Med.(1989)86:308

Pressman, Kidn.Intern.(1993) 43:1134

Young, New Engl.J.med.(1993) 328:1230

sleep apnea reduced survival
Sleep-apnea –reduced survival

Yaggi, New Engl J Med (2005) 353:2034

survival advantage with treatment
Survival advantage with treatment ?

multicenter open label

randomized controlled trial

144 smokers

oxygen vs support ventilation

adj.hazard ratio 0.63 (0.4-0.99) p=0.045

McEvoy, Thorax, e-pub Feb12th

slide45

Nocturnal episodes of arterial oxygen desaturationpredict cumulative CV events and survival in HD patients

cumulative

survival

average nocturnal

oxygen saturation

SaO2

month

Zoccali,J.Am.Soc.Nephrol.(2002)13:729

daily nighttime dialysis impact on neurological and cardiovascular functions
Daily nighttime dialysis –impact on neurological and cardiovascular functions
  • Chan C.T.,Harvey P.J.,Picton P.,Pierratos A.,Miller J.A.,Floras J.S.

Short-term blood pressure, noradrenergic and vascular effects of nocturnal home hemodialysis

Hypertension (2003) 42:925

  • Chan C.T.,Hanly P., Gabor J., Picton P., Pierratos A., Floras J.S.

Impact of nocturnal hemodialysis on variablity of heart rate and duration of hypoxemia during sleep

Kidney Int. (2004) 65:661

  • Chan C.T.,Jain V., Picton P., Pierratos A., Floras J.S.

Nocturnal hemodialysis increases arterial baroreflex sensitivity and compliance and normalizes blood pressure of hypertensive patients with endstage renal disease

Kidney Int. (2005) 68: 338

sleep apnea a novel index of dialysis adequacy?

in the 4D study 70% of sudden death during nighttime !

improvement of sleep apnea with daily hemodialysis at nighttime nhd
Improvement of sleep-apnea with daily hemodialysis at nighttime (NHD)

Hanly, New Engl..J.Med.(2001) 344:102

frequeny of sleeping disorders in dialysis patients
Frequeny of sleeping disorders in dialysis patients

Insomnia

obstructive sleep apnea

restless legs

Epwoth sleepiness scale

nightmares

sleepwalking

behaviour disorder

Narcolepsy

Merlino,Nephrol.Dial.Transpl.(2006) 21:184

slide50
In hamsters disruption of a regulatory protein entraining circadian rhythmcompared to controlscauses- cardiomyopathy-renal disease

Masson

trichrome

Sirius

red

Martino,

Am.J.Physiol.(2008) 294:R1675

slide51

Epidemiological facts

Underlying cardiac disease

New therapeutic targets

- salt and salt mediated hormones

- (phosphate

- vitamin D)

sympathetic activity

Neglected cardiovascular risks

- depression

- sleep apnea

- disrupted biorhythm

Attractive areas for future investigation

- micro-RNA – arhythmia/cardiac fibrosis

- salt and marinobufagenin

- sympathetic overactivity and beta blockers

  • oxydative stress
  • target blodd pressure
slide52
Ich schätze den Mann der so schreibt wie es

einmal Mode werden wird und nicht jenen,

der so schreibt wie es Mode ist

I respect the man who writes what will be

the fashion of tomorrow,

not the man who writes what is

the fashion of today

Lichtenberg G.C.,

1742-1799

slide53

Nature Medicine (2002) 8:1066

“Although we have accomplished much, we still have much to do

to improve the lives and the well being of our patients

….we owe them continued research”.

slide54

Which topics to study?

Why did you rob the bank ?

Because that’s where the money is!

slide55

MicroRNA in the heart

miR-21, -133, -150, -195, -214 → cardiomyocyte hypertrophymiR-1, miR-133 → arrhythmiamiR-21, miR-195 apoptosismiR-208 myosin content ↑ and contractility ↑miR-21, miR-29 cardiac fibrosismiR-126 neoangiogenesis

van Rooij, Circulation Res. (2008) 103: 919

slide56

Endothelial to mesenchymal cell transitioninvolved in myocardial fibrosis of mice with increased afterload TGFβ-SMAD colocalisation in capillary endothelial cells

TGFβ expression

coexpression

of TGFβ (red) +

p-SMAD2/3(green)

Zeisberg, Nature Medicine (2007) 13:952

slide57

Further attractive areas for future investigations into pathomechanisms# (microRNA and arrhythmia/cardiac fibrosis)# marinobufagenin in response to salt loading in CKD and ESRD patients# blockade of marinobufagenin action# study of aldosterone vasculo- / cardiotoxicty# ADMA (not dialysable), homoarginine# cardiac metabolism (from glucose to FFA) # senescence and its role for cardiovascular tissue in uremia (telomers,stress)# experimental and clinical studies on the reduction of oxydative stress in cardiomyopathy of CKD

slide58
so far for basic issues

now urgent clinical issues

- antioxydants

- efficacy of (novel) betablockers

- target blood pressure (observational, not interventional)

- mineralocorticoid receptor blockade

(in anuric patients)

negative studies lowering homocysteine by folate in ckd and dialysis patients
Negative studies lowering homocysteine by folate in CKD and dialysis patients

Mann, Nephrol.Dial.Transplant.(2008) 23:645

Jamison, JAMA (2007) 298:1163

but studies using alternative antioxydant

medications certainly worthwhile :

why ?

slide60
Early onset of uremic cardiomyopathy -uninephrectomy (UNX) of ApoE knock-out miceprevented by reduction of oxydative stress

Vv

interstitial

cells (%)

sham-op 1.5 ± 0.6 3706 ± 571 5.16 ± 0.97

UNX 2.1 ± 0.4 2709 ± 407 7.00 ± 2.02

UNX + 1.3 ± 0.3 3776 ± 534 4.85 ± 0.68

Tempol

Lv

capillary length

density (mm/mm3)

IMT (µ)

intramyocardial

arteries

fibrosis

capillary

deficit

arterial

thickening

reversal of

oxydative stress

Piecha, J.Hypertens.(2008) 26: 2220

slide61

In the long term –

hypertension powerful predictor of mortality on hemodialysis

Charra, Kidney International (1992) 41:1286

mean arterial pressure % patients surviving

years

5 10 15 20

< 99 mm Hg 93 85 67 53

> 99 mm Hg 81 65 43 -

slide62

Target blood pressure : the lower,the better ?

Primary endpoint in ON TARGET study:

adjusted risk according to tertiles of systolic baseline pressure

Changes SBP

Reduced Risk

Increased Risk

HR

(95%CI)

p-value (changes SBP as continuous)

Q1: baseline SBP <= 130

p=0.0066

T1: <= -9.17

1

risk increase

T2: > -9.17 & <= 0.22

1.2

( 1.04 , 1.4 )

T3: > 0.22

1.19

( 1.02 , 1.38 )

Q2: baseline SBP > 130 & <= 142

p=0.0004

T1: <= 0

1

risk decrease

T2: > 0 & <= 8.36

0.89

( 0.76 , 1.04 )

T3: > 8.36

0.81

( 0.69 , 0.95 )

Q3: baseline SBP > 142 & <= 154

p<0.0001

T1: <= 5.5

1

risk decrease

T2: > 5.5 & <= 14

0.77

( 0.67 , 0.89 )

T3: > 14

0.59

( 0.5 , 0.69 )

Q4: baseline SBP > 154

p<0.0001

T1: <= 11.92

1

risk decrease

T2: > 11.92 & <= 21.71

0.72

( 0.63 , 0.82 )

T3: > 21.71

0.57

( 0.5 , 0.66 )

0.2

0.4

0.6

0.8

1.0

1.2

HR(95% CI)

Sleight P.  ESH/ISH Meeting, Berlin 2008; ESC Meeting, Munich 2008

diastolic bp 70mmhg more frequently de novo mi but not stroke
Diastolic BP < 70mmHg : more frequently de novo MI, but not stroke

MI

stroke

Messerli, Ann.Int.Med.(2006) 144:884

blood pressure amplitude and mortality type 2 diabetic nephropathy idnt study
Blood-pressure amplitude and mortalityType 2 diabetic nephropathy(IDNT study)

Greater blood pressure amplitude (loss of vascular elasticity)

higher overall mortality

Berl, J.Am.Soc.Nephrol.(2005) 16:2170

diastolic blood pressure and myocardial infarction type 2 diabetic nephropathy idnt study
Diastolic blood pressure and myocardial infarction – type 2 diabetic nephropathy(IDNT study)

lower diastolic blood pressure

higher incidence of MI

Berl., J.Am.Soc.Nephrol.(2005) 16:2170

slide66

Patients after MI :

(Valsartan in Myocardial Infarction Study)

Relation between blood pressure and:

cardiovascular death

stroke or

combined cardiovascular events

one blood pressure is not optimal

for all endpoints

Thune, Hypertension 2(008) 51: 48

“Blood pressure: lower is better“

is incorrect

Fonarow, J.Am.Coll.Cardio.(2006) 47:2130

cardiovascular events in hd patients effect of antihypertensive treatment metaanalysis
Cardiovascular events in HD patients-effect of antihypertensive treatment – metaanalysis

Heerspink, Lancet (2009) 373: 1009

slide69
All cause mortality and CV mortality in HD patients-effect of antihypertensive treatment – metaanalysis

Heerspink, Lancet (2009) 373: 1009

communist view
Communist view

One blood pressure

fits all

define in observational studies

which blood pressure is optimal for

which patient (comorbid conditions)

slide72

Thankyou

foryour

attention

Juan Gris

Retratto de Josette

1916

slide74

Target blood pressure on dialysis

Should we rely on GOBSAT ?

(according to P-Sleight: good old bays sitting and talking)

or

admittedly soft metanalyses of

intervention studies

(e.g. forthcoming metaanalysis in Lancet)

slide75
Renalase
    • novel amino-oxydasesynthesized as precursor in the kidney
    • prorenalase transformed into active renalase by catecholamines or blood pressure increase
    • renalase degrades catecholamines
  • Renalase -/- mice are hypertensive and susceptible to ischemic myocardial damage
  • Potential target for interventions
slide76
Prevention of stroke and myocardial infarction –calcium channel blockers vs ARB ►combine !“not all antihypertensives are created equal”

Wang, Hypertension (2007) 50: 181

slide77

Antihypertensive treatment in hemodialysis patients

Metaanalysis

Heerspink, Lancet (2009) 373: 1009

body mass index and survival on hemodialysis survival of the fattest
Body Mass Index and survival on hemodialysis“Survival of the fattest“

Leavey, Nephrol.Dial.Transplant.(2001) 16: 2386

slide79

Body Mass Index andsurvival on hemodialysis“Survival of thefattest“

Leavey, Nephrol.Dial.Transplant.(2001) 16: 2386

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