scompenso cardiaco, albuminuria e diabete mellitotigulliocardio.com/slide/mangili.pdf · scompenso...

Scompenso Cardiaco, Albuminuria e Diabete Mellito

Ruggero Mangili

Key points:

• 1‐ Diabetes begets excess heart failure (HF)

• 2‐ Raised AER is a risk factor for HF

• 3‐ Raised AER independently predicts death in HF

0

2

4

6

8

10

12

Intermittentclaudication

TotalCVD

CHD Cardiacfailure

Stroke

MenWomen

* **

**

*

*

*

†

Kannel WB et al, JAMA 1979

* P < 0.01, † P < 0.05

Framingham Study: CV Events in Diabetes

Years Since Onset of IDDM

Cum

ulat

ive

Inci

denc

e (%

) Proliferative RetinopathyPersistent Proteinuria

Cumulative Incidence of Retinopathyand Nephropathy in IDDM

AS Krolewski et al, Am J Med 1985

RELATIVE MORTALITY IN PATIENTS WITH T1DM

Patients with Nephropathy

Patients without Proteinuria

F

M

K Borch-Johnsen et al, Diabetologia 1985

The concomitants of raised blood sugar: studies in newly-detected hyperglycaemics. II. Urinary albumin excretion, blood pressure and their

relation to blood sugar levels.Keen H, Chlouverakis C, Fuller J, Jarrett RJ.

Guy’s Hosp Rep 118:247-54, 1969

Rosalyn Yalow1977 Nobel Prize

Harry KeenWHO Diabetes Committee

The Inception of Microalbuminuria

Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus

GC Viberti et al, Lancet, 1982

NA MA PP ESRF0

1020304050607080

Renal Status

711

17

2631

44 43

71CVDTotal

Albuminuria and Mortalityin Long-Standing (30-yr +) Type 1 Diabetes

0.20.30.40.50.60.70.80.9

1

0 1 2 3 4 5 6

NA

MA

PP

ESRF

Non-diabetic

Years

Surv

ival

Rat

e

NA = Normoalbuminuria, MA = Microalbuminuria, PP = Persistent Proteinuria, ESRF = End-Stage Renal Failure

KV Allen et al, Diabetes Care 2003

Mor

talit

y, %

Jarrett RJ et al, Diabetic Med 1984

Microalbuminuria predicts mortality in non-insulin-dependent diabetics.

Proteinuria and Risk of Stroke and CHD Events in Type 2 Diabetes

1.0

0.9

0.8

0.7

0.6

0.5

00 10 20 30 40 50 60 70 80 90 Stroke CHD

events

P<0.001

Incidence (%)

Survival curvesfor CV

mortality

Months

AB

COverall: P<0.001

0

10

20

30

40

A: U-Prot <150 mg/L B: U-Prot 150–300 mg/L C: U-Prot >300 mg/L

Miettinen H et al, Stroke 1996

Yearly Rates of Progression of Nephropathy and Mortality in T2DM

UKPDS 64 - Kidney Int, 2003

D

E

A

T

H

2.0 %

2.8%

2.3 %

Elevated CreatinineOr RRT 19.2 %

Macroalbuminuria 4.6 %

Microalbuminuria 3.0 %

Normoalbuminuria 1.4 %

CONSENSUS STATEMENT ON MICROALBUMINURIA

CE Mogensen et al, Uraemia Invest 1985

DEFINITION OF MICROALBUMINURIA

Excretion rate 20-200 µg/min or 30-300 mg/24 h

A/C ratio 2.5 (M) or 3.5 (F) -25 mg/mmol (Europe)

A/C ratio 30-300 mg/g (USA)

Albumin Concentration 30-300 mg/L

CONFOUNDERS

Variability, Posture, Exercise, UTI, HF, other Disease

Q 1:

Does hyperglycaemia beget heart failure?

0

2

4

6

8

10

12

Intermittentclaudication

TotalCVD

CHD Cardiacfailure

Stroke

MenWomen

* **

**

*

*

*

†

Kannel WB et al, JAMA 1979

* P < 0.01, † P < 0.05

Framingham Study: CV Events in Diabetes

HbAIc, MICRO- AND MACROVASCULAR COMPLICATIONS OF TYPE 2 DIABETES (UKPDS 35):

PROSPECTIVE OBSERVATIONAL STUDY - BMJ, 2000

MI STROKE

MICROVASCULAR

MI

MICROVASCULAR

Heart Failure

Usual HbAIc Level, %

CHARM Program: CV Events in HF and HbAIc

Gerstein HC et al, Arch Intern Med 2008

Primary OutcomeCV DeathWorsening HFDeath

Error bars: 95% CIP for trend <0.001 for all endpoints

Type 2Diabetes Mellitus

IGT aloneIFG alone

NormalBG Hyperglycaemia

CARDIOVASCULAR DEATH

RR2.0-4.0

RR1.2-1.4

RR1.0

10-yr Risk of Hyperglycaemia-related CV MortalityThe DECODE Study

The DECODE Study Group, Diabetologia, 2004

(age, sex, BMI, sBP, cholesterol and smoking status - adjusted RR)

IGT + IFG

Prevalence of HF in Dysglycaemia

The Population-Based Reykjavìk Study

Normal IFG+IGT Diabetes02468

10121416

Prev

alen

ce, %

Blood Glucose Regulation

Male (n=9323)Female (n=10058)All P < 0.0001

Thrainsdottir IS et al, Diabetes Care 2005

Low-normal

High-normal

IFG

New DM

DM

0 0.5 1 1.5 2 2.5 3 3.5 4Age and Sex Adjusted Relative Risk

368 / 11708

24 / 1006

116 / 6650

91 / 6298

69 / 513

Events / Patient #

P for Trend < 0.0001

Held C et al, Circulation 2009

Glucose Levels and 4.5-yr Incidence of HF

The ONTARGET/TRANSCEND Cohort

Q 2:

Does microalbuminuria beget heart failure?

MI, Stroke or CV Death

All-cause Mortality

CHF Hospitalisation

HOPE Study: CV Events and Death

0 1 2 3 4 5 6

Diabetes History

No Diabetes History

Treatment-Adjusted Relative Risk

Gerstein HC et al, JAMA 2001

Relative Risk of Events in Microalbuminuria

DM No DMMA 1,140 823NA 2,358 4,722

3,498 5,545

All P< 0.001

HOPE Study: Incidence of HF by ACR

Gerstein HC et al, JAMA 2001

Incidence of Heart Failure Hospitalisation by ACR

Albumin to Creatinine Ratio Decile

%

ACR quartiledistribution:<0.220.22-0.570.58-1.62>1.62 mg/mmol

MICROALBUMINURIA

P for trend =0.05without MA only

for all participants

Q 3:

Is heart failure always ischemic in origin among patients with microalbuminuria?

The DIABHYCAR Study

Vaur L et al, Diabetes Care 2003

Inclusion CriteriaAge > 50 yearsType 2 Diabetes Mellitus on OHAUalb > 20 mg/LS Creatinine < 150 µmol/LNo history of HFNo history of AMI within 3 months before inclusionNo treatment with ACEI or ARBsNo life-threatening comorbidity

Effects of low-dose ramipril on cardiovascular and renal Outcomes in patients with Type 2 diabetes and raised

excretion of urinary albumin: randomised, double blind,placebo controlled trial

The DIABHYCAR Study


STUDY DESIGN4,937 patients randomised to 1.25 mg/day ramipril vs placebofollowed for 3-6 years

PRIMARY ENDPOINTCombined incidence of:

Cardiovascular deathNon-fatal AMIStrokeHF requiring hospital admissionESRF (requiring HD or RT)

Development of CHF Type 2 Diabetic Patientswith Microalbuminuria or Proteinuria

Observations from the DIABHYCAR Study


187 of 4,912 patients

developed CHF during the study



Base-line characteristics of the patients - 1

No CHF CHF PAge (years) 65±8 69±8 <0.001Male Sex (%) 70 73 0.417BMI (kg/m2) 29±5 29±5 0.693Known DD (years) (np) 8 (4, 14) 10 (5, 17) 0.0005Current smokers (%) 18 16 0.594> 1 drink/ day (%) 46.3 47.5 0.712Hypertension (%) 55 67 0.0016CHD (%) 14 32 <0.001History of stroke (%) 4 6 0.261



Base-line characteristics of the patients - 2

No CHF CHF PHistory of PVD (%) 10 23 <0.001sCreatinine (µmol/L) 89±20 96±21 <0.001Fasting BG (mmol/L) 9.8±3.2 9.8±3.1 0.926HbAIc (%) 7.9±1.8 8.3±1.9 0.0032UAC>200 mg/L (%) 25 44 <0.001UAC mg/L (np) 74 (37, 206) 155 (48, 493) 0.0001sBP (mm Hg) 145±15 148±16 0.045dBP (mm Hg) 82±9 82±8 0.831Ramipril treatment (%) 49.9 45.5 0.232


Characteristics of the patients at the onset of CHF

CHD No CHD P

N 101 86Age (years) 71±8 72±8 0.52Male Sex (%) 77 67 0.14Hypertension (%) 59 74 0.043Prior MI (%) 53 0 NAValvulopathy (%) 13 10 0.66LVEF<40% (%) (44 miss) 61 37 0.018Atrial fibrillation (%) 28 36 0.27

The DIABHYCAR StudySubgroup analysis of new CHF by coronary status

DIABETES MELLITUS

MICROALBUMINURIA

HEART FAILURE

DEATH

CORONARY HEART DISEASE

DIABETIC CARDIOMYOPATHYARTERIAL HYPERTENSION

DIABETES, MICROALBUMINURIAAND HEART FAILURE

DIABETIC CARDIOMYOPATHYMOLECULAR PATHOPHYSIOLOGY

ImpairedInsulin

signaling

GLUT expressionGlucose uptake

Cardiac Dysfunction

Glucotoxicity Fibrosis Mitochondrial uncoupling / CE Lipotoxicity

Cardiac lipidaccumulation

FA uptake

Hyperglycaemia FFA and TGDIABETES

PPARαSignaling

PDK4

PKCAGE Ceramide

ROS ROSFA oxidation

Glucose oxidation

PDH CPT1

MCDMCoA

ACCACoA FA

oxidationgenes

Boudina S et al, Circulation 2007

ATRRAAS

Ca2+

THE STAGES OF DIABETIC CARDIOMYOPATHYEARLY STAGE

Fang ZY et al, Endocrine Reviews 2004

CharacteristicsDepletion of GLUT4Increased FFACarnitine deficiencyCa2+ homeostasis changesInsulin resistance

Functional featuresIf any, slight diastolic dysfunction but normal EF

Structural featuresNormal LV size, thickness and mass

Study methodsStrain rateMyocardial tissue velocity

THE STAGES OF DIABETIC CARDIOMYOPATHYMIDDLE STAGE


CharacteristicsApoptosis and necrosisIncreased AT IIReduced IGF-IIncreased TGF-β1Mild CAN

Functional featuresDiastolic dysfunction but normal or slightly EF

Structural featuresSlightly increased LV size, thickness or mass

Study methodsStrain rate, Myocardial tissue velocityConventional echocardiography

THE STAGES OF DIABETIC CARDIOMYOPATHYLATE STAGE


CharacteristicsMicrovascular changesHypertensionCADSevere CAN

Functional featuresDiastolic dysfunction and EF

Structural featuresSignificantly increased LV size, thickness or mass

Study methodsConventional echocardiography

Q 4:

Is microalbuminuria relevant to prognosisamong patients with heart failure?

The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Programme

Pfeffer MA et al, Lancet 2003

STUDY DESIGN7,599 patients with

NYHA class II-IV heart failures Creatinine < 265 µmol/L (3.0 mg/dL)

s Potassium < 5.5 mmol/LNo ARB treatment

No recent heart surgeryNo critical valvulopathyNo recent MI or Stroke

LVEF > 40% LVEF ≤ 40%on ACEI

LVEF ≤ 40%ACEI-intolerant

Candesartan vs Placebo

Albuminuria in Chronic Heart FailurePrevalence and Prognostic Importance

The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) Programme

Jackson CE et al, Lancet 2009

STUDY DESIGN2,310 North-Americans from the CHARM Programmewith centralised measurements of UACRat base-line, 14 and 38 months and last visitMedian follow-up: 37.7 months

COMPOSITE PRIMARY ENDPOINTDeath for CVDWorsening HF (hospitalisation)Death from any cause



Normo- Micro- Macro-0

10

20

30

40

50

60

70 All patients

No DM

No HT

No DM No HT

PREVALENCE OF RAISED ALBUMINURIA

MICROALBUMINURIA: UACR = 2.5/3.5 (M/W) -25.0 mg/mmolMACROALBUMINURIA: UACR > 25.0 mg/mmol

%

N = 1,447

N = 1,714

N = 796

PREVALENCE OF RAISED AER IN TYPE 1 DIABETESR

ate,

%

Duration of Diabetes, years

0

10

20

30

40

50

1- 5- 10- 15- 20- 25- 30+

MicroalbuminuriaMacroalbuminuriaBoth

EURODIAB IMSG

0

10

20

30

40

50

5-4- 10- 15- 20- 25+

MicroalbuminuriaMacroalbuminuria *Both

*CRF and AHT excluded from selection



CV Death or admission for CHF All-cause mortality

Cumulative Incidence of Endpoints by Albuminuria



Multivariate Analysis of UACR with 33 Baseline Covariates

CV Death or CHFAll-cause mortalityAdmission for HF

* HR increase per 100 mg/mmol

Micro- vs NA Macro- vs NA UACR cont.*0

0.5

1

1.5

2

2.5

HR

P<0.0001 P<0.0001 P<0.02

Prevalence and Prognostic Value of Raised Urinary Albumin Excretion in Patients with Heart Failure

The GISSI-Heart Failure Trial

Masson S et al, Circ Heart Fail 2010

STUDY DESIGNRandomised ω-3 PUFA or rosuvastatin2,131 patients with heart failure and base-line ACR

PRIMARY ENDPOINTAll cause mortality

Prevalence and Prognostic Value of Raised Urinary Albumin Excretion in Patients with Heart Failure

The GISSI-Heart Failure Trial

Masson S et al, Circ Heart Fail 2010

PREVALENCE DATAMicroalbuminuria 19.9%Macroalbuminuria 5.4%

MAJOR FINDINGSOther RF-adjusted HR 1.12 (95% CI: 1.05-1.18) per 1 U increase log 10ACRboth in the study populationand in the subset without diabetes and hypertension

CONCOMITANTS OF KIDNEY DYSFUNCTIONIN HEART FAILURE

Reduced GFR Albuminuria

Reduced renal perfusion +++ +Increased venous congestion ++ +Tubular dysfunction - +Hypertension + ++Diabetes + ++Endothelial dysfunction + / - +Inflammation - ?RAAS activation + ?SNS activation + / - ?

Damman K, Lancet 2009

MICROALBUMINURIA 1969 - 2009:5400+ Papers - 9 Major Clinical Settings

Diabetes MellitusArterial HypertensionRenal Disease and TransplantationPre-eclampsiaSLEICBDHaemochromatosisNormotensive IndividualsHeart Failure

Albuminuria, a Therapeutic Target for Cardiovascular Protection

in Type 2 Diabetic Patients With Nephropathy

D. de Zeeuw, Circulation 2004

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