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Investigating Co-MorbiditiesAggravating Heart Failure

Stefan D Anker, MD PhD

Applied Cachexia ResearchCharité University Medicine BerlinDepartment of Cardiology (CVK)BerlinGermany

s.anker@cachexia.de

ResearchTowards Active &Healthy Ageing

ResearchTowards Active &Healthy Ageing

Modern medicine can impact life expectancy

Lenfant C.NEJM 2003.

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Prevalence of D.m. in Heart Failure trials

0

5

10

15

20

25

30

35

40

CIBIS

-II

VHeFT-II

DIAM

OND-HF

ATLAS

VHeFT-I

CONSENSUS-I

RALES

ELITE-II

COMET

MERIT

-HF

Val-HeF

T

COPERNICUS

SOLVD-TDIG

MACH-I

OVERTURE

BEST

PRAISE-I

Prevalence %

3

7

6

5

4

3

2

1

HR forall-cause mortality

*

<22 22-25 25-30 30-35 ≥≥≥≥35

PROactive population: Type 2 DMplus macrovascular disease

Intervention: Pioglitazone vs placebon=5238 (2605 vs 2633)

BMI (kg/m2)

Placebo groupAll patients

HR 95%CI P

Weight gain (1%) 0.98 0.95-1.02 0.27

Weight loss (1%) 1.14 1.11-1.16 <0.0001

Doehner et al., IJC 2011(supported by SICA-HF)

*

PROactive: BMI vs all-cause mortality in DMT2

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Cardiac Cachexia & Survival

n=171

0

0 6 12 18

20

40

60

80

100

50%cachectic: n=28 (16.4%)

83%

RR 3.73 95% CI 1.93-7.23p=0.0003

Cardiac Cachexia

Prognostic value

independently of:

• Peak VO2

• LVEF

• NYHA class

• Na

• Age

Months Anker et al., Lancet 1997

Survival (%)

15 yrs of HF epidemiology research

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The FP7 SICA call

3 Mill EUR for EU partnersCo-operation with Russian partners (addit. 2 Mill EUR)

General Overview of the Project

• Collaborative Project

• Start date: 1st October 2009

• Duration: 48 months (+6 months extension)

• 11 Partners (7 European & 4 Russian partners)

• 16 Work packages

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Partners Involved in SICA-HF

Charité Berlin, Germany

Military Hospital,Wroclaw, Poland

University of Hull, UK

University of Rostock, Germany

Medizinische Hochschule Hannover, Germany

V.A. Almazov Federal Center for Heart,

Blood & Endocrinology

St. Petersburg, Russia

Russian CardiologyResearch and

Production Complex,Moscow, Russia

IRCCS SanRaffaele

Rome, Italy

GABO:mi,Germany

Institute of Cardiology,Tomsk Research

Centre, Tomsk, Russia

M.V.LomonosovMoscow State

University, MoscowRussia

SICA-HF: Main Objectives

– Characterise the prevalence, incidence, persistence, and phenotype of obesity, cachexia, and T2DM in patients with HF

– Describe patterns of exercise capacity and cardiorespiratory reflex control

– Analyse body composition and its changes over time in patients with heart failure and type 2 diabetes, obesity, or cachexia

– Investigate the incidence and prevalence of sleep disordered breathing and its impact on the clinical severity in patients with HF

– Establish the impact of impaired vascular reactivity on impairedskeletal muscle metabolic and functional capacity including its underlying mechanisms

– Describe the interplay and metabolic signaling pathways between adipose tissue, skeletal muscle, the bone marrow and the heart in patients with HF and type 2 diabetes, obesity, and cachexia

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Patient Recruitment – Inclusion Criteria

• >1600 patients with CHF and

– Obesity and/or

– Cachexia and/or

– Type 2 diabetes mellitus

• >300 patients with diabetes mellitus without HF

• >150 healthy control subjects

• HF patient inclusion criteria: diagnosis of

systolic or diastolic HF with NT-BNP>400,

LVEF<45% or hospitalisation for HF in last 12 mo

Follow-up

Baseline

4 mon

ths

12 m

onth

s

24 m

onths

Clinical examinationResting ECGHR, BP, weight, heightBody composition (DEXA/BIA)EchoExercise test, 6-MWTPlethysmography (blood flow)BloodsQoL

Subgroup AssessmentsivGTT (insulin sensitivity)Muscle/fat tissue biopsyBone marrow biopsySleep studiesEPC isolationReflex control

Central Blood Blood & DNA Bank

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Overview and Interaction of the Work Packages

WP 03-HULL:

Recruitment and

characterisation

WP 10-CHAR:

Blood and DNA bank, biomarker

research

WP 11-MSU:

Blood and DNA bank, biomarker research, gene

identification

WP 07-CHAR: Metabolic and vascular studies &

biopsies (patients)

WP 05-CHAR:Body composition and test

standardisation

WP 16-CHAR/GABO:mi: Training & dissemination

WP 01-GABO:mi: Project Management

WP 06-ROS:Sleep Studies

WP 08-ROME:

Cellular research (human muscle)

WP 09-MHH:Cellular research

(human fat)

EU

RUSSIA

WP 02-CHAR: Statistical support

WP 13-AC:

Cellular mechanisms and therapy

WP 12-CT:Molecular

pathways, cell cultures

WP 14-CRC:

Vascular research, ex vivo

WP 15-AC: Academic coordination (Russia)

WP 04-WROC:QoL, exercise testing & reflex

research

WP08 – Cellular Research on Human Muscle

• Ultrastructural analysis of SMT samples by immuno-histochemistry and microscopy

• Investigate cross-talk between muscle, adipose tissue and the immune system (“ex vivo“)

• Investigate cellular functions potentially affected in CHF or by comorbidities (in vitro)

Muscle Biopsiesfrom Quadriceps Muscle

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WP09 – Cellular Research in Human Fat Tissue

1. Assess circulating adipokine levels and mRNA in adipose tissue samples in ≈125 subjects

-- clarify adipose tissue dysfunction vs adipokine production

2. Analyse dysfunctional lipid mobilization and lipolytic stimuli

3. Provide training & SOPs and build a uniform & high-quality biobank

Subcutaneous biopsy Adipose tissue Cellular studies

SICA-HF – First Results

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Pathophysiology of tissue wasting

Protect muscle for a happy & independent life

"PB Sitting" (Berlin, 2006)Artist: Stephan WeberJCSM – issue 1 (2010)

"Sitzende Alte" (1965)Artist: Prof. Bernd GöbelJCSM – issue 2 (2012)

Standing Women(1955)Artist: Alberto GiacomettiJCSM – issue 4 (2011)

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Targets to treat muscle wasting & cachexia

Problems & solutions in Japan & EU are similar

• Prevention & treatment of cachexia

• Prevention & treatment of muscle wasting of the elderly (i.e. sarcopenia)

• Enhance independent living in good QoL

• Treat co-morbidities of the elderly (particularly HF and DMT2)

• Promote longevity ResearchTowards Active &Healthy Ageing

ResearchTowards Active &Healthy Ageing