Giovanni Cioffi

Trento

«Insight» nello scompenso cardiaco

a frazione d’eiezione conservata

«Bias»:

Essere un ecocardiografista

Il sottoscritto Giovanni Cioffi DICHIARA

che negli ultimi 2 anni NON ha avuto rapporti anche di finanziamento

con soggetti portatori di interessi commerciali in campo sanitario

LV mass (g/m 2.7 )

Rel

ati

ve

wall

thic

kn

ess

10 20 30 40 50 60 70 80 90 100

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

Eccentric

LVH

Concentric

LVH

Concentric

remodeling

Normal

LV geometry

The rainbow of LV geometry

(dilated hypokynetic LV)

GdS/2007

CMP

Dilatativa

Secondaria

Normal

geometry

Ipertens

Diabete

IRC

Alchool

Card. isch

Concentric

remodeling

OSAS

Artrite

Reumatoide

Stenosi aortica

Concentric

hypertrophy

CMP infiltr.

American Indians (age 60 years)

(diab: 1810 / non-diab 944 pts)

Hypertensive pts. = 1950

Diabetes = 386 (20%) No CAD

Other variables independently associated with

concentric LVH: Age, body size, BP.

0

5

10

15

20

25

30

35

40

45

Nu

mb

erp

fp

ati

en

ts(%

)

21%

42%

32%

5%

Normal

geometry

Number of patients 42 83 64 9 198

Impaired sc-MS (%) 9 (21%) 54 (65%) 44 (69%) 3 (33%) 110 (56%)

Concentric

remodeling

Concentric

hypertrophy

Eccentric

hypertrophy

Impaired sc-MS (%)

Total

Cioffi et al. Echocardiography 2016 in press

Distribution of geometric patterns in pts with rheumatoid arthritis (primary prevention)

Growth in series

Eccentric (physiologic)

hypertrophy

Volume overload

Growth

in parallel

Concentric LVH

Ischemia

Disarray

Arrhythmias

Pressure overload

Non-hemodynamic

factors

• Growth factors

• Proto-oncogenes

• Neuro-hormones

• Cytochines

• RAAS system

GdS/2007

Mortalità globale ed eventi cardiovascolari in pazienti

ipertesi con IVS e differenti geometrie ventricolari. (Koren et al. Ann Int Med 1991)

Patient 1

Figure 1

Patient 2

IVSTd = 0.85 mm

PWTd = 0.85 mm

PWTs = 1.78 mm

LVIDd = 5.05 mm

LVIDs = 3.15 mm

SBP = 120 mmHg

Stress-corrected

Midwall

shortening

99%IVSTd = 1.05 mm

PWTd = 1.09 mm

PWTs = 1.77 mm

LVIDd = 4.42 mm

LVIDs = 2.95 mm

SBP = 150 mmHg

Stress-corrected

Midwall

shortening

75%

IVSTd

IVSTs

LVIDdLVIDs

PWTd

PWTs

EDD

Parasternal

short-axis view

IVSTd

IVSTs

LVIDs

PWTd

PWTs

LVIDd

Patient 1

Epicardial longitudinal fibers

helical anticlockwise arrangement

from mitral annulus to apex

Endocardial longitudinal fibers

helical clockwise arrangement

from mitral annulus to apex

Circumferential fibers

Midwall level

Lower R. Tractus de corde, Oxford, Univ. Press, 1932

r

Disposition of LV circumferential

and longitudinal myocardial fibers

………..LV systolic function ?

Funzione Ventricolare Sinistra in Ipertesi con Differenti Pattern Geometrici

Normale

geometria

Rimodell.

Concentrico

Ipertrofia

Eccentrica

Ipertrofia

Concentrica

Massa VS (g/m2) 85±15 92±16 * 126±22 * 142±38 *

Massa VS/Ht 2.7 38±7* 41±7* 60±11* 67±17*

Accorciamento

Endocardico (AE)

36±6 39±7* 35±6 36±9

Accorciamento

Centrop. (AC)

17±2 15±2* 16±2 13±2*

AE predetto dallo

STS (%)

109±12 103±13 110±14 98±14

AC predetto dallo

Stress TS (%)

101±13 84±12* 97±13 75±12*

* p<0.05 vs control subjects

de Simone et al J Am Coll Cardiol 1994;23:1444La Frazione d’eiezione resta costante!!!

La relazione tra accorciamento centroparietale e frazione

d’eiezione è funzione della geometria VS

Midwall Shortening (%)

262422201816141210

Eje

ctio

nF

ract

ion

(%)

70

60

40

50

RWTd > 0.45

Geometria concentrica

RWTd < 0.45

Geometria normale

“The cross-fiber shortening phenomenon”(amplificazione contrattile dall’epicardio all’endocardio)

Spostamento del centro geometrico in epicardio dove si

genera maggiore contrazione.

Migrazione epicardica dei nuclei del sincizio miocardico

Epicardio

Propagazione ed amplificazione

dell’accorciamento

all’endocardio

(proporzionate allo spessore della parete)

Endocardio

Sistole

In sistole le Fibre miocardiche circonferenziali si contraggono e per la teoria della

conservazione della massa il miocardio si ispessisce

0

10

20

30

40

50

60 Normotensives Hypertensives

p<

0.0

2

p<

0.0

05

p<

0.0

01

p<

0.0

01

p<

0.0

00

5

p<

0.0

00

5

p<

0.0

00

1

p<

0.0

00

1

Syst

oli

c in

crea

se i

n

cro

ss s

ecti

onal

are

a (%

)

“The cross-fiber shortening phenomenon” (amplificazione contrattile dall’epicardio all’endocardio)

de Simone G et al: High Blood Press 1997;6:130

Small amounts of myofiber shortening lead to extensive wall thickening.

Deformazione circonferenziale

(circumferential strain)

Strain systolic

and diastolic

velocities

Radial strain rate Radial strain

Accorciamento centroparietale

(midwall shortening)

Accorciamento/rilasciamento longitudinale

Tissue Doppler

S’

E’

20 40 60 80 100 120 14030

40

50

60

70

80

90

Stress-corrected midwall shortening (%)

Lef

t ven

tric

ula

rej

ect

ion

fra

ctio

n(%

)

r = 0.08

p = 0.13

Rheumatoid Arthritis Yes

Healthy Controls

(mean values)

Rheumatoid Arthritis No

Low LVEF = 3%

Low scMFS = 56%

Cioffi et al. Echocardiography 2016 in press

0 2 4 6 8 10 12 14 16 18 20 220,5

0,6

0,7

0,8

0,9

1,0

Card

iovasc

ula

r d

eath

-fre

e s

urv

ival

(%)

Follow – up (years)

Normal sc-Midwall Shortening (> 89%)

Impaired sc-Midwall Shortening (< 89%)

p = 0.006

(Log Rank Test)

Cioffi et al.

Am J Cardiol 2014;113:1409-1414

Aortic stenosis (any degree) 200 patients

Cioffi et al.

Heart Valve Disease J 2016 in press

Aortic stenosis (any degree) 200 patients

Cioffi et al.

Heart valve disease J 2016 in press

83%

Circumferentialdeformation (diabetes)

GdS/2007

CMP

Dilatativa

Secondaria

Normal

geometry

Concentric

remodeling

Concentric

hypertrophy

Ipertens

Diabete

IRC

Alchool

Card. isch

OSAS

Artrite

Reumatoide

Stenosi aortica

CMP infiltr.

La persistance de la memoire

NY, The Museum of modern Art

Giovanni Cioffi

Trento

«Insight» nello scompenso cardiaco

a frazione d’eiezione conservata

«Il paziente diabetico»

LV mass (g/m 2.7 )

Rel

ati

ve

wall

thic

kn

ess

10 20 30 40 50 60 70 80 90 100

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

Eccentric

LVH

Concentric

LVH

Concentric

remodeling

Normal

LV geometry

The rainbow of diabetic heart

(dilated hypokynetic LV)

HFHFpEF

38% DM

(Bursi 2006)

American Indians (age 60 years)

(diab: 1810 / non-diab 944 pts)

Hypertensive pts. = 1950

Diabetes = 386 (20%) No CAD

Other variables independently associated with

concentric LVH: Age, body size, BP.

Excess LVM growth (FIBROSIS)

(inappropriate LVM)

And

Vascular Damage

Pressure LV Overload

Concentric LV geometry

Progression from ADEGUATE to INAPPROPRIATE LV MASS

and LV systolic dysfunction in T2DM

Impaired contractility

Impaired contractility

Non-hemodynamic factors

• Growth factors

• Proto-oncogenes

• Neuro-hormones

• Cytochines (interleukines)

• RAAS system

Hypertension

Diabetes

Mellitus

Observed LVM*100

Predicted LVM

Inappropriate LV mass

Normal distribution of

observ/predic LVM :

145.0135.0

125.0115.0

105.095.0

85.075.0

65.0

Fre

qu

en

cy

50

40

30

20

10

0

95

th%

ile

128%73%

5th

%il

einappropriate LVM

=

Value of LVM > 28% of predicted LVM

The ability to compensate for increasing loading

conditions requires the growth of LV mass

Proportioned to

the magnitude of

overload

Excessive

Appropriate LV

mass(with / without LVH)

Inappropriate LV

mass(with / without LVH)

(Sex, height, SW)

Cioffi et al.

IntJC 2014

Epicardial longitudinal fibers

helical anticlockwise arrangement

from mitral annulus to apex

Endocardial longitudinal fibers

helical clockwise arrangement

from mitral annulus to apex

Circumferential fibers

Midwall level

Lower R. Tractus de corde, Oxford, Univ. Press, 1932

r

Disposition of LV circumferential

and longitudinal myocardial fibers

………..LV systolic function ?

Cioffi et al.

Am J Cardiol 2014

Wackers “DIAD” Diab Care 2004

LVEF

Prevalence 17%

SHORTWAVE study

Cioffi et al. Exp Clin Cardiol 2012

MAC (HR 3.68 [CI 1.93-7.00], p < 0.001)

GFR (HR 0.98 [CI 0.96-0.99], p = 0.007)

LV mass (HR 1.05 [CI 1.02-1.08], p < 0.001)

PCWP (HR 1.11 [CI 1.03-1.20], p = 0.009)

Covariates (multiple logistic regression analysis)

Combined Circumferential and Longitudinal

myocardial dysfunction in T2DM

…….. clinical model of asymptomatic heart failure

LVD function in the healthy aging heart

is modified by biochemical changes which are

very similar to those happening in the diabetic

heart

(i.e. advanced glycation end-products’

crosslinks with connectival proteins of

interstitial myocardial tissue)

Cacciapuoti et al.

Is the aging heart similar to the

diabetic heart? …………….

Aging Clin Exp Res 2009; 21:22-6.

Increased advanced glycation end-products’

accelerate the progress to LVH under

condition of Insulin resistance in presence of

hypertension.

Akihiro et al.

AHA congress Nov. 2014

DM only, or

anything else?

Prevalence of LV diastolic dysfunction in a non-selected population of

asymptomatic patients with diabetes mellitus.

Boyer JK et al. Am J Cardiol. 2004 ; 93:870-575 %

Prevalence of diastolic dysfunction in asymptomatic patients with well-controlled

type 2 diabetes mellitus.

Zabalgoitia M et al. Am J Cardiol. 2001; 87:320-3

Cioffi G et al. (DYDA) Eur J Prev Cardiol. 2012;19: 935-943 34 %

47 %

Prevalence of LV diastolic dysfunction in asymptomatic, normotensive type 2 diabetic

patients…free of microvascular complications.

Cosson S et al. Diabetes and Metabolism 2007; 33:61-67 0 %

DM only, or

anything else?

Heart Failure

Diabetes

Heart Failure

Diabetes

Hypertension

80%

Heart Failure

Diabetes

Hypertension

80%

Metabolic syndrome

(obesity, hypertriglyceridemia)

50%

Heart Failure

Diabetes

Hypertension

80%

Metabolic syndrome

(obesity, hypertriglyceridemia)

50%

CKD

40%

0

20

40

60

80

100%

Renal function

Nu

mb

ero

f p

atie

nts

(%)

GFR

89 – 60

67

100 100

43

53

60

75

Inappropriate LV mass

Prevalence of systolic LV dysfunction (low Sc-MS)

GFR

59 – 30

GFR

29 – 15

GFR

< 15

74

66

25

10

Prevalence of diastolic LV dysfunction

31

60

33

44

GFR

< 90

Prevalence of iLVM, LVS and LVD dysfunction in 400 patients at

high risk for CV events divided according to renal function

Cioffi et al

J Hypert 2011

Heart Failure

Diabetes

Hypertension

80%

Metabolic syndrome

(obesity, hypertriglyceridemia)

50%

CKD

40%

Vitamin D deficiency

100%

Vitamin D

deficiency

Vitamin D and myocardial

tissue

Two main functions on

myocardial tissue:

1) Stimulates the

production of

myocardial proteins

2) activates a number of

metabolic functions

(glucose, calcium, free

fatty acids) influencing

the energy production.

1) Genomic mechanism (actin & myosin production)

2) NON genomic mechanism (energy production)

Ac Arach

Prot C kin

Inosit trifosf

Heart Failure

DiabetesVitamin D deficiency

100%

CKD

40%

Hypertension

80%

Metabolic syndrome

(obesity, hypertriglyceridemia)

50%

Obstructive sleep apnea

50-77%

85%

42 sec

60 /ora

30 /ora

50

PTT

225/300

msec (25%)

FC

50 – 100

bpm100

EmatocritoAdrenalina

aldosterone

Pressione

arteriosa

Funzione Vdx - VS

(ischemia)e

Geometria VS

(ipertrofia)

Ipoventilazione

Aritmie cardiache

(Fibrillazione atriale)

Stroke2

Complicazioni cardiovascolari

dell’OSAS

Ipossiemia

Mortalità globale ed eventi cardiovascolari in pazienti ipertesi con IVS e

differenti geometrie ventricolari. (Koren et al. Ann Int Med 1991)

J Hypertens. 2010; 28(5):1074-82.

Eur J Echocardiogr. 2011; 12(1):61-8.

Impaired function of circumferential

fibers (midwall shortening) found in

69%

3542 adults (Olmsted County)

Polisomnography (1987 – 2003)

Cioffi et al. Intern J Cardiol 2013

1-year mortality KM curves of patients with acute HF and severe renal dysfunction

(DM vs no-DM). Data from the Italian Registry IN-HF Outcome

Diabetes paradox in HF and severe CKD

Heart Failure

Diabetes

Vitamin D deficiency

100%CKD

40%

Hypertension

80%Metabolic syndrome

(obesity, hypertriglyceridemia)

50%

Obstructive sleep apnea

50-77%

Conclusions: Pathophysiology of HF

in DM is complex

and multifactorial Subclinical LV systolic and/or diastolic dysfunction is

widely present and detectable in DM patients many

years before HF syndrome

Several DM-related conditions

contribute to the changes in LV

mass and geometry and

function

It is very difficult to find/imagine a clinical

model of «pure» DM

(do we have clinical data?)

May the control of DM-related conditions

lead to change the pathophysiology of HF in DM?

Architettura del miocardio

ventricolare sinistro

r

Strato miocardico interno

sotto-ENDOCARDICO

fibre longitudinali

elica anti-oraria

Strato miocardico

centrale

CIRCONFERENZIALE

(60%)

MFS = Midwall Fractional

Shortening

(accorciamento

Centroparietale)

FE

(volumi)

MFS

(diametri)

FE

(volumi)

Eco

(Bi-dimensionale)

MFS

(diametri)

Eco

(Mono-dimensionale)

INVESTIGATOR MEETING

STUDIO DYDA 2 TRIAL

RAZIONALE DELLO STUDIO

Bologna, 19 Marzo 2015

DYDA: Patients with ventricular

function measurable (n. 751)

Type 2 DM

50-60 years old

Synus rhythm

No overt cardiac

disease

Left ventricular DYsfunction in DiAbetes

DYDA Study (1)

Effetti dei ormone GLP-1 sull’omeostasi glicemica:

Incremento della sazietà

e riduzione dell’appetito

Beta-cellule

Aumento della secrezione

glucosio dipendente

d’insulina

Fegato

↓ Glucagone =ridotta

produzione epatica

di glucosio

Alfa-cellule

↓ Secrezione

post-prandiale

di glucagone

Stomaco

Rallentamento

dello svuotamento

gastrico

Glucagon-like-peptide (GLP) -1 is degraded by DPP-4

Active

GLP-1 (7-36) Intestine DPP-4

Increases glucose utilisation

by muscle and adipose

Decreased hepatic glucose release

improves overall glucose control

Adapted from Drucker DJ. Expert Opin Invest Drugs. 2003;12(1):87–100

Ahrén B. Curr Diab Rep. 2003;3:365–372

Inactive

GLP-1 (9-36)

amide

His-Ala

cleaved from

amino terminusDPP-4 = Dipeptidyl peptidase-4

Food intake

Pancreas

Glucagon-like-peptide (GLP) -1 is degraded by DPP-4

Active

GLP-1 (7-36) Intestine DPP-4

Increases glucose utilisation

by muscle and adipose

Decreased hepatic glucose release

improves overall glucose control

Adapted from Drucker DJ. Expert Opin Invest Drugs. 2003;12(1):87–100

Ahrén B. Curr Diab Rep. 2003;3:365–372

Inactive

GLP-1 (9-36)

amide

His-Ala

cleaved from

amino terminusDPP-4 = Dipeptidyl peptidase-4

Food intake

Pancreas

Incretine

I recettori per il peptide-1 glucagone-simile (glucagon-like peptide-1, GLP-1)

sono stati identificati nel miocardio e nell’endotelio ed è stata avanzata

l’ipotesi che essi espletino effetti protettivi anti-apoptotici.

Dati sperimentali suggeriscono che il GLP-1, oltre a esercitare le classiche

azioni glucoregolatorie, abbia effetti diretti sul sistema cardiovascolare.

Questi effetti diretti hanno caratteristiche di cardioprotezione e

vasodilatazione.

Alcuni studi clinici preliminari sull’uomo sembrano supportare un

miglioramento della funzione meccanica a seguito della somministrazione di

GLP-1 ai pazienti con ventricolo sinistro disfunzionante.

Negli esperimenti sugli animali (ratto), è stata dimostrata una funzione

cardioprotettiva di linagliptin nel setting dell’infarto miocardico acuto e della

cardiomiopatia uremica.

Razionale «cardiologico»

perché «incretine»?

Si propone la valutazione dell’aggiunta di un’incretina sulla funzione VS in

pazienti con DMT2 adeguatamente controllato con la terapia abituale,

nell’ambito di uno studio randomizzato, controllato con placebo, su soggetti

con geometria VS di tipo concentrico e con disfunzione sistolica VS

asintomatica, definita da una preventiva valutazione ecocardiografica di base.

Obiettivo primario

Valutare l’effetto dell’incretina rispetto al placebo dopo 1 anno di FU sulla

funzione sistolica VS (valutata come percentuale dell’accorciamento delle

fibre circonferenziali miocardiche presenti a livello centroparietale [midwall

shortening]).

Razionale obiettivo

Risultato atteso

(End point primario di efficacia):

Variazione statisticamente significativa (equivalente ad un incremento del

10%) dalla valutazione basale a 1 anno della funzione sistolica LV misurata

mediante analisi del MFS (lettura centralizzata).

End point secondari di efficacia:

Variazioni dal basale a 1 anno della funzione diastolica LV

Variazioni dal basale a 1 anno della funzione sistolica longitudinale

Razionale

Aut tace,

Aut loquere

migliora

silentio

Enfant geopolitique observant

La naissance de l’homme nouveau

Peterburg, collection

Phenotype

Type 2 DM

50-60 years old

Synus rhythm

No overt cardiac disease

No inducible myocardial ischemia

Wackers «DIAD study» (Diabetes Care 2004)

Davis (BMJ 2002)

Charenthaitawee (Am Heart J 2007)

Cioffi «DYDA study» (Eur J CV Prev 2012)