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)