Cardiopatie emboligene Quali le complicanze ? VII° Corso Nazionale Congiunto S.I.D.V-G.I.U.V....

Cardiopatie emboligene

Quali le complicanze ?

VII° Corso Nazionale Congiunto S.I.D.V-G.I.U.V. S.I.N.S.E.C.Ultrasonografia Vascolare

Diagnosi e TerapiaEmbolia e microembolia

Chiara Pedone

U.O. di Cardiologia Ospedale Maggiore, Bologna

Bertinoro, 2 Aprile 2009


• ...dalle Complicanze: - Stroke cardioembolico

• …alle Cardiopatie emboligene:

- Entità rischio embolico

- Fattori di rischio


Mechanism PrevalenceSubtype

Borderzone 5 %

Lacunar 20 %

Cryptogenicand rare causes 20 %

Artery-to-arteryembolism 20 %

Aortic archatheroma 15 %

Cardiacembolism 20 %

Stroke cardioembolico

Stroke cardioembolicoStroke cardioembolico

Diagnosi

Evidenza di fonte

cardioembolica (+ assenza di

lesioni aterosclerotiche

significative)

Neuroimaging Biomarkers(BNP, DD)

Caratteristiche cliniche

DIAGNOSI N° %

DECESSI

N° %

Accessi ischemici transitori 141141 7%7% 0 -

Emorragia (tipica) 188188 9%9% 52 28%

Emorragia (lobare) 113113 5%5% 38 34%

Ictus atero-trombotico 220220 10%10% 22 10%

Ictus cardio-embolico 466466 21%21% 92 20%

Ictus lacunare 427427 20%20% 4 1%

Ictus di incerta eziologia 492492 23%23% 70 14%

Ictus da altre cause 8888 4%4% 9 10%

TOTALETOTALE 21352135 100%100% 287 13%

Stroke Unit Ospedale MaggioreCasistica 2004-2008


Outcome

PROGNOSI ED EZIOLOGIA DELL’ICTUS ISCHEMICO

DIMISSIONE CEN=466

Altri (NO Lac)N=795

OR 95% l.c.

Domicilio (Rankin 0-2) 100 273 0.5 (0.4-0.7)

Morte 92 92 1.9 (1.4-2.4)

Morte/Istituzional. 154 150 2.1 (1.7-2.7)


Outcome


-Anomalie del setto interatrialeAnomalie del setto interatriale PFOPFO DIADIA Aneurisma SIAAneurisma SIA

-- Ecocontrasto spontaneo Ecocontrasto spontaneo

- Prolasso valvolare mitralico con mixomatosiProlasso valvolare mitralico con mixomatosi

- Calcificazioni valvolariCalcificazioni valvolari

Calcificazioni anulus mitralicoCalcificazioni anulus mitralico Stenosi/sclerosi valv. AorticaStenosi/sclerosi valv. Aortica

-- StrandsStrands valvolari valvolari

-Trombosi atriale Trombosi atriale Aritmie atriali Aritmie atriali Fibrillazione AtrialeFibrillazione Atriale Flutter atrialeFlutter atriale Sick sinus syndromeSick sinus syndrome Stenosi mitralicaStenosi mitralica

-Trombosi endoventricolare snTrombosi endoventricolare sn

IMAIMA Cardiomiopatie dilatativeCardiomiopatie dilatative

-Tumori cardiaciTumori cardiaci

Primitivi (mixoma, fibroelastoma)Primitivi (mixoma, fibroelastoma) MetastasiMetastasi

- Vegetazioni Vegetazioni

InfettiveInfettive Non infettiveNon infettive

-Protesi valvolariProtesi valvolari

-Ateromasia aortica complicata Ateromasia aortica complicata

Alto RischioAlto Rischio

Doufekias E et al. JACC 2008; 51: 1049-59

Medio o incerto RischioMedio o incerto Rischio


Sorgenti cardioemboliche

10%

10%

15%

50%

Infarto acuto

Trombosi ventricolare sn

Protesi valvolari

Fibrillazione atrialenon valvolare

10%

5%

Patologia valvolare

Atre cause(PFO, ASA, debris aortici, etc.)


Sorgenti cardioemboliche


• ...dalle Complicanze: - Stroke cardioembolico

- Embolia arteriosa periferica

• …alle Cardiopatie emboligene:

- Entità rischio embolico

- Fattori di rischio


Fibrillazione atriale

Trombosi endoventricolare

Protesi valvolari

Endocardite

PFO/ASA


Entità e fattori di rischio embolico

8%

33%

26%

33% 11%

35%

21%

33%

STROKE CARDIOEMBOLICO (n=466)Altre cause

(n=50)

FA persistenten=164

Anamnesi di FAparossistica

n=96

FA di nuova diagnosin=156

Fibrillazione Atriale e Stroke


Entità del rischio

00

1010

2020

3030

50–5950–59 60–6960–69 70–7970–79 80–8980–89

Prevalenza FAPrevalenza FA

Età (anni)Età (anni)

%%

Stroke secondari a FAStroke secondari a FA

Studio FraminghamStudio Framingham


Wolf PA et al. Stroke 1991; 22: 983-8

Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited

Watson T et al. Lancet 2009; 373: 155-66

I meccanismi I meccanismiFibrillazione Atriale e Stroke

Mitral valve prolapse ?Mitral

annular calcification

LargeLA

Large LV/low EF

Atherosclerosis aortic, cerebrovascular

Frequency ? 75% ? 25% ?

Structural Stasis Risk factors/markersStructural Stasis Risk factors/markers

I meccanismiFibrillazione Atriale e Stroke

RISULTATI AGGREGATI DI 5 TRIAL RANDOMIZZATI(AFASAK, BAATAF, CAFA, SPAF I, SPINAF)

TROMBOEMBOLIA INCIDENZACEREBRALE (% / anno)

• Stroke invalidantiStroke invalidanti 2.52.5

• Stroke ischemici complessiviStroke ischemici complessivi 4.54.5

• Stroke + TIAStroke + TIA 77

• Stroke + TIA + infarti cerebrali silenti*Stroke + TIA + infarti cerebrali silenti* > 7> 7

TROMBOEMBOLIA INCIDENZACEREBRALE (% / anno)

• Stroke invalidantiStroke invalidanti 2.52.5

• Stroke ischemici complessiviStroke ischemici complessivi 4.54.5

• Stroke + TIAStroke + TIA 77

• Stroke + TIA + infarti cerebrali silenti*Stroke + TIA + infarti cerebrali silenti* > 7> 7

* infarti subclinici svelati mediante TAC o RM* infarti subclinici svelati mediante TAC o RM

Entità del rischio Fibrillazione Atriale e Stroke

TAO (INR 2-3) vs controlli 2900 64% (49-74)

ASA vs controlli 4876 22% (6-35)

TAO vs ASA 12721 39% (27-49)

Confronto n° Pts RRR di Stroke (95% CI)

Hart RG et al. Ann Intern Med 2007; 146: 857-67


Impatto della terapia antitrombotica

Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation

4.5

2.4

7.9

2.2

Trials 1980-1990Trials 2000No treatment

Antiplatelets

Str o

ke R

ate

% p

er Y

ear

1.91.1 1.0

012345678

arm 5 RCTATRIACohort

SPAF IIIAspirin +

miniW

ACTIVE-WAspirin +

Clopidogrel

SPAF IIIWarfarin

SPORTIF VWarfarin

ACTIVE-WWarfarin

Anticoagulants

Placebo

Are Absolute Rates of Stroke with AF Lower Today than During the Period of the Original Trials of OAT?


Impatto della terapia antitrombotica

Stratificazione del rischio tromboembolico


Stratificazione del rischio

Stratificazione del rischio

emorragico

Indipendent predictors of stroke Indipendent predictors of stroke - prior stroke/TIA- prior stroke/TIA- age > 65y- age > 65y- hypertension- hypertension- diabetes mellitus- diabetes mellitus

Atrial Fibrillation Investigators (AFI)

Indipendent predictors of strokeIndipendent predictors of stroke - prior stroke/TIA- prior stroke/TIA- age > 75y and female gender- age > 75y and female gender- systolic blood pressure > 160 mmHg- systolic blood pressure > 160 mmHg- history of HF (clinical or echo)- history of HF (clinical or echo)

Congestive Heart failure 1 point

Hypertension 1 point

Age > 75 years 1 point

Diabetes mellitus 1 point

Stroke/TIA 2 points

CHADS2 score

Stroke Prevention and Atrial Fibrillation Investigators (SPAF I-II)

0=low risk (<2%/aa) 1-2=moderate risk (2-6%/aa) 3-6=high risk (6-19%/aa)


Stratificazione del rischio TE

Framingham Risk Score



High RiskHigh Risk Moderate RiskModerate Risk Low RiskLow RiskAny high-risk factorAny high-risk factor No high-risk factorsNo high-risk factors No high-risk factors No high-risk factors>1 moderate-risk factor >1 moderate-risk factor 1 moderate-risk factor 1 moderate-risk factor No moderate-risk factorsNo moderate-risk factors

High RiskHigh Risk Moderate RiskModerate Risk Low RiskLow RiskAny high-risk factorAny high-risk factor No high-risk factorsNo high-risk factors No high-risk factors No high-risk factors>1 moderate-risk factor >1 moderate-risk factor 1 moderate-risk factor 1 moderate-risk factor No moderate-risk factorsNo moderate-risk factors

High-Risk Factors- prior stroke, TIA, or embolism- mitral stenosis- prosthetic heart valve

Moderate-Risk Factors- age 75y- hypertension- heart failure or LV EF 35%- diabetes mellitus

Less validated or weaker RF- age 65 to 74y- coronary artery disease

High-Risk Factors- prior stroke, TIA, or embolism- prior stroke, TIA, or embolism- mitral stenosis- mitral stenosis- prosthetic heart valve- prosthetic heart valve- age - age 75y 75y- hypertension- hypertension- heart failure or LV EF - heart failure or LV EF 35% 35%- diabetes mellitus- diabetes mellitus

Moderate-Risk Factors- age 65 to 74y- age 65 to 74y- coronary artery disease- coronary artery disease

AFI - ACCP 6 2001 ACC / AHA / ESC 2006



High-Risk Factors- prior stroke, TIA, or embolism- prior stroke, TIA, or embolism

Increased-Risk Factors- age > 75 years- age > 75 years- history of hypertension- history of hypertension- diabetes mellitus- diabetes mellitus- impaired LV function- impaired LV function and/or heart failureand/or heart failure

ACCP- 8 2008



Fibrillazione Atriale

Fang MC et al. JACC 2008; 51: 810-5

13559 (10932 no TAO) pts inclusi nello studio AnticoagulaTion and Risk Factors In Atrial Fibrillation

FU 6 anni

Estrema variabilità nella stratificazione della rischio

Limitata capacità di predire eventi tromboembolici


Preadmission medications in patients with AF admitted with acute ischemic stroke

Gladstone DJ et al., Stroke 2009; 40: 235-40

WTherapeutic

10%

Wsubtherapeutic

29%Single antiplatelet agent,

29%

Dual antiplat therapy, 2%

No antithrombotics

29%


Missed Opportunities for Stroke Prevention in AF

WTherapeutic

6% WSubtherapeutic

18%

SingleAntiplatelet agent

46%

No anthithrombotics

30%

Stroke Unit Ospedale Maggiore, Bologna

597 pts with known AF (high risk and no contr.) 260 pts with known AF

0.8 1

3.8

2.3

7.88.7

0

2

4

6

8

10

12

14 IntermittentAF (n= 460)Sustained AF(n= 1,552)

43% 36%43% 36% 32% 34% 24% 30% 32% 34% 24% 30% Low-Risk Moderate-Risk High-RiskLow-Risk Moderate-Risk High-Risk

Hart RG et al, J Am Coll Cardiol 2000; 35: 183-187Hart RG et al, J Am Coll Cardiol 2000; 35: 183-187

Ann

ualiz

ed S

trok

e R

ate

(% /

yr)

Ann

ualiz

ed S

trok

e R

ate

(% /

yr)


FA parossistica vs permanente

Sherman DG Stroke 2007; 38: 615-7


Controllo ritmo vs controllo fc

http://stroke.ahajournals.org/content/vol38/issue2/images/large/66FF1.jpeg



Protesi valvolari

Endocardite

PFO/ASA



Scompenso cardiaco cronico

Quale è il rischio embolico? %

Str

oke

/ A

nn

o

0

1

2

3

4

5

S OL VD S AVE V-H eF T -I V-H eF T -II P R OMIS E C ONS E NS US S C D -H eF T

AF=0%

TAO=63%

AF=10%

TAO=87%

AF=16%

TAO=37%AF=13%

TAO=68%

AF=NA

TAO=81%

AF=42%

TAO=26%

AF=0%

TAO=?

1- 4.5%Pullicino PM et al. Neurology 2000; 54: 288-94

Fibrillazione atriale Storia di tromboembolia (9-10%/aa)Trombosi ventricolare sinistraSeverità dello scompensoEntità della disfunzione VSSesso femminileEziologia ischemica vs non ischemica

Fibrillazione atriale Storia di tromboembolia (9-10%/aa)Trombosi ventricolare sinistraSeverità dello scompensoEntità della disfunzione VSSesso femminileEziologia ischemica vs non ischemica


Quali sono i fattori di rischio?

13

2

0

5

10

15

20

Trombo No Trombo

% Embolie% Embolie

P < 0.01

Stratton et al, Circulation 1987;75:1004

85 pts (90% CP isch.)FUP 22 mesi



TVS CRONICATVS CRONICA 1 studioStratton, 19871 studioStratton, 1987

# TVS 85 # TE 11 (13%)# TVS 85 # TE 11 (13%)

IMA CON TVSIMA CON TVS 5 studi5 studi

# TVS 387 # TE 90 (23%)# TVS 387 # TE 90 (23%)

00

1010

2020

3030

4040

5050

6060

7070

Prev

alen

za T

EPr

eval

enza

TE

MobileMobile ImmobileImmobile Protrudente Protrudente Stratificato Stratificato

6363

1111

5151

88

00

1010

2020

3030

4040

5050

6060

7070

MobileMobile ImmobileImmobile Protrudente Protrudente Stratificato Stratificato

Prev

alen

za T

EPr

eval

enza

TE

3535

55

2222

33



Dunkman WB et al, Circulation 1993; 87 (suppl VI): 87-97Cioffi G et al, Eur Heart J 1996; 17: 1381-1389

VO2 p

eak

(ml/k

g/m

in)

VO2 p

eak

(ml/k

g/m

in)

VO2 p

eak

(ml/k

g/m

in)

VO2 p

eak

(ml/k

g/m

in)

p < 0.03p < 0.03 p < 0.001p < 0.001

p < 0.05p < 0.05

TE absentTE presentTE absentTE present

14.7 13.4 13.8

11.913.5

10.0


Severità SC

10

8

6

4

2

0

10

8

6

4

2

00 10 20 30 40 50 600 10 20 30 40 50 60

Follow-up (months)Follow-up (months)

Rat

e of

Str

oke

(%)

Rat

e of

Str

oke

(%)

LVEF < 28%LVEF < 28%

LVEF 29-35%LVEF 29-35%

LVEF >35%LVEF >35%

p = 0.01p = 0.01

Loh E et al, N Engl J Med 1997; 336: 251-257Loh E et al, N Engl J Med 1997; 336: 251-257

SAVE TrialSAVE TrialSAVE TrialSAVE Trial


Entità della disfunzione Vsn

1.962.021.831.7

0

1

2

3

4

5

1.78

2.41

3.80

4.20

0

1

2

3

4

5

≥ 30 29-21 20-11 ≤ 10 ≥ 30 29-21 20-11 ≤ 10

Dries DL et al, J Am Coll Cardiol 1997; 29: 1074-1080

p = 0.42p = 0.02

SOLVD TrialSOLVD Trial WomenWomen

TE p

er 1

00 p

atie

nt -y

ears

TE p

er 1

00 p

atie

nt -y

ears

MenMen

EF%


Entità della disfunzione Vsn

14.7 13.8

11.913.5

10.0


Quali pz trattare con TAO?

Warfarin is reccomended:

-in pts with HF and permanent, persistent or paroxismal AF (without contraindications)

Class I, level of evidence A

-in patients with intracardiac thrombus detected by imaging or evidence of systemic embolization

Class I, level of evidence C

-In patients with severe systolic disfunction ??? WATCH, WARCEF

-In patients with high risk cardiomyopathy (p.e. non compaction cmp) ???ESC Guidelines 2008

Age (years) 64.3±12.1

Women (%) 86.7

LV EF mean value (%) 37.6±7.7

Location of thrombus apex

Mural thrombus (%) 46.7

Recov. of LV dysfunction (days) 41.4±34.9

Resolution of TF (days) 28.9±25.9

Systemic embolization (%) 33.3

Stroke (%) 21.4

De Gregorio C et al Int J Cardiol 2008; 131: 18-24

-15/600 casi descritti di Takotsubo (2.5%)- 5/15 complicanze cardiemboliche (0.8%)

Takotsubo




Protesi valvolari

Endocardite

PFO/ASA



Filsoufi F et al.Am J Cardiol 2008; 101: 1472-8

Protesi valvolariProtesi valvolari

Post operative strokes

Variable OR (95% CI) p

Women 2.6 (1.5–4.8) 0.001Ejection fraction <30% 2.3 (1.2–4.5) 0.016Diabetes mellitus 2.2 (1.2–4.2) 0.016Age 70 yrs 2.0 (1.1–3.6) 0.024Cardiopulm. BP>120 min 3.7 (1.1–14.4) 0.014Calcified ascending aorta 2.7 (1.3–5.8) 0.011 0,0

1,0

2,0

3,0

<50 yrs 50-79 yrs 80yrs

Indipendent predictors of stroke

Overall incidence 2.2%

http://www.hmc.org.qa/hmc/heartviews/H-V-v4%20N1/image/ApicisFIG1A.jpg

Ruel M et al. Ann Thorac Surg 2004; 78: 77-84

Protesi valvolariProtesi valvolari

Late strokes

3189 pts underwent left-heart valve replacement (1970-2002)FU 6.3±4.5 yrs

Multivariate predictors

Mitral Prosthesis

Aortic Prosthesis

Female gen 1.76 (1.26-2.48)Age > 75 yrs 1.88 (1.11-2.78)Smoking 2.96(1.97-6.12)Prev. Smoking 2.59(1.73-3-71)N° CABG 1.24 (1.02-1.56)Tilting disc 1.74 (1.04-2.90)

Female gen 1.74 (1.15-3.22)Age > 75 yrs 3.06 (1.24-7.70)LVEF <35% 3.08(1.15-8.22)Smoking 2.25 (1.97-9.55)Prev. smoking 2.02 (1.28-3.70)Mechanical valve 1.24 (1.02-1.56)


Protesi valvolari meccanicheProtesi valvolari meccaniche

Fattori di rischio

Modello di valvola

Caged-ball (Starr-Edwards)

2.5% /aa

Tilting disk

0.7%/aa

Bileaflet

0.5%/aa

Posizione della valvola

Mitralica

0.9% /100pz/aa

Aortica

0.5% /100pz/aa

Mitro-aortica

1.2% /100pz/aa

Età

FA

SC

CAD




Protesi valvolari

Endocardite

PFO/ASA



Dickerman SA et al. Am Heart J 2007; 154: 1086-94

Endocardite infettiva e rischio embolicoEndocardite infettiva e rischio embolico

Entità ed andamento temporale

15% pts had a stroke (3.1% after 1° week of tx)

Prospective incindence cohort study (ICE-PCS; 61 centers, 28 countries)1473 pts admitted with left-sided endocarditis (74% native v.)

50.8% 49.2%

4.82

1.7

- 65%

Cabell CH et al.Am Heart J 2001; 142: 75-80

Fattori di rischio

0

10

20

30

40

50

Categoria 1

%

Predictors of stroke:

-Mitral valve infection (OR 1.74)

-Veg. Lenght > 7 mm (OR 1.24)

Endocardite infettiva e rischio embolicoEndocardite infettiva e rischio embolico

MitralValve

AorticValve

32.5%

11.3%Str

oke

ra

te (

%)

p=0.003

145 episodes of EI (Duke Endocarditis DB)

Predictors of stroke:

-Mitral valve prostesis + veg. (OR 2.4)

-Aortic valve prostesis + veg (OR 3.3)

- S. Aureus (OR 2.01)

629 pts with left-sided EI (64% native valve)

Fabri JJr et Int J Cardiol 2006; 110:334-9

- Ruolo determinante della tx antibiotica nel rischio di stroke

- Azione sul milieau biochimico della vegetazione

- Il rischio di stroke non dovrebbe costituire da solo indicazione ad

intervento chirurgico



Protesi valvolari

Endocardite

PFO/ASA



Forame Ovale Pervio

Incidence of asymptomatic patent foramen ovale, by age, in 13 261 patients undergoing cardiothoracic surgery

Hart, S. A. et al. Ann Intern Med 2009;150:431-432

Prevalenza nella “popolazione generale”

17.3%17.3%

Meissner I et. al. JACC 2006;47:440-5

Rischio di stroke nella “popolazione generale”

Patent foramen ovale: innocent or guilty? Evidence from a prospective population-based study (SPARC study)

Forame Ovale Pervio

p = 0.28

Meta-analysis of case-control studiesMeta-analysis of case-control studies

1.832.35

4.96

0

1

2

3

4

5

6

3.10

6.14

15.59

0

5

10

15

20

PFOPFO ASAASA

PFO + ASAPFO + ASA

Patients of any agePatients of any age

15 studies15 studies(n= 2014)(n= 2014)






Od

ds

rati

oO

dd

s ra

tio

Od

ds

rati

oO

dd

s ra

tio

PFOPFO

ASAASA

PFO + ASAPFO + ASA

Young patients (< 55 yrs)Young patients (< 55 yrs)

Overell JL et al, Neurology 2000; 55: 1172-1179Overell JL et al, Neurology 2000; 55: 1172-1179

PFO e stroke criptogeneticoForame Ovale Pervio

Handke M et. al. NEJM 2007;357:2262-8

Patent foramen Ovale and cryptogenetic stroke in older patients

3.12

3.70

3.0

00,5

11,5

22,5

33,5

44,5

5

All pts Pts<55yrs Pts55yrs

Od

ds

rati

oO

dd

s ra

tio

PFO e stroke criptogeneticoForame Ovale Pervio

503 pts (227 cryptogenetic stroke; 276 stroke of known cause)

P<0.001

P=0.008

Embolia paradossa a partenza da TVPEmbolia paradossa a partenza da TVP

Trombosi in situ nel “tunnel”Trombosi in situ nel “tunnel”

Aritmie atrialiAritmie atriali

Stato di ipercoagulabilitàStato di ipercoagulabilità

dimostrata in 5-10% casi

Meccanismi di stroke Forame Ovale Pervio

Goel SS et. al. Am J Cardiol 2009;103:124-9

PFO Morfology (ETE)

Size Tunnel lenght

27

10

31

48

05

101520253035404550

N°

of

pat

ien

ts

PFO size 4mm PFO size < 4mm

P<0.00145

32

13

26

05

101520253035404550

Tunnel l.1cm Tunnel l.<1cm

P<0.001

Fattori di rischio di strokeForame Ovale Pervio

PFO+CVE (58 pts)

asympt. PFO (58 pts)

Severity of shunting

Goel SS et. al. Am J Cardiol 2009;103:124-9


Mild= 3-9 mbs

Moderate= 10-30 mbs

Severe= 30 mbs

PFO+CVE 16%

Asympt PFO 5%

Severe Shunting

P<0.05

Association between the Presence of PFO and Cryptogenic Stroke in both Older Patients and Younger Patients

43.9

14.3

28.3

11.9

0

10

20

30

40

50

< 55 Yr > 55 Yr

13.4

2.0

15.2

4.4

0

5

10

15

20

25

< 55 Yr > 55 Yr

PFOPFO PFO with ASAPFO with ASAPFO with ASAPFO with ASA

Per

cent

of

Per

cent

of

Pat

ient

sP

atie

nts

p < 0.001p < 0.001

p < 0.001p < 0.001 p = 0.03p = 0.03 p < 0.001p < 0.001

Handke M. et al, N Engl J Med 2007; 357: 2262-2268Handke M. et al, N Engl J Med 2007; 357: 2262-2268

Cryptogenic (N= 227)Cryptogenic (N= 227)Known Cause (N= 276)Known Cause (N= 276)

Per

cent

of

Per

cent

of

Pat

ient

sP

atie

nts


FUP 4 yrs

No PFO no ASA 4.2%PFO 2.3%PFO+ASA 15.2%

Mas JL et al., NEJM 2001; 345: 1740-6


Cardiopatie emboligene Quali le complicanze ? VII° Corso Nazionale Congiunto S.I.D.V-G.I.U.V....

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Transcript of Cardiopatie emboligene Quali le complicanze ? VII° Corso Nazionale Congiunto S.I.D.V-G.I.U.V....