““Patients with diastolic heart failure likely Patients with diastolic heart failure likely represent the represent the largest grouplargest group of patients with of patients with a cardiovascular disorder of substantial a cardiovascular disorder of substantial public health impact who have not been public health impact who have not been systematically studied.”systematically studied.”

Am J Med, 2000Am J Med, 2000

““Diastolic Heart Failure: Diastolic Heart Failure: Miles to Go Before We Sleep”Miles to Go Before We Sleep”

Lynne W. StevensonLynne W. Stevenson

SystolicHF

DiastolicHF

Owan ET et al. NEJM 2006Owan ET et al. NEJM 2006

TEMPORAL TRENDS IN THE PREVALENCETEMPORAL TRENDS IN THE PREVALENCE

NL EF51%

NL EF51%Low EF

49%Low EF

49%

Vasan et al J Am Coll Cardiol

1999

Kitzman et alAm J Cardiol

2001

NL EF55%

NL EF55%Low EF

45%Low EF

45%

43% EF>50%57%

EF<50%

Diastolic Heart Failure in the Community:Incident cases(11 to 78%!!!)

Senni et alCirculation

1998

Prognosis of diastolic HF in Olmsted country, Minnesota, 1991 (LVEF 50%)

SENNI et al., Circulation 1998; 98: 2282-2289.

n = 59 (43%)

Age = 7812y

NYHA III-IV = 69%

Female = 69%

HTN = 58%

CAD = 31%

Cardiomegaly = 64%

1 and 5 yrs mortality rate 24% and 52%

Ahmed A et al: Am Heart J 2002

Smith GL et al: JACC 2003

Diastolic and Systolic HF:

Better Prognosis

vs Worst Prognosis

Varadarajan P et al: J Cardiac Fail, 2003

(n = 2.258)

Why so different results?

• Over and underdiagnosis

• Age of patients: it may be that the prognosis of DHF

in elderly pts (>65 yo) is different

• Choice of diagnostic criteria/definition for CHF

• Type of population studied (hospitalized, out-pts,

echo lab, population-based)

• Incident or recurrent CHF

• Timing of EF evaluation

• Racial differences

Senni M & Redfield MM : JACC 2001

Heart Failure with Preserved Systolic FunctionHeart Failure with Preserved Systolic Functionor or

Diastolic Heart Failure Diastolic Heart Failure

““Heart Failure with Preserved Systolic Function is aHeart Failure with Preserved Systolic Function is a descriptivedescriptive approach that makes no assumptions about ourapproach that makes no assumptions about our knowledge about the pathophysiology of this disorder” knowledge about the pathophysiology of this disorder” ((Burkoff D, Maurer MS, Packer M.Burkoff D, Maurer MS, Packer M. Circulation 2003) Circulation 2003)

““TheThe predominant pathophysiological causepredominant pathophysiological cause of heart failure in these patients is abnormal of heart failure in these patients is abnormal diastolic function. Therefore, is appropriate diastolic function. Therefore, is appropriate to use the term “Diastolic Heart Failure”to use the term “Diastolic Heart Failure”to describe the abnormalities in these patients”to describe the abnormalities in these patients”(Zile MR, Baicu CF, Gaash WH.(Zile MR, Baicu CF, Gaash WH. NEJM 2004) NEJM 2004)

Metabolism of collagen and Metabolism of collagen and interstitial e perivascular fibrosis in hypertension interstitial e perivascular fibrosis in hypertension

Metabolism of collagen and Metabolism of collagen and interstitial e perivascular fibrosis in hypertension interstitial e perivascular fibrosis in hypertension

Lopez B et al. Hypertension 2001

Perivascular fibrosis

Decrease coronary reserve

Schwartzkopff B. Circulation 1993

Kozakova M. Hypertension 2003

Progressivo Aumento del Rischio di Scompenso Cardiaco Progressivo Aumento del Rischio di Scompenso Cardiaco

con l’aumento della Massa VScon l’aumento della Massa VS

Gottdiener JS. JACC 2000;35:1628

1,0 1,1

1,5

1,9

2,8

0,0

0,5

1,0

1,5

2,0

2,5

3,0

Ris

chio

Rel

ativ

odi

Sco

mpe

nso

Car

diac

o

Q1 Q2 Q3 Q4 Q5Quintili di Massa Ventricolare Sinistra (ECG)

5888 soggettiEtà > 65 anni

5888 soggettiEtà > 65 anni

The Cardiovascular Health StudyThe Cardiovascular Health Study

Patterns of Left Ventricular Hypertrophy (LVH)

1. Normal Pattern

normal LV Mass

normal RWT (<0.43)

2. Eccentric Hypertrophy

increased LV Mass

normal RWT (<0.43)

3. Concentric Hypertrophy

increased LV Mass

increased RWT (>0.43)

4. Concentric Remodeling

normal LV Mass

increased RWT (>0.43)

1. Normal 2. Eccentric Hypertrophy

4. Concentric Remodeling

Rel

ativ

e W

all T

hick

ness

(R

WT

)

0.43

LV Mass Index (LV MI) g/m2

125 g/m2 for M110 g/m2 for F

Threshold:

3. Concentric Hypertrophy.

Eventi CV +

Eventi CV +++

Eventi CV ++

Cardiovascular events: LV mass and Cardiovascular events: LV mass and Midwall Fractional ShorteningMidwall Fractional Shortening

Cardiovascular events: LV mass and Cardiovascular events: LV mass and Midwall Fractional ShorteningMidwall Fractional Shortening

de Simone G et al. Circulation 1996;93:259-265

?

?

J Card Fail 2002 ; 8(2): 101-7

Ventricular–vascular interactionVentricular–vascular interaction in DHF (arterial elastance) in DHF (arterial elastance)

Ventricular–vascular interactionVentricular–vascular interaction in DHF (arterial elastance) in DHF (arterial elastance)

Kawaguchi M et al. Circ 2003

• Hypertensive pts symptomatic on effortHypertensive pts symptomatic on effort• Handgrip testHandgrip test

Circulation 2008; 117: 2051

Factors Responsible for Factors Responsible for Increased LV Diastolic PressureIncreased LV Diastolic Pressure

Passive

chamber

stiffness

Relaxation

Diastolic

pressure• Asynchrony

• Ischemia

• Abnormal Ca++ flux

• Cellular disarray

• Fibrosis

• Concentric hypertrophy

• Stiff titinaStiff titina

The Natural History of Diastolic Function and LV Filling

4040

00

NormalNormalAbnormalAbnormalrelaxationrelaxation

Pseudo-Pseudo-normalizationnormalization

RestrictionRestriction(reversible)(reversible)

RestrictionRestriction(irreversible)(irreversible)

Mean LAPMean LAP

TAUTAU

NYHANYHA I-III-II II-IIIII-III III-IVIII-IV IVIV

GradeGrade II IIII IIIIII IVIV

Mean LAPMean LAP

TAUTAU

NYHANYHA I-III-II II-IIIII-III III-IVIII-IV IVIV

GradeGrade II IIII IIIIII IVIV

N-N-

Restrictive fillingRestrictive filling

After therapy

Abnormal relaxation

In absence of a comprehensive diastolic assessment

Simple echocardiographic criteria

- left atrial enlargement- normal LV dimension- left ventricular hypertrophy- wall motion abnormalities- elevated pulmonary pressures

Clinical differentiation of Diastolic vs. Systolic Dysfunction in patients with Heart Failure

Systolic function Diastolic functionSex Male FemalePast history Myocardial infarction Hypertension (CHD)

Hypertension CKD, COPD, Obesity, OSASDiabetes Diabetes, AnemiaChronic valvular insuff Aortic stenosisDilated CMP HCMP, Restrictive CMP

Comorbidities Not frequent FrequentPresentation Younger than 65 years 65 years or older

Progressive SOB Acute pulmonary oedemaPhysical examination Displaced PMI Sustained PMI

S3 gallop S4 gallopRadiographic findings Pulmonary congestion Pulmonary congestion

Cardiomegaly Normal sized heartElectrocardiogram Q waves LVH, AFEchocardiogram Decreased LVEF Normal or increased LVEF

Tresh DD et al. J Am Geriatr Soc 1995; 43:1035-1042.

Prevalence of CHD and Hypertension:Prevalence of CHD and Hypertension: Framingham Heart Study Subjects Framingham Heart Study Subjects

With Cardiac Failure With Cardiac Failure

Prevalence of CHD and Hypertension:Prevalence of CHD and Hypertension: Framingham Heart Study Subjects Framingham Heart Study Subjects

With Cardiac Failure With Cardiac Failure

11 15

30 37

4040

1937

0

20

40

60

80

100

Men Women

Fre

qu

ency

(%

)

CHD alone

CHD + HTN

HTN alone

No HTN or CHD

Quality of Life in Older Patients with Quality of Life in Older Patients with Systolic and Diastolic Heart FailureSystolic and Diastolic Heart Failure

Systolic HF (n=150) Diastolic HF (n=36) P value

6 min walk 177+138 155+112 n.s.

MET 4.5+1.7 4.4+1.4 n.s.

Dyspnea 89% 94% n.s.

Fatigue 71% 81% n.s.

No of symptoms 3.9+1.5 4.1+1.2 n.s.

Symptoms severity

7.1+2.2 6.7+2.6 n.s.

PAIS score 36+19 32+17 n.s.

Overall well being 6.4+2.2 6.6+2 n.s.

Jaarsma et al., Eur J Heart Fail 1999

CHF vs. Non CHF and CHF Systol.vs Non-Systol. CHF vs. Non CHF and CHF Systol.vs Non-Systol. In 452 Pts.with CHF: B-Type Natriuretic Peptide In 452 Pts.with CHF: B-Type Natriuretic Peptide

0.0 0.5 1.0

0.5

1.0

0.0 0.5

0.5

1.0

AUC = 0.66;P<0.001

0.0 0.5 1.0

0.5

1.0

300300AUC = 0.90;P<0.001

1-SPEC.1-SPEC.1-SPEC.1-SPEC.0.0 0.5

0.5

1.0

400

200

100

300200

100CHF vs. Non-CHF vs. Non-CHFCHF

CHF Systol. vs. Non-Syst

SENS.SENS.SENS.SENS.

1) BNP is accurate in distinguishing CHF and Non-CHF (BNP=100 pg/ml: Sens 90, Spec 73, Accur. 81)

2) BNP is not accurate in distinguishing Systol. Vs Non-Systol. CHF (BNP=100 pg/ml: Sens 95, Spec 14, Accur. 66)

BNP pg/ml

Maisel et al., JACC.2003

• Clinical presentation– Acute pulmonary edema

• Response to treatment– Generally rapid

• Clinical course– Frequent relapses

– Mild symptoms / Few LV abnormalities between the acute episodes

Diastolic heart failure. Paroxysmal or chronic? Banerjee P, Clark AL, Nikitin N, Cleland JG. (Eur J Heart Fail. 2004 Jun;6(4):427-31)

Diastolic Heart Failure is predominantly Acute Heart Failure

Do they need theDo they need the same treatment?same treatment?

The Italian Network on Congestive Heart Failure (IN-CHF)The Italian Network on Congestive Heart Failure (IN-CHF)

Adjusted survival among outpatients with Adjusted survival among outpatients with CHF, 1995 and 1999CHF, 1995 and 1999

1.0

0.9

0.8

0.7

0.6

0.53 6 9 12

Months

19991995

P=NS

Diastolic HF (FEDiastolic HF (FE>>40%)40%)

P<0.02

TEMPORAL TRENDS IN SURVIVALTEMPORAL TRENDS IN SURVIVAL

1.0

0.9

0.8

0.7

0.6

0.53 6 9 12

Months

19991995

P<0.0001

Systolic HFSystolic HF

P<0.0001

Senni M, De Maria R, Gregori D et al.: J Card Fail 2005

Treatment of Diastolic Heart Failure

There have been no large RCTs to establish the optimal evidence-based treatment

Difficulties inherent in verifying the diagnosis

Heterogeneity of the underlying causes

Occurrence in elderly patients with multiple coexisting

illnesses

In the interim, the treatment remains empirical (aggressive

treatment of underlying disease and precipitating factors)

N Engl J Med 2001; 344: 56-59. Editorial. Diastolic HF – No Time to Relax.

Treatment of cardiac Treatment of cardiac pathophysiologicalpathophysiologicalmechanismsmechanisms

• Control congestion Diuretics• Maintain atrial contraction CV for A Fib, AA drugs• Prevent or reduce LVH Antihypertensive drugs

Surgery (AVR for AS)• Prevent/treat ischemia -blocker, Ca++ entry blocker,

Nitrates, revascularisation• Reduce HR/increase -blocker, Ca++ entry blocker, filling time Digitalis (AF)• Avoid LVOT obstruction Avoid arterial vasodilatators• Reduce interstitial fibrosis Ace-i/ARBs, antialdosterone• Control associated illness Specific interventions

Goal of therapy Methods of treatment

Meta-analysis of randomized, controlled Meta-analysis of randomized, controlled trials of LV hypertrophy regression in trials of LV hypertrophy regression in

essential hypertensionessential hypertension

Meta-analysis of randomized, controlled Meta-analysis of randomized, controlled trials of LV hypertrophy regression in trials of LV hypertrophy regression in

essential hypertensionessential hypertension

-16-16

-14-14

-12-12

-10-10

-8-8

-6-6

-4-4

-2-2

00DiureticsDiuretics b-blockersb-blockers

Ca-antagonist

Ca-antagonist

ACE-inhibitors

ACE-inhibitors ARBsARBs

-8%

-6%

-11%-10%

-13%

LV massreduction

(%)

LV massreduction

(%)

80 randomized controlled trials;4,113 patients

Klingbeil AU et al. Am J Med. 2003;115:41-46.

Greater reduction in LVH during antihypertensive Greater reduction in LVH during antihypertensive therapy is associated with a lower risk of HFtherapy is associated with a lower risk of HF

Greater reduction in LVH during antihypertensive Greater reduction in LVH during antihypertensive therapy is associated with a lower risk of HFtherapy is associated with a lower risk of HF

Okin PM. Ann Intern Med. 2007;147:311-319.

Effects of antihypertensive treatment on the Effects of antihypertensive treatment on the

development of HF in hypertensive patientsdevelopment of HF in hypertensive patients

Effects of antihypertensive treatment on the Effects of antihypertensive treatment on the

development of HF in hypertensive patientsdevelopment of HF in hypertensive patients

ACEI vs. placebo

CA vs. placebo

More vs. less

ARB vs. control

ACEI vs. D/BB

CA vs. D/BB

ACEI vs. CA

219/8233

104/3382

54/7494

302/5935

547/12498

732/23425

502/10357

269/8246

88/3274

72/13394

359/5919

809/18652

850/29734

609/10345

-5/-2

-8/-4

-4/-3

-2/-1

+2/0

+1/0

+1/+1

0.82 (0.69-0.98)

1.21 (0.93-1.58)

0.84 (0.59-1.18)

0.84 (0.72-0.97)

1.07 (0.96-1.19)

1.33 (1.21-1.47)

0.82 (0.73-0.92)

0.5 1.0 2.0

Heart Failure Events/participants

1st Listed 2nd Listed

Difference in BP(Mean, mmHg)

Relative risk(95% CI)

Relative RiskFavours 1st listed Favours 2nd listed

1. Table adapted from Blood Pressure Lowering Trialists’ Collaboration. Lancet. 2003;362:1527-1535.2. Gottdiener JS et al. Ann Intern Med. 2002;137:631-639.

CHARM: CV death or hospitalisation for CHF

candesartan better

Hazard ratio

placebo better

0.6 0.8 1.0 1.2 1.4

Age <65 384/1614 413/1642(yrs) >65 <75 416/1337 476/1270

>75 350/852 421/884

LVEF <40 817/2287 944/2292>40 333/1516 366/1504

Gender Male 813/2617 917/2582Female 337/1186 393/1214

NYHA II 359/1730 415/1686III/IV 791/2073 895/2110

Overall 1150/3803 1310/3796

Candesartanevent/n

Placeboevent/n

p=0.26

p=0.93

p=0.63

p=0.40

Test for interaction

Limiti…• Non TDI• 14% con riconoscimento pattern pseudonormale• 86% pattern pseudonormale “riconosciuto” con il BNP (?)

Hazard ratio and 95% CI

Death or CV Hospitalisation by SubgroupDeath or CV Hospitalisation by SubgroupFavours NebivololPlaceboPlaceboNebivololNebivolol

Favours Placebo

0.50 0.60 0.70 0.80 0.90 1.00 1.10 1.20

125 (33.6%)110 (28.9%)> 35 %

LVEFLVEF

249 (36.3%)219 (32.1%) 35 %

125 (33.3%)101 (24.6%)Female

SexSex

250 (36.4%)231 (35.2%)Male

199 (37.1%)184 (34.8%)> 75 y

AgeAge

176 (33.5%)148 (27.5%)70-75 y

375 (35.3%)332 (31.1%)Total

• TDI non sistematicamente utilizzato• 41% BMI>30 kg/m2• 25% BNP <139-131 pg/ml• PAS all’ingresso 137-136 mmHg• 33% dei pz hanno sospeso il farmaco• diuretici già in terapia nell’82-84%• ++ pz già in inibitori RAAS prima dell’arruolamento

Ma per validare una terapia per lo scompenso diastolico dobbiamo

escludere (o trattare) …• Malattia coronarica associata

• Diabete mellito

• Obesità/OSAS

• Distiroidismi

• Insufficienza renale

• BPCO

• Anemia

• ….

BOOKLET”SCOMPENSO CARDIACO”

• Coordinamento: • Alberto Gianmarini Barsanti (CEFORMED);• Valentino Moretti(FADOI); • Andrea Di Lenarda(ANMCO)

• CEFORMEDBattigelli D.Cuzzato A.L.Lucchini G.Ponga B.Potente D.Prelli L.Toffolo M.

• FADOIBulfoni A.Bernardis V.Caliandro D.De Carli M.Donada C.Gerloni R.Iacono M.A.

• ANMCOAlbanese M.C.Bonin M.Borgioni L.Chiozza R.Di Piazza R.Lo Giudice F.Pavan D.Zecchin M.

Booklet “Scompenso Cardiaco”“Punti chiave”

• “Implementazione” delle LG sullo SC nel mondo reale dell’assistenza multidisciplinare al paziente con SC

• Condivisione del PDT tra i protagonisti dell’assistenza al paziente con SC (MG, internisti, cardiologi)

• Apertura all’utilizzo del BNP (per escludere) in MG• Apertura ad una crescita culturale e professionale

delle Medicine per la gestione del paziente con SC senza prospettive di intervento