Etiopathogenesis of heart failure

and pathophysiology of therapy

Fedor Šimko

ÚPF LFUK, Bratislava

Disclimer slide –prednáška je určená len na

výučbové potreby medikov LFUK v Bratislave

Fedor Šimko

Heart failure –

the cardiovascular problem No. 1

Frequent (above 70 years - 10 % prevalence)

Poor prognosis – 5-year mortality - 50%

Economic burden

Factors regulating the

pumping function of the heart

preload

contractility

afterload

heart rate

synergism of individual heart parts

Preload

Is the load present in the left

ventricle before starting the

contraction – systole

//

- end-diastolic volume

- end diastolic pressure

Preload is associated with Frank-

Starling mechanism:

The force of contraction during

systole depends on the initial

length of muscular fibres

(up to 2,2 um sarcomer size) – in

this point the maximal number of

act-myosin bridges can be

formed

ContractilityIs a factor modifying the contractile

ability independently from end-diastolic

length of fibres (sarcomeres)

but depending from positive or negative

inotropic factors

(Positive inotropic substances increase

the speed of actino-myosine bridges

formation)

Afterload- wall tension during

systole

depending from:

– Aortic compliance

- Peripheral arteriolar resistance

- Blood volume in arterial bed

T= P x r/2h – La-Place law

Heart rate increases minute volume

by more frequent emptying the

ventricles

- Frequency effect

-critical value of heart rate

- Unfavorable in aortic or mitral valve

stenosis

Synergism of heart

parts

Base, middle part, apex

Right and left ventricles

Atrias and chambers

Heart failure is the state, when

the heart is not able to maintain

the adequate perfusion of the

periphery

despite normal or increased

filling pressure

Heart failure:

Systolic vs. Diastolic

Acute vs. Chronic

Left HF vs. right HF

Etiology of HF

1. Myocardial damage

Ischemic heart disease

cardiomyopathies

myocarditis

toxic damage

heart damage in endocrinopathies

2. Chronic hemodynamic overload

presure

volume

3. Heart rythm disorders

4. Restricted filling of the ventricles

Most frequent reasons of HF

HYPERTENSION

ISCHEMIC

HEART

DISEASE

Forward failure -hypoperfusion of the periphery

Backward failure - blood

congestion in front of the

failing ventricle

2 types of HF manifestations

Forward failure - hypoperfusion

of the periphery (muscles!!!, skin,

kidney, other organs)

Backward failure - congestion (LV,

LA, lungs!!!)

Dyspnea

Fatigue, weekness,

renal failure, cold extremities, cachexia

Compensatory mechanisms of

HF

1. Frank- Starling mechanism

2. Neurohumoral activation

(SNS, RAAS, ADH)

Physiologic myocardium Concentric hypertrophyin pressure oveload

Excentric hypertrophy in volume overload

Primary dilatation Secondary dilatation

Hypertrophy of the heart

Oedema model of HF

• Impaired pumping

function

• Reduction of renal

flow

• Impaired water

secretion

• Oedema

• Increased ventricular

pressure

• Increase in venous

pressure

• Impaired venous return

from kidney

• oedema

Prognosis predictors in CHHF

Norepinephrine level

Renin level

Ejection faction

Size of the LV in diastole

Obrázok noradrenalínovej

závislosti

Hemodynamic overload /loss of myocytes

Stroke volume Proliferative effect

AdrenalinNoradrenalin

Ang IIEndothelin

Arg.-vasopressin

Aldosterone

Retention ofNa+, H2O

Tension in LV wall

endothelial dysfunction,

atherosclerosis

O2 demands O2 supply

Myocardial ischaemia,LV remodelling, LV dysfunction

Myocardial hypertrophy and fibrosis

frequency

contractility

Neurohumo-

ral model of

HF

Pathophysiology of HF

therapy

Original approach:

Increased contractility: positive

inotropic drugs

Reduction of volume retention –

diuretics

Reduction of heart burden -decrease of preload/afterload

vasodilatation

Positive effect –

Enhancement of contractility

and heart rate

MV = SV x P

Neurohumoral activation -

acute

Positive effect

Increased

contractility and HR

Neurohumorl activation –

chronic HF

Negative effect

Pathologic

remodeling

ATP

devastation

Angiotensin II

Aldosterone

Catecholamines

Endothelin

Bradykinin

NO – nitric oxide

Prostacycline

Natriuretic peptide

Pathologic heart remodeling

Trial ACE I % mortality

SAVE captopril from 25 to 20%

TRACE trandolapril from 42 to 35%

AIRE ramipril from 23 to 17%

SOLVD enalapril from 40 to 35%

ACE inhibitors

Trial AT1 blocker % mortality

ELITE losartan from 9 % to 5%

ELITE II losartan from 16 % to 17.7%

Angiotensin receptor blockers

Trial ACEI + AldB % mortality

RALES spironolactone reduction by 30%

Ephesus eplerenone reduction by 16%

Aldosterone receptor blocker

Trial ACEI + Drug % mortality -

increased

PROMISE Milrinone from 24 % to 30 %

XAMOTEROL Xamoterol from 4 % to 9 %

VEST Vesnarinone from 19 % to 23 %

PRIME - II Ibopamine from 20 % to 25 %

Inotropic trials

Trial ACEI + inotr.drug % mortality

-

increased

DIG digoxin from 35,1% to 34,8%

+ sympt. improvement

Inotropic trialsInotropic trials

Trial ACEI + BB % mortality

CIBIS II bisoprolol from 17 to 12%

Merit HF metoprolol from 11 to 7%

COPERNICUS carvedilol from 20 to 12%

N. America carvedilol from 7.8 to 3.2%

Beta blockers

Hemodynamic overload /loss of myocytes

Stroke volume Proliferative effect

AdrenalinNoradrenalin

Ang IIEndothelin

Arg.-vasopressin

Aldosterone

Retention ofNa+, H2O

Tension in LV wall

endothelial dysfunction,

atherosclerosis

O2 demands O2 supply

Myocardial ischaemia,LV remodelling, LV dysfunction

Myocardial hypertrophy and fibrosis

frequency

contractility

SHIFT:

Primary endpoint : combined CV death + hospit. HF

Ivabradine – reduction of HR by 10/min

and of prim. endpoint by 18%

5.Elevated HR as a risk: beside BB

Ivabradine (If channel blocker

in SA node

Neprilisin inhibitor AT1 blocker+

ANPAdrenomeduline

Bradykinin

Antiremodeling

vasodilatation

Angiotensin II

effect

Antiremodeling

vasodilatation

Additive mortality reduction in HF

compared to ACEI

SACUBITRIL VALSARTAN

Pathomechanisms of HF therapy

Reduction of neurohumoral activation

(ACEI, ARB, BB, AldB, sacub.+ARB)

Reduction of fibrosis

(ACEI,ARB, AldB, sacub.+ARB

Reduction of hemodynamic load

(ACEI, ARB, sacub.+ARB)

Reduction of catecholamine danger

-BB (reduction of uncoupling + reduction of HR+

reduction of dysrrhytmias)

HR reduction

(ivabradine)

remodeling

ATP

first choice – positive

inotropic drugs

betablockers- contraindicated

in HF

Why did pathophysiological

considerations fail?Calcium is not decisive in heart failure

Calcium is decisive, but not the amount but the compartmentalisation

ATP is more decisive than calcium

Neurohormonal activation is decisive, but not through inotropy but through remodeling or

everything is different

Recent 30 years – great advance in HF treatment

still -

we are at the beginning