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General Cardiac Pathophysiology II
1. Cardiac failure – a survey
2. Pathological overload of the heart
2.1 Pathological volume overload
2.2 Pathological pressure overload
3. Systolic and diastolic dysfunction
3.1 Systolic dysfunction
3.2 Diastolic dysfunction
4. Compensation mechanisms of the failing heart
4.1 Frank-Starling mechanism
4.2 Neurohumoral activation
4.3 Wall stress and hypertrophy
5. From hypertrophy to dilation and manifest failure
5.1 Cellular and molecular mechanisms
5.2 Neurohumoral hypothesis and vitious circles
6. Organismic consequencies of the heart failure
7. Signs and symptoms in heart failure, therapy
1. Cardiac failure – a survey
Definition:
Pathophysiologic: Condition in which the heart is not able to pump blood adaquately
to the metabolic needs of the body under normal filling pressures
Clinical: Syndroma in which a ventricular dysfunction is connected with lowered
capacity to cope with physical loading, encompassing dyspnea, venostatic
edema, hepatomegaly, jugulary venous distention, pulmonary rales
The term „congestive“ is too restricted and should be avoided
Cardiac failure is a culmination of ventricular dysfunction which develops for a rather long
time (in case of a chronic cardiac failure)
Types: latent, manifest („cardiac decompensation“)
chronic, acute (sudden, abrupt – more consequential)
Systolic dysfunction
Diastolic dysfunction
Forwards
unable to enhance filling
pressures
Backwards
able to enhance filling
pressures
(unable to enhance filling
pressures)
able to enhance filling
pressures
(nearly synonymous)
The failure „forwards“ and „backwards“ are connected vessels – ability/unability to enhance
filling pressures is decisive in both conditions
Etiology – Fig. 1
Pathogenesis – Fig 2: A survey of some interconnections among the components of cardiac
failure.  = wall stress, Ø = Frank-Starling mechanism ceases to work
Systolic and diastolic dysfunction represent an early stage of later manifest failure and its
immediate hemodynamic mechanism
Neural and endocrine compensatory reactions are originally useful physiological feedback
reactions; their effectivity, however, presupposes the functioning „regulatory organ“ = heart
and vessels. If the regulatory organ is not able to respond properly the SAS and RAS reactions
overshoot and become detrimental:
peripheral resistance & fluid retention & myocardial hypertrophy  vicious circles 
pathological reversal  myocardial dysfunction   SAS  RAS
Both dysfunction and compensatory reactions are stretched in time just from the action of
etiological factors to the definitive failure. The role of compensatory reactions is, however,
different in different phases: compensatory and advantageous at the beginning, overshooting
and detrimental later (vicious circles)
2. Pathological overload of the heart
1/3 of all failure
2.1 Pathological volume overload
Causes see Fig. 1
Stages:
- acute volume overload, F-S  end-systolic volume maintained
- slippage of myocardial fibers  compliance of myocardium (not dilation)
- excentric hypertrophy
- (lasting overload   and hypertrophy)  internal irreversible changes of the
myocardium  systolic and diastolic function (Fig. 3)
- ESV, ejection fraction = emptying
EDV  , coronary perfusion  ischemia  fibrotization  active
relaxation (diastolic dysfunction)
Disruption of aortal valve in endocarditis, mitral regurgitation with disruption of papillary
muscle  acute volume overload  no compliance  acute pulmonary edema
2.2 Pathological pressure overload
Stroke volume declines linearly with the afterload (Fig. 4)
Systolic work, effectivity (Fig. 5)
Causes see Fig. 1
aortic or pulmonary stenosis, coarctation of aorta, hypertrophic cardiomyopathy,
systemic or pulmonary hypertension
right ventricle: persisting ductus arteriosus, mitral stenosis
Stages:
acute pressure overload: Anrep´s phenomenon + F-S  maintaining of stroke
volume (SV)
- sympaticus  contractility (Fig. 6)
- concentric hypertrophy
- hypertrophy  compliance  systolic and diastolic dysfunction (Fig. 3)
-
3. Systolic and diastolic dysfunction
8% of population: asymptomatic left ventricle dysfunction and manifest failure (1:1)
 cardiac failure from inherent cause
3.1 Systolic dysfunction
Systolic dysfunction  contractility
Etiology see Fig. 1
Overload  hypertrophy  contractility (mechanisms known only partially)
Working diagram: Fig. 3
Failure forwards: tissue perfusion (calm and sticky skin), renal perfusion (oliguria),
cerebral perfusion (confusion)
Failure backwards: pressure in pulmonary veins (left v.) or in systemic veins (right v.)
What should be known in a particular case:
- preload (EDV or EDP)
- afterload (arterial pressure)
- contractility (SV and EF)
A compromise between forward and backward failure (Fig. 7)
Therapy see Fig. 8
 preload by volume expansion (cave pulmonary congestion and edema!)
 afterload by vasodilators (cave hypotension!)
arteriolar (hydralazine)
„balanced“ (IACE)
contractility by inotropic drugs (cave arrhythmias and other side-effects!)
3.2 Diastolic dysfunction
Diastolic dysfunction  compliance
Etiology see Fig. 1
Pressure overload  mainly diastolic dysfunction (possibly with intact systolic
function)
Working diagram: Fig. 3
Although the pathogenesis of systolic and diastolic dysfunction is different, the consequences
for the pumping function (and for the patient) are the same – forward or backward
failure
Moreover, EDP  pressure gradient ventricle – aorta  coronary perfusion  ischemia
4 Compensation mechanisms of the failing heart
Fig. 2 Three types of compensatory mechanisms of the primary damaging factors
4.1 Frank-Starling mechanism
Volume or pressure overload  utilization of F-S = of diastolic reserve
diastolic reserve: the work which the heart is able to perform beyond that required
under the ordinary circumstances of daily life, depending upon the degree to which the
cardiac muscle fibers can be stretched by the incoming blood during diastole
contractility  utilization of F-S
Dilation  utilization of F-S (strongly limited)
4.2 Neurohumoral activation
Fig. 9 – regulation of blood pressure
Cardiac failure  CO  lowered pressure is indicated  sympatoadrenal system 
generalized vasoconstriction 
 venous return  F-S (fails later)
 maintaining of blood pressure (and cutting off kidneys, skin, GI etc.)
Fig. 10 – a simple scheme of volume regulation
Fig. 11
Already before manifest cardiac failure, plasma norepinephrine and atrial natriuretic factor
levels are enhanced – physiological reactions merge smoothly into pathological ones
4.3 Wall stress and hypertrophy
Definition of cardiac hypertrophy: left ventricle muscular mass per unit of the body surface
Presupposes protein synthesis (dilation does not!)
Pathogenesis: wall stress ()
Hypertrophy = important compensatory mechanism normalizing the wall stress.
However, a risik factor of morbidity and mortality at the same time
muscle mass, but contractility/gram of tissue not changed
There is probably a qualitative difference between physiological and pathological hypertrophy
(Tab. 1 )
Pathological hypertrophy of the myocardium
Fig. 12
Volume overload  excentric hypertrophy
Prolongation of myocytes by serial apposition of sarcomeres  velocity and extent
of shortening with an unchanged tension
Less internal work expended than in pressure overload
Pressure overload  concentric hypertropy
Thickening of myocytes by parallel apposition of sarcomeres  tension with an
unchanged extent of shortening
Hypertrophy generally:
ratio capillaries/cardiomyocytes  ischemization 
  contractility temporary maintaining od CO  later cardiac failure
 fibrotization  compliance
  active relaxation
thickening  compliance = diastolic dysfunction
Acute
volume
overload
Excentric
hypertrophy
P * r
D  ~
P * r
D ~
h
Acute
pressure
overload
h
Concentric
hypertrophy
P * r
S  
P * r
S 
h
 Wall stress
(normalization
of )
h
 SV
 Stiffness 
 diastolic
failure
Late effect :
dilation  
Physiological hypertrophy
No dysfunction, the overload is intermittent, mitochondrias proportional to myofibrills, no
fibrosis. Complete reversibility
Molecular biological and biochemical characteristics of the hypertrophy
500 g  not only hypertrophy, but also hyperplasia
protein synthesis
Hemodynamic stimuli  hypertrophy mechanisms (Fig. 13) :
- mechanical distention of cardiomyocytes  PKC, Ca2+
- agonists (AG II, catecholamins, endothelin)  PKC  MAPkinase  activation of
nuclear protooncogens
- growth factors (IGF-1, TGF1, PDGF, FGF)  tyrosin-kinases  activation of
nuclear protooncogens
Slow izoenzymes are produced
expression of 1-adrenergic receptor  contractility
expression of SERCA pump, Na/Ca exchanger etc.  slowering of contraction-relaxation
cycle, prolongation of action potential
Expression of foetal phenotype in production of ANF etc.
Fibrosis  dysfunction and irreversibility
5 From hypertrophy to dilation and manifest failure
5.1 Cellular and molecular mechanisms
Dilation: radius, thickness   with normal P  oxygen consumption
Final stage of myocardial dysfunction
Morphological changes in cardiomyocytes: dehiscences, stripping, disseminated necroses
Mutual slippage of sarcomeres  contractility
Pathogenesis:
Energy deficit as a consequence of hypertrophy:
 EDP
inadequate
accomodation
of coronary
vessels to hypertrophy

prolongation
 duration
of contract-  of diastole
ion & relaxation
 heart
rate

muscle
mass
lowered
coronary
reserve

lack of
energy

enhanced O2
consumption


lowered
contractility
reserve
 proteosynth.

 cell growth

disorganization
of myofibrills
micronecroses,
dehiscenses
mitochondrial function  lack of energy
Bouts of ischemia  fibrotization  compliance
Abnormal propagation of excitation  coordination of contraction
Molecular level:
expression of the SERCA2a gene  relaxation
expression of the ryanodin-receptor gene
(hypoxia, cytosolic Ca2+, reperfusion damage, tension)  apoptosis  attenuation
of the myocardial wall?
catecholamine concentration in plasma  down regulation of -receptors 
catecholamines in the myocardium
The mechanisms of the cardiac failure are heterogenous
5.2 Neurohumoral hypothesis and vitious circles
Fig. 11
Neural and endocrine compensatory reactions are originally useful physiological feedback
reactions; their effectivity, however, presupposes the functioning „regulatory organ“ = heart
and vessels. If the regulatory organ is not able to respond properly the SAS and RAS reactions
overshoot and become detrimental:
peripheral resistance & fluid retention & myocardial hypertrophy  vicious circles 
pathological reversal  myocardial dysfunction   SAS  RAS
Angiotensin II  thirst   ADH  hyponatremia
 Retention of Na  H2O   preload (volume overload)  further
extra burden
Antidiuretic hormone
Baroreceptors  AG II   ADH   circ. volum 
  EDV   output
 Endothelin  vasoconstriction, cellular hypertrophy
Atrial natriuretic peptide
Counter regulatory hormone, but target organs are hyporesponsive to it now.
Vasodilatory mechanisms (local prostaglandins, NO ·) less potent than
vasoconstrictory ones
6. Organismic consequencies of the heart failure
„Forward“ and „backward“ failure (Fig. 14 b)
Systemic blood pressure of about 90 mmHg must be allways secured
Means :
 contractility,  pulse frequency,  systemic vascular resistence,
selective of course
Adrenergic nervous system
 Output  sensed as decreased perfusion pressure   parasymp.  sympat. activation (and adrenal medulla)   heart
rate, contractility, vasoconstriction (venous  arterial)
veins   EDV  F - S   SV
constriction
of
arterioles: BP =  output * R 
„important” organs enhance resistance
less than „unimportant”, of course
Excessive vasoconstriction   afterload (pressure overload)  extra
burden to already failing heart
Renin - angiotensin system (endocrine)
 perfusion
of art. renalis

activation
of adrenerg.
systém
 R systemic  maintenance of systemic BP
  RAS
 circ. volume   EDV
 F - S   output

 vitious circle analogical to that in hypertension
Specific organ performance
- left: brain, muscles, kidneys, GIT, pulmonary edema, afterload to right ventricle
- right: pulmonary gas exchange, systemic venostasis, thromboses; ascites
7. Signs and symptoms in heart failure, therapy
Both „forward” (weakness, fatigue) and „backward” (dyspnea) signs
Signs of pulmonary edema
3rd heart sound (ventricular „gallop”) in ventricular rapid filling phase,
abrupt tensing of chordae tendineae. Signalizes increase in diastolic
ventricular filling and/or flabby left ventricle
th
4 heart sound (atrial „gallop”) in „A” wave phase, atrium contracts
against stiffened ventricle
Prognosis: Ejection fraction ! PlNa , PlNOREPIN.
Progressive failure, or arrhytmias  sudden death
Treatment (Fig. 8)
Moderates „compensatory” neurohumoral stimulations
Principle : to increase cardiac output and to reduce elevated ventric. filling
pressures
Inotropic drugs (digitalis, -adren.agonists, fosfodiesterase inhibitors   cAMP),
in systolic dysfunction only.
Long-term use of potent inotropic drugs and antiarrhytmic agents
worsen prognosis
Diuretics only in pulmon./peripher. congestion (point b or b´)
pure venous - nitrates, point b, b´
vasodilators
arteriolar - hydralazine, point d
„balanced” - ACE inhbitors, point d;
improve survial !