METABOLISM OF MYOCARDIUM
ISCHEMIC HEART DISEASE
MYOCARDIAL INFARCTION
VLA November 1, 2016
METABOLISM OF THE HEART
 The heart is an omnivore organ, which utilizes a
diverse set of fuel substrates, including lactate,
glucose, amino acids, ketones, and particularly
free fatty acids.
 Newborns –preferentially-glucose (Fas with a
long chains are needed for myelinisation)
 Healthy adults - lipids
 Ischemic adults - anaerobic glycolysis only
(ATP)
 Diabetic adults – also ketones
 Patients with heart failure - toxic effects of both
glucose and lipid metabolism
EPICARDIAL ADIPOSE TISSUE
Epicardial portion – between inner surface of
visceral layer of pericardium and myocardium
(without fascia- common microcirculation)origin-splanchnopleuric
mesoderm- supplied by
aa. coronarie. Similar to brown tissue (high
expression UCP-1, modulation of the heat
production for heart during changes of
thermoregulation, protection against effects of
ischemia/ hypoxia with great hemodynamical
effects, maybe characteristics of beige fat)
EPICARDIAL ADIPOSE TISSUE
 Pericardial (paracardial) portionbetwwen
external surface of external
pericardial layer and thoracic wall –
primitive thoracic mesenchym –supplied
by a. mammaria int.
NORMAL CARDIAC FUNCTION
 Cardiac Output = Heart rate x Stroke volume
 Heart rate – controled by SNS and PNS
 Stroke – dependent on preload, afterload and
contractility
 Preload = LVEDP and is measured as PCWP
(Pulmonary Capillary Wedge Pressure)
 Afterload = SVR (Systemic Vascular Resistance)
 Contractility: ability of contractile elements to
interact and shorten against a load
(+ inotropy - inotropy)
Working diagram
Sum of the external and internal
work represents the total
mechanical work of contraction
and this is directly proportional to
oxygen consumption of the
myocardium.
Pressure work of the heart
consumes more oxygen than
volume work, so that the effectivity
of the former is lower than that of
the latter.
SYSTOLIC DYSFUNCTION
 Impairment of the contraction of the left
ventricle leads to reduction of stroke
volume (SV) for any given end-diastolic
volum (EDV)
 Ejection fraction (EF) is reduced (below
40-45%)
 EF=SV/EDV
DIASTOLIC DYSFUNCTION
 Ventricular filling rate and the extent of
filling are reduced or a normal extent of
filling is associated with an inappropriate
rise in ventricular diastolic pressure.
COMPENSATORY MECHANISMS FOR
DECREASED CARDIAC OUTPUT
 Increased SNS activity
Increase HR and SVR which increases BP
 Frank-Starling mechanism:
LVEDP = SV
 Activation of renin-angiotensin-aldosterone
 system (RAAS)
 Myocardial remodeling
- Concentric hypertrophy
- Eccentric hypertrophy
Pathological hypertrophy of the myocardium
ATHEROSCLEROSIS DEVELOPMENT
 Initiation
 Inflammation
 Fibrous cap formation
 Plaque rupture
 Thrombosis
FUNCTIONAL ENDOTHELIUM
 Constant vasodilation
 Antiadhesive state (NO, PGI2)
 Constant local anticoagulation and
fibrinolytic state (increase of AT III,
protein C, protein S, tPA, PAI-1)
ENDOTHELIAL DYSFUNCTION- CAUSES
 LDL modification (oxidation, glycation,
immune complex formation).
 Expression of adhesive molecules
 Cytokines release (attraction and migration
of proinflammatory cells to subendothelial
space).
 Prothrombotic phenotype of dysfunctional
endothelium
Crossection of normal vessel
Stable angina pectoris
Unstable angina pectoris
Myocardial infarction
Decreasedbloodflow
„RESPONSE-TO-RETENTION“ MODEL OF ATHEROGENESIS
 Atherogenesis is initiated by focal retention of ApoB on molecules of
subendothelial matrix, especially on proteoglycans.
 Adherent lipoproteins are modified (by aggregation and/ or oxidation),
which lead to maladaptive inflammatory response. Monocytes enter
subendothelial space, differentiate to macrophages and that
phagocyte adherent and modified lipoproteins. They become
gradually foam cells. Another cells as T-lymphocytes, mast cells and
other ones enter the developing lesion and take part in maladaptive
inflammatory response. The process is accelerating by increased
retention of lipoproteins in atherosclerotic plaques.
 Smooth muscle cells (SMCs) migrate to intima and support production of
collagen fibrous cap which seems to be remodelling response of
vascular wall (similar to scar) to damage.
 During atherosclerotic lesion progression focal necrotic lesions with
death macrophages are formed. In these lesions accumulation of
extracellular debris, cholesterol crystals, proteases and procoagulation/
trombogenic material can be observed. This leads to attenuation of
fibrous cap, erosion and/ or rupture of the plaque and development of
acute thrombotic vascular event (MI, cerebral stroke).
„RESPONSE-TO-RETENTION“ MODEL OF ATHEROGENESIS
 Cytokine release (platelet-derived growth factor a transforming
growth factor-β (TGF-β) from monocytes, macrophages and/ or
damaged endothelial cells support further accumulation of
macrophages and migration and proliferation of smooth muscle
cells
Tabas: Circulation, 116,
2007: 1832-1844
MYOCARDIAL ISCHEMIA
 Myocardial ischemia results in numerous deleterious
consequences at the level of the cardiac myocyte that, if
left uncorrected, culminate in necrotic cell death.
 A major consequence of myocardial ischemia is the
depletion of adenosine triphosphate (ATP) and other high
energy phosphates due to cessation of aerobic metabolism
and oxidative phosphorylation. Because the continually
contracting myocardium is highly dependent on aerobic
metabolism, ATP depletion occurs rapidly in the ischemic
heart and contractility is halted within 60 s.
 ATP depletion is leading to: decreased relaxation of
myofilaments, glycogen depletion, disruption of ionic
equilibrium and cell swelling.
MYOCARDIAL ISCHEMIA
 Nevertheless, these effects can be reversed and normal myocyte
contractile function restored if the duration of ischemia is
sufficiently brief (generally considered to be less than 20 min of
severe ischemia).
 If the ischemia is prolonged, irreversible injury will develop, which is
characterized by damage and/or disruption of the myocyte
sarcolemmal membrane.
 Plasma membrane damage leads to loss of osmotic balance and
the leakage of cellular metabolites into the extracellular space.
 Damage to the mitochondrial membranes compromises the cell's
ability to generate ATP upon reperfusion, as well as results in
release of mitochondrial proteins that can directly stimulate the
apoptotic cell death pathway.
 Disruption of lysosomal membranes is especially dire, as this can
lead to the release of degradative enzymes capable of digesting
essentially all cellular constituents, invariably leading to cellular
necrosis.
ACUTE MYOCARDIAL ISCHEMIA
 Acute myocardial ischemia was find to induce early
increases (10 min) of circulating glucose, lactate,
glutamine, glycine, glycerol, phenylalanine, tyrosine,
and phosphoethanolamine; decreases in cholinecontaining
compounds and triacylglycerols; and a
change in the pattern of total, esterified, and
nonesterified fatty acids. Creatine increased 2 h
after ischemia.
 Using multivariate analyses, a biosignature was
developed that accurately detected patients with
MIS both in the setting of angioplasty-related MIS
(area under the curve 0.94) and in patients with
acute chest pain (negative predictive value 95%).
ISCHEMIA/REPERFUSION-INDUCED CELL DEATH
 In addition to necrosis, apoptosis also contributes
significantly to myocyte death during
ischemia/reperfusion-induced cell death (IR).
While apoptotic myocyte death is most
pronounced in the reperfused myocardium,
apoptosis has also been shown to contribute to
cell death in ischemic-only hearts.
 In addition, a more recently defined form of cell
death known as necroptosis or “programmed
necrosis,” a form of cell death with
characteristics of both necrosis and apoptosis,
has been suggested to contribute to myocyte
death during IR.
MYOCYTE CALCIUM HOMEOSTASIS
 Loss of myocyte calcium homeostasis results in a number of
cellular changes that predispose the myocyte to irreversible injury.
 Mitochondrial calcium overload is the primary stimulus for
mitochondrial permeability transition (MPT), a stress response
mediated by the opening of a high conductance pore located
on the inner mitochondrial membrane. While enhanced
intracellular calcium concentration is capable of directly
stimulating apoptosis, elevated calcium levels can also stimulate
the activation of numerous intracellular degradative enzymes with
the potential to damage several different cellular structures and
precipitate cell death, including phospholipases, proteases and
endonucleases. Activation of phospholipases can lead to the
damage of cellular membranes which, as described above, can
lead to necrotic cell death as a consequence of disruption of
cellular osmotic balance and the release of lysosomal enzymes in
the cytoplasm. The ionic imbalances have further consequences.
Causes and consequences of
ionic imbalances during
ischemia.
Ischemia results in a cessation of aerobic
metabolism and a reliance on anaerobic
metabolism, resulting in cellular and tissue
acidosis. Accumulation of intracellular H+
stimulates NHE, resulting in accumulation of
intracellular Na+. Accumulation of
intracellular Na+, in turn, stimulates reverse
activity of the NCX, resulting in intracellular
Ca2+ accumulation. If ischemia is sustained,
cellular Ca2+ overload may develop, resulting
in activation of degradative enzymes (e.g.,
proteases, phosphatases and
endonucleases), and stimulation of MPT,
culminating in myocyte death. NHE, Na+/H+
exchanger; NCX, Na+/Ca2+ exchanger; MPT,
mitochondrial permeability transition.
Adam J. Perricone , Richard S. Vander Heide
Novel therapeutic strategies for ischemic heart disease
Pharmacological Research, Volume 89, 2014, 36 - 45
http://dx.doi.org/10.1016/j.phrs.2014.08.004
METABOLISM OF THE HEART IN ISCHEMIC CONDITIONS
 Dramatic and immediate changes take
place in cardiac and global metabolism
as a consequence of insufficient blood
flow to meet the myocardium energy
needs and secondary to the subsequent
stress response.
 These mechanisms include a decrease of
β-oxidation and an increase of glycolysis
and lactate release among others.
CORONARY ARTERY DISEASE (CAD)
 Multifactorial etiology, frequent risk factors
 Uninfluenced: genetics, age, sex, rase, family
history, low socioeconomic state (?)
 Influenced: total cholesterol, smoking, diabetes
mellitus, hypertension, life style,
 We can observe patients with CAD without these
risk factors.
ACUTE AND CHRONIC ISCHEMIC HEART DISEASES
 Acute coronary syndrom – generally
related to unstable angina pectorismyocardial
infarction
 Stable angina pectoris – chest pain
during exercise
 Unstable angina pectoris – chest pain in
rest conditions
 Prinzmetal´s angina pectoris – due to
spasms
Relations among coronary arteries state and clinical
syndrome.
MYOCARDIAL INFARCTION
 Clinical signs:
 Pain, angina-like after exercise. Brief onset,
during rest, several hours. Pain intensity
oscillating, in 20% patients without pain feeling.
S.c. ‚silent' MI usually in diabetic patients and
older individuals.
 Vegetative nerve system activation: sweat,
nausea, vomiting, fatique, unrest,
 Patents pale, grey, sweaty
 Sinus tachykardia (sympathetic nerve systém
activation)
 Slight fever (to 38°C) during 5 first days
DIAGNOSIS OF MI
At least two signs:
Chest pain
Corresponding changes on ECG
Increase of cardiac biomarkers
MI Signs on ECG
Q wave, ST elevation, T wave inversion
MI on ECG
HEART BIOMARKERS
Another markers of acute coronary syndrome
SIGNS AND SYMPTOMS
Acute MI can have unique manifestations in individual patients. The degree
of symptoms ranges from none at all to sudden cardiac death. An
asymptomatic MI is not necessarily less severe than a symptomatic event,
but patients who experience asymptomatic MIs are more likely to be
diabetic. Despite the diversity of manifesting symptoms of MI, there are some
characteristic symptoms.
 Chest pain described as a pressure sensation, fullness, or squeezing in the
midportion of the thorax
 Radiation of chest pain into the jaw or teeth, shoulder, arm, and/or back
 Associated dyspnea or shortness of breath
 Associated epigastric discomfort with or without nausea and vomiting
 Associated diaphoresis or sweating
 Syncope or near syncope without other cause
 Impairment of cognitive function without other cause
An MI can occur at any time of the day, but most appear to be clustered
around the early hours of the morning or are associated with demanding
physical activity, or both. Approximately 50% of patients have some warning
symptoms (angina pectoris or an anginal equivalent) before the infarct.
PATHOPHYSIOLOGY SUM OF MI
 Most myocardial infarctions are caused
by a disruption in the vascular
endothelium associated with an unstable
atherosclerotic plaque that stimulates
the formation of an intracoronary
thrombus, which results in coronary artery
blood flow occlusion. If such an
occlusion persists for more than 20
minutes, irreversible myocardial cell
damage and cell death will occur.
 flow, an MI can result.
PATHOPHYSIOLOGY SUM OF MI
 The development of atherosclerotic plaque occurs over a
period of years to decades.
 The two primary characteristics of the clinically symptomatic
atherosclerotic plaque are a fibromuscular cap and an
underlying lipid-rich core. Plaque erosion can occur
because of the actions of matrix metalloproteases and the
release of other collagenases and proteases in the plaque,
which result in thinning of the overlying fibromuscular cap.
The action of proteases, in addition to hemodynamic forces
applied to the arterial segment, can lead to a disruption of
the endothelium and fissuring or rupture of the fibromuscular
cap. The loss of structural stability of a plaque often occurs
at the juncture of the fibromuscular cap and the vessel wall,
a site otherwise known as the shoulder region. Disruption of
the endothelial surface can cause the formation of
thrombus via platelet-mediated activation of the
coagulation cascade. If a thrombus is large enough to
occlude coronary blood flow, an MI can result.
PATHOPHYSIOLOGY SUM OF MI
 The death of myocardial cells first occurs in the area of
myocardium most distal to the arterial blood supply: the
endocardium. As the duration of the occlusion increases,
the area of myocardial cell death enlarges, extending from
the endocardium to the myocardium and ultimately to the
epicardium. The area of myocardial cell death then
spreads laterally to areas of watershed or collateral
perfusion.
 Generally, after a 6- to 8-hour period of coronary occlusion,
most of the distal myocardium has died. The extent of
myocardial cell death defines the magnitude of the MI. If
blood flow can be restored to at-risk myocardium, more
heart muscle can be saved from irreversible damage or
death.
PATHOPHYSIOLOGY SUM OF MI
 The severity of an MI depends on three factors:
 the level of the occlusion in the coronary artery,
 the length of time of the occlusion, and
 the presence or absence of collateral circulation.
Generally, the more proximal the coronary occlusion, the more extensive the
amount of myocardium that will be at risk of necrosis. The larger the
myocardial infarction, the greater the chance of death because of a
mechanical complication or pump failure. The longer the period of vessel
occlusion, the greater the chances of irreversible myocardial damage distal
to the occlusion.
STEMI (=MI with ST elevation) is usually the result of complete coronary
occlusion after plaque rupture. This arises most often from a plaque that
previously caused less than 50% occlusion of the lumen.
NSTEMI (= MI without ST-elevation) is usually associated with greater plaque
burden without complete occlusion. This difference contributes to the
increased early mortality seen in STEMI and the eventual equalization of
mortality between STEMI and NSTEMI after 1 year.
PRECIPITATING CAUSES OF HEART FAILURE
1. ischemia
2. change in diet, drugs or both
3. increased emotional or physical stress
4. cardiac arrhythmias (eg. atrial fib)
5. infection
6. concurrent illness
7. uncontrolled hypertension
8. new high output state (anemia, thyroid)
9. pulmonary embolism
10. mechanical disruption (sudden MR…)
NYHA FUNCTIONAL CLASSIFICATION
 Class I: patients with cardiac disease but
no limitation of physical activity
 Class II: ordinary activity causes fatigue,
palpitations, dyspnea or anginal pain
 Class III: less than ordinary activity causes
fatigue, palpitations, dyspnea or
angina
 Class IV: symptoms even at rest conditions
STAGES OF HEART FAILURE
 Stage A
 High risk for development of heart failure
 Stage B
 Structural heart disease
 No symptoms of heart failure
 Stage C
 Symptomatic heart failure
 Stage D
 End-stage heart failure
DÍKY ZA POZORNOST