biochemistry of heart and lungs2018 -...

Biochemistry of Heart andLungs

Karel Kotaska

Contraction in heart muscle

Polarisation and repolarisationof heart muscle

Mechanism of myocardialcontraction

Regulation of heartcontraction

Myosinkinase (MLCK) and regulationof contraction

Contraction regulation

Specifity of Cardiac Metabolism

• Myocardial function depends on a fine equilibrium between the work the heart has to perform to meet the requirements of the body & energy that it is able to synthesize and transfer in the form of energy-rich phosphate bonds to sustain excitation-contraction coupling.

• To support high rates of cardiac power, metabolism is design to generate large amount of ATP.


• Heart muscle is highly oxidative tissue.

• Mitochondrial respiration produces more than 90% of

energy.

• Mitochondria occupy ~30% of cardiomyocyte space.

• >95% of ATP formation comes from oxidative phosphorylation in mitochondria.

• ~ 60-70% of ATP hydrolysis is used for muscle contraction,

~30 - 40% for the sarcoplasmic reticulum (SR) Ca2+-ATPase and other ion pumps.

• ATP turn over rate in ATP pool is very fast – 10-15 sec. in normal condition


• The heart can metabolize fatty acids, carbohydrates andketone bodies as a primary substrates.

• Fatty acids are the resting heart´s fuel of choice.

• Upon the work load increases dramatically, the heart

greatly increases its rate of consumption of glucose or

begin to use glucose derived mostly from its own relatively limited glycogen store.

Myocardium metabolic pathway

Processes in which ATP is used

• Cardiomyocyte - myofibrilar actin-myosin ATPase � contraction and relaxation processes

• Ca+ ATPase in sarcoplasmic reticulum � Ca+ reuptake

• Sarcolemmal Na+/K+ ATPase � membrane potential

• Anabolic reactions and signaling systems

• Creatine phoshate (PCr) – other major high-energy phosphate –ATP formation in creatine kinase (CK) reation:

• creatine kinase reation – temporal buffer to maintain high ATP and low ADP, spatial buffer, intracellular tranfer of high-energy phosphates from the sites of generation to the sites of utilization (mitochondrial CK and cytoplasmic form of CK)

creatine phosphate + ADP + H+ � creatine + ATP

Fatty Acid Metabolism

FFA enter the cardiomyocyte by: – passive diffusion– protein-mediated transport across sarcolema – fatty acid translocase (FAT) or

plasma membrane fatty acid binding protein (FABPpm).

Acyl-CoA synthase (FACS) activates nonesterified FA by esterification to fatty acyl-CoA.

W.C. Stanley et all. Physiol. Rev. 85, 2005


Long chain fatty acyl-CoA can be:– esterified to triglyceride (glycerolphosphate acyltransferase)

or– condenses with carnitine to long chain fatty acylcarnitine by carnitine

palmitoyltransferase-I (CPT-I) between inner and outer mitochondria membranes.



Carnitine acyltranslocase (CAT) transports long-chain acylcarnitineacross the inner membrane in exchange for free carnitine.

Carnitine palmitoyltransferase II (CPT-II) regenerates long chain acyl-CoA .



Regulation : malonyl CoA 1 strongly inhibits CPT (the cytosolic side of the enzyme).

Two isoforms of CPT-1:

– liver CPT-1α and heart CPT-1β– CPT-1β is 30-fold more sensitive to malonyl-CoA inhibition.



• Malonyl-CoA - key physiological regulator of FA oxidation in heart (� in malonyl-CoA � FA uptake and oxidation).

– malonyl-CoA – in cytosol � acetyl-CoA carboxylation (acetyl-CoAcarboxylase –ACC)

– inhibition of ACC activity by fosforylation of AMPK � acceleration of FA oxidation.



β-oxidation generates NADH+H+ and FADH2

Acetyl-CoA formed in β-oxidation generate more NADH+H+ in citric acid cycle (CAC).

NADH and FADH2 � electron transport chain


PPARαααα - regulation

• PPARαααα ((((peroxisome proliferator-activated receptor-α) α) α) α) – member of nuclear receptor suprafamily

• Control of gene transcription as promotor

• Genes transribed affected FFA beta oxidation and

carbohydrate metabolism and include:

– FFA transporters and FFA binding protein

– acetyl-CoA dehydrogenase, malonyl-CoA decarboxylase, acetyl-CoA synthase, carnitine palmitoyl transferase (CPT)

– pyruvate dehydrogenase kinase (PDHK)

Carbohydrate Metabolism

• Glycolytic substrate is derived from exogenous glucose and glycogen stores.

• Glycogen pool in the heart is relatively small (~30

µmol/g wet wt compared with ~150 µmol/g wet wt in skeletal muscles).

• Glucose transport into cardiomyocyte is regulated by transmembrane glucose gradient and the content of

glucose transporter in the sarcolema – GLUT-4 (lesser

extent GLUT-1).


• Insulin stimulation, increased work demand, or ischemia increase glucose transport and rate of glucose uptake.

• Glycolytic pathway converts glucose 6-phosphate and

NAD+ to pyruvate and NADH+H+, generate 2 ATP for

each glucose molecule.

• Pyruvate and NADH+H+ are shuttled to the mitochondrial matrix to generate CO2 and NAD+ - complete aerobic oxidative glycolysis.

Carbohydrate Metabolism• Phosphofructokinase-1 (PFK-1) –

key regulatory enzyme in glycolyticpathway – catalyzes the first irreversible step.

• PFK-1 utilized ATP � fructose 1,6-bisphosphate,

• Enzyme is activated by ADP, AMP and Pi and inhibited by ATP and fall in pH.

• PFK-1 can be also stimulated by fructose 2,6-bisphosphate (formed from fructose 6-phosphate by bi-functionalenzyme phosphofructo-2 kinase/fructose-2,6,-bisphosphatase, PFK-2).



• Low glucose level � glucagon is

released � cAMP signal cascade is

triggered � protein kinase A activates

the PFK-2 domain of the bifunctional

enzyme via phosphorylation,

• F-2,6-BPase domain is then activated

which lowers F-2,6-BP level,

• Increased glucose level � F6P level

subsequently rises � phosphoprotein

phosphatase 1 is stimulated and

phosphoryl group from the bifunctional

protein is removed � PFK2 domain is

activated and the kinase catalyzes the

formation of F-2,6-BP � glycolysis is stimulated.

• Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) reaction →production of NADH � major regulatory step.

• Accumulation of NADH within cytoplasm inhibits and NAD+ activates the GAPDH activity

• Severe ischemia in heart → lactate and NADH accumulation → interruption of oxidative metabolism and lactate production.

• Under anaerobic condition pyruvate is converted to lactic acid – non-oxidative glycolysis.

• Lactate is released in the blood stream through specific monocarboxylate transporter (MCT).

– Critical role of transporter in maintaining the intracellular pH (removes also the protons produced by glycolysis).

GAPDHNAD+

NADH+H-

+


• The fate of pyruvate in mitochondria:

– dexarboxylation and oxidation into acetyl CoA by pyruvatedehydrogenase (PDH)

– or carboxylation into oxalacetate by pyruvate carboxylase.

• The control of PDH activity is an essential part of overall control of glucose metabolism.

• PDH – mitochondrial multicomplex, activity is controlled by work, substrate and hormones.

Interregulation of fatty acid andcarbohydrate oxidation

• The primary physiologicalregulator of flux through PDH and the rate of glucose oxidation in the heart is fatty acid oxidation.

• PDH activity is inhibited by high rate of FA oxidation via an increase in mitochondrial acetyl-CoA/free CoA and NADH/NAD+ which activates

PDH kinase.

Interregulation of fatty acid andcarbohydrate oxidation

• Inhibition of FA oxidation increases glucose and lactate uptake and oxidation by:

1. decreasing citrate levelsand inhibition of PFK

2. lowering acetyl CoAand/or NADH levels in the mitochondria matrix.

Ketone Body Metabolism

• During starvation or poorly controlled diabetes the heart

extracts and oxidized ketone bodies (β-hydroxybutyrate andacetoacetate).

• Low insuline and high fatty acids � ketone bodies.

• Ketone bodies become a major substrate for myocardium.

• Ketone bodies inhibit PDH (inhibition of glucose oxidation) and fatty acid ββββ-oxidation.

Cardiomyocyte metabolism in various clinical states

Some Aspects of MyocardialBiochemistry of Heart Failure

• Heart failure reduces the capacity to transduce the

energy from foodstuff into ATP.

• In the advanced stage of HF �

– down regulation in FA oxidation;

– increased glycolysis and glucose oxidation;

– reduced respiratory chain activity.

Abnormal metabolism and energyregulation in the failing heart

Estrogen related factor

Cardiac Muscle and Ischemia

• Coronary artery occlusion →ischemia → significant change in cell structure, chemistry and function

– loss of contractile function

– arrhythmias

– cell death

• The decrease of the ATP / ADP, theaccumulation of AMP, inorganicphosphate, metabolic products are removed (lactate).

• The rapid decline in creatinephosphate - creatine kinase reaction isonly short-term mechanism to compensatefor reduced ATP production in mitochondria

Cardiac Muscle and Ischemia

• mild ischemia reduces the concentration of ATP andcreatine phosphate,

•• increasesincreases thethe levellevel ofof inorganicinorganic phosphatephosphate → activation of

glycolysis (glucose needed from the bloodstream into the heart cells) →increase in the concentration of pyruvate → conversion by LDH to lactate.

• Prolonged ischemia - the accumulation of substrates (lactate, NADH

and H+) → inhibition of glycolysis at the level of phosphofructokinase and

glyceraldehyde-3-dehydrogenase.

Metabolism in heart ischemiaCardiac hypertrophy Cardiac hypertrophy - compensationFatty acid oxidation is impaired

reduced ATP production Anaplerosis and alternative non-ATP generating pathways

pentose

hexosamine

ROS and mytochondrial damage

Doenst et al., Circ Res 2013

Cardiac Markers

• Troponin T (cTnT) or troponin I (cTnI) - the most sensitive and specific test for myocardial damage

• released during MI from the cytosolic pool of the myocytes.

• Approximate peak release in 12 hours in MI

Cardiac Markers

• Creatin kinase (CK) is relatively specific when skeletal muscle damage is not present.

• CK has two subunits – CK-M (muscle), CK-B (brain) and mitochondrial CKmi

• CK-MM (CK-1) - skeletal muscle 95%, heart 42%, smooth muscle 2 – 3%

• CK-MB (CK2) – skeletal muscle 3%, heart 28%, smooth muscle 1 – 5%

• CK-BB (CK-3) – skeletal muscle 1%, heart 1%, smooth muscle 87%

• Approximate peak release in 10 to 24 hours.

Cardiac Markers

• Lactate dehydrogenase (10 – 24 hours) is not as specific as troponin.– LDH is tetramer with 2 subunits – H – heart, M - muscle

– Isoenzymes• LDH1 (4 H) – heart and red blood cells,

• LDH2 (3HM) – heart and reticuloendothelial system,

• LDH3 (2H2M) - lungs,

• LDH4 (H3M) – kidneys, placenta, pancreas,

• LDH5 (4M) – liver and striated muscles

– In normoxia – LDH2 is higher than LDH1

– A high LDH1 level to LDH2 suggest MI

• Myoglobin (2 hours) has low specificity for MI – it is high when muscle tissue is damaged but it lacks specificity.

Cardiac Markers

• Aspartate transaminase (AST)– was the first used

– it is also one of the liver function test

• Glycogen phosphorylase isoenzyme BB (GPBB)– One of 3 isoforms of glycogen phosphorylase exists in

heart and brain tissue

– Because of the blood-brain barrier GP-BB can be seen as heart muscle specific.

– One of the "new cardiac markers" which are discussed to improve early diagnosis in acute coronary syndrome.

– Elevated 1–3 hours after process of ischemia.

Natriuretic peptides

Function of NP

Natriuretic peptides as endogenous vasodilators

Reactive oxygen andcardiovascular disease

Ischemia-reperfusion relationship with myocardial injury

Biochemistry of Reperfusion

Mo Yin Mok & Chak Sing LauNature Reviews Rheumatology 6, 430-434 (July 2010)doi:10.1038/nrrheum.2010.65

Myocardial reperfusion

Major reactive oxygen species (ROS) generationpathways in cardiac myocytes

Yang et al. Circ Res 2015

Oxidative phosphorylation and ROS production in mitochondria

Sokolova N, Pan S, PSrovazza S, Beutner G, Vendelin M, Birkedal R, Sheu SS

PLoS ONE 2013;8(12):e83214

Mitochondrial

permeability

transition pore

mitochondrial calcium channels

ADP as a main regulator of ROS generation

Metabolism in heart ischemia

Overview of metabolic remodeling and proposed mechanisms linking it to other processes in theprogression to heart failure

Electron transport chain

Ubiqiuinone protease

(bold lines are dominant processes)

Metabolism in heart ischemia

Simplified illustration of the relationship between cardiac metabolism and contractile function, reflecting therole of ATP production and non–ATP

Biochemistry of Lungs

Lungs Compartment and composition

1. Alveolar macrophages2. Alveolar pneumocytes type II3. Alveolar fibroblasts4. Capillaries with endotelial

layer and RBC5. Alveolar pneumocyte type I

mito – mitochondriaMVB – multivesicular bodiesN – nucleus of AT II cellsTM – Tubular myelinSM – surfactant monolayer

CB – Composite bodyEndo – endocytosisExo – exocytosisGB – Golgi appartusLB – lamellar bodies

• Produce: surfactant

collagen + elastin

mucus (mucopolysacharides + IgA)

• Activate: angiotensin (ACE in luminal surface of the pulmonary endothelium)

• Inactivate: ROS

kinins (hydrolysis of peptide bonds in bradykinin)

serotonin (from mast cells, from blood - MAO)

acetylcholin

detoxication of foreign components (cytochrom P450 in microsomes)lbiochemistry oflungs



• Major metabolic substrate – glucose

• Numerous cells with relativelly sparse

mitochondria – limited CAC activity, high

production of lactate

• Energy dependent functions – bronchial ciliary

activity, glands secretion, synthetic pathways

(phospholipids), secretion of surfactant

Pulmonary Surfactant

• surface-active lipoprotein complex formed by type II alveolar

cells

• complex of proteins and lipids with a hydrophilic and a

hydrophobic region

• the hydrophilic head groups facing towards the water and the

hydrophobic tails facing towards the air

• reduces surface tension

• surface tension is an effect within the surface layer of a

liquid that causes that layer to behave as an elastic sheet

• increases pulmonary compliance (the ability of the lungs to stretch

in a change in volume relative to an applied change in pressure).

Properties of Surfactant

• Once secreted to alveolar space, surfactant absorbs rapidly to the air-liquid interface (a newborn baby´sfirst breath).

• Once in the interface, surfactant films reduces surface tension when compressed during expiration (lungs don´t collapse).

• Surfactant proteins recognize and opsonize bacterial, fungal, viral surface oligosaccharides.

Composition of the surfactant

http://herkules.oulu.fi/isbn9514270584/html/c273.html

Structure of Alveolus

Nonpolar tail Polar head

Phospholipides

Synthesis - epitelial cells

SP-A and SP-D� large glykosylated proteins ( SP-D has 355 AA)� water-soluble� members of calcium-dependent carbohydrate-binding collectin family

SP-B and SP-C � small peptides (35 AA), highly

hydrophobic

� confer surface tension-lowering properties� important for spreading of the surfactant

Proteins

SP-A is responsible for:

• formation of tubular myelin

• regulation of phospholipid insertion into the monolayer

• modulation of uptake and secretion of phospholipids by type II cells

• activation of alveolar macrophages

• binding and clearance of bacteria and viruses

• chemotactic stimulation of alveolar macrophages

SP-D plays important role in pathogen defense

SP-B and SP-C:

• enhance the biophysical properties of surfactant

• assist in rapid insertion of phospholipids into the monolayer and

molecular ordering of the monolayer

Proteins

Synthesis Degradation

Deposition

Fibrosis Emphysema

Degradation – specific MMP´s

TIMP´s – tissue inhibitors of MMP´s

Collagen

90% I and III, type II, V, VIII

Lyra,P.P. R.; de Albuquerque Diniz, E.M. Clinics 62: 181, 2007

� DPPC is synthesized

in rER.

� Transferred to the

lamellar bodies together

with SP-B and SP-C (the

lamellar bodies are the

storage and secreting

granules surrounded by

a limiting membrane that

fuses with the plasma

membrane).

� Surfactant secretion

can be stimulated by the

stretching of the type II

epithelial cells, by the

action of beta-agonists,

and purinergic agonists,

such as ATP

Surfactant Metabolism

• Lamellar bodies and tubular myelin• Lamellar bodies have an acidic internal environment and have high calcium content.

Distortion of cells

Hyperventilation - deep breath, yawn

acetylcholine (large doses)

beta-agonists

purinoreceptors

corticoids (maturity after pre-term birth)

thyroxin

Control of Surfactant Release

glycerol glucose from circulation (glykogen)

polar heads cholin, inositol from circulation

fatty acids endogenous from lactate

exogenous

Synthesis

glycerol-3-phosphate

palmitoyl-G3P

dipalmitoylphosphatidic acid

dipalmitoylglycerol

DPPC

Choline

phosphocholine

CDP-choline

palmitoyl-CoA

CoASH

palmitoyl-CoA

CoASH

H2O

Pi

ATP

ADP

CTP

PPi

CMP

Glucose Glycogen

DHAPNAD+ NADH

Synthesis of DPPC de novo

O2- + e + H+ HO2

.hydroperoxid radical

HO2

.H+ + O2

-.

superoxid radical

O2- + 2H+ + e.

H2O2hydrogen peroxide

H2O2 + e OH- + OH.

hydroxyl radical

OH + e + H+.

H2O

Reactive Oxygen Species - ROS

.

peroxidation of lipids (phospholipids) aldehydes (malondialdehyde)

O3, NO, NOx, SiO2, smoking, infection, radiation, hypoxia/reoxygenation, ischemia/reperfusion

O2 + 2H2 2H2O

O2 e O2

- e 2H H2O2e H OH e H H2O

Fe3+ MPO Px

OH H2O

HClO

. .

.

Cu,Zn-SOD

Cu+

Reactive Oxygen Species - ROS

Reactive Nitrogen Species - RNS

L-arginine

NOS

L-citrulline + NO

HbO2 O2

O2-

NO3- + metHb NO2- HOCl + MPO

ONOOH

oxidation nitration

nitrosation

thiyl radical S-nitrosothiol nitrotyrosine

nitrate nitrite

peroxinitrite

Enzymatic Antioxidative Defence

tetravalent reduction (ROS generated during oxidative phosphorylation)

acceleration of monovalent reduction: SOD cytosolic (Cu-Zn) 5

mitochondrial (Mn) 1extracellular (Cu-Zn)

catalase (heme-containing)

glutathione system GPx (Se)

2 cytosolic, membrane-ass., extracellular

2H2O 2GSH NADPH Rib-6-P

GPx GR

reductase

H2O2 GSSG NADP+ Glucose

vitamin E - lipid peroxyl radicals

vitamin C - O2-, .OH , Fe3+ Fe2+

β-carotene (O2-), uric acid (O2

-), glucose (OH),

bilirubin (LOO.)

Nonenzymatic Scavengers

• Surfactant reduces tension of the air/liquid interface to near zero• Surfactant aids the oxygen to perfuse from the atmosphere into the pulmonary capillaries

During the breathing cycle :

• DPPC is insert into the monolayer, lowers the surface tension of air/liquid interface

• surfactant changes it´s properties during the breathing cycle:- very low surface tension at the beginning of expiration (oxygendiffusion)- at the end of expiration surfactant surface tension increase (prevention of alveolar collapse)

• Proteins accelerate the process to lower tension

Function of Surfactant

Effect of physical parameters on surfactant metabolism

• Temperature and hydrostatic pressure

– maintaining optimal fluidity/rigidity of the surfactant

unsaturated PL and cholesterol maintain the optimal fluidity at lower temperatures, SP-B and SP-C increrase the spreadabilty at high pressure

• Hypoxia

– induction of HIF -1 transcription factor crucial for fetal lung deveopment and PL

production

– increase sympathetic activity lead to increase in lipid biosynthesis

– prolonged hypoxia with maternal anemia, hypertension and placental infarctioncauses growth retardation with impaired lung development

– acute hypoxia in adults at high altitude– hemodynamic alterations of surfactant,

pulmonary hypertension and oedema – surfactant aggregates at the alveolar surface and fail

to organize into stable monolayer resulting in severe surfactant insuficiency.

Effect of inhaled toxicants on surfactant metabolism

• Ozone

– excessive oxidative damage to the tissues

alterations of fatty acid composition of the surfactant phospholipides and ultrastructural

alteration in lamelar bodies and impairs SP-A activity

• Nitrogen dioxide (NO2)

– induction of oxidative damage

causes lipid autooxidation and alters the lipid composition of the surfactant

• Sulphur dioxide (SO2)

– H2SO4 damages the epitelial layers of the tissues

– alteration of the structure and function of the AT-II cells

– decrease of the synthesis of pulmonary surfactant

Effect of inhaled toxicants on surfactant metabolism

• Aerosols (tear gasses -1- chlor acetophenone, detergents)– inflammation, damage of the alveolar capillary membrane, pulmonary oedema, surfactant

destruction

– detergents – increasing vascular permeability of the surfactant

• Artificial ventilation– alteration of the surfactant homeostasis during long term ARDS treatment

– free radicals formation

– alteration in lipid formation and aggregation

– release of inflammatory mediators (TNFα, IL-6 and IL-10) interfering with signaling pathways

• Smoke– reduced the SP-A and SP-D protein in surfactant

– decrease the phospolipid/protein ratio in BAL

– decrease the properties of surfactant monolayer

• Dust– reduced the SP-A and SP-D in BAL

– alveolar proteinosis (Asbestosis, Cadmium chloride)

Effect of inflammatory mediatorson surfactant metabolism

• TNF-α, IL-1, IFN-γ, Endotelin -1

alter surfactant biosynthesis (TNF-α andendotelin ↓, IL-1↑)

• NO – promotes surfactant secretion

• cAMP –increase the surfactant biosynthesis

– activate gene expression

Surfactant in Diseses

• Surfactant biosynthesis is developmentally regulated (30 – 32

weeks of gestation)

• Respiratory distress syndrome (RDS) – consequence of

prematurity is leading cause of neonatal morbidity and mortality

– therapy - administration of synthetic or natural pulmonary sufactant

intratracheally to preterm infants

• The synthesis of surfactant is regulated by: glucocorticoids, thyroid

hormones, prolactin, estrogens, androgens, catecholamines (β-

adrenergic receptors), growth factors and cytokines.

• Glucocorticoids, thyroids stimulate lung maturation

Factors that contribute RDS phenotype

Function of Surfactant

• Acute respiratory distress syndrome (ARDS) in adults – massive

influx of activated neutrophils (endothelium and alveolar epithelium

damage) pulmonary edema, impairment of surfactant function

• Neutrophil proteases (elastase) breakdown surfactant proteins.

• Potential therapeutic strategy – administration of both surfactant and

antiproteases (α1-antitrypsin)

Diseases associated with surfactantinsufficiency

• Emphysema or chronic obstructive pulmonary disease (COPD)

and cystic fibrosis

• characterized by higher-than-normal levels of pulmonary proteases: serine, cysteinyl, aspartyl and metalloproteases which normally regulate tissue

remodeling, mucin expression, neutrophil chemotaxis and bacterial killing) –

most important neutrophil elastase

• resulting in narrowing of the small airways and breakdown of lung tissue (emphysema)

• To harmful effects of pulmonary proteases, a battery of antiproteasesexists in the lungs

– serine antiproteases - α1AT,– secretory leucocyte protease inhibitor (SLPI), and elafin

– cystatins – cysteinyl catepsins

– TIMPs – tissue inhibitors of matrix metalloproteinases

Pneumoconiosis

• Pneumoconiosis is an occupational and restrictive lung disease and a caused by the inhalation of dust, often in mines, characterized by fibrosis (deposition of fibrous tissue – collagen, elastin)

• Fibrosis tends to stiffen the lung tissue and restrict its expansion• Depending upon the type of dust, the disease is given different

names: – Coalwork´s pneumoconiosis (antracosis) – coal, carbon

– Asbestosis – asbestos

– Silicosis – silica

– Siderosis – iron

– Bauxite fibrosis – bauxite

– Berylliosis – beryllium

– Byssinosis – cotton

• There is a long delay between the time of exposure to the dust and the onset of the actual pneumoconiosis disease – often 10 years or more.

Literature• Mudd, JO and Kass DA.: Tackling heart failure in the twenty-first century. Nature, Vol 451(21

February): 919 -928, 2008.

• Zhou L. et al.: Regulation of myocardial substrate metabolism during increased energyexpenditure: insights from computational studies. Am J Physiol Heart Circ Physiol 291: H1036–H1046, 2006

• Yang, KC et al.: Mechanisms of Sudden Cardiac Death Oxidants and Metabolism. Circ Res. 116:1937- 1955, 2015

• Stanley, WC et al.: Myocardial Substrate Metabolism in the Normal and Failing Heart. PhysiolRev 85: 1093–1129, 2005

• Doenst, T et al.: Cardiac Metabolism in Heart Failure - Implications Beyond ATP Production, Circ Res. 113:709-724, 2013.

• Akella, A. et al.: Pulmonary surfactants and thei r role in patophysiology of lung disorders. Ind J Exp Biol 51: 5-22, 2013

• Chakraborty, M. et al.: Pulmonary surfactant in newborn infants and children. Breathe, Vol 9., No 6: 476-488, 2013

biochemistry of heart and lungs2018 -...

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