CV and Resp Control Flashcards

Question

Ejection fraction

Answer 1

SV/EDV | End diastolic volume

Answer 2

Sv- volume of blood ejected during ejection phase | ESV- what remains at end of systole period

Answer 3

Long and narrow 60-140um length 20um diameter Volume 15000-45000 um3 Lots of t tubules Prominent end to end intercalated discs for transmission Mitochondria, sarcomeres very abundant, rectangular branching bundles with little interstitial collagen.

Answer 4

Elliptical shape, 20um length 5-6 diameter, 500um3, rare/no t tubules, side to side and end to end intercalated discs for transmission, contain bundles of atrial tissue separated by wide areas of collagen

Answer 5

Force | Ions/action potentials

Answer 6

Electrically continuous sheets - syncitium

Answer 7

Starts with cardiac potential generated by ionic gradients and sequential ion channel activation Resting potential -80mV from K+ moving from intercellular out of the myocytes via K+ channels so inside cell is slightly negative Voltage gated Na channels admit brief influx of positive ions into cell at the start of an AP and depolarise the cell (phase 0) Membrane begins to repolarise (phase 1) Activation of long opening Ca2+ channels allows influx of calcium nearly counterbalancing K current generating a long plateau around 0 potential lasting 200-400ms (phase2) called excitation contraction coupling. The plateau is terminated by efflux of K ions which re polarises the cell (phase3) Resting potential (phase4)

Answer 8

Excitation contraction coupling and theCa2+ cycle Ca cycle: Release of intracellular Ca during systole following membrane depolarisation down t tubule and Ca channel activation. Ca released from sarcoplasmic reticulum via activated ryanodine receptors. Increased cytoplasmic Ca binds to tropinin C and actin myosin cross bridge formation contraction cycle begins. Relaxation- ryanodine receptor closes and Ca pumped back into SR via SERCA2a/PLB channel complex or expelled from cardiomyocyte by Ca channels. Deactivates contraction actin myosin cycle.

Answer 9

Rapid enhancement of cardiac contractility caused by sudden exercise or stress Catecholamines like adrenaline or noradrenaline released in blood activating chain involving increased phosphorylation of RyR2 ryanodine receptor by protein kinase A releasing Ca into cytoplasm and increasing cardiomyocyte contraction.

Answer 10

Changes in the permeability to calcium and potassium Adrenaline increases Ca release so increases contractile force (positive inotrope) Increases K permeability results in a negative inotropic effect reducing contractile force.

Answer 11

``` Stimulus initiated in SAN Diffuses into atria 1m/sec AVN conduction 0.05m/sec Dispersion via bundle of His and purkinji fibres 4m/sec Endocardium to epicardium 0.3m/sec ```

Answer 12

-70 to -60

Answer 13

Absolute- period of time where a new action potential cannot be initiated Relative- period of time when new action potential of limited magnitude can be initiated or greater stimulation is needed to generate an action potential

Answer 14

Filling pressure (preload) - only as much as venous return Arterial pressure opposing ejection (afterload) Contractility from sympathetic nerves and circulating agents Energy of contraction Total peripheral resistance

Answer 15

``` Preload (diastolic wall stress) depends on the end diastolic pressure, chamber radius and walk thickness, Laplace’s law. The afterload (systolic wall stress) depends on arterial pressure, chamber radius and walk thickness, Laplace’s law. ```

Answer 16

Stretching sarcomeres increases contractile energy and an raise contractile force without increasing Ca. Stretch reduces filament overlap and increases Ca sensitivity

Answer 17

The greater the stretch of the ventricle in diastole the greater the stroke work achieved in systole The right atrial pressure determines preload filling pressure The energy of contraction is proportional to the initial fibre length Mechanism: balances output of right and left ventricles, mediates postural hypotension- fall in CO and BP with standing Mediates hypovolaemic hypotension following haemorrhage or dehydration Fall in SV during forced expiration Increased SV in exercise

Answer 18

The forcefullness of myocardial contraction when other effectors like stretch and HR are held constant Can be changed by autonomic nervous system and specific drugs (inotropes) Due to increased cytosolic Ca There is disagreement as to whether an increase in Ca sensitivity is inotropy. When contractility is depressed it can result in heart failure

Answer 19

Frank starling mechanism increasing force/Ca relationship Inotropes increasing cystolic Ca Duration of cardiac cycle - only important at very high heart rates that affect ventricular filling time Force frequency- faster heart rates produce more forceful contractions Bainbridge reflex- veno-atrial stretch leads to increased contractility

Answer 20

As HR increases the time for filling is reduced This has little impact with moderate HR increase Cardiac output is maintained as any reduction in SV is compensated for by increase in rate As filling time is reduced the contribution made by atrial systole becomes of greater importance

Answer 21

As HR increases so does contractile force | Effect is hypothetically due to an accumulation of Ca in the cytosol with increasing stimulation rate

Answer 22

Stretch receptors in both atria feedback to the ANS to regulate heart rate indirectly Prevents blood building up in the great veins and pulmonary circulation Further assisted by the stretching of the SAN

Answer 23

Mechanical stretching of SAN increases heart rate up to 15%

Answer 24

Equivalent to MABP Acutely an increase in afterload reduces SV however long term reduced Sv leads to blood accumulation, increased CVP and activation of the frank starling mechanism Prolonged left ventricle dilation causes further increases in contractility (anrep effect) Increased MAP activates the baroreflex depressing cardiac function Long term effect of increased afterload arises from all these influences

Answer 25

Blood volume Cardiac output - Darcys law P=F(CO)*R Peripheral resistance Venous capacitance - reduction in VC frees up venous blood increasing filling pressure and boosting cardiac output via the frank starling mechanism Gravity- hydrostatic pressure Arteriolar constriction from increased CO increases MAP also thus increasing PVR

Answer 26

Pressure sensors in the carotid sinuses and aortic arch respond rapidly to acute changes in pressure by modulating the ANS via the nucleus solitarius Adjusts CO and peripheral vascular tone to stabilise arterial blood pressure Provides acute control of arterial pressure The carotid sinus is stimulated by the carotid sinus nerve branching from the glossopharyngeal IX cranial nerve and the aortic nerve supplies the aortic arch branching from the vagus X cranial nerve Increased AP firing decreases SNS and increases PNS to lower HR, LV contractility and vasodilation and increase venous capacitance. Decreases CO and peripheral resistance to correct AP. Decreased AP does the opposite.

Answer 27

The effect of gravity means blood pressure in the feet should be approx. 90mmHg greater than at the heart - hydrostatic pressure The full effect is not normally exerted because of the venous valves Contraction of the leg muscles expels blood from the microvascular combined with the valves - system is called the muscle pump Because of this hydrostatic pressure only increases venous pressure by roughly 20mmHg in a walking adult

Answer 28

Rental regulation of ECF by two methods: Circulating levels of excretion related hormones eg ADH, angiotensin-II, aldosterone and ANP is controlled by CV receptors - the renin angiotensin system Or by pressure natriuretsis causes and increase in salt and water excretion when renal artery pressure rises Chronic intake of water and salt and the left to right shift of the renal function curve affect long term ABP

Answer 29

Increasing arterial pressure causes a corresponding rise in renal urinary output (diuresis) as well as sodium output (natiuresis)

Answer 30

Renin (enzyme) produced from prorenin and released by kidneys is first step in the RAS cascade Combines with angiotensinogen from the liver to form angiotensin I which is converted to ang II in pulmonary circulation by ACE enzyme. This causes a right to left shift in the renal function curve meaning ang II causes water and salt retention increase plasma volume and blood pressure. Aldosterone secreted by adrenal glands acts on the kidney to increase Na reabsorption, stimulates thirst centres and causes increased ADH release from pituitary. ADH stimulates water retention also.

Answer 31

Contains both inspiratory and expiratory neurones - active during respective phase of breathing - rostral nucleus retroambigualis (rNRA) contains inspiratory neurones - caudal NRA contains expiratory neurones - nucleus ambiguous including premotor inspiratory neurones to external intercostal and accessory inspiratory muscles and motor neurones to the laryngeal muscles VRG neurones mostly inactive during quiet breathing - just repetitive inspiratory activity from DRG and passive elastic recoil from chest wall/lung. VRG expiratory neurones activate expiratory muscles when ventilation increases and expiratory becomes active. Activated by the spillover of DRG activity. Reciprocal activity with DRG - VRG expiratory neurones also inhibit DRG inspiratory neurones during expiration acting as inspiratory switch off.

Answer 32

Pre-Botzinger complex thought to be the key centre of respiratory rhythmogenesis - contains neurones with intrinsic pace making capabilities - demonstrate cyclical firing without additional synaptic input. Contains both expiratory neurones, vagal and glossopharyngeal motor neurones. Input from the lung and peripheral chemoreceptors to the complex via the NTS botzinger and pre-botzinger complexes provide input to the DRG and VRG

Answer 33

Role of PRG in generation and control of respiratory rhythm is not fully established PRG compromised of medial parabrachial nucleus - expiratory neurones. Lateral parabrachial nucleus and Kolliner-Fuse nucleus - inspiratory neurones. Reciprocal connections with the medulla Involved with phase switching - inspiration to expiration and control of respiratory rate - secondary mechanism to lung stretch receptor feedback - increased PRG activity shortens medullary inspiratory neuronal activity and switches to expiration earlier - Respiratory rate increased - lesions/absence result in increased tidal volume and decreased rate PRG connections to medullary circuits appear critical for coordinating activity of expiratory and upper airway muscles during expiration. Has involvement in control of foetal breathing movements.

Answer 34

Cerebral cortex - descending influencers allow voluntary control of breathing - neurones bypass ponto-medullary centres and synapse directly with spinal respiratory motor neurones - proof from congenital central hypoventilation syndrome CCHS where autonomy control is lost by cortical control remains the same, so they have adequate ventilation while awake but loose this during sleep Hypothalamus - temperature, pain and emotion influence breathing Cerebellum - centre of sensorimotor coordination, coordinated equilibrium, posture, muscle tone, has considerable input from sensory systems but operates as part of motor systems. Has deep cerebellar nuclei involved in respiratory control. Fastigial nucleus involved in response to CO2 and O2 - activation increases ventilation and is also a chemosensitive site. Dentate nucleus involved in maintaining muscle tone in upper airway. Role of cerebellum in SIDS in posture

Answer 35

Ventilation is sufficient to ensure Hb is close to 100% saturation to support O2 demand CO2 closely regulated as variations in this directly affect pH, small variations in which can alter physiological function widely. PaO2 not as closely regulated PaCO2. Adequate Hb saturation is achieved over a wide range of PaO2 levels Complex mechanisms maintain gas homeostasis - chemoreceptors central and peripheral.

Answer 36

Located on the ventrolateral surface of medulla, the pre-Botzinger complex, retrotrapezoid nucleus in Pons, parafacial respiratory group in medulla, raphe nuclei in brainstem reticular formation, locus ceruleus in Pons, nucleus tractus solitarius in medulla, fastigial nucleus in cerebellum. They respond to changes in PaCO2 (account for 70% response to CO2) and pH but not O2 due to blood brain barrier permeability to CO2 but not HCO3- or H+ Affected by changes in arterial PCO2 not arterial pH Respond to pH of CSF via PCO2 changes Increase in PCO2 causes near linear increase in ventilation rate Provides main drive for ventilation normally Comparatively slow to respond as needs changes in CSF to occur

Answer 37

Main oxygen sensors Located in bifurcation of common carotid arteries (stimulated by IXth cranial/glossopharyngeal nerve) and aortic arch (stimulated by achy cranial/vagus nerve) Fast response due to large blood flow being highly vascularised Detect PaO2, PaCO2 and pH Decrease in O2 or pH or increase in CO2 causes increased ventilation 10-40% of total hypercapnic response

Answer 38

Both central and peripheral chemoreceptors

Answer 39

Carotid chemoreceptors as aortic arch is mostly baroreceptors

Answer 40

Nasal - sneeze and diving reflex Epipharyngeal - aspiration reflex Pharyngeal - swallowing Laryngeal - cough and apnea Slowly adapting receptors in trachea/bronchi - hering-Breuer inflation and deflation reflex, bronchodilation and tachycardia Rapidly adapting receptors in trachea/bronchi - hering-Breuer deflation, cough, bronchocinstriction, mucus secretion C-fibre endings - pulmonary chemoreflex, rapid shallow breathing, bronchocinstriction, mucus secretion, bradycardia, hypotension.

Answer 41

Upper airway: Irritant receptors provide protective reflexes to dust etc. And expiratory reflexes like coughing, apnea and laryngeal narrowing Pulmonary stretch receptor reflexes: Hering-Breuer inflation reflex prevents lung over inflation for protection SAR stimulated by lung inflation results in cessation of inspiratory activity but this has little importance on breathing at rest Hering-Breuer deflation reflex: Helps maintain FRC and prevent actelectasis RAR stimulated by deflation below FRC provoking strong inspiration, commonly seen in neonates. Heads paradoxical reflex: RAR stimulation by lung inflation produces augmented inspiration eg in first breath in perinatal period only or sighing in adults

Answer 42

Pulmonary vascular receptors Juxta-capillary receptors/pulmonary C-fibre receptors - activated by physical engorgement of pulmonary capillaries or increased pulmonary interstitial volume, stimulation results in rapid shallow breathing, bronchoconstriction and mucus secretion. Unsure of relevance at rest. Airway mucosa C-fibres cause coughing

Answer 43

Very unsure of mechanisms likely multiple involved Respiratory regulation by feedback control? PaO2, CO2 and pH remains relatively unchanged by moderate exercise so what drives these compensatory changes? Feedforward control by central command - parallel stimulation of resp centre by limb movement motor commands - motor cortex and hypothalamus Feedback from group III-IV limb afferents experiments show this. iii For movement, local touch, pressure and tendon or muscle stretch IV for mechanical distortion, chemical (H+,La, K+), thermal stimuli Feedback proved important by intrathecal injection blunting response. PECO experiments discount presence of meta bore rotor in muscle. Other mechanisms include K+ release by exercising muscles stimulates peripheral chemoreceptors - sinusoidal changes in work rate indicated disproportional relationship between K+ and VE during moderate exercise Oscillations - rate of breath oscillations in PaCO2 resulting from phasic fluctuations in PACO2 matching those of carotid chemoreceptors firing. However bilateral carotid body resection has no effect on magnitude of exercise hyperpnoea Vestibular feedback - head movement sensed at onset increasing ventilation Behavioural response- phase 1 a learned response from repeated exercise

Answer 44

Ventilation and pulmonary flow must increase in tandem as there is no hyperventilation and a fall in PaCO2 at the onset of exercise Hyperpnoea is mechanically mediated via cardiac afferents in response to the right ventricular strain Heart transplantation sir artificial hearts had no effect on exercise hyperpnoea

Answer 45

Phase 1 if exercise is neurally mediated by feedforward control (motor command) and feedback (movement) Phase 2 and 3 controlled by neural mechanisms muscle and vascular augmented by humoral PCO2 feedback from chemoreceptors A feedforward feedback mechanism that maintains such a close regulation of PaCO2 makes detecting an error signal very very difficult in experiments

Answer 46

Contractile cells - cardiomyocyte Vasculature Stem cells Extra cellular matrix

Answer 47

``` Myocardial mass - non replicating terminally differentiated myocytes Ageing myocytes p16POS dying myocytes Stem cells and progenitors Cycling immature myocytes Back to myocardial mass ``` Used to believe the heart was post mitotic and any change in heart mass was due to cell growth alone not replication

Answer 48

Rats- Exercise training improved max exercise capacity (VO2max) Walk thickness increased Increased end diastolic and systole diameter Increased fractional shortening Increased ejection fraction Increased left ventricular mass Increased heart weight through cardio myocytes hypertrophy

Answer 49

Hypertrophy of cardiomyocyte and cardiomyocyte hyperplasia increasing size and number There is a drop out loss of CM that increases with age There is ongoing cell death and regeneration throughout heart lifespan

Answer 50

Studied individuals born around or after nuclear bomb tests c14 concentration of cardiomyocyte nuclei DNA corresponded to atmospheric concentrations of c14 several years after birth suggesting post natal cardiomyocyte DNA synthesis and renewal Cardiomyocyte renew at rate of 1% per year at age of 25 and 0.45% at age of 75. 50% heart replaced over a lifetime Critique- Patient cohort, patient pathological and physiological status will effect turnover How do we know cells were in isolation completely from heart no contaminating cells. Data analysis mathematical model means assumptions were made including that cardiomyocyte renewal is 0 which is not true as this would mean no heart changes in mass ever.

Answer 51

``` Stem cells (cardiac stem cells) Division of pre-existing cardiomyocyte ```

Answer 52

Unspecialised cells can give rise to many cell types Can divide without limit to replenish themselves- clonogenic and self-renewing Differentiate into diverse range of specialised cell types such as muscle cell, RBC, neural cell - pluripotent or multipotent Found in embryonic tissue (blastocyst) or tissue specific stem cells

Answer 53

``` Haematopoietic and mesenchymal in bone marrow Satellite in skeletal muscle Neural in neuronal tissue Epithelial In digestive system Epidermal in skin Cardiac in heart Umbilical cord and amniotic in cord blood and amniotic fluid Adipocyte In fat Tendon in tendon and cartilage ```

Answer 54

Capillary Myocytes Arteries

Answer 55

Clonogenic self renewal phase Differentiation and multipotency - expression of different cardiac genes and proteins to determine contractile cell, vascular smooth muscle or endothelial cell.

Answer 56

C-kit - receptor from KIT gene Alpha sarc actin - protein Nkx-2.5 - transcription factor specific to heart development MEF2C - specific transcription factor to heart development

Answer 57

Results- Up to 1 year normal ageing no change in GFP+ CMs and stem cells don’t refresh at significant rate After myocardial infarction or trans aortic constriction - GFP+ CMs decreases by around 15% so stem cells do replenish CMs at a significant rate Hsieh et al. 2007 Second paper shows after ISO injury GFP+ CMs decreases around 10% so stem cells replenish CMs after ISO injury Ellison et. Al. 2013 Third paper total of 6 nuclei out of 4190 myocytes analysed in normal adult heart which are diploid, mononucleated and GFP+. Therefore 0.14% claimed to originate from pre-existing myocytes in normal heart. Consistent with 2007 data. 11 nuclei 7063 myocytes analysed in infarcted heart which are diploid, mononucleated and GFP+ meaning 0.16% claimed to originate from pre-existing monocytes In injured heart vs 15% from stem cells. Senyo et al 2013.

Answer 58

C-kit+ stem cells do contribute significantly to Cm renewal after DMI Cardiac stem cells proliferate after isopropanol ISO injury and express specific cardiac factors like NKX-2.5 etc. Cardiomyocytes also go into division (very small numbers) By 28 days 5% of mass has been restored (compared to the 8% lost therefore almost 100%) After 3 days histology shows infiltration of inflammatory cells in subendocardial layer of heart followed by spontaneous regeneration By 28 days all rats were indistinguishable from non injured rats and cardiac function is completely normal. No scarring or fibrosis etc. Ablation of eCSCs blocks myocyte regeneration and cardiac functional recovery leading to death by heart failure - removed stem cells with chemotherapeutic drug to kill all proliferating cells Ellison et. Al 2013

Answer 59

From endogenous cardiac stem cells not division of pre existing CM after injury

Answer 60

700mg ATP 6000grams per day for function Almost entirely dependent on mitochondria oxidative phosphorylation - 35% of cardiac mass is mitochondria Myocardial oxygen consumption can intense up to 6fold during max exercise

Answer 61

70-80% has very high capillary density in tissue approx 4000 capillaries per mm3

Answer 62

Average aortic pressure/total coronary resistance (including epicardial, inner layer and whole cycle resistance pressure)

Answer 63

Right CA arises from the right aortic sinus gives off branch to upper right atrium then runs down in the right atrioventricular groove supplying the right ventricle Passes round to underside of the heart- terminal branch is the right interventricular artery Left CA arises from the left aortic sinus behind the pulmonary trunk. Divides quickly into the circumflex branch and several others to the left ventricle, longest of which is called the left interventricular artery or left anterior descending (LAD). Circumflex runs to the underside of heart in left atrioventricular groove sending more branches to the LV. All major CA divide into epicardial arteries and intramuscular arteries penetrate the myocardium perpendicularly to form subendocardial arterial plexuses.

Answer 64

Ability of the coronary arteries to increase blood flow under stress It’s the ratio of maximal flow to resting coronary blood flow

Answer 65

Computer tomography coronary angiography CTCA is a technique proved to provide high sensitivity and negative predictive value for identification of anatomically significant coronary artery disease

Answer 66

To avoid being compressed during systole of the cardiac cycle and avoid excess stress or leaking of the vessel which could lessen blood perfusion

Answer 67

Heart rate - doubling heart rate doubles oxygen consumption effectively

Answer 68

Most blood from the left ventricle drains into the coronary sinus The anterior cardiac vein receives blood from the right ventricle Both open into the right atrium Thebesian veins drain a small portion of coronary blood directly into the cardiac chambers and account for true shunt

Answer 69

Perfusion pressure - during systole blood vessels are compressed mostly affected in the subendocardial layers. Intramyocardial blood is propelled forward to the coronary sinus into epicardial vessels in this time. Flow resumes during diastole with relaxed muscle. Perfusion time - increase in heart rate reduces diastole time and therefore perfusion time Vessel wall diameter - vasomotor tone and deposits inside the vascular linen determine diameter. Various mechanisms regulate this tone usually favouring dilation.

Answer 70

Myocardial metabolism - tone almost exclusively determined by local metabolic oxygen demand. Hypoxia causes coronary vasodilation directly and also releases adenosine and opens ATP- sensitive K channels. Pre-capillary sphincters relaxed and more capillaries recruited. Autoregulation - at rest CBF remains between 60-140mmHg but beyond this flow becomes pressure dependent. Probable mechanisms include myogenic response to intraluminal pressure changes and metabolic regulation. Myocardial oxygen tension and presence of vasoconstrictors or dilators influence lumen size. Nervous control - generally weak Humoral control Vascular endothelium - modulates contractile activity of underlying smooth muscle via vasoactive substances such as NO and bradykinin for relaxants or endothelin for constrictors.

Answer 71

Arterioles

Answer 72

Capability of heart to self determine how much blood it draws from aortic blood.

Answer 73

1.5m/second

Answer 74

Transient ischaemia - across all layers of the vessel wall

Answer 75

To keep heart perfusion to match metabolic oxygen demand. Without requiring too much blood from circulation At rest it is a linear relationship between coronary flow and perfusion however with increasing perfusion pressure flow plateaus to create a greater coronary flow reserve by favouring vasoconstriction therefore allowing more vasodilation to be possible as oxygen demand increases. With atherosclerosis this vasodilation reserve can be used to compensate for loss of perfusion rather than autoregulation however as it worsens there is less and less coronary flow reserve available until it can no longer cope or compensate resulting in angina/heart failure

Answer 76

When oxygen is short less ATP is synthesised making the heart stiffer and diastole less effective increasing the end diastolic pressure creating extra pressure and fluid in lungs presenting clinically as breathlessness

Answer 77

Can almost triple flow

Answer 78

Epicardial coronaries (>500um) have 10% resistance, 5% of coronary blood volume Pre arterioles (500-200um) 30% resistance, 2-3% blood volume regulated by shear stress and sympathetic control Arterioles (200-10um) 50% resistance, 2-3% blood volume regulated by shear stress, myogenic control, metabolic control. Capillaries (10um) receptors to pH, adenosine etc. Which quickly produce vasodilation or constriction response Venous system shares 10% resistance with capillaries and 90% of blood volume in coronary circulation

Answer 79

``` Reduced blood flow or increased metabolic demand not met Cellular hypoxia Abnormal relaxation Abnormal contraction Abnormal repolarisation - ECG Angina Infarction arrhythmia and heart failure ```

Answer 80

Statins to reduce cholesterol and evidence suggests can reduce plaque size

Answer 81

Endothelium innermost layer Internal elastic lamina and fibrecollageninous tissue make up the tunica intima Smooth muscle makes up tunica media Fibrocollaginous tissue, external elastic lamina and another F.C. tissue layer makes up the tunica adventitia

Answer 82

Synthesised from L-arginine and oxygen released by endothelial cells accounts for relaxation of strips of vascular tissue and inhibition of platelet aggregation and adhesion attributed to the endothelium derived relaxing factor.

Answer 83

Enzymes convert L-arginine with oxygen to NO. eNOS- endothelial constitutive isoform is calcium calmodulin dependent iNOS- inducible isoform with high NO output released from smooth muscles and macrophages is calcium independent nNOS- neuronal constitutive isoform is calcium dependent All bind calmodulin and contain haem.

Answer 84

Ca2+ enters cell and NO synthase converts L-arginine to NO and citrulline NO travels to smooth muscle and binds guanylyl Cyclase converting guanosine triphosphate to cyclic GMP and protein kinase which causes a cascade to relax smooth muscle.

Answer 85

BH4 is an essential cofactor for NOS activity Reduced BH4 or L-arginine uncouples NO synthesis from NADPH consumption to generate superoxide OONO- (oohnooo) Reduced NO and increased oxidative stress impair vascular reactivity further

Answer 86

ENOS bound to cav with Ca bonding gives eNOS and Calmodulin which binds to hsp90 Phosphorylated removing CaM leaving two phosphates in place with Akt at residues Thr495 And Ser1177 Calcium binds and removes one phosphate resulting in NO production?

Answer 87

Endothelial hyperpolarising factor - factor which reduces intracellular Ca in smooth muscle cells (k+, cytochrome P450 metabolite, gap junctions) Prostacyclin PGI2 - generated in arachodonic acid by cycloxoygenase. Activates cAMP pathway in smooth muscle cells to reduce intracellular Ca2+ and myosin light chain kinase activity

Answer 88

Endothelin - binds ET receptors in smooth muscle cells to increase intracellular Ca and smooth muscle cell contraction

Answer 89

At rest blood vessels are under sympathetic constrictor tone Arteriole and venous tone regulated at local and central levels Local control allows matching between tissue metabolic needs and blood flow Physical factors, local metabolites, local mediators, Nerves and hormones control tone Growth of new blood vessels used to regulate tissue blood supply

Answer 90

Vascular resistance not constant with pressure Also changes with local metabolic rate and oxygen delivery Acute regulation requires rapid change in resistance of blood vessels locally Long term regulation involves remodelling of existing vessels or formation of new vessels - angiogenesis

Answer 91

Maintains tissue perfusion Changes in arteriolar diameter take 30-60 seconds to develop fully Only operates sober limited range of pressures Important in renal, coronary and cerebral circulations to regulate capillary pressure and prevent oedema Mechanisms- Myogenic Vasodilator removal Tissue fluid pressure

Answer 92

Involved in acute AR Increased pressure increases arteriolar wall tension Vascular smooth muscle contracts when stretched and relaxed when passively shortened Action is purely myogenic no mediators needed Involved activation of stretch sensitive L type Ca channels on cell membrane and protein kinase C to enhance contractility ‘Braking’ mechanisms- Ca activated K channels which hyperpolarise smooth muscle cell to attenuate depolarisation Shear induced endothelial NO release

Answer 93

Involved in acute AR Increased perfusion pressure increases bulk outflow of capillaries Locally increased tissue volume increases tissue pressure Elevated tissue pressure reduces transmural pressure distending micro vessels Reduced vessel diameter increases resistance Mainly increases capillary and venue resistance

Answer 94

Increased blood flow removed vasodilators and local metabolites this lowering interstitial concentration to increase vessel tone

Answer 95

An excess of blood in vessels supplying an organ or other part of the body! Active/metabolic type- important in active tissues like skeletal muscle, heart and brain Increased tissue activity causing local vasodilation Fall in vessel resistance occurs due to local release of metabolites Eg adenosine, K ions, acidosis, local hypoxia, phosphate ions, hyperosmolarity or CO2 Reactive/ischaemic type- if blood flow to tissue is transiently stopped or slowed significantly vasodilation occurs after flow is restored Myogenic response and local accumulation of vasodilators facilitate Reperfusion injury occurs after long periods of ischaemia

Answer 96

Physiologically active substances produced by the body active for localised brief periods of time Histamine- from mast cells and leukocytes in response to injury, vasodilator produces extravasation of plasma proteins. Responsible for local oedema and inflammation. Increases NO release from endothelium via histamine receptors Bradykinin- vasodilator formed by enzyme kallikrein during inflammation, contributes to hyperaemia by increasing NO release from endothelium. Pain producing Serotonin- derivative of tryptophan, released from platelets to cause vasoconstriction of arteries and veins Thromboxane- formed from aracidonic acid and released from platelets to cause vasoconstriction. Synthesis inhibited by aspirin.

Answer 97

Parasympathetic and cholinergic sympathetic dilatory fibres Sympathetic vasoconstrictor fibres Cholinergic receptors for vasodilation Beta receptors for vasodilation Alpha receptors for constriction in response to blood catecholamines

Answer 98

Most vascular beads are under sympathetic constrictor tone Stimulation of alpha receptors by noradrenaline or adrenaline produces vasoconstriction Skeletal muscle also has beta receptors that vasodilate when stimulated Some tissues (skin and skeletal muscle) have sympathetic cholinergic nerves that produce vasodilation Very few tissues have parasympathetic nerves to blood vessels (some glands and erectile tissue)

Answer 99

Random clinical trials - intervention trials compare clinical end point But are costly and time consuming Surrogate markers can be used in place of hard clinical endpoint to allow measurement of factors to indicate and prevent CV disease in patients

Answer 100

A bio marker intended to substitutes for clinical endpoints Expected to predict clinical benefit based on epidemiological, therapeutic, pathophysiological or other scientific evidence

Answer 101

Parallel - able to predict without being involved in cause or pathway Direct - more common, surrogate can have direct causal role in disease outcome therefore can be used to predict outcome. More robust measures

Answer 102

Linkage- must relate to clinical endpoint parallel or directly and be established by epidemiology and clinical studies Efficiency- must be easy to measure, availability, with change preceding outcome eg before disease occurs Congruency- anticipated benefits or harm in outcome measures

Answer 103

Blood pressure - closely related to CV events Estimated a decrease in 5mmHg there is a decreased risk of stroke by 14% and CHD by 9% Lipids - LDL cholesterol Closely related to Coronary artery disease Large number of clinical trials supporting reducing LDL reducing CAD related endpoints Vascular function and structure newly investigated surrogates

Answer 104

Flow mediated dilation Intima-media thickness and plaque Pulse wave velocity - aortic stiffness

Answer 105

``` Endothelium derived mediators eg NO Inhibit adhesion molecules Are anti inflammatory Antithrombotic Anti proliferative of smooth muscle Regulate vascular tone - assessing this function is most practical way of measuring endothelial function ```

Answer 106

Study assessing coronary endothelial function predicts CV disease 147 patients administered acetylcholine into coronary blood vessels and assessed dilation response In healthy arteries causes vasodilation With endothelial damage the response in blunted or leads to vasoconstriction Patients experiencing CV events during follow up had significantly increased vasoconstrictor responses to Ach infusion meaning increased risk of CAD. Good link to CV events however need non invasive technique and need to assess congruency and efficiency More recent techniques including Doppler echocardiography, position emission tomography and magnetic resonance imaging for assessment can be non invasive measurements of coronary vasculature YAY, Best validated technique to date is ultrasound of brachial artery reactivity (Cohn et al.,2004)

Answer 107

Synthesised from L arginine by eNOS reducing NADPH to NADP in endothelium then NO released and acts on smooth muscle causing relaxation by activating soluble guanylyl cyclase which converts GTP to cGMP activating cGMP protein kinases causes relaxation

Answer 108

NO relaxation pathway Increasing blood flow increases NOS release and so NO release and smooth muscle relaxation increasing artery diameter Assessed by ultrasound usually in upper arm in brachial artery Non invasive Blood pressure cuff used to stop blood flow and release to increase flow Measure baseline for 1 min diameter recorded Cuff inflated for 5 mins Post hyperaemia recorded for 2-5min with blood flow released again Reduced diameter indicates reduced endothelial function Infusion of L-NMMA (NOS blocker) prevents the dilatory response of vessels indicating this is hugely controlled by NO release Technique needs experienced sonographer, operator dependent and sensitive to arm position. Needs very strict protocols to standardise procedure. Many studies show FMD is closely related to risk factors for CVD so may be useful surrogate A higher FMD is associated with a lower event rate of CVD Some improvement in FMD shown with statin and anti hypertensive therapy but not conclusive - antioxidants inconclusive mostly no improvement in large studies

Answer 109

2d ultrasonography measure distance between intima and media for IMT using edge detection software very accurate Any thickness in IMT suggested to result from plaque development Can measure very early or advanced stages of plaques Carotid artery used as bifurcation is prone to atherosclerosis Non invasive Some training needed and mostly operator dependent Very reproducible results Increased carotid IMT is associated with risk factors of CVD so can indicate nicely Strong predictor of CVD bEtter predictor of MI and CAD reduction in IMT improves clinical outcome with statin therapy ACAPS trial 40-79 year olds with elevated LDL-c lovastatin therapy had regression in IMT. Indirect evidence.

Answer 110

Visco-elastic arteries increase diameter with left ventricle contraction or increase in pressure Elastin very high concentration Can increase stiffness with gradual pressure increase constantly With age there is a reduction in compliance and diameter increase is less further increasing intra-aortic pressure Consequence is eventually the artery can no longer propel blood increasing chance of clotting

Answer 111

Distensibility = difference in volume/difference in pressure * volume In practice is measured as max-min diameter/pulse pressure*diameter Pulse wave velocity - in stiff arteries pressure increase is greater and speed of blood while is less in an elastic one. Inverse association between PWV and change in volume and pressure. Carotid and femoral pressures measured and PWV calculated. PWV= distance/transit time A High value indicates stiff aorta Non invasive Some training needed mostly operator dependent and reproducible results PWV increases with age and blood pressure but has little association with other factors for CVD. However is a novel surrogate factor as a high PWV shows increase in likelihood of CVD later on No current therapies targeting aortic stiffness so Unknown if able to improve outcome but reducing blood pressure reduces PWV so could potentially have beneficial effect.

Answer 112

No correlation between either factors due to having very different pathologies in wall of blood vessel so although often concurrently occur do not have an effect on one another and often also occur independently of one another

Answer 113

Two Z lines, myomesin in the centre two c proteins either side and distance between is the M line Actin extends from z lines inwards overlapping with myosin thick fibres Length of myosin is the A band Length between ends of actin molecules is the H band Length between myosin of different sarcomeres is the I band Tropomyosin and troponin bound to actin Nebulin extends from z band along length of the actin filament. Acts as a template for regulation of filament length Titin extends from z disc to the M line closely associated segment with myosin and maintains central positioning in sarcomere. During relaxation also generates passive tension through elastic extension when sarcomere is stretched

Answer 114

Regular lattice

Answer 115

Very similar Myofilaments bound by sarcolemma which dives down at every z line forming blind ended invaginations called transverse (t) tubules T tubules are absent in atrial, neonatal and avian heart cells. Just under t tubules membrane is terminal cisternae of intracellular SR Intimate association between SR And Ttubules essential for excitation contraction coupling T tubules In cardiac muscle are larger and fatter than skeletal Cardiac muscle has more mitochondria as cannot anaerobically respire and cannot be allowed to fatigue while skeletal muscle can Only significant difference is fine structure of junctional SR In skeletal muscle the SR t tubules SR interface forms a triad structure In cardiac cells the terminal cisternae are more discrete and tend to appear as double structure with t tubules called dyads

Answer 116

Brick like to fit together and form a syncytium - single cell or cytoplasmic mass containing several nuclei formed by fusion of cells or nuclei division. Ends of cells form intercalated discs

Answer 117

High K inside cell at rest giving negative cell potential -90mV During action potential Na and Ca permeability increases and channels open depolarising cell as ions enter cell Repolarisation caused by delayed increase in K permeability and K+ ions leave the cell Too many leave initially causing hyperpolarisation followed by stable resting again

Answer 118

Skeletal - 1ms Cardiac - 200-400ms long depending on heart rate and species Cardiac much slower to prevent tetany and protect against re-entrant arrhythmias whereas this is not the case in skeletal muscle so they favour faster summated contractions

Answer 119

Ion channels - ions move down their electrochemical gradient Ion pumps - ions driven across membrane using metabolic energy usually ATP usually against their concentration gradient Ion exchangers/symports - ions driven by another ions ionic gradient often exploiting the Na gradient eg glucose/Na transport

Answer 120

Extracellular Ca is essential to initiate cardiac ventricular myocyte contraction however is not needed in skeletal muscle initiation

Answer 121

Action potential triggers an intracellular transient of Ca Cardiac electrical activation is closely followed by a rise in intracellular Ca Resting Ca is roughly 100nM and rises to peak of 1uM in about 30ms before falling back to resting and this activates contraction after slight delay.

Answer 122

voltage induced - Action potential travels down t tubule and voltage gated L type Ca channels open Ca induced - Ca influx activates RyR receptors and causing Ca release Ca channels positioned just under Ca channels of t tubule (T tubule contains clusters of L type Ca channels aka dihydropyridine DHP receptors) DHP receptors are voltage gated so open when depolarised the mouth of these is very close to the SR Ca release channels (ryanodine receptors) These are very huge - can be seen by electron microscope sticking out of SR Rest of SR membrane covered in Ca ATPase pumps to pump Ca back into stores after excitation. (SERCA pumps) surrounded by accessory protein called phospholamban PLB

Answer 123

Attachment- myosin head tightly bound to actin molecule of thin filament (rigor state) Release- ATP binds to myosin head indices release of actin and muscle relaxes - without ATP can stay in state of rigor Bending- ATP causes myosin head to bend and initiates breakdown of ATP to ADP and inorganic phosphate which remain there Myosin head binds to new actin site and iP is released Release increases binding affinity Myosin generates force to straighten and in doing so performs power stroke moving 5nm shortening the sarcomere ADP lost during this stage Release of ADP results in reattachment of myosin head to actin filament and rigor state reestablished

Answer 124

Sigmoidal curve Ca sensitivity and max activated force of contraction can be altered by drugs and other factors Temperature PH - acidosis decreases force Inorganic phosphate - increased Pi decreases force Drugs

Answer 125

Increasing sarcomere length initially facilitates overlap between actin and myosin hence increases force produced by increasing cross bridge formation In cardiac muscle is about 2.25um before this stretch becomes too great pulling the sarcomeres apart and losing cross bridge formations causing force to decline again In cardiac muscle this accounts for 20% increase in force but rest is determined by length dependence of Ca sensitivity while skeletal muscle is mostly determined by this model

Answer 126

Increasing sarcomere length increases Ca sensitivity and maximally activated force Effect is mediated by sensitivity of troponin C for Ca Increase in max activated force is mediated by effects of myofilament overlap from length tension relationship.

Answer 127

Increasing the rate of cardiac contraction results in increased tension development The staircase effect/treppe effect When the frequency of heart rate increases so does the SR Ca content and the force of contraction

Answer 128

In failing hearts the force frequency becomes negative and force decreases with increasing frequency Due to down regulation of SERCA and up regulation of Na/Ca exchange and elevation of Na intracellularly These combine to result in more Ca extrusion between beats and less Ca cycling through SR Key feature of why many failing hearts don’t respond properly to exercise or beta receptor stimulation

Answer 129

Inability to provide adequate CO to support needs of tissues or can do so but only at the expense of increased filling pressure Types- cardiogenic shock (acute heart failure) or chronic heart failure

Answer 130

Systemic veins 5mmHg Pulmonary artery 30mmHg Aortic pressure kept constant by baroreceptors at about 100mmHg

Answer 131

Impaired pumping causes output of both ventricles to reduce so CO falls Fall in right side causes fall in left Systemic venous pressure rises to 10mmHg because right ventricular end diastolic pressure increases Circulatory reflexes tend to maintain mean pulmonary artery pressure, Left ventricular end diastolic pressure and aortic pressure and relatively normal levels

Answer 132

Pressure overload - hypertension, aortic stenosis Volume overload - aortic or mitral valve regurgitation Contractile dysfunction - ischaemic heart disease, myocardial disease, pregnancy, congenital cardiomyopathies

Answer 133

Impaired pumping causes output of both ventricles to reduced and CO falls Pulmonary venous pressure rises eg to 18mmHg because left ventricular end diastolic pressure increases and backs up Circulatory reflexes tend to maintain mean aortic pressure at virtually normal levels Elevated pulmonary venous pressure is transmitted through lungs because they’re low resistance causing slight rise in pulmonary artery pressure eg to 40mmHg

Answer 134

Principally due to left heart failure in turn affecting the right ventricle When moderately severe is accompanied by fall in CO Significant elevation of pulmonary venous pressure eg 16mmHg because LEDP increases Modest elevation of MPAP eg to 40 MmHg and systemic veins eg 8mmHg backs up Reflexes tend to keep MABP virtually normal

Answer 135

States for fixed wall stress (fixed muscular effort) a small ventricle can generate bigger higher pressures than a large ventricle When the heart gets bigger for it to generate the same pressure it did it either increases work done or increases wall thickness In compensatory phase it increases wall thickness however eventually the heart dilates causing pressure drop pushing the heart into spiral of decompensated phase of failure as heart myofibrils work harder and harder to maintain wall stress

Answer 136

During severe aortic stenosis or hypertension the acute affect is increased wall stress Heart responds by thickening wall so during the compensating phase wall stress is normalised by concentric hypertrophy However when dilation occurs the radius of ventricle increases and wall stress rises again Hypertrophic wall and dilation causes excessive myofibril work

Answer 137

Occurs in aortic or mitral valve regurgitation initially leads to ventricular dilation Some hypertrophy can normalise wall stress however when failure sets in the degree of dilation exceeds the degree of hypertrophy and wall stress increases

Answer 138

Either compensated concentric hypertrophy causing hypertrophic cardiomyopathy leads to normal relation between wall thickness and wall stress Or dilated cardiomyopathy where initial phase compensated where hypertrophy is proportional to degree of enlargement followed by excessive enlargement and inadequate hypertrophy

Answer 139

Male 450g Female 400g LV weight/body height = ratio of normal weight of heart

Answer 140

Myocytes lose ability to divide after birth most subsequent heart growth occurs through increase in cell size - hypertrophy Exact hypertrophy stimulus is unknown for pathological conditions likely the heart responds to increase in wall stress and myocyte stretch for protein synthesis and cellular growth Stresses can also cause cells to go into apoptosis Concentric hypertrophy - fatter heart Eccentric hypertrophy - elongated heart These cells express embryonic genes previously switched off in order to grow again

Answer 141

Short term acute failure - functional reserves overwhelmed by overload Compensatory hypertrophy - heart enlarges and adapts Chronic failure - exhaustion, apoptosis and necrosis

Answer 142

Immediate response of circulatory system is to decrease CO mediated via baroreceptors reflex to increase sympathetic outflow Increased sympathetic stimulation causes peripheral vasoconstriction Increased HR and contractility and returns blood pressure to normal Constriction of renal arteries is reflex response initiated to try and retain salt and water and hence maintain blood pressure Essential for acute survival of heart failure eg cardiogenic shock Divert blood to brain and essential organs to maintain blood pressure However this is not good for long term effects

Answer 143

Sensing stretch - direct myocyte stretch, non-myocyte stretch eg VSMCs, fibroblasts and endothelium Release of paracrine factors like FGF, TGF-beta, IGF-1, VEGF, endothelin-1, angiotensin-II, NO, ANP, cytokines etc. Or systemic neurochemical activation - sympathetic activation, release of hormones and neurotransmitters like alpha agonists, beta agonists, renin/angiotensin-I, thyroxine, insulin, growth hormone, glucocorticoids, aldosterone etc.

Answer 144

Integrins - cell surface receptors that link the ECM to cellular cytoskeleton at focal adhesion complexes FACs Sense mechanical stress by deformation Stabilise cytoskeleton and directly activate chromatin and gene expression Variety of signalling molecules - focal adhesion kinase, Src kinases, small G proteins (RAS and Rho), Erk/jnk kinases Stretch activated channels - Ca influx and activation of Ca dependent kinases and phosphatases Na/H exchange - regulates intracellular pH and activation causes alkalisation, blockade prevents stress induced ERK activation and protein synthesis so may be linked to mechanical stress detection All these will activate nuclear transcription factors causing RNA and DNA synthesis causing cell growth

Answer 145

Mitogen activated protein MAP kinase pathway Stress causes JNKs release which activates nuclear transcription factors GPCR RAS activates PKC which activates JNKs and ERKS GPCR RAS also activates ERKS and p38 (also activates by stress causing TGFR release) All activate nuclear transcription factors and promote RNA and DNA synthesis Calcineurin pathway also has evidence of hypertrophy involvement Ca/calmodulin dependent protein phosphatase causes dephosphorylation Affects TFs - Ca changes need to be low amplitude and sustained Inhibited by cyclosporin A /FK506

Answer 146

To hypertrophy the cells switch on genes expressing foetal cell genes once again to allow growth that have been switched off since adulthood Activation of immediate early genes c-myc, c-fos, Erg1, c-jun, HSP-70 Re expression of foetal gene products beta MHC (slow), ANP, BNP, beta tropomyosin, skeletal alpha actin Up regulation of cardiac genes - cardiac alpha actin, myosin light chain 2 General increase in protein RNA formation

Answer 147

Addition of sarcomeric units Change in sarcomeric proteins - lower tension Changes in mitochondria to myofibrillar ratio Changes in gap junctions Action potential prolongation (changes in Ca handling) Conduction velocity reduction Changes in channel expression eg increased T type Ca channels DNA synthesis and attempted cell cycle entering

Answer 148

In attempt to increase contractility and partly consequence of reversion of myocytes to foetal pattern of gene expression there are changes to cellular process leading to contraction Both action potential and intracellular Ca transient are prolonged and Ca uptake and extrusion is compromised Particularly apparent when HR increases and cell is unable to relax between beats Systolic dysfunction - loss of force as well as diastolic dysfunction due to prolonged contraction leading to heart failure

Answer 149

Expression of Ca extrusion proteins is altered Less SERCA and more Na/Ca exchange protein NCX1 Loss of SR Ca uptake explains why systolic Ca transient is smaller as less Ca available for release as more has been ejected by Na/Ca exchange from cells. Also explains slower relaxation, major Ca uptake pathway has been removed now dependent on Na/Ca exchange only This in severe failure causes Ca transient to creep up slowly during long action potential and only recovers when AP recovers due to Na/Ca channels being voltage gated

Answer 150

Gene therapy to increase expression of SERCA in heart failure patients to restore expression and short sharp large contractions and Ca transients in failing myocytes Potential therapy

Answer 151

Beta receptors also down regulated in heart failure due to excessive sympathetic drive Heart becomes less responsive to catecholamines Beta blockers prevent this and are very effective in treating to prevent the heart overworking

Answer 152

Collagen I increases compared to type III disproportionate fibroblast proliferation (produces type I collagen) Excess collagen production type III over type I from angiotensin-II, ET-1, TGFbeta, FGF, stretch Reduced collagen breakdown Replacement fibrosis of necrotic cells Reactive fibrosis around vessels, interstitium which improves force initially but not long term

Answer 153

With exercise angiogenesis keeps pace with muscle mass however doesn’t occur in pathological hypertrophy Intima thickens by medial proliferation increase Perivascular fibrosis by PDGF, VEGF, alphaFGF etc. Atherogenesis Endothelial dysfunction Ischaemia - necrosis and apoptosis

Answer 154

``` In- diaphragm Parasternal intercostal muscles External intercostal Accessory muscles (sternocleidomastoid, scalenes, spinal and neck muscles) Ex- internal intercostal muscles Abdominal muscles rectus abdominis, transveresus abdominis, internal and external oblique muscles ```

Answer 155

All skeletal muscles when loaded excessively will fatigue However resp muscles are adapted to prevent this particularly the diaphragm as consequences would be fatal therefore these skeletal muscles don’t fatigue

Answer 156

Primary respiratory muscle engaged in continuous activity Most fatigue resistant of all skeletal muscle High aerobic enzyme capacity -55% slow type fibres 21% type IIA oxidative and 24% type IIB glycolytic Multiple arterial sources including phrenic, intercostal and internal mammary arteries so lots of oxygen availability Resistant to vasoconstriction influences in vascular diameter unlike peripheral skeletal muscles where vasomotor influences are very important

Answer 157

Volitional test - patient asked to contract muscles etc. And does so Non-volitional tests- electronic stimulation passed through to depolarise phrenic nerve and cause muscle contraction for patients with breathing difficulty etc. Struggle to control contractions- bilateral phrenic stimulation Catheters passed through nose to just above and below the diaphragm to measure thoracic and abdominal pressure Pdi (trans-diaphragmatic pressure)= Pgastric - P oesophageal

Answer 158

Loss of capacity to develop force and/or velocity in response to load which is reversible by rest Can be demonstrated in both peripheral and central muscles Central fatigue in CNS peripheral fatigue - failure of contractile apparatus High and low frequency fatigue

Answer 159

Muscle force generation during sustained or repetitive volitional contractions becomes limited due to decline in motorneuronal output Progressive exercise induced reduction in voluntary activation or neural drive to muscle Max voluntary effort produces less force than by electrical stimulation Demonstrated using twitch interpolation. Difficult to study experimentally and is dependent of task involved. More CF after prolonged boring tasks than short term fatiguing loads, some studies unable to produce CF in limb muscles Response in diaphragm is variable depending on fatiguing manoeuvre employed - repeated efforts 50% Pdi max. Reduce voluntary dive by 50%. 3.5% decline during inspiratory contractions and 31% decline in expulsive manoeuvres Respiratory sensations may limit ability to induce fatigue Transcranial magnetic stimulation - removes volitional component by measuring EMG response as the motor evoked potential MEP this indicates how excitable the muscle is. A fall in MEP is indicative of CF- fall following incremental exercise to exhaustion, no low frequency muscle fatigue.

Answer 160

Reduced activity from motor neurone pool Spinal and supraspinal mechanisms involved: intrinsic motor neurones membrane properties like reduced excitability with sustained activity(contraction) Serotonin release in spinal cord increases in proportion to strength of contraction - 5-HT increases excitability of motorneurons via 5-HT2 receptors. Decreased release with prolonged activity reducing motorneurones excitability. 5-HT spillover reaches extrasynaptic inhibitory 5-HT1A receptors on Axonal initial segment inhibiting AP generation Recurrent inhibition from Golgi tendon organ and renshaw cell (limited role as activity diminished by fatigue) Feedback from intramuscular receptors: decreased afferent feedback from muscle spindles occurs during fatiguing contractions leading to no facilitation of MNs. Group III and IV receptors affecting voluntary drive via spinal and intracortical inhibition plus conscious sensations of muscle discomfort and fatigue Muscle/central wisdom

Answer 161

Gradual reduction in central firing frequency during prolonged muscle voluntary contractions Matches the motor unit discharge rate with fatigue related contractile properties of muscle - optimises force generation - avoids peripheral (high and low frequency) fatigue Spinal and supraspinal mechanisms signal motorneuron pool to lower discharge rate of motor unit This is central fatigue protective especially in respiratory system

Answer 162

Group III are mechanically sensitive afferents which respond to contraction and stretch Group IV afferents sensitive to metabolites like lactate, ADP and H+ and noxious mechanical strain Feedback can be blocked by intrathecal injection of fentanyl Increased CMD, more muscle fatigue, shorter exercise time and increase rate of fatigue in 67% patients III/IV muscle afferents limit CMD and hence development of peripheral fatigue

Answer 163

Failure to generate force as result of failure at NMJ or distal contractor apparatus NMJ propagation of AP along sarcolemma or into t tubules Changes in excitation contraction coupling Changes within muscle cell - metabolism and contractile proteins etc Subdivided depending on response of muscle to electrical stimulation Losses explained by underlying mechanisms High frequency fatigue : depression of forces at 50-100Hz, only occurs with low frequency fatigue, resolves quickly, failure at NMJ/propagation of AP in sarcolemma or t tubules from reduced ion channel activity Low frequency fatigue- depression of forces at 1-20Hz, occurs in isolation, long lasting, decrease ATP, increased metabolites, decreased pH and Ca release by SR, decreases Ca sensitivity, decreases intracellular K and myofilament damage. Naturally occurring from exercise eg weights.

Answer 164

Generates max tension but force is lost rapidly Not demonstrated in normal exercise Doubtful if such fatigue contributes to force failure Ischaemia and shortened muscle length can cause this Significant HFF of respiratory muscles would result in catastrophic force loss and respiratory pump failure NMJ problems Propagation of AP along sarcolemma or t tubules Strategies adopted by body to maximise tension but avoid HFF

Answer 165

Marked force reductions at low frequency stimulations - response to High frequencies is unimpaired Induced using inspiratory resistive loading/maximal voluntary ventilation breathing hard and fast. Reductions are relatively small around 20% Not typically seen following whole body exercise Extensively studied using 1Hz twitch response - tolerable fatigue, fixed relation between 1:100Hz with fall in diaphragm twitch less than 15% indicating low frequency fatigue

Answer 166

LFF respiratory muscle fatigue isn’t seen in clinical models when respiratory system is heavily loaded eg lung diseases COPD or in ICU patients with ventilation failure Overt LFF doesn’t occur as the CNS will not drive peripheral contractile apparatus sufficiently hard enough to cause fatigue in order to protect itself

Answer 167

Normal response to excessive load Dangerous energy depletion leading to rigor, muscle damage and excitation failure precipitating catastrophic force loss does not occur - adaptation of central drive

Answer 168

Relaxation rate slows early in response to excessive loads that can’t be sustained Related to rate of energy turnover in contracting muscle - ATP depletion, intracellular acidosis, change in transmembrane ion conductance Early signal of fatigue process Slowing is an adaptive process to preserve force generation

Answer 169

Highly fit marathon runners underwent volitional testing and showed significant reduction in force production of respiratory muscles Volitional testing makes it doubtable Loke 1982 12 healthy subjects roughly 33yrs VO2max 61ml kg-1 min-1 exercised at 85 and 95% VO2 max to exhaustion Small but significant reductions in twitch force of trans-diaphragmatic pressure - removes volitional testing problems. No indication of induced arterial hypoxaemia

Answer 170

Only studied in very fit individuals able to push muscles to extreme and these factors below may be why they can do this Aerobic fitness studies proves this is not the case Exercise induced atrial hypoxaemia - some fit people induce hypoxia from exercise. Proved not true by providing more oxygen and still saw fatigue - saw more fatigue from extra oxygen giving more ability to exercise. Mechanical constraint - athletes have much higher resp flow volume and Can get much closer to maximal respiratory flow volume. also not thought to be cause of fatigue. Ventilation and work of breathing - exercise at 80-90% VO2 max to fatigue but when asked to respire the same amount while at rest no fatigue was seen. still not sufficient to produce fatigue fully but must be to do with work of breathing while exercising. Competition for blood flow - Diaphragm must compete with locomotor muscles for blood flow in heavy exercise - inadequate o2 transport to diaphragm potentially leads to fatigue. Fatiguing contractions and accumulation of metabolites activates unmyelinated type IV phrenic afferents - increases sympathetic vasoconstrictor activity to peripheral muscle via spinal reflex Protective effect limiting exercise to prevent respiratory fatigue before it begins!! Trained athletes have severe competition and may override this protective affect! Central fatigue / muscular wisdom - not proved

Answer 171

Is there genetic predisposition or training or both that allow protection to be over ridden? In athletes respiratory fatigue can be seen slightly unlike in normal fitness due to overriding the protective defence of blood flow competition - when the muscles begin to fatigue the amount of exercise that can be performed is limited (may not be this exactly may be due to competition for blood flow and peripheral muscle fatigue) to enable rest while in athletes this can be overridden

Answer 172

Increases angiotensin II and decreases bradykinin are key features of neurohumoral response to heart failure Leads to endothelial dysfunction and increases endothelin-1 production and decreases NO production Leads to inappropriate vasoconstriction which raises afterload and preload and exacerbated failure ACE inhibitors both decrease levels of angiotensin II and increase bradykinin by decreasing activity of kinase which breaks down bradykinin

Answer 173

Renin angiotensin system activated by fall in CO Renin secreted by juxtaglomerular cells in kidney in response to hypoperfusion and sympathetic stimulation Circulating renin stimulates plasma substrate to convert angiotensinogen to angiotensin I which is converted to angiotensin II by ACE enzymes causing vasoconstriction at tissues raising blood pressure Also causes release of aldosterone increasing salt and water retention maintaining blood pressure and renal perfusion. Together these raise central venous pressure and preload on heart helping maintain CO but at cost of raised left ventricular end diastolic pressure Rise in CVP causes atria to stretch in turn stimulating production and release of atrial natriuretic peptide ANP. Most of neurohumoral responses to acute failure have immediate beneficial effects but can in longer term worsen the disease. ANP seemingly primarily beneficial. Has diuretic action directly vasodilates and inhibits aldosterone secretion. Also inhibits release of noradrenaline from terminal neurones which further promotes vasodilation. Endogenous antagonist for angiotensin II and ANP in heart increases proportionally to extent of congestive heart failure. Increase in ANP is overwhelmed by vasoconstriction and salt and water retention induced by activation of renin/angiotensin system. ANP secretion becomes down regulated and vascular ANP receptors desensitised

Answer 174

All mammals apart from man fall in straight line relating to heart rate to life span Species with high heart rate live a short time while animals with slow hearts live much longer On this basis humans should live about 20-25 years and so our bodies are designed to cope with immediate life threatening stresses but not long term consequences of this ie the acute response to heart failure is beneficial however the long term consequences are detrimental to the disease All animals have roughly the same amount of heart beats in a life time - about 3x10 to power of 8!!

Answer 175

Adapts to save heart initially however causes increase risk of ischaemia, incidences of arrhythmias, sudden death and is very detrimental to heart health Consumes more oxygen and growth outcompetes angiogenesis so cant keep up Compromises coronary vascular reserve so heart can’t respond to changes in demand Can lead to ischaemia, fibrosis and collagen deposition etc. Focal fibrosis makes the heart stiffer and harder for myofibrils to generate force decreasing contractility. This worsens the hearts dilation and failure in turn increasing wall stress cycling over and over

Answer 176

Normally fluid forces out at arteriole end into tissues drained into lymph or venous vessels resulting in bonnet fluid movement as flow is constant. In the lungs there is a net loss of fluid which isn’t problematic due to the constant intake of humidified air and lungs are kept from accumulating fluid In heart failure fluid movement in lung is reversed and hydrostatic pressure in the pulmonary circulated is raised hence hydrostatic pressure is higher than colloidal osmotic pressure on arterial side of capillary bed Leads to net gain of fluid in the lungs causing major breathlessness and potential drowning from alveoli filling and reducing area for gas exchange. Oedema starts in high blood pressure areas like ankles as well.

Answer 177

Air to alveolus travels by convection, to arteries by diffusion, to arterioles by convection, pre capillary artierioles, capillaries both convection and diffusion, tissue interstitium and cytosol by diffusion. Decreasing oxygen partial pressure further into body, varies from sea level to altitude etc.

Answer 178

Douglas, C. G., et al 1913 Fast ascent up to pikes peak measuring their ventilation as function of expired CO2 or O2 uptake while walking various speeds on level or uphill. Showed increase in ventilation to sustain intake of oxygen Alveolar PCO2 fell during five weeks at pikes peak and slowly recovered to its sea level value around a week after arrival. Progressive rise in ventilation represents acclimatisation Following rapid ascent haemoglobin content changed. Within weeks increased by 28-30% and remained elevated while at altitude and returned to normal at sea level again. Fitzgerald MP 1914 took measurements of Hb in fully acclimatised people - Hb increases linearly with altitude. Oxygen content stayed virtually constant, meaning the quantity of O2 carried per litre of blood increases which should decrease the work of the heart in theory. In practice the increased RBC increases viscosity and work of heart increases so very large increases in haematocrit are counterproductive.

Answer 179

Increase HR and ventilation immediately | Increase haemoglobin conc and capillarity density long term

Answer 180

Stimulates increase in erythropoietin following the drop in Hb from blood donation causing rise in Hb again.

Answer 181

Increases at altitude linearly So the quantity of O2 carried per litre of blood increases which should decrease the work of the heart in theory. In practice the increased RBC increases viscosity and work of heart increases so very large increases in haematocrit are counterproductive. this can cause excessive desaturation of oxygen in capillaries especially causing blue colour of lips etc. Therefore those at altitude well adapted have relatively low haematocrit levels eg Tibetans.

Answer 182

In normoxia HIF-alpha is rapidly hydroxylated, binds to VHL and is ubiquinated and broken down In hypoxia its able to translocates to the nucleus and bind to HIF-beta functioning as a transcription factor to increase synthesis of RBC proteins for increased Hb

Answer 183

Smith TG et al 2006 Condition with mutated VHL (partially inactive R200W VHL allele) protein so HIF alpha degradation is reduced and HIF is active even at normal oxygen levels resulting in increased haematocrit They have increased hypoxia response from modest HIF activation

Answer 184

Low haematocrit and pulmonary artery pressure compared to sea level individuals Carry unique genes EPAS1 for HIF2alpha protein associated with low haemoglobin conc. Beall CM et al 2010.

Answer 185

Decrease PaO2, increased HIF-alpha and gene transcription releasing erythropoietin and increased bone marrow and erythropoiesis

Answer 186

Decrease PaO2 increases HIF-alpha and gene transcription leading to increased vascular endothelial growth factor and angiogenesis

Answer 187

Determines ventilatory rise in response to reduction in PaO2 Weight about 5mg but have highest blood flow in body 2000ml/100g/min Taste arterial blood for PO2 and PCO2/pH and excite the drive to breathe by increasing AP firing in carotid sinus nerve Found in bifurcation of common carotid artery. Hypoxic stimulus from O2 is only strong below 70mmHg unlike CO2 which is always strong Made of carotid body glomus cells, many capillaries and nerves present Removal of carotid bodies communication (vagus nerve) prevents hyperventilation response

Answer 188

Proximal pathway in type one cell - hypoxia inhibits k channels causing membrane depolarisation and Ca influx and release and increased action potentials in carotid nerve sinus If membrane potential is clamped at -60mV hypoxia no longer leads to this pathway so Ca influx needs this depolarisation to occur Cytosolic Ca usually rises sharply as O2 falls below 60mmHg stimulating dopamine release - marker for release

Answer 189

Stimulus transduction cascade in oxygen sensitive cells in carotid body in hypoxia Decrease in oxygen tension in type one cells detected by primary oxygen sensors that rapidly communicate with k channels (mitochondria could also sense changes in pO2 and communicate with k channels) Leads to k channels closing and membrane depolarisation, ca influx and release of neurotransmitters Acetylcholine and ATP thought to excite afferent nerve endings of fibres that run in carotid sinus nerve

Answer 190

Condition in pregnancy with elevated blood pressure, often proteinurea and fluid retention can be fatal if untreated Two stage pathology - poor placentation at 8-18 weeks followed by stage two placental dysfunction after 20 weeks causing preeclampsia and foetal growth restriction Cure for preeclampsia is birth but if premature this I not often the best or possible solution Preeclampsia causes increased risk of complications like eclampsia, HELLP syndrome, stillbirth, placental abruption, prematurity

Answer 191

As gestation length increases maternal heart rate and CO increases while Total peripheral vascular resistance falls which wouldn’t both occur in non pregnant women This occurs due to mass vessel dilation in maternal circulation to increase flow of blood to uterus If vessels don’t dilate mother is at risk of hypertension and preeclampsia from poor circulation to placenta

Answer 192

Increased oestrogen increases renin and aldosterone release Progesterone and vasodilatory PGs increase aldosterone Shunting of blood to uterine circulation stimulates sympathetic activity increasing renin secretion from kidneys Renal Na loss due to increased GFR increases renin secretion further hCG hormone increases renin release too All these lead to increased CO in normal pregnancy

Answer 193

Blood pressure is a very good indicator of preeclampsia - above 90 is concerning Haematocrit content decreases decreasing viscosity of blood making it flow easier with less work heart good for mother and foetus circulation

Answer 194

Pacemaker activity remains the same but conductivity is altered and the expression of HCN2 ion channels increases causing greater excitability and conduction increasing heart rate Khoury et al 2013

Answer 195

Blood vessels all dilate in pregnancy causing mass increase in blood flow to all organs due to vessels increased elasticity and decreased resistance

Answer 196

Reduced constrictor response not due to absence of stimuli - vessels less sensitive (less believed now) Increased synthesis of NO and prostacyclin from the endothelium

Answer 197

ACh good stimulus of NO production but in pregnancy is stimulated by oestrogen and this produces higher than normal levels of NO dilating the vessels in the body beyond normal Sheer stress can also cause vasodilation by inducing NOS and NO and cells align in favour of blood flowing giving less resistance Have so much dilation causes women to become very hot, hair, nails fast growing cells grow more from increased blood flow etc Aortic compliance also increases in pregnancy (poppas et al 1997)

Answer 198

In rats is mediated by relaxin binding to endothelin receptor B causing NO release and vasodilation increasing GFR and ERPF

Answer 199

Involved in structure determining vessel walk rigidity and stiffness by number of crossings MMPs decrease in pregnancy and remodel vessels to increase compliance and favour relaxation as less collagen present etc MMPs also involved in retiring uterus structure to original size post parturition Also involved in pathologies like rheumatoid arthritis or tumour cell invasions There are hundreds of types of MMPs and some specifically change in adaptation to pregnancy - MMPs in aortas of pregnant rats upregulate MMP2 and 3 (kelly et al 2003)

Answer 200

Not much change but some structural adaptations seen such as capillary proliferation unknown why this is stimulated but may just decrease risk of thrombosis etc.

Answer 201

Uterine artery dilated in response to increased NOS and NO in circulation Myogenic tone of uterine artery decreased Allowing lower blood pressure Spiral arteries are plugged for first 6 weeks of gestation by trophoblasts- large cells can see nuclei in histology. These gradually eat down into maternal wall unplugging spiral arteries allowed hypoxic environment of uterus to become normoxic by remodelling arteries which become like small veins very dilated with little resistance Very disputed events - as trophoblasts enter maternal wall Decidual NK cells (70% immune cells in decidua) bind and prevent trophoblasts being recognised as foreign antigens from paternal DNA by interaction of HLAC molecules with NK receptors. Absence of this means TB are recognised as foreign and arteries aren’t properly unplugged leading to poor circulation In preeclampsia this remodelling doesn’t occur causing hypoxic problems for foetus growth restriction and poor circulation Ashley King et al A failure to unplug can be seen by ultrasound using uterine waveform altered frequency can can show high resistance in vessels may be indicating preeclampsia

Answer 202

Thought to be NOS likely activates MMPs as when vessel treated with NOS inhibitor wall thickened and lumen shrunk whereas with NOS present and active lumen widened and walls remained elastic and less collagen stiffened due to MMP rearrangement Hale S A et al 2011

Answer 203

HLA C is dominant ligand for NK cells NK cells are abundant in decidua of uterus wall Some NK cell receptors bind HLA C. These belong to members of killer immunoglobulin like receptor gene family HLA C to KIR binding may play a role in facilitating trophoblast invasion by synthesis of permissive cytokines

Answer 204

Clark et al 2018 | Shunts found between spiral artery and vein contribute to increased resistance and may also increase preeclampsia risk

Answer 205

Placental dysfunction Preeclampsia Foetal growth restriction Adulthood cardiovascular dysfunction - abnormal vessel endothelium functioning (Payne et al 2003) showed hypertension common. To test for this can take blood from the mother and a few foetal placental cells will be present from sloughing off placenta and can be used to detect foetal disorders like Down’s syndrome at 99% accuracy but if there are elevated levels of foetal placenta cells can indicate high blood pressure causing excess sloughing maybe causing increased clotting factors or clamping of uterine arteries increasing risk of these disorders

Answer 206

Maternal susceptibility factors genes, weight and diet etc Reduced intermittent placental perfusion leads to oxidative stress and ER stress Maternal vascular endothelial dysfunction, anti angiogenic factors, platelet activation inflammatory response Maternal disease Thought to lead to long term CV problems in mother eg those with diabetes already have dysfunctional endothelium are therefore more prone to preeclampsia from exacerbation of the problem

Answer 207

Increased unfolded proteins from a non functioning ER due to stress from placental ischaemia resulting in inflammation, cell death in maternal endothelium Proteins can also be altered by microRNAs in foetal endothelial cells causing post translational protein changes altering protein function, if these are reduced in maternal and foetal circulation it reduces the rate of normal foetal endothelial cells

Answer 208

Placenta growth factor PIGF is an endothelium dependent vasodilator Soluble flt-1 is a soluble receptor for PIGF and is produced by placenta Soluble flt -1 increases in preeclampsia Hypothesised this reduces available PIGF which leads to preeclampsia Levine, karumanchi, many studies Also can be tested for detecting preeclampsia can be very reliable - normal shows no risk May also increase stroke volume (aasa et al 2015) Maybe foetus drives preeclampsia by mutated genome FLT1

Answer 209

Kalafat 2017 not very well believed study or theory Placental dysfunction is secondary to maternal CV maladaptation in pregnancy causing poor circulation and placenta problems rather than placenta dysfunction followed by poor circulation Now apparent that CV dysfunction precedes preeclampsia and predominates as clinical syndrome and persists several decades postpartum

Answer 210

``` Hypertension Increased arterial stiffness in childhood Aortic wall thickening Narrowing of coronary arteries Carotid atherosclerotic lesions Reduced aortic size and compliance Abnormal endothelial function Retinal arteriolar narrowing ```

Answer 211

Aatola H et al 2010 Studied relationship of fruit and veg consumption following subjects for 27 years to see affects on PWV in adulthood. Veg consumption inversely related to PWV and was an independent predictor for PWV Low consumption of fruit and veg in particular related to arterial stiffness in young adults

Answer 212

Atkinson CL et al 2015 Flow mediated dilation measured before and after incremental exercise at different intensities to assess local factors such as blood flow and shear rate on post exercise brachial artery function. Hand grip exercise leads to intensity and time dependent changes in conduit artery function possibly mediated by local increases in shear with improvement in function evident 1 hour post exercise when performed at higher intensity (15%)

Answer 213

Haynes WG et al 1994 Forearm blood flow measured with blood pressure cuff (venous occlusion plethysmograph) Endothelin 1 does contribute to nasal vascular tone by binding to ETa receptors in smooth muscle cells of blood vessels Proendithelin1 converted to endothelin 1 via endothelin converting enzyme (ECE) ECE inhibitors such as phosphoramidon and ETa antagonists have good potential for therapy in vasoconstrictive conditions such as hypertension, chronic renal failure or cardiac conditions by preventing endothelin 1 vasoconstriction and causing vessel dilation.

Answer 214

Perri et al 2015 Atrial fibrillation associated with many atherosclerotic risk factors and CV events Aim of study to evaluate association between endothelial dysfunction by flow mediated dilation and occurrence of CV events in atrial fibrillation patients. Conclusion - in AF patients with a flow FMD associated an increased risk of CV events suggesting impaired artery dilation predisposes people to atherosclerotic complications

Answer 215

Traverse JH et al 2007 K+ATP channels important in coronary blood flow CBF regulation activated when ATP or perfusion pressure is reduced At rest blocking these channels reduced CBF ~20% but not at exercise Vice versa is true with adenosine receptor blockade Congestive heart failure CHF associated with decrease in CBF matched to a decrease in myocardial oxygen consumption Study examined dogs with pacing induced CHF and role of these channels Findings demonstrate K+ATP channels contribute to regulation of resting MBF in CHF and endogenous adenosine may act to inhibit MVO2(myocardial oxygen consumption) in the failing heart

Answer 216

Hsieh PC et al 2007 Degree of which stem cells or precursors contribute to new cardiomyocytes is very controversial Study shows they do contribute to renewal after injury however not significantly during normal ageing

Answer 217

Senyo SE 2013 Recent studies reveal heart cells generated in adults but frequency and contribution is still unknown and controversial Some suggest high rates of activity from stem cells other suggest very low rates insignificant to growth possibly derived from pre existing cardiomyocytes This study revealed pre existing cardiomyocytes as the main source of replacement in normal myocardial homeostasis as well as after injury

Answer 218

Grossman W 1975 Chronic left ventricle pressure overload results primarily in wall thickening and concentric hypertrophy while chronic LV volume overload is associated with chamber enlargement and eccentric hypertrophy Measured wall stresses throughout cardiac cycle in 30 patients at time of cardiac catheterisation 6 LV pressure overload patients 18 LV volume overload patients 6 health control Found that hypertrophy develops to normalise systolic but not diastolic wall stress Increased systolic tension resulted in myocardial fibres thickening to return systolic stress to normal while increasing diastolic tension appeared to gradually elongate fibres which improved ventricular chamber efficiency but couldn’t recover normal diastolic wall stress

Answer 219

Gwathmey JK et al 1987 Intracellular Ca release and uptake essential for contraction and relaxation of normal heart muscle Intracellular Ca transients we’re measured with aequorin during isometric contraction in patients with end stage heart failure Compared to controls transients were markedly longer. Showed diminished capacity to restore low resting Ca levels during diastole Results show evidence for abnormal Ca handling in failing hearts may be causing heart failure

Answer 220

Hein S et al 2002 Progression of compensated hypertrophy to heart failure is still debated Investigated patients with isolated Valvular aortic stenosis and differing degrees of LV systolic dysfunction to test is structural remodelling and cell death contributing to transition to heart failure Conclusions show structure function correlations confirm that the transition to heart failure occurs by fibrosis and myocyte degeneration partially compensated by hypertrophy. Cell loss mainly by autophagy and Oncosis contributes significantly to pregression of LV systolic dysfunction

Answer 221

Smith et al 2006 The Von Hippel-Lindau tumour suppressor protein hypoxia indicible factor VHL-HIF pathway is of interest in controlling cellular responses to hypoxia Study investigated patients with Chuvash polycythaemia (rare congenital disorder with elevated endothelial growth factor, low blood pressure, varicose veins and early death secondary to cerebral vascular events or peripheral thrombosis) in order to analyse the role of the VHL-HIF pathway in systemic human cardiopulmonary physiology Features involved in small patient group are highly characteristic with those with acclimatisation of hypoxia of high altitude. Demonstrates that VHL plays a major role in underlying calibration and homeostasis of respiratory and CV systems most likely through central role in regulation of HIF.

Answer 222

Bishop T et al 2013 Oxygen dependent prolyl hydroxylation of HIF by set of closely related prolyl hydroxylase domain enzymes (PHD1-3) regulates a range of transcriptional responses to hypoxia. Investigated the effect of genetic deficiency and inhibition on the change in ventilation in response to acute hypoxic stimulation in mice. Findings demonstrate that PHD enzymes modulate ventilatory sensitivity to hypoxia and identify PHD2 as most important enzyme in this response. Also reveal that differences between genetic inactivation of PHDs response to hypoxia and responses to pharmacological inhibition demonstrating the need for caution in predicting effects of therapeutic modulation of HIF hydroxylase system on different physiological responses.

Answer 223

Basaran KE et al 2016 Ventilatory acclimatisation to hypoxia is a time dependent increase in ventilation and the hypoxic ventilatory response HVR that involves neural plasticity in both carotid body chemoreceptors and brain stem respiratory centres. Mechanisms not completely known. Tested hypothesis that ibuprofen would block increase in HVR with chronic hypoxia in humans (15 healthy men and women) in double blind placebo controlled cross over trial. Ibuprofen significantly decreased the HVR after acclimatisation to high altitude compared to placebo but didn’t affect ventilation or arterial O2 saturation breathing ambient air at high altitude. First evidence showing HVR in humans not just animals. Establishes future experiments to test potential role of mechanisms for neural plasticity and ventilatory acclimatisation in humans with chronic hypoxaemia from lung disease

Answer 224

Steier J et al 2015 The load improved on ventilation by increased body mass contributes to respiratory symptoms caused by obesity. Study tried to quantify ventilatory load and respiratory drive in obesity in both upright and supine postures Conclusion - obese patients have substantially increased neural drive related to BMI and develop positive end expiratory pressure PEEPi when supine. Continuous positive airway pressure CPAP abolishes PEEPi and reduces neural respiratory drive in patients. Findings highlight the adverse respiratory consequences of obesity and have implications for the clinical management of patients particularly when supine.

Answer 225

Sharma et al 2015 Study documents the impact of different exercise modalities on dyspnea and leg fatigue during equivalent cardiopulmonary stress in healthy subjects 20 subjects performed 5 min exercise tests and reported either dyspnea or leg fatigue during each test:l. VO2, ventilation and respiratory rate and HR measured Findings indicate that at equivalent levels of cardiopulmonary stress reflected by similar VO2 levels and HR the perceived level of exertional dyspnea is not influenced by different patterns of neuromuscular activity and intensity of leg fatigue primarily reflects while body work and is independent of different patterns of neuromuscular activity.

Answer 226

Discovered blood circulated within foetus Artworks duct and umbilical vessels closed after birth Right and left ventricles work in parallel during foetal life rather than series like in postnatal life

Answer 227

Left and right ventricular pressures are equal Injected cornstarch granules into blood from IVC and SVS seen to mix in the right atrium and patency of the foramen ovale was confirmed. Data provided on blood pressure, cardiac output and oxygen concentrations in different parts of foetal circulation Flow through different parts of circulation and relative flows using dye dilution techniques mostly studied in sheep and pigs However animal studies are limited as not entirely similar to humans. Carried out between 1944-1960

Answer 228

Nyberg and westin 1962 and Rudolph 1971 Studies on exteriorised human foetuses terminated by hysterectomy Data collected on heart rate, blood pressure and oxygen uptake Relative flow to organs measured

Answer 229

Placenta - respiration for foetus Umbilical vein - oxygenated blood to foetus, travels from placenta to foetal liver then becomes ductus venosus joining with the IVC entering the RA containing deoxygenated (from IVC) and oxygenated blood (from DV) round heart via shunts or normal pathway partially oxygenated blood then to tissues then back to heart. Fluid in lungs creates high pulmonary vascular resistance (8-10% blood flow passing to the lungs) non inflated and not being used so little need for blood to travel there so heavy right to left shunt from foramen ovale (RA to LA) and ductus arteriosus (pulmonary artery to aorta) Four shunts - placenta, foramen ovale, ductus venosus and ductus arteriosus. Ductus arteriosus and foramen ovale cause right to left shunt. Ductus arteriosus takes most of the RV output into the descending aorta. The shunts cause the head to receive more oxygenated blood then that passing through the arterial duct Umbilical artery - deoxygenated blood from foetus circulation branching off internal iliac artery back to placenta. Aim to oxygenated blood from maternal circulation. Blood from maternal and placenta doesn’t actually mix, oxygen transferred via diffusion gradients, O2 from mum and CO2 from foetus. Foetal RBC has much higher O2 affinity and more Hb molecules therefore O2 taken from maternal blood. Travels back to foetus via umbilical vein. Foetal tissues - oxygen offloaded to tissues for respiration. CO2 diffuses into blood removed via bicarbonate ion formation HCO3. HCO3 then binds to H+ forming water and CO2 once at boarder of maternal and placenta circulation, removed by maternal RBCs. There is slight RV dominance in terms of volume flow around 1.2:1 from RV:LV

Answer 230

In the right atrium blood from the IVC is divided into two streams by the crista dividens Well oxygenated blood is directed to left atrium at the foramen ovale (40% blood) - preferred streaming for oxygenated blood Deoxygenated blood directed towards LV via RA

Answer 231

Oxygenated blood travels via umbilical vein from placenta to foetus, through ductus venosus joining IVC (partially deoxygenated) through foramen ovale, LA then LV then into ascending aorta to tissues Deoxygenated blood travels through SVC and IVC through RA and RV to the pulmonary artery and ductus arteriosus to descending aorta Both sides pump into the systemic circulation!

Answer 232

``` SVC -40 RV/pulmonary artery - 55 moving along vessel to 60 LV/aorta- 65 Umbilical vein/ductus venosus - 80 IVC-70 ```

Answer 233

Wide communication between the atria equalises the pressures Openness of arterial duct equalises pressures in great arteries

Answer 234

Heart rate Filling pressure (preload) Resistance against which ventricles eject (afterload) Myocardial contractility

Answer 235

In the umbilical vein

Answer 236

Regulating flow into the heart Directing blood flow to the left heart Ensuring highly saturated blood to the brain

Answer 237

Invasive techniques not ready for human studies - only animals Cardiac ultrasound applied by cross sectionally or via Doppler echocardiography Doppler equation - flow Q= v*r2*pi/cos(angle between ultrasound beam and direction of flow) Permits high resolution imaging Colour flow Doppler - colouring of images 3/4D imaging Detailed ultrasound allows sequential assessments and absolute volume flow measurements technically now feasible. Foetal MRI also evolving.

Answer 238

Placenta removed from circulation, Wharton’s jelly contracts from a decrease in temperature, ie from internal maternal temperature to room temp. This clamps the vessels inside the umbilical cord and increases the resistance in the vessels and blood starts clotting off no flow in first few days after birth. Umbilical vein and ductus venosus stops being used in first few days. IVC no longer has oxygenated blood only deoxygenated blood from baby circulation. As the chest passes through the birth canal the lungs are compressed, after birth the chest wall recoils and produces passive inspiration of air into the lungs. Lungs take in air And replaces the fluid sitting in the lungs. Fluid will enter the capillaries, arterioles dilate and resistance falls creating low resistance in lungs. Pulmonary pressure and Right side of heart pressure falls and blood travels into the pulmonary circulation as well as systemic. Pressures in the RA decrease significantly and the LA increases pressure and foramen ovale flap closes over hole this occurs in first few mins after birth. First few hours the ductus arteriosus smooth muscle constricts due to high oxygen levels preventing shunt of blood flow eventually closing vessel off. Detects also the fall in prostaglandin fall from placenta removal. Umbilical artery branching from internal iliac artery also has increased resistance therefore preventing blood flow in this vessel. Smooth muscles also constricts to high levels of oxygen and low prostaglandin levels. Eventually close vessels off completely and become ligaments of the liver. Takes a few hours. Systemic vascular resistance increases from loss of placental circulation and sympathetic drive Heart changes from parallel to series circuit.

Answer 239

Visual Tactile sensation Auditory Thermal

Answer 240

Reduced foetal cerebral oxygen consumption associated with smaller brain size associated with congenital heart disease Transposition of great arteries - deoxygenated blood flows from the aorta into the pulmonary artery via the ductus arteriosus which remains open instead of closing off after birth. Causes less oxygen levels in brain may affect development later on. PGE needed to maintain openings. Symptoms result from desaturation and acidosis. Balloon septostomy as temporary measure to arterial switch. Hypoplastic left heart syndrome - left side of heart not formed correctly and LV is underdeveloped and too small/mitral valve too small or aortic valve too small or not formed. Ascending aorta can also be too small etc. Often have atrial septal defect where foramen ovale does not close as LA pressure doesn’t increase when born. Systemic CO very decreased from left heart. Blood bypasses this via the ductus arteriosus and foramen ovale and the right side pumps blood to lungs and body. When these openings close CO very poor and circulation collapses Tetralogy of Fallots - four defects: pulmonary stenosis (narrowing of pulmonary valve) blood has difficulty getting from RV to PA. Ventricular septal defect: foramen ovale doesn’t close Over riding aorta: RV pumps some deoxygenated blood directly into it. Right ventricular hypertrophy: RV hypertrophies from forcing blood into narrowed pulmonary arteries.

Answer 241

Evidence of impaired brain maturation for neurocognition in CHD. Eg hypoplastic left heart syndrome, transposition of great arteries and tetralogy of Fallots where oxygen saturation in cerebral blood flow is altered regardless of operation show immature brain development

Answer 242

Pulmonary valve not formed correctly Pulmonary blood flow maintained by arterial duct If duct closes death results Urgent PGE administration needed to prevent closure

Answer 243

``` Essential to sustain ventilation Important to consider in patients with Unexplained dyspnoea (difficult or laboured breathing) Neuromuscular disease Ventilatory failure Difficulty weaning from the ventilator ```

Answer 244

Sternocleidomastoid muscles Scalenes Parasternals ``` Diaphragm Rectus abdominis Internal oblique External oblique Transversus abdominis ```

Answer 245

VA= VE (minute ventilation)-VD (dead space) Min ventilation = tidal volume*resp rate Vd= dead space*resp rate PCO2 inversely related to alveolar ventilation.

Answer 246

Central drive from cortex and brainstem via spinal motor neurones phrenic nerves transmit signal to respiratory muscles to breathe in and contract etc.

Answer 247

Critical and brainstem lesions: Encephalitis, ischaemia, haemorrhage, cheyne-strokes respiration (CHF), trauma Drugs: sedatives, opioids Metabolic alkalosis: loop diuretics

Answer 248

Nerves and NMJ problems: spinal cord lesions, polio, motor neurone disease, phrenic nerve injury, guillian-barre syndrome (chronic demyelination syndrome), critical illness neuromyopathy, neuromuscular blocking agents, aminoglycosides and myasthenia graves

Answer 249

``` Muscular dystrophies Inflammatory myopathies Malnutrition myopathy Acid Maltase deficiency Thyroid myopathy Biochemical anomalies like hypokalaemia and hypophosphataemia ```

Answer 250

Reduced muscle drive and capacity outweighed by increased respiratory load decreasing alveolar hypoventilation breathlessness. Elastic loads: pulmonary infection, alveolar oedema, atelectasis, pleural effusion, obesity, abdominal distension Resistive loads: bronchospasm, Upper airways obstruction, obstructive sleep apnea, secretion retention in endothelial tube Threshold: intrinsic positive end expiratory pressure, dynamic hyperinflation eg COPD or Asthma

Answer 251

Pressure transducer inserted into oesophagus measures oesophageal pressure and gastric pressure and difference between these is calculated to give the diaphragmatic pressures Pdi=Pgas-Poes Volitional testing Or non volunitional by phrenic nerve stimulation Or magnetic stimulation - apply magnetic field to phrenic nerves for short time inducing electric current contracting the diaphragm. Twitch transdiaphragmatic pressure measured

Answer 252

Measure oesophageal pressure, see how much pressure patient can generate before inspiratory flow begins Measured from end of expiration indicated by 0 flow to end of inspiration indicated by 0 flow

Answer 253

Ratio of change in volume to the change in pressure generated

Answer 254

An indicator of either a normal or pathogenic process or response to therapeutic interventions that can be objectively measured and evaluated Essential in diagnosis of disease and assessing response to therapy Increasing quantitative rigor and efficiency of these tests have lead to possibility of personalised medicine Advanced bio markers can be used as a diagnostic marker of disease severity, progression and effects/failure.

Answer 255

Acute care organisations have incorporated early warning scores integrating basic cardiorespiratory and other physiological variables into a composition score as predictors of clinical deterioration Clinical usefulness remains unproven All these monitoring systems require accurate characterisation of disease severity and response to treatment Identify patients that are either deteriorating or only slowly improving to allocate patients to higher levels of clinical care Heterogenous cohort studies of acutely unwell patients show few biomarkers have sufficient sensitivity and specificity

Answer 256

EMG of diaphragm Despite clinical usefulness has limited application in acute setting as it needs the placement of oesophageal electrode in oesophagus

Answer 257

Non invasive alternative to diaphragm electromyography Second intercostal parasternal muscles are obligate muscles of inspiration (stabilise) and are accessible for surface EMG. Neurorespiratory drive index= EMGpara%*respiratory rate Reproducible technique in health and stable COPD subjects. Strong relationship between dyspnoea and NRD

Answer 258

correlate with changes in dyspnoea and overall symptoms Predict changes in multivarate linear regression NRD is feasible measurement in acute cate setting NRD may provide useful data on clinical progress and has potential to be used to risk stratify patients for readmission.

Answer 259

Respiratory muscle EMG Is marker of disease severity, disease progression, treatment effect, and reflects underlying pulmonary mechanics but further studies need to validate

Answer 260

Imbalance between load and capacity and drive

Answer 261

20% patients breathless at rest 24% while talking 70% while walking up first flight of stairs Causes distress, insufficient inspiration, chest tightness and effortful breathing

Answer 262

Contracting muscles can instantaneously increase metabolic needs by 100-fold and more over resting values But ATP conc still remains relatively constant Only aerobic respiration can fuel long term exercise so anything longer than 10-20 seconds will include aerobic respiration. Body has limited ability to tolerate changes in pO2 and CO2 therefore the CV system quickly needs to adapt if muscle contractions can continue and homeostasis is maintained.

Answer 263

Supply metabolic needs of muscle via central (increase flow and CO) and peripheral mechanisms (redistribute blood flow) Dissipate heat Maintain other organ needs

Answer 264

CO = HR * SV 70 kg person roughly 70b/min HR, 70ml SV therefore 5L/min CO. Entire blood volume passes through LV every minute Exercise: HR roughly 200b/min SV 125ml CO=25l/min. Entire blood passes through LV every 12 seconds roughly!

Answer 265

VO2 rises linearly with external work rate. Achieved by increased blood flow and increased oxygen extraction from each ml of blood passing through tissues due to decreasing intramuscular PO2 creating steeper diffusion gradient and decreased Hb affinity for o2 (Bohr shift).

Answer 266

Calculates oxygen uptake VO2= Q(flow)* a-v O2 difference.

Answer 267

Responsible for most of the CO increase Can raise from 60-200bpm. Mediated by vagal parasympathetic withdrawal and beta adrenergic sympathetic stimulation. Essentially linear relationship between relative workload and HR independent of training status. Maximal HR is almost fixed (maybe slightly reduced in endurance training) and age related. 220-age is equation to predict max HR. Munch et al 2014 Was proven not to limit CO in study on HR, SV and CO in healthy humans with and without RA electrical pacing during graded exercise. Increasing the HR didn’t increase Qmax due to the decreased SV thought to be due to decreased filling time.

Answer 268

Isometric - increases muscle tension with constant muscle length. Decreased SV, only modest CO increased only due to HR increased not metabolic needs. Increased vascular resistance. Increased sympathetic drive. Increased TPR, MABP, diastole and systolic pressure. Dynamic - rhythmic cycles of contraction and relaxation where muscles change lengths. High O2 demand, increased contractility, SV, sympathetic activity, HR, atrial filling (venous return). Decreased TPR, increase systolic BP, diastolic may decrease/stay same. Modest MABP increase.

Answer 269

Sympathetic fibres innervate SAN and ventricular myocytes. Post ganglionic symp fibres release NA which binds to beta 1 adrenoreceptors. Parasympathetic fibres in vagus innervate SAN post ganglionic fibres release acetylcholine bind to M2 receptors decreasing HR and contractility. PNS stimulation of HR has faster time response Both systems always active but PNS inhibitory effects predominate at rest In exercise initial increase predominantly via PNS stimulation withdrawal then SNS dominates.

Answer 270

Concept where higher brain areas (cerebral cortex, subcortical nuclei) simultaneously activate two separate networks Neuromotor control systems of active skeletal muscles Autonomic neural control of CV system and possibly respiratory control centres. Theorised that CV can anticipate demands of exercise Idea originated from Johansson 1895 and Krogh and Lindhard 1913,1917 work.

Answer 271

Sv Rises during exercise as result of increases in LV end diastolic volume (EDV) from increased central venous pressure (filling pressure) and increased atrial contractility causing increased preload (end diastolic wall stress) increasing energy of contraction (frank starling mechanism) And a decrease in LV ESV due to sympathetically mediated increase in ventricular contractility.

Answer 272

CO, there is close association between the two max perfusion of skeletal muscle during exercise is 250ml.100g-1.min-1 which would mean CO would need to be 75l/min which is impossible (highest ever recorded ~45) Capacity of skeletal muscle much exceeds that of central circulations supply therefore CO limits VO2 max in dynamic whole body exercise.

Answer 273

Good for close relationship with CO however not always accurate. Individuals with similar VO2 max can have very different performance outcomes but largely different VO2 max could indicate potential performances Other predictors such as work rate at lactate threshold are more accurate (Joyner and coyle 2008) work rate at which lactate increases - largely determined by peripheral factors such as skeletal muscle capillary density and oxidative capacity etc.

Answer 274

Regulation of autonomic output and local muscle vasodilation

Answer 275

Central command- signals from higher brain centres concurrently activate motor regions and medullary CV control centres exercise initiation. Reflex control of CVS - metabolically and mechanically sensitive skeletal muscle afferents stimulate CV centres (EPR). Arterial baroreceptor afferents also feed into these centres and regulate CV response Results in coordinated autonomic adjustments increasing HR, BP and flow(q)

Answer 276

Essentially two groups of studies: Manipulating amount of central motor drive needed to perform same exercise workload can alter CV responses - eg motor paralysis and partial neuromuscular blockage or voluntary exercise vs electrically stimulated contractions And central regions of brain identified that may be part of neurocirculatory of central command.

Answer 277

Krogh and Lindhard 1913 noticed at onset of exercise HR increased immediately suggesting it’s not due to a feedback mechanism, electrical induced stimulation vs voluntary contractions showed delayed HR response with electrical stimulation compared to voluntary supporting it’s not feedback. Iwamoto et al 1987. theory also suggests might be mediated by vagal withdrawal. Study supporting by this by fisher et al 2015. Atropine (muscarinic receptor antagonist blocks vagal activity) prevents initial HR rise in exercise. Control and propanol (beta adrenergic receptor blocker) HR still rises at similar rate. Reduced HR variability.

Answer 278

Stretch reflex - caused by activation of muscle spindles. Group Ia afferent nerves which have mechanogated ion channels sensitive to change in muscle length and velocity. Excitation of alpha motorneurones innervating the receptor bearing muscle via monosynaptic pathway. Inhibition of alpha motorneurones innervating antagonist muscle via inhibitory interneurone. Tendon vibration is a potent activator of muscle spindles. Goodwin et al 1972. Vibrating active muscle tendon reduces central motor drive needed to generate Given force as part of neural input originates from local spinal reflex. Conversely vibrating the antagonist will increase motor drive needed. Lower central command lowered BP response and higher CC raised BP response supporting theory.

Answer 279

Subthalamic nucleus and periaqueductal grey. Eldridge et al 1981 - Cat experiments support - paralyse cat no neural feedback from muscle and results still show increased BP and phrenic nerve action so still CV response even without feedback Human studies - stereotaxic placement of electrodes In an awake Parkinson’s patient undergoing neurosurgery. Subthalamic nucleus in basal ganglia stimulated and resulted in raised HR and MABP maintained for duration of stimulation.

Answer 280

Green et al 2007. Electrodes implanted sterotaxically for later treatment of movement disorder or chronic pain Carry out light exercise 15W Local field potential of STN only increases during exercise not in anticipation Basal ganglia of STN project to number of nuclei which affect CV function in addition to projections to thalamus for movement control so STN thought to be involved in central command

Answer 281

Green et al 2007 Electrodes implanted sterotaxically for later treatment of movement disorder or chronic pain Light exercise 15W Activity of PAG increases during exercise and in anticipation supporting central command evidence. No evidence PAG is involved with locomotion control so not considered a classical central command site. Region thought to be important in preparing body for action ie defence response so may be important in CV response to exercise anticipation. May also be integrator of CV control mechanisms in exercise

Answer 282

Alam and smirk 1937 First evidence of feedback control using post exercise circulatory occlusion showing metabolites trapped in the leg were driving an exercise press or reflex Mitchell JH 2012. Laminectomy performed in cat with central roots l7-s1 sectioned. Peripheral ends stimulated inducing hindlimb contraction. Recorded CV responses and tensions. Pressure response occurred. Cut dorsal root to demonstrate reflex nature of response and no response was seen. McCloskey and Mitchell 1972. Stimulated ventral roots for muscle interaction and increased BP. Post exercise occlusion sustains BP. Cutting dorsal roots of group I-IV abolishes BP response. Selective block of larger myelinated afferents via anodal block failed to abolish BP response (groups I and II). However selective block of small myelinated iii And IV fibres Via local anaesthetic did abolish response. Demonstrated group iii And IV afferents are responsible for exercise pressor reflex.

Answer 283

Thinly myelinated afferent fibres, conduction velocities between 2.5-30m.s-1 Located near myotendinous junction Sensitive to mechanical stimuli, muscle contraction, tendon stretch(both 50%+ for response), other non-noxious mechanical stimuli such as stroking or probing receptive fields of group III fibres or squeezing or external compression of muscle. Mechanics stimuli detected by mechanogated ion channels on free nerve endings on group iii and some Iv afferents which can depolarise membrane.

Answer 284

Non myelinated afferent fibres, conduction velocities <2.5.s-1 Often located near blood vessels Sensitive to chemical or metabolic stimuli. Some respond to mechanical. Response delay to contraction usually 5-30 seconds making them good candidates as metaboreceptors But sometimes one or two impulses excited at exercise onset Metabolic stimuli detected by variety of afferent receptor subtypes each sensitive to different metabolites.

Answer 285

ATP (P2X) hanna and Kaufman 2004 Lactic acid/H+ (ASIC) li et al 2004 Prostaglandin E2 (EP4) rotto and Kaufman 1988 Bradykinin (kinin B2) Kaufman et al 1982 TRPV1 receptors - still role controversial kindig et al 2005.

Answer 286

Several studies show reduced or similar HR and BP responses to exercise with lumbar epidural anaesthesia eg lidocaine (fernades et al 1990 and Friedman et al 1992) Confounding effects of muscle wracking and increased central motor drive These studies not very robust Intrathecal injection L3-4 of u opioid agonist fentanyl can inhibit sensory afferents without altering efferent outflow and central motor drive Reduced HR and MAP and Ve during cycling exercise (amnn et al 2010) More robust study.

Answer 287

Under rest BP heavily regulated by arterial baroreceptor feedback Increased BP increased BR firing signals back to NTS resulting in alteration of ANS outflow to maintain BP homeostasis by decreasing HR, CO AND TPR. However in exercise there is a work rate dependent increase in HR and CO driving up BP. Should trigger rest response reducing HR but this is not the case. During exercise BR is reset and there’s an upward right shift in the BR function curve for both HR and MAP therefore they can increase unimpressed. BP still regulated by BR just at higher set point. Resetting caused by combination of skeletal muscle afferent feedback and central command input.

Answer 288

Shows a classic sigmoidal curve between HR or Map And carotid sinus pressure where BR located. Increases in carotid sinus pressure result in reflex decreases in HR/MAP. The slope of the curve is the sensitivity of the BR. In exercise the set point is raised causing the shift to move up and right.

Answer 289

Vascular tone - artierole radius main controller of resistance and local blood flow. Vessel radius is regulated by tone of vascular smooth muscle. Mechanisms: Endothelial - nitric oxide, prostaglandins, EDHP factors Neural - sympathetic adrenergic fibres cause vasoconstriction via alpha receptors and sympathetic cholinergic fibres vasodilate Circulating factors - hormones (adrenaline, noradrenaline), ATP from RBCs. Mechanical - pressure response of vascular smooth muscle, muscle pump. Metabolic - ATP, adenosine, pH, K, lactate, hypoxia.

Answer 290

Sympathetic nerves innervate due to SNS activity. Mostly release NA and stimulate alpha1 or 2 adrenergic receptors mediating constriction Important role in supporting BP in face of local dilation in exercise Some organs receive cholinergic post ganglionic fibres that release ACh and cause dilation eg to the skin

Answer 291

Circulating catecholamines - adrenaline and NA adrenaline - constrictor binds to alpha receptors in most blood vessels eg skin Dilator binds to beta receptors in skeletal muscle vessels so A and NA have different effects in skeletal muscle Angiotensin - stimulated aldosterone for water retention, activates sympathetic system, constrictions. Atrial natriuretic peptide - distension of aria by blood volume, vessel dilation especially in kidneys increasing fluid filtration.

Answer 292

Skeletal muscle blood flow changes proportionally with tissue metabolism as with most organs Major component of exercise hyperaemia is from vasoactive metabolites produced in skeletal muscle. Local metabolite mechanisms Can act directly or indirectly to decrease vascular tone. Indirectly done by functional sympatholysis - local metabolites can inhibit SNA vasoconstriction through alpha receptors. Adenosine remains the only compound demonstrated as obligatory to exercise hyperaemia in leg because inhibition of purinergic-1 receptors found on vascular smooth muscle lowers exercise blood flow by 15-20%. Doesn’t account for entire response as this is a cocktail effect of multiple factors. Other factors - ATP, K (may account for rapid rise in BF at onset), lactate(poor correlation and temporal relationship), hypoxia(poor temporal relationship), low pH(poor temporal relationship by likely enhances dilator effects of other metabolites) etc. Redundancy of mechanisms (more than one in play therefore removal of one has no effect of response).

Answer 293

Exercise increases MSNA in resting and contracting skeletal muscle Inactive muscle causes constriction but in active there is dilation Due to exercise mediated inhibition of constriction caused by increased sympathetic drive. Local constriction effects of increased SNA induced by lower body negative pressure (Hansen et al 2000) and increased NA from sympathetic nerve endings from tyramine infusion (rosenmeirer et al 2004). Circulating ATP may drive the effect. Effect is abolished by exercise

Answer 294

Lung development not complete when born - primarily have alveolar growth for several years O2 association curve is different to adults with leftward shift higher o2 affinity from foetal Hb Neonatal chest wall more compliant than adults can have paradoxical breathing movements - hard breaths can move the ribs and chest wall in rather than the lungs out making less efficient breathing. Have smaller less differentiated muscles Innervation of one muscle fibre by more than one motor neurone - this is lost with age Immature spinal reflexes and incomplete brainstem synaptic growth

Answer 295

Shows respiratory movements despite not being needed Trachea and lungs filled with viscous lung fluid First observed by Preyer 1888 in foetal lambs. First shown in humans by ultrasonography Boddy et al 1974 Can be detected early as 11 weeks gestation, rapid shallow breathing 1-1.5 per second, continuous and irregular tonic movement in conjunction with similar activity of other somatic muscles 20 weeks to term rate decreases and becomes more regular, random tonic activity of diaphragm decreases and increased centrally mediated phasic phrenic activity By third trimester 28-40weeks spends 30-40% time breathing. Human FBM approximately 50bpm, TI 0.45s, TE 0.75s. Pattern and pressure swings similar to those in postnatal life In later gestation FBM related to behavioural state of foetus, occurs during active sleep (low voltage ECoG activity in REM sleep) Absent REM sleep (high voltage ECoG) shoes descending inhibitory pathways from lateral pons/midbrain to medullary Rhythm generating centre and midcollicular brain stem transection or lateral pontine lesion, causes FBM to become continuous, independent of sleep state. Cardiac rhythm is minimal at 7pm, heightened between 4-7am. Increasing FBM - maternal meals, more glucose, hypercapnia, cocaine, methodone Decrease - prostaglandins, hypoxia, alcohol, smoking, glucocorticoids.

Answer 296

Needed for normal growth and maturation of lung - removal of movements by spinal cord transection led to decreased lung growth (wigglesworth 1979) Does this by two mechanisms - Small changes in lung dimensions stimulate growth, decreased distension decreases pulmonary growth causing hypoplasia. And FBM helps maintain nasal level of lung volume by opposing loss of lung liquid due to elastic recoil and mechanical stretch promotes alveolar type I and II cell numbers and type II differentiation (surfactant) Lungs needed for gas exchange immediately at birth therefore must develop to point of readiness, with adequate respiratory rhythm and Tidal volume able to be produced.

Answer 297

Peripheral chemoreceptors are functional but have greatly reduced sensitivity, resection had no effect on FBM or Onset of breathing at birth (Jansen 1981). Central chemoreceptors stimulated by H/CO2 causing FBM. Foetus resides in hypoxic environment and lung not needed for gaseous exchange. Foetus PaO2 25-28 vs adult 80-100mmHg.

Answer 298

Lungs needed for gas exchange immediately at birth therefore must develop to point of readiness, with adequate respiratory rhythm and Tidal volume able to be produced. However newborn ventilatory control is unstable and immature, maturation takes weeks or months, premature infants are forced into independent air breathing much earlier than anticipated Physiological immaturity is associated with apnoea, respiratory dysthymia and impaired responses to hypoxia and hypercapnea. Long gestation/post natal maturation allows potential alterations by hypoxia, hyperoxia, drugs, stress etc influencing development further. Postnatal immaturity leaves infants vulnerable to stressors - possible cause of sudden infant death syndrome?

Answer 299

Respiratory patterns more influenced by respiratory reflexes than in child or adult Receptors in airways and chest wall or upper airway Reflexes arising from pulmonary stretch receptors - hering-Breuer inflation, dilation reflex, Heads paradoxical reflex, intercostal phrenic inhibitory reflex Upper airway reflexes - laryngeal chemoreflex, irritant reflex. Respiratory reflexes arising from pulmonary vascular receptors (J juxtacapillary receptors/C fibres)- pulmonary embolism, congestion - stimulation results in tachypnoea.

Answer 300

Reflex stimulated by lung inflation resulting in cessation of respiratory activity In neonates helps to regulate rhythmic ventilation Safety mechanism to prevent over inflation - provoked by CPAP mechanical ventilation or airway occlusion. Evoked in tidal volume range in newborns - occlude airway at end inspiration increasing TE through stretch receptor stimulation and occlude airway at end expiration increasing TI no stimulation of stretch receptors. Mediated by slowly adapting stretch receptors in airways - afferent path in vagus nerve. Adult reflex only evoked in tidal volume above 1-1.5L, reflex declines in strength from 6weeks to 2 year. Stronger in infants with low lung compliance. Effect on maturity controversial.

Answer 301

Rapid lung deflation by suction or pneumothorax initiated a strong prolonged inspiration Evoked in infants by vigorous expiratory effort pushing lung volume below end expiratory level Mediated by rapidly adapting stretch receptors in larger airways - vagus nerve Function to maintain FRC and lessen end expiratory actelectasis - FRC actively determined Investigated by reducing lung volume using inflatable jacket around chest and abdomen.

Answer 302

Aka inspiratory augmenting reflex/ provoked augmented inspirations Mediated by rapidly adapting stretch receptors Underlying mechanisms of first breath in infants and augmented breaths/sighing in adults Improves lung compliance and reopens partially collapsed airways Important in promoting lung expansion during resuscitations Frequency increased by low compliance, hypercapnea and hypoxia.

Answer 303

Rapid chest wall distortion results in shortened inspiratory efforts. Usually seen in REM sleep Drive to non diaphragmatic muscles decreased leading to chest wall distortion Inhibited by increases in FRC- CPAP acts to stabilise chest wall

Answer 304

Subepithelial chemoreceptors in trachea, bronchi and bronchioles detect insults to epithelial surface Tactile stimulation, irritant gasses and deflation all change frequency and depth of respiration Maturational effect Suctioning, intubation at <35weeks gestation - inspiratory effort followed by apnoea At term shows marked hyperventilation Fewer small myelinated vagal fibres in very premature infants.

Answer 305

Irritation of nasal mucosa can lead to apnoea and CV responses thought to be part of diving reflex (bradycardia, peripheral vasoconstriction) - vigourous nasopharyngeal suction can elicit reflex. Laryngeal chemoreflex defends lower airway from inhalation - small quantities of water in pharynx cause apnoea, both central and obstructive cause laryngeal constriction, apnoeic response greater prone than supine, can be present up to 3 months of age

Answer 306

Increased PCO2 increases tidal volume, respiratory rate when in REM sleep (low voltage ECoG) but no change when not in REM (Hugh ECoG) Rigatto et al 1989 Hypocapnia abolishes foetal breathing movements Indirectly studied in humans by percentage time of FBM correlation with maternal PCO2 Increased fbm during maternal inhalation of CO2 decreased fbm with hyperventilation. Response is increased with GA. also studies indirectly in sheep by increasing PCO2 in maternal circulation- Moss and Scarpelli 1979.

Answer 307

Hypoxia - cessation of respiratory activity and general movement (opposite response to post natal) boddy et al 1974. Hyperpxia - no fbm change during moderate. Both responses associated with low voltage ECoG Oxygen delivery in uterine matches o2 consumption and allows foetal activity and growth. Increasing ventilation in hypoxia is counterproductive and wasteful of energy. Fbm and other movements account for at least 17% foetal oxygen consumption so only move when normoxic. Rurak JAP 1983.

Answer 308

Cessation of rapid eye movement HR slowing due to increased vagal activity Increased sympatho-adrenal activity resulting in vasoconstriction and increased catecholamines Release of vasopressin and adrenocorticotrophic hormone from pituitary - stress response General decrease of muscle activity and loss of postural muscle tone Cessation minimises oxygen consumption and redistributes CO2 to maintain oxygen delivery to heart and brain

Answer 309

Central chemoreceptors - mediate CO2 response Peripheral - functional but gated out or overridden by central mechanism - response to hypoxia unaffected by bilateral carotid denervation and vagal section. Behavioural (ECoG) and hypoxic response interrelated. Pools of neurones in rostral pons activated during hypoxia - lateral parabrachial nucleus, locus coeruleus and subcoeruleus. Inhibit DRG and VRG rhythmic activity and possibly direct inhibition of spinal motor neurones Lesion of rostral lateral pons- dissociated fbm from ECoG activity reversed depressive response to hypoxia. Hypercapnea causes almost continuous fbm both high and low ECoG. Adenosine increased in brain during hypoxia - adenosine bonding A2a receptors inhibits low ECoG in REM and foetal breathing. Infusion of Ado virtually eliminates REM and breathing. A2a receptor blockade abolishes hypoxia induced arrest of REM and breathing.

Answer 310

Usually apnoeic at birth must establish breathing - mechanisms unclear Neuromodulators involved in inhibition of foetal breathing may be involved in initiation of breathing - prostaglandin, g-aminobutyric acid GABA, endorphins, adenosine. Disappearance of placental inhibitory factor after cord occlusion may be involved Peripheral chemoreceptors unlikely important as denervation doesn’t prevent initiation of activity Continuous breathing established by 100% o2 without sensory stimuli such as cold or touch suggesting increase in PaO2 essential

Answer 311

Respiratory rate increases over first two weeks in quiet sleep from 40-45 bpm and rate subsequently falls Tidal volume approximately 6ml/kg Display periodic breathing 15-20s rapid shallow breathing separated by pause (apnoea), 5% birth, 8% 1 month and 4-5% decrease after Apnoea common after birth periods lasting 20seconds mostly occur in REM sleep along with periodic breathing Maturational effect.

Answer 312

CO2 response proportional to growth, increase per unit body weight. Mediated by peripheral and central chemoreceptors Response of respiratory pattern similar to adult - mild hypercapnea 1-2% CO2 increases tidal volume - modest HC 5% CO2 increases TV and respiratory rate Rate of response matures over first seven days Hypercapnea and hypoxia interact positively to increase magnitude of ventilatory response - response matures initially additive becoming multiplicative after number of weeks Sovik and Lossius 2004

Answer 313

More immature and flatter response than full term infant Reduction in response due to central unresponsiveness Mechanism difficult to study - Lower lung compliance in premature babies possible reduced mechanical efficiency rather than sensitivity. Influence of sleep state, CO2 less important for respiratory drive in active sleep (predominant sleep state in premature babies) High individual variation Maturational effect depends on postconceptional and postnatal age. Animal models show different response PCO2 and po2 interact negatively unlike in term and adults

Answer 314

Same as adults Hyperoxia - initial negative followed by positive Secondary increase due to parallel increase in PCO2 caused by initial decrease Hypoxia - adults show sustained increase while neonates have less initial increase in ventilation followed by decrease below normal. Late decline causes hypoxic ventilatory depression or roll off. Initial increase mediated by peripheral chemoreceptors and afferent NTS pathways. Response eliminated by carotid body denervation. Magnitude of response related to peripheral chemoreceptor maturation Late decrease complex but likely involved inhibitory neuromodulation in brainstem. Biphasic response disappears 10-14 days after birth. Peripheral CR reset to higher PaO2 (25 to 100mmHg). Maturation of Type 1 CB cells and carotid sinus nerve activity (increased nerve terminals and catecholamines release) and of neurotransmitter/modulator pathways from strengthening of excitatory and wearing of inhibitory signalling.

Answer 315

Is it carried over from foetal life where o2 is respiratory suppressant? Pontine inhibition of DAG/VRG or direct inhibition of motor neurones? Mechanism timing is unknown C-Fos staining showed neurones in subcoeruleus region of pons activated by hypoxia in foetus cause fbm cessation but not in newborn lamb. Multiple other mechanisms involved - Accumulation of inhibitory neurotransmitters in brainstem, reduced chemoreceptor responsiveness, decreased inputs from carotid bodies to NTS in brainstem, reduced PaCO2, decreases metabolic rate

Answer 316

Change in neuromodulator activity during hypoxia is primarily in NTS main site of peripheral CR input separate from foetal mechanisms Temporal accumulation of glutamine, nNOS vs GABA, serotonin and adenosine PDGF. Initial release of excitatory glutamine, nNOS in early response, stead release of inhibitory GABA, 5-HT and Adenosine overrides early response, fewer glutamine receptors And nNOS expression but more PDGF release and adenosine and PDGF receptors in neonate leads to unsustained hypoxic ventilatory response. Blocking depressant action of GABA, adenosine, opiates and platelet derived growth factor (PDGF) prevents late hypoxia depression.

Answer 317

Reduced metabolic rate - fall in VO2 occurs within 10 mins in newborn animals - up to 40% of nasal metabolic activity directed to growth and can be temporarily suspended without affecting survival. Metabolic response appears centrally mediated Decreasing chemoreceptor input - controversial and species specific. Piglets decline in CB discharge over similar time course as decline in ventilation. Kittens hypoxia caused sustained increase in CB discharge while ventilation decreased.

Answer 318

Hypoxia - very immature foetal response, apnoea. Moderately premature shows mixed responses, less initial increase in ventilation followed by larger decrease. Pattern influenced by sleep state decreasing ventilation response in non REM sleep. Hyperoxia - 36-40 weeks high o2 depresses ventilation. 36 weeks is slower to respond

Answer 319

``` Release substances to dilate or constrict smooth muscle in vessels Relax: NO Prostaglandins EDHF Contract: Endothelin-1 ``` Released in response to: Metabolic or chemical factors like ATP Mechanical factors like frictional drag force of blood - sheer stress This causes release of endothelium derived relaxing factors - flow mediated dilation Provides feedback to maintain sheer stress. Only downstream resistance vessels within muscle are exposed to vasodilator metabolites while upstream feed and conduit vessels outside muscle are not so these rely on sheer stress. Both systems must dilate for optimum flow.

Answer 320

Muscle interstitial and circulating ATP increase with exercise and infusion causes marked increase in muscle blood flow. Gonzalez-Alonso 2008. Strong evidence is lacking as there is no selective receptor antagonist for humans (p2x and p2y receptors) However atp has potential as master regulator of blood flow to muscle because: Interstitial atp may stimulate p2y located on vascular smooth muscle also cause formation of NO and prostaglandin from skeletal muscle inducing dilation. Degraded into adenosine also potent dilator via p1 receptors RBCs may release atp when unloading oxygen increasing plasma atp stimulating release of EDRF like NO and PG. atp can inhibit constricting effects of SNS in exercising muscle (functional sympatholysis) Can stimulate p2x receptors in group III and IV muscle afferents increasing sympathetic activity

Answer 321

Slingo et al 2014 HIF family transcription factors coordinates diverse cellular and systemic responses to hypoxia. Chuvash polycythemia CP (autosomal recessive disease of impaired oxygen dependent degradation of HIF causing high HIF) patients demonstrate features of hypoxic acclimatisation and elevated ventilation. Investigated mice ventilatory and carotid body phenotype with CP. study demonstrated HIF plays major role in regulating Euoxic ventilatory control and sensitivity to response to hypoxia and determining morphology of carotid body.

Answer 322

Green et al 2007 Local field potentials recorded directly in number of deep brain nuclei during exercise task designed to dissociate exercise from peripheral feedback Provided direct evidence showing PAG as important subcortical area in neural circuitry of CV response to exercise. Stimulation known to alter blood pressure in awake humans.

Answer 323

Amann et al 1985 Investigated role of somatosensory feedback on CV responses to rhythmic exercise in five men. Performed leg cycling exercises Demonstrated essential contribution of muscle afferent feedback to ventilatory, Cv and perceptual responses to rhythmic exercise in humans even in presence of contributions from other major inputs to CV control.

Answer 324

Malhotra et al 2018 11168 patients screened mean age 16.4 95% males. 42 found to have cardiac disorders associated with sudden death. 225 with congenital or valvular abnormalities. After screening there was 23 deaths from any cause, 8 attributed to cardiac events. 6 of the deaths had normal cardiac results. Conclusion- most deaths were not detected by screening

Answer 325

Basavarajaiah et al 2008 Evaluate differences in LV remodelling between highly trained athletes of African descent and Caucasian athletes 300 black male athletes compared 12 lead ECG to 150 black and white sendentary individuals and 300 white athletes matched for size, age, sport. Black athletes exhibited higher LV wall thickness. Concluded black athletes had greater magnitude of LVHypertrophy compared to white athletes. drawing conclusions from White athletes has potential of generating false positive diagnoses of hypertrophic cardiomyopathy in black athletes.

Answer 326

Fisher et al 2006 Sought to examine important of cardiac component of carotid baroreflex CBR in control of blood pressure during isometric exercise. Data suggested alterations in vasomotor tone are primary mechanism by which CBR modulates blood pressure during low intensity isometric exercise

Answer 327

Aasa et al 2015 In human pregnancies placental growth factor PGF concentrations rise in maternal plasma during early gestation, peak over 26-30 weeks then decline. Investigated PGF contributes to pregnancy induced maternal CV adaptations. CV structure and function assessed in virgin, pregnant and and pospartum mice. Results showed PGF is associated with systemic maternal CV adaptations in pregnancy

Answer 328

Peng et al 1985 Carotid bodies are functionally immature at birth and have poor hypoxia sensitivity. Previous studies shown continuous hypoxia at birth impairs hypoxic sensing at carotid body. Intermittent hypoxia more frequently experienced in neonatal life. Experiments on 2 day old rat pups exposed to 16 hours of IH soon after birth. Results demonstrate neonatal IH facilitates carotid body sensory response to hypoxia and augments hypoxic ventilatory chemoreflex.

Answer 329

Kraaijenga et al 2015 To determine effect of caffeine on diaphragmatic activity, tidal volume, end expiratory lung volume in preterm infants. Used transcutaneous electromyography of diaphragm dEMG for 30 mins before and 3 hours after given intravenous caffeine based dose in spontaneously breathing preterm infants. Concluded caffeine increases dEMG. Treatment results in rapid and sustained increase in diaphragmatic activity and tidal volume in preterm infants

Answer 330

Bhat et al 2005 Term newborns can’t compensate fully for imposed dead space by increasing minute ventilation Tested hypothesis that infants of smoking mothers would’ve an impaired response to tube breathing Breath by minute volume measured at baseline and when a dead space of 4.4 ml/kg was incorporated into breathing circuit. Concluded intrauterine exposure to smoking is associated with dampened response to tube breathing.

Answer 331

During healthy pregnancy women experience CV and haemodynamic changes and normal ranges of LV function on 2D speckle training ECG aren’t well defined. Aim of study was to describe Cv Changes that occur during 2nd and 3rd trimester of healthy pregnancy using STE. Conclusion- despite extensive heart remodelling many STE derived parameters of LV function in healthy pregnant women remain unchanged and valid for women in 2nd and 3rd trimester. Future studies investigating early detection of pregnancy related heart disease can refer to these parameters as reference ranges.

Answer 332

Central medullary rhythm pattern generator and integrator Extensive sensory inputs to integrator Precise synchronous distribution of motor output to respiratory musculature - muscles of upper airway - chest wall muscles - muscles of abdominal wall

Answer 333

3 phases 1- rapid and immediate increase in Ve, VO2 and VCO2. Occurs before any change in venous gas content. Hence increased has exchange due to increased CO and pulmonary blood flow 2- exponential rise in Ve, VO2 and VCO2 3-appearing asymptote at new steady state Half times are: 60s Ve, 30-35s VO2 and 40-50s VCO2. Ventilation is slowest to change!

Answer 334

Increased rate and or depth of breathing during exercise In healthy humans ventilatory response to exercise is to produce up to 10 to 20 times increase in ventilation above resting levels. Is achieved with remarkable precision and efficiency with respect to pH, CO2 and O2 regulation of arterial blood and economy of effort or respiratory muscles

Answer 335

Near isocapnic hyperpnea PaO2, PaCO2 and pH broadly unchanged Heavy exercise causes lactoacidosis and PaCO2 decreases 10mmHg but PaO2 drops minimally Steep increase in ventilation rate in heavy exercise

Answer 336

Iii - thin myelinated respond to movement, local touch, pressure and tendon or muscle stretch Iv - unmyelinated respond to mechanical distortion, chemical H, K or lactate and thermal stimuli.

Answer 337

Show compounds trapped in leg muscles were driving a pressor reflex response in humans so they are important for CV control However experiments in Ve control show they’re not. Occlusion of metabolites theorised to slow Ve recovery if they are involved in maintaining Ve in exercise however had opposite effect due to trapped CO2 not stimulating chemoreceptors to raise Ve therefore Ve recovers faster than normal and once cuff released Ve raises due to released CO2. Suggests metaboreceptors aren’t important for Ve in healthy humans.

Answer 338

Although PaCO2 and O2 and pH remain roughly constant in exercise carotid bodies can’t be ruled out. Eg may produce greater drive to breathe at same PaCO2 (increased gain) Theories - respond to increased oscillations in blood gas tensions - response to increased plasma potassium. Number of studies used sustained and brief hypoxia to silence carotid bodies. Sustained hypoxia thought to have secondary effects complicating interpretation eg superoxide induced increases in neural sensitivity may affect results. Results show carotid bodies don’t contribute to exercise onset phase 1 Contribute substantially to phases 2 and 3 hyperpnoea. However hypoxia studies aren’t applicable to normoxia response. Some evidence of role for potassium mediating exercise hyperpnoea via peripheral chemoreceptors

Answer 339

Respond to oscillations in blood gas tension - Currently very little support for this theory Respond to increased plasma potassium -has been shown to stimulate carotid body chemoreceptors and Ve using IV injections of 0.045 mmol KCL in anaesthetised cat. Linton and Band 1985. Possibly increases sensitivity to O2?

Answer 340

Evidence that vestibular system contributes to cardiac autonomic and respiratory control during movement Yates and Bronstein 2005 Learned phenomenon - adaptive feedforward control to provide error free Ve response Dampsey eg al 2014 Good evidence for cardiac mechanoreceptors modulating breathing - Cardiodynamic theory - number of studies have conflicting results. Plausible theory but likely to only make small insignificant contribution.

Answer 341

Heavy exercise VO2 max beyond 60-70% Ve increases disproportionally to VCO2 This increase in usually coincident with exercise induced lactic acidosis leading to conclusion of peripheral chemoreceptor involvement. Because exponential increase in plasma lactate once thought to be caused by tissue hypoxia this is termed anaerobic threshold. Problems with concept - patients with McArdles disease lack glycogen phosphorylase so don’t produce lactate and still have anaerobic threshold. Studies in normal glycogen depleted patients show decoupling of Ve and lactate thresholds (Ve comes earlier and lactate later) making theory controversial

Answer 342

Cessation of tidal breathing Brief apnoea can occur in sleep In infancy >15 sec considered pathological apnoea In neonates is longer than 20 sec or <20 sec if cyanosis or bradycardia

Answer 343

Central- breathing efforts cease (58%) caused by immaturity of respiratory control mechanisms including central and peripheral chemoreceptors Obstructive - airflow ceases but breathing efforts continue (6%) caused by congenital upper airway disorders and functional closure of upper airway Mixed (36%) usually central followed by airway occlusion. All apnoea over 20 seconds are mixed

Answer 344

Devices monitor chest and abdominal wall movement - air filled apnoea mattress - pressure sensitive capsules under infant - capsule attached to abdominal wall - respiratory impendance ECG oximetry

Answer 345

Sleep state - more common in active REM sleep Hypoxia Infection CNS disorders like IVH, meningitis Environmental temp Gastro oesophageal reflux - laryngeal chemoreflex Anaemia PDA - patent ductus arteriosus (duct doesn’t close) immunisation Drugs

Answer 346

Deleterious effects from recurrent hypoxaemia, redistribution of blood flow away from gut and kidneys, fall in anterior cerebral blood flow velocities during apnoea Increasing evidence that preterm infants who have high incidence of apnoea have worse developmental outcomes

Answer 347

Kinaesthetic stimulation - rocking beds, oscillating mattress Tilt Changing position Altering environmental temp Correcting hypoxia Methylxanthines - reduce apnoea, competitive antagonism between adenosine and xanthines, blockade of adenosine receptors of GABAergic neurones (GABA inhibitory effect on breathing), improve CO2 sensitivity, decrease hypoxic depression of breathing and improve diaphragmatic contractility, reduced BPD, cerebral palsy, developmental delay. CPAP continuous positive airway pressure. : a technique for relieving breathing problems (such as those associated with sleep apnea or congestive heart failure) by pumping a steady flow of air through the nose to prevent the narrowing or collapse of air passages or to help the lungs to expand

Answer 348

The sudden death of an infant under one unexplained after thorough case investigation including performance of complete autopsy, examining death scene and review of clinical history New Zealand has highest rate - 0.8 per 1000 live births Uk 0.41 Peaks at 2-4 months of age 90% occur within first 6 months More boys than girls 60:40 2/3 times more likely in African And Native American. AA twice as likely to place baby in prone sleep position and share beds. Smoking more frequent in native Americans and Maori’s.

Answer 349

Maternal smoking Prone to side sleeping Soft bedding and soft surfaces Warmer room temps Bed sharing, particularly in mothers who smoke or if parent is asleep on chair or sofa etc. Triple risk triad - vulnerable baby, age of baby (2-4 months most vulnerable), environmental risk factors all accumulate together to cause SIDS

Answer 350

Infants born at term have 2/4 fold Increased risk and 6 fold risk of other risk factors present of SIDS preterm infants have increased risk of 19.6 Association between smoking can be explained by neurodevelopmental abnormalities of ventilatory control Prenatal nicotine exposure results in cell death in brainstem of animal models Foetal hypoxia occurs as nicotine is powerful vasoconstrictor and raises carboxyhaemoglobin. Nicotine is a neuroteratogen. Infants with ND abnormalities may not respond appropriately to hypercarbia Hypercarbia is most important stimulus during tube breathing Term babies can fully compensate for imposed dead space tube breathing

Answer 351

Large number of experiments carried out in suggest that both mechano-feedback and feedforward mechanisms are involved in mediating phase one in exercise - rapid Ve increase response. Unknown how this works

Answer 352

Large number of experiments carried out in humans using spinal afferent blocking anaesthetics to block. However difficult to interpret due to also blocking efferent signalling beefing higher central motor drive leading to ablation induced hypoventilation to be masked by increased central command. Recent experiments from Dempsey carefully select anaesthetics like fentanyl and controls like muscle EMG Findings suggest afferent feedback is involved in mediating exercise hyperpnoea. Ve decreased when afferents III blocked now thought to be involved by sensing vascular distension and hence hyperaemia. Theory directly links muscle blood flow to CV and respiratory responses. However needs more research in humans. Anaesthetised dogs had IVC and aortic balloons inflated in vessels to occlude blood flow - eliminates central command only tests muscle afferent feedback. Deflating aortic balloon increased distension and Ve then deflating IVC balloon decreased distension and hence Ve. Supports conclusion

Answer 353

Aim to test infants of smoking mothers have impaired response to tube breathing 38 infants 14 smoking mothers Infants studied when awake but quiet breathing Found that the time taken to reach full ventilation is shorter in babies whos mothers don't smoke

Answer 354

Premature infants at risk of SIDS Approximately 10-20% SIDS occurs in premature babies Prone sleeping been shown to be important risk factor Odds ratio for SIDS and prone sleeping in premature infants is 48.8 64% of 167 infants slept non prone at post conceptional age of term 37% slept non prone at a corrected age of two months Mothers of less than 20 years old, lower educational levels and are single are more likely to have prone infants

Answer 355

Bhat et al 2006 Video recordings for 2 days Each sleeping posture maintained for 3 hours then turned over Order of sleeping positions was randomised 18 preterm infants participated Measured ECG, EOG (determine sleep state), limb movements by two activity meters, respiratory movements, nasal airflow, oxygen saturation. Results show prone sleeping more likely deeper REM sleep, less arousal and awakening, higher central apnoea index twice that of supine sleeping.

Answer 356

Lower oesophageal pH measured and video recorded of nasal airflow, chest and abdomen wall movements and oxygen saturation measured 21 infants studied median gestation 36 weeks. Results show that supine position of sleep much more likely to have reflux and obstructive apnoea three times greater than prone sleeping However no significant correlation between apnoeas and gastro-oesophageal reflux seen.

Answer 357

Smith et al Used breathing apparatus to measure CO2 response in ventilation Supine position was much more sensitive to CO2 while prone dampened response significantly

Answer 358

Prone position - increased oxygenation, lung volume, tidal volume, sleep efficiency, quiet sleep, central apnoea Supine position - increased respiratory muscle strength, arousal, obstructive apnoea, higher gastro-oesphophageal reflux but not associated with apnoeas.

Answer 359

Bowel obstruction most common at duodenal-jejunal junction due to malrotation in development Abdominal distension

Answer 360

Genetic deficiency - PHOX 2B mutation Characterised by hypoventilation most prominent in sleep Frequently associated with abnormalities of autonomic nervous system particularly Hirschprungs disease Paired like homeobox 2B gene is transcription factor crucial to development of ANS reflex pathways Absence of phox2B expressing retrotrapezoid nucleus neurones early death in mice due to lack of ventilatory response to hypercapnia Number of alanine repeats is associated with severe genotype

Answer 361

Ultrasound - real time imaging, structure, function, valves seen etc. Called echocardiography

Answer 362

Strength training increases wall hypertrophy Endurance training increases volume load on heart and chamber size increases Most athletes show both hypertrophy types this is called eccentric hypertrophy

Answer 363

Men - <12mm wall thickness, <60mm cavity | Women - <11 thickness and <54 cavity diameter

Answer 364

LV - Show hugely increased cavity diameters compared to non athletes difficult to distinguish if from pathology or physiology. Mostly from physiology. Athletes have higher end of wall thickness values and <2% have abnormally thick walls but this isn’t necessarily from pathology. RV- 7-20% athletes have increased cavity dimensions in right heart can be confused with arrhythmogenic right ventricular cardiomyopathy disease so must be screened. LA diameter can also increase above 45mm in athletes as Can their aortic root dimensions without being pathology. However values above 40 mm in males or 34mm in females is very rare. Athletes also have a very slow heart rate due to the increase Co from cavity size and wall strength around 51bpm.

Answer 365

Vagus nerve more active than in non athletes SAN reduces sympathetic drive and slows heart rate - bradycardia around 50bpm. Increased wall thickness needs larger voltages for contraction and P-R interval on ECG increases from slowed conduction HR.

Answer 366

Vagus - releases neurotransmitter at SAN And AVN to decrease heart rate Accelerator - release NT at SAN and AVN to increase HR also innervates myocardium to increase force of contraction

Answer 367

Hypertrophy cardiomyopathy vs athletes ECG can show similarities such as T wave inversions - if athlete stops exercise their T waves will return to normal if this is just physiological but if HCM the T waves remain inverted. Also share increased wall thickness however if physiological is likely to be across the whole wall while pathological can just be in segments of the wall. A wall thickness of >50mm in athletes is suspicious. Very rare in Caucasian athletes but very common in patients with inherited heart conditions implicated in exercise related sudden death such as HCM or arrhythmogenic right ventricular cardiomyopathy. HCM causes myocytes disarray and fibrosis between cels and disrupts their electrical activity causing arrhythmias and sudden death so important to distinguish this in athletes.

Answer 368

2% of the UK are black but make up 20% elite athletes In USA 13% population compared to 70% elite sports. This is because they develop more significant structural and electrical changes in their heart compared to Caucasians They have slightly larger aortic root dimensions and LA diameter. LV hypertrophy is hugely increased compared to white athletes with 12.4% exceeding the 12mm wall thickness while only 1.6% white athletes exceed this in men and 0% white in women, 3% in black women. T wave inversions are more common in black athletes too almost 1/4 show t inversion while only less than 1% white athletes do. Therefore the guidelines in athletes health must adapt for each ethnicity to distinguish correctly between pathology and physiology.

Answer 369

Usually fatal but can recover if CPR and defibrillation occurs fast enough. Athletes have an increased risk compared to general population this is unknown why as of yet. 90% occurs during physical activity, 80-90% cases were asymptomatic beforehand, 40-65% were under 18, male to female ratio 2-9:1. More common in short sharp bursts of exercise and higher risk in black athletes. In most studies coronary atheroma is the largest cause. 56% cases were from congenital conditions or gene mutations etc. 2-7 athletes in 1000 are at risk via inheritance. 50% caused by cardiomypathies eg wall thickness problems. Needs extensive screening and guidelines to avoid false negatives or false positives and reduce risk of sudden deaths in sport. ECG is an effective screening method and an 89% reduction was seen due to screening with no change in background reduction in a study by Corrado et al 2006. Must be managed with CPR, defibrillation and emergency treatment to increase survival chances.

Answer 370

Commotio cordis Myocarditis Electrolyte disorders