Control Of Cardiac Output PDF

Life Sciences & Medicine Control of cardiac Prof James Clark output School of Cardiovascular and Metabolic Medicine and Sciences PHYSIOLOGY AND ANATOMY OF SYSTEMS Learning Outcomes...

Life Sciences & Medicine Control of cardiac Prof James Clark output School of Cardiovascular and Metabolic Medicine and Sciences PHYSIOLOGY AND ANATOMY OF SYSTEMS Learning Outcomes Explain the meaning of the terms preload and afterload, and their influence on cardiac function Explain the relationship between EDV/EDP and ventricular function and draw a cardiac function curve. Explain the cellular mechanisms by which changes in EDV/EDP affect ventricular output Explain the implications of the Frank-Starling law for cardiac function. Explain the meaning of the term contractility and describe how it is influenced by the autonomic nervous system Describe how the Frank-Starling and Anrep responses allow the heart to maintain a constant CO when over a wide range of afterloads Describe the factors which control preload, and give examples of circumstances in which changes in preload increase or decrease cardiac output. Important concepts to remember Cardiac output (CO) must be adjusted to meet the metabolic needs of the body’s tissues. The systemic and pulmonary circulations are in series, and the cardiovascular system is closed. The outputs of the left and right ventricles must be the same over time... (COLV = CORV) The venous return must be the same as cardiac output, although transient differences can occur in both cases (e.g., when you stand up) What mechanisms exist to ensure that COLV = CORV? hat determines cardiac output? ? ? What can affect HR andFilling SV? pressure Resistance to outflow of right ventricle from left ventricle Preload Afterload Pump function Heart rate Contractility Only 4 things can directly affect cardiac output  The degree of stretch of a ventricle immediately before it contracts Preloa A function of the end-diastolic volume d (EDV) Related to the filling pressure of the ventricle Preload for the right side of the heart = 3-8mmHg Right ventricular end diastolic pressure (RVEDP)= Right atrial pressure (RAP) = Central venous pressure (CVP) Preload for the left ventricle is LVEDP = Left atrial pressure = pulmonary venous pressure Afterload The force against which a ventricle pumps to eject blood LV afterload mainly due to aortic blood pressure 95 mmHg Is also influenced by total peripheral resistance (TPR) and aortic stiffness Afterload for the RV is mainly due to main pulmonary artery pressure The effect of altered School of Medicine preload on the heart Otto Frank Otto Frank showed that isovolumetric pressure development in frog heart (with a ligated aorta) depended on diastolic distension ‘Active’ = peak systolic – diastolic pressure The effect School of altered preload on the heart of Medicine Ernest Starling Ernest Starling showed that the same relationship was present in an intact circulation Frank-Starling Law of the Heart “The total energy liberated at each heartbeat is determined by the diastolic volume of the heart and therefore by the muscle fiber length at the beginning of contraction” Note: this energy is equivalent to the pressure generated by a ventricle to eject blood, which is proportional to its output (stroke volume). Frank-Starling Relationship Physiological range Ventricular work or stroke volume Extent of ventricular stretch Preload End diastolic volume (EDV) Frank-Starling Relationship Cardiac work or Force of contraction or Energy of contraction or Tension or Stroke volume or Cardiac output Physiological range End diastolic pressure (EDP) or End diastolic volume (EDV) or Right or left atrial pressure or Central venous pressure or Myocyte/sarcomere length or Venous return or Preload What mechanisms actin myosin explain how force increases with stretch? Z-lines 1. Ca2+ binds to TnC 2. TnI moves away from actin and tropomysin, freeing tropomysin to move 3. TnT moves tropomysin away from actin exposing the myosin binding site Length dependent activation: actin - myosin overlap myosin actin z Sarcomere length Skeletal muscle a b c d e a 1.25µm 100 % max tension b 1.65µm cardiac muscle c 2.00µm d 2.25µm e 3.65µm 3µm 4µm 1µm 2µm Sarcomere length Length dependent activation of cardiac muscle Sarcomere length Ca2+ sensitivity cellular [Ca2+] 2.2 microns 2.0 microns Force development 1.8 microns 0.1 mM 1.0 mM 10.0 mM [Ca2+]i Redrawn from Land et al (2017) DOI: https://doi.org/10.1016/j.yjmcc.2017.03.008 Titin and length dependent activation 1.Increasing sarcomere length draws actin and myosin closer to each other 2. Titin acts on myosin binding protein C, causing changes in the myosin head group orientation and the structure of the thin filament, increasing the sensitivity of troponin for Ca2+. Redrawn from Link,W.A. doi: 10.1146/annurev-physiol-021317-121234 Consequences of the Frank-Starling Law  The stroke volumes of the left and right ventricles are perfectly matched (except very transiently).  At any given rate and functional state of the heart (contractility), CVP will determine CO.  It helps maintain CO even in the face of an increased afterload or decreased contractility. Matching the outputs from right and left ventricles Increased volume e.g., Increase of blood in in RV output pulmonary veins Increased filling of the LA LV output matches RV output Increased filling LV and of LVEDP Increased stroke volume and LV output Cardiac contractility = inotropy Defined as the strength of contraction. This is reflected by the amount and rate of cardiac tension development, and the ability of the heart to eject a stroke volume at a given preload and afterload. Sympathetic stimulation Regulated by intracellular [Ca2+] in the cardiac myocytes (sympathetic nervous Increased SV/Tension contractility system). Basal conditions Also affected by the pH and pO2. Noradrenaline (norepinephrine) increases contractility by stimulating b1 (and to a lesser extent b2) adrenergic receptors EDP The Frank-Starling mechanism can compensate for decreased cardiac contractility Heart failure: “When CO falls to the point where it its insufficient to provide Normal enough blood for the body’s metabolic needs, or when CO can only be maintained at sufficient levels by an SV HF elevated end-diastolic pressure/volume.” Can occur acutely (during MI) or long term (chronic heart failure) EDP Characterised by a lower amplitude curve  Compensatory mechanisms activated by heart failure Fall in CO reduces renal excretion of fluid, thus increasing the blood volume, particularly in the veins. Reduced BP activates the sympathetic nervous system, to increases contractility and rate and venocontriction. The renin-angiotensin-aldosterone system (next lecture) is also activated, further promoting fluid retention and venoconstriction. Increased venous blood volume and venoconstriction increase CVP = RVEDP Due to fluid retention, Normal venoconstriction Compensated HF HF SV Due to ↓ cardiac reserve De-compensated HF Due to ↑ cardiac contractility EDP  The effect of afterload on cardiac output….it’s complicated The direct effect of ↑afterload is to reduce stroke volume (ejection time) Cardiac contractility may also fall if the BP has increased, due to the baroreceptor reflex (next lecture) However, secondary effects occur which tend to overcome these effects in the normal range of aortic pressures: As the ejection fraction falls, more blood remains in the heart at the end of systole (Frank-Starling mechanism) SV Anrep response - Stretch due to the ↑ LVEDV – release of Ang 2 and endothelin which (over 10-15 min) increase the Ca2+ transient. This increases contractility and the stroke volume. LVEDP Afterload has little effect on the cardiac output in the normal range of blood pressures 5 4 Normal Cardiac Output (litres/min) Range However, aortic valve stenosis 3 increases afterload enough to reduce stroke volume and 2 cardiac output 1 0 0 100 200 300 400 Mean arterial pressure (mmHg) Modified from Guyton - Textbook of Medical Physiology Preload: review of venous blood flowsystem collects blood from the microcirculation and brings it The venous back to the heart. This can be accomplished with a small pressure gradient (5-10 mmHg) between the microcirculation to the right heart. Because: Very low resistance of the veins (≤ 10% of arterial resistance) The skeletal muscle pump - One-way venous valves mean that muscle contraction ‘milks’ the veins The respiratory pump - inspiration reduces intra-thoracic pressure. This decreases pressure within the vena cavae, increasing the pressure gradient between the venules and the right heart.  Preload 2: regulation CVP is a function of the amount of blood in the veins and also the vein capacitance When the veins are constricted (e.g., SNS) this decreases venous capacitance and increases CVP. e.g., Venoconstriction in exercise, thus increasing CVP. This allows the output of the RV and LV to match to bring more blood to working muscle. Increases or decreases in blood volume cause corresponding changes in CVP e.g., In haemorrhage, blood loss decreases CVP (since ~65% of the blood is in the systemic veins at any given moment) and therefore decreases CO (future lecture) e.g., If exercise is sustained, progressive loss of fluid (sweating) reduces CVP, reducing CO and therefore exercise capacity. e.g., Orthostasis causes increased pooling of blood in the lower extremities, decreasing CVP and CO and BP will fall. Not all venous beds are equal…. CVP left heart pulmonary vascular Splanchnic veins right bed 20% of blood heart low flow Other veins Constriction of splanchnic veins by 45% of blood the SNS increases CVP and mobilizes higher flow 500-700 ml of blood into the heart and arterial system without affecting venous return because flow through this part of the circulation is slow. Learning Outcomes Explain the meaning of the terms preload and afterload, and their influence on cardiac function Explain the relationship between EDV/EDP and ventricular function and draw a cardiac function curve. Explain the cellular mechanisms by which changes in EDV/EDP affect ventricular output Explain the implications of the Frank-Starling law for cardiac function. Explain the meaning of the term contractility and describe how it is influenced by the autonomic nervous system Describe how the Frank-Starling and Anrep responses allow the heart to maintain a constant CO over a wide range of afterloads Describe the factors which control preload, and give examples of circumstances in which changes in preload increase or decrease cardiac output. Recommended reading Silverthorne’s Human Physiology: An Integrated Approach, Global Edition and for those who want to know a lot more: https://derangedphysiology.com/main/cicm-primary-exam/required-reading/cardiovascular-system/Chapter%