Presentation on theme: "The heart as a pump: outline Structure of cardiac muscle Excitation contraction coupling Autonomic effects on the heart Cardiac Function Curve Cardiac."— Presentation transcript:
The heart as a pump: outline Structure of cardiac muscle Excitation contraction coupling Autonomic effects on the heart Cardiac Function Curve Cardiac cycle Ventricular pressure volume loops Control of heart rate and stroke volume
Characteristics of cardiac muscle Branching fibers with gap junctions at intercalated discs. Electrical syncytium Aerobic metabolism Graded contraction Stretch leads to increased force of contraction Automaticity & Rhythmicity Branching muscle fiber Intercalated disc Arrows show RBCs Purkinje Fibers
Ca ++ binding to troponin C allows actin and myosin to form a cross bridge During a myocardial infarction, cardiac troponins are released into the circulation. Cardiac and skeletal muscle TnC are identical, but cardiac & skeletal muscle TnI & TnT have different amino acid sequences so they can be differentiated. Detection of cardiac TNi and TnT in the circulation suggests myocardial damage. Tropomyosin blocks myosin binding sites on actin. Ca ++ binds to troponin C and then Troponin I moves tropomyosin, exposing the myosin binding site on actin. Troponin T holds troponin complex to tropomyosin. Tn-I Tn-T Tn-C actin tropomyosin Ca ++
Pathway for Ca ++ entry in myocytes Sarcolemma (cell membrane) Sarcomere Transverse tubule Sarcoplasmic reticulum stores Ca ++ During excitation extracellular Ca ++ enters myocytes via transverse tubules Cytosol
Excitation contraction coupling T-tubule Extracellular Ca ++ Ca ++ Na + Ca ++ Ca ++ stores Ca ++ Ryanodine receptor (SR Ca ++ release channel) Contractile mechanism AP 200 msec Ca ++ influx contraction Sarcoplasmic recticulum SR Ca ++ ATPase Ca ++ SERCA = sarcoplasmic reticulum Ca ++ ATPase Ca ++ -Induced Ca ++ Release L-type Ca ++ channel (dihydropyridine receptor)
Sympathetic stimulation of the myocardium increases rate and force of contraction and rate of relaxation Force Time Sympathetic stimulation At rest Sympathetic stimulation increases Force of contraction (positive inotropic effect) Rate of relaxation (positive lusitropic effect) Heart rate (positive chronotropic effect) Conduction velocity (positive dromotropic effect)
Cellular mechanism of sympathetic effects on myocardium 1 adrenergic receptor Ca ++ Ca ++ stores Ca ++ Ryanodine receptor Contractile mechanism Ca ++ L-type Ca ++ channel SR Ca ++ ATPase NE Gs cAMP Protein kinases Adenylate cyclase Phosphorylation Norepinephrine inotropic effects act by [Ca ++ ] inside: 1) opening of L type Ca ++ channels 2) Ca ++ release from sarcoplasmic reticulum Norepinephrine: activity of SERCA which removes Ca ++ from tropinin C ( + lusitropic) & stores more Ca ++ in SR for next contraction ( + inotropic) + + +
Within the normal range as ventricular muscle is stretched the force of contraction increases. Preload: the degree to which the myocardium is stretched just before contraction. Preload for the right ventricle is estimated as central venous pressure (CVP) or right atrial pressure. Preload for the left ventricle is estimated as left atrial pressure by measuring PCWP (Pulmonary capillary wedge pressure) Afterload: the pressure against which blood is ejected from the heart. Afterload for the right ventricle is pulmonary artery pressure during ejection. Afterload for the left ventricle is aortic pressure during ejection. The Frank-Starling Mechanism: stretch (preload) affinity of troponin C for Ca ++ force of contraction. An equivalent statement is: EDVV stroke volume Initial myocardial fiber length or EDVV or atrial pressure Force of contraction or Stroke Volume Cardiac function curve The cardiac function curve is an expression of the Frank Starling mechanism CVP is blood pressure at the entrance to the right ventricle
Pulmonary Capillary Wedge Pressure (PCWP) estimates: left atrial pressure = preload for left ventricle left ventricular pressure during diastole To measure PCWP a catheter is passed from the femoral vein into the right heart and advanced as far as possible into a branch of the pulmonary arteries. Blood flow around the catheter is blocked by inflating a balloon. In the absence of flow, pressure is the same everywhere in the column of fluid between the tip of the catheter & the left atrium. Further, when the mitral valve is open during diastole pressure at the catheter estimates left ventricular pressure (also an estimate of preload for the left ventricle). PCWP is measured in the ICU to monitor cardiac function. Pulmonary artery Pressure is measured at the tip of the catheter Left atrium & ventricle Pulmonary vein
Venous return & cardiac output are equal except for momentary adjustments. What comes in goes out. Equality of venous return and cardiac output is the result of Frank Starling mechanism (intrinsic to the heart) Autonomic reflexes (extrinsic to the heart; to be discussed in a subsequent lecture) Venous return is the blood flow at the entrance to the right atrium End-diastolic ventricular volume Stroke Volume Cardiac function curve Systemic vasculature Venous return Cardiac output Heart
The Frank-Starling mechanism maintains equal cardiac output from the left and right heart For example, when a person lies down blood pooled in the veins in the legs and abdomen shifts to the thorax, increasing CVP and right atrial preload. As blood shifts to the thorax,CVP increases & SV from rt ventricle > SV from lft ventricle. Within a few heart beats, SV from the lft ventricle increases to equal SV from the rt ventricle Blood shifts to thorax ↑ central venous pressure (CVP) ↑ stroke volume from right ventricle ↑ pulmonary arterial blood flow ↑ left atrial pressure ↑ stroke volume from left ventricle Recumbency Preload for right side Preload for left side CVP is blood pressure at the entrance to the right ventricle Any maneuver that causes a change in stroke volume in one ventricle will rapidly result in a parallel change in stroke volume in the other ventricle.
Ejection fraction and contractility Contractility: a change in stroke volume at any given preload & afterload Sympathetic stimulation: Positive inotropic effect Normal Heart failure: Negative inotropic effect End-diastolic ventricular volume Stroke Volume Ejection fraction: EF = SV/EDVV (stroke volume/end diastolic ventricular volume) Normal EF = 0.60 or 60% Vagal stimulation has a small negative inotropic effect. Changes in contractility Cardiac function curve
dP/dt, ejection fraction & contractility Two indices of contractility: Change in dP/dt; dP/dt = the rate of change of ventricular pressure during ejection at a given end diastolic volume (preload) Change in EF; EF = SV/EDVV increased dP/dt = contractility normal dP/dt decreased dP/dt = contractility LV pressure, mm Hg seconds
Pressure-volume work & myocardial QO 2 RELATIONSHIP BETWEEN CARDIAC OUTPUT AND OXYGEN UPTAKE R 2 = 0.88 for linear regression OXYGEN UPTAKE (QO 2 ) 2 CARDIAC OUTPUT, L/min Three components of cardiac work Volume work related to stroke volume Pressure work related to arterial pressure during systole Kinetic work related to velocity of blood during ejection At rest: Cardiac work ~ stroke volume x arterial pressure Kinetic component negligible (kinetic component increases in strenuous exercise) O 2 requirement is greater for pressure work than volume work Aortic stenosis resistance Ventricular pressure Pressure work Cardiac QO 2 Coronary flow angina
Ventricular pressure - volume loop A pressure-volume loop shows changes in ventricular volume and pressure during one cardiac cycle Filling represents passive characteristics of the ventricle. Isometric contraction and ejection represent active force of myocardial contraction Pressure, mm Hg Volume, ml Isometric contraction Isometric relaxation ESVEDV filling ejection Stroke volume
Compliance Compliance is the change in unit volume of a structure per unit change in pressure. More compliant structures get bigger for a given increase in pressure, compared to less compliant ones. Veins are 19 times more compliant than arteries. The filling of the ventricles is determined partly by their compliance. In people with chronic heart failure, ventricular compliance decreases, limiting filling and stroke volume.
Effect of an increase in preload on PV loop (change in diastolic function) Stroke volume = end diastolic volume minus end systolic volume Filling of the ventricle is determined by two factors: Preload Ventricular compliance Pressure, mm Hg Volume, ml filling End systolic volume End diastolic ventricular volume If afterload & contractility are constant, an increase in preload increases end diastolic ventricular volume & stroke volume (Frank-Starling mechanism) Preload is increased by Atrial contraction Blood volume Venous tone Skeletal muscle pump Respiratory pump
At constant preload & contractility, an increase in afterload decreases stroke volume (change in systolic function) An increase in afterload requires more energy to eject blood against the increased arterial pressure so less energy is available for fiber shortening. As a result stroke volume is decreased (end systolic volume is increased). Pressure, mm Hg Volume, ml Ventricular filling End systolic volume End diastolic ventricular volume afterload
An increase in afterload decreases stroke volume so end systolic volume is greater AP ESV SV An increase in end systolic volume means stroke volume is decreased. Volume, ml Ventricular filling End diastolic ventricular volume Pressure, mm Hg End Systolic Volume, ml End systolic volume SV
Normally when afterload increases SV is maintained by an increase in contractility HR* MAP* SV CI* TPR/ ExerciseRest Asterisk indicates statistically significant change During exercise MAP (afterload) increases with no change in stroke volume. Cardiac contractility must have increased to maintain stroke volume with increased afterload. Cardiac work is increased also. Cardiac index increased from 3.5 to 4.4 L/min x m 2 3 min isometric handgrip exercise
The failing heart may not be able to increase contractility when afterload increases UpToDate; Pathophysiology of heart failure: Left ventricular pressure-volume relationships. W. S Colucci. Therapy for heart failure includes agents that lower afterload SVR = systemic vascular resistance (TPR)
Beta 1 adrenergic stimulation increases stroke volume Pressure, mm Hg Volume, ml Ventricular filling End systolic volume End diastolic ventricular volume normal stimulated Norepinephrine: contractility end systolic volume stroke volume end systolic pressure Norepinephrine (in blood & from sympathetic nerves) acts on ventricular 1 adrenergic receptors to increase contractility (positive inotropic effect)
Systolic dysfunction: a decrease in contractility Pressure, mm Hg Volume, ml normal decrease in stroke volume Filled shape shows smaller pressure volume loop with systolic dysfunction contractility End systolic ventricular volume stroke volume ejection With systolic dysfunction both stroke volume and peak arterial pressure are decreased
Compensation for systolic dysfunction stroke volume (left ventricle) left atrial, pulmonary & right atrial pressure preload end diastolic ventricular volume stroke volume Partial compensation occurs for the initial decrease in stroke volume. The initial decrease in stroke volume results in blood “backing up” on the venous side of the circulation which results in increased venous pressure, preload & stroke volume. Compensation occurs commonly in heart failure, for example. Pressure, mm Hg Volume, ml normal Initial decrease in stroke volume Partial compensation: end diastolic volume & stroke volume are increased.
Diastolic function, compliance & relaxation SERCA = sarcoplasmic reticulum Ca ++ ATPase Compliance is defined as how much the volume of a vessel changes per unit change in pressure: Changes in the compliance of the heart or blood vessels affect their function. A decrease in compliance of the ventricles occurs in heart failure due to changes in both active and passive relaxation Active relaxation refers to the activity of the SERCA transporter that sequesters Ca ++ in the sarcoplasmic reticulum during relaxation. This ATP dependent process is inhibited in ischemia, impairing relaxation of the contractile proteins. Passive relaxation refers to the compliance of the myocardial tissue. Fibrosis or other cardiomyopathies may produce a chronic decrease in compliance Compliance is different from conductance, also abbreviated C. Conductance is the inverse of resistance:
Diastolic dysfunction Diastolic dysfunction is due to decreased compliance of the ventricle resulting from impaired active and/or passive relaxation ventricular compliance ventricular pressure filling end diastolic ventricular volume stroke volume cardiac output Pressure, mm Hg Volume, ml compliance normal End diastolic ventricular volume Ventricular pressure Filling of the ventricle is determined by preload and ventricular compliance
Stroke volume is a function of preload, contractility and afterload Stroke volume = end diastolic volume minus end systolic volume Stroke volume afterload End systolic volume Contractility End diastolic ventricular volume Preload Stroke volume afterload End systolic volume Contractility End diastolic ventricular volume Preload Preload drives filling Contractility affects force of contraction Afterload resists ejection
Mean arterial pressure is determined by cardiac output and total peripheral resistance Since CVP ~ zero, using MAP for the average driving pressure in the circulation, and TPR for total peripheral (systemic) resistance:
Cardiac output, heart rate and stroke volume CO = HR x SV CO (cardiac output, ml/min) = heart rate (beats/min) times stroke volume (ml/beat) HR is regulated primarily by the autonomic nervous system SV is regulated by the Frank Starling mechanism (intrinsic) and by the autonomic nervous system (extrinsic)
Sympathetic stimulation increases heart rate Sympathetic activity Slope of pacemaker potential Heart rate Threshold for AP more negative Resting heart rate Slope Sympathetic stimulation Slope Increasing the slope of the pacemaker potential means the action potential for the next beat occurs sooner. A more negative threshold means less depolarization is needed to elicit an action potential
Parasympathetic effects on heart rate parasympathetic activity Slope of pacemaker potential Heart rate Hyperpolarize resting membrane (more negative) Normally parasympathetic tone keeps the resting HR lower than the intrinsic HR The intrinsic HR is the rate in the absence of nerves or hormones Resting HR = 60 to 70 B/min Intrinsic HR = 100 B/min Resting HR Slope Threshold for AP = – 55 mV at rest Parasympathetic stimulation Slope
Summary of factors regulating heart rate Sympathetic activity Parasympathetic activity Circulating epinephrine Heart rate The HR is set by the balance between sympathetic and parasympathetic tone acting on the SA node. HR is due to parasympathetic and sympathetic stimulation HR is due to parasympathetic and sympathetic stimulation Blood borne epinephrine has a minor effect on HR similar to sympathetic tone
Summary of factors regulating stroke volume Stroke volume is a determined by preload, contractility and afterload. Contractility and rate of relaxation of the ventricles are both increased by 1 adrenergic stimulation. Indices of contractility: Change in dP/dt Change in EF: Sympathetic activity Preload epinephrine Contractility Stroke volume Force of contraction Extrinsic Intrinsic afterload
Effect of sympathetic stimulation on force & duration of contraction Force Time Sympathetic stimulation Rest Sympathetic activity & Parasympathetic activity Heart rate As HR increases from 75 to 200 B/min, duration of systole decreases 41%, duration of diastole decreases 74% At HR > 180 B/min, ventricular filling is compromised. Tachycardia > 180 B/min may limit cardiac output.
Autonomic effects on ventricular myocardium Sympathetic stimulation: Force of contraction (positive inotropic effect) Rate of relaxation (positive lusitropic effect) Conduction velocity (positive dromotropic effect) Parasympathetic stimulation: conduction velocity in the AV node (negative dromotropic effect) Ventricular contractility (negative inotropic effect, weak effect compared to sympathetic stimulation of contractility). Terms relating to cardiac function: Chronotropic: affecting heart rate Dromotropic: affecting conduction velocity Inotropic: affecting contractility Lusitropic: affecting rate of relaxation
Natriuretic peptides The heart synthesizes and secretes peptide hormones in response to increased stretch of the cardiac chambers. These hormones act to increase urinary Na + excretion. Cardiac natriuretic hormones: Atrial Natriuretic peptide (ANP): 28 amino acid peptide secreted from the atria in healthy people in response to increased NaCl intake or blood volume. B – type Natriuretic Peptide (BNP): secreted from ventricles in heart failure. Increasing plasma BNP concentration correlates with worsening cardiac function. BNP can be measured rapidly at the bedside: to assist in differential diagnosis of dyspnea & as an indication of the degree of heart failure. C-type Natriuretic Peptide: secreted by vascular endothelial cells. ANP was originally called ANF (atrial natriuretic factor) BNP is also called brain natriuretic peptide because it was first found in the CNS.
After cardiac transplantation the heart adapts to exercise by increasing SV exercise QO 2 Cardiac output Heart Rate Stroke Volume NormalCardiac Transplant Normally the increase in CO with exercise is mostly due to increased HR. After transplantation (which denervates the heart) increased SV due to the Frank Starling mechanism maintains CO with exercise.
Effect of age on cardiac function Problem of separating effects of aging from disease & cumulative injury Aortic compliance resistance to ejection systolic pressure Number of myocytes compensatory hypertrophy Ventricular active & passive relaxation Maximal heart rate These changes contribute to decreased maximal oxygen consumption and exercise capacity with age. The effects of aging can be ameliorated by exercise.