The Failing Heart and EC-coupling Flashcards
What is excitation-contraction coupling?
The process whereby action potential triggers myocyte to contract
Describe the B-adrenergic receptor signalling pathway
Noradrenaline/ adrenaline B1-adrenergic receptor Activates GTP-binding protein (Gs) Stimulates adenylyl cyclase (AC) cAMP PKA Phosphorylates several proteins related to EC-coupling (e.g. PLV, L-type Ca2+ channels, RyRs, Tropinin I and myosin binding protein C)
What is heart failure
Inability of the heart to supple adequate blood flow (and oxygen deliver) to tissues and organs).
Decreased perfusion of organs leads to
Reduced exercise capacity
Shortness of breath
Fatigue
Organ dysfunction (e.g. renal failure)
Symptoms of heart failure
Enlarges heart Weakened heart muscle Blood is pumped at reduced volume Less blood fills the chambers Weakness and fatigue Shortness of breath Swollen feet, ankles, abdomen, or veins in the neck.
What is myocardial infarction?
Heart attack
Progression to Heart failure begins with stage A causing diastolic dysfunction. What can cause this?
Hypertension, coronary artery disease, valvular disease, obesity, diabetes and kidney disease
What stages occur after stage A of heart dysfunction?
Diastolic dysfunction, Increase in atheroscelerosis, Cardiac ischemia, arrhythmias and ventricular dysfunction, ventricular enlargement, heart failure, pump failure, death.
Pathophysiology of cardiac heart failure
Decreased SV and CO
Increased ED pressure
Ventricular dilation or hypertrophy
Impaired filling (diastolic dysfunction)
Reduced ejection fraction (systolic dysfunction)
Pathophysiology of vascular heart failure
Increased systemic vascular resistance Decreased arterial pressure Impaired arterial pressure Impaired organ dysfunction Decreased venous compliance Increased venous pressure Increased blood volume
What compensatory mechanisms of heart failure (Cardiac)
Cardiac:
Frank-starling mechanisms- reduce output. Cardiac force therefore increase due to starling law; but at the expense of increase filling pressure (EDP).
Ventricular dilation
Tachycardia
What compensatory mechanisms of heart failure (Autonomic Nerves)
Autonomic Nerves:
Reduced BP initiates baroreceptor reflex - increases sympathetic adrenergic activity.
Reduced vagal activity to heart.
What compensatory mechanisms of heart failure (Hormones)
Hormones: Vasoconstriction of renal arteries increases hormone release.
Hormones Renin-angiotensin-aldosterone system
Vasopressin (antidiuretic hormone)
Circulating catecholamines
Natriuretic peptides
What are the cellular and molecular alterations in heart failure?
Changes occur in myocytes:
- alters contractile proteins
- alters calcium homeostasis
- alters signal transduction pathways (e.g. B adrenergic receptor signalling pathway
How are the contractile proteins altered in the failing heart?
Expression of myosin heavy chain isoforms are unchanged
ATPase activity are unchanged
Cross-bridge cycle rate is slower = causes a decrease in the maximal force developed
Phosphorylation state of troponin I is reduced due to decrease ac-cAMP-PKA pathway and affects the calcium sensitivity of the myofilament.
How is calcium homeostasis altered in the failing heart?
Decline in intracellular calcium homeostasis.
Prolonged duration of action potential.
Systolic Ca2+ concentration (less clear whether it changes), increases threshold for Ca2+ release from SR, increases diastolic Ca2+ concentration. Decrease in Ca2+ reuptake of SR (due to dysfunction in the sarcoplasmic Calcium pump) and an increase in Na/Ca exchanger protein content.
What happens to the signal transduction in the failing heart?
Decrease in B-adrenoreceptor number
Causing biochemical alteration in cAMP signalling pathway.
E-C coupling can be impaired at several different sites during heart failure.
SR calcium stores are significantly reduced - depleted Ca2+ stores results in decreased contractile force.
Upregulation of Na/Ca exchanger- promotes removal of vital Ca2+ from the cell. Development of delayed depolarisation and triggers arrhythmias - impaction AP’s
Hyperphosphorylation of RyRs by adrenergic stimulation
Occurs as a compensatory mechanism to overcome this deficiency
PKA causes RyR malfunction and thus causing depletion of SR calcium and aberrant release of calcium during diastole (Calcium leak)
What is the effect of Na+ causing intracellular Na and Ca overload?
Contractile dysfunction and arrhythmias
Treating heart failure with ionotropic drugs
Ionotropic agents required to increase muscular contractile force.
Endogenous inotropic mechanisms include:
Contraction frequency dependent activation of contractile force.
Drugs currently used to treat heart failure
Positive inotropic drugs:
Phosphodeisterase inhibitors
Catcholamine-mediated inotrophy
How do inotropic agents regulate cardiac activity
- Increase force by the B-adrenoceptor-AC-cAMP system, PKA release phosphorylates L-type Ca channels, increase Ca influx and RyRs stimulation, increases SR calcium release thereby activation of cross bridges and contraction.
- Increase force by the B-adrenoceptor-AC-cAMP system, PKA release phosphorylates PLB, this accelerates SR accumulation of Ca2+ and relaxation.
Catecholamine-mediates inotropy
Increase force by the B-adrenreceptor-AC system.
Stimulation of alpha-receptors.
Nitric oxide causes
Defective NO release is one of the major factors involved in vasoconstriction in congestive heart failure.
Phosphodiesterase 3 inhibitor example and effect
Milrinone (prevents conversion of cAMP to AMP therefore restores cAMP levels in cardiac myocytes and increases heart contractility)
Increases heart contractility
Vasodilators vessels
Helps to alleviate increased pressure (afterload) on the heart)
B-adrenoreceptor stimulation drug treatment
dopamine, dobutamine
Phosphodiesterase inhibition drug treatment
milrinone, enoximone
Calcium sensitization drug treatment
Levosimendan
Na-K ATPase inhibition plus SERCA activation drug treatment
Mercarbil
SERCA activation plus vasodilation drug treatment
nitroxyl donor
RyR stabilization drug treatment
Ryandodine receptor stabilizer S44121
Energetic modulation drug treatment
Pyruvate
