Myocardium
The heart muscle itself: the layer that converts an electrical signal into a squeeze, and so decides how much blood leaves the heart with every beat.
What it normally does
Contraction is calcium-driven. Depolarisation opens L-type calcium channels in the T-tubules; that small trickle of calcium opens the ryanodine receptors (RyR2) on the sarcoplasmic reticulum, releasing the much larger internal store (calcium-induced calcium release), and that calcium binds troponin C so actin and myosin can cycle. How hard the heart squeezes comes down to how much calcium reaches troponin C — this is excitation-contraction coupling.
so anything that reduces calcium entry per beat (a beta blocker) or increases the stored calcium load (digoxin) changes the force of contraction directly, and losing contractile myocytes to infarction removes cross-bridges that cannot be replaced.
Relaxation is active and costs ATP. SERCA pumps calcium back into the sarcoplasmic reticulum and the sodium-calcium exchanger extrudes the remainder from the cell; only when cytosolic calcium falls do the cross-bridges let go and the ventricle fill. A myocyte short of ATP cannot let go any better than it can pull, so a stiff ventricle and a weak one can share the same energy problem.
so ischaemia and hypertrophy stiffen the ventricle (diastolic failure, and the calcium overload of infarction) before, or without, any fall in ejection fraction.
The myocardium already extracts roughly 70% of the oxygen from the blood passing through it at rest, close to the practical ceiling, so extra demand is met mainly by increasing coronary flow rather than by extracting more. The left ventricle is perfused almost entirely in diastole, because in systole its own contraction compresses its intramural arteries. Anything that shortens diastole (a fast heart rate) therefore cuts its own supply.
so a fixed coronary narrowing or a hypertrophied wall produces ischaemia the moment rate and force rise, and slowing the heart is itself an anti-ischaemic treatment.
Force is adjustable in two ways. Noradrenaline on beta-1 receptors raises cyclic AMP, and protein kinase A phosphorylates the L-type calcium channels (more calcium enters per beat) and phospholamban, lifting its brake on SERCA (calcium cleared faster) — so the beat is both stronger and quicker to release (positive inotropy and lusitropy). Separately, stretching the muscle before it contracts increases force (the Frank-Starling relationship), so more filling gives a bigger stroke volume — up to a plateau, beyond which further stretch adds pressure but not force.
so the failing heart can compensate for a while with sympathetic drive and retained volume, and so the chronic neurohormonal compensation itself becomes the target of treatment once the plateau is reached.
What goes wrong
A fixed atherosclerotic narrowing caps coronary flow. At rest that cap is above resting demand. On exertion rate and force rise, so demand rises — and because oxygen extraction is already near maximal and the faster rate has shortened diastole, supply cannot rise to meet it. The muscle switches to anaerobic metabolism, ATP falls, and it hurts. Stop, and demand falls back under the ceiling.
Demand-led ischaemia against a fixed supply ceiling: predictable, exertional, relieved by rest or GTN in minutes, normal resting ECG, no troponin rise.
You would find: Central chest heaviness or tightness brought on by exertion or cold, sometimes radiating to the jaw or left arm, settling within minutes of rest or of sublingual glyceryl trinitrate. The resting ECG is often normal — the diagnosis rests largely on the story.
- Myocardial infarction← from “Relaxation is active and costs ATP. SERCA pump…”
A plaque ruptures and thrombus occludes the artery. Oxidative ATP production collapses and anaerobic glycolysis cannot keep pace, so cross-bridge cycling and the SERCA pump both fail: contraction of that segment stops within about a minute, and calcium — neither pumped back into the store nor exported — accumulates in the cytosol to toxic levels. Irreversible myocyte injury begins within roughly 20 to 30 minutes, starting in the subendocardium (furthest from the epicardial vessel) and spreading outwards as a wavefront. Dead myocytes spill troponin into the blood and the dead segment stops moving. Lost muscle is replaced by scar rather than regrown, which is why the pump stays permanently weaker and why the scar border later hosts re-entrant ventricular arrhythmias.
Time is muscle — reperfusion is the priority, because contraction stops in about a minute but cell death takes 20-30 minutes and spreads subendocardium outwards; troponin rises and falls, the wall motion defect is regional, and the scar is permanent.
You would find: Prolonged chest pain not relieved by rest, ST elevation in the leads of one coronary territory (or ST depression and T-wave inversion without it), and a rising and falling troponin. On echocardiography, a regional wall motion abnormality in that territory.
- Heart failure with reduced ejection fraction← from “Force is adjustable in two ways. Noradrenaline…”
Lose enough contracting muscle — to infarction, to alcohol, to a dilated cardiomyopathy — and there are too few cross-bridges to generate a normal stroke volume. The body compensates with sympathetic drive and renin-angiotensin-aldosterone activation with salt and water retention, which stretches the ventricle further. Past the plateau of the Frank-Starling relationship that stretch buys little extra force and mainly raises filling pressure, so the ventricle dilates, remodels and worsens. Much of the long-term damage comes from the compensation itself, which is why the treatments that improve survival are the ones that block it.
EF 40% or less; the neurohormonal compensation drives remodelling, so the four pillars (beta blocker, ACE inhibitor or ARNI, mineralocorticoid receptor antagonist, SGLT2 inhibitor) are disease-modifying while diuretics only relieve congestion.
You would find: Breathlessness lying flat (orthopnoea) and waking at night gasping, raised jugular venous pressure, an apex beat displaced towards the axilla, a third heart sound, ankle swelling, raised BNP or NT-proBNP, and an ejection fraction of 40% or less on echocardiography (41 to 49% is classified as mildly reduced).
- Heart failure with preserved ejection fraction (the stiff ventricle)← from “Relaxation is active and costs ATP. SERCA pump…”
Long-standing hypertension, ischaemia or diabetes thickens the myocardium and lays down fibrous tissue between the myocytes. Active calcium removal slows and the wall is physically stiffer, so the ventricle resists filling. It takes a much higher pressure to load a normal volume, and that pressure passes back through the left atrium into the pulmonary circulation — even though the squeeze itself is normal.
Normal EF, high filling pressure: a diastolic problem from slowed calcium removal plus fibrosis — congestion with a 'normal' echo report, and rate-and-rhythm sensitive because the atrial kick matters.
You would find: An older, often hypertensive patient, breathless on exertion with pulmonary congestion, and an echocardiogram reporting a normal ejection fraction (50% or more) with a thick left ventricle and abnormal diastolic indices. Such patients depend heavily on the atrial kick to fill a stiff chamber, so the onset of atrial fibrillation can tip them into pulmonary oedema.
- Hypertrophic cardiomyopathy← from “The myocardium already extracts roughly 70% of…”
An inherited (usually autosomal dominant) fault in a sarcomere protein makes the myocardium thicken, most often the interventricular septum, with myocyte disarray and interstitial fibrosis. Three consequences follow: the chamber is stiff and fills poorly; the thickened muscle outgrows its own blood supply and becomes ischaemic without any epicardial coronary disease; and the disarrayed, scarred tissue supports re-entrant ventricular arrhythmias — a leading cause of sudden cardiac death in young athletes.
Thick muscle outstrips its own supply and disarray plus fibrosis feeds re-entry: exertional syncope in a young patient, murmur louder on standing/Valsalva (opposite to aortic stenosis), family history of sudden death.
You would find: A young person with exertional breathlessness, chest pain or syncope, and an ejection systolic murmur that becomes louder on standing or with Valsalva (less filling, so the thickened septum obstructs outflow more). Ask about sudden cardiac death in the family. Left ventricular hypertrophy on the ECG of someone with normal blood pressure should prompt an echocardiogram.
What we give, and how it works
Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.
- Binds
- beta-1 adrenoceptor (a Gs-coupled receptor) on myocytes and nodal cells; carvedilol additionally beta-2 and alpha-1.
- Which does
- blocks catecholamine signalling, so adenylyl cyclase makes less cyclic AMP and protein kinase A phosphorylates fewer L-type calcium channels; less calcium enters per beat, and in nodal cells the funny current and calcium current run more slowly.
- So you see
- slower heart rate, weaker contraction and a longer diastole — so myocardial oxygen demand falls at the same time as coronary filling time rises; over months in heart failure, reverse remodelling and improved survival.
- And the same mechanism causes
- the same blunted beta-1 signalling that lowers demand also removes the sympathetic support the failing heart is leaning on — bradycardia, atrioventricular block, fatigue and transient worsening of heart failure on initiation or up-titration.
- Handling
- carvedilol's alpha-1 blockade makes first-dose hypotension more likely than with bisoprolol; metoprolol is CYP2D6-metabolised, so exposure varies between people.
Catches people out: A weaker, slower beat is exactly the point in stable disease, but it is hazardous in a patient who is acutely decompensated and depending on sympathetic drive to stay perfused. In practice they are introduced in heart failure only once the patient is euvolaemic and stable, from a low dose with slow up-titration, and are not started during acute pulmonary oedema or cardiogenic shock.
- Binds
- vascular smooth muscle soluble guanylate cyclase, activated by the nitric oxide the drug releases (glyceryl trinitrate via mitochondrial aldehyde dehydrogenase-2).
- Which does
- cyclic GMP rises, protein kinase G is activated, myosin light chain phosphatase activity increases and intracellular calcium falls, so the smooth muscle cell relaxes — predominantly in veins at usual doses.
- So you see
- reduced preload, so lower ventricular wall stress and lower myocardial oxygen demand, plus epicardial coronary and collateral dilation; angina and pulmonary congestion settle.
- And the same mechanism causes
- the same generalised vasodilation causes throbbing headache from cerebral vessel dilation, flushing, postural hypotension and reflex tachycardia — and profound hypotension in a preload-dependent state such as severe aortic stenosis or right ventricular infarction.
- Handling
- continuous exposure produces tolerance within about 24 hours, which is why long-acting preparations are dosed with a nitrate-free interval (patches removed overnight).
Catches people out: Contraindicated within 24 hours of sildenafil or vardenafil, and within 48 hours of tadalafil: the nitrate drives cyclic GMP production while the phosphodiesterase-5 inhibitor prevents its breakdown, and together they can drop the blood pressure catastrophically.
- Binds
- angiotensin converting enzyme on vascular endothelium (ACE inhibitor); the AT1 receptor plus neprilysin (ARNI).
- Which does
- less angiotensin II is generated or its receptor is blocked, so vascular smooth muscle tone, aldosterone release and the pro-hypertrophic, pro-fibrotic signalling in cardiac myocytes and fibroblasts all fall; ACE inhibition also spares bradykinin, and neprilysin inhibition spares natriuretic peptides.
- So you see
- lower afterload and filling pressure, less ventricular remodelling and dilatation, fewer heart failure admissions and improved survival in HFrEF and post-infarct left ventricular dysfunction.
- And the same mechanism causes
- losing angiotensin II removes efferent arteriolar tone, so glomerular filtration pressure falls and creatinine rises; losing aldosterone drive raises serum potassium; and sparing bradykinin gives the dry cough and, uncommonly, angioedema. The same interference with fetal renal development makes these agents contraindicated in pregnancy.
- Handling
- an ARNI replaces an ACE inhibitor rather than being added to it, and at least a 36-hour washout is left after the last ACE inhibitor dose before starting sacubitril/valsartan, because overlapping the two markedly raises angioedema risk.
Catches people out: They interrupt the very compensation that is holding perfusion pressure up, so blood pressure, kidney function and potassium are checked after starting and after dose changes. The dry cough is bradykinin, not the heart failure. Contraindicated in pregnancy and in bilateral renal artery stenosis, and avoided in previous angioedema.
- Binds
- the intracellular mineralocorticoid receptor, in the myocardium and in the distal nephron.
- Which does
- competitively blocks aldosterone binding, so the receptor does not translocate to the nucleus to switch on epithelial sodium channel and Na/K-ATPase transcription in the nephron, and does not drive the profibrotic transcriptional programme in cardiac fibroblasts.
- So you see
- less myocardial fibrosis and remodelling, modest natriuresis with potassium retention, and improved survival in HFrEF added to the other pillars.
- And the same mechanism causes
- blocking renal potassium excretion causes hyperkalaemia — the dose-limiting effect. Spironolactone is not receptor-selective and also antagonises androgen receptors and has progestogenic activity, hence breast tenderness, gynaecomastia in men and menstrual disturbance; eplerenone is far more selective and causes these much less often.
- Handling
- given with an ACE inhibitor or ARNI that also raises potassium, so potassium and kidney function are rechecked after starting and after every dose change, and the drugs are held in acute kidney injury or intercurrent illness with dehydration.
Catches people out: Hyperkalaemia is the main hazard, compounded by concurrent ACE inhibitor or ARNI, by potassium supplements, and by declining renal function. Not suitable when renal function is significantly impaired or potassium is already high.
- Binds
- the alpha subunit of the sarcolemmal Na+/K+-ATPase (potassium competes with digoxin at this site); indirectly, vagal efferents to the AV node.
- Which does
- partial pump inhibition raises intracellular sodium, which reduces the driving gradient for the sodium-calcium exchanger, so cytosolic and sarcoplasmic reticulum calcium load rises; vagal stimulation slows AV nodal conduction and prolongs its refractory period.
- So you see
- a stronger contraction without raising heart rate or oxygen demand much, and a slower ventricular response in atrial fibrillation at rest.
- And the same mechanism causes
- the same calcium loading that strengthens the beat causes delayed afterdepolarisations and triggered arrhythmias (ventricular ectopy, atrial tachycardia with block), while the vagal action gives bradycardia and AV block; pump inhibition in the retina gives the yellow-green visual haloes, and in the area postrema the nausea, vomiting, anorexia and confusion.
- Handling
- narrow therapeutic index and renal clearance — falling kidney function raises the concentration without any dose change, and hypokalaemia (classically from a loop or thiazide diuretic) increases binding to the pump and so increases toxicity at any given level. Lower serum concentrations are targeted in heart failure than were once accepted.
Catches people out: Toxicity is the constant concern: nausea, confusion, yellow-green visual disturbance and arrhythmias, made more likely by hypokalaemia, hypomagnesaemia, renal impairment, age, and interacting drugs such as amiodarone and verapamil which raise digoxin levels.
Relaxation costs ATP, just as contraction does. That one fact explains why an ischaemic or hypertrophied ventricle stiffens long before its ejection fraction falls — and why a patient can be drowning in pulmonary oedema while the echo report says "normal systolic function". A normal ejection fraction does not exclude heart failure.
Now test whether it stuck
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