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The mitral valve serves to ensure one-way blood flow from the left atrium to left ventricle of the heart. It opens when left atrial pressure is higher than left ventricular pressure, allowing blood to fill the left ventricle; and closes when the ventricles contract, to prevent blood from flowing back to the atrium. The mitral valve has 2 flaps, or leaflets, supported by a fibrous ring.
Mitral stenosis occurs when these leaflets thicken and become stiff, causing the valve opening to narrow, reducing blood flow. As a result, blood volume and pressure in the left atrium increases, and, over time, this may have several consequences.
First, the left atrium enlarges and becomes a risk factor for developing atrial fibrillation, a condition in which the atria beat rapidly and irregularly. The atrium quivers rather than contracts, and does not empty completely into the ventricle. Ineffective pumping causes the blood to stagnate, facilitating the formation of blood clots. These clots may then pass into the bloodstream, get stuck in small arteries and block them, resulting in stroke and other problems.
Second, because the left atrium receives blood from the lungs, pulmonary pressure may increase, causing secondary pulmonary hypertension, which in turn, may lead to right ventricular heart failure, as well as tricuspid or pulmonary valve regurgitation.
Mitral stenosis is most commonly caused by rheumatic fever, a complication of untreated strep throat or scarlet fever during childhood. For this reason, it is most prevalent in developing countries where rheumatic fever is more common. Rarely, mitral stenosis may develop with age, as a result of accumulated calcium deposits on the valve. Mitral stenosis can also be congenital.
Symptoms progress slowly, over years or even decades, so patients may not be aware until atrial fibrillation or heart failure develops. Symptoms may appear or worsen with increased heart rates, such as during exercise or stress. Women may suddenly discover they have the condition as they become pregnant.
Mitral stenosis produces a characteristic heart murmur that can be heard with a stethoscope. Diagnosis is confirmed with echocardiography, which uses ultrasound to visualize cardiac structures and blood flow. Echocardiography also helps determine the severity of the disease by measuring the mitral valve area. ECG recordings and chest X-ray may show signs of left atrial enlargement.
Because most cases of mitral stenosis are caused by rheumatic fever, prompt treatment of strep throat with antibiotics effectively prevents both rheumatic fever and mitral stenosis.
Treatment is not needed for asymptomatic patients. Patients with mild symptoms may be treated with diuretics to reduce blood pressure; beta-blockers or calcium channel blockers to control heart rates; and anticoagulants to prevent blood clots.
Valve repair or replacement surgery may be indicated for moderate to severe cases.
In percutaneous valvuloplasty, a catheter with a balloon is threaded through a vein and into the heart. The balloon is inflated to widen the opening of the valve, then deflated and removed.
Patients with heavy calcification may require open heart surgery to repair the valve. Valve replacement is considered when repair is not possible. Artificial valves can be mechanical or bio-prosthetic. Mechanical valves last longer but usually require life-long anticoagulation to prevent formation of blood clots.

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Hypertension is most commonly associated with an increase in vascular resistance caused by narrower or stiffer blood vessels; but other mechanisms, including increased cardiac output, large blood volume, or excess venous return, are possible. These factors are the targets of antihypertensive agents, which can be grouped into several categories:
– Diuretics, which promote sodium and water excretion by the kidneys and thereby decrease blood volume.
– Medications that inhibit the sympathetic nervous system or the renin-angiotensin system.
– And vasodilators, which dilate blood vessels, and thereby decrease vascular resistance.
Of the three classes of diuretics used for treating hypertension, thiazides are the most commonly prescribed. Thiazides act on the distal tubule of nephrons, which reabsorbs only a small portion of the sodium load, so their diuretic effect is less powerful than that of loop diuretics, which act on the thick ascending limb of the loop of Henle. However, thiazides also have a vasodilation effect by an unknown mechanism. The two classes produce similar side effects, but the side effects are more severe with loop diuretics.
Potassium-sparing diuretics act mainly in the collecting duct and have only a mild diuretic effect, but they can compensate for the potassium loss induced by other diuretics, and are therefore commonly used in conjunction with thiazide or loop diuretics.
Sympathetic inhibitors, or sympatholytics, act on adrenergic receptors to block sympathetic activity. There are beta-blockers, alpha-blockers, mixed alpha and beta-blockers, and central sympatholytics.
Beta blockers are typical first-line treatment for hypertension. They reduce heart rate and cardiac contractility and thus decrease cardiac output.
Alpha-1 blockers are effective in reducing sympathetic vasoconstriction, but their action can lead to an excessive baroreceptor-mediated reflex that increases heart rate and produces tachycardia.
Non-selective adrenergic antagonists block both alpha and beta receptors. By inhibiting beta receptors in the heart, they are able to lower blood pressure without inducing reflex tachycardia.
Central sympatholytics stimulate alpha-2 receptors in the brainstem to reduce sympathetic tone. They reduce heart rate, contractility and vasoconstriction, but may also cause sedation.
Renin-angiotensin system blockers include ACE inhibitors and angiotensin receptor blockers.
ACE inhibitors are commonly used as first-line treatment for hypertension. They block the conversion of angiotensin-I to angiotensin-II, which in turn leads to a reduction in aldosterone. Their action reduces systemic vasoconstriction and increases sodium and water excretion by the kidneys.
Angiotensin receptor blockers inhibit the effects of angiotensin-II. Their indications are similar to those of ACE inhibitors.
Vasodilators include calcium channel blockers, direct arterial vasodilators and nitrodilators.
Calcium channel blockers inhibit L-type calcium channels that are responsible for smooth muscle contraction, cardiac myocyte contraction, and action potential generation in cardiac nodal tissue.
The dihydropyridine class acts on peripheral blood vessels. They are powerful vasodilators but their action can lead to reflex tachycardia and increased cardiac contractility.
Non-dihydropyridine agents, on the other hand, primarily act to decrease heart rate, contractility and cardiac conduction speed; and are less effective on peripheral vessels. By having cardiac depressant effect, they can reduce blood pressure without producing reflex cardiac stimulation. However, they should not be used for patients with systolic heart failure.
The mechanisms of direct arterial vasodilators are not entirely clear. They can cause reflex tachycardia and are only used for short-term treatment of refractory hypertension.
Nitrodilators act by releasing nitric oxide, a powerful vasodilator. They are administered intravenously to manage hypertensive crises and to control blood pressure during surgery.

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Mechanisms of action of positive inotropes: calcitropes (catecholamines, phosphodiesterase-3 inhibitors, digoxin), Levosimendan and Omecamtiv mecarbil
Inotropes are medicines that alter the force of contraction of the heart. By definition, there are positive inotropes that strengthen cardiac contraction, and negative inotropes that weaken it. However, when not specified otherwise, the term “inotrope” usually refers to positive inotropes, which are the topic of this video. Negative inotropes, such as beta blockers and calcium channel blockers, significantly overlap with antiarrhythmic agents, and are covered in another video.
Inotropes are used in conditions where there is a sudden low cardiac output, such as acute heart failure or cardiogenic shock. Cardiac output is the product of stroke volume – the amount of blood pumped in one heartbeat, and heart rate – the number of beats in one minute. More forceful contractions induced by inotropes pump more blood out of the heart, increasing stroke volume. Many inotropes also accelerate heart rate, which contributes to increased cardiac output.
Cardiac muscle contractions are triggered by a surge in intracellular calcium concentration. When cardiac muscle cells are stimulated by action potentials, calcium channels open, allowing calcium to rush in. This calcium influx activates ryanodine receptor on the membrane of the sarcoplasmic reticulum, the SR, causing more calcium release from the SR, in a process known as “calcium-induced calcium release”. Calcium then binds to troponin units on actin myofilaments and sets off muscle contraction by the sliding filament mechanism.
Most inotropes act by raising the levels of intracellular calcium; they can also be called calcitropes.
Many calcitropes operate via the catecholamine pathway. They bind to beta-adrenergic receptor, activating a signaling cascade that leads to production of cyclic-AMP, cAMP, a second messenger. cAMP promotes phosphorylation and hence activation of both L-type calcium channel that allows calcium influx from the extracellular fluid, and ryanodine receptor that mediates calcium release from the SR. The result is an increase in intracellular calcium that drives a stronger contraction. Most catecholamines have a short half-life and are given by continuous infusion.
Some other agents are inhibitors of the enzyme phosphodiesterase-3, PDE3. Because PDE3 breaks down cAMP, inhibition of PDE3 results in accumulation of cAMP and subsequent increase in intracellular calcium.
Digoxin, a widely used inotrope, acts by inhibiting the sodium-potassium pump, causing intracellular sodium concentration to rise. This then leads to higher levels of intracellular calcium via the action of sodium-calcium exchanger.
The problem with most calcitropes is that they increase contractility at the expense of cellular energy, meaning the heart muscle requires more oxygen to operate. This may lead to adverse effects including higher mortality. Other strategies have been explored to design inotropes that can boost cardiac output without increasing myocardial oxygen demand.
Levosimendan is a calcium sensitizing drug. It enhances troponin C sensitivity to intracellular calcium, thereby increasing the force of contraction without consuming more cellular energy.
Omecamtiv mecarbil, OM, is a new drug that is still under investigation. OM increases the efficiency of heart muscle contraction. It binds to cardiac myosin, stabilizing myosin-actin connection. This increases the number of myosin heads bound to actin, producing more force during cardiac contraction.

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Long QT syndrome, LQTS, is a condition that affects the heart’s electrical activities. LQTS is largely a genetic disorder: children inherit mutations from their parents that either cause the disease since birth, or make them more susceptible to develop it later in life when triggered by certain medications or metabolic imbalances.

LQTS itself is not the problem, many people with the syndrome don’t have any symptoms and may not even be aware of it. However, it predisposes the patient to a life-threatening type of abnormal heart rhythm, known as torsades de pointes, which may lead to fainting, seizures, or sudden cardiac arrest. This complication is usually triggered when heart rate accelerates by adrenergic stimulation, such as during exercise, stress or strong emotions. LQTS can cause sudden death in seemingly healthy young people.

On an electrocardiogram that records electrical activities of the heart, P wave represents atrial depolarization, QRS complex is produced by ventricular depolarization, and T wave corresponds to ventricular repolarization. The QT interval, measured from the start of Q wave to the end of T wave, reflects the time taken for ventricular depolarization and repolarization, which is basically the duration of action potentials in the cells of the ventricles.

An action potential is essentially a brief reversal of electric polarity of the cell membrane. It is made possible by the flow of ions in and out of the cell, through specific ion channels. Basically, the depolarizing phase is caused by sodium influx; early re-polarization is due to initial outflow of potassium; plateau phase occurs when potassium efflux is balanced by calcium influx, and repolarization is when potassium efflux dominates calcium influx. The duration of repolarization is determined by the balance of current flow through these ion channels.

The rate of repolarization is slightly different for the 3 layers of the heart wall: the epicardium, mid-myocardium or M-cells, and endocardium. Because M-cells have less potassium channels and more sodium channels, they repolarize more slowly. On an ECG, the peak of T wave reflects repolarization of epicardial cells, while the end of T wave corresponds with repolarization of M-cells.

Long QT syndrome is due to prolongation of underlying action potential durations, and is most commonly caused by mutations in various ion channels that affect the balance of ion flow. Specifically, a reduced outward current caused by loss of function of potassium channels, or an increased inward current caused by gain of function of sodium or calcium channels, would increase the duration of repolarization. If inward currents exceed outward currents during the plateau phase, early after-de-polarizations and consequently extra heartbeats can be triggered. Mutations in ion channels also disproportionately lengthen action potentials in M-cells, increasing the difference in refractoriness of the different layers.  This can cause electrical impulses to travel around in loops, known as re-entrant pathways, producing the characteristic wave pattern of torsades de pointes.

For diagnosis, patient’s QT interval is measured. But because QT interval varies with heart rate, a corrected QT interval, QTc, is calculated after measurement. Diagnosis, however, cannot rely on QTc values alone.  Asymptomatic patients can have longer than normal QTc and develop no arrhythmias, while patients with established long QT syndrome may have normal QT intervals at rest. Diagnosis must therefore also include genetic testing, personal history of fainting, and family history of sudden death.

Treatment aims to prevent a long QT heart from developing dangerous arrhythmias. Most patients are treated with beta-blockers, which blunt the heart’s response to adrenaline produced during exercise and stress, making the heart beat slower, thus reducing the risks for torsades de pointes. Medications that shorten QT interval may also be prescribed. On the other hand, medications that prolong QT interval or precipitate development of torsades de pointes must be avoided. Patients are also advised to seek immediate treatments for conditions that may result in low potassium in the blood.

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Angina pectoris, or simply angina, refers to chest pain or discomfort caused by reduced blood flow to the heart, in a condition known as myocardial ischemia. Angina is described as a squeezing pain or heaviness in the chest, which may also spread to the neck, arms, shoulders and back; or in the stomach area, particularly after meals. Women are more likely to experience a burning sensation or tenderness instead of squeezing pain. Angina is not the same as heart attack. It is associated with transient ischemia of the heart without permanent damage, while heart attack is when a patch of the heart muscle dies from lack of oxygen. But having angina significantly increases the risks for heart attacks, especially when left untreated.
Angina is most commonly caused by the narrowing of one or more coronary arteries that supply the heart. This can result from a fixed obstruction by cholesterol plaques, or a temporary constriction due to blood vessel spasms. Angina can also be caused by anemia, when the flow is adequate, but the blood does not have enough red blood cells to carry oxygen.
There are several types of angina.
Stable angina, the most common form, is usually caused by a fixed obstruction, a plaque. Stable angina is predictable, with familiar pain patterns, and typically prompted by physical exertion, when the heart requires more oxygen than it can get from narrowed vessels. Factors that constrict blood vessels or increase blood pressure, such as emotional stress, cold temperatures or heavy meals, may also induce angina. Stable angina does not happen at rest, when the reduced flow is sufficient for the low demand of the heart. It usually subsides when the inducer is removed and responds well to medications.
Unstable angina, on the other hand, may occur unexpectedly, even at rest, with a changed pattern from the usual stable angina. It is more severe, lasts longer, does not respond to rest or medications, and is often the sign that a plaque has ruptured or a clot has formed. Unstable angina is a medical emergency as it often precedes a heart attack.
Electrocardiograms of patients with obstructive angina commonly show ST-segment depression during attacks. Diagnosis is confirmed with stress test, where patients are monitored while exercising. The site of obstruction can be detected with imaging techniques, such as angiography.
It appears, however, that a significant number of patients with stable angina symptoms have more or less normal coronary arteries on angiograms. These cases are now recognized as microvascular angina (Cardiac syndrome X), where the problem lies not in the large coronary arteries, but their tiny branches, and is therefore undetectable by angiography. Microvascular angina is much more common in women than in men.
Variant angina (Prinzmetal angina), a less common type, is caused by vascular spasms of coronary arteries. Variant angina can occur during rest, usually at certain times of the day, often at night. Emotional stress, smoking and use of cocaine are known triggers. Variant angina is often severe, but responds well to medications. Diagnosis is by presence of ST-segment elevation during attacks, and provocative testing with drugs that induce coronary artery spasms (ergonovine, acetylcholine).
Treatment of angina aims to relieve symptoms, reduce frequency of future anginas, but most importantly, reduce risks of heart attacks. Apart from lifestyle changes to modify risk factors, treatment options include a number of medications and surgical procedures.
Nitroglycerin, a potent vasodilator, is most effective for acute anginal attacks. Long-lasting nitrates, antiplatelet drugs (aspirin…), beta-blockers, and calcium channel blockers can be prescribed to prevent future anginas.
Several revascularization procedures are available to restore normal blood supply to the heart. Coronary angioplasty makes use of a balloon, and sometimes a stent, to widen the affected artery. Coronary bypass uses a graft to create an alternative route for blood to flow beyond the site of blockage.

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Jugular venous pressure, JVP, also known as jugular venous pulse, is the pressure within the jugular vein. Because the right internal jugular vein communicates directly with the right atrium via the superior vena cava, JVP essentially reflects the central venous pressure; and its cyclic changes with each heartbeat accurately mirror the dynamics of blood flow to the right atrium.

JVP can be recorded precisely by inserting a central line; or assessed, non-invasively, by observing the pulsation of the vein on the right side of the patient’s neck.

The mean JVP, measured at the highest point of jugular pulsation, serves as an indicator of fluid status. A higher than normal JVP indicates hypervolemia, while lower values are associated with hypovolemia. Generally, fluid overload is diagnosed when the jugular vein is distended to the jaw in upright position.

Understanding JVP waveforms:

A normal JVP waveform has 3 positive waves: A, C and V, of which only A and V can be seen by looking at the vein; and their corresponding descents.

Reminder: blood flows from higher to lower pressure; contraction increases the pressure within a chamber, while relaxation lowers the pressure.

The A wave represents atrial contraction, which actively pushes blood into the right ventricle. Contraction increases pressure inside the atrium, pushing blood both downward and upward, creating a distension in the jugular vein.

The X descent is generated by the subsequent relaxation of the right atrium. The resulting reduced pressure pulls the blood down from the jugular vein.

As the right ventricle starts to contract, blood pushes against the closed tricuspid valve, causing it to bulge into the right atrium. This slightly raises right atrial pressure, producing the small positive C wave in the middle of the X descent.

V wave reflects the passive rise in pressure and volume of the right atrium as it fills, reaching the peak right before the tricuspid valve reopens.

Opening of tricuspid valve allows blood to flow down the ventricle, emptying the right atrium, reducing its pressure, and resulting in the Y descent.

Abnormalities in JVP waveforms can help with diagnosis of a number of cardiac and pulmonary diseases:

– Absence of proper atrial contraction, such as in atrial fibrillation, leads to absence of A waves.

– Abnormally large A waves occur when the right atrium contracts against a higher-than-usual resistance. Examples include right ventricular hypertrophy, tricuspid valve stenosis, and obstruction of right ventricular outflow. These conditions produce giant A waves that are uniform and occur on every beat.

– Cannon A waves, on the other hand, are also large, but occur intermittently, and usually of various height. Cannon A waves typically result from cardiac arrhythmias, when there is a disconnection between atrial and ventricular activation, and the right atrium contracts against a closed tricuspid valve, in some but not all beats. Examples include premature beats, complete atrioventricular block, and ventricular tachycardia.

– A large V wave occurs when there is increased atrial filling during ventricular contraction. The most common cause is tricuspid regurgitation. Because regurgitation begins during C wave (when the ventricle starts to contract), the large V wave is commonly FUSED with C wave, forming a so-called CV wave.

Atrial septal defects may also result in larger V waves.

– Unusually steep X and Y descents can be observed as abrupt collapse of the neck vein, in conditions such as constrictive pericarditis. The reduced elasticity of the pericardial sac raises atrial pressure while also limiting ventricular filling to early diastole.

– Cardiac tamponade, on the other hand, attenuates the Y descent as it impedes ventricular filling.

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The major purpose of the circulatory system is to bring oxygen and nutrients to body tissues and remove wastes. This exchange happens in the smallest blood vessels called the capillaries. The walls of capillaries consist of a single layer of endothelial cells. Substances move between the blood and surrounding tissue in several ways:
– Diffusion through the plasma membranes of endothelial cells: the hydrophobic nature of the cell membrane makes it intrinsically permeable to small lipid-soluble molecules and small gases. Oxygen moves down its concentration gradient, from the blood to the surrounding tissue, while carbon dioxide diffuses in the reverse direction. Glucose and other small water-soluble molecules move, in part, by facilitated diffusion: they use special channels, called transporters, to cross the cell membrane. Water moves by osmosis.
– Transcellular vesicle transport, or transcytosis: some proteins and hormones are packaged into lipid vesicles and transported through endothelial cells by endocytosis and exocytosis.
– In most tissues, however, the bulk exchange of fluids and solutes is through the gaps between endothelial cells, called intercellular clefts; and, in some tissues, through the pores of so-called fenestrated capillaries. Blood plasma containing nutrients moves out of capillaries at the arterial end of capillary beds, in a process called filtration, while tissue fluid containing wastes reabsorbs back in at the venous end. This movement, called bulk flow, is driven by the balance between two forces:
– Hydrostatic force, generated by the difference in hydrostatic pressures inside and outside the capillaries. Hydrostatic pressure is defined as the pressure of fluids in a closed space. Inside capillaries, this is the same as capillary blood pressure. As tissues generally contain much less fluid than blood, hydrostatic pressure from inside capillaries is considerably higher than that from outside. Thus, hydrostatic force drives fluids, and blood solutes, out of capillaries.
– Hydrostatic force is opposed by osmotic force. Osmotic force, also called oncotic pressure, is generated mainly by the difference in protein concentrations between the blood and interstitial tissue. The blood has a much higher protein content, due to albumin, and this draws water into blood vessels.
Because the arterial end of a capillary bed is relatively closer to the heart than the venous end, capillary blood pressure and, by extension, hydrostatic pressure, is higher at the arterial end. With osmotic pressure remaining the same throughout, the balance shifts from net outward flow at the arterial end to net inward flow at the venous end. Note that the net outward filtration pressure is greater than the net inward reabsorption pressure. This means more fluid is filtered out than reabsorbed back in. In fact, about 15% of the fluid is left in the tissues after capillary exchange. This fluid is picked up by the lymphatic system and returned to the circulation at a later point.
Edema refers to abnormal accumulation of excess fluid in a tissue. It manifests as external swelling or enlarged internal organs. There are 3 principal groups of causes:
– Increased filtration, either from increased blood pressure or increased capillary permeability,
– Decreased reabsorption due to reduced blood albumin concentrations,
– and obstruction of lymphatic drainage.
Excess fluid hinders the exchange of nutrient/waste and gases and may lead to tissue necrosis. Severe edema may also be accompanied by critically reduced blood volume which may result in circulatory shock.