Lecture 1

The heart

• beats over 40 million times per year

• pumps more than 750 liters of blood per dat

• first functional organ system in utero (8 weeks gestation)

• main function: pump blood

Systole

Contraction of heart

Diastole

dilation of heart

ejection fraction

amount of blood pumped at end of systole

fractional shortening

related to cardiomyocyte contraction

tricuspid valve

connects right atrium and ventricular

mitral valve

connects left atria to ventricular

Myocardial oxygen supply and demand

myocardial oxygen supply and demand should be balanced for adequate tissue perfusion

Ischemia

decreased perfusion leads to O2 deficit

Hypoxia

O2 is deprived despite adequate perfusion

Left ventricle is ?% of heart

70%

must be big to be able to pump blood to entire body

Sinoatrial node

biological pacemaker

Venous capitance

regulation of volume of blood returning to the heart, which is a major determinant of end-diastolic volume of the heart

Preload

end-diastolic ventricular wall stress or the stress of the ventricular fibers just before contraction

coronary arteries

myocardial o2 supply

line the heart

arterioles

• afterload

• myocardial o2 demand

• regional myocardial perfusion

capacitance veins

venous pooling

preload

myocardial o2 demand

peripheral veins

Pathophysiology of the heart

• cardiovascular disease is leading cause of death worldwide

• account for ¼ deaths in US

• one death every minute (610,000 deaths per year)

• annual economic impact of cardiac disease exceeds 200 billion with ischemic heart disease contributing over half

Pathways to heart diseases

• failure of pump (systolic and diastolic dysfunctions)

• obstruction of flow

  • calcific aortic valve stenosis

  • systemic hypertension or aortic coarctation

• regurgitant flow

• shunted flow (congenital or acquired)

• disorders of cardiac conduction

• rupture of the heart or major vessel

Angina

• atherosclerotic disease of the coronary arteries

• aka coronary artery disease (CAD) or ischemic heart disease (IHD)

• most common cause of mortality world wide

• chest pain: angina pectoris

  • symptom of myocardia ischemia

Angina pectoris

sudden, severe, crushing chest pain that may radiate to the neck, jaw, back, and arms

Classifications of ischemic heart disease

• chronic coronary artery disease (stable)

• acute coronary syndromes

Acute coronary syndrome

• unstable angina

• non-ST elevation myocardial infarction

• ST elevation myocardial infarction

Types of angina pectoris

• stable, effort-induced, classic, typical

• unstable

• prinzmetal, variant, vasospastic, rest

Stable angina

• lumen narrowed by plaque

• inappropriate vasocontriction

Unstable angina

• plaque ruptured

• platelet aggregation

• thrombus formation

• unopposed vasocontriction

Variant angina

• no overt plaques

• intense vasospasm

Effect of coronary artery occlusion on resting and maximal coronary blood flow

• occulsion affects maximal coronary flow faster than resting coronary flow

Acute coronary syndromes

• most often caused by the fissuring or rupture of atherosclerotic plaques

  • unstable/vulnerable plaques

unstable/vulnerable plaques

characterized by thin fibrous caps that are prone to rupture

Clinical management of IHD

• different in patients with chronic coronary artery disease compared to patients with acute coronary syndromes

• chronic CAD results from imbalance between myocardial oxygen supple and demand, and treatment of chornic CAD focuses on modulating this balance, usually by reduction of oxygen demand

• treatment of acs relies on re-establishing and maintaining the patency of the occuldde epicardial coronary artery as rapidly as possible

• all patients with CAD, irrespective of clinical presentation, also require modification of underlying risk factors, including aggressive lipid lowering therapy and blood pressure control

treatment goal in chronic CAD

• restore balance between myocardial oxygen supply and myocardial oxygen demand

• pharmacologic therapies concentrate on the reduction of myocardial oxygen demand, which is governed bt heart rate, contrscility, and ventricular wall stress

Nitroglycerin

• NTG

• aka glyceryl trinitrate

• first employed for relief of angina symptoms over 100 years ago

• decreases vascular tone

• decreases o2 supply nd demand

• NO reacts with variety of biomolecules

• soluble guanylyl cyclase: primary physiologic receptor

• MOA: activation of guanylyl cyclases by NO induces smooth muscle relaxation

Nitric Oxide

• donors:

  • organix nitrates

  • sodium nitroprusside

  • inhaled NO itself

• nitrates do have a coronary vasodilator effect in patients with vasospastic angina

• nitrates also have anti-aggregatiry effects on platelets

Organic nitrates

• MOA of organic nitrates: dilation of peripheral capacitance veins

  • results in decreased preload, myocardial O2 demand

Sodium Nitroprusside

• complex of iron, cyanide, and nitrosyl group

• spontaneously decomposes to relase NO and cynaide

• NO effects vasodilation

• releases NO spontaneously without enzymatic aid (vs organic nitrates, which need enzyme help)

• cyanide is metabolized in liver to thiocyanate, undergoes renal excretion

• cyanide toxicity can result from prolonged admin of drug or renal insufficiency

cardiovascular and peripheral effects of NO

• NO causes venous dilatation

• increases venous capacitance

• decrease in the venous return of blood to right side of heart

• cause decrease in right and left ventricular end-diastolic pressure and volume

• decrease in preload causes decrease in myocardial O2 demand

Pharmacological tolerance

• desirable effects of nitrates can be offset by compensatory sympathetic nervous system responses (reflex increase in sympathetic vascular tone) and compensatory renal responses (increased salt and water retention)

• important, clinically relevant phenomenon that limits efficacy of this class of vasodilators

• ex. workers at ammunition facility exposed to volatile organic nitrates

  • suffered headaches at start of workweek, disappeared as week progressed and returned upon returning to work after weekend

  • nitrate free intervals

  • patients may experience rebound angina during nitrate free hours

  • oral isosorbide 5-mononitrate has clear advantages for some issues

Oral isosorbide 5-mononitrate

• advantages:

  • the pharmacokinetic properties make it attractive for nitrate tolerance and angina rebound

  • high bioavailability and high half life periods produce high therapeutic plasma concentrations of plasma

  • high periods of plasma concentration is followed by low levels rather than zero levels

  • transdermal ntg or oral isosorbide 5-mononitrate illustrate how pharmacokinetic properties of similar acting drugs can have different therapeutic utility

• mech of tolerance:

  • sulfhydryl hypothesis

  • formation of peroxynitrate

NO contraindications

• patients with hypotension

• patients with elevated intracranial pressure (bc can further dilate vessels and increase pressure)

• caution in diastolic heart failure patients

  • can cause heart failure bc diastole is relaxation of heart

Aspirin

• platelet activation is critically important in initiation of thrombus formation

• antiplatelet agents play a central role in treatment of patients with CAD

• MOA: irreversible inhibits platelet COX, enxyme required for generation of pro=aggregatory compound thromboxane A2 (TxA2)

• platelet inhibition that follows aspirin admin persists for lifespan of platelet (appx 10 days)

• most effective as a selective antiplatlet agent when taken at low doses and/or infrequent intervals

• contraindication:

  • known allergy (alternative: clopidogrel)

  • predisposes to GI adverse effects (gastritis, peptic ulcer disease)

B-Adrenoceptor antagonists

• activation of b1-adrenergic receptors leads to increase in heart rate, contractility, and conduction through AV node

• reduce myocardial oxygen demand by decreasing heart rate and contractility

• drug-induced decrease in heart rate may also increase myocardial perfusion via prolongation of the diastolic filling time

• in chronic angina, decrease resting heart rate and peak heart rate achieved during exercise and delay time to onset of angina

• frequently co-admin with organic nitrates in patients with stable angina

  • dosing regimens are drug specific

Ca2+ channel blockers

• calcium channel blockers decrease influx of calcium through voltage-gated L-type calcium channels in the plasma membrane

• resulting decrease in intracellular ca2+ conc leads to reduced contraction of both cardiac myocytes and vascular smooth muscle cells

• decrease myocardial oxygen demand by decreasing systemic vascular resistance and by decreasing cardiac contractility

• blocking calcium entry, CCDs cause relaxation of vascular smooth muscle and thereby reduce systemic vascular resistance

• various classes have distinctive inotropic effects on cardiac myocytes

• can be used either in combo with b-blockers or monotherapy

• usually nitreates used in combo with ccbs when treating vasospastic angina