Karimi Cronic Coronary Disease

Define Coronary Artery Disease (CAD) and Chronic Coronary Disease (CCD)* 

• Coronary Artery Disease is an umbrella term that encompasses both chronic coronary disease and acute coronary syndrome (ACS)

• Chronic Coronary Disease (CCD): note that term has shifted from “stable ischemic heart disease” to CCD. Major manifestation is the buildup of atherosclerotic plaques (fatty deposits) in the epicardial vessels, and it frequently presents as chronic stable angina. 

Know the main risk factors for CAD

• Prevention: a healthy weight + lifestyle with tobacco cessation, physical activity, and control of BP can prevent 80%

Describe the pathophysiology of different types of angina and the major determinants of cardiac oxygen demands

• Atherosclerotic (classic) Angina: Triggered by exertion and relieved by rest. Pain is partially caused by metabolites (like lactic acid, adenosine, and bradykinin) produced during anaerobic oxidation 

• Microvascular Angina: caused by atherosclerosis in the endocardial vessels rather than epicardial vessels; more common in females

• Vasospastic (Prinzmetal) Angina: caused by reversible spasms of epicardial coronary vessels, often occurring at rest or even during sleep 

• Unstable Angina: precipitated by unstable plaque rupture and typically does not subside with rest

• Oxygen demands: Intramyocardial fiber tension is the primary determinant of myocardial oxygen demand (higher tension = higher oxygen requirement). This tension is influenced by diastolic factors (blood volume and venous tones) and systolic factors (peripheral resistance, heart rate, heart force, and ejection time). All these factors, except blood volume, are controlled by sympathetic discharge 

Atherosclerotic (classic) Angina

Microvascular Angina

Vasospastic (Prinzmetal) Angina

Unstable Angina

Physiological Determinants of Myocardial Oxygen Demand

Physiological Determinants of Myocardial Oxygen Demand

• The intramyocardial fiber tension determine the myocardial oxygen demand: increase tension = increase oxygen requirement 

• All factors, except the blood volume are influenced by sympathetic discharge

• Reducing any of these factors improve angina 

Define the underlying cause for an atherosclerotic plaque

Plaque Formation 

• Manifestation of CCD is buildup of atherosclerotic plaques (fatty deposits) in epicardial vessels

• Atherosclerosis begins early 20s and becomes pathologic as people get closer to 50s and beyond

• Irritants (like smoking, stress, LDL, hypertension) damage the endothelial cells lining blood vessels. This attracts LDL, which oxidizes and forms fatty streaks. Monocytes become macrophages, engulf the oxidized LDL, and turn into foam cells. Foam cells release cytokines, attracting more monocytes in vicious cycles. Smooth muscle cells eventually secrete a fibrous cap and release calcium to harden the plaque creating a brittle obstruction. 

Define the underlying cause for substernal and referred pain in angina

Angina Pectoris (Chest Pain)

• “Strangling” pressure-like pain

• Manifestation most often substernally but can occur in other areas shown here

• Other symptoms: nausea, vomiting, dyspnea, diaphoresis

• Can be provoked by emotion, cold, temperatures, stress, or heavy meals

• It is relieved by rest or sublingual nitroglycerin (decrease oxygen demand and increase oxygen delivery)

Referred Pain in Angina

• Non-substernal pain is referred pain

  • Ex. patient senses pain in the arm and parts of the stomach but the original site of injury is the heart 

• This is due to a mix-up of nervous coming from regions of the body where they intersect (for instance, somatic neurons (T1-T4) with a sympathetic neuron in the spinal cord

  • Results in a convergence of these neurons with a single higher order neurons

Treatments of Angina 

• Goal in atherosclerosis and microvascular angina: balance O2 supply and demand

• Vasospastic angina goal: reduce spasms to increase O2 supply 

• Short-term treatment: 

  • symptom management

  • decreased duration

  • Frequency and intensity of angina symptoms

  • Maintain daily activities 

• Long-term treatment:

  • Decrease morbidity (prevent MI, HF, need for revascularization)

  • Decrease mortality 

  • Decrease adjustable risk factors 

Recall the strategies and drug targets for relief of anginal pain

• Increase oxygen delivery or reduced oxygen demand

• For atherosclerotic and microvascular angina, the goal is to balance O2 supply and demand

• For vascular angina, the goal is to reduce spasms to increase O2 supply

• Short-term treatments aim to manage symptoms, decrease the intensity of pain, and maintain daily activities 

Contrast the therapeutic and major adverse effects of nitrates, β blockers, and calcium channel blockers when used for angina

• Drugs strategies for treatment include increasing O2 delivery or reducing O2 demands 

• Traditional pharmacologic therapies include nitrates, calcium channel blockers, and B blockers, and metabolism modifiers, that are able to reduce the cardiac O2 demand

  • Also, nitrates and CCBs increase oxygen delivery by reducing spasm in vasospastic angina

Beta Blockers

• All B blockers are effective in the prophylaxis and atherosclerotic angina attacks (particularly for ongoing angina and have no value in acute attack)

• 1st line for atherosclerotic angina (not useful in vasospastic angina)

• B blockers reduce cardiac work and oxygen demand

  • Decrease BP (decrease renin release) and decrease HR (decrease chronotropy)

  • Decrease contractility (decrease inotropy)

• Metoprolol succinate: 1st line BB but be careful with abrupt D/C → exacerbations of angina pectoris and possibly MI

Nitrates 

• Nitroglycerin; isosorbide mononitrate; isosorbide dinitrate

• The above agents have identical mechanics of action and similar toxicities

• Aldehyde dehydrogenase-2 (ALDH2) catalyzes nitroglycerin to nitric oxide (NO) which in turn activates the soluble guanylyl cyclase to convert GTP to cGMP

• cGMP dephosphorylates myosin ight chains which leads to the relaxation of vascular smooth muscle cells 

Nitrate selectivity: veins > arteries > arterioles

• Nitrates encourage a high degree of venodilation (primarily effect to reduce O2 demand)

  • They reduce venous tone

• They also dilate arteries at higher doses (secondary effect)

  • Moderately decrease afterload and helps coronaries deliver O2

  • Predominantly dilates the epicardial coronary arteries

  • As opposed to the small coronary arterioles 

Toxicity 

• ADEs: tachycardia, orthostatic hypotension, dizziness, and throbbing headache

•  Nitrates promote synthesis of cGMP in the vascular smooth muscle cells (leading to smooth muscle relaxation)

  • Phosphodiesterase isoform (PDE5) metabolized (reduces) cGMP which results in the smooth muscle constriction

  • Sildenafil (viagra) as a PDE5 inhibitor increases inflow of blood to treat erectile dysfunction

• Nitrates should NOT be used in combo with sildenafil or other PDE-5 inhibitors due to severe hypotensive effect

• Both increase cGMP and result in significantly lower organ perfusion

• Patients should be advised to not take andy PDE5 inhibitors when they take any form of nitrates (at least within 24hrs, with tadalafil is used bc has plunged t ½ )

Calcium Channel Blockers

• The L-type calcium channel is the dominant type of calcium channel in cardiac and smooth muscle. A few calcium channels blockers:

  • Amlodipine 

  • Felodipine

  • Nifedipine

• Diltiazem

• Verapamil 

• CCBs are useful as prophylactic therapy in both atherosclerotic angina and vasospastic angina

• CCBs can cause constipation, peripheral edema, nausea, flushing, and dizziness

Physiologic Effects

• CCBs block voltage gated L-type calcium channels in cardiac and smooth muscle:

• DPHs

  • Decrease BP, increase HR

  • Increase coronary vasodilation (increase O2 delivery)

  • Increase arterial vasodilation

• Verapil and diltiazem

  • Decrease BP and HR

  • Increase vasodilation (increase O2 delivery)

  • Decrease contractility

• Combo

  • HTN - monotherapy with CCB or BB

  • Doesn't work → combination of two (especially with MI hx) or 2 diff CCB (DHP/NDHP)

Sodium Channel Blockers 

• Ranolazine is a selective inhibitor of late Na+ influx into cardiomyocytes. By blocking the lat sodium current, it is though to reduce calcium overload, increasing relaxing of the heart muscle (decrease O2 demand)

• While it can be used in combo with other 3 classes, often used with patients cannot tolerate beta blockers, CCBs, or long acting nitrates (transdermal

• Minor, useful effects:

  • Increased glucose oxidation that leads to more ATP production for each consumed oxygen molecule

  • Small amount of beta blocking activity