PHAR 7442 Cardio B4

Etiology - Risk Factors

!!!!!! Hypertension Diabetes Metabolic Syndrome Atherosclerotic Disease

HF with preserved LVEF

(HFpEF)

Adenosine: Other Prophylactic or Treatment Options for Angina

a natural antiarrhythmic drug, also a vasodilator;

Increased venous return increased

Preload

Compensatory Mechanism Neurohormones

Angiotensin II Norepinephrine (NE) Aldosterone B-type Natriuretic Peptide (BNP) Endothelin-1 Neprilysn Other biomarkers

CCB: Indications

CCB are used in stable angina that is not controlled by nitrates and beta-blockers. Also in patients who can't tolerate beta-blockers. CCB, alone or with a nitrate, are particularly valuable in the treatment of Prinzmetal angina.

Classification of HF

ACCF/AHA - evolution and progression of HF NYHA - classify symptoms according to clinician's subjective evaluation

β-blockers:

Atenolol Metoprolol Nadolol ******Propranolol

JVD

Jugular venous distension

Symptoms of SIHD

Nausea Fatigue Shortness of breath Sweating Dizziness

Renin-angiotensin-aldosterone system

RAAS

Lusitrope

Ventricular relaxation

Ischemic heart disease (IHD)

imbalance between myocardial oxygen supply & demand --> myocardial hypoxia

Euvolemia

normal volume

Angiotensin II Drugs that affect (-) --> ACEi & ARBs

o Direct Vasoconstriction (increases afterload) o Stimulates NE and aldosterone release o Ventricular hypertrophy and cardiac remodeling

β-blockers Precautions and monitoring effects Please always remember β-blockers may induce bradycardia. Patients should be monitored for excessive negative inotropic effects. (fatigue, shortness of breath, and edema.)

!!!!!! β-blockers should be avoided in Prinzmetal angina (caused by coronary vasospasm) because they increase coronary resistance and may induce vasospasm. !!!!!!! Asthma is a contraindication because all non-selective β-blockers increase airway resistance and have the potential to induce bronchospasm in susceptible patients. Diabetic patients should be warned that β-blockers mask tachycardia, which is a key sign of developing hypoglycemia. DO NOT discontinue β-blocker therapy abruptly. The dose should be gradually tapered off over 5 to 10 days to avoid rebound angina or hypertension.

HF with reduced LVEF

(HFrEF)

Miscellaneous drugs:

*****Ranolazine Adenosine Aspirin Statins

Digitalis glycoside: Digoxin ECG effects

-- Digoxin is a complex drug and has a lot of different effects on the heart electrophysiology, which leads to variable ECG findings --- The most common ECG finding in Digitalis Toxicity is Premature Ventricular Contractions (PVCs)

Cangrelor (Kengreal®)

-- Intravenous P2Y12 antagonist indicated in the setting of PCI -- 30 mcg/kg bolus 4 mcg/kg/min for at least 2 hours or the duration of PCI, whichever is longer -- To transition to oral P2Y12s: give loading dose immediately after discontinuing cangrelor infusion -- Frequently used off label as bridging therapy prior to cardiac surgery at a lower dose

Positive inotropic drugs - Adrenoreceptor agonist Dobutamine Is administered by intravenous infusion

-- Used for cardiac stimulation during surgery -- Also used or short-term management of acute heart failure and cardiogenic shock -- Elimination half-life: 2 min Adverse effects: excessive vasoconstriction and tachyarrhythmia

Digitalis glycoside: Digoxin Effects

1. Positive inotropic effect (an increase in the force of contraction) 2. A negative chronotropic effect (a decrease in the heart rate) 3. A negative dromotropic effect (a decrease in conduction velocity, because of decrease in intracellular potassium)

Aldosterone Antagonist

Agents (know initial and target dose; Table 16 2013 ACCF/AHA GF guidelines) -- Spironolactone -- Eplerenone Monitoring -- Renal function (renal dose adjustment) -- Potassium

Therapeutics in HF

Angiotensin-converting enzyme inhibitors (ACE-I) Angiotensin Receptor Blockers (ARBs) Beta-blockers (BB) Diuretics Aldosterone antagonist Digoxin Hydralazine/isosorbide dinitrate Ivabradine Sacubitril/valsartan

Digoxin Adverse Effects Non-cardiac

Anorexia, nausea, vomiting, abdominal pain Visual disturbances Halos, photophobia, problems with color perception (yellow-green, red-green), scotomata Fatigue, weakness, dizziness, headache, neuralgia, confusion, delirium, psychosis

Stroke Volume (SV)

Blood pumped out by ventricle per contraction

Blood Flow

Blood returned to the heart via venous system --> superior vena cava & inferior vena cava --> right atrium --> right ventricle --> pulmonary arteries --> lungs for oxygenation --> pulmonary veins --> left atrium --> left ventricle --> aorta --> systemic circulation (body)

Heart Failure Drug Treatment

ACEI ARBs β-blockers Diuretics Vasodilators Calcium channel blockers Positive inotropic agents

Types of Angina Prinzmetal's or variant or vasospastic angina

AVOID β-BLOCKERS

Cardiac Index Hemodynamic parameter that relates to CO from left ventricle in one minute to body surface area (BSA) -- Relates heart performance to the size of the individual Normal: 2.8 - 3.6 L/min/m2

Adequacy of perfusion (relates to CO) o Reflects the adequacy of perfusion o Often used for determining the subset of acute decompensated heart failure -- A cardiac index less than 2.2 L/min/m2 indicates hypoperfusion and is considered "cold"

Positive inotropic drugs Phosphodiesterase inhibitor: Milrinone Administered intravenously for short term heart failure management Has been used for infants and children awaiting for cardiac transplantation requiring cardiac stimulation

Adverse effects: Arrhythmias, hypotension, liver toxicity and thrombocytopenia

Vasoconstriction increases

Afterload

Angina Major risk factors

Age (≥ 55 for men, ≥ 65 for women) Cigarette smoking Diabetes mellitus (DM) Dyslipidemia Family History Hypertension (HTN) Kidney disease Obesity Physical inactivity Medications

HF ACE-INHIBITORS Cornerstone of pharmacotherapy in HF

Agents (class effect) (know initial and target doses) -- Enalapril -- Ramipril -- Lisinopril -- Captopril (typically used in hospital setting)

Ca2+ Channel Blocker (CCB) Drugs for Angina

All are synthetic compounds; Structurally diverse; divided into 3 classes; Formulations and routes of administration: mostly in slow-releasing tablet format for oral administration, also available for IV injection; Are rapidly and completely absorbed after oral administration; but undergo hepatic first-pass metabolism by CYP3A4 and CYP2D6; Mainly prophylactic use for the prevention of angina; Adverse effects: Headache, fatigue, dizziness, flushing, peripheral edema constipation (probably because of relaxation of gastrointestinal smooth muscle and reduced peristalsis) Drug interactions: Ca2+ channel blockers positively interact with other vasodilators, alcohol, CYP3A4 inhibitors (such as grapefruit juice), HIV protease inhibitors, and erythromycin; negatively interact with CYP3A4 inducers (such as rifampin or phenobarbital).

HF Guidelines

American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Guideline for the Management of Heart Failure Numerous large, randomized, double-blinded, multi-center trials guide treatment options in HFrEF (refer to handout) No randomized trials conducted in HFpEF

Ca2+ channel blockers

Amlodipine Felodipine Isradipine Nicardipine *****Nifedipine *****Diltiazem *****Verapamil

Organic nitrates:

Amyl nitrite *****Nitroglycerin Erythrityl tetranitrate Pentaerythritol tetranitrate Isosorbide dinitrate Isosorbide mononitrate

Mean Arterial Pressure (MAP)

Average blood pressure during one cardiac cycle Affected by CO & SVR

Diagnosis of HF Laboratory tests (think differential diagnosis)

BNP or NTproBNP CBC CMP - goal K > 4.0 mEq/L (to help w/ arrhythmia issue) Renal and hepatic function (AST/ALT increases) Urinanalysis Lipid profile A1C profile Thyroid function tests 12-lead ECG

Infrequently Used Therapies Tolvaptan

o Vasopressin antagonist o Tx of hyponatremia in euvolemic or hypervolemic states o Oral o Must be given in hospital o Na will drop after discontinuation !!High cost!!

Organic nitrates: Adverse effects and interactions

Caused by excessive vasodilation: -- Headache -- Hypotension -- Dizziness -- Reflex tachycardia o Tachycardia increases the demand of oxygen -- Counteracts the beneficial effects of nitrates -- So excessive doses of nitrates should be avoided o To prevent reflex tachycardia, a β-blocker can be used with an organic nitrate o The hypotensive effect of organic nitrates can be enhanced by sildenafil and other 5-phosphodiesterase inhibitors

Digitalis glycoside: Digoxin Adverse Effects A classic (board-tested) symptom is visual disturbances, specifically halos around objects and/or yellow or green color aberrations. Also blurred vision.

Common adverse effects are: gastrointestinal, cardiac, and neurological reactions The earliest sign of toxicity are anorexia, nausea, and vomiting, which are associated with an elevated levels of serum digoxin concentrations Other adverse effects in heart: - inhibition of the Na/K/ATPase leads to increase excitability which leads to ectopy and tachycardia - decreased conduction in the AV node leads to bradycardia and AV blocks o Digoxin has a very narrow therapeutic window. A blood level of 0.5-0.9 ng/mL is considered therapeutic while >1.2 ng/mL may cause severe side effects.

Digitalis glycoside: Digoxin Drug interactions

Common drug interactions: Antacids, cholestyramine, diltiazem, quinidine, and verapamil Antacids and cholestyramine can reduce the absorption of digoxin and decrease its therapeutic effects, their administration should be separate from that of digoxin by at least 2 hours. Diltiazem, quinidine, and verapamil reduce digoxin clearance and increase serum digoxin levels, hence contributing to digoxin toxicity

Digitalis glycoside: Digoxin

Composed of a steroid nucleus, a lactone ring, and three sugar residues linked by glycosidic bonds The steroid chemical configuration is different from that of human steroids, thus lacks most of the effects produced by gonadal or adrenal steroids Adequately absorbed from the gut, half-life: 36 hours Mainly eliminated by renal excretion of the parent compound

Consequences of HF

Death -- Pump failure -- Arrhythmias Risk of arrhythmias Poor quality of life Hospitalizations Cardiac transplant/left ventricular assist device Co-morbidities -- Sleep apnea -- Anemia -- Renal insufficiency -- Chronic pulmonary obstructive disease

Classification and Therapeutic Goals for Different Forms of Angina For variant angina (due to acute vasospasm):

Decrease vasospasm of coronary vessels (increase oxygen delivery).

Dilation of venous vessels

Decreases Preload

Dilation of arterial vessels

Decreases afterload (BP)

Echocardogram A sonogram that uses standard two-dimensional, three-dimensional, and Doppler ultrasound to create images of the heart. NOT an ECG!!!!

Echocardiography has become routinely used in the diagnosis, management, and follow-up of patients with any suspected or known heart diseases. It is one of the most widely used diagnostic tests in cardiology. It can provide a wealth of helpful information, including the size and shape of the heart (internal chamber size quantification), pumping capacity, and the location and extent of any tissue damage. An echocardiogram can also give physicians other estimates of heart function, such as a calculation of the cardiac output, ejection fraction, and diastolic function (how well the heart relaxes).

Hypovolemia

Dehydrated

Positive inotropic drugs Three classes (increase heart contractility)

Digitalis glycoside: Digoxin Digoxin immune Fab Adrenoreceptor agonist: Dobutamine Phosphodiesterase inhibitor: Milrinone

Diuretics Clinical Pearls

Do not use as monotherapy Use lowest effective dose Bioavailability differs among agents o Furosemide IV to PO conversion - 1:2 (e.g., 20 mg IV = 40 mg PO) o Torsemide and Bumetanide IV to PO conversion - 1:1 (i.e., 20 mg IV = 20 mg PO) o Furosemide 40 mg PO = Bumetanide 1 mg = Torsemide 10 - 20 mg Onset 15-60 minutes; peak effect within 30-90 minutes Reduce dose when patient not volume overloaded Counsel patients on weight status

ADHF Diuretic resistance

Due to altered PK/PD, neurohormonal activation, low CO, reduced renal perfusion decreased drug delivery to kidney Overcome by: o Higher doses o Continuous infusion -- DOSE trial: controversial efficacy o Add a second diuretic o Sodium & fluid restriction

HF Desired Outcomes

Improve patient's quality of life (morbidity) -- Relieve or reduce symptoms Prevent or minimize hospitalizations for exacerbations of HF Slow progression of disease Prolong survival (reduce mortality)

Hypervolemia

Excessive volume (usually presents with edema)

HF Diuretics Preferred agents Agents (loops preferred agents; identify appropriate, safe doses; Table 14 2013 ACCF/AHA HF Guidelines)

Furosemide Bumetanide Torsemide Metolazone - not typically used daily; know initial and max dose (max dose rarely used)

Endogenous Nitric oxide production and its effects

Glucose is the donor for NADPH. Shortage of NADPH can be disastrous!!!

Types of HF

HFpEF HFrEF o HFpEF, borderline: 41-49% (similar to those with HFpEF) o HFpEF, improved: > 40% (patients with HFpEF who previously had HFrEF; improvement or recovery in EF may be distinct from those with persistently preserved or reduced EF - need future research)

Nitrate ADRs

Headache Hypotension Orthostatic hypotension Tachycardia Peripheral edema Tolerance: maintain nitrate free interval!

Chronotrope

Heart rate o Chronotropic drugs may change the heart rate and rhythm by affecting the electrical conduction system of the heart and the nerves that influence it, such as by changing the rhythm produced by the sinoatrial node. -- Positive chronotropes increase heart rate; -- Negative chronotropes decrease heart rate.(beta blockers)

Cardiac output (CO) Normal: 4-7 L/min

Heart rate (HR) x SV --Absolute (i.e., mL) amount of blood pumped out by the ventricle during a contraction per minute

ADHF Diagnosis

Hemodynamics Pulmonary artery (Swan-Ganz) Catheterization BNP, NT-proBNP, cardiac troponin Chest X-ray Echo

Diagnosis of HF

History and physical examination -- Jugular venous distension (JVD) -- Hepatojugular reflux -- Pitting edema -- Temperature of lower extremities -- Pulmonary status (rales, crackles) Medication history Imaging -- Chest x-ray -- Echocardiogram Cardiac catheterization - Swanz-Ganz

Antianginal therapy o Goal is reduction of myocardial O2 consumption by ↓ 1 or more of the determinants of MVO2: End-diastolic volume, BP, HR, contractility

↓

Pharmacotherapy for SIHD

Indicated for all patients with CAD [SIHD + ACS], often referred to as "chronic therapy"

Positive inotropic drugs Phosphodiesterase inhibitor: Milrinone

Is used in conditions requiring myocardial stimulation Inhibits type 3 phosphodiesterase (PDE) that converts cAMP to inactive 5'-AMP Hence, it increase cAMP concentration, which activates PKA that in turn increases calcium release that stimulates cardiac contractility It also increases cAMP in vascular smooth muscle and produces vasodilation

Compensatory Mechanism #4 Ventricular Hypertrophy and Remodeling

Key components in pathogenesis of progressive myocardial failure Ventricular hypertrophy - increase in ventricular muscle mass Remodeling - broader term describing changes in myocardial cells and extracellular matrix that result in changes in size, shape, structure, and function of heart Result in change in shape from ellipse to sphere Neurohormones - angiotensin II, NE, endothelin, aldosterone, vasopressin, cytokines

Compensatory Mechanism #2 Fluid Retention and Increased Preload Aldosterone antagonists can help reverse effects

Kidneys sense decreased organ perfusion and release renin from juxtaglomerular cells to compensate -- Reduced renal perfusion and increased sympathetic tone stimulate renin release, leading to angiotensin II production -- Angiotensin II stimulates aldosterone release, an additional mechanism for renal sodium and water retention -- Retention increases venous return to the heart, causing fiber stretch (increased contraction) and higher preload pressures Increases in preload in chronically failing heart leads to pulmonary or systemic congestion because heart unable to move fluid forward (detrimental result) Neurohormones: aldosterone, angiotensin II

Digoxin immune Fab An antidote for severe digoxin toxicity

Made from immunoglobulin fragments taken from sheep previously immunized with a digoxin derivative Administered intravenously and can rapidly reverse digoxin toxicity by binding to digoxin

Causes of ADHF

Non-adherence Acute Myocardial Ischemia Uncorrected hypertension Atrial fibrillation, Arrhythmias Negative Inotropes Drugs --> salt & water retention Alcohol Infections Pulmonary Embolism

Heart Rate

Normal: 60-80 beats/min

Digoxin Clinical Pearls Narrow therapeutic range -- Monitor digoxin blood levels (goal: 0.5-0.9 ng/mL) -- Blood levels may be different in various disease states (e.g., atrial fibrillation) -- Not necessary to monitor routinely unless suspected digoxin toxicity, worsening renal function, interacting drug, or other conditions that may affect blood levels Toxicity -- Hypokalemia -- Hypomagnesemia -- Hypercalcemia

Most patients will need 0.125 mg - 0.25 mg QD Lower initial dose (0.125 mg QD or QOD) for certain patient populations -- Elderly patients (> 70 years) -- Patients with renal dysfunction -- Low lean body mass -- Patients with interacting drugs (e.g., amiodarone) Loading doses of digoxin generally not needed in chronic HF

Deleterious Medications in HF

NSAIDs and COX-2 Inhibitors - fluid retention Metformin - lactic acidosis TZD - fluid retention Non-dihydropyridine CCBs - weakens ventricular contraction (negative inotrope) TNF-alpha antagonist - increase mortality and hospitalizations Serotonin agonist - increases afterload

Neprilysn

Neutral endopeptidase Degrades endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin Inhibition of neprilysn increases levels of the these substances, countering neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling

Symptoms of SIHD

Pain is likely due to another cause if: -- Described as sharp or stabbing -- Chest wall tenderness -- Changes with position or breathing patterns

Types of Angina Mixed forms of angina

Patients with advanced coronary artery disease may present with angina episodes during effort as well as at rest, suggesting the presence of a fixed obstruction associated with endothelial dysfunction.

Ejection Fraction (EF) Related to CO -- Commonly measured by echocardiogram

Percentage of blood pumped out by ventricle during contraction (Normal EF ~55-65%)

β-blockers With β-blockers, the demand for oxygen by the myocardium is reduced both during exercising and at rest.

Propranolol is the prototype for this class of compounds, but it is not cardioselective. Thus, other β-blockers, such as metoprolol or atenolol, are preferred. All β-blockers are nonselective at high doses and can inhibit β2 receptors. This is particularly important to remember in the case of asthmatics. Agents with intrinsic sympathomimetic activity (for example, pindolol) are less effective and should be avoided in angina. The β-blockers reduce the frequency and severity of angina attacks. β-blockers are particularly useful in the treatment of patients with myocardial infarction and have been shown to prolong survival. The β-blockers can be used with nitrates to increase exercise duration and tolerance (improve the quality of life).

Compensatory Mechanism #1 Tachycardia and Increased Contractility Beta Blockers can help reverse effects of NE

Rapidly occurs in response to decreased CO Sympathetic nervous system -- NE determines concentration of calcium ions in the cytosol of cardiac muscle cells -- Stimulates beta receptors Contractility: increases in intracellular calcium during contraction Increased HR via NE can reduce lusitropy and increase myocardial oxygen demand Neurohormone: NE

Compensatory Mechanism #3 Vasoconstriction and Increased Afterload ACEi or ARBs and Beta Blockers

Redistribution of blood in response to decreased CO Impedes forward ejection of blood from the ventricle further decreasing CO and increasing afterload Neurohormones - NE, angiotensin II, endothelin-1, and others

HFpEF HFpEF, borderline: 41-49% (similar to those with HFpEF) Etiology typical of HTN

Referred as diastolic HF Condition in which myocardial relaxation and filling are impaired and incomplete and/or increased diastolic stiffness -- Decreased CO, normal to elevated EF -- Usually thing, non-compliant ventricle Characterized by signs and symptoms of HF with preserved LVEF defined as 50% or greater

HFrEF Etiology typically MI

Referred as systolic HF Ventricle too weak to pump sufficient blood for adequate perfusion Characterized by signs and symptoms of HF and reduced LVEF defined as 40% or less

Frank-Starling Mechanism

Relationship between stretch of cardiovascular fibers and the force of the cardiovascular contraction

Systemic Vascular Resistance (SVR) Calculation: [(MAP - CVP)/CO] * 80 Normal: 800-1200 dynes*second*cm-5

Resistance to flow that must be overcome to push blood through the circulatory system o Vasoconstriction can increase SVR o Vasodilation can decrease SVR o Don't want systemic vascular resistance in heart failure patient

ADHF Vasodilators Adjunctive therapy to diuretics to relieve pulmonary congestion

o Used in "wet" subsets -- All warm & wet -- Cold & wet with adequate perfusion (MAP >50/SBP >90) o Venous vasodilation reduced PCWP and acute relief of SOB while awaiting diuretic effects o Arterial vasodilation can be used as alternative to inotropes in patients with elevated SVR and low CO o Preferred over inotropes when adjunct therapy required

Positive inotropic drugs - Adrenoreceptor agonist Dobutamine

Selectively stimulates cardiac contractility by activating β1 receptor It also activates β2-adrenoceptors in vascular smooth muscle decreasing vascular resistance and cardiac afterload, therefore augmenting cardiac output. Usually causes less tachycardia than other beta-agonists Increases cAMP levels by stimulating adenylate cyclase

Orthopnea

Shorties of breath while laying down. Relieved by sleeping on increased number of pillows

ARB Summary

Similar clinical benefits as ACE-I - good for the heart, patient, and institution! Use in patients who cannot tolerate ACE-I Titrate to target dose or max tolerated dose Adverse effects similar to ACE-I but with different frequencies (e.g., lower incidence of cough) Know monitoring for safety and efficacy

Poiseuille's law:

Small decrease in radius will significantly decrease the blood flow

Vasodilators:

Sodium nitroprusside -- ProDrug Hydralazine Nesiritide

β-Blocker Antianginal Drugs Representative drugs: atenolol, metoprolol, nadolol, and propranolol

They slow down heart rate; are important antiarrhythmic drugs; They have negative inotropic effects; also used in typical angina pectoris (exertional angina) and acute MI; They are NOT vasodilators; not used in vasospastic angina or acute anginal attacks. Synthetic compounds; nonselective β-blockers; an isopropyl (large but not very bulky) substitution on the amino nitrogen is critical for binding to β-receptors; Propranolol is the prototype compound of this class; see Session 5 for SAR. Administered orally and/or intravenously; Often used in combination therapy with nitrates and/or Ca2+ channel blockers.

Digoxin Adverse Effects Cardiac

Ventricular arrhythmias Premature ventricular depolarizations, bigeminy, trigeminy, ventricular tachycardia, ventricular fibrillation Atrioventricular (A-V) block First degree, second degree, third degree block Atrial arrhythmias Sinus bradycardia Potassium abnormalities

Inotrope

Ventricular contractility o An agent that alters the force or energy of muscular contractions. -- Negatively inotropic agents weaken the force of muscular contractions. (CCB) -- Positively inotropic agents increase the strength of muscular contraction.

HF Beta-Blockers Summary

Very beneficial treatment for HF with reduced EF! -- Decreases afterload, reverse remodeling - good for the heart! -- Outcomes - good for patient and institution! Only initiate in stable patients (do not use in acute decompensated heart failure) Know initial/target doses and dose titration Know contraindications/precautions (who to avoid these therapies in) Monitor for safety (e.g, HR, BP) and efficacy (e.g., symptoms, imaging) Patient education

ACE-Inhibitors Summary

Very beneficial treatment for all HF patients (unless contraindicated)! -- Decreases afterload and preload, reduces remodeling - good for the heart! -- Outcomes - good for the institution and patient! -- Many favorable effects for the patient! Titrate slow to reach target dose or tolerated dose Avoid in certain patients (e.g., history of angioedema, bilateral renal artery stenosis, severe aortic stenosis, pregnancy, labile BP and hypotension [systolic < 80 mm Hg]) Important to monitor safety (e.g., kidney function, BP, potassium) and efficacy (e.g., symptoms, imaging)

Evolution of Myocardial Infarction

We are competing with time!!

Pharmacological modification of the major determinants of myocardial O2 supply.

When myocardial O2 requirements exceed O2 supply, an ischemic episode occurs.

Cardiac stimulants and Inotropes: Pharmacology of Heart Failure

With heart failure, the weakened heart can't supply your body with enough blood. This results in fatigue, shortness of breath, and some people have coughing.

Ischemia

an inadequate blood supply to an organ or part of the body, especially the heart muscles.

Anterior View of Coronary Arteries

left anterior descending coronary artery. Abbreviation: LAD coronary artery. One of two major branches of the left coronary artery. RCA-Right Coronary Artery

Right-sided HF

o Usually occurs as a result of left-sided failure or pulmonary disease o Left ventricle fails causing increased fluid pressure transferred back through the lungs, ultimately damaging the heart's right side o Blood backs up in the body's vein causing swelling in legs and ankles

Angina pectoris Prinzmetal's angina

o AKA vasospastic angina AKA variant angina o Unprovoked coronary artery spasm --> chest pain o Not an atherosclerotic syndrome o Often occurs in young patients with few to no cardiac risk factors

Epidemiology

o About 5.1 million people in the US have HF o One in 9 deaths in 2009 included HF as a contributing cause o About half of people who develop heart failure will die within 5 years of diagnosis o Estimated $32 billion each year (includes the cost of health care services, medications, and missed days of work)

ADHF Acute Treatment - Diuretics Initial dose: o At least as high (numerically) as TOTAL daily oral home dose o Administer as -- IV bolus therapy -- Continuous infusion

o Administer loop diuretics intravenously promptly in evidence of fluid overload o Ensure salt & fluid restriction o Reduces morbidity -- Decreases preload, decreases PCWP o Frequent dosing important

Aldosterone Antagonist Contraindications

i. Spironolactone 1. Anuria 2. CrCl < 10 mL/min 3. Hyperkalemia 4. K + supplements and K+ sparing diuretics ii. Eplerenone 1. CrCl < 30 mL/min all patients 2. CrCl < 50 mL/min in patients with elevated SCr (>1.8 mg/dL in women or 2.0 mg/dL in men) 3. Type 2 diabetes with microalbuminuria iii. Both: Concurrently with ACE-I + ARB (hyperkalemia risk)

Left-sided HF

includes HFrEF and HFpEF

Aspirin: Other Prophylactic or Treatment Options for Angina

inhibitor of cyclooxygenases (COXs); regular doses (160-325 mg) of aspirin reduces the incidence of MI and death in patients with unstable angina; prophylactic use of low doses (~81 mg per day) of aspirin reduces inflammation and platelet clotting, which translates into the reduction of incidence of MI in patients with chronic stable angina;

Statins: Other Prophylactic or Treatment Options for Angina

inhibitors of HMG CoA-reductase to reduce cholesterol biosynthesis and coronary atherosclerosis, thus to reduce the incidence of both stable and unstable angina.

Cardiac Remodeling

changes in size, shape, structure, and physiology of the heart after injury to myocardium (we don't want this!)

Aldosterone Antagonist a. Adverse effects

i. Gynecomastia (higher incidence with spironolactone) ii. Hyperkalemia (refer to 2013 ACC/AHA Heart Failure Guideline: Table 17. Strategies to Minimize the Risk of Hyperkalemia in Patients Treated With Aldosterone Antagonists for recommended strategies for reducing risk for hyperkalemia with aldosterone antagonists) iii. Hyponatremia

CCB: Indications o Verapamil mainly affects the myocardium, o Nifedipine exerts a greater effect on smooth muscle in the peripheral vasculature. o Diltiazem is intermediate in its actions.

o All calcium-channel blockers lower blood pressure. They may worsen heart failure due to their negative inotropic effect. o Variant angina caused by spontaneous coronary spasm rather than by increased myocardial oxygen requirement is controlled by organic nitrates or calcium-channel blockers; β-blockers are contraindicated.

Infrequently Used Therapies Midodrine

o Alpha-1 agonist --> increased arteriolar/venous tone --> increased BP o Indicated for orthostatic hypotension o Also used for prevention of HD-induced hypotension o Usual dose: 10mg TID before meals

Risk factor modification for SIHD

o Also indicated in any patient who experienced ACS o Smoking cessation o Blood pressure control o Treatment of hyperlipidemia o Treatment of DM o Weight loss in obesity o Exercise o Diet (saturated fat <7% total calories and cholesterol <200 mg/day)

Medical therapy to support stenting

o Aspirin o P2Y12 Antagonist -- Use of ASA + P2Y12 antagonist is called dual antiplatelet therapy (DAPT) o ± GP IIb/IIIa inhibitors o Anticoagulation

Nitroglycerine Effects on the cardiovascular system o All these agents are effective, but they differ in their onset of action and rate of elimination. o For quick relief of an ongoing attack of angina precipitated by exercise or emotional stress, sublingual (or spray form) nitroglycerin is the drug of choice.

o At therapeutic doses, nitroglycerin has two major effects. First, it causes dilation of the large veins, resulting in pooling of blood in the veins. o This diminishes preload (venous return to the heart) and reduces the work of the heart. o Second, nitroglycerin dilates the coronary vasculature, providing an increased blood supply to the heart muscle. Nitroglycerin decreases myocardial oxygen consumption because of decreased cardiac work.

Aspirin

o Available OTC o 81mg and 325mg most common strengths in the USA o Often enteric coated -- Reduces risk of ulcers -- Slows absorption in ACS must chew aspirin -- Non-enteric coated is preferred in the guidelines o Loading dose at 162-325mg in ACS or prior to PCI or CABG in SIHD o 75-100mg preferred in DAPT o Remember, never more than 100mg with ticagrelor!!!

CCB: Mechanism of action

o CCB prevent and reverse coronary spasm by inhibiting calcium influx into vascular smooth muscle and myocardial muscle. This results in increased blood flow and oxygen supply. o CCB decrease coronary vascular resistance and increase coronary blood flow, also resulting in increased oxygen supply. o CCB decrease systemic vascular resistance and arterial pressure. o CCB decrease inotropic effects, resulting in decreased oxygen demand.

Vasodilators: hydralazine (Apresoline) o The precise mechanism of action of hydralazine is not fully understood. o Preferentially relaxes arterial smooth muscle, so is good for fatigue from congestive heart failure.

o Can be used together with isosorbide dinitrate that primarily relaxes venous smooth muscle. o Well-absorbed through the GI tract, but systemic bioavailability is low (<40%). o Half-life in the body is 1 hour. o Is rapidly acetylated, and forms hydrazones after reacting with alpha keto acids. o Common side effects: -- Headache, nausea, flushing, hypotension, flushing, dizziness, palpitation, tachycardia.

Angina pectoris Chronic stable angina (SA)

o Chronic and predictable development of chest pain (CP) upon exertion or emotional stress o Patients have a fixed angina threshold o Relieved by nitroglycerin and rest

IHD Epidemiology

o Coronary artery disease is the leading cause of death in the US o In the US, 23% of men and 15% of women between 60-79 years of age have IHD; incidence increases with age o Costs of IHD care exceed $150,000,000,000 annually in the US

Decision to revascularize Revascularization benefits

o Decreased frequency of angina symptoms o Little to no improvement in mortality or MI risk (COURAGE trial) -- Improves survival in certain high-risk patients such as Left Main Coronary disease

Left Ventricular End Diastolic Volume (LVEDV)

o Determined by the amount of blood returned to the atria. o Primary determinant of preload

Non-Pharmacological Management

o Dietary modification Sodium restriction: 2 g/day Fluid restriction: 2 L/day (from all sources) Not necessary in all patients o Risk factor reduction Smoking cessation Manage hyperlipidemia and hypertension Immunizations Physical activity as tolerated Weight reduction if overweight

CCB Diltiazem

o Diltiazem has cardiovascular effects that are similar to those of verapamil. Both drugs slow AV conduction and decrease the rate of firing of the sinus node pacemaker. o Diltiazem reduces the heart rate, although to a lesser extent than verapamil, and also decreases blood pressure. o In addition, diltiazem can relieve coronary artery spasm and, therefore, is particularly useful in patients with variant angina. It is extensively metabolized by the liver. o The incidence of adverse side effects is low (the same as those for other calcium-channel blockers). Interactions with other drugs are the same as those indicated for verapamil.

Vasodilators

o Diverse structures or nature of substances: from inorganic salt to synthetic small molecules to natural peptide; o True and pure vasodilators, no effects on cardiac contractility, rhythm or conductivity; o Minoxidil was once a major anti-hypertensive drug, but presently is used mainly for hair regeneration. Not further discussed.

Angina pectoris

o Due to myocardial ischemia o Clinical syndrome typically characterized by pain or discomfort in the chest, jaw, shoulder, back or arm o Occurs in some patients with CAD of at least one coronary vessel

Clinical Presentation

o Dyspnea, especially on exertion o Peripheral edema o Fatigue, weakness, lethargy o Orthopnea (pillow-orthopnea) o Shortness of breath o Paroxysmal nocturnal dyspnea o Exercise intolerance o Tachypnea o Cough o Nocturia/Polyuria o Bloating o Mental status changes

Diagnosis of SIHD

o EKG -- Usually normal -- May have artifact from past MIs -- Complete to rule out ACS o Stress test o cardiac catheterization

NE

o Vasoconstriction (increases afterload) o Tachycardia (increases heart rate) o Contractility o Down-regulation of beta-receptors o Ventricular hypertrophy and cardiac remodeling o Lowers threshold for arrhythmias

Ranolazine (Ranexa) Mechanism of action: inhibits late sodium current that facilitates calcium entry via the sodium-calcium exchanger. The resulting decrease in [Ca2+] reduces cardiac contractility.

o Effects: reduces cardiac oxygen demand, fatty acid oxidation modification may improve efficiency of cardiac oxygen utilization. o Clinical applications: prophylaxis of angina. (Can be used with nitrates and β-blockers) o Pharmacokinetics: oral, duration 6-8 h. o Toxicity: QT-interval prolongation (but not TDP), nausea, constipation, dizziness.

BNP B-Type Natriuretic Peptide (Found predominantly in ventricles) Overall: protects cardiovascular system from negative effects of fluid overload

o Elevated in response to ventricular injury o Natriuresis (removes Sodium) o Diuresis (removes water) o Vasodilation (reduces vascular resistance) o Decreases preload, systemic vascular resistance, arterial pressure, increases GFR, reduces renin release o Broken down by endopeptidase neprilysin

Discharge criteria for ADHF admissions

o Exacerbating factors addressed o Near optimal fluid status o Medications changed IV PO x24h successfully o Patient & family education o Medications optimized as much as possible o Follow-up visit scheduled in a week

Central Venous Pressure (CVP) Pressure of the blood in the thoracic vena cava (Same as right atrial pressure)

o Good indicator of right ventricle preload (indirect measurement of left ventricle preload) o Changes in CVP determined by change in volume of blood within the thoracic veins by the compliance of the veins -- CVP increases by either an increase in venous blood volume or by decrease in venous compliance-->increases venous vascular tone --> decreases muscle compliance

Frank-Starling Mechanism a. As myocardial sarcomere length is stretched, there is an increase in force of contraction b. The length of sarcomere is determined primarily by the volume of blood in the ventricle (LVEDV)

o In normal hearts, increasing end-diastolic volume enhances cardiac performance -- Increases in venous return --> increases in ventricular filling (end-diastole volume) --> increases preload --> initial stretching of cardiac myocytes prior to contraction --> increases sarcomere length --> increase in force of contraction --> increase in stroke volume (and cardiac output) -- This allows the heart to eject additional venous return -- Independent of neural and humoral influences of the heart o In failing hearts, the muscle is less able to alter the force of contraction when the fiber is stretched. Therefore, when the amount of blood that is returning to the heart is increased (increased preload), the heart is not able to contract strongly enough to move that blood forward, resulting in decreased cardiac output (decreased stroke volume) o This contraction is also adversely affected in patients with high systemic vascular resistance (increased afterload)

Acute Decompensated Heart Failure (ADHF)

o Inability of the heart to provide sufficient perfusion to meet the body's metabolic demands o HFrEF & HFpEF account for approximately 50% of ADHF admissions, each

Classification and Therapeutic Goals for Different Forms of Angina For stable angina (due to atherosclerosis and/or exertion):

o Increase myocardial blood flow by dilating coronary arteries and arterioles (increase oxygen delivery), o Decrease cardiac load (preload and afterload; decrease oxygen demand), and o Decrease heart rate (decrease oxygen demand);

Etiology - Causes Diastolic Dysfunction (Restricted Ventricular Filling)

o Increased ventricular stiffness -- Ventricular hypertrophy -- Infiltrative myocardial diseases (e.g. sarcoidosis) -- Myocardial ischemia and infarction Mitral or tricuspid valve stenosis Pericardial disease (pericarditis, pericardial tamponade)

Pulmonary Capillary Wedge Pressure (PCWP) Normal value 8-12 mm Hg

o Indirect measurement of LVEDV Fluid status o High PCWP (>18 mm Hg) reflect congestion and considered "wet"

Classification and Therapeutic Goals for Different Forms of Angina For unstable or acute angina (due to plaque rapture and/or platelet aggregation):

o Inhibit platelet aggregation and thrombus formation (increase oxygen delivery), o Decrease cardiac load (decrease oxygen demand), and o Decrease vasodilate coronary arteries (increase oxygen delivery);

Types of stents Bare Metal Stent

o Made of metal o Older technology o Risk of restenosis ~25% o Endothelium typically coats stent in <3 months o Requires at least 1 month of DAPT after stenting for stable ischemic heart disease

Vorapaxar (Zontivity®) Place in therapy in US not well established

o Mechanism: competitive PAR-1 antagonist -- Thrombin is most potent platelet activator and acts at nanomolar concentrations -- Interaction between thrombin and platelets is mediated by protease activated receptors, especially PAR-1 o Dosing: 2.08mg (equivalent to 2.5m vorapaxar sulfate) PO daily in combination with aspirin and/or clopidogrel o Adverse reactions: -- Bleeding, anemia, rash (2%), depression (2%), retinopathy/diplopia

Types of stents Drug Eluting Stent

o Metal stent coated with antiproliferative drugs that slowly release to block cell proliferation reduces rate of restenosis to ~10% o Newer technology o Endothelium typically grows around stent in ~12 months o Common drugs: -- Everolimus -- Sirolimus -- Zotarolimus

Diuretic Resistance Causes -- Advanced heart failure -- Renal dysfunction -- NSAIDs, thiazolidinediones (TZDs) -- Hyponatremia -- Hypotension -- Lifestyle (e.g., fast food)(Salty foods-should refer to dietician)

o Metolazone -- Inhibits sodium reabsorption at cortical diluting segment of nephron when sodium absorption blocked at ascending loop of Henle -- Creates synergistic diuresis - can be profound (must monitor closely) -- Preferred to thiazide diuretics - longer duration, does not reduce GFR **Not typically used daily due to major electrolyte deficiencies**

Endogenous Nitric Oxide (NO) Production and Degradation

o NO is a gaseous free radical o NO is synthesized from L-arginine by nitric oxide synthases (NOSs) o NO is an important signaling molecule: very small and lipid soluble for easy diffusion between cell membranes o NO is short-lived, usually reacted or degraded within a few seconds o Effects of NO is concentration-dependent

Organic Nitrates NOT EFFECTIVE in UNSTABLE angina

o Organic nitrates (and nitrites) used in the treatment of angina pectoris are simple nitric and nitrous acid esters of glycerol. o These compounds cause a rapid reduction in myocardial oxygen demand, followed by rapid relief of symptoms. o They are effective in stable and variant angina pectoris. (not effective in unstable angina)

CCB Nifedipine a dihydropyridine derivative, functions mainly as an arteriolar vasodilator. This drug has minimal effect on cardiac conduction or heart rate

o Other members of this class, amlodipine, nicardipine, and felodipine, have similar cardiovascular characteristics except for amlodipine, which does not affect heart rate or cardiac output. o admin is orally, usually as extended-release tablets. o It undergoes hepatic metabolism to products that are eliminated in both urine and the feces. o The vasodilation effect is useful in the treatment of variant angina caused by spontaneous coronary spasm.

Types of revascularization

o PCI ± stenting o CABG o Fibrinolytics are NOT considered revascularization -- They ARE considered "reperfusion therapy" which includes lytics, PCI, and CABG

Nitrate tolerance Nitrate tolerance is a major problem with the long-term use of nitroglycerin and long-acting nitrates.

o Possible mechanisms: --- activation of neurohormonal mechanisms, --- plasma volume expansion, --- and depletion of intracellular sulfhydryl cofactors. o How to avoid: 1) regimens should be tailored to provide a 10- to 12-hour nitrate-free interval when possible. 2) supplementation of cysteine and ACE inhibitors may reverse nitrate tolerance by providing reduced sulfhydryl donors (-SH).

Afterload

o Pressure in ventricles at peak of systolic heart phase -- Vasoconstriction results in increased SVR & afterload Some medications can help reduce the afterload to help a patient with heart failure

Preload Affected by venous return

o Pressure or volume in ventricles at end of diastolic heart phase -- Increased venous return --> increased end-diabolic volume --> increased the preload

Myocardial infarction

o Region of myocardial necrosis due to prolonged cessation of blood supply o Could be a non-ST elevation MI or an ST-elevation MI

Stenting complications

o Restenosis -- Occurs 30-50% of the time in ballooning only -- Occurs 10-25% of the time in PCI + stenting -- 50% or more of the lumen at the site of PCI becomes re-occluded, usually in first 3-6 months -- 2/3 of restenosis events result in death or a large MI -- Attempt to prevent this with DAPT o Bleeding at access site o Surgical complications o Heart failure due to volume overload o Acute kidney injury due to contrast o Allergic reaction to contrast o Technical complications

Definition of Heart Failure o Inadequate ability of the heart to pump enough blood to meet metabolic demands of the body

o Results from structural and functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood -- Systolic dysfunction: reduced ventricular contraction -- Diastolic dysfunction: reduced ventricular filling

General approach to therapy for SIHD

o Risk factor modification plus o Medical management (MM) vs. MM + revascularization

Other considerations

o Salt restriction -- Conflicting evidence -- Hospitalized patients: <3g/day o Avoid medications causing salt retention

Aldosterone

o Sodium and water retention o Production of cardiac fibrosis o Lowers threshold for arrhythmias

Decision to revascularize o If revascularization is selected, the team decides if the patient should undergo

o Stenting with a drug-eluting stent o Coronary artery bypass surgery -- Preferred in complex and diffuse CAD -- >50% left main coronary stenosis -- >70% stenosis of proximal LAD and proximal left circumflex arteries -- Three vessel disease -- Especially in patients with ejection fraction <50% -- Similar outcomes to stenting in patients with relatively uncomplicated and lesser degrees of CAD

Organ Perfusion in Setting of Decreased CO -- Decreased CO results in activation of compensatory responses to maintain the circulation - make sure the organs get perfused

o Sympathetic nervous system -- Increased contractility, vasoconstriction, tachycardia -- Faster HR improves perfusion -- Vasoconstriction preserves blood supply o RAAS Sodium and water retention to increase blood volume and preserve blood supply

Summary on routes of administration for organic nitrates

o The sublingual: most useful for treatment of acute attacks of angina pectoris o Oral and transdermal: -- Slow onset, long duration of action 1. Usually used for prophylactic purpose 2. Given in sufficient dosage (to saturate liver's capacity to degrade them)

Nitroglycerine Pharmacokinetics

o The time to onset of action varies from 1 minute for nitroglycerin to more than 1 hour for isosorbide mononitrate. o Significant first-pass metabolism of nitroglycerin occurs in the liver. Therefore, it is common to take the drug either sublingually or via a transdermal patch, thereby avoiding this route of elimination. o Isosorbide mononitrate has improved bioavailability, long duration of action, and stability against hepatic breakdown. o Oral isosorbide dinitrate undergoes denitration to two mononitrates, both of which possess antianginal activity.

β-Adrenergic Blockers

o The β-adrenergic blocking agents decrease the oxygen demands of the myocardium by lowering both the rate and the force of contraction of the heart. o They suppress the activation of the heart by blocking β1 receptors, and they reduce the work of the heart by decreasing heart rate, contractility, cardiac output, and blood pressure.

ADHF Acute Treatment - Diuretics

o Titrate to response -- Can increase dose up to "ceiling dose" -- Once ceiling dose is reached, must add additional doses or change diuresis strategy o Re-dose bolus 2-4 times/day o Adjust drip rate as needed

Antianginal drugs

o Traditional Organic nitrates--NO-Vasodialaion β-blockers Calcium channel blockers Newer antianginal drugs -- Ranolazine -- hydralazine

ACE-Inhibitors Clinical Pearls

o Under-used and under-dosed -- Safety concerns -- Adverse reactions (e.g., AKI, hypotension, angioedema) o Start low and titrate appropriately to predetermined target proven to be beneficial in clinical trials (unless these doses are not tolerated)

Angina pectoris Unstable angina (USA)

o Unpredictable development of chest pain at rest or during minimal exertion o Often increases in frequency and/or severity over weeks o Typically not relieved by nitroglycerin

Endothelin-1 Released by endothelial and vascular smooth muscle cells

o Vasoconstrictor o Decreases renal blood flow o Ventricular hypertrophy o Pro-arrhythmic o Positive inotrope

CCB Verapamil Diphenylalkylamine verapamil slows cardiac atrioventricular (AV) conduction directly, and decreases heart rate, contractility, blood pressure, and oxygen demand. (-) inotrope (-) chronotrope

o Verapamil causes greater negative inotropic effects than nifedipine, but it is a weaker vasodilator. o The drug is extensively metabolized by the liver; therefore, care must be taken to adjust the dose in patients with liver dysfunction. o Verapamil is contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities. It also causes constipation. !!!!! Verapamil should be used with caution in patients taking digoxin, because verapamil increases digoxin levels. !!!!!

Blood Vessels

o When blood vessels dilate, they can hold more blood, hence less blood to return to the heart, hence blood pressure decreases o Therefore, vessel dilation by antianginals and dilators benefits angina patients

CCB Nifedipine Side effects

o can cause flushing, headache, hypotension, and peripheral edema as side effects of its vasodilation activity. As with all calcium-channel blockers, constipation is a problem. Because it has little to no sympathetic antagonistic action, nifedipine may cause reflex tachycardia if peripheral vasodilation is marked. The general consensus is that short-acting dihydropyridines should be avoided in coronary artery disease.

Etiology - Causes Systolic Dysfunction (↓ Contractility)

o ↓ Muscle mass (post-MI) o Dilated cardiomyopathy -- Idiopathic, viral, alcoholic Ventricular hypertrophy o Pressure overload -- HTN -- Pulmonary HTN -- Aortic or pulmonic valve stenosis o Volume overload -- Valvular regurgitation -- Shunts -- High-output states

Mechanotherapies: Other Prophylactic or Treatment Options for Angina

stents and drug-eluting intravascular stents can ameliorate angina and reduce adverse effects in patients with acute coronary syndromes.

Coronary artery disease (CAD)

synonymous with ischemic heart disease

Lusitropy

the rate of myocardial relaxation The increase in cytosolic calcium of cardiomyocytes via increased uptake leads to increased myocardial contractility (positive inotropic effect), but the myocardial relaxation, or lusitropy, decreases

Ventricular hypertorphy

thickening of ventricular walls