CV Pathophysiology Heart Failure and Arrhythmias 2024 PDF

Cardiac Pathophysiology Heart Failure and Arrhythmias Lisa Cohen, Pharm.D., CDCES, CDOE, CVDOE Heart Failure: Definition A complex clinical “SYNDROME” resulting from any STRUCTURAL or FUNCTIONAL cardiac disorder that impairs the ability of the ventricle to fill with or to eject blood. W...

Cardiac Pathophysiology Heart Failure and Arrhythmias Lisa Cohen, Pharm.D., CDCES, CDOE, CVDOE Heart Failure: Definition A complex clinical “SYNDROME” resulting from any STRUCTURAL or FUNCTIONAL cardiac disorder that impairs the ability of the ventricle to fill with or to eject blood. What is Ejection Fraction (EF)? EF is defined as the amount of blood pumped out of the ventricle divided by the total amount of blood in the ventricle. EF=SV/EDV The EF is considered important in HF, not only because of its prognostic importance (the lower the EF the poorer the survival) but also because most clinical trials selected patients based upon EF (usually measured using a radionuclide technique or echocardiography). The major trials in patients with HF and a reduced EF(HFrEF), or ‘systolic HF’, mainly enrolled patients with an EF ≤35% or ≤40%, and it is only in these patients that effective therapies have been demonstrated to date. ACCF/AHA guideline refers to HF as HF with preserved EF (HFpEF) and HF with reduced EF (HFrEF).  Heart failure can be associated with a wide spectrum of left ventricular functional abnormalities, which may range from patients with normal LV size and preserved EF to those with severe dilation and/or markedly reduced EF Heart Systolic dysfunction: An abnormality in systolic function whereby myocardial contraction is impaired. Failure Diastolic dysfunction: An abnormality in diastolic function whereby myocardial relaxation is impaired causing impaired filling of the ventricle. Abnormalities of systolic and diastolic dysfunction frequently coexist.  Type of Heart Failure Criteria Heart Failure HFrEF (Heart failure with LVEF ≤ 40% reduced EF) Ejection HFimpEF (HF with improved EF) Previous LVEF ≤ 40% and follow up LVEF>40% Fraction HFmrEF (HF with mildly reduced EF) LVEF 41-49% Classification HFpEF (HF with preserved EF) LVEF ≥ 50%  Example Etiologies of Heart Failure HFrEF Systolic Heart Failure HFpEF Diastolic Heart Failure (not enough ventricular contraction) (not enough ventricular filling) Reduction in Muscle Mass Increased Ventricular Stiffness Myocardial Infarction Ventricular Hypertrophy from pressure Dilated Cardiomyopathy overload: Infection; Ethanol; Cardiotoxins Hypertension Progression from Ventricular Hypertrophy Aortic Stenosis Pressure Overload Infiltrative Myocardial Disease Hypertension Myocardial Infarction Aortic Stenosis Pericardial Disease Volume Overload Valvular Regurgitation Examples of Medications That Can Precipitate Heart Failure Symptoms Drugs that Reduce Contractility Drugs that cause Sodium and Water Retention Antiarrhythmic drugs such as flecainide and Nonsteroidal anti-inflammatory drugs, such as propafenone ibuprofen Calcium channel blockers, such as verapamil and Glucocorticoids diltiazem Thiazolidinediones, such as rosiglitazone Beta-blockers, such as propranolol and carvedilol (however, these drugs have an important role in treating HF)  HFpEF: Diastolic Dysfunction Heart failure with normal contraction but impaired ventricular filling as a result of increased afterload, wall tension. Compensatory ventricular hypertrophic remodeling with concentric hypertrophy. Reduction in compliance(becomes “stiff”)→decrease EDV and greater EDP SV decrease but EF stays roughly the same depending on relative change in SV and EDV. (EF= SV/EDV) P.Petropolous HFrEF: Systolic Dysfunction Example of HFrEF after a MI where there is destruction of muscle tissue leading to decrease contractility. Alexandre Khan 2013; Creative Commons CCO 2018  DOE PND JVD Heart Failure Symptoms and Signs ORTHOPNEA EDEMA  DOE= Dyspnea (breathlessness/air hunger) on exertion. Orthopnea refers to dyspnea in the supine Heart Failure: (lying down) position, evaluated by number of pillows needed (consider now that Respiratory patients can have beds that elevate the head) Symptoms Paroxysmal nocturnal dyspnea (PND) refers to attacks of severe shortness of breath and coughing that occurs at night when patients are supine.  Cerebral symptoms: confusion, difficulty in concentration, headache, insomnia, anxiety. Nocturia (urination at night) Other Clinical Symptoms of Heart Failure Fatigue and weakness Abdominal symptoms: anorexia (decreased appetite), nausea, right upper quadrant abdominal discomfort/fullness New York Class I Class I: No limitation of physical activity. Heart Association Class II Class II: Slight limitation of activity. Dyspnea and fatigue with ordinary physical activity (e.g. walking up stairs quickly). (NYHA) Functional Class III Class III: Marked limitation of activity. Dyspnea with minimal Classification (less than ordinary) activity (e.g. slowly walking up stairs). of Heart Class IV: Severe limitation of activity. Symptoms are present Failure Class IV even at rest. Physical Signs of Heart Failure Physical Signs of Heart Failure Physical Signs of Heart Failure Chest X-Ray: Cardiomegaly Depending on the cause of heart failure, the chest radiograph may show cardiomegaly, defined as a cardio-thoracic ratio of greater than 0.5 on the x-ray film Chest X-Ray: Pulmonary Edema As the pressure in the LA and LV increases causing increased volume/pressure in the pulmonary vasculature, alveolar edema occurs giving a cloudlike appearance.  Echocardiography Common Testing Method in HF patients Use to Assess LV systolic function & estimate ejection fraction. Left ventricle (LV) Left atrium (LA) Right ventricle (RV) Right atrium (RA) P.Petropolous  Echocardiography Dilated LV from prior MI with severely depressed left ventricular function. Systolic heart failure-- HFrEF P.Petropolous  Stage A: Patient at Risk Example: patient with of Developing Heart hypertension or diabetes Failure Example: patient with Stage B: Patient with reduced left ventricular Structural Heart Disease ejection fraction, or hypertrophy of the left but No Symptoms Stages of Heart ventricle Failure (A-D) Stage C: Patient with Structural Heart Disease and Current or Past Symptoms of Heart Failure Stage D: Patient with End-Stage Heart Failure  Over 5 million persons in the US have clinically manifest HF. Over 800,000 new cases HF dx annually. Heart The lifetime risk of developing HF is 20% for Americans ≥ 40 years of Failure- age. Incidence doubles each decade older than 45 years of age. Importance HF is the primary diagnosis in >1 million hospitalizations annually. to You as a HF is the only cardiovascular disease with increasing prevalence. Pharmacist Although survival has improved, the mortality rates for patients with HF remain approximately 50% within 5 years of diagnosis. Large role of medication management to decrease symptoms, hospitalizations and death.  Demonstrate understanding of normal cardiac electrical function at the cellular level. Demonstrate knowledge of the normal electrocardiogram, including familiarity with normal values for intervals and Learning complexes. Demonstrate understanding of electrophysiologic mechanisms Objectives for the development of supraventricular and ventricular arrhythmias. For ventricular and supraventricular arrhythmias, list major causes, identify the likely etiology, and describe likely signs and symptoms in a given patient. Demonstrate understanding of atrial fibrillation classification with regards to the terms paroxysmal, persistent, long-standing persistent, permanent and nonvalvular. Readings for Lecture For Content Area #2 Read Chapter 10 of Lange’s 8th edition Pathophysiology of Disease, section on pathophysiology of selected cardiovascular disorders, arrhythmias. Read Chapter 39 (The Arrhythmias) of DiPiro’s 12th edition Pharmacotherapy: A Pathophysiologic Approach, sections on pathophysiology, supraventricular arrhythmias and ventricular arrhythmias. Use these readings as enhancement to your understanding of the lecture material only. Recommended Video on normal sinus rhythm: “Normal Sinus Rhythm on an EKG” in Khan Academy by Bianca Yo https://www.youtube.com/watch?v=lRHq7sMRWpU Heart Electrical Function and Dysfunction Normal Electrical Conduction SA node Distribution thru atrial muscle cells Atrial contraction AV node Bundle of His Left Bundle Branch Right Bundle Branch Purkinje fibers Distribution thru ventricular muscle cells Ventricular contraction  Electrical Conduction Velocities of Cardiac Cells In total, the electrical conduction of each beat normally takes less than one quarter of one second to complete. CVPhysiology.com RE Klabunde Review of the Electrocardiogram (ECG) ECG indirectly records the electrical activity of the heart Impulse generated from the SA node→ AV node→ Bundle of His→ Left and Right Bundle Branches→ Purkinje fibers Review of the Electrocardiogram (ECG) P wave: atrial depolarization PR interval: Time impulse travels from SA node to Purkinje fibers QRS complex: ventricular depolarization ST segment: = ischemia, = injury T wave: ventricular repolarization  Impulse Formation: Automaticity Automaticity is defined as a cell’s ability to depolarize itself to threshold and generate an action potential. SA node, AV node, Bundle of His, bundle branches and Purkinje fibers all have some degree of natural automaticity. Atrial and ventricular muscle cells do NOT have natural automaticity. P.Petropolous  Normal Impulse Formation: Automaticity Firing rate of intrinsic (natural) automaticity: SA node with an inherent firing rate of 60 to 100 beats per minute AV node 40 to 60 beats per minute. Bundle of His 40 to 60 beats per minute. Purkinje network 20 to 40 beats per minute. SA node normally functions as “primary pacemaker” and the rest of the conduction system just distributes the electricity in an organized manner However, the remainder of conduction system will also act as “latent” pacemakers and each in order will naturally take over the job if faster impulses are not detected from above. P.Petropolous Automaticity: Physiologic Mechanisms Automaticity can increase and decrease either through normal physiologic mechanisms or as a result of cell injury Most important influence increasing “normal” automaticity of the SA node is the adrenergic nervous system *Increase in rate with increase in slope of phase 4 of depolarization. What are Arrhythmias? Mechanisms of rhythm disorders are classically thought to occur either from alterations in “impulse formation” or from alterations in “impulse conduction” or from both Alterations in Impulse Formation (Automaticity): Example of Pathologic Mechanism If catecholamine concentrations are increased locally at a group of abnormal or diseased cardiac cells, the automaticity of these cells could be enhanced, resulting in an ectopic* tachyarrhythmia originating from that site. *ectopic= coming from an abnormal place Alterations in Impulse Formation (Automaticity): Example of Pathologic Mechanism Ventricular Tachycardia Ischemia injures the membranes of myocytes allowing the cells to become “leaky” and unable to maintain normal ion concentration gradients. This results in a less negative resting membrane potential and if reduced close to the threshold potential, automaticity can be demonstrated even among these non-pacemaker cells. Supraventricular Tachycardia Alterations in Impulse Formation (Triggered Activity): Example of Pathologic Mechanism Under certain conditions, the action potential of cellular depolarization can “trigger” a second action potential called “afterdepolarizations”, and if the amplitude of the second action potential reaches a threshold potential, they can lead to repetitive firing. Torsade de pointes P.Petropolous  Alterations in Impulse Conduction (Heart Block) Conduction blocks can occur anywhere within the specialized conducting system Between sinus node and atrium (SA block) Between atrium and ventricle (AV block) Also within myocardial conducting tissue Within atria (interatrial block) Within ventricles (intraventricular block) P.Petropolous Alterations in Impulse Conduction (Heart Block): Example of Pathologic Mechanism Conduction blocks between the atria and ventricles are Atrioventricular (AV) Block termed AV block AV block exists when the atrial impulse is conducted with delay or is not conducted at all to the ventricle. Block can occur at the level of the AV node, the Bundle of His, and bundle branches. Commonly seen in clinical practice Caused by ischemia, fibrosis, trauma & drugs Three degrees of types of AV block: 1st, 2nd & 3rd degree Alterations in Impulse Conduction (Re-Entry) Action Normal Conduction: cells Potential sequentially depolarizing with both pathways conducting simultaneously; impulse dies out at the XX. x The  and  pathways can differ in their speed of conduction and in their   refractory periods, but both must be fully recovered (repolarized) and ready to accept a new action potential for normal conduction to occur. XX Distal conduction tissue Alterations in Impulse Conduction (Re-Entry) Premature (early) Beat * In order for reentry to occur, three conditions must exist: 1) One pathway with slower recovery time and faster conduction ( in the picture) 2) One pathway with slower conduction and faster recovery time ( in the picture) a  3) Early or “premature” action potential that reaches the two pathways before the  pathway has fully recovered and can accept the impulse (unidirectional block) Alterations in Impulse Conduction (Re-Entry) Conduction then proceeds through the heart and reenters the area of the block. In other Premature (early) Beat words, after the beat travels slowly down the right side ( pathway), it finds the left side( pathway) ready to conduct the beat back up * (orange arrow). The re-entry circle continues until the delicate balance of conduction and repolarization between the two pathways is altered. Recognizing the three elements needed (premature beat and two pathways with precise differences in conduction and refractory periods) leads to identifying causes  and treatments of arrhythmias caused by re-  entry. Reentry Alterations in Impulse Conduction (Re-Entry): Example of Pathologic Mechanism Reentry tachycardia is most commonly seen in the AV node but can also occur within the atrium and ventricle and is the mechanism for the frequently seen arrhythmias such as paroxysmal supraventricular tachycardia, atrial flutter and atrial fibrillation as well as ventricular arrhythmias. P.Petropolous Alterations in Impulse Conduction (Re-Entry): Example of Pathologic Mechanism Bypass Track In some individuals, there is an additional track of conducting tissue between the atria and the ventricle. In patients with antidromic (down from atria to ventricle) conduction down this pathway, impulses from the atria travel through this conducting tissue, bypassing the AV node and depolarizing the ventricles earlier than normal. This is very important because the number of atrial impulses reaching the ventricle cannot be controlled via slowing of the AV node.  Principles Underlying ECG Intervals & Complexes Length of interval=speed of conduction (short=fast; long=slow) P wave: atrial depolarization PR interval: Time impulse travels from SA node to Purkinje fibers QRS complex: ventricular depolarization Normal values noted; QT is corrected for heart rate Each small box = 0.04 seconds (40 milliseconds) ST segment: = ischemia, = injury Each large box = 0.20 seconds (200 milliseconds) T wave: ventricular repolarization Example of a normal rhythm strip Lead 2. Normal sinus rhythm at 75 beats per minute  ECG Leads Electrodes placed on the chest and limbs 12 leads 3 bipolar limb leads: I, II, III 3 unipolar limb leads: aVR, aVL, aVF 6 unipolar chest leads: V1-V6 6 limb leads provide a frontal view of the heart 6 precordial chest leads provide a horizontal view of the heart  Standard 12-Lead ECG Localization of the Left Ventricle V-V2: Septum V3-V5: Anterior wall V1-V4: Anteroseptal V1-V6: Anterolateral wall I & aVL: High lateral wall II, III, aVF: Inferior wall P.Petropolous  Abnormalities in normal conduction system  Sinus Node Tachycardia (>100 bpm)  Sinus Node Bradycardia (100 beats per minute (definition of “tachycardia”) Mechanism: increased automaticity Can you give an example of when you might have sinus tachycardia? (e.g., fever, exertion (appropriate physiologic response), drugs such as caffeine, sympathomimetics, anticholinergics) Sinus bradycardia 0.2 seconds (>5 small boxes) Mechanism impacting AV node: increased vagal (cholinergic) tone, decreased sympathetic tone Can you think of what kinds of drugs might cause first degree AV block? Atrioventricular (AV) Block-Second and Third Degree Second Degree: Intermittent failure of conduction between the atria and ventricle such that not every P wave is followed by a QRS complex Third Degree: No relationship between the P waves and the QRS complexes. Atria depolarize in response to SA node activity, while an escape rhythm drives the ventricles independently at an intrinsic rate of 30 to 50 beats per minute Supraventricular Arrhythmias The term supraventricular = Arrhythmia exists above the ventricles and therefore conduction of impulses is through the AV node/HIS bundle/purkinje fibers to the ventricles. The Important Principle: Atrial arrhythmias originate depolarization of the ventricle is normal and fast within the atrial myocardium but outside the SA (as indicated by narrow QRS complexes). The node. Therefore giving drugs that alter the SA corresponding ventricular contraction is normal. node firing will not alter the arrhythmia. The rare exception to this rule is if the patient has an additional direct electrical pathway from the atria to the ventricle (antegrade bypass track), as described previously. Supraventricular Arrhythmias There are several types of atrial arrhythmias and they can form because of abnormal automaticity in atrial myocardial cells or by developing re-entry circuits. Common causes of these arrhythmias include structural heart disease (valve disease, alterations in the myocardium), electrolyte abnormalities such as low potassium, and ischemic heart disease (decreased oxygenation of the myocardial tissue) Examples: Premature Atrial Complex (PAC) ; Atrial Tachycardia Most Common Supraventricular Arrhythmia: Atrial Fibrillation/Atrial Flutter Atrial Fibrillation Frequently initiated by PAC (premature atrial complex) from tissue surrounding pulmonary veins ( ) Multiple reentry wavelets propagating in different directions within the atria (NOT generated or propagated by the SA node) Causes disorganized atrial depolarizations producing no effective atrial contraction Arrhythmias: Importance to You as a Pharmacist Atrial fibrillation affects approximately 2.5 million Americans every year, with an increase in incidence due to age Significant stroke risk associated with atrial fibrillation means that most of these patients require anticoagulant medications that have bleeding risks Recognition of the critical role that the AV node plays in filtering the number of impulses from the atria from reaching the ventricles Understanding the location of arrhythmias, the sites of action of antiarrhythmics and the expected outcomes of their use so that patient care is optimal Unlike atrial arrhythmias, arrhythmias generated within the ventricle have no intrinsic control mechanism (ie, AV node acting as a filter of excess beats). Patients with underlying structural heart disease or ischemic heart disease are most likely to develop life-threatening ventricular arrhythmias. Recognition of conditions and drugs (antiarrhythmic and non-antiarrhythmic) that prolong the repolarization time of the ventricle (evidenced by a prolonged QT interval) to avoid development of the ventricular arrhythmia, Torsades de Pointes.  Atrial Fibrillation Electrocardiogram: Small undulating waves (no clear p waves) Atrial rate: 350 to 600 beats per minute SA node is “turned off” because of the fast atrial tissue firing rate AV node acts as filter for most of the beats Irregularly irregular ventricular response conducting between 100 and 160 beats per minute Irregularly irregular rhythm with no discernable “p” waves Cardiac Arrhythmia Institute Atrial Fibrillation: Symptoms Symptoms determined by multiple factors: Underlying cardiac status– loss of atrial contraction means that patients with heart failure lose about 20% of their LV stroke volume so they can develop worsening symptoms (e.g., shortness of breath, weakness and fatigue) Resulting rapid ventricular rate– 1) increases oxygen demand by the heart, causing myocardial ischemia; 2) the rate can be so fast that the ventricles don’t have enough time to produce an effective contraction, decreasing cardiac output. Palpitations (perception of fast heart rate) is the most common symptom, however, some patients have no symptoms at all.  Atrial Fibrillation: Classification Parosxymal: AF that terminates spontaneously or with intervention within 7 days of onset Persistent: continuous AF that is sustained >7days Long Standing Persistent: continuous AF > 12 months in duration Permanent: Patient and clinician make joint decision to stop further attempts to restore and/or maintain normal sinus rhythm Nonvalvular AF: AF in the absence of moderate to significant mitral stenosis or in the absence of a mechanical heart valve (AHA/ACC 2019) Important Issue with Atrial Fibrillation: Risk of Stroke Noncontracting atrium → stagnant blood flow → clot formation → left atrial appendage → embolizing to the brain Atrial Flutter Due to a single large reentrant circuit that involves the lower lateral right atrium ECG demonstrates characteristic flutter waves forming the classic “sawtooth” pattern Atrial depolarization occurs ~300 beats/min usually conducting through the AV node in a 2:1 or 4:1 ratio (2 or 4 flutter waves for each QRS) Atrial flutter unlike atrial fibrillation tends to be a very regular rhythm (QRS complexes are evenly spaced apart) Causes, symptoms and embolization risk similar to atrial fibrillation Cardiac Arrhythmia Institute Paroxysmal Supraventricular Tachycardia (PSVT) AV Nodal Reentrant Tachycardia (AVNRT) Abrupt onset and termination Triggered by a PAC Narrow QRS complex tachycardia (QRS men Most patients have structurally normal hearts Can occur in patients with rheumatic heart disease, pericarditis, MI or mitral valve prolapse Cardiac Arrhythmia Institute Paroxysmal Supraventricular Tachycardia (PSVT) AV Reentrant Tachycardia (AVRT) AVRT is different from AVNRT Reentry circuit with AVNRT contained within the AV node AVRT usually Reentry circuit with composed AVRT of one requirespathway accessory both atrium and and ventricle the AV node and conducting tissue called an “accessory pathway” bridging the atrium and ventricles outside of the AV node Patients whose accessory pathway conducts downward from atria to ventricle are considered to have “Wolff-Parkinson- White” syndrome. This antegrade pathway does NOT respond to drugs that slow down AV node conduction and puts patients at high risk if they develop an atrial arrhythmia. Cardiac Arrhythmia Institute  Ventricular Arrhythmias Premature Ventricular Complexes (PVCs) Ventricular Tachycardia Ventricular Fibrillation What differences do you see compared to normal sinus rhythm? P.Petropolous  Premature Ventricular Complexes (PVC’s) Most common of the ventricular arrhythmias May arise from a ventricular focus with enhanced automaticity or may represent a form of reentry Single PVC’s, sporadic or in a periodic pattern, are sometimes referred to as “simple” ventricular ectopy Multiform PVC’s, ventricular couplets, and non-sustained ventricular tachycardia are referred to as “complex” ventricular ectopy Single PVC Multiform PVCs  Premature Ventricular Complexes (PVC’s) PVC’s increase in frequency with age Can occur in patients with and without structural heart disease PVC frequency and complexity have NO prognostic significance for patients WITHOUT structural heart disease (i.e., normal heart) Patients with prior myocardial infarction, both frequent PVC’s (>10 PVC’s/hr) and complex ventricular ectopy are associated with an increased risk of death  Ventricular Tachycardia Series of three or more PVC’s in a row at a rate of 100-200 beats/min Divided arbitrarily into two categories Sustained: V tach persisting > 30 seconds or requires termination because of severe symptoms Nonsustained: 3 or more consecutive PVC’s lasting 440 milliseconds) Some categories of antiarrhythmic drugs (Class Ia and Class III) Other non-antiarrhythmic drugs Electrolyte imbalance (Low K (potassium) and Mg (magnesium) levels) Congenital prolongation of the QT interval Usually symptomatic, can be self-limited but also can result in poor outcomes Syncope (loss of consciousness due to drop in blood pressure) Ventricular fibrillation Because of concern of risk, there are many drugs that have been pulled from the market or stopped in production because they caused prolonged QT  Ventricular Fibrillation Life-threatening Disordered rapid stimulation of the ventricles preventing coordinated contraction= no cardiac output, no blood pressure, no perfusion of organs Major cause of death with MI ECG: chaotic irregular complexes of varying amplitude & morphology without discrete QRS waveforms Treatment: Immediate Electrical Cardioversion. If resuscitated, look for structural heart disease; ischemic heart disease P.Petropolous QT Prolongation Normal QT = 0.25 – 0.45sec or 250-450ms QTc is the corrected value of the QT interval Normal QTc = 350-450ms men; 360-460ms women 10% of the population may have QTc values outside of this range Causes Genetic: long QT syndrome, medications (antiarrhythmics, antipsychotics, antibiotics), electrolyte abnormalities (K+, Mg+) Age, sex, HTN, BMI, medication interactions, low calorie diets, K+ levels