(4/2) Groo Lecture: Pharmacotherapy of Chronic Heart Failure (HF) Part I: Pathophysiology Treatment Introduction Heart Failure (HF) formerly referred to as congestive heart failure, HF is a clinical syndrome caused by the inability of the heart to pump enough blood to meet the metabolic demands of the body. It is a progressive disorder if left untreated. The cardinal manifestations include: Dyspnea/SOB, Fatigue, Fluid retention

- Epidemiology: 20% prevalence for subjects over 40yo. It is the most common admission diagnosis, for which 25% of patients admitted under a HF diagnosis will return to the hospital within 30 days

Contributing Elements of the Working Engine (Heart) Preload: Left ventricular volume at the end of diastole. It is affected by sarcomere length ~ how stretched the muscle is Afterload: The opposing force the left ventricle works against to eject blood. It is the vascular resistance (status of systemic Contractility: The intrinsic strength of the cardiac muscle • These 3 parameters determine the Stroke Volume (SV) and are therefore directly proportional to Cardiac Output (CO) • CO directly contributes to mean arterial pressure (MAP) which regulates the degree of tissue perfusion – metabolic exchange Ejection Fraction (EF): The portion of total ventricular blood volume that is ejected during each contraction. It is used to measure cardiac function. It should be ³ 50%, no one is 100%. • ECG and Cardiac MRI are the most accurate imaging methods

Fluid Dynamics of the Failing Engine (Heart Failure) Heart Failure with Reduced Ejection Fraction

(HF-rEF) Heart Failure with Preserved Ejection Fraction

(HF-pEF)

Direct Cause: Impaired ventricular contraction EF £ 40% Patho: A significant loss of muscle mass due to cardiac insult impairs volumetric ejection and is threatened by compensatory mechanisms • Initial cardiac insult induces primary damage and reduced EF • Coronary disease (Hx MI) and HT are most common causes • Body recognizes decreased O2 supply (low tissue perfusion)

• Compensatory mechs induce secondary damage via neurohormones • Increased preload, vasoconstriction, tachycardia, remodeling

Reduced EF may also be related to low pressure or volume overload

Direct Cause: Impaired ventricular relaxation EF ³ 50% Patho: Thickening and stiffening of the ventricular walls decreases the ventricular volume but does not alter the EF • Left Ventricular Hypertrophy (LVH) secondary to HT • Post-MI • Infiltrative diseases (amyloid, sarcoid) • Endomyocardial fibrosis

Clinically: 50% of HF pts. Lower mortality, higher Sx burden

Compensatory Mechanisms - Increased Preload

o A decrease in cardiac output will lead to reduced renal tissue perfusion o Kidney thinks ‘low blood volume’, and responds by activating the RAAS system (Na+ and H2O retention) o As a result, there is an increased return from the venous system, improving SV and CO o Over time, chronic volume overload and increased myocardial work (MVO2) stress and damage the heart

- Increased Afterload o A decrease in cardiac output will lead to a reduced blood pressure [MAP = ( CO * SVR ) + CVP] o Kidney thinks ‘low blood volume’, and responds by activating RAAS and Sympathetic Nervous System o As a result, there is increased vasoconstriction in effort to redistribute blood flow to the vital organs o Over time, Ýafterload and ÝMVO2 will weaken the heart – further decreasing cardiac output

- Tachycardia o A decrease in cardiac output will lead to reduced O2 supply to the tissues o This activates the SNS, which releases catecholamines to act upon ionotropic b receptors of the heart o HR increases, helping to maintain cardiac output o Over time, this will decrease diastolic filling time such that the extra preload has nowhere to go which

may result in backflow. Overall, this increases myocardial oxygen demand, may precipitate arrhythmias, and lead to a down-regulation of b receptors.

§ Also, long-term exposure to NE is toxic for the heart - Detrimental overshoot of these compensatory mechanisms produces symptoms and worsening cardiac function.

The goal of therapy in heart failure it to stop the decline in cardiac function by inhibiting or blocking these detrimental neurohormones.

The Beneficial Neurohormones - Nitric Oxide (NO): Is a vasodilator that effectively offsets the vasoconstriction conferred by AngII (RAAS) and

therefore protects against ventricular remodeling. However, the bioavailability of NO in HF is ß - Natriuretic Peptides: These are vasodilators and natriuretics, hence, these hormones inhibit SNS and offset RAAS

o Natriuretic effect involves the promotion of Na+ and H2O loss o They are synthesized in the myocardium (ANP – atria, BNP – ventricle)

Diagnosing Heart Failure (HF) - Clinical Presentation - Sx and PE are generally related to low output or fluid backing up

o Sx: Abdominal pain, bloating/constipation, tachypnea, dyspnea on exertion, early satiety, confusion § Paroxysmal Nocturnal Dyspnea (PND): Waking up unable to breathe due to blood accumulation

o PE: Pitting edema, hepatomegaly, ascites, weight gain, tachycardia, pulmonary edema, cyanosis of digits § Jugular Venous Distension (JVD): Neck veins engorged with extra fluid § Hepatojugular Reflux (HJR): Push on the belly, neck veins get engorged § Displaced PMI: Point of maximal impulse. Feel size/displacement of pt heart through the ribs

Clinical Presentation Symptoms Physical Exam Backward Flow PND, Tachypnea, Abdominal pain,

bloating, Cough Pitting edema, JVD, HJR, Pulmonary edema

Forward Flow Exercise intolerance, Fatigue, confusion, altered mental status

Tachycardia, Pallor, Cyanosis

- Tools o Chest X-Ray: Can detect cardiomegaly, pulmonary edema o Electrocardiogram (EKG): Can detect prior MI Hx, LVH, and assess heart rhythm o Echocardiogram (ECG, Echo) and Cardiac MRI: May assess ejection fraction

- Labs o Natriuretic Peptides: They are released by the myocardial tissue in response to stretch on the ventricle. If

BNP > 400, it is an inclusion criteria suggestive of HF o Baseline labs: CBC, electrolytes, LFT, Lipid panel, Fasting BG, TSH

§ CBC? TSH?: Anemia + Hyperthyroidism induce High Output States, which may provoke HF-rEF - Distinguishing HF-pEF from HF-rEF

o Both have very similar presentations in their Sx, PE, and CXR. The difference is the cause Classifying Heart Failure (HF)

- New York Heart Association (NYHA) Functional Class o I No Sx with ordinary physical activity o II Sx with ordinary physical activity o III Sx with less than ordinary exertion (performing ADLs) o IV Sx at rest

- American Heart Association (AHA) Stages o A Patient at high-risk for HF but without structural heart disease or Sx o B Structural heart disease identified (EF < 40%) without S/Sx o C Structural heart disease with prior or current Sx. [Once C, always at least C, even if FCß to 1] o D Refractory HF requiring specialized interventions (end-stage)

Treatment Goals of Chronic Heart Failure (HF-rEF) - Relieve Sx and improve QoL Improve Survival - Reduce hospitalizations Slow disease progression

Patient Education For new HF patients, it is important that we explain to them each of their medications uses and purposes. It may seem nonsensical to the patient when doses are increased or additional medications are added even though they are improving. Knowing how to reassure the patient that these therapies are to improve their heart’s functions and have been proven to have beneficial outcomes is critical to dissolving barriers to adherence and compliance.

- Diet: Avoid processed foods, don’t add extra salt, learn how to read nutrition labels o Sodium Restriction: 2-3g per day is reasonable. Severe restriction is not associated with better outcomes o Stop Boozing

- Check your body weight everyday: Monitor for sudden weight changes. Sudden weight gain is generally water, it must be caught early and reported to MD

o More advanced patients may need to be fluid-restricted to ~2L daily - Exercise: Weight reduction of obese - Avoid drugs that exacerbate HF: Most anti-arrhythmics, Non-DHP, Some Chemo, COX-2, Rosi/Pioglitazone,

GC, Gabapentin, Lyrica. NSAIDs: Affect renal function and can lead to increased Na+ and water retention Treatment Goals for HF-pEF

- Reduce Congestion: Salt restriction and diuretics Low dose diuretics –beware- dehydration is poorly tolerated - Treat HT: Come on

o Results from clinical trials investigating ACE-I, ARB, and Spiro for HF-pEF have not shown too great of data. The level of evidence is poor, and we think it is associated with enrolling the wrong patient groups

- Maintain Atrial Contraction/Prevent Tachycardia: BB, Non-DHP - Treat and Prevent Myocardial Ischemia: Nitrates, BB, DHP - Avoid positive ionotropic agents: Digoxin

RAAS Inhibitors and Beta-Blockers are the mainstay of HF-rEF therapy