rogenic causes (e.g., anthracycline agents, alcohol, and cocaine) viral, familial, congenital, and metabolic disorders. The evolving shift from ischemic etiology to non-ischemic causes suggests con- cern and the need to control comorbid conditions better. The life- time risk of HF at age 50 has increased from 20 to 30% in the last 25 years, and those with obesity, hypertension, and diabetes incur a higher relative risk (Vasan et al., 2022). Some risk factors are Pathophysiology Heart failure may result from previously described conditions that damage or weaken the heart, and the ventricles become too weak to supply oxygenated blood to the body sufficiently. In response, the body activates two main neurohormonal com- pensatory mechanisms to maintain an adequate cardiac output: the renin-angiotensin-aldosterone-system (RAAS) and sympatho- adrenergic systems (see Figure 1). As the sympathetic nervous system releases catecholamines (e.g., norepinephrine) to increase inotropy and chronotropy, this process contributes to renal hy- poperfusion and ultimately the release of renin by the juxtaglo- merular cells in the kidney. This process initiates the RAAS system (a neurohormonal cascade) that, through downstream signaling, ultimately produces aldosterone ((Libby et al., 2021). The final re - sult is an increase in salt and water retention. Aldosterone and other vasoconstrictors of the RAAS system, coupled with cat- echolamines, increases systemic and renal vascular resistance. In- fluenced by vascular resistance, cardiac afterload is the pressure against which the heart has to pump. Furthermore, the volume overload associated with the RAAS system activation leads to in- creased left ventricular volume and pressure that causes cardiac myocytes to stretch. The stretching prior to contraction is called preload. In a normal heart, increasing preload and decreasing afterload will increase cardiac output; however, in a weakened heart, the increase in preload via compensation will only maintain stroke vol- ume to a certain extent before a plateau effect is observed (the Frank-Starling principle). These adaptive mechanisms, while ini- tially helpful, lead to a perpetual vicious cycle that causes cardiac remodeling and further symptoms of HF. With HFpEF accounting for half of HF cases, understanding the pathological differences between the two main HF subtypes is paramount for treatment strategies. Events or conditions causing cardiac myocyte destruction resulting in contractility issues are characteristic of HFrEF. Meanwhile, the exact underlying mecha- nisms of HFpEF are complex and not fully understood. Proposed theories involve pathways relating to inflammation and dysfunc - tion of endothelial cells, which lead to impaired relaxation and filling of the ventricles (Rech et al., 2018; Schwinger, 2021). Diagnosis No single test exists to diagnose HF definitively. Instead, clinicians should evaluate the patient using physical examination, medical history, various diagnostic tests (e.g., echocardiogram), and labo- ratory values. The 2017 ACC/AHA focused update guidelines for HF management gives a 1/A class of recommendation/ level of evidence (COR/LOE) (see Appendix B for recommendation class and level of evidence definitions) for the use of clinical biomarkers to determine the presence and severity of HF (Yancy et al., 2017). The B-type natriuretic peptide (BNP) and N-terminal-proBNP (NT-proBNP) are two biomarkers released endogenously due to elevated ventricular pressures that provide a diuretic and natri-
shared between HFrEF and HFpEF; however, HFpEF is linked to chronic conditions, such as T2DM, obesity, arterial hypertension, sleep apnea, and aortic valve disease, while coronary artery dis- ease predominantly leads to HFrEF (Libby et al., 2021; Schwinger, 2021). Understanding the etiology and treatment targeting those specific origins of HF may help to improve outcomes. The type of symptom manifestation of HF depends on whether the dysfunction is predominantly located within the left or right ventricle (or both). For example, with left ventricular dysfunction, retained blood in the left ventricle increases pulmonary pressure that manifests in symptoms, such as dyspnea, tachypnea, and crackles. Meanwhile, right-sided HF occurs when blood backflows into the periphery, producing edema, weight gain, and additional volume overload that affects various organs (e.g., increased pres- sure in the liver leading to ascites) (Schwinger, 2021). Figure 1: Pathophysiology: Vicious Cycle of Heart Failure.
(Original figure by author, information sourced from: Libby, P., et al. (2021). Braunwald’s Heart Disease, 2 Vol Set, 12th Edition (12th ed., Vol. 1–2). Elsevier.) Note. ANG I= angiotensin I; ANG II= angiotensin II; AVP= arginine vasopressin; CO= Cardiac Output; SNS=Sympathetic Nervous System
uretic response while additionally antagonizing the RAAS system. Guidelines recommend using biomarkers early in screening for at-risk patients as a HF preventive tool (IIa/B). The B-type natri- uretic peptide helps exclude a HF diagnosis because of the high sensitivity when used as a diagnostic tool (Yancy et al., 2017). For example, a BNP level greater than 100 pg/mL may support a di- agnosis; however, concentrations less than 100 pg/mL reduce the likelihood of a diagnosis of HF, and a differential diagnosis should be evaluated. Healthcare institutions may use either of the two biomarkers for evaluation; however, the laboratory values may not be interchanged.
PHARMACOLOGY OF HEART FAILURE
The following sections will focus on evidence-based recommen- dations at stage C of the ACC/AHA guidelines for the treatment of HFrEF and HFpEF. While important, the pharmacologic op- tions at stage D are beyond the scope of this activity. Addition- Heart failure with reduced ejection fraction The goal of pharmacotherapy intervention is to reduce morbidity (e.g., decrease hospitalization and HF symptoms) and mortality; this may be achieved by decreasing cardiac preload and after-
ally, guidelines from large international societies (e.g., European Society of Cardiology) highlight the differences in clinical practice with other countries; however, this activity will focus on recom- mendations exclusively from the ACC/AHA guidelines.
load by blunting the effects of the RAAS and sympathoadrenergic systems.
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