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Heart failure (HF) is a syndrome of reduced cardiac output (CO) resulting from impaired ventricular ejection, impaired filling, or components of both. HF with reduced ejection fraction (HFrEF) was formerly known as systolic dysfunction, and HF with impaired filling or HF with preserved ejection fraction (HFpEF) was formerly known as diastolic dysfunction. Although half of HF cases are due to HFpEF, the majority of studies enrolled patients with HFrEF. Chronic HFrEF management includes lifestyle modifications, medications, and implantable devices. However, there are few therapeutic approaches for HFpEF management.

Etiology and Pathophysiology

The etiology of HF is classified as ischemic or nonischemic. The most common cause is ischemic cardiomyopathy as a result of coronary artery disease. Nonischemic etiologies include uncontrolled hypertension, viral diseases, sarcoidosis, peripartum cardiomyopathy, uncorrected valvular heart disease, alcohol, or thyroid disease.

The pathophysiology of HFrEF is characterized by compensatory mechanisms intended to maintain systemic perfusion in response to a decline in CO (Figure 5-1). The sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS) are responsible for this compensatory response (although vasopressin and nitric oxide are also involved). Norepinephrine is released from the SNS in an effort to maintain CO by increasing contractility and heart rate (HR). Renal hypoperfusion results in RAAS activation with a resultant rise in serum angiotensin II and aldosterone concentrations. As potent vasoconstrictors, norepinephrine and angiotensin II compromise CO by increasing afterload while aldosterone increases preload via enhanced sodium and fluid retention. Increased preload and afterload initially improve organ perfusion but ultimately result in a decline in CO as a consequence of ventricular remodeling and hypertrophy. This cycle is propagated as further declines in CO produce additional release of compensatory neurohormones.


Activation of neurohormonal system in heart failure. Reproduced with permission from Mann DL, Chakinala M. Heart Failure and Cor Pulmonale. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012:chap 234.

The pathophysiology of HFpEF has not been well elucidated, although impaired diastolic function is thought to play a major role. Therapies aimed at disrupting the neurohormonal systems responsible for HFrEF have not substantially improved outcomes in HFpEF, suggesting different pathophysiologic features are involved.

Clinical Presentation

HF patients present with signs and symptoms of volume overload, low CO, or both. Patients with volume overload present with signs and symptoms of pulmonary congestion (eg, dyspnea, orthopnea, rales on auscultation) or peripheral congestion (eg, ascites, jugular venous distension, lower extremity edema). Weight gain is a helpful marker of volume status as it often precedes signs and symptoms. Signs and symptoms of low CO are challenging to identify and may be subjective. Vague symptoms such as fatigue or nausea and vomiting are common. ...

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