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, whereas HF with preserved ejection fraction (HFpEF) was formerly known as diastolic dysfunction. Although half of HF cases are due to HFpEF, the majority of clinical studies enroll 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 often classified as being ischemic or nonischemic. Ischemic causes are more common and may result from a sudden event such as a myocardial infarction (MI) or from longstanding coronary artery disease. Nonischemic etiologies include uncontrolled hypertension (HTN), 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 1-1). The sympathetic nervous system (SNS) and renin angiotensin aldosterone system (RAAS) are primarily 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.
Pharmacotherapy of heart failure.
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.
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, crackles on auscultation) or peripheral congestion (eg, ascites, jugular venous distension, lower extremity edema). Weight gain can be a helpful marker of volume status for patients to self-monitor, as it often precedes signs and symptoms. Signs and symptoms of low CO are more challenging to identify and may be subjective. Vague symptoms such as fatigue or nausea and vomiting are common. Worsening renal function is a common objective measure of low CO, whereas exercise intolerance and early satiety may be present with either volume overload ...