Physiology of Heart Failure

Heart Failure

• Heart failure is a condition in which the heart is unable to pump enough blood to meet the body's needs.
• Compensatory mechanisms are activated in heart failure to enhance cardiac output, including:
  • Increased sympathetic activity, which increases heart rate and force of contraction, and vasoconstriction to enhance venous return and cardiac preload.
  • Activation of the renin-angiotensin-aldosterone system, which increases peripheral resistance and retention of sodium and water, leading to increased blood volume and pressure.
  • Activation of natriuretic peptides, which leads to vasodilation, natriuresis, inhibition of renin and aldosterone release, and reduction of myocardial fibrosis.
• Myocardial hypertrophy is a compensatory response in heart failure, where the heart increases in size, and the chambers dilate and become more globular.
• There are two types of heart failure:
  • Systolic failure (HFrEF), where the ventricle is unable to pump effectively due to excessive elongation of fibers, resulting in weaker contractions.
  • Diastolic failure (HFpEF), where the ventricle does not fill adequately due to thickening of the ventricular wall and subsequent decrease in ventricular volume.

Acute (Decompensated) Heart Failure

• Acute heart failure occurs when the adaptive mechanisms fail to maintain cardiac output, leading to worsening signs and symptoms of heart failure.
• Typical signs and symptoms of heart failure include:
  • Dyspnea on exertion
  • Orthopnea
  • Paroxysmal nocturnal dyspnea
  • Fatigue
  • Peripheral edema

Therapeutic Strategies in Heart Failure

• Heart failure is typically managed by:
  • Fluid limitations (less than 1.5 to 2 L daily)
  • Low intake of sodium (less than 2000 mg/d)
  • Treatment of comorbid conditions
  • Diuretics, inhibitors of the renin-angiotensin-aldosterone system, and inhibitors of the sympathetic nervous system
  • Inotropic agents (reserved for acute heart failure signs and symptoms in mostly the inpatient setting)
• Drugs that may precipitate or exacerbate heart failure, such as:
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Alcohol
  • Non-dihydropyridine calcium channel blockers
  • Some antiarrhythmic drugs

Angiotensin-Converting Enzyme (ACE) Inhibitors

• ACE inhibitors are a part of standard pharmacotherapy in HFrEF.
• ACE inhibitors block the enzyme that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II.
• ACE inhibitors also:
  • Diminish the inactivation of bradykinin
  • Reduce the secretion of aldosterone
  • Decrease vascular resistance (afterload) and venous tone (preload), resulting in increased cardiac output
• Actions on the heart:
  • Decrease vascular resistance (afterload) and venous tone (preload)
  • Blunt the usual angiotensin II–mediated increase in epinephrine and aldosterone seen in HF
• Indications:
  • Patients with asymptomatic and symptomatic HFrEF
  • Patients with all stages of left ventricular failure
• Pharmacokinetics:
  • Orally active
  • Food may decrease the absorption of captopril, so it should be taken on an empty stomach
  • Except for captopril, ACE inhibitors are prodrugs that require activation by hydrolysis via hepatic enzymes
  • Renal elimination of the active moiety is important for most ACE inhibitors except fosinopril
• Adverse effects:
  • Postural hypotension
  • Renal insufficiency
  • Hyperkalemia
  • A persistent dry cough
  • Angioedema (rare)

Angiotensin Receptor Blockers (ARBs)

• ARBs are orally active compounds that are competitive antagonists of the angiotensin II type 1 receptor.
• Actions on the cardiovascular system:
  • Similar to ACE inhibitors, ARBs decrease vascular resistance (afterload) and venous tone (preload)
  • Mainly used as a substitute for ACE inhibitors in patients with severe cough or angioedema
• Pharmacokinetics:
  • Orally active
  • Dosed once-daily, with the exception of valsartan which is twice a day
  • Highly plasma protein bound and, except for candesartan, have large volumes of distribution
  • Elimination of metabolites and parent compounds occurs in urine and feces
• Adverse effects:
  • Similar to ACE inhibitors

Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)

• ARNIs are a combination of an angiotensin receptor blocker and a neprilysin inhibitor.
• Actions on the cardiovascular system:
  • Similar to ACE inhibitors, ARNIs decrease vascular resistance (afterload) and venous tone (preload)
  • Reduce the heart rate, leading to increased stroke volume and improved symptoms of HF
• Pharmacokinetics:
  • Sacubitril is transformed to active drug by plasma esterases
  • Both drugs have a high volume of distribution and are highly bound to plasma proteins
  • Elimination of metabolites and parent compounds occurs in urine and feces
• Adverse effects:
  • Similar to ACE inhibitors, with the added potential for hypotension and bradykinin-mediated angioedema

Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channel Blockers

• HCN channel blockers, such as ivabradine, selectively slow the (If) current in the SA node, reducing the heart rate.
• Actions on the cardiovascular system:
  • Reduction of heart rate without a reduction in contractility, AV conduction, ventricular repolarization, or blood pressure
  • Increases stroke volume and improves symptoms of HF
• Indications:
  • Patients with HFrEF who are in sinus rhythm with a heart rate above 70 beats per minute and are on optimized HF pharmacotherapy
  • Patients who are on an optimal dose of β-blocker or have a contraindication to β-blockers
• Pharmacokinetics:
  • Administered with meals to increase absorption
  • Has a high volume of distribution and is highly bound to plasma proteins
  • Elimination of metabolites and parent compounds occurs in urine and feces