Heart failure

Definition

It is important to note that heart failure is not a diagnosis. Rather, it represents a constellation of signs and symptoms resulting from the inability of the heart to pump blood forward at a sufficient rate to meet the metabolic demands of the body (forward failure) or the ability to do so only if the cardiac filling pressures are abnormally high (backward failure), or both. Often, it is the final and most severe manifestation of almost any form of cardiac disease.

Extra-cardiac conditions resulting in inadequate tissue perfusion, such as severe hemorrhage, or increased metabolic demands, such as in hyperthyroidism, can also cause the above definition to be met, but will not be addressed here.

Etiology

Predominantly systolic dysfunction is seen in a majority of patients, while others exhibit mainly diastolic dysfunction. Components of both can also be found.

Systolic dysfunction – diminished ability to eject blood due to:

• Impaired ventricular contractility: destruction or abnormal function of myocytes, fibrosis
• Increased afterload – increases resistance to flow

Diastolic dysfunction

• Impaired ventricular relaxation
• Impaired ventricular filling due to increased ventricular wall stiffness

This classification may help distinguish causes in terms of their impact on normal heart physiology, heart failure can also be thought of clinically as right- versus left-sided heart failure.

Systolic and diastolic dysfunction leading to left- and right-sided heart failure

NOTE: In contrast to the left ventricle, the right ventricle is thin-walled and highly compliant, and therefore adapts well to a wide range of filling volumes when working against a low pulmonary vascular resistance.  However, it is quite susceptible to failure when there is a sudden increase in afterload, such as in left-sided heart failure (retrograde pressure transmission to the pulmonary circulation).  Consequently, the most common cause of right-sided heart failure is left-sided heart failure.  Although less common, isolated right heart failure does arise as a result of primary lung pathology and in such cases is referred to as cor pulmonale.

Pathogenesis

Myocyte loss and/or dysfunction

In addition to global mechanical dysfunction in heart failure, another key player in this process may be dysfunction at a cellular level.

• Myocyte loss
  • Necrosis – resulting from insults such as MI or exposure to cardiotoxic drugs
  • Apoptosis (programmed cell death) from elevated catecholamines, angiotensin II, inflammatory cytokines, and mechanical strain from increased wall stress
• Changes activated in expression of contractile proteins, ion channels, enzymes, receptors and secondary messengers
  • Reduced cellular ability to maintain calcium homeostasis
  • Changes in handling of high-energy phosphates

Compensatory mechanisms

These mechanisms attempt to maintain sufficient blood pressure to perfuse vital organs by compensating for the decrease in cardiac output that occurs in heart failure.

Frank-Starling mechanism

• Frank-Starling relationship: Ventricular output increases in relation to preload, i.e. with a greater stretch of myocardial fibers (larger diastolic volume), there will be a greater force of contraction generated
• In heart failure, a decreased stroke volume results in reduced chamber emptying, with higher than normal diastolic volume
  • This induces a greater stroke volume for the subsequent contraction to help empty the ventricle and preserve forward cardiac output
• However this mechanisms has limits, and at markedly elevated diastolic volumes, the stretch of myofibers becomes too great and suboptimal for generating a strong contraction

Myocardial hypertrophy

• Wall stress is often increased in heart failure due to either ventricular dilatation or the need to generate high systolic pressures to overcome excessive afterload
  • Wall stress is estimated from LaPlace’s relationship, in which the wall stress (σ) is proportional to ventricular pressure (P) and ventricular chamber radius (r), and inversely proportional to ventricular wall thickness (h)

• In response to a sustained increase in pressure and chamber radius, hypertrophy of the ventricular myocytes is stimulated
  • The increased mass of muscle fibers serves to maintain contractile force and counteract the elevated ventricular wall stress
• Eventually, the chamber may dilate out of proportion to wall thickness, resulting in excessive hemodynamic burden on the contractile units, rapid deterioration of ventricular function and worsening of symptomatology
• Lowering wall stress as a way to slow the remodelling process is a common therapeutic target

Neuro-hormonal mechanisms

• In the early stages of heart failure, these mechanisms help maintain a near normal perfusion to vital organs by increasing systemic vascular resistance as a way to balance the fall in cardiac output (blood pressure (BP) = cardiac output (CO) × total peripheral resistance (TPR)). In addition, activation of neuro-hormonal mechanisms leads to salt and water retention with a consequent increase in intravascular volume and preload, which maximizes stroke volume via the Frank-Starling mechanism.
• Renin-angiotensin-aldosterone system (RAAS): (See Nephrology for details of physiology). The pathway leads to the activation of angiotensin II.
  • Angiotensin II
    • Vasoconstriction: Increases TPR to maintain BP.
    • Increased intravascular volume to increase preload to raise the SV via Frank-Starling mechanism. Angiotensin II does this by (i) stimulating thirst at hypothalamus and (ii) increasing aldosterone secretion at adrenal cortex.
  • Aldosterone
    • Increased water retention via increased sodium resorption. This increases preload, in turn increasing the SV
• Antidiuretic hormone (ADH, aka vasopressin)
  • Increased secretion thought to be induced by arterial baroreceptors (detecting decreased CO) and increased angiotensin II levels.
  • Promotes water retention in the distal collecting tubule, in order to increase preload.

Adrenergic nervous system

• Decreased CO results in decreased perfusion pressure sensed by baroreceptors in carotid sinus and the aortic arch. Central and peripheral chemoreflex activation induces epinephrine, norepinephrine, and vasopressin release. This results in an increased sympathetic outflow to heart and peripheral circulation, and decreased parasympathetic tone.
  • Increased HR and contractility directly increase cardiac output (CO = HR × SV)
  • Peripheral vasoconstriction
    • Venous: Increases preload (venous return).
    • Arteriolar: Raises peripheral vascular resistance, to maintain BP.

Unfortunately, despite these compensatory mechanisms, there is progressive decline in the heart’s ability to contract and relax in the face of persistent hemodynamic challenges. Furthermore, chronic activation of the above mechanisms ultimately becomes maladaptive and induces further worsening of cardiac performance.

Deleterious consequences of compensatory mechanisms

• Continuous sympathetic activation results in downregulation of β-adrenergic receptors with decreased sensitivity to circulating catecholamines and less inotropic response.
• Increased heart rate augments metabolic demands and can further reduce performance by increasing myocardial cell death.
• Increased circulating volume and preload ultimately overwhelm Frank-Starling mechanism and heart’s ability to maintain forward flow, resulting in worsening of lung vasculature congestion.
• Increased total peripheral resistance results in higher afterload, impeding the left ventricle’s stroke volume and reducing cardiac output.
• Chronically elevated angiotensin II and aldosterone trigger production of cytokines, which activate macrophages an stimulate fibroblasts resulting in adverse heart remodelling.

Exacerbating factors in compensated heart failure

Heart failure can be clinically silent (i.e. asymptomatic) if compensatory mechanisms are sufficient to balance the degree of cardiac dysfunction, or alternatively if it is adequately managed medically.  However, patients can become symptomatic, if decompensation occurs.

Pathophysiology

Treatment 

Principles: The main goal of therapy is first and foremost to identify and aim to correct any underlying conditions causing heart failure. In an acute decompensation, the goal also includes eliminating acute precipitating causes that turned a compensating heart failure state into a decompensated state.  Symptomatic management and modulation of neurohormonal mechanisms are also important therapeutic targets.

Chronic management

Non-pharmacologic management

Lifestyle modification:

• 10% weight loss
• Sodium < 2gm/day
• Fluid restriction (<2L/day)
• Smoking and drinking cessation

Pharmacologic management

• β-blockers: (Lancet. 1999 Jun 12;353(9169):2001-7, Lancet. 1999 Jan 2;353(9146):9-13. Lancet. 2003 Jul 5;362(9377):7-13)
  • Counteract the harmful effects of sympathetic nervous system activation, may also assist in preventing tachyarrhythmias and myocardial ischemia
  • Of all beta blockers, only metoprolol succinate (MERIT-HF trial), carvedilol (COMET trial), and bisoprolol (CIBIS-II trial) have demonstrated mortality benefit
    • COMET – carvedilol superior to metoprolol reducing mortality in NYHA II+ & EF <35%
    • CIBIS II – significant reduction in all-cause mortality and hospitalization in NYHA II+
• ACE inhibitors (ACEi) / angiotensin receptor blockers (ARBs): (N Engl J Med. 1992 Sep 3;327(10):685-91)
  • Counteract the activated mediators of the RAAS to prevent their deleterious consequences and ultimately minimize cardiac remodelling
  • Enalapril shown to have significant morbidity and mortality benefit (SOLVD & CONSENSUS trials)
  • For patients unable to tolerate ACEi, both candesartan and valsartan have been studied and have been shown to have mortality benefit (CHARM & V-HeFT trials) – no added benefit to ACEi
• Hydralazine + nitrates (N Engl J Med. 2004; 351:2049-2057)
  • Consider if patients unable to tolerate ACEi/ARBs or in African American patients with NYHA class III/IV
  • A-HEFT trial – 40% reduction in mortality
• Aldosterone antagonists (N Engl J Med. 2011 Jan 6;364(1):11-21, N Engl J Med. 1999 Sep 2;341(10):709-17.)
  • Aldosterone antagonist counteracts the harmful effects of aldosterone including salt retention, myocardial hypertrophy and potassium excretion
  • Spironolactone: RALES trial – 34% mortality benefit in patients with heart failure NYHA Class III+ (patients already optimized on beta blocker and ACEi therapy)
  • Epleronone: EMPHASIS-HF trial – 37% reduction in death from CV causes or hospitalization for HF NYHA Class II+
• Digoxin (N Engl J Med. 1997 Feb 20;336(8):525-33):
  • Enhances cardiac contractility, but also blunts the compensatory sympathetic drive by increasing the sensitivity of baroreceptors, which decreases afterload
  • No mortality benefit; only decreased hospitalizations (DIG trial)
• ICDs and cardiac resynchronization therapy (N Engl J Med. 2005 Jan 20;352 (3):225-37, N Engl J Med. 2009 Oct 1;361 (14):1329-38.):
  • Pacemaker-based approach to treat patients with a wide QRS complex
  • Purpose is to provide electromechanical coordination and improve ventricular synchrony in patients with severe systolic dysfunction and significant intraventricular conduction defects such as left bundle-branch block
  • ICDs in patients with NYHA II/III HF & EF<35% significantly reduced mortality (SCD-HEFT)
  • CRT, when further added to ICDs, reduces HF exacerbations by 41%. Similar benefits for ischemic and non-ischemic cardiomyopathy as well as significant reduction in LV volume & EF improvement (MADIT-CRT)
• Mechanical circulatory support (i.e. intra-aortic balloon pump, IABP)
  • An IABP deflates in diastole and inflates in systole to decrease impedance to LV ejection of blood and increase coronary perfusion
  • Used in extreme cases of unstable hemodynamics 
• Diuretics
  • Mainstay of symptomatic congestion control; may help improve stroke volume by eliminating excessive circulating volume and decreasing preload, therefore reducing “backup” of fluid into pulmonary interstitium and peripheral tissues. Diuretics have not shown mortality benefit.

Acute decompensation

It is important to identify the precipitant of heart failure and treat as the HF episode is being treated.

• Diuretics: Lasix (furosemide)
  • Helps eliminate excess fluid that the heart cannot accommodate (preload) and improve stroke volume, thereby decreasing pulmonary and peripheral edema
• Morphine:
  • Decreases preload by acting as a venodilator, and reduces sympathetic activation and consequently demand on heart by procuring pain relief
• Nitrates:
  • Decrease preload via venodilation, and improve oxygen delivery to the heart
• Oxygen:
  • Oxygen +/- noninvasive ventilation – preserve ventilator drive and maintaining blood oxygen saturation
• Positioning:
  • Sit patient upright with legs dangling down to promote blood pooling in the lower extremities and decrease preload