Congestive heart failure (CHF) or congestive cardiac failure (CCF) affects about 5 million individuals in the United States and accounts for more than half a million deaths a year. Congestive heart failure is a condition characterized by the inability of the heart to pump adequate blood to meet the requirements of the body. It begins with cardiac dysfunction and reduced cardiac output. It leads to inadequate blood supply to different sites especially during exertion. The body tries to compensate by increasing the blood volume by retaining more water and salt. Heart failure is thus characterized by fatigue, breathlessness, and swelling (edema) of dependent parts of the body. The primary problem in heart failure is inability of the the heart to fill or empty the left ventricle completely.
Treatment of heart failure (systolic failure) has dramatically changed with the advancement in the understanding of the disease development and its progression. The current drug therapy approach for congestive cardiac failure involves :
- reducing venous blood returning to the heart (preload).
- reducing the peripheral resistance (afterload).
- improvement in the heart contractions.
Dietary modification for heart failure includes moderate sodium restriction and mild fluid restriction. Moderate salt restriction (limited to a total of 2-3 gram per day) is advised to all patients with clinically significant cardiac dysfunction. Over restriction of salt intake can lead to hyponatremia (reduced sodium levels in the blood) and hypokalemia (reduced potassium levels in the blood) when combined with diuretic therapy.
The current drug therapy for congestive heart failure includes :
- Angiotensin modulators
- Beta-adrenergic blockers
- Vasopeptidase inhibitors
- Cardiac glycosides
- Other inotropic drugs
Diuretics for Heart Failure
Diuretics still retain a significant role in the management of the CHF and is most useful in patients with acute exacerbation heart failure with lung congestion. It is also of use in relieving the congestive symptoms associated with chronic heart failure and improving exercise capacity. Diuretics reduce the total body water and reduce the preload. This allows more effective pumping of the blood that reaches the heart and reduces the congestive symptoms. The diuretic dose is usually reduced to the minimal that is necessary to maintain normal blood volume once fluid retention has resolved. Low potassium levels (hypokalemia) which is seen with diuretic therapy is usually corrected with potassium supplements or with addition of a potassium-sparing diuretic.
Loop diuretics like furosemide, bumetanide, and torsemide are commonly used in heart failure. It exerts its action by inhibiting an ion transport protein present in the nephron called as Na+-K+-2Cl- symporter. This reduces the normal sodium absorption by the nephron and the unabsorbed sodium ions cause more water to remain in the urine. Loop diuretics also cause increased potassium excretion due to increased exchange of sodium with potassium towards the terminal parts of nephron. This is mostly due to the action of aldosterone and this is effectively blocked by combining it with aldosterone antagonists (potassium sparing diuretics).
The role of thiazide diuretics in cardiac failure treatment is limited as a monotherapy agent. It may be of use in hypertensive patients with milder forms of heart failure, in combination with loop diuretics in patients who are minimally responsive to loop diuretic therapy or in some selected patients with chronic cardiac failure. Thiazide diuretics act on the Na+-Cl- cotransporter present towards the distal part of the nephron.
Potassium-sparing diuretics are either aldosterone antagonists (spironolactone, eplerenone) or drugs that directly inhibit the Na+ exchange with K+ (amiloride, triamterene) at the most distal part of the nephron. Potassium-sparing diuretics are weak diuretics and do not contribute much to the blood volume reduction. The role of these drugs is primarily to limit the loss of potassium associated with thiazide or loop diuretic therapy.
Angiotensin modulators like ACE inhibitors (enalapril and captopril) and angiotensin receptor antagonists (losartan and valsartan) play the central role in management of cardiac failure at present. These drugs counteract the numerous negative effects of angiotensin II on the cardiovascular system, namely the constriction of arteries and retention of sodium and water through its effect on aldosterone secretion. Other effects that are counteracted by angiotensin modulators include stimulation of catecholamine (adrenaline, noradrenaline) release from adrenal gland, stimulation of vascular hyperplasia and myocardial hypertrophy, and stimulation of cardiac muscle cell death.
ACE inhibitors (captopril, enalapril, ramipril, lisinopril, quinapril, fosinopril, perindopril) suppress angiotensin II production and aldosterone secretion, increase bradykinin levels by inhibiting its breakdown and decrease sympathetic nervous system activity. The increase in bradykinin levels with ACE inhibitor treatment may also contribute to the therapeutic effects in cardiac failure. ACE inhibitors also potentiate the beneficial effects of diuretics in cardiac failure. ACE inhibitors are used for the treatment of patients with heart failure of all grades. ACE inhibitors are started at low dose and slowly increased to the optimal dose based on the clinical response, serum electrolytes and serum creatinine levels.
Angiotensin receptor blockers (losartan, valsartan, candesartan, irbesartan) produce similar beneficial effects as that of ACE inhibitors by blocking angiotensin II at the receptor level. It has a stronger effect than ACE inhibitors. However, angiotensin receptor blockers lack the effect on bradykinin levels unlike ACE inhibitors.
A number of vasodilators can improve cardiac failure symptoms but only a few have proven efficacy in improving survival. This includes organic nitrates (like isosorbide dinitrate), hydralazine and angiotensin modulators.
Organic nitrates currently in use for heart failure are nitroglycerin (primarily intravenous), nitroprusside (only intravenous), and short-acting oral agent isosorbide dinitrate. Nitrates relax vascular smooth muscle by releasing NO (nitrous oxide) and activating soluble guanylyl cyclase. In heart failure nitrates reduce the left ventricular filling pressure. Nitrates also may enhance the cardiac function by increasing coronary blood flow.
Intravenous nitroprusside and nitroglycerin are fast acting drugs with onset of action of less than 5 minutes. Both the drugs are short-acting and this makes it useful only in acute settings for rapid effects. Hydralazine exerts its vasodilator action by mechanisms not clearly understood. Hydralazine reduces the right and left ventricular workload by reducing the pulmonary and the systemic vascular resistance. This results in improvement of cardiac function in heart failure. Hydralazine also improves renal blood flow by reducing renal vascular resistance.
Beta-Adrenergic Receptor Antagonists
In heart failure when the cardiac output falls, the adrenergic system is stimulated to compensate it. The sympathetic stimulation results in enhanced contractility of heart (inotropic effect) and increased heart rate (chronotropic effect). Beta blockers were considered to be contraindicated in heart failure in the past, but some beta blockers have been found to produce benefits in heart failure patients.
Selected beta 1 receptor antagonists (like metoprolol, carvediolol, bisoprolol) improved exercise tolerance and reduced symptoms of heart failure in patients with heart failure. Improvement was more pronounced in heart failure associated with idiopathic dilated cardiomyopathy or coronary artery diseases. Other important benefits which contribute to reduced cardiovascular death with beta blockers include its anti-ischemic actions and its ability to control or prevent dangerous cardiac arrhythmias.
Beta blocker therapy is usually started at low dose and carefully increased slowly to the target dose as there is a risk of worsening of heart failure with this therapy. Rapid increase of dose or starting at standard dose can result in adverse outcome. The tendency to retain water during the initial days after starting beta blocker therapy is minimized with the appropriate diuretic therapy. The most important drawback of beta blocker therapy is worsening of heart failure in some patients.
Vasopeptidase inhibitors (nesiritde) inhibit the neural endopeptidase enzyme. These enzymes are responsible for degradation of atrial and brain natriuretic peptides (ANP and BNP) which increase the sodium and water excretion. By increasing levels of ANP and BNP, the blood volume is lowered due to increased excretion of sodium and water. Additionally nesiritde has vasodilator action and also it inhibits ACE. Nesiritide thus decreases the symptoms of cardiac failure by reducing cardiac filling pressure and systemic vascular resistance.
Cardiac glycosides (digoxin, digitoxin) were the drugs of choice in cardiac failure before the arrival of angiotensin modulators. These s are inotropic drugs and currently digoxin is the only oral inotropic agent that is currently available for chronic use in patients with cardiac failure. It is obtained from the digitalis (foxglove) plant. Currently it has only a limited role as a primary drug for cardiac failure. It nevertheless is an important drug for heart failure and stimulates the heart (cardiac stimulating effect). By doing so, it increases the cardiac output from the failing heart and controls the atrial fibrillation. Digoxin therapy is usually started with a loading dose and then maintained on a lower daily dose. Due to toxicity, safe levels have to be maintained at all times throughout therapy. Fall in potassium levels (hypokalemia) is known to increase susceptibility for digoxin toxicity.
Other Inotropic Drugs
Patients with low output cardiac failure, who are severely decompensated usually require intensive therapy that stimulate cardiac contraction (inotropic drugs). Increase in the cardiac output is the primary aim of this therapy. These patients are treated with parenteral drugs like adrenergic-dopaminergic agonists (dopamine and dobutamine), phosphodiesterase inhibitors (inamrinone and milrinone) and calcium sensitizers (levosimendan).
Adrenergic and Dopaminergic Agonists
Adrenergic and dopaminergic agonists are commonly used drugs for short term management of severe heart failure. Dobutamine is the adrenergic agonist of choice for the management of ventricular dysfunction and CHF. The primary effect of dobutamine is to increase cardiac output by its positive inotropic action.
Dopamine stimulates the heart through adrenergic and dopaminergic receptors. It is believed to increase renal blood flow and enhance urinary output, in addition to the effects on heart. High-dose dopamine is more likely to worsen the heart failure due to its constricting effect on blood vessels and subsequent increase in blood pressure.
The phosphodiesterase inhibitors (inamrinone and milrinone) reduce the break down of cyclic AMP. Increased levels of cyclic AMP exert positive inotropic effect on heart and dilation of both peripheral arteries and veins. The net result is increase in the cardiac output due to the inotropic action and the reduction in left ventricular workload due to vasodilatation. Intravenous infusion of inamrinone and milrinone are recommended for short-term circulatory support in severe cardiac failure.
Levosimendan is a calcium sensitizer available outside the US. The calcium sensitivity of the heart is increased by levosimendan. This increases the cardiac contractility. It also exerts a vasodilatory effect by its action on potassium channels. It is available in some countries for short term treatment of acutely decompensated severe cardiac failure.