HEART FAILURE

HEART FAILURE

HF is a clinical syndrome caused by the inability of the heart to pump sufficient blood to meet the metabolic needs of the body. It can results from any disorder that reduces the ventricular filling (diastolic dysfunction) and/or myocardial contractility (systolic dysfunction).

PATHOPHYSIOLOGY

• Causes of systolic dysfunction (decreased contractility) are reduction in muscle mass (e.g., myocardial infarction [MI]), dilated cardiomyopathies, and ventricular hypertrophy. Ventricular hypertrophy can be caused by pressure overload (e.g., systemic or pulmonary hypertension, aortic or pulmonic valve stenosis) or volume overload (e.g., valvular regurgitation, shunts, high-output states).

• Causes of diastolic dysfunction (restriction in ventricular filling) are increased ventricular stiffness, ventricular hypertrophy, infiltrative myocardial diseases, myocardial ischemia and infarction, mitral or tricuspid valve stenosis, and pericardial disease (e.g., pericarditis, pericardial tamponade).

• The leading causes of HF are coronary artery disease and hypertension.

• As cardiac function decreases after myocardial injury, the heart relies on the following compensatory mechanisms: (1) tachycardia and increased contractility through sympathetic nervous system activation; (2) the Frank-Starling mechanism, whereby increased preload increases stroke volume; (3) vasoconstriction; and (4) ventricular hypertrophy and remodeling. Although these compensatory mechanisms initially maintain cardiac function, they are responsible for the symptoms of HF and contribute to disease progression.

CLINICAL MANIFESTATIONS:

• The patient presentation may range from asymptomatic to cardiogenic shock.

• The primary symptoms are dyspnea (particularly on exertion) and fatigue, which lead to exercise intolerance. Other pulmonary symptoms include orthopnea, paroxysmal nocturnal dyspnea, tachypnea, and cough.

• Fluid overload can result in pulmonary congestion and peripheral edema.

• Nonspecific symptoms may include nocturia, fatigue, abdominal pain, hemoptysis, anorexia, nausea, bloating, ascites, , mental status changes, poor appetite, ascites and weight gain.

• Physical examination findings may include pulmonary crackles, Cheyne-Stokes respiration, an S3 gallop, cool extremities, tachycardia, cardiomegaly, narrow pulse pressure, symptoms of pulmonary edema (extreme breathlessness, anxiety, sometimes with coughing pink, frothy sputum), peripheral edema, jugular venous distention, hepatojugular reflux, and hepatomegaly.

DIAGNOSIS

• A diagnosis of HF should be considered in patients exhibiting characteristic signs and symptoms. A complete history and physical examination with appropriate laboratory testing are essential in the initial evaluation of patients suspected of having HF.

• Laboratory tests for identifying disorders that may cause or worsen HF include serum electrolytes (including calcium and magnesium); compete blood count; renal, hepatic, and thyroid function tests; lipid profile; urinalysis; and hemoglobin A1C.

• Ventricular hypertrophy can be demonstrated on ECG or chest x-ray. Chest x-ray may also show pleural effusions or pulmonary edema.

• The echocardiogram is the single most useful evaluation procedure because it can identify abnormalities of the pericardium, myocardium, or heart values and quantify the left ventricular ejection fraction (LVEF) to determine if systolic or diastolic dysfunction is present.

DESIRED OUTCOME:

• The therapeutic goals for chronic HF are to improve quality of life, relieve or reduce symptoms, prevent or minimize hospitalizations, slow disease progression, and prolong survival.

TREATMENT:

Digitalis: Digitalis is the genus name for the family of plants that provide most of the medically active cardiac glycosides, eg, digoxin.

Pharmacokinetics: Digoxin, the only cardiac glycoside used in the USA, is 65–80% absorbed after oral administration. Absorption of other glycosides varies from zero to nearly 100%. Once present in the blood, all cardiac glycosides are widely distributed to tissues, including the central nervous system. Digoxin is not extensively metabolized in humans; almost two thirds is excreted unchanged by the kidneys.

Pharmacodynamics: Digoxin has multiple direct and indirect cardiovascular effects, with both therapeutic and toxic consequences. In addition, it has undesirable effects on the central nervous system and gut. At the molecular level, all therapeutically useful cardiac glycosides inhibit Na +/K + -ATPase, the membrane-bound transporter often called the sodium pump.  Inhibition of this transporter over most of the dose range has been extensively documented in all tissues studied. It is probable that this inhibitory action is largely responsible for the therapeutic effect (positive inotropy) as well as a major portion of the toxicity of digitalis.

A. Cardiac Effects:

1. Mechanical effects: Cardiac glycosides increase contraction of the cardiac sarcomere by increasing the free calcium concentration in the vicinity of the contractile proteins during systole.

The increase in calcium concentration is the result of a two-step process: first, an increase of intracellular sodium concentration because of Na + /K + -ATPase inhibition; and second, a relative reduction of calcium expulsion from the cell by the sodium-calcium exchanger caused by the increase in intracellular sodium. The increased cytoplasmic calcium is sequestered by SERCA in the SR for later release.  The net result of the action of therapeutic concentrations of a cardiac glycoside is a distinctive increase in cardiac contractility. In isolated myocardial Preparations, the rate of development of tension and of relaxation are both increased, with little or no change in time to peak tension. This effect occurs in both normal and failing myocardium, but in the intact patient the responses are modified by cardiovascular reflexes and the Pathophysiology of heart failure.

2. Electrical effects: The effects of digitalis on the electrical properties of the heart are a mixture of direct and autonomic actions. Direct actions on the membranes of cardiac cells follow a well-defined progression: an early, brief prolongation of the action potential, followed by shortening (especially the plateau phase). The decrease in action potential duration is probably the result of increased potassium conductance that is caused by increased intracellular calcium. All these effects can be observed at therapeutic concentrations in the absence of overt toxicity. At higher concentrations, resting membrane potential is reduced (made less negative) as a result of inhibition of the sodium pump and reduced intracellular potassium. As toxicity progresses, oscillatory depolarizing after potentials appear following normally evoked action potentials.The most common cardiac manifestations of digitalis toxicity include atrioventricular junctional rhythm, premature ventricular depolarization, bigeminal rhythm, and second-degree atrioventricular blockade. However, it is claimed that digitalis can cause virtually any arrhythmia.

B. Effects on Other Organs: Cardiac glycosides affect all excitable tissues, including smooth muscle and the central nervous system. The gastrointestinal tract is the most common site of digitalis toxicity outside the heart. The effects include anorexia, nausea, vomiting, and diarrhea. This toxicity is caused in part by direct effects on the gastrointestinal tract and in part by central nervous system actions. Central nervous system effects include vagal and chemoreceptor trigger zone stimulation. Less often, disorientation and hallucinations, especially in the elderly and visual disturbances are noted. The latter effect may include aberrations of color perception. Gynecomastia is a rare effect reported in men taking digitalis.

C. Interactions with Potassium, Calcium, and Magnesium: Potassium and digitalis interact in two ways. First, they inhibit each other’s binding to Na + /K + -ATPase; therefore, hyperkalemia reduces the enzyme-inhibiting actions of cardiac glycosides, whereas hypokalemia facilitates these actions. Second, abnormal cardiac automaticity is inhibited by hyperkalemia. Moderately increased extracellular K + therefore reduces the effects of digitalis, especially the toxic effects.

Calcium ion facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular calcium stores that appears to be responsible for digitalis-induced abnormal automaticity. Hypercalcemia therefore increases the risk of a digitalis-induced arrhythmia. The effects of magnesium ion are opposite to those of calcium. These interactions mandate careful evaluation of serum electrolytes in patients with digitalis-induced arrhythmias.

Other positive inotropic drugs used in heart failure:

Istaroxime is an investigational steroid derivative that increases contractility by inhibiting Na + /K + -ATPase (like cardiac glycosides) but in addition facilitates sequestration of Ca 2+ by the SR. The latter action may render the drug less arrhythmogenic than digoxin. Drugs that inhibit phosphodiesterases, the family of enzymes that inactivate cAMP and cGMP, have long been used in therapy of heart failure. Although they have positive inotropic effects, most of their benefits appear to derive from vasodilation.

Bipyridines: Inamrinone (previously called amrinone) and milrinone are bipyridine compounds that inhibit phosphodiesterase isozyme 3 (PDE-3). They are active orally as well as parenterally but are available only in parenteral forms. They have elimination half-lives of 3–6 hours, with 10–40% being excreted in the urine.

Pharmacodynamics: The bipyridines increase myocardial contractility by increasing inward calcium flux in the heart during the action potential; they may also alter the intracellular movements of calcium by influencing the sarcoplasmic reticulum. They also have an important vasodilating effect. Inhibition of phosphodiesterase results in an increase in cAMP and the increase in contractility and vasodilation. The toxicity of inamrinone includes nausea and vomiting; arrhythmias, thrombocytopenia, and liver enzyme changes have also been reported in a significant number of patients. Milrinone appears less likely to cause bone marrow and liver toxicity than inamrinone, but it does cause arrhythmias. Inamrinone and milrinone are now used only intravenously and only for acute heart failure or severe exacerbation of chronic heart failure.

Beta-adrenoceptor agonists: The selective β 1 agonist that has been most widely used in patients with heart failure is dobutamine. This parenteral drug produces an increase in cardiac output together with a decrease in ventricular filling pressure. Some tachycardia and an increase in myocardial oxygen consumption have been reported. Therefore, the potential for producing angina or arrhythmias in patients with coronary artery disease is significant, as is the tachyphylaxis that accompanies the use of any β stimulant. Dopamine has also been used in acute heart failure and may be particularly helpful if there is a need to raise blood pressure.

Drugs without positive inotropic effects used in heart failure: These agents not positive inotropic drugs are the first-line therapies for chronic heart failure. The drugs most commonly used are diuretics, ACE inhibitors, angiotensin receptor antagonists, aldosterone antagonists, and β blockers. In acute failure, diuretics and vasodilators play important roles.

Diuretics: Diuretics, especially furosemide, are drugs of choice in heart failure. They have no direct effect on cardiac contractility; their major mechanism of action in heart failure is to reduce venous pressure and ventricular preload. This results in reduction of salt and water retention and edema and its symptoms. The reduction of cardiac size, which leads to improved pump efficiency, is of major importance in systolic failure. Spironolactone and eplerenone, the aldosterone antagonist diuretics, have the additional benefit of decreasing morbidity and mortality in patients with severe heart failure who are also receiving ACE inhibitors and other standard therapy. One possible mechanism for this benefit lies in accumulating evidence that aldosterone may also cause myocardial and vascular fibrosis and baroreceptor dysfunction in addition to its renal effects.

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, & related agents:

These versatile drugs reduce peripheral resistance and thereby reduce afterload; they also reduce salt and water retention (by reducing aldosterone secretion) and in that way reduce preload. The reduction in tissue angiotensin levels also reduces sympathetic activity through diminution of angiotensin’s presynaptic effects on norepinephrine release. Finally, these drugs reduce the long term remodeling of the heart and vessels, an effect that may be responsible for the observed reduction in mortality and morbidity. Angiotensin AT 1 receptor blockers such as losartan

 appear to have similar but more limited beneficial effects. Angiotensin receptor blockers should be considered in patients intolerant of ACE inhibitors because of incessant cough. Aliskiren, a renin inhibitor recently approved for hypertension, is in clinical trials for heart failure. Preliminary results suggest an efficacy similar to that of ACE inhibitors.

Vasodilators: Vasodilators are effective in acute heart failure because they provide a reduction in preload (through venodilation), or reduction in after load (through arteriolar dilation), or both. Some evidence suggests that long-term use of hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart. A synthetic form of the endogenous peptide brain natriuretic peptide (BNP) is approved for use in acute (not chronic) cardiac failure as nesiritide. This recombinant product increases cGMP in smooth muscle cells and reduces venous and arteriolar tone in experimental preparations. It also causes diuresis. The peptide has a short half-life of about 18 minutes and is administered as a bolus intravenous dose followed by continuous infusion. Excessive hypotension is the most common adverse effect.

Beta-adrenoceptor blockers: Most patients with chronic heart failure respond favorably to certain β blockers in spite of the fact that these drugs can precipitate acute decompensation of cardiac function. Studies with bisoprolol, carvedilol, metoprolol, and nebivolol showed a reduction in mortality in patients with stable severe heart failure, but this effect was not observed with another β blocker, bucindolol. A full understanding of the beneficial action of β blockade is lacking, but suggested mechanisms include attenuation of the adverse effects of high concentrations of catecholamines (including apoptosis), up-regulation of β receptors, decreased heart rate, and reduced remodeling through inhibition of the mitogenic activity of catecholamines.

Heart failure, blood pumping, coronary arteries