1. Heart Failure

2. 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. HF can result from any disorder that reduces ventricular filling (diastolic dysfunction) and/or myocardial contractility (systolic dysfunction).

3. 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).

4. 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).

5. The leading causes of HF are coronary artery disease and hypertension
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) vasoconstriction; (3) 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

6. The neurohormonal model of HF recognizes that an initiating event (e.g., acute MI) leads to decreased cardiac output but that the HF state then becomes a systemic disease whose progression is mediated largely by neurohormones and autocrine/paracrine factors. These substances include angiotensin II, norepinephrine, aldosterone, natriuretic peptides, arginine vasopressin, proinflammatory cytokines (e.g., tumor necrosis factor αinterleukin-6 and interleukin-1 β), and endothelin-1.

7. 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 fatigue, nocturia, hemoptysis, abdominal pain, anorexia, nausea, bloating, ascites, poor appetite, ascites, mental status changes, and weight gain.

8. 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 compete blood count; serum electrolytes (including calcium and magnesium); renal, hepatic, and thyroid function tests; urinalysis; lipid profile; and hemoglobin A1C.

9. Ventricular hypertrophy can be demonstrated on chest x-ray or ECG
Ventricular hypertrophy can be demonstrated on chest x-ray or ECG. 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, oheart values and quantify the left ventricular ejection fraction (LVEF) to determine if systolic or diastolic dysfunction is present.

10. GENERAL APPROACH
The first step in managing chronic HF is to determine the etiology or precipitating factors. Treatment of underlying disorders (e.g., anemia, hyperthyroidism) may obviate the need for treating HF. Non pharmacologic interventions include cardiac rehabilitation and restriction of fluid intake (maximum 2 L/day from all sources) and dietary sodium (approximately 2 to 3 g of sodium per day).

11. Stage A: The emphasis is on identifying and modifying risk factors to prevent development of structural heart disease and subsequent HF. Strategies include smoking cessation and control of hypertension, diabetes mellitus, and dyslipidemia according to current treatment guidelines. Angiotensin-converting enzyme (ACE) inhibitors (or angiotensin recep-tor blockers [ARBs]) should be strongly considered for antihypertensive therapy in patients with multiple vascular risk factors.

12. Stage B: In these patients with structural heart disease but no symptoms, treatment is targeted at minimizing additional injury and preventing or slowing the remodeling process. In addition to treatment measures outlined for stage A, patients with a previous MI should receive both ACE inhibitors (or ARBs in patients intolerant of ACE inhibitors) and β- blockers regardless of the ejection fraction. Patients with reduced ejection fractions (less than 40%) should also receive both agents, regardless of whether they have had an MI.

13. Stage C: Most patients with structural heart disease and previous or current HF symptoms should receive the treatments for Stages A and B as well as initiation and titration of a diuretic (if clinical evidence of fluid retention), ACE inhibitor, an β-blocker (if not already receiving a β- blocker for previous MI, left ventricular [LV] dysfunction, or other indication). If diuresis is initiated and symptoms improve once the patient is euvolemic, long-term monitoring can begin.

14. If symptoms do not improve, an aldosterone receptor antagonist, ARB (in ACE inhibitorintolerant patients), digoxin, and/or hydralazine/isosorbide dinitrate (ISDN) may be useful in carefully selected patients. Other general measures include moderate sodium restriction, daily weight measurement, immunization against influenza and pneumococcus, modest physical activity, and avoidance of medications that can exacerbate HF.

15. Stage D: Patients with symptoms at rest despite maximal medical therapy should be considered for specialized therapies, including mechanical circulatory support, continuous intravenous positive inotropic therapy, cardiac transplantation, or hospice care.

16. pharmacotherapy
ACE inhibitors decrease angiotensin II and aldosterone, attenuating many of their deleterious effects, including reducing ventricular remodeling, myocardial fibrosis, myocyte apoptosis, cardiac hypertrophy, norepinephrine release, vasoconstriction, and sodium and water retention.

17. Clinical trials have produced unequivocal evidence that ACE inhibitors improve symptoms, slow disease progression, and decrease mortality in patients with HF and reduced LVEF (stage C). These patients should receive ACE inhibitors unless contraindications are present. ACE inhibitors should also be used to prevent the development of HF in at-risk patients (i.e., stages A and B).

18. β-Blockers
There is clinical trial evidence that certain β-blockers slow disease progression, decrease hospitalizations, and reduce mortality in patients with HF. Beneficial effects of β-blockers may result from antiarrhythmic effects, slowing or reversing ventricular remodeling, decreasing myocyte death from catecholamine-induced necrosis or apoptosis, preventing fetal gene expression, improving LV systolic function, decreasing heart rate and ventricular wall stress and thereby reducing myocardial oxygen demand, and inhibiting plasma renin release.

19. The ACC/AHA guidelines recommend use of β-blockers in all stable patients with HF and a reduced LVEF in the absence of contraindications or a clear history of β-blocker intolerance. Patients should receive a β- blocker even if symptoms are mild or well controlled with ACE inhibitor and diuretic therapy. It is not essential that ACE inhibitor doses be optimized before a β-blocker is started because the addition of a β-blocker is likely to be of greater benefit than an increase in ACE inhibitor dose.

20. β-Blockers are also recommended for asymptomatic patients with a reduced LVEF (stage B) to decrease the risk of progression to HF. Because of their negative inotropic effects, β-blockers should be started very low doses with slow upward dose titration to avoid symptomatic worsening or acute decompensation. Patients should be titrated to target doses when possible to provide maximal survival benefits.

21. Metoprolol XL, carvedilol, and bisoprolol are the only β-blockers shown to reduce mortality in large HF trials. It cannot be assumed that immediate-release metoprolol will provide benefits equivalent to metoprolol XL.

22. Angiotensin II Receptor Blockers The angiotensin II receptor antagonists block the angiotensin II receptor subtype AT1, preventing the deleterious effects of angiotensin II, regardless of its origin. They do not appear to affect bradykinin and are not associated with the side effect of cough that sometimes results from ACE inhibitor– induced accumulation of bradykinin. Also, direct blockade of AT1 receptors allows unopposed stimulation of AT2 receptors, causing vasodilation and inhibition of ventricular remodeling.

23. Although some data suggest that ARBs produce equivalent mortality benefits when compared to ACE inhibitors, the ACC/AHA guidelines recommend use of ARBs only in patients with stage A, B, or C HF who are intolerant of ACE inhibitors. Although there are seven ARBs on the market in the United States, only candesartan and valsartan are FDA-approved for the treatment of HF and are the preferred agents.

24. Blood pressure, renal function, and serum potassium should be evaluated within 1 to 2 weeks after therapy initiation and dose increases. Cough and angioedema are the most common causes of ACE inhibitor intolerance. Caution should be exercised when ARBs are used in patients with angioedema from ACE inhibitors because cross-reactivity has been reported. ARBs are not alternatives in patients with hypotension, hyperkalemia, or renal insufficiency due to ACE inhibitors because they are just as likely to cause these adverse effects.

25. Combination therapy with an ARB and ACE inhibitor offers a theoretical advantage over either agent alone through more complete blockage of the deleterious effects of angiotensin II. However, clinical trial results indicate that the addition of an ARB to optimal HF therapy (e.g., ACE inhibitors, β-blockers, diuretics) offers marginal benefits at best with increased risk of adverse effects. Addition of an ARB may be considered in patients who remain symptomatic despite receiving optimal conventional therapy.

26. Aldosterone Antagonists
Spironolactone and eplerenone block the mineralocorticoid receptor, the target site for aldosterone. In the kidney, aldosterone antagonists inhibit sodium reabsorption and potassium excretion. However, diuretic effects are minimal, suggesting that their therapeutic benefits result from other actions.

27. Effects in the heart attenuate cardiac fibrosis and ventricular remodeling. Recent evidence also suggests an important role in attenuating the systemic proinflammatory state and oxidative stress caused by aldosterone. Spironolactone also interacts with androgen and progesterone receptors, which may lead to gynecomastia and other sexual side effects; these effects are less frequent with eplerenone because of its low affinity for androgen and progesterone receptors.

28. Based on clinical trial results demonstrating reduced mortality, low-dose aldosterone antagonists may be appropriate for:
patients with moderately severe to severe HF who are receiving standard therapy
those with LV dysfunction early after MI.

29. Data from clinical practice suggest that the risks of serious hyperkalemia and worsening renal function are much higher than observed in clinical trials. This may be due in part to failure of clinicians to consider renal impairment, reduce or stop potassium supplementation, or monitor renal function and potassium closely once the aldosterone antagonist is initiated. Thus, aldosterone antagonists must be used cautiously and with careful monitoring of renal function and potassium concentration. They should be avoided in patients with renal impairment, recent worsening of renal function, high-normal potassium levels, or a history of severe hyperkalemia.

30. Digoxin
Although digoxin has positive inotropic effects, its benefits in HF are related to its neurohormonal effects. Digoxin attenuates the excessive sympathetic nervous system activation present in HF patients, perhaps by reducing central sympathetic outflow and improving impaired baroreceptor function. It also increases parasympathetic activity in HF patients and decreases heart rate, thus enhancing diastolic filling. Digoxin does not improve survival in patients with HF but does provide symptomatic benefits.

31. In patients with HF and supraventricular tachy arrhythmias such as atrial fibrillation, digoxin should be considered early in therapy to help control ventricular response rate. For patients in normal sinus rhythm, effects on symptom reduction and quality-of-life improvement are evident in patients with mild to severe HF. Therefore, it should be used together with standard HF therapies (ACE inhibitors, β-blockers, and diuretics) in patients with symptomatic HF to reduce hospitalizations.

32. Nitrates and Hydralazine
Nitrates (e.g., ISDN) and hydralazine were combined originally in the treatment of HF because of their complementary hemodynamic actions. Nitrates are primarily venodilators, producing reductions in preload. Hydralazine is a direct vasodilator that acts predominantly on arterial smooth muscle to reduce systemic vascular resistance (SVR) and increase stroke volume and cardiac output. Evidence also suggests that the combination may provide additional benefits by interfering with the biochemical processes associated with HF progression.

33. The combination of nitrates and hydralazine improves the composite endpoint of mortality, hospitalizations for HF, and quality of life in African Americans who receive standard therapy. A fixed-dose combination product is available that contains ISDN 20 mg and hydralazine 37.5 mg . Practice adding ISDN and hydralazine as part of standard therapy guidelines recommend in African Americans with moderately severe to severe HF. The combination is also appropriate as first-line therapy in patients unable to tolerate ACE inhibitors or ARBs because of renal insufficiency, hyperkalemia, or possibly hypotension.

34. TREATMENT OF ACUTE DECOMPENSATED HEART FAILURE
The term decompensated HF refers to patients with new or worsening signs or symptoms that are usually caused by volume overload and/or hypoperfusion and lead to the need for additional medical care, such as emergency department visits and hospitalizations. The goals of therapy are to relieve congestive symptoms, optimize volume status, treat symptoms of low cardiac output, and minimize the risks of drug therapy so the patient can be discharged in a compensated state on oral drug therapy.

35. Hospitalization should occur or be considered depending on each patient’s symptoms and physical findings. Admission to an intensive care unit may be required if the patient experiences hemodynamic instability requiring frequent monitoring, invasive hemodynamic monitoring, or rapid titration of IV medications with close monitoring of arterial pressure.

36. Cardiopulmonary support must be instituted and adjusted rapidly
Cardiopulmonary support must be instituted and adjusted rapidly. Electrocardiogram (ECG) monitoring, continuous pulse oximetry, urine flow monitoring, and automated blood pressure recording are necessary.

37. Reversible or treatable causes of decompensation should be addressed and corrected. Drugs that may aggravate HF should be evaluated carefully and discontinued when possible.

38. The first step in managing decompensated HF is to ascertain that optimal treatment with oral medications has been achieved. If there is evidence of fluid retention, aggressive diuresis, often with IV diuretics, should be accomplished.

39. Optimal treatment with an ACE inhibitor should be a priority
Optimal treatment with an ACE inhibitor should be a priority. Although β-blockers should not be started during this period of instability, they should be continued, if possible, in patients who are already receiving them on a chronic basis. Most patients should be receiving digoxin at a low dose prescribed to achieve a trough serum concentration of 0.5 to 1 ng/mL.

40. Appropriate management of decompensated HF is aided by determination of whether the patient has signs and symptoms of fluid overload (“wet” HF) or low cardiac output (“dry” HF) .
Invasive hemodynamic monitoring should be considered in patients who are refractory to initial therapy, whose volume status is unclear, or who have clinically significant hypotension such as systolic BP <80 mm Hg.

41. PHARMACOTHERAPY OF ACUTE DECOMPENSATED HEART FAILURE
Diuretics
IV loop diuretics, including furosemide, bumetanide, and torsemide, are used for acute decompensated HF, with furosemide being the most widely studied and used agent. Bolus diuretic administration decreases preload by functional venodilation within 5 to 15 minutes and later (>20 min) via sodium and water excretion, thereby improving pulmonary congestion.

42. Because diuretics can cause excessive preload reduction, they must be used to obtain the desired improvement in congestive symptoms while avoiding a reduction in cardiac output, symptomatic hypotension, or worsening renal function.
Diuresis may be improved by adding a second diuretic with a different mechanism of action (e.g., combining a loop diuretic with a distal tubule blocker such as metolazone or hydrochlorothiazide).

43. The loop diuretic thiazide combination should generally be reserved for inpatients who can be monitored closely for the development of severe sodium, potassium, and volume depletion. Very low doses of the thiazide-type diuretic should be used in the outpatient setting to avoid serious adverse events.

44. Positive Inotropic Agents
Dobutamine Dobutamine is a β1- and β2-receptor agonist with some α1-agonist effects. The net vascular effect is usually vasodilation. It has a potent inotropic effect without producing a significant change in heart rate. Initial doses of 2.5 to 5 mcg/kg/min can be increased progressively to 20 mcg/kg/min on the basis of clinical and hemodynamic responses.

45. Dobutamine increases cardiac index because of inotropic stimulation, arterial vasodilation, and a variable increase in heart rate. It causes relatively little change in mean arterial pressure compared with the more consistent increases observed with dopamine.
Although concern over attenuation of dobutamine’s hemodynamic effects with prolonged administration has been raised, some effect is likely retained. Consequently, the dobutamine dose should be tapered rather than abruptly discontinued.

46. Milrinone
Milrinone is a bipyridine derivative that inhibits phosphodiesterase III and produces positive inotropic and arterial and venous vasodilating effects; hence, milrinone has been referred to as an inodilator. It has supplanted use of amrinone, which has a higher rate of thrombocytopenia. During IV administration, milrinone increases stroke volume (and cardiac output) with little change in heart rate. It is particularly useful in patients with a low cardia index and an elevated LV filling pressure. However, this decrease in preload can be hazardous for patients without excessive filling pressure, leading to a decrease in cardiac index.

47. Milrinone should be used cautiously as a single agent in severely hypotensive HF patients because it will not increase, and may even decrease, arterial blood pressure.
The most notable adverse events are arrhythmia, hypotension, and, rarely, thrombocytopenia. Patients should have platelet counts determined before and during therapy.
Routine use of milrinone (and perhaps other inotropes) should be discouraged because recent studies suggest a higher in-hospital mortality rate than with some other drugs. However, inotropes may be needed in selected patients such as those with low cardiac output states with organ hypoperfusion and cardiogenic shock.

48. Dopamine
Dopamine should generally be avoided in decompensated HF, but its pharmacologic actions may be preferable to dobutamine or milrinone in patients with marked systemic hypotension or cardiogenic shock in the face of elevated ventricular filling pressures, where dopamine in doses greater than 5 mcg/kg/min may be necessary to raise central aortic pressure.

49. Dopamine produces dose-dependent hemodynamic effects because of its relative affinity for α1-, β1-, β2-, and D1- (vascular dopaminergic) receptors.
Positive inotropic effects mediated primarily by β1-receptors become more prominent with doses of 2 to 5 mcg/kg/min. At doses between 5 to 10 mcg/kg/min, chronotropic and α1-mediated vasoconstricting effects become more prominent. Especially at higher doses, dopamine alters several parameters that increase myocardial oxygen demand and potentially decrease myocardial blood flow, worsening ischemia in some patients with coronary artery disease.

50. Vasodilators
Arterial vasodilators acting on reducing afterload and causing a reflex increase in cardiac output. Venodilators act as preload reducers by reducing symptoms of pulmonary congestion in patients with high cardiac filling pressures.
Mixed vasodilators act on both arterial resistance and venous capacitance vessels, reducing congestive symptoms while increasing cardiac output.

51. Nitroprusside
Sodium nitroprusside is a mixed arterial-venous vasodilator that acts directly on vascular smooth muscle to increase cardiac index and decrease venous pressure. Despite its lack of direct inotropic activity, nitroprusside exerts hemodynamic effects that are qualitatively similar to those of dobutamine and milrinone. • Hypotension is an important dose-limiting adverse effect of nitroprusside. .

52. Nitroprusside is effective in the short-term management of severe HF in a variety of settings (e.g., acute MI, valvular regurgitation, after coronary bypass surgery, decompensated HF). Generally, it will not worsen, and may improve, the balance between myocardial oxygen demand and supply.
However, an excessive decrease in systemic arterial pressure can decrease coronary perfusion and worsen ischemia.

53. Nitroglycerin
The major hemodynamic effects of IV nitroglycerin are decreased preload because of functional venodilation and mild arterial vasodilation. It is used primarily as a preload reducer for patients with pulmonary congestion. In higher doses, nitroglycerin displays potent coronary vasodilating properties and beneficial effects on myocardial oxygen demand and supply, making it the vasodilator of choice for patients with severe HF and ischemic heart disease.

54. Nesiritide
Nesiritide is manufactured using recombinant techniques and is identical to the endogenous B-type natriuretic peptide secreted by the ventricular myocardium in response to volume overload. Consequently, nesiritide mimics the vasodilatory and natriuretic actions of the endogenous peptide, resulting in venous and arterial vasodilation; increases in cardiac output; natriuresis and diuresis; and decreased cardiac filling pressures.

55. The precise role of nesiritide in the pharmacotherapy of decompensated HF remains controversial. Compared to nitroglycerin, it appears to produce little improvement in clinical outcomes and is substantially more expensive. Two recent meta analyses suggest an increased risk of worsening renal function as well as an increase in mortality with nesiritide.

56. Thank you