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1. Hypertension

2. Introduction 2 Hypertension is a common disease that is simply defined as persistently elevated arterial blood pressure (BP). Hypertensive crisis is categorized as hypertensive emergency (extreme BP elevation with acute or progressing end-organ damage) or hypertensive urgency (extreme BP elevation without acute or progressing endorgan injury). Although elevated BP was perceived to be “essential” for adequate perfusion of vital organs, It has been identified as one of the most significant risk factors for cardiovascular (CV) disease for decades.

3. Classification of Blood Pressure in Adults 3

4. Epidemiology 4 Almost half (46%) of American adults age 20 years and older have hypertension according to the ACC/AHA definition. The overall incidence of hypertension is similar between men and women but varies depending on age. The prevalence of high BP is higher in men than women before the age of 65 and is similar between the ages 65 and 74.

5. 5 BP values increase with age, and hypertension (persistently elevated BP values) is very common in older patients. Most patients have elevated BP before they are diagnosed with hypertension, with most diagnoses occurring between the third and fifth decades of life.

6. Etiology 6 In most patients, hypertension results from unknown pathophysiologic etiology (essential or primary hypertension). A smaller percentage of patients have a specific cause of their hypertension (secondary hypertension). In most of these cases, renal dysfunction resulting from severe CKD or renovascular disease is the most common secondary cause. Certain agents (drugs or other products), either directly or indirectly, can increase BP and cause or exacerbate hypertension.

7. Secondary Causes of Hypertension 7

8. Pathophysiology 8 Multiple physiologic factors control BP and abnormalities of these factors are potential contributing components in the development of essential hypertension. Factors contributing to development of primary hypertension include: Humoral abnormalities involving the renin–angiotensin–aldosterone system ( RAAS ), natriuretic hormone, and hyperinsulinemia; Disturbances in the CNS, autonomic nerve fibers, adrenergic receptors, or baroreceptors;

9. 9 Abnormalities in renal or tissue autoregulatory processes for sodium excretion, plasma volume, and arteriolar constriction; Deficiency in synthesis of vasodilating substances in vascular endothelium (prostacyclin, bradykinin, nitric oxide) or Excess vasoconstricting substances (angiotensin II, endothelin I); High sodium intake or lack of dietary calcium.

10. 10 Major causes of death include Cerebrovascular events, Cardiovascular (CV) events, and  Renal failure. Probability of premature death correlates with the severity of BP elevation.

11. Renin–angiotensin–aldosterone system 11

12. Clinical presentation 12 Patients with uncomplicated primary hypertension are usually asymptomatic initially. Patients with secondary hypertension may have symptoms of the underlying disorder: Pheochromocytoma —headaches, sweating, tachycardia, palpitations, orthostatic hypotension; Primary aldosteronism —hypokalemic symptoms of muscle cramps and weakness; Cushing syndrome —moon face, buffalo hump, hirsutism, weight gain, polyuria, edema, menstrual irregularities, acne, muscle weakness.

13. Diagnosis 13 Elevated BP may be the only sign of primary hypertension on physical examination. Diagnosis should be based on the average of two or more readings taken at each of two or more clinical encounters. Signs of end-organ damage occur primarily in the eyes, brain, heart, kidneys, and peripheral vasculature. Funduscopic examination may reveal Arteriolar narrowing, focal arteriolar constriction, arteriovenous nicking, Retinal hemorrhages and exudates, and disk edema.

14. 14 Presence of papilledema usually indicates a hypertensive emergency requiring rapid treatment. Cardiopulmonary examination may reveal abnormal heart rate or rhythm, LV hypertrophy, coronary artery disease, or HF. Peripheral vascular examination may reveal aortic or abdominal bruits, distended veins, diminished or absent peripheral pulses, or lower extremity edema. Patients with renal artery stenosis may have an abdominal systolic-diastolic bruit. Baseline hypokalemia may suggest mineralocorticoid-induced hypertension.

15. 15 Treatment

16. 16 Goals of Treatment: The overall goal is to reduce morbidity and mortality from CV events. The 2017 ACC/AHA guideline recommends a goal BP of <130/80 mm Hg for most patients, including those with clinical arteriosclerotic cardiovascular disease (ASCVD), diabetes, or CKD. For older ambulatory, community-dwelling patients, the goal is SBP <130 mm Hg. For institutionalized older patients and those with a high disease burden or limited life expectancy, consider a relaxed SBP goal of <150 mm Hg (or <140 mm Hg if tolerated).

17. Nonpharmacologic therapy 17 Implement lifestyle modifications in all patients with elevated BP or stage 1 or 2 hypertension. These measures alone are appropriate initial treatment for patients with elevated BP or stage 1 hypertension who are at low risk of ASCVD. Start drug therapy for these patients when BP is ≥140/90 mm Hg. For patients with stage 1 or 2 hypertension who already have ASCVD (secondary prevention) or an elevated 10-year ASCVD risk ≥10%,

18. 18 The threshold for starting drug therapy is ≥130/80 mm Hg with a goal BP of <130/80 mm Hg. Lifestyle modifications shown to lower BP include (1) weight loss if overweight or obese, (2) the Dietary Approaches to Stop Hypertension (DASH) eating plan, (3) reduced salt intake, ideally to 1.5 g/day sodium (3.8 g/day sodium chloride), (4) physical activity (90–150 min/week of aerobic or dynamic resistance training), and

19. 19 (5) moderation of alcohol intake (≤2 drinks/day in men and ≤1 drink/day in women).

20. Pharmacologic therapy 20 General Approach to Treatment Initial drug selection depends on the degree of BP elevation and presence of compelling indications for certain drugs. Use a single first-line drug as initial therapy in most patients with newly diagnosed stage 1 hypertension. Start combination drug therapy (preferably with two first-line drugs) as the initial regimen in patients with newly diagnosed stage 2 hypertension.

21. 21 The four first-line options are Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), and thiazide diuretics. β-Blockers should be reserved to treat a specific compelling indication or in combination with a first-line antihypertensive agent for patients without a compelling indication. Other antihypertensive drug classes (α1-blockers, direct renin inhibitors, central α2-agonists, and direct arterial vasodilators) may be used for select patients after implementing first-line agents.

22. 22 They are generally reserved for resistant hypertension or as add-on therapy with multiple other first-line agents .

23. Compelling indications 23 Compelling indications are specific comorbid conditions for which clinical trial data support using specific antihypertensive drug classes to treat both hypertension and the compelling indication.

24. 24 HFrEF GDMT consists of three to four drugs: ACE inhibitor or ARB plus diuretic, followed by addition of an evidence-based β-blocker and possibly a mineralocorticoid receptor antagonist. Start an ACE inhibitor or ARB in low doses to avoid orthostatic hypotension because of the high renin state in HF. Diuretics reduce edema, and loop diuretics are often needed, especially in patients with advanced HF and/or CKD. β-Blockers modify disease in HFrEF and are part of standard treatment; adding a β-blocker to a diuretic with an ACE inhibitor or ARB reduces CV morbidity and mortality.

25. 25 After implementation of a standard three-drug regimen, other agents may be added to further reduce CV morbidity and mortality, and reduce BP if needed. A mineralocorticoid receptor antagonist (spironolactone or eplerenone ) may be considered at this point. Unlike interventions in HFrEF that decrease morbidity and mortality, trials using the same medications in HFpEF have not shown similar benefits.

26. 26 Stable Ischemic Heart Disease (SIHD) β-Blockers (without ISA) are first-line therapy in SIHD; they reduce BP and improve angina symptoms by decreasing myocardial oxygen consumption and demand. β-Blockers should be used for hypertension treatment in patients with SIHD. An ACE inhibitor or ARB has been shown to reduce CV events as an add-on to a β-blocker. A long-acting nondihydropyridine CCB is an alternative to a β-blocker in SIHD, but β-blockers are the therapy of choice.

27. 27 All four first-line antihypertensive classes reduce CV events in patients with diabetes. Regardless of the initial agent selected, most patients require combination therapy, which typically includes an ACE inhibitor (or ARB) with a CCB or thiazide. After first-line agents, a β-blocker is a useful add-on therapy for BP control in patients with diabetes. A thiazide diuretic, either alone or combined with an ACE inhibitor, is recommended for patients with history of stroke or transient ischemic attack.

28. Algorithm for treatment of elevated BP and hypertension based on BP category at initial diagnosis 28

29. Compelling indications for individual drug classes 29

30. 30 First-line antihypertensive agents

31. Angiotensin-Converting Enzyme Inhibi tors 31 ACE inhibitors block conversion of angiotensin I to angiotensin II, a potent vasoconstrictor and stimulator of aldosterone secretion. ACE inhibitors also block degradation of bradykinin and stimulate synthesis of other vasodilating substances. Starting doses should be low with slow dose titration. Acute hypotension may occur at the onset of therapy, especially In patients who are sodium or volume depleted, in HF exacerbation, very elderly, or on concurrent vasodilators or diuretics.

32. 32 ACE inhibitors decrease aldosterone and can increase serum potassium concentrations. AKI is an uncommon but serious side effect; preexisting kidney disease increases risk. Bilateral renal artery stenosis or unilateral stenosis of a solitary functioning kidney renders patients dependent on the vasoconstrictive effect of angiotensin II on efferent arterioles, making them particularly susceptible to AKI.

33. 33 GFR decreases somewhat when ACE inhibitors are started because of inhibition of angiotensin II vasoconstriction on efferent arterioles. Angioedema occurs in <1% of patients. Drug withdrawal is necessary, and some patients may require drug treatment and/or emergent intubation to support respiration. A persistent dry cough occurs in up to 20% of patients and is thought to be due to inhibition of bradykinin breakdown. ACE inhibitors (as well as ARBs and direct renin inhibitors) are contraindicated in pregnancy.

34. Angiotensin II Receptor Blockers 34 Angiotensin II is generated by the renin–angiotensin pathway (which involves ACE) and an alternative pathway that uses other enzymes such as chymases . ACE inhibitors block only the renin–angiotensin pathway, whereas ARBs inhibit angiotensin II generated by either pathway. The ARBs directly block the angiotensin II type 1 receptor that mediates the effects of angiotensin II. All ARBs have similar antihypertensive efficacy and fairly flat dose-response curves. Addition of a CCB or thiazide diuretic significantly increases antihypertensive efficacy

35. Calcium Channel Blockers 35 Dihydropyridine and nondihydropyridine CCBs are first-line antihypertensive therapies and Are also used in addition to or instead of other first-line agents for the compelling indication of ischemic heart disease. CCBs cause relaxation of cardiac and smooth muscle by blocking voltage-sensitive calcium channels, thereby reducing entry of extracellular calcium into cells. This leads to vasodilation and a corresponding reduction in BP.

36. 36 Verapamil decreases heart rate, slows atrioventricular (AV) nodal conduction, and produces a negative inotropic effect that may precipitate HF in patients with borderline cardiac reserve. Diltiazem decreases AV conduction and heart rate to a lesser extent than verapamil. Both can cause peripheral edema and hypotension. Verapamil causes constipation in about 7% of patients. Dihydropyridines cause a baroreceptor-mediated reflex increase in heart rate. Dihydropyridines do not decrease AV node conduction and are not effective for treating supraventricular tachyarrhythmias .

37. Diuretics 37 Thiazides are the preferred type of diuretic and are a first-line option for most patients with hypertension. Chlorthalidone is preferred over hydrochlorothiazide, especially in resistant hypertension. Loop diuretics are more potent for inducing diuresis but are not ideal antihypertensives unless edema treatment is also needed. Potassium-sparing diuretics are weak antihypertensives when used alone and provide minimal additive effect when combined with a thiazide or loop diuretic. Their primary use is in combination with another diuretic to counteract potassium-wasting properties.

38. 38 Mineralocorticoid receptor antagonists (spironolactone and eplerenone ) are also potassium-sparing diuretics that are usually used to treat resistant hypertension because elevated aldosterone concentrations are prevalent in this setting. Acutely, diuretics lower BP by causing diuresis. The reduction in plasma volume and stroke volume associated with diuresis decreases cardiac output and BP. The initial drop in cardiac output causes a compensatory increase in peripheral vascular resistance. Reduced peripheral vascular resistance is responsible for persistent hypotensive effects .

39. 39 Combining diuretics with other antihypertensive agents usually results in an additive hypotensive effect because of independent mechanisms of action. Furthermore many nondiuretic antihypertensive agents induce sodium and water retention, which is counteracted by concurrent diuretic use. Side effects of thiazides include Hypokalemia, hypomagnesemia, hypercalcemia, hyperuricemia, hyperglycemia, dyslipidemia, and sexual dysfunction.

40. 40 Hypokalemia and hypomagnesemia may cause muscle fatigue or cramps, and severe electrolyte abnormalities may result in serious cardiac arrhythmias. Potassium-sparing diuretics may cause hyperkalemia. Spironolactone may cause gynecomastia in up to 10% of patients; this effect occurs rarely with eplerenone .

41. Most Common First-Line and Other Antihypertensive Agents 41

42. Most Common First-Line and Other Antihypertensive Agents …………….. 42

43. Most Common First-Line and Other Antihypertensive Agents …………….. 43

44. Most Common First-Line and Other Antihypertensive Agents …………….. 44

45. 45 Alternative antihypertensive agents

46. β-Blockers 46 Evidence suggests that β-blockers may not reduce CV events as well as ACE inhibitors, ARBs, CCBs, or thiazides when used as the initial drug in patients who do not have a compelling indication for a β-blocker. β-Blockers are appropriate first-line agents when used to treat specific compelling indications or when an ACE inhibitor, ARB, CCB, or thiazide cannot be used. Their hypotensive mechanism may involve Decreased cardiac output through negative chronotropic and inotropic cardiac effects and inhibition of renin release from the kidney.

47. 47 Cardiac side effects include bradycardia, AV conduction abnormalities, and acute HF. Blocking β2-receptors in arteriolar smooth muscle may cause cold extremities and aggravate intermittent claudication or Raynaud phenomenon. Increases in serum lipids and glucose appear to be transient and of little clinical significance. Abrupt cessation of β-blocker therapy can produce Cardiac ischemia (angina, chest pain), a CV event, or even death in patients with coronary artery disease.

48. α1 -Receptor Blockers 48 Prazosin, terazosin, and doxazosin are selective α1 -receptor blockers that inhibit catecholamine uptake in smooth muscle cells of peripheral vasculature, resulting in vasodilation and BP lowering. A first-dose phenomenon characterized by orthostatic hypotension accompanied by Transient dizziness or faintness, palpitations, and even syncope may occur within 1–3 hours of the first dose or after later dosage increases. Occasionally, orthostatic hypotension and dizziness persist with chronic administration.

49. 49 Sodium and water retention can occur; these agents are most effective when given with a thiazide to maintain antihypertensive efficacy and minimize edema. Although they can provide symptomatic benefit in men with benign prostatic hyperplasia, They should be used to lower BP only in combination with first-line antihypertensive agents.

50. Central α2 - Agonists 50 Clonidine, guanfacine , and methyldopa lower BP primarily by stimulating α2 -adrenergic receptors in the brain, which reduces sympathetic outflow from the vasomotor center and increases vagal tone. Stimulation of presynaptic α2- receptors peripherally may contribute to reduced sympathetic tone. Consequently, there may be decreases in heart rate, cardiac output, total peripheral resistance, plasma renin activity, and baroreceptor reflexes.

51. 51 Chronic use results in sodium and fluid retention. Other side effects include Depression, orthostatic hypotension, dizziness, and anticholinergic effects (eg, dry mouth, sedation). Abrupt cessation may lead to rebound hypertension. Methyldopa rarely causes hepatitis or hemolytic anemia.

52. Direct Arterial Vasodilators 52 Hydralazine and minoxidil directly relax arteriolar smooth muscle, resulting in vasodilation and BP lowering. Compensatory activation of baroreceptor reflexes increases sympathetic outflow, Thereby increasing heart rate, cardiac output, and renin release. Direct vasodilators can precipitate angina in patients with underlying SIHD unless the baroreceptor reflex mechanism is blocked with a β-blocker.

53. 53 Hydralazine may cause a dose-related, reversible lupus-like syndrome. Minoxidil is a more potent vasodilator than hydralazine, and compensatory increases in heart rate, cardiac output, renin release, and sodium retention are more dramatic.

54. Hypertensive urgencies and emergencies 54 Hypertensive urgencies are ideally managed by Adjusting maintenance therapy, Adding a new antihypertensive, increasing the dose of a current medication, or Treating anxiety as applicable. Acute administration of a short-acting oral drug (captopril, clonidine, or labetalol) followed by careful observation for several hours to ensure a gradual BP reduction is an option.

55. 55 Hypertensive emergencies require immediate BP reduction with a parenteral agent to limit new or progressing end-organ damage. The rate of BP reduction depends on whether the patient has aortic dissection, severe preeclampsia or eclampsia, or pheochromocytoma with hypertensive crisis. For patients with a hypertensive emergency without aortic dissection, severe preeclampsia or eclampsia, or pheochromocytoma with hypertensive crisis, The initial target is reduction in mean arterial pressure of up to 25% over the first hour.

56. 56 Precipitous drops in BP may cause end-organ ischemia or infarction. If BP reduction is well tolerated, additional gradual decreases toward the goal BP can be attempted after 24–48 hours. Nitroprusside is the agent of choice for minute-to-minute control in most cases. When the nitroprusside infusion must be continued longer than 72  hours, measure serum thiocyanate levels, and discontinue the infusion if the level exceeds 12 mg/ dL (~2.0 mmol /L. Other adverse effects are nausea, vomiting, muscle twitching, and sweating.

57. Parenteral Antihypertensive Agents for Hypertensive Emergency 57

58. Evaluation of therapeutic outcomes 58 Both clinic-based and self-measurement home BP monitoring are important for monitoring and managing hypertension. Evaluate BP response in the clinic 4 weeks after initiating or making changes in therapy and compare the results to home BP readings. Once goal BP is obtained, monitor BP every 3–6 months, assuming no signs or symptoms of acute end-organ damage. Evaluate more frequently in patients with a history of poor control, nonadherence, progressive end-organ damage, or symptoms of adverse drug effects.

59. 59 Monitor patients routinely for adverse drug events, which may require dosage reduction or substitution with an alternative antihypertensive agent. Perform laboratory monitoring 4 weeks after starting a new agent or dose increase, and then every 6–12 months in stable patients. For patients treated with a mineralocorticoid receptor antagonist Monitor potassium concentrations and kidney function within 3 days of initiation and again at 1 week to detect potential hyperkalemia. Monitor patients for signs and symptoms of hypertension-associated complications.

60. 60 Take a careful history for ischemic chest pain (or pressure), palpitations, dizziness, dyspnea, orthopnea, headache, sudden change in vision, one-sided weakness, slurred speech, and loss of balance. Monitor funduscopic changes on eye examination, LV hypertrophy on ECG, albuminuria, and changes in kidney function periodically. Assess patient adherence with the regimen regularly. Ask patients about changes in their general health perception, physical functioning, and overall satisfaction with treatment.

61. 61 Heart Failure

62. Introduction 62 Heart failure (HF) is a progressive syndrome that can result from any changes in cardiac structure or function that impair the ability of the ventricle to fill with or eject blood. HF may be caused by an abnormality in systolic function, diastolic function, or both. HF with reduced systolic function ( ie , reduced left ventricular ejection fraction, LVEF) is referred to as HF with reduced ejection fraction (HFrEF). Preserved LV systolic function ( ie , normal LVEF) with presumed diastolic dysfunction is termed HF with preserved ejection fraction ( HFpEF ).

63. 63 HF is the final common pathway for numerous cardiac disorders including Those affecting the pericardium, heart valves, and myocardium.

64. Epidemiology 64 HF is an epidemic public health problem in the United States. Approximately 6.5 million Americans have HF with 1,000,000 new cases diagnosed each year. A large majority of patients with HF are elderly, with multiple comorbid conditions that influence morbidity and mortality. Although the mortality rates have declined over the last 50 years, the overall 5-year survival remains approximately 42% for all patients with a diagnosis of HF, with mortality increasing with symptom severity.

65. Etiology 65 HF can result from any disorder that affects The ability of the heart to contract (systolic function) and/or relax (diastolic dysfunction). The leading causes of HF are coronary artery disease and hypertension.

66. Causes of Chronic Heart Failure 66

67. Pathophysiology 67 HFrEF is a progressive disorder initiated by any event that impairs the ability of the heart to contract and sometimes relax resulting in a decrease in CO. The index event may have An acute onset, as with MI, or The onset may be slow, as with long-standing HTN. Regardless of the index event, a decrease in CO results in activation of compensatory responses to maintain the circulation:

68. 68 (1) Tachycardia and increased contractility through sympathetic nervous system activation, (2) The Frank–Starling mechanism, whereby increased preload (through sodium and water retention) 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.

69. Relationship between cardiac output and preload 69

70. Relationship between stroke volume and systemic vascular resistance 70

71. Beneficial and Detrimental Effects of the Compensatory Responses in Heart 71

72. Key components of the pathophysiology of cardiac remodeling 72

73. 73 In the neurohormonal model of HF, an initiating event (eg, acute MI) leads to decreased CO; The HF state then becomes a systemic disease whose progression is mediated largely by neurohormones and autocrine/paracrine factors that drive Myocyte injury, oxidative stress, inflammation, and extracellular matrix remodeling. These substances include angiotensin II, norepinephrine, aldosterone, natriuretic peptides, and arginine vasopressin (AVP).

74. 74 Chronic activation of the neurohormonal systems results in a cascade of events that affect the myocardium at the molecular and cellular levels. These events lead to changes in Ventricular size (left ventricular hypertrophy), shape, structure, and function known as ventricular remodeling. The alterations in ventricular function result in further deterioration in cardiac systolic and diastolic functions that further promotes the remodeling process.

75. 75 Common precipitating factors that may cause a previously compensated HF patient to decompensate include Myocardial ischemia and MI, pulmonary infections, Nonadherence with diet or drug therapy, and Inappropriate medication use. Drugs may precipitate or exacerbate HF through negative inotropic effects, direct cardiotoxicity, or increased sodium and water retention.

76. Clinical presentation 76 Patient presentation may range from asymptomatic to cardiogenic shock. Primary symptoms are dyspnea (especially on exertion) and fatigue, which lead to exercise intolerance. Other pulmonary symptoms include orthopnea, paroxysmal nocturnal dyspnea (PND), 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 or early satiety, and weight gain or loss.

77. 77 Physical examination may reveal Pulmonary crackles, S3 gallop, cool extremities, Cheyne–Stokes respiration, Tachycardia, narrow pulse pressure, cardiomegaly, Symptoms of pulmonary edema (extreme breathlessness and anxiety, sometimes with coughing and pink, frothy sputum), peripheral edema, jugular venous distention (JVD), Hepatojugular reflux (HJR), hepatomegaly, and Mental status changes.

78. Diagnosis 78 Consider the diagnosis of HF in patients with characteristic signs and symptoms. A complete history and physical examination with appropriate laboratory testing are essential in evaluating patients with suspected HF. Laboratory tests for identifying disorders that may cause or worsen HF include CBC; serum electrolytes (including calcium and magnesium); renal, hepatic, thyroid function tests, and iron studies; urinalysis; lipid profile; and A1C.

79. 79 Hyponatremia Serum creatinine may be increased due to hypoperfusion ; preexisting renal dysfunction can contribute to volume overload. B-type natriuretic peptide (BNP) is usually >100 pg /mL (29 pmol /L) and NT- proBNP >300 pg /mL (35 pmol /L). Ventricular hypertrophy can be demonstrated on chest radiograph or electrocardiogram (ECG). Chest radiograph may also show pleural effusions or pulmonary edema.

80. 80 Echocardiogram can identify abnormalities of the pericardium, myocardium, or heart valves and quantify LVEF to determine if systolic or diastolic dysfunction is present. The New York Heart Association Functional Classification System is intended primarily to classify symptoms according to the physician’s subjective evaluation. Functional class (FC)-I patients have no limitation of physical activity, FC-II patients have slight limitation, FC-III patients have marked limitation, and FC-IV patients are unable to carry on physical activity without discomfort. The ACC/AHA staging system provides a more comprehensive framework for evaluating, preventing, and treating HF.

81. Treatment of chronic heart failure 81 Goals of Treatment: Improve quality of life, relieve or reduce symptoms, prevent or minimize hospitalizations, slow disease progression, and prolong survival. General approach The first step is to determine the etiology or precipitating factors. Treatment of underlying disorders (eg, hyperthyroidism) may obviate the need for treating HF. ACC/AHA Stage A: These are patients at high risk for developing HF.

82. 82 Identify and modify risk factors to prevent development of structural heart disease and subsequent HF. Strategies include smoking cessation and control of hypertension, diabetes mellitus, and dyslipidemia. Although treatment must be individualized, ACE inhibitors or ARBs are recommended for HF prevention in patients with multiple vascular risk factors. ACC/AHA Stage B: These patients have structural heart disease but no HF signs or symptoms.

83. 83 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 reduced LVEF (<40%) should receive ACE inhibitors (or ARB) and an evidence-based β-blocker to prevent development of HF, regardless of whether they have had an MI. Patients with a previous MI and reduced LVEF should also receive an ACE inhibitor or ARB, evidence-based β-blockers, and a statin.

84. 84 ACC/AHA Stage C: These patients have structural heart disease and previous or current HF symptoms and include both HFrEF and HFpEF . In addition to treatments for stages A and B, patients with HFrEF in stage C should receive GDMT that includes An ACE inhibitor, ARB, or angiotensin receptor– neprilysin inhibitor together with an evidence-based β- blocker, and an aldosterone antagonist in eligible patients to reduce morbidity and mortality. Loop diuretics, hydralazine–isosorbide dinitrate (ISDN), digoxin, and ivabradine are also used in select patients.

85. 85 ACC/AHA Stage D HFrEF: These patients have persistent HF symptoms despite maximally tolerated GDMT. They should be considered for specialized interventions, including Mechanical circulatory support, continuous IV positive inotropic therapy, cardiac transplantation, or hospice care (when no additional treatments are appropriate).

86. GDMT algorithm for patients with ACC/AHA stage C HFrEF 86

87. NONPHARMACOLOGIC THERAPY OF CHF 87 Interventions include cardiac rehabilitation and restriction of fluid intake and dietary sodium intake (<2–3 g of sodium/day) with daily weight measurements. In patients with hyponatremia (serum sodium <130 mEq /L [ mmol /L]) or persistent volume retention despite high diuretic doses and sodium restriction, limit daily fluid intake to 2 L/day from all sources. Revascularization or anti-ischemic therapy in patients with coronary disease may reduce HF symptoms. Drugs that can aggravate HF should be discontinued if possible.

88. Pharmacologic therapy for stage C HFrEF 88 In general, patients with stage C HFrEF should receive an ACE inhibitor, ARB, or ARNI along with an evidence-based β-blocker, plus an aldosterone antagonist in select patients. Administer a diuretic if there is evidence of fluid retention. A hydralazine–nitrate combination, ivabradine , or digoxin may be considered in select patients.

89. Diuretics 89 Compensatory mechanisms in HF stimulate excessive sodium and water retention, often leading to systemic and pulmonary congestion. Consequently, diuretic therapy (in addition to sodium restriction) is recommended for all patients with clinical evidence of fluid retention. However, because they do not alter disease progression or prolong survival, Diuretics are not required for patients without fluid retention.

90. 90 Thiazide diuretics (eg, hydrochlorothiazide) are relatively weak and are infrequently used alone in HF. However, thiazides or the thiazide-like diuretic metolazone can be used in combination with a loop diuretic to promote very effective diuresis. Loop diuretics are usually necessary to restore and maintain euvolemia in HF. Unlike thiazides, loop diuretics maintain their effectiveness in the presence of impaired renal function, although higher doses may be necessary.

91. 91 Adverse effects of diuretics include Hypovolemia, hypotension, hyponatremia, hypokalemia, hypomagnesemia, hyperuricemia, and renal dysfunction.

92. Angiotensin-Converting Enzyme Inhibitors 92 ACE inhibitors decrease angiotensin II and aldosterone, attenuating many of their deleterious effects that drive HF initiation and progression. ACE inhibitors also inhibit the breakdown of bradykinin, which increases vasodilation and also leads to cough. ACE inhibitors improve symptoms, slow disease progression, and decrease mortality in patients with HFrEF. Current guidelines recommend that all patients with HFrEF, regardless of whether or not symptoms are present, should receive an ACE inhibitor to reduce morbidity and mortality, unless there are contraindications.

93. 93 Clinical trials have documented favorable effects of ACE inhibitors on symptoms, HF progression, hospitalizations, and quality of life. ACE inhibitors improve survivalby 20%–30% compared with placebo. The benefits are independent of HF etiology (ischemic vs nonischemic ) and are greatest in patients with the most severe symptoms. Start therapy with low doses followed by gradual titration as tolerated to the target or maximally tolerated doses. Dose titration is usually accomplished by doubling the dose every 2 weeks.

94. 94 Evaluate blood pressure (BP), renal function, and serum potassium at baseline and within 1–2 weeks after the start of therapy and after each dose increase. Although symptoms may improve within a few days of starting therapy, it may take weeks to months before the full benefits are apparent. Even if symptoms do not improve, continue long-term therapy to reduce mortality and hospitalizations. The most common adverse effects include hypotension, renal dysfunction, and hyperkalemia.

95. 95 A dry, nonproductive cough (occurring in 15%–20% of patients) is the most common reason for discontinuation. Because cough is a bradykinin mediated effect, replacement with an ARB is reasonable; however, caution is required because crossreactivity has been reported. Angioedema occurs in approximately 1% of patients and is potentially life threatening; ACE inhibitors are contraindicated in patients with a history of angioedema. ACE inhibitors are contraindicated in pregnancy due to various congenital defects.

96. Angiotensin Receptor Blockers 96 The ARBs block the angiotensin II receptor subtype AT1 , preventing the deleterious effects of angiotensin II on ventricular remodeling. Because they do not affect the ACE enzyme, ARBs do not affect bradykinin, which is linked to ACE inhibitor cough and angioedema. ARBs are now a guideline-recommended alternative in patients who are unable to tolerate an ACE inhibitor due to cough or angioedema. Although numerous ARBs are available, only candesartan, valsartan, and losartan are recommended in the guidelines because efficacy has been demonstrated in clinical trials.

97. 97 As with ACE inhibitors, initiate therapy with low doses and then titrate to target doses. Evaluate BP, renal function, and serum potassium within 1–2 weeks after starting therapy and after dosage increases, with these parameters used to guide subsequent dose changes. ARBs are not suitable alternatives in patients with hypotension, hyperkalemia, or renal insufficiency due to ACE inhibitors because they are just as likely to cause these adverse effects.

98. 98 Careful monitoring is required when an ARB is used with another inhibitor of the renin-angiotensin-aldosterone (RAAS) system Because this combination increases the risk of these adverse effects. Because ARBs do not affect bradykinin, they are not associated with cough and have a lower risk of angioedema than ACE inhibitors. Similar to ACE inhibitors, ARBs are contraindicated in pregnancy.

99. Angiotensin Receptor– Neprilysin Inhibitor 99 Valsartan/ Sacubitril is an ARNI approved to reduce the risk of cardiovascular death and hospitalization for HF in patients with NYHA class II–IV HF and reduced LVEF. In patients with HFrEF and NYHA class II–III symptoms tolerating an ACE inhibitor or ARB, current guidelines recommend replacing those drugs with the ARNI to further reduce morbidity and mortality. Discontinue ACE inhibitors 36 hours prior to initiating the ARNI; no waiting period is needed in patients receiving an ARB.

100. 100 Titrate the initial starting dose to the target dose after 2–4 weeks. Closely monitor BP, serum potassium, and renal function after the start of therapy and after each titration step. The most common adverse effects include hypotension, dizziness, hyperkalemia, worsening renal function, and cough. Sacubitril /valsartan is contraindicated in patients with a history of angioedema associated with an ACE inhibitor or ARB. It is also contraindicated in pregnancy and should not be used concurrently with ACE inhibitors or other ARBs.

101. β-Blockers 101 β-Blockers antagonize the detrimental effects of the sympathetic nervous systems in HF and slow disease progression. Clinical trial evidence demonstrated that certain β-blockers reduce HF mortality, all-cause hospitalizations, and hospitalizations for worsening HF, among other endpoints. The ACC/AHA guidelines recommend use of β-blockers in all stable patients with HFrEF 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.

102. 102 It is not essential that ACE inhibitor doses be optimized before a β-blocker is started. β-Blockers are also recommended for asymptomatic persons with a reduced LVEF (stage B) to decrease the risk of progression to HF. Carvedilol, metoprolol succinate (CR/XL), and bisoprolol are the only β-blockers shown to reduce mortality in large HF trials. Because bisoprolol is not available in the necessary starting dose of 1.25 mg, the choice is typically limited to either carvedilol or metoprolol succinate.

103. 103 Initiate β-blockers in stable patients who have no or minimal evidence of fluid overload. Because of their negative inotropic effects, start β-blockers in very low doses with slow upward dose titration to avoid symptomatic worsening or acute decompensation. Doses should be doubled no more often than every 2 weeks, as tolerated, until the target or maximally tolerated dose is reached. In addition, dose titration is a long, gradual process; response to therapy may be delayed; and HF symptoms may actually worsen during the initiation period.

104. 104 Adverse effects include Bradycardia or heart block, hypotension, fatigue, impaired glycemic control in diabetic patients, bronchospasm in patients with asthma, and worsening HF. Absolute contraindications include uncontrolled bronchospastic disease, symptomatic bradycardia, advanced heart block without a pacemaker, and acute decompensated HF. However, β-blockers may be tried with caution in patients with asymptomatic bradycardia, COPD, or well-controlled asthma.

105. Aldosterone Antagonists 105 Spironolactone and eplerenone block mineralocorticoid receptors, the target for aldosterone. In the heart, aldosterone antagonists inhibit cardiac extracellular matrix and collagen deposition, thereby attenuating cardiac fibrosis and ventricular remodeling. Aldosterone antagonists also attenuate the systemic proinflammatory state, atherogenesis , and oxidative stress caused by aldosterone.

106. 106 Current guidelines recommend adding a low-dose aldosterone antagonist to standard therapy To improve symptoms, reduce the risk of HF hospitalization, and Increase survival in select patients provided that serum potassium and renal function can be carefully monitored. Start with low doses (spironolactone 12.5 mg/day or eplerenone 25 mg/day) especially in older persons and those with diabetes or a creatinine clearance.

107. Ivabradine 107 Ivabradine inhibits the If current in the sinoatrial node that is responsible for controlling HR, thereby slowing spontaneous depolarization of the sinus node and resulting in a dose-dependent slowing of the HR. Ivabradine is indicated to reduce the risk of hospitalization for worsening HF in patients with LVEF ≤35% who are in sinus rhythm with resting HR ≥70 bpm and are either on a maximally tolerated dose of a β-blocker or have a contraindication to β-blocker use. The usual starting dose is 5 mg twice daily with meal. After 2 weeks of treatment, if the resting HR is between 50 and 60 bpm, the dose should be continued.

108. Digoxin 108 It attenuates the excessive sympathetic nervous system activation in HF and increases parasympathetic activity, thereby decreasing HR and enhancing diastolic filling. Based on available data, digoxin is not considered a first-line agent in HF, but a trial may be considered in conjunction with GDMT including ACE inhibitors (or ARBs), β-blockers, and diuretics in patients with symptomatic HFrEF to improve symptoms and reduce hospitalizations. In the absence of digoxin toxicity or serious adverse effects, digoxin should be continued in most patients. Digoxin withdrawal may be considered for asymptomatic patients who have significant improvement in systolic function with optimal ACE inhibitor and β-blocker treatment.

109. Drug Dosing Recommendations for Stage C HFrEF 109

110. Drug Dosing Recommendations for Stage C HFrEF…. 110

111. PHARMACOLOGIC THERAPY FOR HFpEF 111 Treatment includes controlling HR and BP, alleviating causes of myocardial ischemia, reducing volume, and restoring and maintaining sinus rhythm in patients with atrial fibrillation. A loop or a thiazide diuretic should be considered for patients with volume overload. Avoid lowering preload excessively, which may reduce stroke volume and CO. ACE inhibitors may be considered in all patients, especially patients with symptomatic atherosclerotic cardiovascular disease or diabetes and one additional risk factor.

112. 112 Aldosterone antagonists can reduce the risk of hospitalization in patients who do not have contraindications and are not at risk for hyperkalemia. Nondihydropyridine calcium channel blockers should be considered for patients with atrial fibrillation warranting ventricular rate control who either are intolerant to or have not responded to a β-blocker. A nondihydropyridine or dihydropyridine (eg, amlodipine) CCB can be considered for symptom-limiting angina or hypertension.

113. 113 Treatment of acute decompensated heart failure (ADHF)

114. General approach 114 Acute decompensated heart failure involves patients with new or worsening signs or symptoms (often resulting from volume overload and/or low CO) requiring medical intervention, such as emergency department visit or hospitalization. The overall goals are to relieve symptoms, improve hemodynamic stability, and reduce short-term mortality so the patient can be discharged in a stable compensated state on oral drug therapy. Consider hospitalization based on clinical findings. Focus the history and physical exam on potential etiologies of ADHF; presence of precipitating factors; onset, duration, and severity of symptoms; and a careful medication history.

115. 115 Symptoms of volume overload include dyspnea, orthopnea, PND, ascites, GI symptoms (poor appetite, nausea, early satiety), peripheral edema, and weight gain. Low output symptoms include altered mental status, fatigue, GI symptoms (similar to volume overload), and decreased urine output. Signs of volume overload include pulmonary crackles, elevated jugular venous pressure, HJR, S3 gallop, and peripheral edema.

116. 116 Low output signs include tachycardia, hypotension (more commonly) or hypertension, narrow pulse pressure, cool extremities, pallor, and cachexia. Laboratory testing may include BNP or NT- proBNP , thyroid function tests, complete blood count, cardiac enzymes, and routine serum chemistries (eg, serum creatinine, liver function tests). Ascertain hemodynamic status to guide initial therapy. Patients may be categorized into one of four hemodynamic subsets based on volume status ( euvolemic or “dry” vs volume overloaded or “wet”) and CO (adequate CO or “warm” vs hypoperfusion or “cold”.

117. 117 Reserve invasive hemodynamic monitoring for patients refractory to initial therapy, whose volume status is unclear, or who have significant hypotension or worsening renal function despite appropriate initial therapy. If fluid retention is evident on physical exam, pursue aggressive diuresis, preferably with IV diuretics. In the absence of cardiogenic shock or symptomatic hypotension, strive to continue all GDMT for HF. β-blockers may be temporarily held or dose-reduced if recent changes are responsible for acute decompensation. Other GDMT may also need to be temporarily withheld in the presence of renal dysfunction, with close monitoring of serum potassium. Most patients may continue to receive digoxin at doses targeting a trough serum concentration of 0.5–0.9 ng/Ml.

118. N onpharmacologic therapy for ADHF 118 Place all patients with congestive symptoms on sodium restriction (<2 g daily) and consider fluid restriction for refractory symptoms. Consider noninvasive ventilation for patients in respiratory distress due to acute pulmonary edema, particularly those at risk for intubation. Provide pharmacologic thromboprophylaxis with UFH or LMWH for most patients with limited mobility. Most nonpharmacologic therapies for ADHF are reserved for patients failing pharmacologic therapy Temporary mechanical circulatory support (MCS) with an intra-aortic balloon pump (IABP), ventricular assist device (VAD), or extracorporeal membrane oxygenation (ECMO) may be considered for;

119. 119 Hemodynamic stabilization until the underlying etiology of cardiac dysfunction resolves or has been corrected (“bridge to recovery”) or Until evaluation for definitive therapy (eg, durable MCS or cardiac transplantation) can be completed (“bridge to decision”). Durable MCS with temporary device implantation is used for patients awaiting heart transplantation who are unlikely to survive until a suitable donor is identified (“bridge to transplantation”). Cardiac transplantation is the best option for patients with irreversible advanced HF.

120. General management algorithm for ADHF based on clinical presentation. 120

121. 121 PHARMACOLOGIC THERAPY FOR ADHF

122. Loop Diuretics 122 Current guidelines recommend IV loop diuretics (furosemide, bumetanide) as firstline therapy for ADHF patients with volume overload. Bolus administration reduces preload by functional venodilation within 5–15 minutes and later (>20 minutes) via sodium and water excretion, thereby improving pulmonary congestion. Although patients with HFrEF can tolerate significant reductions in preload without compromising stroke volume, excessive diuresis can decrease CO. Excessive reductions in venous return may also compromise CO in diastolic dysfunction, intravascular volume depletion, or patients in whom CO is significantly dependent on adequate filling pressure.

123. 123 Reflex increases in neurohormonal activation may result in arteriolar and coronary vasoconstriction, tachycardia, and increased myocardial oxygen consumption. Use low doses (equivalent to IV furosemide 20–40 mg) initially in ADHF patients who are naïve to loop diuretics. Higher doses are associated with more rapid relief of congestive symptoms but may also increase the risk of transient worsening of renal function. Diuretic resistance may be improved by administering larger IV bolus doses, transitioning from IV bolus to continuous IV infusions, or adding a second diuretic with a different mechanism of action.

124. Vasopressin Antagonists 124 Vasopressin receptor antagonists affect one or two AVP (antidiuretic hormone) receptors, V1A or V2 . Tolvaptan selectively binds to and inhibits the V2 receptor. It is an oral agent indicated for hypervolemic and euvolemic hyponatremia in patients with SIADH, cirrhosis, or HF. Conivaptan nonselectively inhibits both the V1A and V2 receptors. It is an IV agent indicated for hypervolemic and euvolemic hyponatremia due to a variety of causes but is not indicated for patients with HF. The role of vasopressin receptor antagonists in the long-term management of HF is unclear.

125. Vasodilators 125 Venodilators reduce preload by increasing venous capacitance, improving symptoms of pulmonary congestion in patients with high ventricular filling pressures. Arterial vasodilators counteract the peripheral vasoconstriction and impaired CO that can result from Activation of the sympathetic nervous system, RAAS, and other neurohormonal mediators in HF. Mixed vasodilators act on both arterial resistance and venous capacitance vessels, reducing congestive symptoms while increasing CO.

126. 126 IV vasodilators should be considered before positive inotropic therapy in patients with low CO and elevated SVR (or elevated BP in those without a pulmonary artery catheter). However, hypotension may preclude their use in patients with preexisting low BP or SVR. IV nitroglycerin is often preferred for preload reduction in ADHF, especially in patients with pulmonary congestion. It reduces preload and PCWP via functional venodilation and mild arterial vasodilation.

127. 127 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. Initiate nitroglycerin at 5–10 mcg/min (0.1 mcg/kg/min) and increase every 5–10 minutes as necessary and tolerated. Maintenance doses usually range from 35 to 200 mcg/min (0.5–3 mcg/kg/min). Hypotension and excessive decrease in PCWP are important dose-limiting side effects. Tolerance to the hemodynamic effects may develop over 12–72 hours of continuous administration.

128. 128 S odium nitroprusside is a mixed arteriovenous vasodilator that increases cardiac index (CI) to a similar degree as dobutamine and milrinone despite having no direct inotropic activity. However, nitroprusside generally produces greater decreases in PCWP, SVR, and BP. Hypotension is an important dose-limiting adverse effect of nitroprusside, and its use should be primarily reserved for patients with elevated SVR.

129. 129 Nitroprusside has a rapid onset and a duration of action <10 minutes, necessitating continuous IV infusions. Initiate therapy with a low dose (0.1–0.2 mcg/kg/min) to avoid excessive hypotension, and increase by small increments (0.1–0.2 mcg/kg/min) every 5–10 minutes as tolerated. Usual effective doses range from 0.5 to 3 mcg/kg/min.

130. Inotropes 130 Prompt correction of low CO in patients with “cold” subsets (III and IV) is required to restore peripheral tissue perfusion and preserve end-organ function. Although IV inotropes can improve hypoperfusion by enhancing cardiac contractility, potential adverse outcomes limit their use to select patients with refractory ADHF. Inotropes should be considered only as A temporizing measure to maintain end-organ perfusion in patients with cardiogenic shock or severely depressed CO and low systolic BP ( ie , ineligible for IV vasodilators) until definitive therapy can be initiated,

131. 131 as a “bridge” for patients with advanced HF who are eligible for MCS or cardiac transplantation, or for palliation of symptoms in patients with advanced HF who are ineligible for MCS or cardiac transplantation. Dobutamine and milrinone produce similar hemodynamic effects, but Dobutamine usually causes more pronounced increases in HR, and milrinone is associated with greater relaxation in arterial smooth muscle.

132. 132 Dobutamine is a β1 - and β2 - receptor agonist with some α1 - agonist effects; its positive inotropic effects are due to effects on β1 - receptors. The net vascular effect is usually vasodilation. Milrinone inhibits phosphodiesterase III and produces positive inotropic and arterial and venous vasodilating effects. During IV administration, milrinone increases stroke volume and CO with minimal change in HR. However, the vasodilating effects may predominate, leading to decreased BP and a reflex tachycardia.

133. 133 Norepinephrine and dopamine have combined inotropic and vasopressor activity. Although therapies that increase SVR are generally avoided in ADHF, They may be required in select patients where marked hypotension precludes use of traditional inotropes (eg, septic shock, refractory cardiogenic shock).

134. 134 10Q