Congestive heart disease

A 68-year-old retired salesman has a history of an acute myocardial infarction complicated by congestive heart failure (CHF) 1 year ago. Although under appropriate medical management and in sinus rhythm, he presented with a 4-week history of progressive cardiac failure. He had 2 episodes of nocturnal cardiac dyspnea in the past week and was progressively limited in ordinary house and backyard activities. Medications for the management of his CHF were furosemide 20 mg daily, enalapril 20 mg daily, eplerenone 50 mg twice a day, carvedilol 25 mg twice a day, atorvastatin 10 mg daily, and a salt-poor, low-cholesterol-forming diet. On physical examination, he presented with 2+ ankle edema, blood pressure in the right arm was 140/75 mm Hg, respirations 20/min, height 1.75 m (5 ft 9 in), and weight 72 kg (160 lb). There was a positive hepatojugular reflux, fine moist rales at the lung bases, and the heart rate was 88 beats/min with a diastolic gallop rhythm heard at the apex. A 2/6 systolic aortic murmur due to aortic valve sclerosis was heard at the second intercostal space at the fight sternal margin and a 2/6 mitral regurgitant murmur was heard at the apex. The point of maximal impulse was diffuse and extended laterally. An electrocardiogram revealed a regular sinus rhythm at a rate of 88 beats/min, evidence of an old anteroseptal infarction, left atrial enlargement, and a QRS duration of 0.10 s. The glycohemoglobin level was 5.8% [A.sub.1c] and electrolyte levels were normal. A lipid profile revealed low-density lipoprotein (LDL), 95 mg/dL (2.46 mmol/L); cholesterol, 190 mg/dL (4.91 mmol/L); high-density lipoprotein (HDL), 45 mg/dL (1.16 mmol/L); very low density lipoprotein (VLDL), 20 mg/dL (0.52 mmol/L); and triglycerides 135 mg/dL (1.52 mmol/L). On detailed questioning, the patient admitted that he had failed to adhere to a restricted sodium diet as had been advised. The dose of furosemide was increased to 40 mg daily and he was told to be "lazy" for several days, sleep with the head of his bed at a 45[degrees] angle, and to return in 6 days. He was instructed as to the importance and critical need for strict adherence to a low-sodium diet. Following an increase in diuretics, symptoms and signs improved in a few days.

The family physician reviewed the patient's medical history with a cardiologist, who concurred with the management but recommended an increase in the dose of atorvastatin to 20 mg daily and to add ezetimibe 10 mg daily. Ezetimibe inhibits cholesterol absorption and is complementary to a statin by further reducing LDL cholesterol level without the need for an increase in the statin dose. The aim was a reduction in LDL cholesterol level to 50 mg/dL (1.29 mmol/L). A lipid profile and hepatic function panel was to be ordered in 4 weeks. The consultant reemphasized the primary importance of a low-sodium diet and adequate use of diuretics in the management of CHE

1. Which one of the following medications is vital in the management of CHF?

a. digoxin

b. diuretic

c. angiotensin-converting enzyme inhibitor or blocker

d. aldosterone receptor blocker (eplerenone, spironolactone)

e. aspirin

f. a-blocker, long acting (metoprolol)

g. [alpha]- and [3-blocker (carvedilol).

2. Since the patient's LDL cholesterol was 95 mg/dL (2.46 mmol/L) and generally considered appropriate for a patient with this history, why advise greater reduction of the LDL cholesterol level?

a. statin therapy is effective in ischemic and nonischemic CHF

b. over the years, recommended goals for LDL cholesterol levels have been "off the wall" (beyond the realm of reasonableness)

c. statins have salutary effects on the endothelium

d. the consultant is on the speakers bureau for Pfizer Laboratories (producers of atorvastatin)

e. the cardiologist felt obliged to come up with some recommendation for a patient who was receiving appropriate therapy

f. the cardiologist's family has a vested interest in pharmaceutical companies that produce statins

g. LDL cholesterol at levels as low as 50 mg/dL (1.29 mmol/L) or less have been shown to reduce acute coronary events and mortality due to atherosclerotic heart disease (ASHD).

ANSWERS

1. b. diuretic

Sodium retention resulting in volume overload (hypervolemia) occurs early in CHE As a consequence, besides a low-sodium diet, a diuretic is the best and the most effective therapy in treating CHE Despite the advent of new drugs for CHF, or the use of biventricular pacing with cardiac resynchronization or arteriovenous hemofiltration in "refractory" CHF, diuretics continue to be the most commonly prescribed and most effective drugs in the world for treating CHF.

Digoxin is an inotrope and not considered critical or in fact necessary by some in the management of CHF. There is potential harm in the use of digoxin for CHF in sinus rhythm because by definition the basic action of digoxin is to stimulate the heart to contract more forcibly when in fact, the myocardium is in a weakened state (heart failure), unable to meet the normal circulatory demands of the body. To employ a drug that stimulates a myocardium weakened by disease and unable to meet the circulating demands of the body would be incongruous. As a consequence, many would not prescribe an inotrope (digoxin) for CHF when in sinus rhythm. In sharp contrast to the rather weak recommendations in the literature for the use of digoxin (a positive inotrope) for heart failure, strong recommendations are made for the routine use of a [beta]-blocker (negative inotrope) in the routine treatment of CHF. By titrating the dose of a [beta]-blocker, heart rate and contractility

can be controlled, and thus cardiac work reduced, allowing myocardial recovery.

2. a. statin therapy is effective in ischemic and nonischemic CHF

c. statins have salutary effects on the endothelium

g. LDL cholesterol at low levels as low as 50 mg/dL (1.29 mmol/L) or less have been shown to reduce acute coronary events and mortality due to ASHD.

Coenzyme A reductase inhibitors (statins) inhibit cardiac hypertrophy and improve symptoms of heart failure. Statins have been shown to increase angiogenesis, increase myocardial perfusion, decrease apoptosis, and improve endothelial and cardiac function. (1)

Statins have lowered mortality in elderly persons with CHF. Mortality due to acute myocardial infarction or stroke was significantly lower in persons taking statin drugs. (2) These drugs have also been credited with attenuating cardiac remodeling and protecting patients with CHF from death. (3-5) Statin therapy inhibits and decreases levels of inflammatory cytokines (tumor necrosis factor [TNF-[alpha]], interleukin [IL-6]), increases nitric oxide (NO) synthesis, normalizes autonomic functions, and reverses pathological myocardial remodeling. (6-10) While statins increase the bioavailability of NO, a powerful vasodilator, statins also decrease the synthesis and reduce the levels of endothelin, a powerful vasoconstrictor in endothelial cells. (11)

It is logical to assume that aggressive reduction in LDL cholesterol would enhance the salutary response to statin therapy provided that there is no increase in adverse effects.

Abnormal endothelial function is key to the pathophysiology of heart failure and responsible for the initiation of CHF. (2) Reduced endothelial function down-regulates NO production, endothelial NO synthase gene expression. (12-14) Reduced NO contributes to myocyte apoptosis (programmed cell death), which is critical in cardiac remodeling and progression of heart failure. Oxygen consumption was significantly lowered and myocardial oxygen reserve increased by greater NO production in statin-treated animals with CHF. In a placebo-controlled study in 51 patients with CHF due to dilated cardiomyopathy, those resuming statin therapy demonstrated remarkable improvement; for example, lower New York Heart Association Functional class, improved exercise endurance, and increased left ventricular ejection fraction. (13) Plasma concentrations of TNF-[alpha], IL-6, and brain-type naturetic peptide were lower in the statin group.

It is evident from experimental animal studies and from human studies that statins have salutary effects in heart failure. CHF is a prevalent worldwide disease progressively increasing in incidence directly in relation to the increase in longevity. The population living longer succumbs to a disease common to aging.

The dose of statins requires modification to attain LDL cholesterol levels that favorably effect endothelial function. The serum LDL cholesterol levels of 40 to 50 mg/dL (1.03-1.29 mmol/L) can be achieved without added risks. (15) Optional CHF therapy requires the use of multiple pharmaceuticals, and each medication has a specific salutary effect in this complex disease.

ACKNOWLEDGMENT

Supported in part by a grant from the Applebaum Foundation in loving memory of Mr Joseph Applebaum.

REFERENCES

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(2.) Ray JG, Gong Y, Sykora K, et al. Statin use and survival outcomes in elderly patients with heart failure. Arch Intern Med. 2005; 165:62-67.

(3.) Horwich TB, Fonarow GC. Statin therapy in heart failure. Cardiol Review. 2004;21:23-28.

(4.) Mozaffarian D, Nye R, Levy WC. Statin therapy is associated with lower mortality among patients with severe heart failure. Am J Cardiol. 2004;93: 1124-1129.

(5.) Hayashidani S, Tsutsui H, Shiomi T, et al. Fluvastin, a 3-hydroxy-3methylglutarylcoenzyme a reductase inhibitor, attenuate left ventricular remodeling and failure after experimental myocardial infarction. Circulation. 2002;105:868-873.

(6.) Lefer DJ. Statins as potent antiinflammatory drugs. Circulation. 2002;106: 2041-2042.

(7.) vonHaehling S, Anker SD, Bassenge E. Statins and the role of nitric oxide in chronic heart failure. Heart Fail Rev. 2003;8:99-106.

(8.) Rosenson RS, Tangney CC, Casey LC. Inhibition of proinflammatory cytokine production by pravastatin. Lancet. 1999;353:983-984.

(9.) Deehend R, Fiebeler A, Park JK, et al. Amelioration of angiotensin II-induced cardiac injury by a 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor. Circulation. 2001; 105:576-581.

(10.) Pliquett RU, Cornish KG, Peuler JD, et al. Simvastatin normalizes autonomic neural control in experimental heart failure. Circulation. 2003; 107:2493-2498.

(11.) Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al. Effects of the 3-hydroxy-3-methyglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998;101:2711-2719.

(12.) Smith CJ, Sun D, Hoegler C, et al. Reduced gene expression of vascular endothelial NO synthase and cyclooxgenase-1 in heart failure. Circ Res. 1996; 78:58-64.

(13.) Treasure CB, Vita JA, Cox DA, et al. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation. 1990;81:772-779.

(14.) Kuoppala A, Shiota N, Kokken JO, et al. Down-regulation of cardioprotective bradykinin type-2 receptors in the left ventricle of patients with end-stage heart failure. J Am Coil Cardiol 2002;40:119-125.

(15.) Hasegawa H, Takano H, Mizukami M, et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors prevent the development of cardiac hypertrophy and heart failure in rats. J Molec Cell Cardiol. 2003;35:953-960.

SELECTED REFERENCES

Ashton E, Liew D, Krum H. Should patients with chronic heart failure be treated with "statins"? Heart Fall Monit. 2003;3(3):82-86.

Horwich TB, MaeLellan WR, Fonarow GC. Statin therapy is associated with improved survival in ischemic and non-ischemic heart failure. J Am Coll Cardiol. 2004;43:642-648.

Kathryn Buchanan Keller, RN, PhD, and Louis Lemberg, MD. From the Florida Atlantic University Christine E. Lynn College of Nursing, Boca Raton, Fla (KBK), and the Division of Cardiology, Department of Medicine, University, of Miami School of Medicine, Miami, Fla (LL).

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