What is the role of nitrates in left ventricular dysfunction?

Rationale of nitrate use in chronic heart failure longs survival in heart failure. The dinitrate-hydralazine combination offers an alternative for patients with severe renal failure, in whom ACE inhibitors and angiotensin II receptor antagonists are contraindicated. It has also been added, on rational grounds, in patients who remain severely symptomatic despite optimal doses of ACE inhibitors, but no large-scale trial has demonstrated added benefit.

The organic nitrates are potent venodila-tors and mild arteriolar vasodilators. In particular, they produce the most extensive epicardial coronary vasodilation of any class of vasodilator. This relatively selective effect enables them to increase systolic and diastolic ventricular function directly by improving coronary flow in ischemic cardiomyopathy. Nitrates are also effective in reducing systemic vascular resistance, pulmonary capillary wedge pressure, and right atrial pressure.

Recent clinical trials testify to their extensive use in chronic heart failure. The clinical rationale is based on their hemodynamic benefits, alleviation of myocardial ischemia, decrease in mitral regurgitation, and enhancement of endothelial function, cardiac remodeling, and exercise capacity. In addition, when combined with hydralazine, nitrates improve maximum oxygen consumption, the left ventricular ejection fraction, and survival. They can thus be used if patients remain symptomatic despite a maximum tolerated dosage of angiotensin-converting enzyme (ACE) inhibitor and/or angiotensin receptor antagonist, especially in the presence of concomitant hypertension or severe mitral regurgitation. Nitrates may be also used to treat concomitant angina or relieve acute dyspnea.

The main problem with the use of organic nitrates over the longer term (>24 hours) is the development of tolerance (tachyphylaxis). Most efficacy data on intermittent vs continuous nitroglycerin dosing protocols have been obtained in patients with angina rather than congestive heart failure. Indeed, some doubt whether heart failure patients should be exposed to a long nitrate-free period. Nevertheless, it seems prudent to recommend nitrate-free intervals in patients on chronic isosorbide dinitrate therapy. This is best achieved by taking the last daily dose in the early evening. Hemodynamic tolerance develops rapidly with frequent dosing (every 4 to 6 hours), but less rapidly with dosing at intervals of 8 to 12 hours, or in conjunction with ACE inhibitors or hydralazine.

Role of nitrates in advanced heart failure

The spectrum of activity of 5-isosorbide mononitrate would not be expected to differ from that of isosorbide dinitrate in heart failure. Although isosorbide mononitrate has the pharmacokinetic advantages of greater bioavailability and a longer elimination half-life, isosorbide dinitrate is the only nitrate that increases exercise tolerance and, in combination with hydralazine, pro-

Nitroglycerin and nitroprusside are effective in decreasing regurgitant volume and left ventricular filling pressure, and in increasing cardiac output. They restore diastolic reserve and improve the atrial contribution to diastolic filling. In heart transplantation candidates, chronic intermittent nitroprusside infusion appears safer and more effective than dobutamine in relieving symptoms, facilitating unloading therapy management, and improving survival. Whether it could also represent a feasible strategy in outpatients with severe heart failure remains to be investigated. Patients with decompensated advanced heart failure can be stabilized using tailored therapy, a strategy that aims to meet prespecified hemodynamic goals, measured by an indwelling right-sided heart catheter, using intravenous infusions of sodium nitroprusside and bolus doses of diuretics in the initial stages, followed by high-dose oral vasodilators. However, as nitroprusside has potential toxicities, including cyanide accumulation and death, alternatives may be preferable for longterm treatment. Thus, Drazner et al found that tailored therapy using dobutamine and nitroglycerin significantly improved hemodynamic parameters in patients with severe secondary pulmonary hypertension, allowing escalation of the oral vasodilator dose, and resulting in a low 90-day hospital readmission rate. Patients whose left ventricular filling pressures fail to respond to tailored therapy, in particular those with coronary artery disease, should be considered for early transplantation.

Further reading

Braunwald E, Libby P, Zipes DP, eds. Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, Pa: WB Saunders Co; 2001:570-571. Capomolla S, Febo O, Opasich C, et al. Chronic infusion of dobutamine and nitroprusside in patients with end-stage heart failure awaiting heart transplantation: safety and clinical outcome. Eur J Heart Fail. 2001 ;3:601 -610. Capomolla S, Pozzoli M, Opasich C, et al. Dobutamine and nitroprusside infusion in patients with severe congestive heart failure: hemodynamic improvement by discordant effects on mitral regurgitation, left atrial function, and ventricular function. Am Heart J. 1997;134:1089-1098.

Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Am J Cardiol. 1999;83:1A-38A. Drazner MH, Solomon MA, Thompson B, Yancy CW. Tailored therapy using dobutamine and nitroglycerin in advanced heart failure. Am J Cardiol. 1999,84:941 -943.

Elkayam U, Johnson JV, Shotan A, et al. Double-blind, placebo-controlled study to evaluate the effect of organic nitrates in patients with chronic heart failure treated with angiotensin-converting enzyme inhibition. Circulation. 1999,99:2652-2657.

Masuyama T, St Goar FG, Alderman EL, Popp RL Effects of nitroprusside on transmitral flow velocity patterns in extreme heart failure: a combined hemodynamic and Doppler echocardiographic study of varying loading conditions. J Am Coll Cardiol. 1990; 16:1175-1185.

Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Task Force for the Diagnosis and Treatment of Chronic Heart Failure, European Society of Cardiology. Eur Heart J. 2001 ;22:1527-1560. Steimle AE, Stevenson LW, Chelimsky-Fallick C, et al. Sustained hemodynamic efficacy of therapy tailored to reduce filling pressures in survivors with advanced heart failure. Circulation. 1997;96:1165-1172.

Tavazzi L, Opasich C. Scompenso Cardiaco Giorno per Giomo [Heart failure day by day], Turin, Italy: Edizioni Minerva Medica;! 999:79.


drug; nitrate; nitroglycerin; isosorbide mononitrate; isosorbide dinitrate; nitroprusside; advanced heart failure; tolerance; tachyphylaxis

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