EDITORIAL
The Mystery
of Nitrate Resistance Jonathan Abrams, MD
lthough nitrate tolerance is a well-recognized phenomenon in angina pectoris and congestive heart failure (CHF), the problem of primary resistanceor nonresponsivenessto nitroglycerin (NTG) and the organic nitrates is not widely recognized. In this issue of the Journal, Varriale and colleagueshave replicated the results of previous clinical investigations that have documentednitrate resistancein patients with severe CHF.i-9 In addition, the authors have again demonstrated that a high systemic venous pressure (manifest by a mean right atria1 pressure of 17 f 4 mm Hg) or gross-dependentedema, or both, are vari: ables that predict an increased likelihood of nitrate resistance.r,2sT9 The current report, while devoid of data regarding the underlying mechanisms of nitrate resistance, should serve to remind clinicians that resistance is a potential problem in subjects with heart failure treated with nitrates as adjunctive therapy. The study demonstrated that a substantial proportion of sick (class III to IV) patients with CHF may not respond to intravenous NTG with a desirable decrease in left or right ventricular preload, despite administration of very large doses. Magrini and Niarchos2 Armstrong,1,7 Elkayam,3T6Kulicks and their coworkers previously documented this phenomenon in similar patient cohorts. Furthermore, this study mirrors the earlier Italian experiencedemonstrating that vigorous diuretic therapy restoresnitrate responsiveness,2 although the mechanism(s) is unclear. These observationsare important for clinicians. Nitrate therapy is effective in patients with CHF, and, in class III to IV patients, can improve the signs and symptoms of heart failure with substantial hemodynamic benefit. Furthermore, in combination with hydralazine, isosorbidedinitrate has been shown to reduce mortality in patients with class II to III CHF in 2 randomized trials.‘O~ll Thus, it is essential to administer organic nitrates in an effective manner. The data of
A
From the Department of Medicine/Cardiology Division, the University of New Mexico School of Medicine, University of New Mexico Hospital, Albuquerque, New Mexico. Manuscript received August 20, 1991, and accepted August 25. Address for reprints: Jonathan Abrams, MD, the Department of Medicine/Cardiology Division, the University of New Mexico School of Medicine, University of New Mexico Hospital, 7 South, 2211 Lomas Boulevard NE, Albuquerque, New Mexico 87131.
Varriale et al, when put into context with earlier trials, indicate that severely ill subjects with CHF, typically with biventricular failure, require particular vigilance in documenting a nitrate response. For the investigator, this study raises important questions about the pathophysiology of nitrate resistance. Future well-designed trials of nitrate resistance are indicated to establish the true prevalence of resistance, provide a better understanding of the neurohumoral interrelations, and carefully assessregional blood volume, venous capacitanceand arterial vascular resistance. Which patients are nitrate resistant? This study demonstratesthe benefits that can be derived when individual patient data are presented along with group data in the assessmentof clinical responsesto a particular therapy. Most studies of vasodilator therapy in CHF report mean group data. Thus, the problem of individual subjectswith poor responseto a therapy may not be obvious. Many studiesof nitrates in heart failure do not report resistanceas a problem, despitethe use of high doses of NTG or isosorbide dinitrate. Furthermore, the criteria used to define nitrate resistancevary from study to study. Finally, increasing the nitrate dose can diminish the apparent frequency of the problem in the same patient cohort.1~3,4~5~8~9 The prevalenceof nitrate resistancein a variety of investigations documenting this problem rangesfrom 12.54to 50%.3,7Although New York Heart Association classor ejection fractions are not always provided in these reports, hemodynamic monitoring suggestsa comparable degree of elevation of left and right ventricular filling pressuresin the various patient cohorts.I-9 Subjectswith systolic or diastolic dysfunction, or both, are included in some studies; it is unknown if nitrate resistanceis a common occurrence in patients with the CHF syndrome and intact left ventricular function (isolated diastolic dysfunction) because data are not available to allow such analysis. It is clear that nitrate resistanceis present only in severe CHF, often but not always including subjects with peripheral edema.1-8 In the present study and in someother reports (but not all), the presenceof an elevated right atria1 pressure,as well as dependentedema, have been found to be helpful in predicting the likelihood of nitrate resistance.‘,2,8,9 Edema as a “risk factor” is specifically cited in a minority of studies, and
EDITORIAL
1393
was apparently not present in the reported largest cohort6 It is unclear if nitrate resistance is an important problem in the therapy of angina pectoris. Most subjects with chest discomfort due to coronary atherosclerosis predictably respond to sublingual NTG. Only group data are generally reported in angina protocols, and NTG “nonresponders” are often excluded from the actual studies. Nevertheless,my impression is that patients with angina pectoris rarely experiencetrue nitrate resistance, and almost all patients obtain relief from ischemic pain with rapid-acting NTG formulations within 4 to 8 minutes. What is the basis for nitrate resistance? Varriale et al proposea variety of possiblemechanisms,as do other investigators,1,5~8,9 which include: mechanical compression of the peripheral vasculature or surrounding tissue, or both; salt and water infiltration of the blood vessels; an overly engorged and noncompliant venous circulation, presumably unable to further dilate; decreased bioavailability of delivered drug; altered nitrate metabolism (sulfhydryl depletion) within the vascular smooth muscle cell; and excessiveneurohumoral activation with marked systemic arterial (and venous) vasoconstriction. None of these factors have been systematically investigated. Several studies have measured plasma nitrate levels in resistant subjects,and have demonstratedadequate drug concentrations.1*7,9 Neurohumoral activation is a particularly attractive candidate. The hypothesisis that subjectswho are resistant to nitrates have more intense systemic venous and arterial constriction due to excessiveelevationsof catecholamines, angiotensin II, and other bioactive substances,such as renin or arginine vasopressin.Furthermore, the recent documentation that plasma endothelin levels are increasedin CHF12 suggestthat endogenous endothelial vasodilator activity is likely to be attenuated in CHF, and that endogenous vasoconstrictor substancesare dominant. NTG is consideredto be an exogenousendothelial-relaxing factor,13and works in the absenceof normal endothelial function; therefore, endothelial dysfunction, per se, is not a plausible explanation for nitrate resistance,becauseNTG is consideredto be actually more potent in the presenceof abnormal endothelial function. l4 Extrapolation of data from Elkayam et al do not suggest that neurohumoral activation is greater in nitrate-resistant patients; these workers measuredplasma renin, epinephrine and norepinephrine before and during a 24-hour infusion of intravenous NTG, and were unable to demonstrate any differences in patients with CHF who did or did not subsequentlydevelop nitrate toleranuz5 However, no measurementsof renin or cate-
1394
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
cholamineswere reported in patients (5 of 40) who did not respond to the initial intravenous NTG infusion. Thus, rapid and excessiveelevation of plasma and tissue levelsof various vasoconstrictorsubstances(norepinephrine, epinephrine, angiotensin II, endothelin and arginine vasopressin)remain a possiblemechanism for nitrate resistance. Is nitrate resistance an exaggerated variant of nitrate tolerance? Many studies have documented a re-
markably rapid onset of tolerance or attenuation to nitrates, beginning within severalhours of administration, and reaching a significant degree of vascular hyporesponsivenesswithin 24 hours.4-6,9J5-19 It is attractive to view nitrate resistanceas a compressedmodel of nitrate tolerance, manifesting an immediate rather than delayed failure of the vasculature to respond to organic nitrates. Tolerance in general, and in CHF in particular, is a complex phenomenon,with multiple causation. The sulfhydryl or cysteine depletion theory remains an important concept underlying attenuation to nitrate action. Armstrong’ and Elkayam’j and their co-workers suggestedrapid intracellular sulfhydryl depletion as a possiblemechanism for resistance;some studies,16but not a11,15have demonstrated reversal of nitrate tolerance in CHF with sulfhydryl donors in patients given high doses of intravenous NTG. Investigations using prior or simultaneous administration of sulfhydryl donors, such as methionine or N-acetylcysteine, could be designedto answer this question. I believe that sulfhydry1 depletion or unavailability is an unlikely single cause for nitrate resistance. Two recent studies have documented remarkably rapid alterations in plasma volume and onset of neurohumoral activation in patients with CHF15 and in normal subjects26with induced NTG tolerance. Dupuis et all5 confirmed a plasma volume shift within the first hour of NTG therapy, as well as increasesin arginine vasopressinand epinephrine in several subjects within a similar time interval. Parker et a120demonstrated a prompt decreasein hematocrit and increase in weight, consistent with salt and water retention due to documented neurohormonal activation after transdermal NTG application. These changes occur quite rapidly. Thus, it is conceivablethat extremely fast shifts of plasma volume or neurohumoral activation, or both, could play a role in nitrate resistance. Elevated right atrial pressure and edema: Finally, it may be useful to speculate on the significance of the elevation in right atria1 pressure and the presenceof peripheral edema as markers for nitrate resistance. Both are indicative of severebiventricular heart failure and marked engorgement of the venous capacitance system.Tissue or vascular compressiondue to intersti-
NOVEMBER 15, 1991
tial and cellular edema could play a role in the hypore- as suggested by Varriale, although vigorous diuresis sponsivenessof the venous system to nitrates in the should first be performed in edematouspatients. Such presenceof resistance.Nitrate efficacy in CHF is mod- an approach should optimize nitrate therapy in these ulated by both venous and arterial vasodilation. De- seriously ill patients. For investigators,nitrate resistanceremains an enigcreasesin right or left ventricular filling pressuresare ma that deservesfurther attention. I believe that carepresumed to be due to regional and systemic venodilafully designedtrials would unravel the mysteries of nltion. After NTG administration, the circulating blood volume is redistributed away from the heart and lungs trate resistanceand provide important new clues as to to the mesentericand splanchnic circulations and to the the mechanisms of nitrate vasodilatation and nitrate legs and arms.21-23A high right atria1 pressureappears tolerance. to be a marker for an impaired ability of the venous bed(s) to vasodilate, probably due to a combination of mechanical (high tissue and intravascular pressure)and REFERENCES vasoconstrictor forces. Reduction of tissue edema with 1. Armstrong PW, Armstrong JA, Marks GS. Pharmacokinetic-hemodynamic diuretics may act mechanically on the blood vessels,but studies of intravenous nitroglycerin in congestive cardiac failure. Circuhtion 1980;62:160-166, is unlikely to reduce vasoconstrictorforces. Perhapsthe 2. Magrini F, Niarchos AP. Ineffectiveness of sublingual nitroglycerin in acute efficacy of diuretics in restoring nitrate responsiveness left ventricular failure in the presence of massive peripheral edema. Am J Cardiol indicates that neurohumoral mechanisms are less im- 3.1980;45:841-847. Elkayam U, Henriquez B, Weber L, Tonnemacber D, Rahimtoola SH. Lack of portant. Elkayam,4,6 Kulick,8 Packer9 and their co- hemodynamic effect of high dose transdermal nitroglycerin in severe heart failure workers showed that increasing the nitrate dose can (abstr). Circulation 1984;7O(suppl 11):11-I 14. 4. Elkayam U, Roth A, Henriquez B, Weber L, Tonnemacher D, Rahimtoola usually overcome nitrate resistance,although this may SH. The hemodynamic and hormonal effects of high dose transdermal nitroglycrequire huge doses, and not all subjects will respond. erin in patients with chronic congestive heart failure. Am J Cardiol 1985;56: Resistanceis to some degree a dose-responseproblem; 555-559. 5. Roth A, Kulick D, Freidenberger L, Hong R, Rahimtoola SH, Elkayam U. larger NTG dosesare usually required in patients with Early tolerance to hemodynamic effects of high dose transdermal nitroglycerin in CHF, and conventional nitrate dosing may not work in responders with severe chronic heart failure. J Am Co/l Cardiol 1987;9:858-864. 6. Elkayam U, Kulick D, McIntosh N, Roth A, Hsueh W, Rahimtoola SH. the sickest patients. Incidence of early tolerance to hemodynamic effects of continuous infusion of An elevated right atria1 pressurehas also been asso- nitroglycerin in patients with coronary artery disease and heart failure. Circulaciated with resistance to other vasodilators in CHF, tion 1987;76:577-584. 7. Armstrong PW. Pharmacokinetic-hemodynamic studies of transdermal nitroincluding hydralazine24and captopril.25Thus, the prob- glycerin in congestive heart failure. J Am Cofl Cardiof 1987;9:420-425. lem of tolerance to vasodilators may be relatively com- 8. Kulick D, Roth A, McIntosh N, Rahimtoola SH, Elkayam U. Resistance to dinitrate in patients with severe chronic heart failure: incidence mon in patients with severebiventricular failure, per- isosorbide and attempts at hemodynamic prediction. J Am Col[ Cardiol 1988;12:1023haps helping to explain why these subjects often do 1028. poorly once refractory CHF has appeared, especially 9. Packer M, Medina N, Yushak M, Lee WH. Hemodynamic factors limiting the response to transdermal nitroglycerin in severe chronic congestive heart failure. those with peripheral edema. It is possiblethat a very Am J Cardiol 1986;51:260-261. high systemic venous pressure is related to decreased 10. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on renal function and blood flow, which might worsen af- mortality in chronic congestive heart failure. Results of a Veterans Administrative Cooperative Study. N Engl J Med 1986;374:1547-1552. ter administration of a potent vasodilator,26increasing Il. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with vasoconstrictor forces. This could help explain the pre- hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failN Engl J Med 1991;325:303-310, liminary report that hydralazine preventednitrate toler- ure. 12. Margolies KB, Hildebrand FL, Lerman A, Perella MA, Burrett JC, Jr. ance in a rat model of CHF27; it was postulated that Increased endothelin in experimental heart failure. Circulation 1990$2:2226renal blood flow was preservedby the co-administration 2230. 13. Luscher TF. Endothelium-derived relaxing and contracting factors: potential of hydralazine. In any case,the clinical paradox is that role in coronary artery disease. Eur Heart J 1989;10:847-856. patients most in need of vasodilator therapy may be 14. Rafflenbeul W, Bassenge E, Lichtlen P. Competition between endotheliumdependent and nitroglycerin-induced coronary vasodilation. Z Kardiol 1989;78 least likely to respond. (suppl 2):45-47. Conclusion: Clinicians need to be more aware of the 15. Dupuis J, Lalonde G, Lemieux R, Rouleau JL. Tolerance to intravenous problem of nitrate resistance.Careful assessmentof pa- nitroglycerin in patients with congestive heart failure: Role of increased volume, neurohumoral activation and lack of prevention with N-acetylcysteine. J Am Coil tients with CHF with physical examination and chest Cardiol 1990:16:932-934. x-ray can help identify those most likely to be resistant. 16. Packer M, Lee WH, Kessler PD, Gottlieb SS, Medina N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart Thus, a high jugular venous pressureand the presence failure. N Engl J Med 1987;317:799-804. of peripheral edema are good indicators that nitrate re- 17. Jordan RA, Seth L, Casebolt P, et al. Rapidly developing tolerance to sistanceis likely to be present (perhaps as high as 50% transdermal nitroglycerine in congestive heart failure. Ann Intern &fed 1986; 104295-298. in some class III to IV subjects). A poor clinical re- 18. Parker JO. Intermittent transdermal nitroglycerin therapy in the treatment of sponse may mandate a pulmonary artery catheter, chronic stable angina. J Am Call Cardiol 1989;13:794-795.
EDITORIAL 1395
19. Silber S, Vogler AC, Krause KH, Vogel M, Thiesen K. Induction and circumvention of nitrate tolerance applying different dosage intervals. Am J Med 1987;83:860-870. 20. Parker JD, Farrell B, Fenton J, Cohanim J, Parker JO. Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin. Circulation in press. 21. Loos D, Schneider R, Schorner W. Changes in regional body blood volume caused by nitroglycerin. 2 Kurdiol 1983;72(suppl 3):29-34. 22. Manyari DE, Smith ER. Spragg J. Isosorbide dinitrate and glyceryl trinitrate: demonstration of cross tolerance in the capacitance vessels. Am J Cardiol 1985;55:921-933. 23. Abrams J. Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 1985;l l&216-224.
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JOURNAL
OF CARDIOLOGY
VOLUME
68
24. Packer M, Meller J, Medina N, Gorlin R, Herman MV. Dose requirements of hydralazine in patients with severe chronic congestive heart failure. Am J Cardiol 1980;45:655-660. 25. Packer M, Lee WH, Medina M, Yushak M, Kessler P. Identification of patients with severe heart failure most likely to fail long-term therapy with converting-enzyme inhibitors (abstr). / Am Co0 Cardiol 1986;7:18A. 26. Leier C, Majorien RD. Desch CE, Thompson MJ, Unverferth DV. Hydralazine and isosorbide dinitrate: comparative central and regional bemodynamic effects when administered alone or in combination. Circulation 1981;63:102109. 27. Bauer JA, Fung H-L. Concurrent hydralazine administration prevents nitroglycerin-induced hemodynamic tolerance in experimental heart failure. Circuhtion 1991;84:35-39.
NOVEMBER
15, 1991
The Mystery
of Nitrate Resistance Jonathan Abrams, MD
lthough nitrate tolerance is a well-recognized phenomenon in angina pectoris and congestive heart failure (CHF), the problem of primary resistanceor nonresponsivenessto nitroglycerin (NTG) and the organic nitrates is not widely recognized. In this issue of the Journal, Varriale and colleagueshave replicated the results of previous clinical investigations that have documentednitrate resistancein patients with severe CHF.i-9 In addition, the authors have again demonstrated that a high systemic venous pressure (manifest by a mean right atria1 pressure of 17 f 4 mm Hg) or gross-dependentedema, or both, are vari: ables that predict an increased likelihood of nitrate resistance.r,2sT9 The current report, while devoid of data regarding the underlying mechanisms of nitrate resistance, should serve to remind clinicians that resistance is a potential problem in subjects with heart failure treated with nitrates as adjunctive therapy. The study demonstrated that a substantial proportion of sick (class III to IV) patients with CHF may not respond to intravenous NTG with a desirable decrease in left or right ventricular preload, despite administration of very large doses. Magrini and Niarchos2 Armstrong,1,7 Elkayam,3T6Kulicks and their coworkers previously documented this phenomenon in similar patient cohorts. Furthermore, this study mirrors the earlier Italian experiencedemonstrating that vigorous diuretic therapy restoresnitrate responsiveness,2 although the mechanism(s) is unclear. These observationsare important for clinicians. Nitrate therapy is effective in patients with CHF, and, in class III to IV patients, can improve the signs and symptoms of heart failure with substantial hemodynamic benefit. Furthermore, in combination with hydralazine, isosorbidedinitrate has been shown to reduce mortality in patients with class II to III CHF in 2 randomized trials.‘O~ll Thus, it is essential to administer organic nitrates in an effective manner. The data of
A
From the Department of Medicine/Cardiology Division, the University of New Mexico School of Medicine, University of New Mexico Hospital, Albuquerque, New Mexico. Manuscript received August 20, 1991, and accepted August 25. Address for reprints: Jonathan Abrams, MD, the Department of Medicine/Cardiology Division, the University of New Mexico School of Medicine, University of New Mexico Hospital, 7 South, 2211 Lomas Boulevard NE, Albuquerque, New Mexico 87131.
Varriale et al, when put into context with earlier trials, indicate that severely ill subjects with CHF, typically with biventricular failure, require particular vigilance in documenting a nitrate response. For the investigator, this study raises important questions about the pathophysiology of nitrate resistance. Future well-designed trials of nitrate resistance are indicated to establish the true prevalence of resistance, provide a better understanding of the neurohumoral interrelations, and carefully assessregional blood volume, venous capacitanceand arterial vascular resistance. Which patients are nitrate resistant? This study demonstratesthe benefits that can be derived when individual patient data are presented along with group data in the assessmentof clinical responsesto a particular therapy. Most studies of vasodilator therapy in CHF report mean group data. Thus, the problem of individual subjectswith poor responseto a therapy may not be obvious. Many studiesof nitrates in heart failure do not report resistanceas a problem, despitethe use of high doses of NTG or isosorbide dinitrate. Furthermore, the criteria used to define nitrate resistancevary from study to study. Finally, increasing the nitrate dose can diminish the apparent frequency of the problem in the same patient cohort.1~3,4~5~8~9 The prevalenceof nitrate resistancein a variety of investigations documenting this problem rangesfrom 12.54to 50%.3,7Although New York Heart Association classor ejection fractions are not always provided in these reports, hemodynamic monitoring suggestsa comparable degree of elevation of left and right ventricular filling pressuresin the various patient cohorts.I-9 Subjectswith systolic or diastolic dysfunction, or both, are included in some studies; it is unknown if nitrate resistanceis a common occurrence in patients with the CHF syndrome and intact left ventricular function (isolated diastolic dysfunction) because data are not available to allow such analysis. It is clear that nitrate resistanceis present only in severe CHF, often but not always including subjects with peripheral edema.1-8 In the present study and in someother reports (but not all), the presenceof an elevated right atria1 pressure,as well as dependentedema, have been found to be helpful in predicting the likelihood of nitrate resistance.‘,2,8,9 Edema as a “risk factor” is specifically cited in a minority of studies, and
EDITORIAL
1393
was apparently not present in the reported largest cohort6 It is unclear if nitrate resistance is an important problem in the therapy of angina pectoris. Most subjects with chest discomfort due to coronary atherosclerosis predictably respond to sublingual NTG. Only group data are generally reported in angina protocols, and NTG “nonresponders” are often excluded from the actual studies. Nevertheless,my impression is that patients with angina pectoris rarely experiencetrue nitrate resistance, and almost all patients obtain relief from ischemic pain with rapid-acting NTG formulations within 4 to 8 minutes. What is the basis for nitrate resistance? Varriale et al proposea variety of possiblemechanisms,as do other investigators,1,5~8,9 which include: mechanical compression of the peripheral vasculature or surrounding tissue, or both; salt and water infiltration of the blood vessels; an overly engorged and noncompliant venous circulation, presumably unable to further dilate; decreased bioavailability of delivered drug; altered nitrate metabolism (sulfhydryl depletion) within the vascular smooth muscle cell; and excessiveneurohumoral activation with marked systemic arterial (and venous) vasoconstriction. None of these factors have been systematically investigated. Several studies have measured plasma nitrate levels in resistant subjects,and have demonstratedadequate drug concentrations.1*7,9 Neurohumoral activation is a particularly attractive candidate. The hypothesisis that subjectswho are resistant to nitrates have more intense systemic venous and arterial constriction due to excessiveelevationsof catecholamines, angiotensin II, and other bioactive substances,such as renin or arginine vasopressin.Furthermore, the recent documentation that plasma endothelin levels are increasedin CHF12 suggestthat endogenous endothelial vasodilator activity is likely to be attenuated in CHF, and that endogenous vasoconstrictor substancesare dominant. NTG is consideredto be an exogenousendothelial-relaxing factor,13and works in the absenceof normal endothelial function; therefore, endothelial dysfunction, per se, is not a plausible explanation for nitrate resistance,becauseNTG is consideredto be actually more potent in the presenceof abnormal endothelial function. l4 Extrapolation of data from Elkayam et al do not suggest that neurohumoral activation is greater in nitrate-resistant patients; these workers measuredplasma renin, epinephrine and norepinephrine before and during a 24-hour infusion of intravenous NTG, and were unable to demonstrate any differences in patients with CHF who did or did not subsequentlydevelop nitrate toleranuz5 However, no measurementsof renin or cate-
1394
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
cholamineswere reported in patients (5 of 40) who did not respond to the initial intravenous NTG infusion. Thus, rapid and excessiveelevation of plasma and tissue levelsof various vasoconstrictorsubstances(norepinephrine, epinephrine, angiotensin II, endothelin and arginine vasopressin)remain a possiblemechanism for nitrate resistance. Is nitrate resistance an exaggerated variant of nitrate tolerance? Many studies have documented a re-
markably rapid onset of tolerance or attenuation to nitrates, beginning within severalhours of administration, and reaching a significant degree of vascular hyporesponsivenesswithin 24 hours.4-6,9J5-19 It is attractive to view nitrate resistanceas a compressedmodel of nitrate tolerance, manifesting an immediate rather than delayed failure of the vasculature to respond to organic nitrates. Tolerance in general, and in CHF in particular, is a complex phenomenon,with multiple causation. The sulfhydryl or cysteine depletion theory remains an important concept underlying attenuation to nitrate action. Armstrong’ and Elkayam’j and their co-workers suggestedrapid intracellular sulfhydryl depletion as a possiblemechanism for resistance;some studies,16but not a11,15have demonstrated reversal of nitrate tolerance in CHF with sulfhydryl donors in patients given high doses of intravenous NTG. Investigations using prior or simultaneous administration of sulfhydryl donors, such as methionine or N-acetylcysteine, could be designedto answer this question. I believe that sulfhydry1 depletion or unavailability is an unlikely single cause for nitrate resistance. Two recent studies have documented remarkably rapid alterations in plasma volume and onset of neurohumoral activation in patients with CHF15 and in normal subjects26with induced NTG tolerance. Dupuis et all5 confirmed a plasma volume shift within the first hour of NTG therapy, as well as increasesin arginine vasopressinand epinephrine in several subjects within a similar time interval. Parker et a120demonstrated a prompt decreasein hematocrit and increase in weight, consistent with salt and water retention due to documented neurohormonal activation after transdermal NTG application. These changes occur quite rapidly. Thus, it is conceivablethat extremely fast shifts of plasma volume or neurohumoral activation, or both, could play a role in nitrate resistance. Elevated right atrial pressure and edema: Finally, it may be useful to speculate on the significance of the elevation in right atria1 pressure and the presenceof peripheral edema as markers for nitrate resistance. Both are indicative of severebiventricular heart failure and marked engorgement of the venous capacitance system.Tissue or vascular compressiondue to intersti-
NOVEMBER 15, 1991
tial and cellular edema could play a role in the hypore- as suggested by Varriale, although vigorous diuresis sponsivenessof the venous system to nitrates in the should first be performed in edematouspatients. Such presenceof resistance.Nitrate efficacy in CHF is mod- an approach should optimize nitrate therapy in these ulated by both venous and arterial vasodilation. De- seriously ill patients. For investigators,nitrate resistanceremains an enigcreasesin right or left ventricular filling pressuresare ma that deservesfurther attention. I believe that carepresumed to be due to regional and systemic venodilafully designedtrials would unravel the mysteries of nltion. After NTG administration, the circulating blood volume is redistributed away from the heart and lungs trate resistanceand provide important new clues as to to the mesentericand splanchnic circulations and to the the mechanisms of nitrate vasodilatation and nitrate legs and arms.21-23A high right atria1 pressureappears tolerance. to be a marker for an impaired ability of the venous bed(s) to vasodilate, probably due to a combination of mechanical (high tissue and intravascular pressure)and REFERENCES vasoconstrictor forces. Reduction of tissue edema with 1. Armstrong PW, Armstrong JA, Marks GS. Pharmacokinetic-hemodynamic diuretics may act mechanically on the blood vessels,but studies of intravenous nitroglycerin in congestive cardiac failure. Circuhtion 1980;62:160-166, is unlikely to reduce vasoconstrictorforces. Perhapsthe 2. Magrini F, Niarchos AP. Ineffectiveness of sublingual nitroglycerin in acute efficacy of diuretics in restoring nitrate responsiveness left ventricular failure in the presence of massive peripheral edema. Am J Cardiol indicates that neurohumoral mechanisms are less im- 3.1980;45:841-847. Elkayam U, Henriquez B, Weber L, Tonnemacber D, Rahimtoola SH. Lack of portant. Elkayam,4,6 Kulick,8 Packer9 and their co- hemodynamic effect of high dose transdermal nitroglycerin in severe heart failure workers showed that increasing the nitrate dose can (abstr). Circulation 1984;7O(suppl 11):11-I 14. 4. Elkayam U, Roth A, Henriquez B, Weber L, Tonnemacher D, Rahimtoola usually overcome nitrate resistance,although this may SH. The hemodynamic and hormonal effects of high dose transdermal nitroglycrequire huge doses, and not all subjects will respond. erin in patients with chronic congestive heart failure. Am J Cardiol 1985;56: Resistanceis to some degree a dose-responseproblem; 555-559. 5. Roth A, Kulick D, Freidenberger L, Hong R, Rahimtoola SH, Elkayam U. larger NTG dosesare usually required in patients with Early tolerance to hemodynamic effects of high dose transdermal nitroglycerin in CHF, and conventional nitrate dosing may not work in responders with severe chronic heart failure. J Am Co/l Cardiol 1987;9:858-864. 6. Elkayam U, Kulick D, McIntosh N, Roth A, Hsueh W, Rahimtoola SH. the sickest patients. Incidence of early tolerance to hemodynamic effects of continuous infusion of An elevated right atria1 pressurehas also been asso- nitroglycerin in patients with coronary artery disease and heart failure. Circulaciated with resistance to other vasodilators in CHF, tion 1987;76:577-584. 7. Armstrong PW. Pharmacokinetic-hemodynamic studies of transdermal nitroincluding hydralazine24and captopril.25Thus, the prob- glycerin in congestive heart failure. J Am Cofl Cardiof 1987;9:420-425. lem of tolerance to vasodilators may be relatively com- 8. Kulick D, Roth A, McIntosh N, Rahimtoola SH, Elkayam U. Resistance to dinitrate in patients with severe chronic heart failure: incidence mon in patients with severebiventricular failure, per- isosorbide and attempts at hemodynamic prediction. J Am Col[ Cardiol 1988;12:1023haps helping to explain why these subjects often do 1028. poorly once refractory CHF has appeared, especially 9. Packer M, Medina N, Yushak M, Lee WH. Hemodynamic factors limiting the response to transdermal nitroglycerin in severe chronic congestive heart failure. those with peripheral edema. It is possiblethat a very Am J Cardiol 1986;51:260-261. high systemic venous pressure is related to decreased 10. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on renal function and blood flow, which might worsen af- mortality in chronic congestive heart failure. Results of a Veterans Administrative Cooperative Study. N Engl J Med 1986;374:1547-1552. ter administration of a potent vasodilator,26increasing Il. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with vasoconstrictor forces. This could help explain the pre- hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failN Engl J Med 1991;325:303-310, liminary report that hydralazine preventednitrate toler- ure. 12. Margolies KB, Hildebrand FL, Lerman A, Perella MA, Burrett JC, Jr. ance in a rat model of CHF27; it was postulated that Increased endothelin in experimental heart failure. Circulation 1990$2:2226renal blood flow was preservedby the co-administration 2230. 13. Luscher TF. Endothelium-derived relaxing and contracting factors: potential of hydralazine. In any case,the clinical paradox is that role in coronary artery disease. Eur Heart J 1989;10:847-856. patients most in need of vasodilator therapy may be 14. Rafflenbeul W, Bassenge E, Lichtlen P. Competition between endotheliumdependent and nitroglycerin-induced coronary vasodilation. Z Kardiol 1989;78 least likely to respond. (suppl 2):45-47. Conclusion: Clinicians need to be more aware of the 15. Dupuis J, Lalonde G, Lemieux R, Rouleau JL. Tolerance to intravenous problem of nitrate resistance.Careful assessmentof pa- nitroglycerin in patients with congestive heart failure: Role of increased volume, neurohumoral activation and lack of prevention with N-acetylcysteine. J Am Coil tients with CHF with physical examination and chest Cardiol 1990:16:932-934. x-ray can help identify those most likely to be resistant. 16. Packer M, Lee WH, Kessler PD, Gottlieb SS, Medina N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart Thus, a high jugular venous pressureand the presence failure. N Engl J Med 1987;317:799-804. of peripheral edema are good indicators that nitrate re- 17. Jordan RA, Seth L, Casebolt P, et al. Rapidly developing tolerance to sistanceis likely to be present (perhaps as high as 50% transdermal nitroglycerine in congestive heart failure. Ann Intern &fed 1986; 104295-298. in some class III to IV subjects). A poor clinical re- 18. Parker JO. Intermittent transdermal nitroglycerin therapy in the treatment of sponse may mandate a pulmonary artery catheter, chronic stable angina. J Am Call Cardiol 1989;13:794-795.
EDITORIAL 1395
19. Silber S, Vogler AC, Krause KH, Vogel M, Thiesen K. Induction and circumvention of nitrate tolerance applying different dosage intervals. Am J Med 1987;83:860-870. 20. Parker JD, Farrell B, Fenton J, Cohanim J, Parker JO. Counter-regulatory responses to continuous and intermittent therapy with nitroglycerin. Circulation in press. 21. Loos D, Schneider R, Schorner W. Changes in regional body blood volume caused by nitroglycerin. 2 Kurdiol 1983;72(suppl 3):29-34. 22. Manyari DE, Smith ER. Spragg J. Isosorbide dinitrate and glyceryl trinitrate: demonstration of cross tolerance in the capacitance vessels. Am J Cardiol 1985;55:921-933. 23. Abrams J. Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 1985;l l&216-224.
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24. Packer M, Meller J, Medina N, Gorlin R, Herman MV. Dose requirements of hydralazine in patients with severe chronic congestive heart failure. Am J Cardiol 1980;45:655-660. 25. Packer M, Lee WH, Medina M, Yushak M, Kessler P. Identification of patients with severe heart failure most likely to fail long-term therapy with converting-enzyme inhibitors (abstr). / Am Co0 Cardiol 1986;7:18A. 26. Leier C, Majorien RD. Desch CE, Thompson MJ, Unverferth DV. Hydralazine and isosorbide dinitrate: comparative central and regional bemodynamic effects when administered alone or in combination. Circulation 1981;63:102109. 27. Bauer JA, Fung H-L. Concurrent hydralazine administration prevents nitroglycerin-induced hemodynamic tolerance in experimental heart failure. Circuhtion 1991;84:35-39.
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