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Nitrate therapy of heart failure in valvular heart disease
Nitrate Therapy of Heart Failure in Valvular Heart Disease Importance of Resting Level of Peripheral Vascular Resistance in Determining Cardiac Output Response
SHELDON GOLDBERG, M.D. TlFT MANN, M.D. WILLIAM
GROSSMAN,
M.D.
l
Boston, Massachusetts
From the Departments of Medicine, Peter Bent Brii Hospital and the Harvard Medical School, Boston, Massachusetts. This study was supported in part by a U.S. Public Health Service Grant HL 19246 from the National Heart and Lung lnstiiutes and by a grant from the Burroughs-Wellcome Company. Requests for reprints should be addressed to Dr. William Grossman, Department of Medicine, Peter Bent Brigham Hospital, Boston, Massachusetts 02115. Established Investigator, American Heart Association. l
Although oral nitrates are widely used as therapy for patients with congestive heart failure, their effectiveness in increasttqj cardiac output is highly variable. in order to identify predictors of outcome, we studied the effects of 6rithrityi tetranitrate (ETN) on preioad, afterioad and cardiac output in 15 patients with chronic congestive heart failure and mitral or aortic insufficiency who were undergoing diagnostic cardiac catheterization. There were signifkant reductions in right atriai, pulmonary capillary wedge and mean arterial pressures in nearly ail patients. Augmentation in cardiac output by I 10 per cent occurred in eight patients (responders), whereas no change (or decline) occurred in seven patients (nonresponders). The level of peripheral vasoconstriction, as reflected by resting systemic vascular resistance was significantly higher for responders than for nonresponders (2,602 f 251 versus 1,744 f 193 dynes-set-cm+, p <0.02). FurWrmore, a stgnifkant reduction in systemic resistance occurred only in responders, and the decline was a linear function of resting resistance (r = 0.93). thus, atthough reductions in arterial pressure, and left and right ventricular filling pressures are a constant resutt of nitrate therapy, signifkant aqmentatton in forward cardiac output is likely only in those patients with the most intense resting peripheral vasoconstriction. The concept of afterload mismatch and preioad reserve best explains the variable effects of nitrates in congestive heart failure. As has been pointed out by the other participants in this symposium, vasodilator drugs have assumed a major role in the treatment of patients with congestive heart failure. That vasodilator therapy may be particularly effective in congestive heart failure due to mitral or aortic insufficiency has been shown by several groups over the past five years [l--5], but the physiologic basis for this observation was demonstrated over 50 years ago by Carl Wiggers [6]. In 1922, Wiggers reported a series of experiments in which experimental mitral insufficiency was induced in dogs. He found that the regurgitant volume in this experimental mitral insufficiency preparation was strongly influenced by aortic resistance to left ventricular ejection. In his experiments, the regurgitant volume could be increased by aortic constriction or decreased by administration of nitrates. In 1958, Braunwald et al. [ 71 reported a study on the effects of altered systemic vascular resistance on the left atrial pressure pulse in patients with mitral insufficiency. In our own studies of vasodilator therapy for severe mitral regurgitation [2,3], we noted a relationship between the level of resting
July 1978
The American Journal of Medicine
Volume 85
191
NITRATE THERAPY IN VALVULAR HEART DISEASE-GOLDBERG
---
ET AL.
Grovp 1 n.8 GrovplIn.7
igure 1. Mean arterial pressure, pulmonary .-. capillary _ wedge pressure and right atria/ pressure at rest (C)and following the administration of 10 mg eritfuifyl tetranitrate (ETN) in responders (group I, those who increased cardiac output by I 10 per cent) and nonresponders (group II, those who showed no change or a decrease in cardiac output).
systemic vascular resistance and the likelihood of hemodynamic improvement. There is great variability among vasodilator agents, and the relative effects of a particular drug on arteriolar resistance and venous capacitance is of major importance in predicting its hemodynamic effects [8-161. This problem may become complex in the circumstance in which a particular drug may have different effects depending on the level of resting tone in resistance and capacitance beds. For example, nitrate preparations are well known to influence venous capacitance; this is presumably responsible (at least in part) for the fact that ventricular filling pressures and pulmonary congestion are consistently improved when nitrate therapy is given to patients with congestive
-
GROUP I in.81
.----
GROUP II (n-7)
60 t
I
._
_
-..
.
C .
I
ETN
.
lgure 2. Stroke volume and systemic vascular resistance at rest (C) and folio wing the administration of 10 mg erithrityl tetranitrate (ETN).
162
July 1979
The American Journal of Medicine
Volume 65
failure [ 17-261. Despite this consistent effect on preload, the effect of nitrates on forward cardiac output has been variable, and studies have reported decreases [17,18,20,22,23], increases [21,27,19], or mixed effects [ 25,19,26], on cardiac output in normal subjects and in patients with heart failure. Ross [28] has recently pointed out the dependence of cardiac output on a complex interaction of preload and afterload, and has described the nature of this interaction in terms of the concepts of afterload mismatch and preload reserve. In this context, it seemed likely that the variable effect of nitrates on cardiac output could be explained in terms of the relative extent to which left ventricular preload and afterload were affected in a given patient. Furthermore, it seemed possible that the extent to which an oral nitrate altered left ventricular preload and afterload might be predicted on the basis of resting hemodynamics. The present study represents an attempt to test these hypotheses in 15 patients undergoing cardiac catheterization as part of the diagnostic evaluation of their chronic congestive heart failure. METHODS AND MATERIALS The study population consisted of eight women and seven men, ranging in age from 15 to 74 years, who were undergoing cardiac catheterization as part of the diagnostic evaluation of their chronic congestive heart failure. All patients had mitral or aortic regurgitation of varying extent. Eight patients had a diagnosis of congestive cardiomyopathy with secondary mitral regurgitation, and seven had heart failure due to rheumatic valvular heart disease with mitral and/or aottic regurgitation. Symptoms ranged in severity from New York Heart Association Class II to IV; all patients were receiving digitalis and diuretic therapy. Informed consent was obtained prior to study in each patient. All patients were studied in the supine, fasting state after being premeditated with diazepam, 10 mg given orally, and diphenhydramine, 50 mg given orally. Measurements of simultaneous mean right atrial, pulmonary capillary wedge and systemic arterial pressures were made through fluid-filled catheter systems attached to P23Db pressure transducers. The pulmonary capillary wedge pressure was confirmed by demonstrating 195 per cent oxygen saturation of blood obtained from the distal lumen of the wedge catheter. Cardiac output was measured by the Fick method, with arterial blood sampled from the brachial or femoral artery and mixed venous blood sampled from the main pulmonary artery simultaneously. Base line measurements of cardiac output and intracardiac pressures were followed by the administration of 10 mg of chewable erithrityl tetranitrate (buccal absorption). Right atrial, systemic arterial and pulmonary capillary wedge pressures were then recorded continuously for 20 minutes at which time measurement of cardiac output was repeated. Systemic vascular resistance (SW), in dynesset-cm+, was calculated according to the formula: SVR = (arterial
mean pressure - right atrial mean pressure) cardiac output
X80
NImATE
THERAPY fN VALVULAR HEART DISEASE-GOLDBERG
ET AL.
Patients were arbitrarily divided into two groups on the basis of an augmentation in forward stroke volume by 10 per cent or more (eight patients, responders) or no significant change (or a decrease) in stroke volume (seven patients,
nonresponders). Data analysis was performed using Student’s t tests, when appropriate,
and Pearson’s
rank correlation
coefficient
WI.
RESULTS The hemodynamic parameters at rest and following the administration of IO mg of chewable erithrityl tetranitrate are shown in Figures 1 and 2. Heart Rate. For the entire patient population, heart rate remained unchanged (91 f 4 beats/min to 89 f 3 beats/min). There was no significant difference in resting heart rate or heart rate changes between those patients in whom cardiac output increased (responders, heart rate 87 f 5 to 84 f 6 beats/min) and those in whom there was no increase in cardiac output (nonresponders, heart rate 95 f 5 to 95 f 5 beats/min) following the administration of erithrityl tetranitrate. Mean Arterial Pressure. There was a statistically significant decline in mean arterial pressure for the entire population, from a resting value of 99 f 3 to 82 f 3 mm Hg (p CO.01). This was true for each subgroup, with mean arterial pressure of responders declining from 99 f 4 to 85 f 3 mm Hg (p CO.01) and nonresponders mean arterial pressure falling from 98 f 3 to 78 f 4 mm Hg (p
r = 0.93 n - 15
-+’ 1000 ’ htm 2ooo 2500 3ooo 3500 4000 RESTINGSYSTEMICVASCULARRESISTANCE tdyner/k/cm-‘1
Figure 3. The change in systemic vascular resistand plotted as a function of resting systemic vascukw resistance. Those patients with the greatest degree of artefioiar vasoconstriction at rest demonstratf3d the greatest decline in systemic resistance following the administration of eritfdtyl tetfanitrate.
nonresponders, there was essentially no change in stroke volume (47 f 5 to 46 f 5 cc/beat) or cardiac output (4.3 f 0.3 to 4.2 f 0.3 liters/min). Resting cardiac output and stroke volume were significantly lower in patients who had augmentation of cardiac output (responders) than in patients who exhibited no such augmentation (nonresponders). Systemic Vascular Resistance. Systemic vascular resistance decreased in 13 of the 15 patients. Resting systemic vascular resistance was significantly greater for responders than for nonresponders (2,602 f 251 versus 1,744 f 193 dynes-set-cmW5, p <0.02). Furthermore, there was a significant decline in systemic vascular resistance in responders (2,602 f 251 to 1,783 f 101 dynes-set-cm-5, p
occurs
primarily
in patients
with
substantial 163
NITRATE
THERAPY
IN VALVIJLAR
HEART
DISEASE-GOLDBERG
ET AL.
resting vasoconstriction of the peripheral arteriolar bed as reflected by high resting systemic vascular resistance. Prior studies, on the hemodynamic effects of nitrate preparations in normal subjects [30-321 and in patients with heart failure [ 19,21,23,25,27], have yielded vari-
r
Figure 4. A, schematicrepresentationof a pressure volume loop of the left ventricle. D = mitral valve opening; DA = diastolic fillip of the ventricle; A = end-diastolicvolume and pressure achieved;AB = isovolumic contraction; B = aortic valve opening; BC = left ventricular ejection; C = beginning of isovolumic relaxation; CD = relaxation phase until mitral valve opening. B, the influence of alterations in preload and afterload on the pump function of the left ventricle. Reductions in afterload lead to augmentation of stroke volume if preload is held constant, whereas reduction in preload diminishes stroke volume if afterload is constant. If both are reduced, the final effect on stroke volume is dependent on the degree of reduction in each variable. The control loop is inscribed by points A, B, C, D and E; a’loop demonstrating pure afterload reduction points A, B, F and G; a loop demonstrating bbth preload and afterload reduction points Ii, I, F and G. S V represents the stroke volume of the control loop; SV,, = the augmented stroke volume effected by afterload reduction and S V, = the stroke volume with combinedpreload and afterload reduction.
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able and conflicting results. Gold et al. [ 191 and Bussman et al. [26] reported augmentation in cardiac output in their patients with acute myocardial infarction complicated by severe congestive failure, whereas Williams [23] demonstrated a significant reduction in cardiac output in the same clinical setting. In all these studies, nitrate administration resulted In a significant reduction in left ventricular filling pressure. Thus, although there is general agreement concerning the effect of nitrates on preload, the influence of these agents on cardiac output and stroke volume is inconsistent. Our results indicate that afterload reduction and consequent augmentation in forward output are most marked in those subjects with the highest resting systemic vascular resistance. Those patients with the greatest degrees of vasoconstriction at rest demonstrated the greatest decrease in systemic vascular resistance (Figure 3). One possible explanation for these observations is that in patients with normal resting systemic resistance, nitrates have a more pronounced effect on venous than on arterial tone. Thus, as cardiac output decreases due to diminished venous return, arterial blood pressure is reflexly maintained by systemic vasoconstriction, negating the direct effect of nitrates on the arterial tree. On the other hand, in patients with increased systemic vascular resistance due to resting arteriolar vasoconstriction, the afterload reducing effect of the drug might predominate; the result would be transient reduction in arterial pressure and augmentation of stroke volume provided preload is not excessively reduced. In this latter situation, the predominant effect of nitrates would be similar to the effects of phentolamine or hydralazine, which exert their main action on arteriolar tone [ 11,12,16]. An alternative explanation for our findings is that the decreased venous return was counterbalanced by substantial improvement in forward stroke volume due to the lowered aortic pressure and consequent lessening of mitral or aortic regurgitation. However, patients with significant valvular insufficiency were found in both groups I and II in our study, so that the presence or degree of valvular insufficiency does not seem to be the primary factor determining response of cardiac output. To clarify the interrelationships between preload, afterload, stroke volume and contractility, it may be helpful to analyze our observations in terms of Ross’ concept of afterload mismatch and preload reserve [ 281. In Figure 4A of the left ventricular pressure-volume diagram, a single cardiac cycle (ABCD) is illustrated against the background of resting and active left ventricular pressure-volume curves. Point D indicates mitral valve opening and segment, DA represents left ventricular filling. At point A, left ventricular end-diastolic pressure and volume are reached, and following
NITRATE
ventricular activation, segment AB (isovolumic contraction) ensues. Aortic valve opening occurs at point B and segment BC represents ejection of blood into the aorta. Point C indicates end-systolic pressure and volume, and is followed by isovolumic relaxation, segment CD. The active pressure curve represents the maximum pressure that the left ventricle can generate (at a fixed level of contractility) in nonejecting beats originating from a series of different end-diastolic volumes. Evidence suggests that this curve represents the endsystolic pressure-volume relationship for ejecting beats [33-371. Alterations in contractility would be represented by an upward and leftward shift of this active pressure curve. Figure 48 illustrates how alterations in preload and afterload can affect stroke volume at constant contractility. In the control state, a single cardiac cycle is represented as ABCDE, having a stroke volume SV,. With afterload reduction produced by an agent affecting primarily the systemic ar-teriolar vessels, the pressure volume relation is initially altered such that a single cardiac cycle is now represented by ABFG, with a substantially increased stroke volume (SV, > SV,). If an agent which affects both capacitance (venules) and resistance vessels is used, a different alteration in the pressure volume loop occurs and a single cardiac cycle might be represented by HIFG. The degree of afterload reduction in this situation is the same as for loop ABFG;
THERAPY
IN VALVULAR
HEART
DISEASE-GOLDBERG
ET AL.
however, since preload has also been reduced, the augmentation in stroke volume that would have been produced by pure afterload reduction is attenuated (SV, < SV,). The final effect on stroke volume compared to control therefore depends on the relative extent to which afterload and preload are reduced. In our study, patients with high resting systemic vascular resistance demonstrated a relatively greater effect of afterload reduction than preload reduction with resulting augmentation of stroke volume. In patients with lower resting systemic vascular resistances, the effect of reduction in afterload was counterbalanced by reduced preload; as a result, stroke volume remained unchanged or declined. In summary, the ultimate hemodynamic effect of nitrates is dependent on several variables. Although preload reduction occurs consistently, augmentation of cardiac output appears most likely in those patients with increased filling pressures and high resting systemic vascular resistance. Vasodilator therapy with nitrates can have varying effects on individual patients. We urge that careful hemodynamic monitoring be undertaken in patients begun on therapeutic trials with these agents. If cardiac catheterization is planned, testing of the agent in this controlled setting can help to evaluate an individual patient’s response to these potent drugs.
REFERENCES 1.
2.
3.
8. 9.
10.
Chatterjee K, Parmley WW, Swan HJC, et al.: Beneficial.effects of vasodilator agents in severe mitral regurgitation due to dysfunction of the subvalvular apparatus. Circulation 46: 664, 1973. Grossman W, Harshaw CW, Munro AB, et al.: Lowered aortic impedance as therapy for severe mitral regurgitation. JAMA 230: 1011, 1974. Harshaw CW, Grossman W, Munro AB, et al.: Reduced systemic vascular resistance as therapy for severe mitral regurgitation of valvular origin. Ann Intern Mad 83: 312, 1976. Bolen JL, Alderman EL: Hemodynamic consequences of afterload reduction in patients with chronic aortic regurgitation. Circulation 53: 879, 1976. Goodman DJ, Rossen RM, Holloway EL, et al.: Effect of nitroprusside on left ventricular dynamics in mitral regurgitation. Circulation 50: 1025, 1974. Wiggers CJ. Feil H: The cardiodynamics of mitral insufficiency. Heart 9: 149, 1922. Braunwald E, Welch GH Jr., Morrow AG: Tha effects of acutely increased systemic resistance on the left atrial pressure pulse: a method for the clinical detection of mitral insufficiency. J Clin Invest 37: 35, 1958. Chatterjee K: Vasodilator therapy for heart failure. Ann Intern Med 83: 421. 1975. Cohn JN: Vasodilator therapy for heart failure. The influence of impedance on left ventricular performance. Circulation 48: 5, 1973. Honig CR, Tenney SM, Gabel PV: The mechanism of cardiovascular action of nitroglycerin: an example of integrated
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July 1978
response during the unsteady state. Am J Med 29: 910, 1960. Chatterjee K, Parmley WW, Massie B, et al.: Oral hydralazine therapy for chronic refractory heart failure. Circulation 54: 879, 1976. Majid PA, Sharma B, Taylor SH: Phentolamine for vasodilator treatment of severe heart failure. Lancet 2: 7 19, 197 1. Miller RR, Vismara LA, Zelis R, et al.: Clinical use of sodium nitroprusside in chronic ischemic heart disease. Effects on peripheral vascular resistance, venous tone, and on ventricular volume, pump and mechanical performance. Circulation 51: 328, 1975. William DO, Hilliard GK, Cantor SA, et al.: Comparison of nitroprusside and phentolamine in left ventricular impedance reduction therapy in cardiac failure. Clin Res 23: 88A, 1975. Loeb HS, Stern M, Gohlke H, et al.: Acute hemodynamic effects of alpha receptor blockade in patients with chronic low output cardiac failure. Clin Res 24: 227A, 1976. Franciosa JA, Pierpont G, Cohn JN: Hemodynamic improvement after oral hydralazine in left ventricular failure. Ann Intern Med 86: 388, 1977. Ferrer MI, Bradley S, Wheeler HO, et al.: Some effects of nitroglycerin upon the splanchnic, pulmonary and systemic circulations. Circulation 33: 357, 1966. Williams JF, Glick G, Braunwald E: Studies on cardiac dimensions In intact unanesthetized man V. Effects of nitroglycerin. Circulation 32: 767, 1965. Gold HK, Leinbach RC, Sanders CA: Use of sublingual nitroglycerin in congestive failure following acute myocardial
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20.
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24.
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infarction. Circulation 46: 369. 1972. DeMaria AN, Vismara LA, Auditors K, et al.: Effects of nitroglycerin on left ventricular cavitary size and cardiac performance determined by ultrasound in man. Am J Med 57: 754, 1974. Gray R, Chatterjee K, Vyden JK, et al.: Hemodynamic and metabolic effects of isosorbide dinitrate in chronic congestive heart failure. Am Heart J 90: 346, 1976. Sweatman T, Strauss G, Selzer A, et al.: The long acting hemodynamic effects of isosorbide dinitrate. Am J Cardiol 29: 475, 1972. Williams DO, Amsterdam EA, Mason DT: Hemodynamic effects of nitroglycerin in acute myocardial infarction: decrease in ventricular preload at the expense of cardiac output. Circulation 51: 431, 1975. Majmi M, Griggs DM, Kasparian H, et al.: Effects of nitroglycerin on hemodynamics during rest and exercise in patients with coronary insufficiency. Circulation 35: 46, 1967. William DO, Bommer WJ, Miller RR. et al.: Hemodynamic assessment of oral peripheral vasodilator therapy in chronic congestive heart failure: prolonged effectiveness of isosorbide dinitrate. Am J Cardio139: 84, 1977. Bussmann WD, Lohner J, Kaltenbach M: Orally administered isosorbide dinitrate in patients with and without left ventricular failure due to acute myocardial infarction. Am J Cardio139: 91, 1977. Kovick RB, Tillisch JH, Berens SC, et al.: VaSodilatOr therapy for chronic left ventricular failure. Circulation 53: 322, 1976.
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28.
29. 30. 31.
32.
33.
34.
35.
36.
37.
Ross J Jr: Afterload mismatch and preload reserve: a conceptual framework for the analysis of ventricular function. Prog Cardiovasc Dis 18: 255, 1976. Colton H: Statistics in Medicine. Boston, Little, Brown & Co., 1974, pp 99, 189. Gaisbock F, Jarisch A: Euber den einfluss von natrium nitrosum auf den kreislauf. Wien Klin Wochenschr 40: 1540, 1927. Starr I, Gamble CJ, Margolies A, et al.: A clinical study of the actions of 10 commonly used drugs on the cardiac output, work and size; on respiration, metabolic rate and on the electrocardiogram. J Clin Invest 16: 799, 1937. Wegria R, Nickerson JL, Case RB, et al.: Effect of nitroglycerin on the cardiovascular system of normal persons. Am J Med 10: 414, 1951. Monroe RG, French GN: Left ventricular pressure-volume relationships and myocardial oxygen consumption in the isolated heart. Circ Res 9: 362, 1961. Suga H, Sagawa K, Shoukas AA: Load independence of the instantaneous pressure volume ratio of the canine left ventricle and effects of epinephrine and heart rate on the ratio. Circ Res 32: 314, 1973. Suga H, Sagawa K: Instantaneous pressure-volume relationships and their ratio in the excised, supported canine left ventricle. Circ Res 35: 117, 1974. Weber KT, Janicki JS, Hefner LL: Left ventricular force length relations of isovolumic and ejecting beats. Am J Physlol 231: 337.1976. Grossman W, Braunwald E, Mann T, et al.: Contractile state of the left ventricle in man as evaluated from end systolic pressure-volume relations. Circulation 56: 845. 1977.
SHELDON GOLDBERG, M.D. TlFT MANN, M.D. WILLIAM
GROSSMAN,
M.D.
l
Boston, Massachusetts
From the Departments of Medicine, Peter Bent Brii Hospital and the Harvard Medical School, Boston, Massachusetts. This study was supported in part by a U.S. Public Health Service Grant HL 19246 from the National Heart and Lung lnstiiutes and by a grant from the Burroughs-Wellcome Company. Requests for reprints should be addressed to Dr. William Grossman, Department of Medicine, Peter Bent Brigham Hospital, Boston, Massachusetts 02115. Established Investigator, American Heart Association. l
Although oral nitrates are widely used as therapy for patients with congestive heart failure, their effectiveness in increasttqj cardiac output is highly variable. in order to identify predictors of outcome, we studied the effects of 6rithrityi tetranitrate (ETN) on preioad, afterioad and cardiac output in 15 patients with chronic congestive heart failure and mitral or aortic insufficiency who were undergoing diagnostic cardiac catheterization. There were signifkant reductions in right atriai, pulmonary capillary wedge and mean arterial pressures in nearly ail patients. Augmentation in cardiac output by I 10 per cent occurred in eight patients (responders), whereas no change (or decline) occurred in seven patients (nonresponders). The level of peripheral vasoconstriction, as reflected by resting systemic vascular resistance was significantly higher for responders than for nonresponders (2,602 f 251 versus 1,744 f 193 dynes-set-cm+, p <0.02). FurWrmore, a stgnifkant reduction in systemic resistance occurred only in responders, and the decline was a linear function of resting resistance (r = 0.93). thus, atthough reductions in arterial pressure, and left and right ventricular filling pressures are a constant resutt of nitrate therapy, signifkant aqmentatton in forward cardiac output is likely only in those patients with the most intense resting peripheral vasoconstriction. The concept of afterload mismatch and preioad reserve best explains the variable effects of nitrates in congestive heart failure. As has been pointed out by the other participants in this symposium, vasodilator drugs have assumed a major role in the treatment of patients with congestive heart failure. That vasodilator therapy may be particularly effective in congestive heart failure due to mitral or aortic insufficiency has been shown by several groups over the past five years [l--5], but the physiologic basis for this observation was demonstrated over 50 years ago by Carl Wiggers [6]. In 1922, Wiggers reported a series of experiments in which experimental mitral insufficiency was induced in dogs. He found that the regurgitant volume in this experimental mitral insufficiency preparation was strongly influenced by aortic resistance to left ventricular ejection. In his experiments, the regurgitant volume could be increased by aortic constriction or decreased by administration of nitrates. In 1958, Braunwald et al. [ 71 reported a study on the effects of altered systemic vascular resistance on the left atrial pressure pulse in patients with mitral insufficiency. In our own studies of vasodilator therapy for severe mitral regurgitation [2,3], we noted a relationship between the level of resting
July 1978
The American Journal of Medicine
Volume 85
191
NITRATE THERAPY IN VALVULAR HEART DISEASE-GOLDBERG
---
ET AL.
Grovp 1 n.8 GrovplIn.7
igure 1. Mean arterial pressure, pulmonary .-. capillary _ wedge pressure and right atria/ pressure at rest (C)and following the administration of 10 mg eritfuifyl tetranitrate (ETN) in responders (group I, those who increased cardiac output by I 10 per cent) and nonresponders (group II, those who showed no change or a decrease in cardiac output).
systemic vascular resistance and the likelihood of hemodynamic improvement. There is great variability among vasodilator agents, and the relative effects of a particular drug on arteriolar resistance and venous capacitance is of major importance in predicting its hemodynamic effects [8-161. This problem may become complex in the circumstance in which a particular drug may have different effects depending on the level of resting tone in resistance and capacitance beds. For example, nitrate preparations are well known to influence venous capacitance; this is presumably responsible (at least in part) for the fact that ventricular filling pressures and pulmonary congestion are consistently improved when nitrate therapy is given to patients with congestive
-
GROUP I in.81
.----
GROUP II (n-7)
60 t
I
._
_
-..
.
C .
I
ETN
.
lgure 2. Stroke volume and systemic vascular resistance at rest (C) and folio wing the administration of 10 mg erithrityl tetranitrate (ETN).
162
July 1979
The American Journal of Medicine
Volume 65
failure [ 17-261. Despite this consistent effect on preload, the effect of nitrates on forward cardiac output has been variable, and studies have reported decreases [17,18,20,22,23], increases [21,27,19], or mixed effects [ 25,19,26], on cardiac output in normal subjects and in patients with heart failure. Ross [28] has recently pointed out the dependence of cardiac output on a complex interaction of preload and afterload, and has described the nature of this interaction in terms of the concepts of afterload mismatch and preload reserve. In this context, it seemed likely that the variable effect of nitrates on cardiac output could be explained in terms of the relative extent to which left ventricular preload and afterload were affected in a given patient. Furthermore, it seemed possible that the extent to which an oral nitrate altered left ventricular preload and afterload might be predicted on the basis of resting hemodynamics. The present study represents an attempt to test these hypotheses in 15 patients undergoing cardiac catheterization as part of the diagnostic evaluation of their chronic congestive heart failure. METHODS AND MATERIALS The study population consisted of eight women and seven men, ranging in age from 15 to 74 years, who were undergoing cardiac catheterization as part of the diagnostic evaluation of their chronic congestive heart failure. All patients had mitral or aortic regurgitation of varying extent. Eight patients had a diagnosis of congestive cardiomyopathy with secondary mitral regurgitation, and seven had heart failure due to rheumatic valvular heart disease with mitral and/or aottic regurgitation. Symptoms ranged in severity from New York Heart Association Class II to IV; all patients were receiving digitalis and diuretic therapy. Informed consent was obtained prior to study in each patient. All patients were studied in the supine, fasting state after being premeditated with diazepam, 10 mg given orally, and diphenhydramine, 50 mg given orally. Measurements of simultaneous mean right atrial, pulmonary capillary wedge and systemic arterial pressures were made through fluid-filled catheter systems attached to P23Db pressure transducers. The pulmonary capillary wedge pressure was confirmed by demonstrating 195 per cent oxygen saturation of blood obtained from the distal lumen of the wedge catheter. Cardiac output was measured by the Fick method, with arterial blood sampled from the brachial or femoral artery and mixed venous blood sampled from the main pulmonary artery simultaneously. Base line measurements of cardiac output and intracardiac pressures were followed by the administration of 10 mg of chewable erithrityl tetranitrate (buccal absorption). Right atrial, systemic arterial and pulmonary capillary wedge pressures were then recorded continuously for 20 minutes at which time measurement of cardiac output was repeated. Systemic vascular resistance (SW), in dynesset-cm+, was calculated according to the formula: SVR = (arterial
mean pressure - right atrial mean pressure) cardiac output
X80
NImATE
THERAPY fN VALVULAR HEART DISEASE-GOLDBERG
ET AL.
Patients were arbitrarily divided into two groups on the basis of an augmentation in forward stroke volume by 10 per cent or more (eight patients, responders) or no significant change (or a decrease) in stroke volume (seven patients,
nonresponders). Data analysis was performed using Student’s t tests, when appropriate,
and Pearson’s
rank correlation
coefficient
WI.
RESULTS The hemodynamic parameters at rest and following the administration of IO mg of chewable erithrityl tetranitrate are shown in Figures 1 and 2. Heart Rate. For the entire patient population, heart rate remained unchanged (91 f 4 beats/min to 89 f 3 beats/min). There was no significant difference in resting heart rate or heart rate changes between those patients in whom cardiac output increased (responders, heart rate 87 f 5 to 84 f 6 beats/min) and those in whom there was no increase in cardiac output (nonresponders, heart rate 95 f 5 to 95 f 5 beats/min) following the administration of erithrityl tetranitrate. Mean Arterial Pressure. There was a statistically significant decline in mean arterial pressure for the entire population, from a resting value of 99 f 3 to 82 f 3 mm Hg (p CO.01). This was true for each subgroup, with mean arterial pressure of responders declining from 99 f 4 to 85 f 3 mm Hg (p CO.01) and nonresponders mean arterial pressure falling from 98 f 3 to 78 f 4 mm Hg (p
r = 0.93 n - 15
-+’ 1000 ’ htm 2ooo 2500 3ooo 3500 4000 RESTINGSYSTEMICVASCULARRESISTANCE tdyner/k/cm-‘1
Figure 3. The change in systemic vascular resistand plotted as a function of resting systemic vascukw resistance. Those patients with the greatest degree of artefioiar vasoconstriction at rest demonstratf3d the greatest decline in systemic resistance following the administration of eritfdtyl tetfanitrate.
nonresponders, there was essentially no change in stroke volume (47 f 5 to 46 f 5 cc/beat) or cardiac output (4.3 f 0.3 to 4.2 f 0.3 liters/min). Resting cardiac output and stroke volume were significantly lower in patients who had augmentation of cardiac output (responders) than in patients who exhibited no such augmentation (nonresponders). Systemic Vascular Resistance. Systemic vascular resistance decreased in 13 of the 15 patients. Resting systemic vascular resistance was significantly greater for responders than for nonresponders (2,602 f 251 versus 1,744 f 193 dynes-set-cmW5, p <0.02). Furthermore, there was a significant decline in systemic vascular resistance in responders (2,602 f 251 to 1,783 f 101 dynes-set-cm-5, p
occurs
primarily
in patients
with
substantial 163
NITRATE
THERAPY
IN VALVIJLAR
HEART
DISEASE-GOLDBERG
ET AL.
resting vasoconstriction of the peripheral arteriolar bed as reflected by high resting systemic vascular resistance. Prior studies, on the hemodynamic effects of nitrate preparations in normal subjects [30-321 and in patients with heart failure [ 19,21,23,25,27], have yielded vari-
r
Figure 4. A, schematicrepresentationof a pressure volume loop of the left ventricle. D = mitral valve opening; DA = diastolic fillip of the ventricle; A = end-diastolicvolume and pressure achieved;AB = isovolumic contraction; B = aortic valve opening; BC = left ventricular ejection; C = beginning of isovolumic relaxation; CD = relaxation phase until mitral valve opening. B, the influence of alterations in preload and afterload on the pump function of the left ventricle. Reductions in afterload lead to augmentation of stroke volume if preload is held constant, whereas reduction in preload diminishes stroke volume if afterload is constant. If both are reduced, the final effect on stroke volume is dependent on the degree of reduction in each variable. The control loop is inscribed by points A, B, C, D and E; a’loop demonstrating pure afterload reduction points A, B, F and G; a loop demonstrating bbth preload and afterload reduction points Ii, I, F and G. S V represents the stroke volume of the control loop; SV,, = the augmented stroke volume effected by afterload reduction and S V, = the stroke volume with combinedpreload and afterload reduction.
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able and conflicting results. Gold et al. [ 191 and Bussman et al. [26] reported augmentation in cardiac output in their patients with acute myocardial infarction complicated by severe congestive failure, whereas Williams [23] demonstrated a significant reduction in cardiac output in the same clinical setting. In all these studies, nitrate administration resulted In a significant reduction in left ventricular filling pressure. Thus, although there is general agreement concerning the effect of nitrates on preload, the influence of these agents on cardiac output and stroke volume is inconsistent. Our results indicate that afterload reduction and consequent augmentation in forward output are most marked in those subjects with the highest resting systemic vascular resistance. Those patients with the greatest degrees of vasoconstriction at rest demonstrated the greatest decrease in systemic vascular resistance (Figure 3). One possible explanation for these observations is that in patients with normal resting systemic resistance, nitrates have a more pronounced effect on venous than on arterial tone. Thus, as cardiac output decreases due to diminished venous return, arterial blood pressure is reflexly maintained by systemic vasoconstriction, negating the direct effect of nitrates on the arterial tree. On the other hand, in patients with increased systemic vascular resistance due to resting arteriolar vasoconstriction, the afterload reducing effect of the drug might predominate; the result would be transient reduction in arterial pressure and augmentation of stroke volume provided preload is not excessively reduced. In this latter situation, the predominant effect of nitrates would be similar to the effects of phentolamine or hydralazine, which exert their main action on arteriolar tone [ 11,12,16]. An alternative explanation for our findings is that the decreased venous return was counterbalanced by substantial improvement in forward stroke volume due to the lowered aortic pressure and consequent lessening of mitral or aortic regurgitation. However, patients with significant valvular insufficiency were found in both groups I and II in our study, so that the presence or degree of valvular insufficiency does not seem to be the primary factor determining response of cardiac output. To clarify the interrelationships between preload, afterload, stroke volume and contractility, it may be helpful to analyze our observations in terms of Ross’ concept of afterload mismatch and preload reserve [ 281. In Figure 4A of the left ventricular pressure-volume diagram, a single cardiac cycle (ABCD) is illustrated against the background of resting and active left ventricular pressure-volume curves. Point D indicates mitral valve opening and segment, DA represents left ventricular filling. At point A, left ventricular end-diastolic pressure and volume are reached, and following
NITRATE
ventricular activation, segment AB (isovolumic contraction) ensues. Aortic valve opening occurs at point B and segment BC represents ejection of blood into the aorta. Point C indicates end-systolic pressure and volume, and is followed by isovolumic relaxation, segment CD. The active pressure curve represents the maximum pressure that the left ventricle can generate (at a fixed level of contractility) in nonejecting beats originating from a series of different end-diastolic volumes. Evidence suggests that this curve represents the endsystolic pressure-volume relationship for ejecting beats [33-371. Alterations in contractility would be represented by an upward and leftward shift of this active pressure curve. Figure 48 illustrates how alterations in preload and afterload can affect stroke volume at constant contractility. In the control state, a single cardiac cycle is represented as ABCDE, having a stroke volume SV,. With afterload reduction produced by an agent affecting primarily the systemic ar-teriolar vessels, the pressure volume relation is initially altered such that a single cardiac cycle is now represented by ABFG, with a substantially increased stroke volume (SV, > SV,). If an agent which affects both capacitance (venules) and resistance vessels is used, a different alteration in the pressure volume loop occurs and a single cardiac cycle might be represented by HIFG. The degree of afterload reduction in this situation is the same as for loop ABFG;
THERAPY
IN VALVULAR
HEART
DISEASE-GOLDBERG
ET AL.
however, since preload has also been reduced, the augmentation in stroke volume that would have been produced by pure afterload reduction is attenuated (SV, < SV,). The final effect on stroke volume compared to control therefore depends on the relative extent to which afterload and preload are reduced. In our study, patients with high resting systemic vascular resistance demonstrated a relatively greater effect of afterload reduction than preload reduction with resulting augmentation of stroke volume. In patients with lower resting systemic vascular resistances, the effect of reduction in afterload was counterbalanced by reduced preload; as a result, stroke volume remained unchanged or declined. In summary, the ultimate hemodynamic effect of nitrates is dependent on several variables. Although preload reduction occurs consistently, augmentation of cardiac output appears most likely in those patients with increased filling pressures and high resting systemic vascular resistance. Vasodilator therapy with nitrates can have varying effects on individual patients. We urge that careful hemodynamic monitoring be undertaken in patients begun on therapeutic trials with these agents. If cardiac catheterization is planned, testing of the agent in this controlled setting can help to evaluate an individual patient’s response to these potent drugs.
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