92
26. Packer M. Interaction of prostaglandins and angiotensin II in the modulation of renal function in congestive heart failure. Circulation 1988; 77 (suppl I): 64-73. 27. Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992; 85: 790-804. 28. Tan LB, Jalil JE, Pick R, Janicki JS, Weber KT. Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991; 69: 1185-95. 29. Ver Donck L, Wouters L, Olbrich HG, Mutschler E, Borgers M. Nebivolol increases survival in cardiomyopathic hamsters with congestive heart failure. J Cardiovasc Pharmacol 1991; 18: 1-3. 30. Pfeffer JM, Pfeffer MA, Mirsky I, Steinberg CR, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation 1985; 72: 406-12.
JJF, Budges AB, Scott N, Chopra M. Oxygen free radicals and congestive heart failure. Br Heart J 1991; 65: 245-48. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in congestive heart failure. N Engl J Med
31. Belch 32.
1990; 323: 236-41. 33. Gulik T, Chung MK, Pieper SJ, Lange LG, Schreiner GF. Interleukin1 and tumour necrosis factor inhibit cardiac myocyte &bgr;-adrenergic responsiveness. Proc Natl Acad Sci USA 1989; 86: 6753-57. 34. Lefer M, Aoki N. Leukocyte-dependent and leukocyte-independent mechanisms of impairment of endothelium-mediated vasodilatation. Blood Vessels 1990; 27: 162-68. 35. Han JJ, Leeper-Woodford SK, Drenning DH, et al. Circulating tumor necrosis factor and endothelial-derived relaxing factor in severe heart failure. J Am Coll Cardiol 1992; 19: 207A.
Treatment of chronic heart failure
Since heart failure has been thought of as a mechanical treatment has necessarily been focused on achieving haemodynamic goals. This approach may seem logical because heart failure develops after an injury to the heart and can be alleviated with replacement of the heart (eg, by transplantation). However, as I described in my preceding article, the development and progression of heart failure result from a complex interplay of haemodynamic and neurohormonal factors, rather than simply changes in cardiac function. Therefore, the treatment of patients with heart failure should be directed, not to improving systolic performance, but to correcting the primary pathophysiological abnormalities of the circulation, and thus, to improving symptoms and prolonging life. In patients with left ventricular systolic dysfunction, the main pathophysiological features of heart failure are increased cardiac wall stress and increased neurohormonal activity. Both haemodynamic and neurohormonal forces contribute to symptoms and to progression of the underlying disorder. Therapeutic interventions designed to limit the adverse effects of these factors have met with variable success.
disorder, its
Drugs to reduce ventricular wall stress Several therapeutic agents produce haemodynamic benefits in heart failure by antagonising the three pathophysiological factors that contribute to an increase in ventricular wall stress: sodium retention (diuretics), peripheral vasoconstriction (direct-acting vasodilators), and reduced cardiac contractility (positive inotropic agents).
Diuretics Diuretics alleviate the sodium retention of heart failure by
inhibiting sodium and chloride reabsorption at specific sites in the renal tubules. Two classes of diuretic agents have been developed. Drugs that act on the distal tubules (thiazides and potassium-sparing diuretics) increase the fractional excretion of sodium only modestly (up to 5-10% of the filtered load), and they lose their effectiveness when renal function is impaired (when the glomerular filtration rate [GFR] decreases to below 30 ml/min). Agents that act on the loop of Henle (frusemide, ethacrynic acid, bumetanide, and piretanide) increase the fractional excretion of sodium (up to 25% of the filtered load), and they retain their effectiveness until GFR falls below 5 ml/min. Loop diuretics are preferred because of their greater efficacy. However, they may be combined with thiazides (especially
and potassium-sparing diuretics when additional sodium excretion or potassium conservation, respectively, is desired. Diuretics produce consistent haemodynamic and symptomatic benefits in patients with pulmonary or peripheral congestion. These drugs rapidly relieve dyspnoea and oedema, and their natriuretic action may enhance the responsiveness of peripheral blood vessels to direct-acting vasodilators and converting-enzyme inhibitors. Thus, diuretics had long been regarded as the cornerstone of treatment for heart failure. However, controlled clinical trials show diuretics alone cannot maintain the clinical stability of patients with chronic heart failure. Many patients whose symptoms are well controlled deteriorate clinically during long-term follow-up when treated with diuretics alone.2 Furthermore, diuretic use is associated with a high risk of electrolyte depletion (potassium and magnesium) that may predispose to the development of lethal ventricular
metolazone)
arrhythmias. Both the limited efficacy and potential toxicity of diuretic monotherapy seem to be related to drug-induced activation of the renin-angiotensin system. Diuretics are an important cause of increased plasma renin activity in heart failure,3 and angiotensin attenuates the haemodynamic effects and potentiates the potassium-losing effects of these agents. Both the risk of clinical deterioration and the adverse metabolic effects of diuretic therapy can be reduced by simultaneous treatment with a converting-enzyme inhibitor.2 These observations suggest that the efficacy and safety of treatment may be limited if it improves one of the central physiological abnormalities of heart failure (wall stress) but worsens the other (neurohormonal activation). This view has led to attempts to develop diuretic drugs with favourable neurohormonal effects-eg, the atriopeptidase inhibitors.’ By inhibiting the enzyme responsible for degradation of atrial natriuretic peptide, these experimental drugs increase the circulating and renal tubular concentrations of the peptide-the body’s own diuretic. These agents produce natriuretic effects that are accompanied by suppression (rather than augmentation) of plasma renin activity. Studies of the long-term efficacy of these drugs in heart failure are now under way. Division of Circulatory Physiology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA (Dr M Packer, MD). ADDRESS:
93
Direct-acting vasodilators Vasodilators can alleviate the peripheral vasoconstriction of heart failure via direct relaxation of vascular smooth muscle at specific sites in the peripheral circulation. Three classes of oral direct-acting vasodilators have been developed: those that act mainly on peripheral veins (nitrates and molsidomine); those that act mainly on peripheral arteries (hydralazine, minoxidil, and calcium channel blockers); and those with combined actions on both arteries and veins (flosequinan). Many direct-acting vasodilators also have inotropic effects-eg, cardiac contractility is enhanced after treatment with hydralazine or flosequinan and is depressed by calcium channel blockers. However, these direct cardiac effects are not thought to be
important clinically. Although all direct-acting vasodilators produce favourable short-term haemodynamic effects, many of these agents have limited long-term efficacy. Several controlled trials have been unable to show a favourable effect of nitrates or hydralazine on symptoms and exercise tolerance when added to conventional therapy.5 This lack of efficacy has been attributed to tolerance to the vasodilator effects of these drugs during their long-term use.6 Inconsistent results have been observed when these two vasodilators have been combined. Although a hydralazine-nitrate combination improved exercise tolerance in one large study,these drugs did not produce clinical benefits in another large trial, and their use was associated with a high frequency of adverse reactions.s Similarly, although the vasodilator combination tended to improve survival in one study, this effect was less than that achieved by a converting-enzyme inhibitor in a second trial.7 Furthermore, some direct-acting vasodilators may produce adverse effects in patients with chronic heart failure. In controlled trials, patients treated with minoxidil or calcium channel blockers (verapamil, nifedipine, and diltiazem) were at higher risk of worsening heart failure and cardiovascular death than patients not treated with these
drugs.9-11 of diuretics, both the limited efficacy and of potential toxicity direct-acting vasodilators may be related to the predilection of these drugs to activate endogenous neurohormonal systems. Nitrates and hydralazine increase the activity of the sympathetic nervous system and reninangiotensin system, which may blunt the haemodynamic effects of these drugs and contribute to tolerance.5 Longterm calcium channel blocker therapy is also accompanied by an increase in neurohormonal activity, which may be responsible for the poor clinical results with these agents.12 Such findings strengthen the notion that drugs may have limited value and cause considerable toxicity if they ameliorate one of the central pathophysiological abnormalities of heart failure (wall stress) but exacerbate the other (neurohormonal activation). To address these concerns, vasodilator drugs with favourable neurohormonal effects have been developed. Flosequinan exerts relaxant effects on both peripheral arteries and veins by interfering with the phosphoinositide pathway, and it reduces sympathetic outflow to the heart." By contrast with other direct-acting vasodilators, flosequinan has beneficial effects on symptoms and exercise tolerance, both in the presence and absence of convertingenzyme inhibitors.14 Similarly, amlodipine and felodipine are new calcium antagonists that decrease (rather than increase) the activity of the sympathetic nervous system. These calcium channel blockers, in contrast to others, have As in the
case
and exercise tolerance of patients with chronic heart failure in controlled studies." 16 The long-term effects of flosequinan, amlodipine, and felodipine are now being evaluated in large trials.
improved the symptoms
Positive inotropic agents
Positive-inotropic drugs reduce wall stress by augmenting the contractility of the failing heart. Two classes of positive inotropic agents have been developed: those that enhance cardiac contractility by increasing the concentration of intracellular cyclic AMP, either by augmenting its synthesis (beta-adrenergic agonists) or by inhibiting its degradation (phosphodiesterase inhibitors); and those that increase cardiac contractility by cyclic-AMPindependent mechanisms--eg, Na+ - K+ -ATPase inhibition (digitalis). Of the two types of agents, cyclic AMPdependent agents produce a greater reduction in wall stress because they dilate peripheral blood vessels in addition to enhancing contractile force. Furthermore, these agents tend to correct the deficient production of myocardial cyclic AMP in the failing heart, which may be an important cause of contractile dysfunction.17 However, despite their favourable effects on wall stress, cyclic-AMP-dependent positive inotropic agents have not produced consistent benefits in controlled clinical trials. Neither beta-agonists nor phosphodiesterase inhibitors improve symptoms and exercise tolerance of patients with heart failure, and long-term treatment with these drugs is associated with increases in cardiovascular morbidity and mortality. 18,19 These results have raised fears that all types of positive inotropic agents have similar limitations. However, digitalis glycosides are consistently beneficial to patients with heart failure. Long-term therapy with digoxin reduces symptoms, prolongs exercise tolerance, and decreases the risk of clinical deterioration. 12021 These benefits extend to patients with mild or severe symptoms and are found irrespective of treatment with converting-enzyme inhibitors. Why should the results with digitalis differ from those with other positive inotropic agents? Unlike cyclicAMP-dependent drugs, digitalis reduces activation of both the sympathetic nervous system and the renin-angiotensin system. This favourable neurohormonal effect is achieved independently of the drug’s haemodynamic actions, and depends on the drug’s ability to correct the baroreflex dysfunction of heart failure, so restoring the inhibitory effect of cardiac baroreceptors on sympathetic outflow from the central nervous system.22 By contrast, phosphodiesterase inhibitors potentiate (rather than attenuate) the effects of the sympathetic nervous system on the heart. 17 Hence, as with vasodilators, differences in the efficacy and safety of positive inotropic agents may relate to their neurohormonal actions. New types of inotropic agents are being evaluated. Pimobendan enhances cardiac contractility by increasing the sensitivity of myofilaments to calcium; vesnarinone increases the delivery of calcium to myofilaments by enhancing sodium influx into cells. Both agents may alleviate the symptoms of heart failure, but since they are also phosphodiesterase inhibitors, their long-term safety remains uncertain.
Drugs that reduce neurohormonal activity Two types of drug have been developed: those interfering with the renin-angiotensin system (eg, converting-enzyme inhibitors) and those acting on the sympathetic nervous system (eg, beta-blockers).
94
Angiotensin converting-enzyme inhibitors Several controlled clinical trials have shown that converting-enzyme inhibitors produce consistent clinical improvement in patients with chronic heart failure.5 They have long-term haemodynamic effects that are more favourable than those found with other agents and tolerance rarely develops during treatment. They also produce symptomatic benefits that are greater than most vasodilators;"," dyspnoea is relieved, exercise tolerance is prolonged, and the risk of worsening heart failure is reduced. Most importantly, converting-enzyme inhibitors extend life in patients with chronic heart failure, and the size of this effect exceeds that of other therapeutic interventions.7,25,26 These haemodynamic, symptomatic, and prognostic benefits of converting-enzyme inhibitors are seen in patients with mild, moderate, and severe symptoms. These drugs also reduce the mortality rate and the risk of haemodynamic and clinical progression in symptom-free patients with left ventricular dysfunction following an acute myocardial infarction (personal communication, M. Pfeffer).27 Why should converting-enzyme inhibitors have such striking effects? The answer probably lies in their dual actions on both the haemodynamic and neurohormonal mechanisms of heart failure. These drugs attenuate the progressive ventricular dilatation that develops after an acute myocardial injury, and thus they can prevent the structural remodelling that develops after prolonged increases in ventricular wall stress.28 Converting-enzyme inhibitors also reduce the direct toxic effects of angiotensin on myocardial cells, which may lead to cell necrosis, replacement fibrosis, and disease progression.29 Which mechanism is more important in the clinical setting? Two lines of evidence suggest that the beneficial effects of the converting-enzyme inhibitors relate to their neurohormonal actions. First, in two large survival trials,725 convertingenzyme inhibitors reduced mortality mainly among patients who had the most striking neurohormonal activation at the time of starting treatment. Second, converting-enzyme inhibitors reduce mortality to a greater extent than directacting vasodilators even though the latter produce superior haemodynamic effects.7 Drugs that interfere with the activity of renin (renin inhibitors) or with the interaction of angiotensin II and its receptor (angiotensin antagonists) are now being developed. Unlike converting-enzyme inhibitors, these new approaches do not lead to the accumulation of kinins, and so should be less likely to produce some of the side-effects (eg, cough and angio-oedema) associated with existing agents.
Beta-adrenergic antagonists If neurohormonal activation were important in heart failure, drugs that antagonise actions of the sympathetic nervous system might be helpful. Although alphaadrenergic antagonists (eg, prazosin) produce short-term haemodynamic improvements, their long-term use does not favourably affect symptoms, exercise tolerance, or survival;88 this lack of benefit may relate
to
activation of the renin-
angiotensin system.23 Similarly, although beta-adrenergic antagonists (eg, metoprolol and propranolol) have favourable effects on symptoms of patients with an idiopathic dilated cardiomyopathy and on the survival of patients with heart failure secondary to ischaemic heart disease ’30,31 treatment is associated with a substantial risk (5-20%) of worsening heart failure. This risk is probably related to the negative inotropic effects of these drugs.
To obviate this limitation, sympathetic inhibitors with favourable haemodynamic and neurohormonal effects are being developed. Among the most promising agents are new beta-blockers that dilate peripheral blood vessels either
directly (eg, bucindolol) or through alpha-adrenergic antagonism (eg, carvedilol).32 Both drugs have produced beneficial long-term haemodynamic and clinical effects in controlled trials with only a small risk of adverse receptor
cardiovascular reactions.
Conclusion The results of controlled clinical trials reinforce the view that heart failure is both a haemodynamic and a neurohormonal disorder. Drugs can produce favourable haemodynamic effects by reducing ventricular wall stress, but benefits are unlikely to be sustained if these agents activate endogenous neurohormonal systems (eg, directacting vasodilators). Similarly, drugs can exert beneficial neurohormonal actions by antagonising the effects of either the sympathetic nervous system or renin-angiotensin system, but these are unlikely to be well-tolerated if they also depress cardiac function (eg, beta-blockers). Ideally, therapeutic interventions in heart failure should produce favourable effects on both haemodynamic and neurohormonal systems (eg, converting-enzyme inhibitors). Such drugs improve symptoms and prolong life (table). Overall, these data support the use of converting-enzyme inhibitors in all patients with heart failure, irrespective of the severity of symptoms. In patients with symptom-free left ventricular dysfunction, these drugs delay development of heart failure. In patients with symptoms of pulmonary or peripheral congestion, they potentiate the clinical effects and limit the adverse effects of diuretics. These benefits are accompanied by a reduction in morbidity and mortality. If symptoms persist despite the combination of a diuretic and a converting-enzyme inhibitor, physicians should add agents that diminish the haemodynamic and neurohormonal derangements of heart failure (eg, digitalis). Additional choices that are or will soon be commercially available include flosequinan, carvedilol, amlodipine, and felodipine. If all of these interventions fail, clinical stability may only be achieved with mechanical including solutions,
95
cardiomyoplasty, left ventricular assist devices, and cardiac transplantation. Future research on the mechanisms of heart failure should yield promising new treatments. These may include novel vasoconstrictor antagonists (eg, of vasopressin and
endothelin) and cytoprotective agents (eg, free radical scavengers or cytokine inhibitors). REFERENCES 1. Sinoway L, Minotti J, Musch T, et al. Enhanced metabolic vasodilation secondary to diuretic therapy in decompensated congestive heart failure secondary to coronary artery disease. Am J Cardiol 1987; 60: 107-11. 2. The Captopril-Digoxin Multicenter Research Group. Comparative effects of captopril and digoxin in patients with mild to moderate heart
failure. JAMA 1988; 259; 539-44. 3. Francis GS, Benedict C, Johnstone DE,
et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. Circulation 1990; 82: 1724-29. 4. Northridge DB, Jardine AG, Finlay IN, Archibald H, Dilly SG, Dargie HJ. Inhibition of the metabolism of atrial natriuretic factor causes diuresis and natriuresis in chronic heart failure. Am J Hypertension 1990; 3: 682-87. 5. Packer M. Vasodilator and inotropic drugs for chronic heart failure: distinguishing hype from hope. J Am Coll Cardiol 1988; 12: 1299-317. 6. Packer M, Gottlieb SS, Kessler PD, Medina N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med 1987; 317: 799-804. 7. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303-10. 8. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med 1986; 314: 1547-52. 9. Franciosa JA, Jordan RA, Wilen MM, Leddy CL. Minoxidil in patients with left heart failure: contrasting hemodynamic and clinical effects in a controlled trial. Circulation 1984; 70: 63-69. 10. Elkayam U, Amin J, Mehra A, Vasquez J, Weber L, Rahimtoola SH. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy to isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation 1990; 82: 1954-61. 11. Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S, the Adverse Experience Committee, and the Multicenter Diltiazem Post-Infarction Research Group. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. Circulation 1991; 83: 52-60. 12. Packer M. Pathophysiologic mechanisms underlying the adverse effects of calcium channel blocking drugs in patients with chronic heart failure. Circulation 1989; 80 (suppl IV): 59-67. 13. Binkley PF, Nunziata E, Hatton P, Proicou G, Cody RJ. Flosequinan augments parasympathetic tone and attenuates sympathetic drive in congestive heart failure: demonstration by analysis of heart rate variability. J Am Coll Cardiol 1992; 19: 147A. 14. Elborn JS, Stanford CF, Nicholls DP. Effect of flosequinan on exercise capacity and symptoms in severe heart failure. Br Heart J 1989; 61: 331-35. 15. Packer M, Nicod P, Khandheria BR, et al. Randomized, multicenter, double-blind, placebo-controlled evaluation of amlodipine in patients with mild-to-moderate heart failure. J Am Coll Cardiol 1991; 17: 274A. 16. Dunselman PHJM, Kuntze CEE, van Bruggen A, et al. Efficacy of felodipine in congestive heart failure. Eur Heart J 1989; 10: 354-64. 17. Feldman MD, Copelas L, Gwanthmey JK, et al. Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 1987; 75: 331-39. 18. Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet 1990; 336: 1-6. 19. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991; 325: 1468-75. 20. DiBianco R, Shabetai R, Kostuk W, et al. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med 1989; 320: 677-83. 21. Packer M, Gheorghiade M, Young JB, et al. Randomized, double-blind, placebo-controlled, withdrawal study of digoxin in patients with chronic heart failure treated with converting-enzyme inhibitors. J Am Coil Cardiol 1992; 19: 260A.
Ferguson DW, Berg WJ, Sanders JS, Roach PJ, Kempf JS, Kienzle MG. Sympatho-inhibitory responses to digitalis glycosides in heart failure patients: direct evidence from sympathetic neural recordings. Circulation 1989; 80: 65-77. 23. Bayliss J, Noreel MS, Canepa-Anson R, Reid C, Poole-Wilson P, Sutton G. Clinical importance of the renin-angiotensin system in chronic heart failure: double-blind comparison of captopril and prazosin. Br Med J 22.
1985; 290: 1861-65.
Agostoni PG, DeCesare N, Doria E, Polese A, Tamborini G, Guazzi MD. Afterload reduction: a comparison of captopril and nifedipine in dilated cardiomyopathy. Br Heart J 1986; 55: 391-99. 25. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure; results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J 24.
Med 1987; 316: 1429-35. 26. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293-302. 27. Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet 1988; i: 255-59. 28. Pfeffer MA, Lamas GA, Vaughn DE, et al. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988; 319: 80-86. 29. Tan LB, Jalil JE, Pick R, Janicki JS, Weber KT. Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991; 69: 1185-95. 30. Englemeier RS, O’Connell JB, Walsh R, Rad N, Scanlon PJ, Gunnar RM. Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Circulation 1985; 72: 536-46. 31. Chadda K, Goldstein S, Byington R, Curb JD. Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation 1986; 73: 503-10. 32. Gilbert EM, Anderson JL, Deitchman D, et al. Long-term &bgr;-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med 1990; 88: 223-29.
From The Lancet An old solution Handled jugs are often found in excavations on medieval sites.... These... jugs were commonly used in drawing water from the courtyard well, in drawing wine from casks and storing it in the cellar cupboards, and were in frequent use to serve wine at the table. A different purpose is evident for a jug... found about 1903 on the site of the Green Dragon Inn at Hertford.... The inside surface of the jug is covered with a pale buff incrustation, thick and granular on the body of the vessel, thinner and smooth towards the narrow neck.... The pale buff amorphous deposit... consists mainly of sodium urate, which is at times deposited from acid urines, usually adsorbing much urinary pigment on the surface of its particles as it settles.... A solution of the deposit in dilute hydrochloric acid gave a yellow-green fluorescence and a spectrum absorption band in the region of 500 urn, both characteristic of excreted pigments resulting from the normal physiological breakdown of blood pigment. This is a striking illustration of the stability of these pigments, and points to the urinary origin of the deposit. No chlorides or phosphates could be detected and although the concentration of these in the urine may be depressed in certain pathological conditions, such as high fever, this finding taken in conjunction with the presence of sodium urate and the urobilinoid pigment, which indicate that no heat has been applied, gives a fairly adequate proof that it is a urinary deposit and not the medieval "sal urinae", and that it resulted from the evaporation to dryness of the urine contained in the jug... it might be concluded that the vessel had been in use for some time simply as a urinal, but urinals were not introduced until much later. It is more likely that the jug was used for storing urine, the drinking of which was highly recommended in the Middle Ages as a remedy for plague and various ailments.
(July 11, 1942)
26. Packer M. Interaction of prostaglandins and angiotensin II in the modulation of renal function in congestive heart failure. Circulation 1988; 77 (suppl I): 64-73. 27. Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992; 85: 790-804. 28. Tan LB, Jalil JE, Pick R, Janicki JS, Weber KT. Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991; 69: 1185-95. 29. Ver Donck L, Wouters L, Olbrich HG, Mutschler E, Borgers M. Nebivolol increases survival in cardiomyopathic hamsters with congestive heart failure. J Cardiovasc Pharmacol 1991; 18: 1-3. 30. Pfeffer JM, Pfeffer MA, Mirsky I, Steinberg CR, Finn P. Survival after an experimental myocardial infarction: beneficial effects of long-term therapy with captopril. Circulation 1985; 72: 406-12.
JJF, Budges AB, Scott N, Chopra M. Oxygen free radicals and congestive heart failure. Br Heart J 1991; 65: 245-48. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in congestive heart failure. N Engl J Med
31. Belch 32.
1990; 323: 236-41. 33. Gulik T, Chung MK, Pieper SJ, Lange LG, Schreiner GF. Interleukin1 and tumour necrosis factor inhibit cardiac myocyte &bgr;-adrenergic responsiveness. Proc Natl Acad Sci USA 1989; 86: 6753-57. 34. Lefer M, Aoki N. Leukocyte-dependent and leukocyte-independent mechanisms of impairment of endothelium-mediated vasodilatation. Blood Vessels 1990; 27: 162-68. 35. Han JJ, Leeper-Woodford SK, Drenning DH, et al. Circulating tumor necrosis factor and endothelial-derived relaxing factor in severe heart failure. J Am Coll Cardiol 1992; 19: 207A.
Treatment of chronic heart failure
Since heart failure has been thought of as a mechanical treatment has necessarily been focused on achieving haemodynamic goals. This approach may seem logical because heart failure develops after an injury to the heart and can be alleviated with replacement of the heart (eg, by transplantation). However, as I described in my preceding article, the development and progression of heart failure result from a complex interplay of haemodynamic and neurohormonal factors, rather than simply changes in cardiac function. Therefore, the treatment of patients with heart failure should be directed, not to improving systolic performance, but to correcting the primary pathophysiological abnormalities of the circulation, and thus, to improving symptoms and prolonging life. In patients with left ventricular systolic dysfunction, the main pathophysiological features of heart failure are increased cardiac wall stress and increased neurohormonal activity. Both haemodynamic and neurohormonal forces contribute to symptoms and to progression of the underlying disorder. Therapeutic interventions designed to limit the adverse effects of these factors have met with variable success.
disorder, its
Drugs to reduce ventricular wall stress Several therapeutic agents produce haemodynamic benefits in heart failure by antagonising the three pathophysiological factors that contribute to an increase in ventricular wall stress: sodium retention (diuretics), peripheral vasoconstriction (direct-acting vasodilators), and reduced cardiac contractility (positive inotropic agents).
Diuretics Diuretics alleviate the sodium retention of heart failure by
inhibiting sodium and chloride reabsorption at specific sites in the renal tubules. Two classes of diuretic agents have been developed. Drugs that act on the distal tubules (thiazides and potassium-sparing diuretics) increase the fractional excretion of sodium only modestly (up to 5-10% of the filtered load), and they lose their effectiveness when renal function is impaired (when the glomerular filtration rate [GFR] decreases to below 30 ml/min). Agents that act on the loop of Henle (frusemide, ethacrynic acid, bumetanide, and piretanide) increase the fractional excretion of sodium (up to 25% of the filtered load), and they retain their effectiveness until GFR falls below 5 ml/min. Loop diuretics are preferred because of their greater efficacy. However, they may be combined with thiazides (especially
and potassium-sparing diuretics when additional sodium excretion or potassium conservation, respectively, is desired. Diuretics produce consistent haemodynamic and symptomatic benefits in patients with pulmonary or peripheral congestion. These drugs rapidly relieve dyspnoea and oedema, and their natriuretic action may enhance the responsiveness of peripheral blood vessels to direct-acting vasodilators and converting-enzyme inhibitors. Thus, diuretics had long been regarded as the cornerstone of treatment for heart failure. However, controlled clinical trials show diuretics alone cannot maintain the clinical stability of patients with chronic heart failure. Many patients whose symptoms are well controlled deteriorate clinically during long-term follow-up when treated with diuretics alone.2 Furthermore, diuretic use is associated with a high risk of electrolyte depletion (potassium and magnesium) that may predispose to the development of lethal ventricular
metolazone)
arrhythmias. Both the limited efficacy and potential toxicity of diuretic monotherapy seem to be related to drug-induced activation of the renin-angiotensin system. Diuretics are an important cause of increased plasma renin activity in heart failure,3 and angiotensin attenuates the haemodynamic effects and potentiates the potassium-losing effects of these agents. Both the risk of clinical deterioration and the adverse metabolic effects of diuretic therapy can be reduced by simultaneous treatment with a converting-enzyme inhibitor.2 These observations suggest that the efficacy and safety of treatment may be limited if it improves one of the central physiological abnormalities of heart failure (wall stress) but worsens the other (neurohormonal activation). This view has led to attempts to develop diuretic drugs with favourable neurohormonal effects-eg, the atriopeptidase inhibitors.’ By inhibiting the enzyme responsible for degradation of atrial natriuretic peptide, these experimental drugs increase the circulating and renal tubular concentrations of the peptide-the body’s own diuretic. These agents produce natriuretic effects that are accompanied by suppression (rather than augmentation) of plasma renin activity. Studies of the long-term efficacy of these drugs in heart failure are now under way. Division of Circulatory Physiology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA (Dr M Packer, MD). ADDRESS:
93
Direct-acting vasodilators Vasodilators can alleviate the peripheral vasoconstriction of heart failure via direct relaxation of vascular smooth muscle at specific sites in the peripheral circulation. Three classes of oral direct-acting vasodilators have been developed: those that act mainly on peripheral veins (nitrates and molsidomine); those that act mainly on peripheral arteries (hydralazine, minoxidil, and calcium channel blockers); and those with combined actions on both arteries and veins (flosequinan). Many direct-acting vasodilators also have inotropic effects-eg, cardiac contractility is enhanced after treatment with hydralazine or flosequinan and is depressed by calcium channel blockers. However, these direct cardiac effects are not thought to be
important clinically. Although all direct-acting vasodilators produce favourable short-term haemodynamic effects, many of these agents have limited long-term efficacy. Several controlled trials have been unable to show a favourable effect of nitrates or hydralazine on symptoms and exercise tolerance when added to conventional therapy.5 This lack of efficacy has been attributed to tolerance to the vasodilator effects of these drugs during their long-term use.6 Inconsistent results have been observed when these two vasodilators have been combined. Although a hydralazine-nitrate combination improved exercise tolerance in one large study,these drugs did not produce clinical benefits in another large trial, and their use was associated with a high frequency of adverse reactions.s Similarly, although the vasodilator combination tended to improve survival in one study, this effect was less than that achieved by a converting-enzyme inhibitor in a second trial.7 Furthermore, some direct-acting vasodilators may produce adverse effects in patients with chronic heart failure. In controlled trials, patients treated with minoxidil or calcium channel blockers (verapamil, nifedipine, and diltiazem) were at higher risk of worsening heart failure and cardiovascular death than patients not treated with these
drugs.9-11 of diuretics, both the limited efficacy and of potential toxicity direct-acting vasodilators may be related to the predilection of these drugs to activate endogenous neurohormonal systems. Nitrates and hydralazine increase the activity of the sympathetic nervous system and reninangiotensin system, which may blunt the haemodynamic effects of these drugs and contribute to tolerance.5 Longterm calcium channel blocker therapy is also accompanied by an increase in neurohormonal activity, which may be responsible for the poor clinical results with these agents.12 Such findings strengthen the notion that drugs may have limited value and cause considerable toxicity if they ameliorate one of the central pathophysiological abnormalities of heart failure (wall stress) but exacerbate the other (neurohormonal activation). To address these concerns, vasodilator drugs with favourable neurohormonal effects have been developed. Flosequinan exerts relaxant effects on both peripheral arteries and veins by interfering with the phosphoinositide pathway, and it reduces sympathetic outflow to the heart." By contrast with other direct-acting vasodilators, flosequinan has beneficial effects on symptoms and exercise tolerance, both in the presence and absence of convertingenzyme inhibitors.14 Similarly, amlodipine and felodipine are new calcium antagonists that decrease (rather than increase) the activity of the sympathetic nervous system. These calcium channel blockers, in contrast to others, have As in the
case
and exercise tolerance of patients with chronic heart failure in controlled studies." 16 The long-term effects of flosequinan, amlodipine, and felodipine are now being evaluated in large trials.
improved the symptoms
Positive inotropic agents
Positive-inotropic drugs reduce wall stress by augmenting the contractility of the failing heart. Two classes of positive inotropic agents have been developed: those that enhance cardiac contractility by increasing the concentration of intracellular cyclic AMP, either by augmenting its synthesis (beta-adrenergic agonists) or by inhibiting its degradation (phosphodiesterase inhibitors); and those that increase cardiac contractility by cyclic-AMPindependent mechanisms--eg, Na+ - K+ -ATPase inhibition (digitalis). Of the two types of agents, cyclic AMPdependent agents produce a greater reduction in wall stress because they dilate peripheral blood vessels in addition to enhancing contractile force. Furthermore, these agents tend to correct the deficient production of myocardial cyclic AMP in the failing heart, which may be an important cause of contractile dysfunction.17 However, despite their favourable effects on wall stress, cyclic-AMP-dependent positive inotropic agents have not produced consistent benefits in controlled clinical trials. Neither beta-agonists nor phosphodiesterase inhibitors improve symptoms and exercise tolerance of patients with heart failure, and long-term treatment with these drugs is associated with increases in cardiovascular morbidity and mortality. 18,19 These results have raised fears that all types of positive inotropic agents have similar limitations. However, digitalis glycosides are consistently beneficial to patients with heart failure. Long-term therapy with digoxin reduces symptoms, prolongs exercise tolerance, and decreases the risk of clinical deterioration. 12021 These benefits extend to patients with mild or severe symptoms and are found irrespective of treatment with converting-enzyme inhibitors. Why should the results with digitalis differ from those with other positive inotropic agents? Unlike cyclicAMP-dependent drugs, digitalis reduces activation of both the sympathetic nervous system and the renin-angiotensin system. This favourable neurohormonal effect is achieved independently of the drug’s haemodynamic actions, and depends on the drug’s ability to correct the baroreflex dysfunction of heart failure, so restoring the inhibitory effect of cardiac baroreceptors on sympathetic outflow from the central nervous system.22 By contrast, phosphodiesterase inhibitors potentiate (rather than attenuate) the effects of the sympathetic nervous system on the heart. 17 Hence, as with vasodilators, differences in the efficacy and safety of positive inotropic agents may relate to their neurohormonal actions. New types of inotropic agents are being evaluated. Pimobendan enhances cardiac contractility by increasing the sensitivity of myofilaments to calcium; vesnarinone increases the delivery of calcium to myofilaments by enhancing sodium influx into cells. Both agents may alleviate the symptoms of heart failure, but since they are also phosphodiesterase inhibitors, their long-term safety remains uncertain.
Drugs that reduce neurohormonal activity Two types of drug have been developed: those interfering with the renin-angiotensin system (eg, converting-enzyme inhibitors) and those acting on the sympathetic nervous system (eg, beta-blockers).
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Angiotensin converting-enzyme inhibitors Several controlled clinical trials have shown that converting-enzyme inhibitors produce consistent clinical improvement in patients with chronic heart failure.5 They have long-term haemodynamic effects that are more favourable than those found with other agents and tolerance rarely develops during treatment. They also produce symptomatic benefits that are greater than most vasodilators;"," dyspnoea is relieved, exercise tolerance is prolonged, and the risk of worsening heart failure is reduced. Most importantly, converting-enzyme inhibitors extend life in patients with chronic heart failure, and the size of this effect exceeds that of other therapeutic interventions.7,25,26 These haemodynamic, symptomatic, and prognostic benefits of converting-enzyme inhibitors are seen in patients with mild, moderate, and severe symptoms. These drugs also reduce the mortality rate and the risk of haemodynamic and clinical progression in symptom-free patients with left ventricular dysfunction following an acute myocardial infarction (personal communication, M. Pfeffer).27 Why should converting-enzyme inhibitors have such striking effects? The answer probably lies in their dual actions on both the haemodynamic and neurohormonal mechanisms of heart failure. These drugs attenuate the progressive ventricular dilatation that develops after an acute myocardial injury, and thus they can prevent the structural remodelling that develops after prolonged increases in ventricular wall stress.28 Converting-enzyme inhibitors also reduce the direct toxic effects of angiotensin on myocardial cells, which may lead to cell necrosis, replacement fibrosis, and disease progression.29 Which mechanism is more important in the clinical setting? Two lines of evidence suggest that the beneficial effects of the converting-enzyme inhibitors relate to their neurohormonal actions. First, in two large survival trials,725 convertingenzyme inhibitors reduced mortality mainly among patients who had the most striking neurohormonal activation at the time of starting treatment. Second, converting-enzyme inhibitors reduce mortality to a greater extent than directacting vasodilators even though the latter produce superior haemodynamic effects.7 Drugs that interfere with the activity of renin (renin inhibitors) or with the interaction of angiotensin II and its receptor (angiotensin antagonists) are now being developed. Unlike converting-enzyme inhibitors, these new approaches do not lead to the accumulation of kinins, and so should be less likely to produce some of the side-effects (eg, cough and angio-oedema) associated with existing agents.
Beta-adrenergic antagonists If neurohormonal activation were important in heart failure, drugs that antagonise actions of the sympathetic nervous system might be helpful. Although alphaadrenergic antagonists (eg, prazosin) produce short-term haemodynamic improvements, their long-term use does not favourably affect symptoms, exercise tolerance, or survival;88 this lack of benefit may relate
to
activation of the renin-
angiotensin system.23 Similarly, although beta-adrenergic antagonists (eg, metoprolol and propranolol) have favourable effects on symptoms of patients with an idiopathic dilated cardiomyopathy and on the survival of patients with heart failure secondary to ischaemic heart disease ’30,31 treatment is associated with a substantial risk (5-20%) of worsening heart failure. This risk is probably related to the negative inotropic effects of these drugs.
To obviate this limitation, sympathetic inhibitors with favourable haemodynamic and neurohormonal effects are being developed. Among the most promising agents are new beta-blockers that dilate peripheral blood vessels either
directly (eg, bucindolol) or through alpha-adrenergic antagonism (eg, carvedilol).32 Both drugs have produced beneficial long-term haemodynamic and clinical effects in controlled trials with only a small risk of adverse receptor
cardiovascular reactions.
Conclusion The results of controlled clinical trials reinforce the view that heart failure is both a haemodynamic and a neurohormonal disorder. Drugs can produce favourable haemodynamic effects by reducing ventricular wall stress, but benefits are unlikely to be sustained if these agents activate endogenous neurohormonal systems (eg, directacting vasodilators). Similarly, drugs can exert beneficial neurohormonal actions by antagonising the effects of either the sympathetic nervous system or renin-angiotensin system, but these are unlikely to be well-tolerated if they also depress cardiac function (eg, beta-blockers). Ideally, therapeutic interventions in heart failure should produce favourable effects on both haemodynamic and neurohormonal systems (eg, converting-enzyme inhibitors). Such drugs improve symptoms and prolong life (table). Overall, these data support the use of converting-enzyme inhibitors in all patients with heart failure, irrespective of the severity of symptoms. In patients with symptom-free left ventricular dysfunction, these drugs delay development of heart failure. In patients with symptoms of pulmonary or peripheral congestion, they potentiate the clinical effects and limit the adverse effects of diuretics. These benefits are accompanied by a reduction in morbidity and mortality. If symptoms persist despite the combination of a diuretic and a converting-enzyme inhibitor, physicians should add agents that diminish the haemodynamic and neurohormonal derangements of heart failure (eg, digitalis). Additional choices that are or will soon be commercially available include flosequinan, carvedilol, amlodipine, and felodipine. If all of these interventions fail, clinical stability may only be achieved with mechanical including solutions,
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cardiomyoplasty, left ventricular assist devices, and cardiac transplantation. Future research on the mechanisms of heart failure should yield promising new treatments. These may include novel vasoconstrictor antagonists (eg, of vasopressin and
endothelin) and cytoprotective agents (eg, free radical scavengers or cytokine inhibitors). REFERENCES 1. Sinoway L, Minotti J, Musch T, et al. Enhanced metabolic vasodilation secondary to diuretic therapy in decompensated congestive heart failure secondary to coronary artery disease. Am J Cardiol 1987; 60: 107-11. 2. The Captopril-Digoxin Multicenter Research Group. Comparative effects of captopril and digoxin in patients with mild to moderate heart
failure. JAMA 1988; 259; 539-44. 3. Francis GS, Benedict C, Johnstone DE,
et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. Circulation 1990; 82: 1724-29. 4. Northridge DB, Jardine AG, Finlay IN, Archibald H, Dilly SG, Dargie HJ. Inhibition of the metabolism of atrial natriuretic factor causes diuresis and natriuresis in chronic heart failure. Am J Hypertension 1990; 3: 682-87. 5. Packer M. Vasodilator and inotropic drugs for chronic heart failure: distinguishing hype from hope. J Am Coll Cardiol 1988; 12: 1299-317. 6. Packer M, Gottlieb SS, Kessler PD, Medina N, Yushak M. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med 1987; 317: 799-804. 7. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303-10. 8. Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med 1986; 314: 1547-52. 9. Franciosa JA, Jordan RA, Wilen MM, Leddy CL. Minoxidil in patients with left heart failure: contrasting hemodynamic and clinical effects in a controlled trial. Circulation 1984; 70: 63-69. 10. Elkayam U, Amin J, Mehra A, Vasquez J, Weber L, Rahimtoola SH. A prospective, randomized, double-blind, crossover study to compare the efficacy and safety of chronic nifedipine therapy to isosorbide dinitrate and their combination in the treatment of chronic congestive heart failure. Circulation 1990; 82: 1954-61. 11. Goldstein RE, Boccuzzi SJ, Cruess D, Nattel S, the Adverse Experience Committee, and the Multicenter Diltiazem Post-Infarction Research Group. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. Circulation 1991; 83: 52-60. 12. Packer M. Pathophysiologic mechanisms underlying the adverse effects of calcium channel blocking drugs in patients with chronic heart failure. Circulation 1989; 80 (suppl IV): 59-67. 13. Binkley PF, Nunziata E, Hatton P, Proicou G, Cody RJ. Flosequinan augments parasympathetic tone and attenuates sympathetic drive in congestive heart failure: demonstration by analysis of heart rate variability. J Am Coll Cardiol 1992; 19: 147A. 14. Elborn JS, Stanford CF, Nicholls DP. Effect of flosequinan on exercise capacity and symptoms in severe heart failure. Br Heart J 1989; 61: 331-35. 15. Packer M, Nicod P, Khandheria BR, et al. Randomized, multicenter, double-blind, placebo-controlled evaluation of amlodipine in patients with mild-to-moderate heart failure. J Am Coll Cardiol 1991; 17: 274A. 16. Dunselman PHJM, Kuntze CEE, van Bruggen A, et al. Efficacy of felodipine in congestive heart failure. Eur Heart J 1989; 10: 354-64. 17. Feldman MD, Copelas L, Gwanthmey JK, et al. Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end-stage heart failure. Circulation 1987; 75: 331-39. 18. Xamoterol in Severe Heart Failure Study Group. Xamoterol in severe heart failure. Lancet 1990; 336: 1-6. 19. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991; 325: 1468-75. 20. DiBianco R, Shabetai R, Kostuk W, et al. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. N Engl J Med 1989; 320: 677-83. 21. Packer M, Gheorghiade M, Young JB, et al. Randomized, double-blind, placebo-controlled, withdrawal study of digoxin in patients with chronic heart failure treated with converting-enzyme inhibitors. J Am Coil Cardiol 1992; 19: 260A.
Ferguson DW, Berg WJ, Sanders JS, Roach PJ, Kempf JS, Kienzle MG. Sympatho-inhibitory responses to digitalis glycosides in heart failure patients: direct evidence from sympathetic neural recordings. Circulation 1989; 80: 65-77. 23. Bayliss J, Noreel MS, Canepa-Anson R, Reid C, Poole-Wilson P, Sutton G. Clinical importance of the renin-angiotensin system in chronic heart failure: double-blind comparison of captopril and prazosin. Br Med J 22.
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Agostoni PG, DeCesare N, Doria E, Polese A, Tamborini G, Guazzi MD. Afterload reduction: a comparison of captopril and nifedipine in dilated cardiomyopathy. Br Heart J 1986; 55: 391-99. 25. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure; results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J 24.
Med 1987; 316: 1429-35. 26. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293-302. 27. Sharpe N, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet 1988; i: 255-59. 28. Pfeffer MA, Lamas GA, Vaughn DE, et al. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988; 319: 80-86. 29. Tan LB, Jalil JE, Pick R, Janicki JS, Weber KT. Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991; 69: 1185-95. 30. Englemeier RS, O’Connell JB, Walsh R, Rad N, Scanlon PJ, Gunnar RM. Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Circulation 1985; 72: 536-46. 31. Chadda K, Goldstein S, Byington R, Curb JD. Effect of propranolol after acute myocardial infarction in patients with congestive heart failure. Circulation 1986; 73: 503-10. 32. Gilbert EM, Anderson JL, Deitchman D, et al. Long-term &bgr;-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy: a double-blind, randomized study of bucindolol versus placebo. Am J Med 1990; 88: 223-29.
From The Lancet An old solution Handled jugs are often found in excavations on medieval sites.... These... jugs were commonly used in drawing water from the courtyard well, in drawing wine from casks and storing it in the cellar cupboards, and were in frequent use to serve wine at the table. A different purpose is evident for a jug... found about 1903 on the site of the Green Dragon Inn at Hertford.... The inside surface of the jug is covered with a pale buff incrustation, thick and granular on the body of the vessel, thinner and smooth towards the narrow neck.... The pale buff amorphous deposit... consists mainly of sodium urate, which is at times deposited from acid urines, usually adsorbing much urinary pigment on the surface of its particles as it settles.... A solution of the deposit in dilute hydrochloric acid gave a yellow-green fluorescence and a spectrum absorption band in the region of 500 urn, both characteristic of excreted pigments resulting from the normal physiological breakdown of blood pigment. This is a striking illustration of the stability of these pigments, and points to the urinary origin of the deposit. No chlorides or phosphates could be detected and although the concentration of these in the urine may be depressed in certain pathological conditions, such as high fever, this finding taken in conjunction with the presence of sodium urate and the urobilinoid pigment, which indicate that no heat has been applied, gives a fairly adequate proof that it is a urinary deposit and not the medieval "sal urinae", and that it resulted from the evaporation to dryness of the urine contained in the jug... it might be concluded that the vessel had been in use for some time simply as a urinal, but urinals were not introduced until much later. It is more likely that the jug was used for storing urine, the drinking of which was highly recommended in the Middle Ages as a remedy for plague and various ailments.
(July 11, 1942)
