Manipulating afterload for the treatment of acute heart failure

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For decades, digitalis and diuretics presented as the mainstay of the con- ventional treatment of heart failure.

In the late 1960s, however, the use of positive inotropic agents was recon- sidered on account of several studies demonstrating a poor hemodynamic response to digitalis and arrhythmo- genic effects in patients with coronary disease. The beneficial effect of diuretics in relieving pulmonary congestion and acute pulmonary edema was clearly established. But, it was also shown that excessive use could be deleterious, leading to electrolyte imbalance, hypovolemia, low cardiac output and shock.

Before the introduction of bedside hemodynamic investigation in the early 1970s, the assessment of ventricular performance in man was essentially clinical and radiological. In patients with acute left ventricular failure, successive chest X-rays were used to demonstrate a reduction in cardiac size or a clearing of pulmonary congestion. In view of the use- fulness of assessing ventricular function in experimental animals by relating filling pressure to ventricular performance during volume expan- sion, it was thought that a similar ap- proach in man might be of interest.

But the method appeared not to be convenient due to reflex adjustments to the change in blood volume.

In 1964, an important paper, by John Ross and Eugene Braunwald, was published in Circulation [1] de-

scribing a new method to evaluate left ventricular function by increasing resistance to ventricular ejection.

They investigated the ventricular response to graded infusions of angiotensin in patients with and without clinical evidence of impaired left ventricular function. The method used consisted in simultaneous mea- surements of left ventricular pressure, obtained by transseptal left heart catheterization, and cardiac output determined by the indicator- dilution technique. It was thus possi- ble to construct individual function curves while relating stroke work to filling pressure and to compare the response to a progressive increase in resistance to ventricular ejection.

It appeared that, in patients with normal or near normal left ventricular function, there was a steep increase in ventricular stroke work with small elevations in left ventricular end- diastolic pressure. By contrast, in patients with signs of a markedly depressed functional capacity, the initial limb of the curve was flat or even descending, demonstrating a fall in cardiac index and stroke volume as the arterial blood pressure and left ventricular filling pressure rose.

This study was of primary importance for understanding heart function in disease. It demonstrated that the left ventricular response to increased resistance to ejection was highly dependent of its function: in Claude Perret

Jean-François Enrico

Manipulating afterload for the treatment of acute heart failure

A historical summary

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normal hearts stroke work increased with the augmented afterload so that stroke volume was maintained constant; by contrast, in severely depressed hearts, stroke volume decreased with any increase in aortic pressure. Surprisingly, this new con- cept did not give rise to the potential implications it contained for clini- cians and apparently none raised the question: if an increase in resistance to ventricular ejection worsens ventricular performance, might its reduction be used to improve this?

Our personal experience with vasodilators for the treatment of severe acute left ventricular failure began in the early 1960s, with an erroneous diagnosis. It concerned a 60-year-old patient who was hospi- talized in the ICU of the university medical department for severe acute pulmonary edema. Upon admission, he was tachypneic and cyanotic.

Blood pressure was extremely unsta- ble oscillating between 150 and 240 mmHg of systolic and 100 and 140 of diastolic pressures. There were signs of intense peripheral vasoconstriction with a cold and clammy skin. Electrocardiogram showed sinus tachycardia with fre- quent supraventricular ectopic beats and diffuse T wave inversions. Chest X-ray demonstrated marked pulmonary venous congestion and enlarged cardiac silhouette. The patient was immediately treated with high con- centrations of oxygen, diuretics and digitalis. The response was poor.

Hypertension and tachypnea persisted with signs of clinical shock.

A pheochromocytoma was sus- pected and an intravenous infusion of phentolamine, an agent with adrenergic and sympathetic blockade prop- erties, was initiated in an attempt to correct hypertension. The drug produced an immediate and dramatic clinical improvement: peripheral signs of shock subsided, blood pressure progressively normalized and pulmonary venous congestion im- proved. The infusion was progressively discontinued and the patient re- covered uneventfully. The beneficial

response to phentolamine with a positive test for catecholamines in a sample of urine collected during the hypertensive crisis made likely the diagnosis of pheochromocytoma but all subsequent urinary tests were neg- ative. The diagnosis could not be confirmed and the excessive excretion of urinary catecholamines was attributed to an intense and temporary drive in sympathetic activity related to acute left ventricular failure.

The surprising benefit obtained with phentolamine infusion in a patient with acute pulmonary edema lead us to investigate further the role of vasodilation in left ventricular failure [2]. Seven patients were stud- ied, five of whom had a history of acute myocardial infarction. All were admitted to the intensive care unit for refractory acute pulmonary edema, associated with hypertension in six. Arterial blood gas analysis with repeated lactate determinations were used as an index of severity of the patient’s condition. Upon admission, all patients demonstrated marked hypoxemia in spite of oxygen therapy (SaO₂: 56–76%) and severe metabolic acidosis (pH: 7.08–7.33) with a mean lactate concentration of 6.4 mEq/l, indica- tive of severe tissue anoxia. Phento- lamine was administered by a constant infusion at a dose varying between 5 and 20 mg/h. The response was rapid, characterized by the dis- appearance of pulmonary edema, the normalization of arterial blood and central venous pressures and the complete correction of lactic acidosis in a few hours. The series was ex- tended to include finally a total of 15 patients with the same clinical and metabolic response [3]. All patients survived.

These results attested to an important improvement in tissue perfu- sion after vasodilator administration and were attributed to a decreased systolic load due to the fall in systemic resistance combined with bet- ter distribution of peripheral perfu- sion following the relief of excessive adrenergic vasoconstriction.

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As a matter of fact, Taylor et al.

[4] had already investigated the circulatory effects of the acute intravenous injection of phentolamine in normal subjects and in patients with hypertensive disease. The intravenous administration of 5 mg of the drug was shown to produce a prompt reduction in systemic vascular resistance. This resulted in a rapid fall in systemic blood pressure associated with a significant increase in heart rate and cardiac output without large or consistent changes in stroke volume. The response was essentially the same in both groups of subjects, although the time course of their response was different, being significantly slower in the hypertensive group. It was concluded that the pre- dominant vascular activity of phentolamine was to cause a direct relax- ation of vascular smooth muscle on the resistance vessels of the systemic circulation. The drug also developed a moderate antagonism to circulating catecholamines with a weak sympathetic blocking activity.

Considering the circulatory effects of phentolamine observed in normal subjects, it could be assumed that such a vasodilation in patients with acute left ventricular failure would be of particular benefit. It had been previously shown that the onset of pump failure was associated with two “compensatory” mechanisms: a reflex vasoconstriction in systemic vessels causing an increase in left ventricular workload and myocardial oxygen demand and a redistribution of blood volume towards the heart and the lungs. It could then be assumed that pharmacological vasodilation would improve ventricular ejection and possibly produce a shift of blood from the lungs to the pe- riphery by reducing venous tone.

These hypotheses were fully confirmed by Majid, Sharma and Taylor in an article published in the Lancet [5] a few months after our initial presentation. In a series of 12 patients with severe acute or subacute left ventricular failure due to ischemic heart disease, phentolamine 280

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was administered by intravenous infusion. The initial dose was 5 mg/min for 1 min followed by a dose adjusted in each subject to reduce the supine mean systemic arterial pressure by approximately 25 mmHg. The fall in blood pressure produced rapid relief of dyspnea associated with a progressive clearing in pulmonary edema and a significant reduction of heart size, as we had described. But most interesting was the hemodynamic response observed in the group of patients with severe heart failure: phentolamine infusion produced a rapid and substantial reduction in left ventricular end-diastolic and pulmonary-artery mean pressures associated with an increase in stroke volume and cardiac output. These benefits in ventricular performance were attributed essentially to two mechanisms: the reduction in cardiac pressure load obtained by lowering the raised vascular resistance and an increase in the capacity of the peripheral vessels, particularly the veins, which reduced the volume of blood in the dilated heart. A reflex increase in sympathetic activity secondary to the fall in systemic blood pressure could not be definitively discarded. But the ab- sence of significant change in heart rate made an increase in inotropic activity unlikely.

This study was the first to use sophisticated left and right catheterization techniques to measure the response of cardiac output and filling pressures to peripheral vasodilation.

It demonstrated the therapeutic value of reducing systemic vascular resistance in patients with severe left ventricular failure. It showed that relief of the workload of a failing heart could provide significant clinical benefit with apparently no hazard to the cerebral and coronary circula- tions.

During the early 1970s, several studies demonstrated that the inci- dence and severity of left ventricular failure complicating acute myocardial infarction were directly related to the extent of ventricular mass necrosis.

Consequently the ideal therapy would minimize myocardial oxygen demand and raise oxygen delivery to the ischemic area. On a theoretical basis, one could expect that phentolamine, as well as other vasodilators, might improve heart pump function without interfering adversely with the myocardial oxygen metabolism.

In 1973, Kelly et al. [6] used phentolamine to decrease arterial blood pressure in 11 hypertensive patients with acute myocardial infarction and left ventricular dysfunction. Six had a history of chronic hypertension confirmed by ophthal- moscopy and electrocardiographic signs of left ventricular hypertrophy.

The remaining five had no previous history of hypertension. The hemodynamic response to low doses of phentolamine was similar to those previously described with a significant decline in arterial and pulmonary capillary wedge pressures and a concomitant increase in cardiac index. Interestingly, as stroke work index and heart rate were unchanged, the rate-pressure time product thought to be a reasonable index of myocardial oxygen consumption decreased significantly in the group with acute hypertension. The conclusion was that, in such conditions of acute hypertension, reduction of left ventricular afterload might offer ad- vantages over current therapy for left ventricular dysfunction.

A few months later another clinical investigation was published in the same journal by Chatterjee et al.

[7] from the group of Cedars-Sinai Medical Center in Los Angeles, de- scribing the hemodynamic and metabolic responses to vasodilator therapy in patients with acute myocardial infarction. Thirty-eight patients were examined and were divided in three groups according to the severity of left ventricular failure estimated on the initial level of pulmonary capillary wedge pressure and stroke work index. In group III (15 patients) all had clinical evidence of left ventricular failure, 14 had frank pulmonary edema and 8 had clinical features of 366

shock. In 11 patients, phentolamine was used: 5 mg were administered intravenously in the first minute then at a rate of 0.1–0.2 mg/min. In the remaining 27 patients, sodium nitroprusside was infused at a rate of 16–200µg/min. The infusion of the vasodilator was gradually increased until the mean arterial blood pressure decreased by not more than

20 mmHg or when there was a significant decrease in pulmonary capillary wedge pressure. Pressures and cardiac output were measured with a balloon-tip triple lumen catheter us- ing the thermodilution technique.

Coronary sinus flow was determined by the constant infusion technique.

The myocardial extraction ratio for lactate was calculated from arterial and coronary sinus blood samples.

The study showed that the hemodynamic response to phentolamine or nitroprusside was identical to that re- ported previously. But it also demonstrated that the benefit in heart performance was greater in those patients with the most severely depressed cardiac function. The functional improvement was obtained without any increase in metabolic cost. Myocar- dial oxygen demand either remained unchanged or even, in some cases, fell and myocardial lactate extraction did not decrease. Therefore, it appeared that vasodilator therapy might well play an important role in the treatment of pump failure following myocardial infarction.

These expectations were confirmed in another hemodynamic study performed in a series of 15 patients with acute myocardial infarction [8]. It was shown that with a dose of 10 mg/h, phentolamine could be used in normotensive patients without adverse effects; the fall of mean arterial blood pressure was less than 15 mmHg and was associated with a significant increase in cardiac output and a substantial reduction in right and left filling pressures. The overall clinical course appeared surprisingly good with a mortality rate of 13% in a group of high-risk patients.

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In conclusion, for years the therapy of congestive heart failure had focused on trying to influence the factors which at that time were rec- ognized as the determinants of myocardial function, such as reducing the diastolic filling of the ventricle with diuretics or increasing its con- tractility with inotropic drugs. In the early 1960s, several studies demonstrated that the diseased left ventricle was highly dependent on peripheral vascular factors, which had been hitherto relatively neglected. In the normal heart, an increased impedance to ventricular ejection was well tolerated and did not change stroke volume. In the presence of left ventricular dysfunction, an enhanced impedance could lead to a decrease in cardiac output with an increase in ventricular volume and pressure.

This abnormal response appeared of particular importance when it was

shown that heart failure itself produced an arteriolar vasoconstriction and different alterations in vascular wall structure, which increased impedance to ventricular outflow and thus further deteriorated ventricular performance. The pharmacological reduction of impedance with the use of vasodilator drugs led to a new ap- proach. It has proved to be a most important adjunction in the management of both acute and chronic heart failure [9].

References

1. Ross J, Braunwald E (1964) The study of left ventricular function in man by increasing resistance to ventricular ejection with angiotensin. Circulation 29:739–749

2. Enrico JF, Poli S, Grandjean T, Perret C (1971) Utilité de la phentolamine dans le traitement de l’oedème pulmonaire aigu. Schweiz Med Wochenschr 9:325–328

3. Enrico JF, Poli S, Perret C (1971) La phentolamine dans le traitement de l’oedème aigu “réfractaire”. Bull Physio-Path Respir 7:1319–1340 4. Taylor SH, Sutherland GR, MacKenzie

GJ, Staunton HP, Donald KW (1965) The circulatory effects of intravenous phentolamine in man. Circulation 31:741–754

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5. Majid PA, Sharma B, Taylor SH (1971) Phentolamine for vasodilator treatment of severe heart failure. Lancet 2:719–724

6. Kelly DT, Delgado CE, Taylor DR, Pitt B, Ross RS (1973) Use of phentolamine in acute myocardial infarction associated with hypertension and left ventricular failure. Circulation 47:729–735 7. Chatterjee K, Parmley WW, Ganz W,

Forrester J, Walinsky P, Crexells C, Swan HJC (1973) Hemodynamic and metabolic responses to vasodilator therapy in acute myocardial infarction. Cir- culation 48:1183–1193

8. Perret C, Gardaz JP, Reynaert M, Grimbert F, Enrico JF (1975) Phento- lamine for vasodilator therapy in left ventricular failure complicating acute myocardial infarction. Haemodynamic study. Br Heart J 37:640–646

9. ACC/AHA Guidelines for the evalua- tion and management of chronic heart failure in the adult: executive summary (2001). Circulation 104:2996–3007 282