Milton Packer

Prognostic importance of atrial natriuretic peptide in patients with chronic heart failure

Several circulating neurohormones have been shown to have prognostic significance in patients with chronic heart failure, but the relation between plasma levels of atrial natriuretic peptide and mortality in this disorder remains unknown. Plasma levels of immunoreactive atrial natriuretic peptide were measured in 102 patients in whom left ventricular ejection fraction, ventricular arrhythmias on ambulatory electrocardiographic recording and plasma levels of norepinephrine, renin activity, aldosterone and arginine vasopressin were also measured. Compared with patients with atrial natriuretic peptide concentrations below the median value of 125 pg/ml, patients with higher levels of the peptide had a higher plasma renin activity (8.9 +/- 1.8 versus 2.6 +/- 0.4 ng/ml per h) and plasma norepinephrine (858 +/- 116 versus 538 +/- 45 pg/ml), more frequent premature ventricular depolarizations (4,485 +/- 715 versus 2,004 +/- 495/day) and more advanced hemodynamic abnormalities (all p less than 0.05). During the subsequent 13 to 25 months of follow-up, patients with high levels of atrial natriuretic peptide had a significantly lower rate of survival than did those whose initial circulating peptide concentrations were normal or mildly increased (p = 0.01). These data indicate that, in patients with chronic heart failure, plasma atrial natriuretic peptide provides important prognostic information. This may relate to the ability of the hormone to reflect the interplay of several pathophysiologic factors that contribute to mortality in this disease.

Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril.

OBJECTIVESnThis study attempted to evaluate whether neurohumoral activation at the time of hospital discharge in postinfarction patients helps to predict long-term prognosis and whether long-term therapy with the angiotensin-converting enzyme inhibitor captopril modifies this relation.nnnBACKGROUNDnNeurohumoral activation persists at the time of hospital discharge in a large number of postinfarction patients. The Survival and Ventricular Enlargement (SAVE) study demonstrated that the angiotensin-converting enzyme inhibitor captopril improves survival and decreases the development of severe heart failure in patients with left ventricular dysfunction (left ventricular ejection fraction < or = 40%) but no overt postinfarction heart failure.nnnMETHODSnIn 534 patients in the SAVE study, plasma neurohormone levels were measured a mean of 12 days after infarction. Patients were then randomized to receive captopril or placebo and were followed up for a mean (+/- SD) of 38 +/- 6 months (range 24 to 55). The association between activation of plasma neurohormones at baseline and subsequent cardiovascular mortality or the development of heart failure was assessed with and without adjustment for other important prognostic factors.nnnRESULTSnBy univariate analysis, activation of plasma renin activity and aldosterone, norepinephrine, atrial natriuretic peptide and arginine vasopressin levels were related to subsequent cardiovascular events, whereas epinephrine and dopamine levels were not. By multivariate analysis, only plasma renin activity (relative risk 1.6, 95% confidence interval [CI] 1.0 to 2.5) and atrial natriuretic peptide (relative risk 2.2, 95% CI 1.3 to 3.8) were independently predictive of cardiovascular mortality, whereas the other neurohormones were not. Only plasma renin activity and aldosterone, atrial natriuretic peptide and arginine vasopressin were independent predictors of the combined end points of cardiovascular mortality, development of severe heart failure or recurrent myocardial infarction. Except for 1-year cardiovascular mortality, the use of captopril did not significantly modify these relations.nnnCONCLUSIONSnNeurohumoral activation at the time of hospital discharge in postinfarction patients is an independent sign of poor prognosis. This is particularly true for plasma renin activity and atrial natriuretic peptide. Except for 1-year cardiovascular mortality, captopril does not significantly modify these relations.

Hemodynamic and clinical tachyphylaxis to prazosin-mediated afterload reduction in severe chronic congestive heart failure.

Sequential doses of 5 mg of oral prazosin hydrochloride were administered to eight patients with severe chronic congestive heart failure refractory to conventional therapy. Initial doses of the drug produced marked increases in cardiac index (+0.87 I/min/m2) associated with substantial decreases in left ventricular filling pressure (-10.7 mm Hg), total systemic vascular resistance (2118 to 1154 dyn-sec-cm-5), and heart rate (89 to 76 beats/min). However, serial administration of the same dose at 12-24-hour intervals was accompanied by the rapid development of tachyphylaxis, such that the magnitude of hemodynamic effects with second doses was less than 50% of the magnitude of effects seen with first doses (p < 0.01), and third doses produced no overall significant hemodynamic responses. Diuresis with furosemide failed to restore the circulatory effects of prazosin, and the use of 10-mg doses improved cardiovascular performance to only a small extent. Only two of eight patients had sustained hemodynamic responses large enough to justify chronic oral ambulatory therapy. Administration of oral hydralazine caused hemodynamic improvement superior to even high-dose prazosin therapy (p < 0.02).

Hemodynamic and clinical limitations of long-term inotropic therapy with amrinone in patients with severe chronic heart failure.

To determine the hemodynamic and clinical effects of long-term positive inotropic stimulation on the myocardium, we treated 31 patients with severe chronic heart failure with oral amrinone (600 mg daily) and performed invasive hemodynamic studies during short- and long-term treatment with the drug. Stroke volume and stroke work indexes increased markedly during the first 48 hr of therapy (p less than .01) but returned to pretreatment values after 2 to 10 weeks; upon drug withdrawal, both variables deteriorated rapidly to values significantly lower than those observed before treatment with amrinone (p less than .01), despite similar values for left ventricular filling pressure, mean arterial pressure, and systemic vascular resistance. This pattern of response indicated that progression of the underlying heart disease had occurred during treatment with amrinone and contributed importantly to its failure to produce long-term benefits. Progression of left ventricular dysfunction was associated with a progressive increase in heart rate and plasma renin activity and a decline in serum sodium concentration. Clinically, amrinone therapy was complicated by sustained symptomatic ventricular tachycardia in four patients, worsening myocardial ischemia in four patients, and worsening congestive heart failure in eight patients, all of whom had been stable before entry into the study; only three of the 31 patients improved clinically. Ten patients died during the first 2 weeks of treatment, and 16 (52%) were dead within 3 months, a mortality rate twice as great as that seen during comparable trials with vasodilating drugs. Although noncardiac adverse effects were frequent, they were not the primary reason for drug failure. In conclusion, long-term therapy with amrinone may accelerate progression of left ventricular dysfunction, exacerbate myocardial ischemia, and provoke life-threatening ventricular tachyarrhythmias, thereby shortening survival in patients with severe chronic heart failure. Prolonged administration of inotropic drugs may achieve short-term gains at the expense of long-term detrimental effects on the myocardium.

Hemodynamic changes mimicking a vasodilator drug response in the absence of drug therapy after right heart catheterization in patients with chronic heart failure.

We suspected that patients with severe chronic heart failure may show hemodynamic changes after cardiac catheterization in the absence of drug therapy that could complicate assessment of the hemodynamic effects of new vasodilator and inotropic agents. To evaluate this phenomenon prospectively, hemodynamic variables were measured in 21 patients with heart failure 30 min and 2, 6, 24, and (in 12 patients) 48 hr after right heart catheterization, during which time therapy was not altered. During the first 2 hr we noted a significant increase in cardiac index and decreases in left ventricular filling pressure, mean arterial pressure, mean right atrial pressure, and systemic vascular resistance (p less than .01); a further decline in left ventricular filling pressure was noted over the next 24 hr, after which all hemodynamic variables remained stable. The magnitude of these hemodynamic changes resembled the effects of many established vasodilator drugs and was further enhanced after meals. These data indicate that hemodynamic improvement may be observed without any therapeutic intervention during the course of invasive studies in patients with severe chronic heart failure; such changes may lead investigators to attribute efficacy to ineffective drug therapy. To minimize the occurrence of such responses, we recommend that intravascular catheters be inserted the day before drug evaluation and that hemodynamic measurements be made with patients in a postprandial state.

Vasodilator and inotropic therapy for severe chronic heart failure: passion and skepticism.

Although substantial progress has been made in the last 5 years in the development of vasodilator and inotropic drugs for the management of patients with severe chronic heart failure, much of the enthusiasm that surrounded the introduction of many of these agents has subsequently been tempered by reports of drug failure or adverse reactions. In this review and analysis, currently available vasodilator and inotropic agents are critically and comparatively evaluated to assess their respective advantages and limitations. It is apparent that the ability of most of these drugs to produce substantial clinical benefits in patients with severe heart failure has probably been overstated. Therapy fails to achieve the desired clinical results all too frequently, possibly as the result of: the choice of an ineffective drug; the administration of an effective drug in subtherapeutic doses; the administration of an effective drug to improperly selected patients; the failure of initial hemodynamic benefits to be sustained; the occurrence of severe or serious adverse reactions; and the failure to alter concomitant therapy appropriately. The present analysis indicates that there is no uniformly effective or safe vasodilator or inotropic drug for patients with severe heart failure; all agents have important limitations. Of the available therapeutic choices, however, long-term converting enzyme inhibition appears to produce more consistent hemodynamic and clinical benefits with an acceptable degree of adverse reactions than other pharmacologic approaches for the management of these severely ill patients.

Hemodynamic patterns of response during long-term captopril therapy for severe chronic heart failure.

To determine the relationship between the early and late hemodynamic effects of captopril in patients with severe heart failure, we performed serial right heart catheterizations in 51 such patients who were treated with the drug for 2 to 8 weeks. Four hemodynamic patterns of response were observed. Nine patients had minimal responses initially (type I); six failed to improve during long-term treatment, but three showed delayed hemodynamic benefits. Twenty-eight patients had initial beneficial drug effects that were sustained after 48 hr and after 2 to 8 weeks (type II). In seven patients, first doses of captopril produced marked beneficial responses, but these became rapidly attenuated after 48 hr; nevertheless, continued therapy for 2 to 8 weeks was accompanied by spontaneous restoration of the hemodynamic effects of first doses of the drug, i.e., triphasic response (type III). In the remaining seven patients, attenuation of initial response was not reversed by prolonged captopril therapy; hemodynamic variables after 2 to 8 weeks had returned to their pretreatment values, i.e., drug tolerance (type IV). Plasma renin activity was lower in patients with minimal responses (0.6 +/- 0.2 ng/ml/hr) and was higher in patients with triphasic responses (9.4 +/- 2.5 ng/ml/hr) than in patients with types II and IV response patterns (4.4 +/- 0.7 and 2.8 +/- 0.5 ng/ml/hr, respectively; both p less than .05). Although first-dose effects of captopril are frequently sustained, the occurrence of delayed, attenuated, and triphasic responses indicates that a complex and variable relationship may exist between the early and late hemodynamic effects of vasodilator drugs in patients with severe heart failure.

Relation between serum sodium concentration and the hemodynamic and clinical responses to converting enzyme inhibition with captopril in severe heart failure

The relation between pretreatment serum sodium concentration and the early and late effects of captopril was examined in 77 consecutive patients with severe chronic heart failure, in whom cardiac catheterization was performed during initiation of treatment and after 2 to 8 weeks. Two groups of patients were defined: 37 patients had hyponatremia (serum sodium less than 135 mEq/liter, group A) and 40 patients had a normal serum sodium concentration (greater than or equal to 135 mEq/liter, group B). With first doses of captopril, patients in group A showed more marked hemodynamic responses than did patients in group B (p less than 0.02). The changes in mean arterial pressure and left ventricular filling pressure seen with first doses of the drug varied linearly and inversely with the pretreatment serum sodium concentration (r = -0.58 and r = -0.53, respectively); this was likely related to the finding that, before administration of captopril, the serum sodium concentration varied linearly and inversely with the logarithm of the plasma renin activity (r = -0.78). However, the pretreatment serum sodium concentration did not predict the long-term hemodynamic or clinical responses to converting enzyme inhibition. Symptomatic hypotension occurred early in the course of therapy (within 24 hours of initiating captopril therapy) in 9 (12%) of the 77 patients; 8 of these 9 had severe hyponatremia (serum sodium less than 130 mEq/liter) and comprised 53% of the 15 patients in our study with such low serum sodium concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasodilator and inotropic drugs for the treatment of chronic heart failure: Distinguishing hype from hope

During the past 10 years, more than 80 orally active vasodilator and inotropic agents have been tested in the clinical setting to evaluate their potential utility in the treatment of chronic heart failure. Although the initial reports of all of these drugs suggested that each represented a major therapeutic advance, only three agents--digoxin, captopril and enalapril--have produced consistent long-term hemodynamic and clinical benefits in these severely ill patients. Most of the other drugs that have been tested have not (to date) distinguished themselves from placebo therapy in large-scale, controlled trials, even though these agents produce hemodynamic effects that closely resemble those seen with digitalis and the converting-enzyme inhibitors. These observations suggest that the hemodynamic derangements that characteristically accompany the development of left ventricular dysfunction cannot be considered to be the most important pathophysiologic abnormality in chronic heart failure. Although cardiac contractility is usually depressed in this disease, positive inotropic agents do not consistently improve the clinical status of these patients. Similarly, although the systemic vessels are usually markedly constricted, drugs that ameliorate this vasoconstriction do not consistently relieve symptoms, enhance exercise capacity or prolong life. Hence, correction of the central hemodynamic abnormalities seen in heart failure may not necessarily provide a rational basis for drug development, and future advances in therapy are likely to evolve only by attempting to understand and modify the basic physiologic derangements in this disorder.

Determinants of drug response in severe chronic heart failure. 1. Activation of vasoconstrictor forces during vasodilator therapy.

Vasodilator drugs activate neurohumoral forces that produce peripheral vasoconstriction and tachycardia and probably cause the rebound events observed upon abrupt withdrawal of therapy. To determine their role in limiting therapeutic vasodilator responses, these reactive forces were measured in 40 patients with severe chronic heart failure by quantifying the magnitude of rebound change (MRC) after nitroprusside withdrawal. Group 1 patients (n = 22), who had minimal reactive vasoconstriction (MRC ⩽27%), showed marked hemodynamic effects with nitroprusside (4.5 μg/kg/min) and isosorbide dinitrate (40 mg orally), associated with significant decreases in heart rate with both drugs (p < 0.001). Despite administration of the same doses of both drugs, group 2 patients (n = 18), who had marked rebound changes (MRC > 27%), showed significantly smaller changes in cardiac index, systemic vascular resistance and mean arterial pressure (p < 0.001), associated with no change or increases in heart rate. Rebound events were attenuated and the responses to nitroprusside and nitrates were enhanced in four patients in whom these drugs were readministered after pretreatment with i.v. phentolamine (0.3 mg/min). We conclude that activation of neurohumoral forces can limit the hemodynamic responses to vasodilator administration; this supports the use of combination therapy of direct-acting vasodilators and neurohumoral antagonists in selected patients with severe chronic heart failure.