Inotropes and β-blockers: Is there a need for new guidelines?

Journal of Cardiac Failure Vol. 7 No. 2 Suppl. 1 2001

Inotropes and ␤-Blockers: Is There a Need for New Guidelines? MICHAEL R. BRISTOW, MD, PhD, SIMON F. SHAKAR, MD, JENNIFER V. LINSEMAN, PhD, BRIAN D. LOWES, MD Denver, Colorado

ABSTRACT ␤-Adrenergic blocking agents are standard treatment for patients with mild-to-moderate heart failure. When patients receiving ␤-blockers decompensate they often need treatment with a positive inotropic agent. The ␤-agonist dobutamine may not produce much increase in cardiac output during full-dose ␤-blocker treatment and may increase systemic vascular resistance via ␣-adrenergic stimulation. In contrast, phosphodiesterase inhibitors (PDEIs) such as milrinone or enoximone retain full hemodynamic effects during complete ␤-blockade because the site of action of PDEIs is beyond the ␤-adrenergic receptor and because ␤-blockade reverses some of the desensitization phenomena that account for the attenuation of PDEI response in heart failure related to upregulation in G␣i. Inotrope-requiring subjects with decompensated heart failure who are undergoing long-term therapy with ␤-blocking agents should be treated with a type III–specific PDEI, not a ␤-agonist such as dobutamine. Key words: Heart failure, inotropes, ␤-blockers, contractility.

The positive feedback between contractile dysfunction and induction of pathologic hypertrophy and remodeling likely explains the typical progressive natural history and clinical syndrome of dilated cardiomyopathies. Therefore, the appropriate approach to CHF therapy is to develop approaches to interrupt this cycle. Neurohormonal antagonists such as angiotensin-converting enzyme inhibitors and ␤-adrenergic blocking agents are examples of treatment modalities that interrupt this cycle (1). It follows that a therapeutic agent that would enhance contractile function without producing any adverse effects might also improve and change the natural history of heart failure.

Two primary pathophysiologic processes account for the natural history of dilated cardiomyopathy, the natural history of most patients with chronic heart failure (CHF), in the United States. These processes are myocardial dysfunction, which can be traced back to cardiac myocyte dysfunction, and remodeling, which also tracks back to the myocyte via an increase in cell length (Fig. 1) These 2 fundamental processes are interactive, with one process begetting the other. When cardiac myocyte dysfunction develops as the initial problem through activation of neurohormonal and other signaling pathways, hypertrophy and remodeling typically follow. The remodeling process eventually contributes to the development of cardiac myocyte dysfunction through various mechanisms that include greater bioenergetic stress and induction of the fetal gene program.

Possible Approaches to Safe, Effective Positive Inotropic Therapy

From the Department of Cardiology, University of Colorado Health Sciences Center, Denver, CO. Reprint requests: Michael R. Bristow, MD, PhD, Department of Cardiology, University of Colorado Health Sciences Center, 4200 E 9th Ave, Denver, CO 80262. Copyright © 2001 by Churchill Livingstone威 1071-9164/01/0702-1002$35.00/0 doi:10.1054/jcaf.2001.26655

Any consideration of developing a safe and effective positive inotropic therapy requires an appreciation of the different ways in which improvement in contractile

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Fig. 1. Relationship between remodeling and cardiac myocyte dysfunction. RAS, reninangiotensin system; ANS, adrenergic nervous system. Reprinted with permission (3).

function can be produced. Four different approaches are considered: 1) by a pharmacologic agent such as a ␤-agonist or a cardiac glycoside that has the direct property of increasing contractile function; 2) by transgenically altering a mechanism that regulates contractility such as by overexpressing myocardial ␤-adrenergic receptors or ablating phospholamban; 3) by altering the biology of the failing heart through normalizing the expression of contractility-regulating genes, such as occurs with ␤-blocking agents; and 4) by combining certain pharmacologic positive inotropic agents with ␤-adrenergic blocking agents. On examination of these 4 different scenarios it becomes clear that a positive inotropic maneuver is by no means predestined to produce an adverse clinical outcome. Pharmacologic Enhancement of Contractile Function In clinical use are pharmacologic agents that increase contractile function by inhibiting Na⫹,K⫹-adenosine triphosphatase (ATPase) and increasing intracellular Ca2⫹ (digitalis glycosides) concentrations, inhibiting type IIIA phosphodiesterase (milrinone, enoximone), and acting as the agonists for ␤1- and ␤2-adrenergic receptors (dobutamine, epinephrine, isoproterenol). Only 1 of these agents, digoxin, has been shown to be safe and effective in long-term use (2); the others are useful for short-term inotropic support. The key to safe and effective long-term use of digoxin is its gradual evolution to a low-dose, low-plasma concentration strategy (2,3). A similar, low-dose approach is being pursued with type IIIA phosphodiesterase inhibitors (PDEIs) (4). Another key to the use of positive inotropic agents, highlighted by transgenic mouse models, is the site of action. Agents that act through inhibition of phospholamban may be particularly desirable. Type IIIA PDEIs act in this fashion through phosphorylation of phospholamban; in low

concentrations these agents can act selectively on this important regulatory phosphoprotein (5).

Transgenic Enhancement of Contractile Function Studies using certain transgenic mouse models have unequivocally shown that sustained and marked increases in contractile function can be well tolerated and produce favorable effects on the natural history of myocardial failure. In transgenic mouse models directed at altering the ␤-adrenergic–protein kinase A pathways there is marked heterogeneity in the adverse myocardial effects of genetically produced sustained increases in contractile function, which depend on the locus of the genetic manipulation. For example, cardiac-restricted increase in the expression of human recombinant ␤1adrenergic receptors is markedly cardiomyopathic and increases mortality at relatively low levels (15- to 30fold) of overexpression (6,7), whereas it takes much higher (100- to 350-fold) levels of overexpression of human ␤2-receptors to produce a cardiomyopathy (8). When sarcoplasmic reticulum (SR) function is enhanced by phospholamban knockout, a maneuver that mimics phosholamban phosphorylation (9), an increase in contractile function but not heart rate occurs and the increases in systolic and diastolic function are similar to those produced by ␤-adrenergic receptor overexpression. Phospholamban knockout animals do not develop a cardiomyopathy despite a lifelong increase in contractile function, and this genetic alteration can “rescue” models of genetic cardiomyopathy (10,11). In contrast, ␤2 overexpression does not rescue genetic cardiomyopathies and in fact worsens them (11,12). Therefore, in transgenic models the site of action of a positive inotropic intervention appears to be critical, with certain SR-targeted maneuvers being devoid of any adverse myocardial

10 Journal of Cardiac Failure Vol. 7 No. 2 Suppl. 1 2001 effects. Gene therapy approaches in development (13) may be able to effectively utilize these general concepts. Biologic, Time-Dependent Positive Inotropic Agents The treatment that has produced the greatest quantitative effect on the natural history of heart failure, ␤-blockade, ultimately works by becoming a positive inotropic agent through a biologic time-dependent process at approximately 3 months of therapy (1). Generally, intrinsic systolic function is improved and remodeling is reversed. One of the ways ␤-blockade improves myocardial systolic function is by reversing the induction of the fetal gene program, which improves systolic function through directional changes toward normal in the expression of myosin heavy chain isoforms and SR Ca2⫹ ATPase genes (14,15). Ultimately, ␤-adrenergic blockade acts as a biologic positive inotropic agent, with favorable consequences on the natural history of heart failure. Combination of a Type IIIA PDEI With a ␤-Blocking Agent The rationale of combining these agents is that 1) because of their site of action beyond the ␤-adrenergic receptor, type IIIA PDEIs retain their hemodynamic action in the face of ␤-blockade (16–19) and may actually exert enhanced hemodynamic effects related to ␤-blocker–induced decreases in upregulated G␣I (20); and 2) ␤-blockade can reduce the adverse event profile of type III PDEIs by lowering heart rate and decreasing proarrhythmic potential (16,21). In the presence of a ␤1-receptor blocking agent harmful sustained ␤1receptor pathway signaling, some of which is mediated through adenosine 3',5'-cyclic monophosphate–independent Gs␣ coupling to calcium channels (22,23), is eliminated and increased contractile function is delivered through the type III PDEI–mediated phospholamban phosphorylation effect on the SR (5). The combination of a ␤-blocking agent and a III-PDEI may therefore in-

crease the SR specificity of a positive inotropic intervention. Although the data are limited, phase II trials show that when a ␤-blocker and a III-PDEI are coadministerd, the full beneficial effects of each agent are manifest, resulting in the addition of the favorable “biologic” myocardial effects of ␤-blockers (16,21) to the beneficial pharmacologic hemodynamic profile of III-PDEIs (16– 19) (Table 1). However, the efficacy and safety of this combination must be established in phase III trials.

Treatment of Patients With Decompensated Heart Failure Receiving ␤-Blocking Agents Although ␤-blocking agents are highly effective in the treatment of most patients with mild-to-moderate (24–26) or advanced but clinically stable (27) CHF, many patients receiving ␤-blocking agents continue to decompensate and require hospitalization for worsening heart failure. For example, in the MERIT-HF trial (26), conducted in patients with New York Heart Association class II–III heart failure, annualized heart failure hospitalization rate in those receiving metoprolol succinate was 0.27 (28). In the BEST trial (29), conducted in patients with more advanced heart failure, the annualized heart failure hospitalization rate in those receiving bucindolol was 0.54. When subjects receiving ␤-blocking agents are hospitalized the first consideration is what to do about the ␤-blocker. Because patients withdrawn from ␤-blockers may deteriorate further (30), unless the decompensation has occurred repeatedly or there has been a clear-cut and documented decline in left ventricular ejection fraction and/or progression in remodeling (31), an argument can be made to continue the ␤-blocking agent and treat the decompensation with agents whose action is not mitigated by the ␤-blocker. A subset of patients admitted for decompensated heart failure will require treatment with a positive inotropic agent (25,32). Several studies have shown that, as expected, high doses of ␤-blocking agents inhibit the

Table 1. Cardiovascular Effects of ␤-Adrenergic Blocking Agents, PDEIs, or Their Combination in Subjects With Heart Failure Effect Heart rate Systolic function Diastolic function Arterial vasodilation Venodilation Left ventricular filling pressure Myocardial O2 consumption Exercise capacity Proarrhythmia Reprinted from Lowes et al (16).

␤-Blocker Q Q then q ↔ q, ↔ or Q q, ↔ or Q ↔ or q, then Q Q ↔ or Q Q

PDEI ↔ or q q q q q Q ↔ or Q q ↔ or q

␤-Blocker ⫹ PDEI Q qq q q q Q QQ q ↔ or Q

Inotropes and ␤-Blockers

pharmacologic response of dobutamine (16,18,19,33). The degree of inhibition of dobutamine’s effect on cardiac output or stroke volume is much greater when the ␤-blocker is carvedilol compared with metoprolol (18,19,33), because carvedilol blocks both ␤1 and ␤2 receptors. However, the effect of the type IIIA PDEIs milrinone (16,18) or enoximone (19) is not inhibited by carvedilol; in fact, the favorable hemodynamic effects of both agents are enhanced by the presence of ␤-blockade (16–19). Also, in the presence of carvedilol the hemodynamic effects of dobutamine are no longer beneficial because heart rate and systemic vascular resistance are increased and pulmonary wedge pressure is not reduced (18,19). In conclusion, patients with decompensated heart failure receiving long-term carvedilol treatment or high doses of ␤1-selective blocking agents should receive a type IIIA PDEI rather than dobutamine if a positive inotropic therapy is required.

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