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(Circulation. 1998;98:380-381.)
© 1998 American Heart Association, Inc.

Correspondence

ACE Inhibition and Heart Failure

Bruce C. Stein, MD

Cardiology Section and the Laboratory for Cardiovascular Research New York University Medical Center, New York, NY

To the Editor:

The 2 articles by Spinale et al^{1 2} represent an important contribution by demonstrating that combination therapy with both ACE inhibitors (ACEI) and AT₁ angiotensin II (Ang II) receptor blockers provided greater improvement of left ventricular function and isolated myocyte contractile processes than either therapy used alone. Although further studies are necessary, they provided experimental data that may serve as an impetus to modify the clinical therapy of congestive heart failure. There are a few points that require clarification. The authors stated on page 2400 that "There was no significant difference in steady-state myocardial contractile function between the ACEI-alone group and the combined ACEI and AT₁ Ang II blockade group."² This statement is contradicted by Table 1 (page 2401), which notes that both time to peak contraction and total contraction duration were significantly shorter in the combination treatment group than in the ACEI-alone group.² It is also stated on page 2400, "In the AT₁ Ang II receptor blockade and rapid pacing group, the absolute change in myocyte velocity of shortening with ß-receptor stimulation was unchanged from rapid pacing–only values."² However, Figure 2 (page 2402) seems to indicate that the AT₁ Ang II receptor blockade and rapid pacing group had a significantly slower shortening velocity than the rapid pacing–alone group.²

The final problem is the omission in all of the figures and tables of any statistical comparison among the different groups versus the rapid pacing and AT₁ Ang II receptor blocker group. For example, pacing produced a statistically significant increase in pulmonary capillary wedge pressure compared with control (29 versus 8 mm Hg) (see Table 1, page 2389).¹ This increase was significantly attenuated by ACEI therapy alone and in the combined ACEI and AT₁ Ang II receptor blocker group. However, comparisons between monotherapy with the AT₁ Ang II receptor blocker and the other treatment groups are not reported. It is unclear if a difference, statistically significant or otherwise, exists with respect to the hemodynamic parameters in question.

References

1. Spinale FG, de Gasparo M, Whitebread S, Hebbar L, Clair MJ, Melton DM, Krombach RS, Mukherjee R, Iannini JP, O S-J. Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure, I: effects on left ventricular performance and neurohormonal systems. Circulation. 1997;96:2385–2396.[Abstract/Free Full Text]

2. Spinale FG, Mukherjee R, Iannini JP, Whitebread S, Hebbar L, Clair MJ, Melton DM, Cox MH, Thomas PB, de Gasparo M. Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure, II: effects on myocyte contractile processes. Circulation. 1997;96:2397–2406.[Abstract/Free Full Text]

Response

Francis G. Spinale, MD, PhD; Rupak Mukherjee, PhD; Julie P. Iannini, BS; Latha Hebbar, MD; Mark J. Clair, BS; D. Mark Melton, BS; Stephen Krombach, BS; Monty H. Cox, MD; ; Patrick B. Thomas, BS

Medical University of South Carolina, Charleston, SC

Marc de Gasparo, MD; ; Steve Whitebread, BS

Novartis Cardiovascular Pharmaceutical Division, Basel, Switzerland

In the 2-part series,^{1 2} we attempted to address the potential basis by which combined treatment with ACE inhibition and AT₁–Ang-II receptor blockade may have beneficial effects compared with monotherapy treatment in a pig model of pacing-induced congestive heart failure (CHF). Dr Stein has raised several specific and important points regarding these studies that warrant clarification.

In order to more carefully examine the intrinsic effects of the specific treatment interventions on contractility, isolated left ventricular myocyte function was examined in a large number of cells from each group. Myocyte percent and velocity of shortening, which reflect the relative number and rate of cross-bridge formation, respectively, were improved in the ACE inhibition group and the combined treatment group compared with untreated CHF values. As indicated in the myocyte function summary table (page 2401),² specific temporal characteristics of the contractile process, such as time to peak and duration of contraction, were shorter in the combined treatment group than with ACE inhibition alone. Temporal characteristics of the contractile process are influenced by a number of factors that include myofilament Ca²⁺ sensitivity, phosphorylation states, and Ca²⁺ release and sequestration. With combined ACE and AT₁–Ang-II receptor blockade, L-type Ca²⁺ channel and sarcoplasmic reticulum Ca²⁺-ATPase density were increased from untreated CHF values. Thus, the shortened time to peak contraction and contraction duration in the combined treatment group was probably due, at least in part, to improved Ca²⁺ homeostatic processes. In these studies, the capacity of the left ventricular myocyte to respond to an inotropic stimulus was examined through ß-adrenergic receptor stimulation. Left ventricular myocyte contractile response to 25 nmol/L isoproterenol was reduced in all rapid pacing groups compared with control myocytes. Combination therapy improved myocyte ß-adrenergic response to a greater degree than ACE inhibition alone, whereas AT₁–Ang-II receptor blockade with chronic rapid pacing did not result in a positive effect on ß-receptor response. Indeed, as correctly pointed out by Dr Stein and indicated in Figure 2 (page 2402),² the absolute change in myocyte velocity of shortening after ß-receptor stimulation was lower in the AT₁–Ang-II receptor blockade group compared with untreated CHF values. Extrapolation of these isolated myocyte contractile function data to in vivo myocardial performance can be problematic. Nevertheless, we have recently demonstrated that isolated myocyte contractile performance behaves in a predictable fashion with increased loading conditions.³ Thus, the improved capacity of left ventricular myocytes to respond to an inotropic stimulus in the combined ACE inhibition and AT₁–Ang-II receptor blockade group would suggest an improved capacity of these cells to respond to an external load.

The final query raised by Dr Stein was that of specific hemodynamic comparisons with monotherapy and combined therapy. Pairwise comparisons were performed using Bonferroni bounds, a fairly conservative statistical test. On the basis of this analysis, mean pulmonary artery pressure was not different between the untreated CHF group and the AT₁–Ang-II receptor blockade group but was lower in the ACE inhibition and combination treatment groups. From this analysis, mean pulmonary artery pressure was higher in the AT₁–Ang-II receptor blockade–treated group than in the ACE inhibition or combination therapy groups. Pulmonary vascular resistance was reduced in all treatment groups compared with untreated CHF values (Figure 2, page 2390).¹ However, pulmonary vascular resistance was highest in the AT₁–Ang-II receptor blockade group compared with ACE inhibition monotherapy or combination treatment. It is important to point out that all of these measurements were performed in the anesthetized and ventilated animal. Future studies in the intact, conscious CHF preparation will be necessary to more carefully examine the potential differential hemodynamic effects of ACE inhibition and AT₁–Ang-II receptor blockade.

In closing, we wish to thank Dr Stein for his comments and hope that our studies will serve as a catalyst for future basic and clinical investigations regarding the utility of combined ACE inhibition and AT₁–Ang-II receptor blockade in the treatment of heart failure.

References

1. Spinale FG, de Gasparo M, Whitebread S, Hebbar L, Clair MJ, Melton DM, Krombach RS, Mukherjee R, Iannini JP, O S-J. Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure, I: effects on left ventricular performance and neurohormonal systems. Circulation. 1997;96:2385–2396.

2. Spinale FG, Mukherjee R, Iannini JP, Whitebread S, Hebbar L, Clair MJ, Melton DM, Cox MH, Thomas PB, de Gasparo M. Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure, II: effects on myocyte contractile processes. Circulation. 1997;96:2397–2406.

3. Wang Z, Lam CF, Mukherjee R, Hebbar L, Wang Y, Spinale FG. Relation between external load and isolated myocyte contractile function. Am J Physiol. 1997;42:H183–H191.

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