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J Am Coll Cardiol, 1999; 34:2068-2071 © 1999 by the American College of Cardiology Foundation |
a Kaufman Center for Heart Failure, Section of Heart Failure and Cardiac Transplant Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA
Reprint requests and correspondence: Dr. James B. Young, Kaufman Center for Heart Failure, The Cleveland Clinic Foundation, 9500 Euclid Avenue (Desk F-25), Cleveland, Ohio 44195
youngj{at}cesmtp.ccf.org
20% of the target population (10). Absence of the ARB agents’ ability to increase bradykinin likely makes these drugs easier to use and better tolerated, but may account for less pharmacologic benefit in some settings. As the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) trial design suggests, many investigators believe that ACE inhibitors combined with ARBs will benefit heart failure patients more than when either agent is used alone. However, might ACE inhibitor benefit in heart failure patients accrue through pharmacologic actions not previously characterized? In this issue of JACC, Gullestad et al. (11) report data that strengthens already robust clinical trial information supporting the use of ACE inhibitors in heart failure, and thus documenting the fact that large doses of these compounds are necessary to most effectively ameliorate a perturbed humoral milieu, particularly the cytokine environment. Importantly, this study suggests that high doses of enalapril (40 mg daily) in patients with severe congestive heart failure significantly decreased interleukin (IL)-6 activity, which is believed to be important during detrimental heart failure remodeling (12–15). The decrease in IL-6 was associated with diminished interventricular septal thickness observed over time with echocardiography. These findings were not apparent when lower enalapril doses (5 mg daily) were used. Just as we have learned much in the last decade about which drugs to prescribe for patients with heart failure, the importance of proper dosing has also become more clear. We now know that some drugs are best prescribed at a fixed dose, whereas others should be force-titrated to target levels. Still, it was disappointing to see that not all seemingly evil inflammatory humors were interdicted by enalapril even at high doses, and it is likely that more direct immunomodulating treatments will be necessary to further improve the heart failure milieu when symptoms are severe. Also, it is not clear how ACE inhibitors produced the cytokine response noted. It is still uncertain whether there is a direct link between the reduction of IL-6 and inhibition of ACE. Still, this report supports the notion that higher rather than lower doses of ACE inhibitor are superior, and it is particularly intriguing because of the nagging question of just how ACE inhibitors work in heart failure.
Much information now suggests that cytokines, particularly tumor necrosis factor (TNF)-alpha and IL-6, play significant roles in various inflammatory conditions (16). It is not surprising, therefore, to see evidence supporting the contention that inflammatory cytokines are upregulated in patients with advanced heart failure (likely in an attempt to heal the injured myocardium given the fact that inflammation is the crux of our body’s repair mechanism). Almost a decade ago, Levine et al. (17) demonstrated that circulating levels of TNF-alpha are elevated in patients with severe chronic heart failure, and subsequent studies noted that TNF-alpha increased in a variety of cardiac injury states including myocarditis (18) and acute coronary syndromes (19,20). All of these conditions have been shown to benefit from ACE inhibitors prescribed long term, and it is tantalizing to suggest, as have Gullestad et al. (11), that ACE inhibitor benefit relates to downregulation of cytokine activity, at least in part.
Of additional interest is the report from Gurantz et al. (21), that upregulation of the angiotensin type 1 receptor (AT1) on cardiac fibroblasts, which is important with respect to remodeling regulation, occurred after TNF-alpha exposure. Using quantitative competitive reverse transcription–polymerase chain reaction, these investigators found that norepinephrine, endothelin, atrial natriuretic peptide and bradykinin had no significant effect on AT1 messenger ribonucleic acid (mRNA) levels. In contrast, TNF-alpha produced a fivefold increase in AT1 mRNA, whereas angiotensin II, transforming growth factor-beta and basic fibroblast growth factor significantly reduced AT1 mRNA levels. These observations further link cytokine TNF-alpha to detrimental cardiac remodeling in heart failure.
Indeed, cytokines, and TNF-alpha, in particular, are an emerging therapeutic target in patients with heart failure. Important observations with respect to this issue include the fact that drugs that increase intracellular cyclic adenosine monophosphate (cAMP), such as pentoxifylline, amrinone and adenosine, prevent TNF-alpha mRNA accumulation by blocking the transcriptional activation of TNF-alpha (13). Thalidomide, in contrast, appears to diminish TNF-alpha by increasing mRNA degradation (22), whereas steroids (dexamethasone) appear to suppress TNF-alpha biosynthesis at the translational and transcriptional level (23). Whether any of these agents are effective in attenuating long-term heart failure morbidity and mortality is speculative, at best. Nonetheless, the recent report of Deseval et al. (24) is intriguing in that a soluble TNF-alpha receptor that neutralizes the biologic effect of circulating TNF-alpha improved functional status and quality of life in patients with advanced heart failure. This small but well-done study provides support for the concept of giving agents that attenuate cytokine perturbation in heart failure and sets the stage for a large randomized clinical trial of eternacept (14). It would be most interesting if ACE inhibitors, drugs already proven effective in heart failure, could be added to the list of agents that beneficially modulate cytokine production.
Several notes of caution must be raised about the Gullestad et al. study (11), some of which the authors themselves address. All patients were receiving low dose ACE inhibitor therapy at baseline blood sampling, and the effects of ACE inhibition de novo on these patients’ cytokine levels are unknown. Furthermore, no placebo group was included, and we therefore cannot determine whether the changes, or lack thereof, in cytokine activity simply represent the natural variability of circulating levels of cytokines in heart failure. Indeed, Dibbs et al. (25) have recently examined variability in cytokine levels in patients with heart failure as compared with normal control subjects. Circulating levels of TNF-alpha, soluble TNF receptors 1 and 2, IL-6 and IL-6 receptor were measured daily, weekly and monthly in 10 patients with New York Heart Association (NYHA) functional class III congestive heart failure and 10 healthy volunteers. The coefficient of variation for TNF-alpha and IL-6 levels increased with time in patients, with the coefficient of variation in heart failure patients greatest for IL-6. The coefficient of variation in cytokine receptor levels was minimal and did not differ significantly between heart failure patients and control subjects. This study suggests that the sample size needed to show a statistically as well as biologically significant change in the circulating level of a given cytokine will vary depending on the specific cytokine studied and period of observation. The authors stated, for example, that to detect a 15% reduction of either circulating TNF-alpha or IL-6 levels during a 16-week period, at an alpha level of 0.05 and with a power of 80%, a sample size of 21 (for TNF-alpha) and 377 (for IL-6) would be required. Gullestad et al. (11) followed 75 patients with variables assessed at 10 and 32 weeks as compared with baseline.
If the observations made by Gullestad et al. (11) are confirmed, the implication that ACE inhibitors are pleiotropic in their beneficial effects in heart failure should come as no surprise, because heart failure is such a plastic clinical entity and ACE inhibitors have produced remarkably consistent benefits from trial to trial and in a wide range of patients and conditions. However, the issue of high doses versus low doses of ACE inhibitors must again be addressed. In contradistinction to diuretic agents, ACE inhibitors have not been, in large-scale clinical trials, titrated according to an individual’s symptoms. Rather, target doses were picked and forced titration schemes developed (26). Target doses of these agents have generally been equated to 150 to 300 mg/day of captopril or 20 to 40 mg/day of enalapril. Unfortunately, when clinical practice patterns are analyzed, ACE inhibitors, when used, are prescribed at much lower doses (25 to 50 mg/day of captopril and 2.5 to 5.0 mg/day of enalapril) (27,28). However, as the Gullestad et al. study (11) and others demonstrate, higher doses of ACE inhibitors produce greater hemodynamic, neurohormonal, inflammatory cytokine, symptomatic and prognostic benefits than do lower doses. For example, Pacher et al. (29) demonstrated that high dose enalapril treatment proved superior to low dose treatment with respect to symptomatology, despite similar effects on hemodynamic variables and maximal exercise capacity. Levine et al. (30) demonstrated that up-titration of ACE inhibitors to high doses (when accompanied by nitrate therapy) was well tolerated and improved clinical status and left ventricular systolic function. This group subsequently demonstrated that up-titration of lisinopril to a mean dose of 55 mg/day (and isosorbide dinitrate dose up to a mean of 286 mg/day) resulted in significant reversal of left ventricular remodeling (31). Van Veldhuisen et al. (32) evaluated the long-acting ACE inhibitor, imidapril, in 244 patients randomized to receive 2.5, 5 or 10 mg/day. At three-month follow-up, higher doses were superior with respect to a more pronounced effect on exercise capacity and some neurohomones, but this did not seem to be related to the extent of suppression of plasma levels of converting enzyme. Importantly, these higher doses were reasonably well tolerated.
Perhaps the most convincing evidence about higher doses of ACE inhibitors comes from the Assessment of Treatment with Lisinopril And Survival (ATLAS) clinical trial (28,33,34). The ATLAS trial was designed to determine whether high doses of lisinopril would result in lower mortality and morbidity than lower doses in comprable patients. It was a large, randomized, double-blinded, multicenter, international trial (287 clinical centers in 19 countries) in patients with an ejection fraction 
30% (NYHA functional class II, III or IV). Low dose lisinopril was defined as 2.5 to 5 mg/day and high dose 30 to 40 mg/day. The primary outcome evaluated was all-cause mortality, with secondary end points including cardiovascular mortality and morbidity. Patients were followed for an average of 3.5 years and over 3,000 individuals were randomized. By the end of the study, almost 45% of patients in the low dose group had died as compared with 43% in the high dose group, but this difference was not statistically significant (p = 0.128). In contrast, hospital admissions for congestive heart failure were reduced by 24% in the high dose lisinopril group (p = 0.003). In addition, the combined end point of all-cause mortality and cardiovascular morbidity was lower in the high dose group (84% vs. 80%, p = 0.002).
Another complementary but smaller study was done by Luzier et al. (35). This effort evaluated the relation of digoxin, diuretic agents and ACE inhibitors (and dose) to hospital readmission rates over a 36-month period. The ACE inhibitor dose response analysis used the discharge dose and converted this to enalapril equivalent doses, while adjusting for renal dysfunction. Interestingly, only 22% of those patients taking ACE inhibitors in this study of 314 patients received currently recommended doses of enalapril (20 mg/day or its equivalent) and 41% received <5 mg of enalapril (or its equivalent) per day. Time for readmission was increased when an ACE inhibitor was used overall in the study (p = 0.002), and these agents were the principal covariate of 90-day decreased readmission rates. However, readmission rates were not reduced when the daily dose was 5 mg of enalapril equivalents per day. When patients received daily doses >10 mg equivalents, the 90-day readmission rate was decreased by almost 30%, as compared with those receiving a diuretic agent or digoxin alone (p < 0.05). Similarly, Gattis et al. (36) explored ACE inhibitor doses in elderly patients with heart failure and noted them to be less than optimal, with low doses associated with more clinical events. None of these studies give insight into the mechanism of ACE inhibitors’ differential effects based on dose, but they all are in concert with the findings of Gullestad et al. (11). From a pathophysiologic viewpoint, higher doses of ACE inhibitors make sense, and we have learned that much of the beneficial effects of these drugs may be unrelated to de facto hemodynamic changes. We must strive harder to clarify the nuances of ACE inhibitors’ actions in heart failure. One cannot help but wonder whether ACE inhibitor cytokine modulating effects, if, indeed, they are present, would help with the headache associated with this challenge!
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  B. J. Holycross and M. J. Radin Cytokines in Heart Failure: Potential Interactions with Angiotensin II and Leptin Mol. Interv., November 1, 2002; 2(7): 424 - 427. [Abstract] [Full Text]
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