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Clin. Cardiol. Vol. 23 (Suppl. IV), IV-1–IV-3 (2000)
Gary S. Francis, M.D.
Professor of Medicine and Director, Coronary Intensive Care Unit, Cleveland Clinic Foundation, Cleveland, Ohio, USA
Over the last four decades, there has been a remarkable reduction in cardiovascular death and stroke. Nonetheless, cardiovascular disease continues to be the most common cause of death in the Western world, and heart failure has emerged as one of the most important public health issues of the new millennium.1 The principal etiologies of heart failure are ischemic heart disease, coronary artery disease, and hypertension.2, 3 It is now recognized that severe cardiovascular disease can be prevented to some extent through aggressive management of cardiovascular risk factors, including smoking cessation, lowering of elevated blood pressure, and lowering of elevated levels of low-density lipoprotein cholesterol.4
There has been an evolution in knowledge of the renin-angiotensin-aldosterone system (RAAS) and its role in the pathogenesis of cardiovascular disease. Historically, this system evolved as an adaptive mechanism to protect the integrity of the circulatory system and vital organs.5 Scientific research focused initially on the endocrine functions of this important system, including salt and water retention, vasoconstriction, thirst, and the release of aldosterone. The system was thought to be primarily activated by hemodynamic changes in intravascular volume or organ perfusion pressure. It is now clear that the RAAS is inherently more complex and acts in concert with a tissue-based signaling pathway involving angiotensin II.5
The early biological role of angiotensin II most likely was to provide a beneficial reparative response to tissue injury. However, it was eventually recognized that long-term activation of the RAAS, such as in hypertension and heart failure, leads to maladaptive long-term consequences. These deleterious effects include increased systemic vascular resistance, circulatory congestion, myocardial fibrosis and hypertrophy, endothelial dysfunction, rupture of plaques, and reduced fibrinolysis.5 The pathological roles of angiotensin II and aldosterone in cardiovascular disease are now well documented.6, 7 Moreover, the tissue activity rather than the endocrine functions of the RAAS is probably most responsible for its structural and functional influences on the kidneys, heart, and vasculature.5
The problem of heart failure, its etiology, the rationale for angiotensin-converting enzyme (ACE) inhibitor therapy, and the implications of the Heart Outcomes Prevention (HOPE) study results8, 9 were the topics of discussion by a distinguished panel of speakers during the Third Annual Meeting of the Heart Failure Society of America at a satellite symposium entitled Can We Prevent CHF? Many of the discussions in this supplement represent the scientific exchange at this symposium.
Willem J. Remme, M.D., Ph.D., characterized the central role of ischemic events in the etiology of heart failure and the need to prevent these events to forestall the development of congestive heart failure. As the leading cause of heart failure and a prognostic indicator, myocardial ischemia plays an important role in the cardiac remodeling process that progressively alters the shape and size of the heart.10 Although several classes of drugs have been studied as primary and secondary measures for the prevention of heart failure, ACE inhibitors have an advantage because of their multimechanistic effects on the cardiovascular disease process.4 Dr. Remme discussed the cardio- and vasculoprotective effects of ACE inhibitors that contribute to improved patient outcomes, both in the short term by improving hemodynamics and in the long term by affecting vascular structure and function.1
Several large-scale clinical trials have convincingly demonstrated that ACE inhibitors significantly reduce cardiovascular morbidity and mortality in patients with heart failure or left ventricular dysfunction following myocardial infarction.11, 12 These studies have suggested that the benefits could be extended even to patients with preserved ventricular function. Bertram Pitt, M.D., discussed the HOPE study, which is the first large-scale clinical trial to test the hypothesis that ACE inhibitor therapy could reduce cardiovascular morbidity and mortality in a broad range of patients who had cardiovascular risk factors but with preserved left ventricular function.8, 9
The HOPE study was terminated prematurely because of a significant effect of ramipril on study end points. Ramipril's beneficial effects were evident in the population as a whole and in all subgroups. There were also significant reductions in secondary revascularization procedures, hospitalizations due to heart failure, cases of heart failure and cardiac arrest, as well as complications related to, or new diagnoses of, diabetes. The major clinical implications of the HOPE study extend to a broad range of patients at risk of cardiovascular events, but without left ventricular dysfunction, who can benefit from long-term ramipril therapy.
The mechanism by which long-term administration of ACE inhibitors reduce ischemic events is thought to involve modulation of endothelial function, with the endothelium serving as a link between the RAAS and the fibrinolytic system. Furthermore, the fibrinolytic or plasminogen activator system is an important determinant of vascular homeostasis, and is a major defense mechanism against intravascular thrombosis formation. Research by Douglas E. Vaughan, M.D., a pioneer in the field, has defined the inextricable relationship between fibrinolysis and vascular ACE.13 By virtue of its endothelial localization and its dual functional role in activating angiotensin and degrading bradykinin, ACE is strategically positioned to regulate vascular fibrinolytic balance.14
The important components of the fibrinolytic system are plasminogen, plasminogen activators (tPA), and fast-acting plasminogen inhibitors (PAI-1).15 Plasminogen is an inactive precursor, which is proteolytically converted into an active metabolite (plasmin) upon stimulation by tPA. Plasmin has several important functions. In the vascular lumen, plasmin lyses fibrin clots that tend to form proximate to atherosclerotic lesions and that can induce myocardial infarction (MI) and ischemia. Plasmin also plays a role in atherosclerotic lesion formation. By activating transforming growth factor b, plasmin inhibits the proliferation and migration of smooth muscle, which is a key element of atherosclerotic pathophysiology. Plasmin also activates matrix metalloproteinases, which affect luminal remodeling and restenosis that occur following vascular injury or insult; matrix metalloproteinases degrade collagen and other glycoproteins that amass in atherosclerotic plaques.16 The balance between tPA and PAI-1 determines net fibrinolytic activity.13
An imbalance between tPA and PAI-1 can have clinical consequences. Epidemiologic data have linked elevated PAI-1 levels with increased risk of recurrent MI17 as well as with a higher incidence of acute MI in young patients, as opposed to older age-matched controls.18 Angiotensin II and angiotensin IV, products of ACE activity, can induce rapid dose-dependent increases in plasma PAI-1 levels in cell cultures systems and in vivo in humans.19, 20 Bradykinin, in contrast, is one of the most potent stimuli for tPA release.21
Consequently, the RAAS can potentially exert a potent additive effect on the equilibrium of the fibrinolytic system. Pharmacologic interruption of the RAAS by ACE inhibition should exert a beneficial effect on endogenous fibrinolytic activity by blocking the formation of angiotensin II and preventing the degradation of bradykinin. This hypothesis is consistent with a double-blind study using ramipril on patients with acute anterior MI.14 In the Healing and Early Afterload Reduction Therapy (HEART) study, 120 patients with acute anterior MI were randomly assigned to either ramipril or placebo for 14 days within 24 h of symptoms. Compared with the placebo group, PAI-1 antigen levels were 44% lower (p = 0.004) and PAI-1 activity levels were 22% lower (p = 0.02) at day 14 in ramipril-treated patients. Plasma tPA levels were not significantly different between the placebo-treated and ramipril-treated groups.14
Thus, treatment with ramipril has a positive impact on plasma fibrinolytic balance in this patient population. This mechanism may account in part for ramipril's ability to reduce the incidence of recurrent MI and unstable angina pectoris.
Finally, the concept of "class effect" as applied to ACE inhibitors was explored by Curt D. Furberg, M.D., Ph.D. The concept is problematic because it does not yet have a standardized definition, and equipotent doses of member drugs for various effects are unknown. Nonetheless, it raises the frequently-asked question of whether the biological actions or beneficial effects of one member of a drug class apply to all members. This is particularly true when a clinical trial of such magnitude as the HOPE study convincingly demonstrates a therapeutically important drug effect.8, 9 Even within a therapeutic class of drugs, small differences in chemical structure may result in very different pharmacologic effects, whether desired or untoward.22 The usefulness of a given drug, however, is determined by the sum of its favorable and unfavorable effects. Dr. Furberg espoused that untested drugs are unproved drugs and that the practice of medicine must be evidence based.
In summary, cardiovascular risk factors need to be aggressively managed to forestall and perhaps completely prevent the onset of heart failure. Growing evidence indicates that effective prevention and treatment measures are already available, yet are not widely utilized. The results of the HOPE study extend the benefit derived from ACE inhibitor therapy to a broader group of patients--those with coronary artery disease and preserved left ventricular function in addition to those with diabetes. In particular, the ACE inhibitor ramipril significantly reduced the risk for cardiovascular events and the number of hospitalizations due to heart failure. For further reduction of mortality and morbidity caused by cardiovascular disease, the early initiation of proven treatments for patients at risk is paramount.
Supported by a grant from Monarch Pharmaceuticals.
Address for reprints:
Gary Francis, M.D.
Director, Coronary Intensive Care Unit
The Cleveland Clinic Foundation
Department of Cardiology F25
9500 Euclid Avenue
Cleveland, OH 44195, USA