Angina in patients with left ventricular dysfunction or heart failure

by M. Böhm, Germany

Michael BÖHM, MD
des Saarlandes
Klinik für Innere Medizin III
Kardiologie, Angiologie
und Internistische
Homburg, GERMANY

Myocardial ischemia and its symptom angina pectoris contribute to left ventricular dysfunction and the progression of remodeling. Remodeling after myocardial infarction is induced by a loss of functional myocytes and by neuroendocrine activation, and eventually leads to left ventricular dilatation and fibrosis. Vascular mechanisms like endothelial dysfunction and remodeling of atherosclerotic plaques also contribute to the progression of asymptomatic left ventricular dysfunction to heart failure. After a myocardial infarction, patients often have residual angina. β-Adrenergic blockade and heart rate reduction are valuable strategies to reduce angina, in particular in heart failure. Furthermore, β-blockers and heart rate–lowering drugs have been found to have beneficial effects on morbidity and mortality in heart failure. These findings reinforce the importance of optimal therapy in patients with impaired left ventricular function and anginal symptoms to slow the progression of left ventricular dysfunction, and eventually the development of heart failure.

Coronary artery disease—whose most common symptom is angina—is one of the most important comorbidities of heart failure, and is prevalent in approximately 60% of patients.1,2 In the United States, coronary artery disease affects 15.54 million patients and accounts for 538 000 deaths yearly, not including its consequences like acute myocardial infarction, left ventricular dysfunction, and heart failure, which are predicted to affect 8 million patients by 2030.3

Myocardial remodeling

When different loading conditions are imposed on the myocardium, the left ventricle adapts to pressure and volume overload and undergoes structural changes. A loss of myocardial mass after myocardial infarction due to coronary artery disease can alter chamber geometry and wall stress in the left ventricle. Left ventricular hypertrophy and dilatation are two distinct types of cardiac remodeling that occur subsequently in the infarcted and noninfarcted ventricular myocardium, and which were first described following experimental coronary artery ligation in the rat.4 Loss of contractility of the left ventricle in infarcted areas increases wall stress and then causes hypertrophy in remote areas, with secondary global dilatation (Figure 1). Residual ischemia and loss of myocardial tissue can pave the way for global remodeling, and subsequently, for overt chronic heart failure.5 The late Janice Pfeffer showed that ventricular remodeling is sensitive to the application of angiotensin-converting enzyme (ACE) inhibitors, and thus that modeling processes actually respond to treatment.5 This has provided indirect evidence for the role of neuroendocrine activation in the heart, and provided a treatment target to prevent heart failure.5 This concept was swiftly transferred to the clinic for the treatment6 and—interestingly—the prevention of heart failure.7 Meanwhile, left ventricular remodeling is regarded as a broad process involving the myocardium and the endothelium, as well as conditioning processes that occur after myocardial reperfusion injury and vascular and coronary microvascular remodeling.8 Myocardial remodeling is described as maladaptive or decompensative remodeling, and is affected by genetic factors, comorbid conditions, loading conditions, and neuroendocrine activation.9 Ventricular dilatation with impaired ejection fraction is usually referred to as eccentric remodeling, while in concentric remodeling the ejection fraction is preserved and volumes are normal or reduced in the presence of increased left ventricular mass. The clinical phenotype of the latter is usually termed heart failure with preserved ejection fraction.10 The remodeling process is accelerated by ischemia, leading to increased autophagy in ischemia,11 pressure overload,12 and then myocardial infarction.13

Figure 1. Progression of left ventricular dysfunction after myocardial
After acute infarction, myocyte loss induces early contractile dysfunction, which
progresses and can produce reactive hypertrophy in the viable myocardium.
Following an increase in wall stress, activation of neuroendocrine mechanisms,
including renin-angiotensin aldosterone activation in the heart itself, contributes
to hypertrophy in the newly infarcted myocardium. Complete remodeling then
takes place, with wall thinning in areas of the heart remote from the infarction,
followed by progressive dilatation.

Neuroendocrine activation is important to maintain and facilitate remodeling processes. Following an increase in left ventricular wall tension, the angiotensin system is activated14 and aldosterone expression is stimulated,15 which leads to increased intracellular oxidative stress.16 Sympathetic nervous system activation induces myocardial hypertrophy by α-adrenergic stimulation17 and activation of the β-adrenoceptor system.18 β-Adrenergic overstimulation then induces cellular apoptosis19 and desensitization of the β-adrenoceptor–mediated regulation of myocardial contractility.20 Therapeutic approaches involve using β-adrenoceptor antagonists to counteract neuroendocrine activation.21-24 Heart rate lowering is an important therapeutic approach as current evidence suggests that heart rate is closely associated with outcomes in atherosclerosis, coronary artery disease, and heart failure.25 Furthermore, the clinical efficacy of ivabradine has been demonstrated in patients with coronary artery disease and impaired left ventricular function,26 as well as heart failure.27,28Endothelial and vascular remodeling

Other remodeling processes beyond myocardial remodeling have recently attracted attention, such as those involving vascular and endothelial mechanisms. Risk factors—ie, low-density lipoprotein (LDL)-cholesterol and stress—reduce endothelial function and accelerate atherosclerosis.29 High heart rate can further exacerbate atherosclerosis,30 and this process is sensitive to heart rate reduction with ivabradine.31

In atherosclerotic disease, heart rate is associated with a variety of cardiovascular end points like heart failure, cardiovascular death, stroke, but not myocardial infarction.32 Therefore, vascular remodeling may contribute to the progression of coronary disease and the development of angina in the absence or presence of heart failure. Vascular remodeling, microvascular function, ventricular remodeling, and ischemia accentuate the development of clinical vascular events and heart failure complications (Figure 2).

Figure 2. Pathophysiology of cardiac events and progression to heart failure.
Following a vascular event, ischemia and contractile dysfunction induce neuroendocrine activation
in the heart, and the sympathetic nervous system leads to relatively high resting heart
rates. The direct effects of neurohormones and high heart rate induce myocardial, vascular,
and interstitial remodeling, and this leads to cardiomyopathy and progression of atherosclerosis.
In addition, by increasing periperal resistance, high heart rate and neuroendocrine activation
increase oxygen demand, and reduce the duration of diastole, which reduces oxygen supply,
thereby promoting ischemia. This process is accentuated by the progression of atherosclerosis
and endothelial dysfunction. Eventually, heart failure and major cardiovascular events occur
and are promoted by myocardial ischemia.

Outcomes of heart failure in the presence of angina

Angina and coronary artery disease are present as comorbidities in 60% of heart failure patients and significantly contribute to poor prognosis.1,2 Between 16.4% and 21% of patients remain symptomatic and use antianginal drugs 1 to 12 months after a coronary revascularization, coronary intervention, or coronary bypass operation.33 This was confirmed by the Euro Heart Survey of the European Society of Cardiology, which showed that in Europe the majority of patients take at least one antianginal drug, and sometimes more than two,34 even after revascularization. Nevertheless, coronary artery bypass surgery in heart failure patients with ischemic heart disease reduces cardiovascular outcomes,35 and in particular sudden death and fatal pump failure events.36

Angina treatment in heart failure

While there is no doubt that revascularization is a necessity, antianginal treatment represents the mainstay in the presence of anginal symptoms. Heart rate reduction favorably influences the relation between myocardial oxygen supply and myocardial oxygen consumption.37 β-Blockers are the mainstay in the guidelines for the treatment of angina, besides calcium antagonists.38 However, the use of β-blockers and calcium antagonists is often limited by adverse effects. Therefore, maximum doses can often not be tolerated.38 High heart rates increase oxygen consumption and are often a trigger for myocardial infarction and angina pectoris. Heart rate reduction with ivabradine in the absence of β-blockers reduces anginal symptoms and improves exercise tolerance.39 In patients with treatment-resistant anginal symptoms, ivabradine reduces angina and improves exercise tolerance in patients already treated with β-blockers40 or amlodipine.41 Even in the presence of β-blockers, ivabradine strongly reduces heart rate (Figure 3).40

Anginal symptoms and their adverse effects on morbidity and mortality have not been evaluated in patients with impaired left ventricular function. Recently, a study in more than 19 000 patients investigated whether ivabradine improves outcomes in patients with stable coronary artery disease without heart failure or left ventricular dysfunction.42 There was no change in cardiovascular death, myocardial infarction, or stroke.42 In patients with impaired left ventricular function and angina pectoris, ivabradine was associated with a 24% reduction in the primary end point (cardiovascular mortality, hospitalization for fatal and nonfatal myocardial infarction or heart failure).26 Interestingly, outcomes were worse in the presence of angina26 compared with patients with left ventricular dysfunction with and without angina symptoms.43 In turn, in patients with impaired left ventricular function and symptomatic chronic heart failure, a subanalysis of the SHIFT trial (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) showed that in patients with concomitant angina pectoris, ivabradine was associated with a significant reduction in cardiovascular death and myocardial infarction that was comparable to that seen in the whole heart failure population of the trial.44

Figure 3. Heart rate reduction following ivabradine treatment in
patients with stable angina treated with atenolol.
A further heart rate reduction of approximately 8 beats per minute can be brought
about by adding ivabradine (7.5 mg bid) to a preexisting treatment with a
β-blocker. Heart rate was measured at baseline, after 2 months (M2), and after
4 months (M4 = end of study).
Based on data from reference 40: Tardif et al. Eur Heart J. 2009;30:540-548.


Evidence has accumulated that ischemia contributes to myocardial remodeling and the subsequent development of heart failure. In 60% of patients with heart failure, coronary artery disease and ischemia contribute to the development and progression of the heart failure syndrome. Remodeling of the heart extends beyond myocardial remodeling and involves vascular effects, which are mechanistically driven by neuroendocrine activation and heart rate elevation. Neuroendocrine antagonists and heart rate reduction are treatment options for heart failure and left ventricular dysfunction. Anginal symptoms can be treated by heart rate reduction either with ivabradine, β-blockers, or both types of drugs combined. The pathophysiological concept described above and the data available reinforce the importance of using optimal antianginal and anti-ischemic therapy in patients with impaired left ventricular function or heart failure in order to slow the progress of left ventricular remodeling and heart failure and to control symptoms.■

Keywords: angina; heart failure; heart rate; left ventricular dysfunction; neuroendocrine activation; remodeling

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