by M. Böhm, J . -C. Rei l , and F. Cus todi s , Germany



Michael BÖHM, MD, PhD

Jan-Christian REIL, MD

Florian CUSTODIS, MD

Internal Medicine Clinic III University Clinic of Saarlandes Homburg

Saar, GERMANY

Elevated heart rate and atherosclerosis: pathophysiology and clinical outcomes

A high heart rate is associated with an elevated mortality rate both in the general population as well as populations with hypertension or established cardiovascular disease like coronary artery disease (CAD) and heart failure. In view of this epidemiological background, it has been suggested that pharmacological heart rate reduction might improve cardiovascular complications. This pharmacological approach became available after the development of the I f channel inhibitor ivabradine. Ivabradine reduces heart rate by depressing the phase of spontaneous depolarization of the sinus node. The sinus node activity of the drug is specific, and therefore no cardiodepressant effects on atrioventricular conduction or inotropy are induced. In experimental models of atherosclerosis, ivabradine was able to reduce endothelial dysfunction and inhibit plaque formation. In the large outcome trial, BEAUTIFUL (morBidity-mortality EvAlUaTion of the I f inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction), ivabradine was able to reduce ischemia-related outcomes like reinfarction or the necessity for coronary revascularization in patients with known CAD after myocardial infarction. Furthermore, ivabradine has an established role in the symptomatic treatment of CAD and angina syndromes to reduce myocardial ischemia—alone, and even in the presence of β-blockers. A trial of ivabradine in chronic heart failure, the end stage of CAD, is currently being performed (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial; SHIFT). The data of this large outcome trial will establish whether the beneficial effects in experimental models might translate into a reduction of hard clinical end points in clinical practice in patients with advanced CAD or heart failure.

Medicographia. 2009;31:356-363 (see French abstract on page 363)

Heart rate is highly variable, and acts as the predominant driving force for cardiovascular regulation in mammals, including humans. Heart rate contributes closely to myocardial work and energy requirements, thus influencing the balance of cardiac performance and economy. It seems plausible that, via myocardial mechanical and metabolic stimulation, heart rate could impose stress on the myocardium and may therefore play an important role in determining life expectancy as well as lifespan in all individuals. This biological background is supported by many studies and investigations.1 The myocardium with compromised function shows a significant rightward shift of the normal physiological pressurevolume curves (Figure 1). The external work is greatly decreased, whereas much more internal energy is generated, which consequently decreases efficiency.2,3 These energy considerations are in line with the specific interrelation between heart rate and life expectancy (Figure 2). It is striking that mammals with the highest heart rates at rest have the shortest lifespan. The opposite holds true for those mammals with the lowest heart rates (Figure 2). Lowering heart rate reduces the ischemic threshold of diseased hearts, reduces heart work, and thus might be a potential therapeutic target of treatment in heart disease. According to detailed calculations, heart rate reduction of 10 beats per minute (bpm) can save about 5 kg of adenosine triphosphate per lifetime in humans.4



Figure 1. Panel A: normal pressure-volume relationship in the healthy heart.

The external work (kinetic energy) is the quadrangular-like area. The internal work is the triangular-like area (potential energy) between the contractility line (Es) and the isovolumetric relaxation curve. The total pressure-volume area represents the sum of internal and external work performed by the cardiac cycle.

Panel B: pressure-volume loop of a heart with severe diastolic and systolic heart failure (arrows).

The internal work of the heart is markedly increased compared with the external work, as well as with its normal value (see triangle-like area in panel A). LV, left ventricular.

Modified from reference 2: Opie LH, ed. Heart Physiology: From Cell to Circulation. 4th ed. Copyright © 2004, Lippincott, Williams & Wilkins.

An increase in sympathetic activity and a decrease in parasympathetic activity increases heart rate. Stimulation of the sympathetic nervous system can cause myocardial apoptosis as well as sudden cardiac death.5,6

Consequently, it is difficult to distinguish between the influence on life expectancy of increased heart rate itself (metabolic demand), and the potential imbalance between sympathetic and parasympathetic neuroendocrine regulation. Experimentally, the pharmacological reduction of heart rate with cardiac glycosides like digitalis has been found to cause a 30% prolongation of survival time in healthy mice (Figure 3, page 358).7 This may support the notion that reduction of heart rate could itself prolong survival time in mammals, at least in part independently of the activity of the autonomic nervous system. The open question is whether these effects of heart rate modulation primarily act on the vessels or on the myocardium.



Figure 2. Inverse linear relationship between heart rate and life expectancy in different species. Bpm, beats per minute.

Modified from reference 1:Levine JH. J Am Coll Cardiol. 1997;30:1104-1106. Copyright © 1997, Elsevier.

Heart rate and survival in healthy and hypertensive individuals

Epidemiological studies investigating approximately 30 000 individuals in total over a time period of between 5 and 36 years have revealed an inverse relationship between heart rate and survival time.8-13 The risk for total mortality, coronary artery disease (CAD), stroke, and death caused by noncardiovascular diseases significantly increased in an age- and gender- independent manner with higher heart rates (Figure 4).11



Figure 3. Comparison of survival time in normal mice and mice treated with digitalis.

Modified from reference 7: Coburn FA, Ross MG, Rivera MS. Johns Hopkins Med J. 1971;128:169-193. Copyright © 1971, Johns Hopkins University Press.



Figure 4. Relationship between heart rate and the incidence of total mortality, coronary heart disease (CHD), cancer, other deaths, and stroke. Bpm, beats per minute.

Modified from reference 11: Wilhelmsen I, Berglund G, Elmfeldt D, et al. Eur Heart J. 1986;7:279-288. Copyright © 1986, The European Society of Cardiology.

More specifically, by comparing data on individuals with a heart rate lower than 60 bpm to that of individuals with a heart rate of 90 to 99 bpm, it was estimated that there is a threefold increased mortality risk associated with the higher heart rate.11 According to the CArdiovascular Study in the ELderly (CASTEL), this relationship is especially true for patients older than 65 years.14 In clinical practice, it can be assumed that high heart rate is correlated with an increase in mortality caused by CAD, and is associated with an increased risk of sudden cardiac death.9,12,15 Maximal heart rate developed during exercise, the difference between this heart rate value and the resting heart rate, and the time course of the heart rate returning to normal values after exercise are risk factors for sudden cardiac death if abnormal.16,17 Compared with resting heart rates of about 60 to 65 bpm, resting heart rates of about 88 to 99 bpm are associated with a five- to sixfold increase in the risk of sudden cardiac death in men and a twofold increase in women.9,10,15 The total mortality rate doubles with a rise in heart rate of about 40 bpm.15,18,19 This correlation is strengthened when further risk factors like older age, hypertension, diabetes mellitus, and high body mass index are present. The association between heart rate and the development of arterial hypertension was first demonstrated in soldiers after their return from the First World War.20 Follow-up in these individuals revealed a significant correlation between heart rate and the development of hypertension, cardiovascular disease, and chronic renal failure. These findings were supported by the prospectively designed Hypertension and Ambulatory Recording VEnetia STudy (HARVEST),21 which showed a link between high heart rates and a further increase in blood pressure in stage 1 hypertensive individuals. Additionally, Gillum et al demonstrated that patients with arterial hypertension have higher heart rates compared with healthy individuals.22 Complications of cardiovascular disease as well as total mortality double as heart rate increases by 40 bpm.23,24 Heart rate therefore appears to be associated with vascular risk factors like hypertension.

Atherosclerotic heart disease – heart rate and mechanisms of atherosclerosis

Experimentally, in vitro studies have demonstrated that the stretching of human smooth muscle cells enhances the release of angiotensin II in a frequency-dependent manner and thereby stimulates the production of collagen in the vessel wall. This effect can be antagonized by angiotensin receptor 1 antagonists.25 Corresponding to this result, the stiffness of the arterial vessel wall rises with increasing heart rates. This close correlation has especially been revealed in individuals suffering from hypertension. The combination of increased blood pressure with repetitive pressure changes caused by higher heart rates imposes an additional mechanical load on the vessel wall, potentially increasing the risk of clots.26 Mangioni et al demonstrated that tachycardic pacemaker stimulation increases the stiffness of carotid arteries.27 In monkeys, a strong correlation was shown between an increased hemo- dynamic stress index (heart rate multiplied by mean arterial blood pressure) and the development of atherosclerosis in the aorta or iliac vessels.28



Figure 5. Atherosclerotic lesions in the aortic sinus (upper panels) and the

ascending aorta (lower panels) in ApoE knockout mice treated with vehicle and ivabradine.

The original slices demonstrate a marked reduction in plaque burden.

Modified from reference 31: Custodis F, Baumhäkel M, Schlimmer N, et al. Circulation. 2008;117:2377-2387. Copyright © 2008, American Heart Association, Inc.

Experimental heart rate reduction

Heart rate reduction caused by sinus note ablation in monkeys fed with a cholesterol-rich diet was found to be associated with a decrease in coronary atherosclerotic lesions.29 Additionally, in young patients with myocardial infarction, there is a strong positive relationship between higher heart rates and the extent of atherosclerotic coronary lesions.30 Pharmacological inhibition of heart rate was possible after the development of the I f channel inhibitor ivabradine. In ApoE knockout mice, cholesterol-induced atherosclerosis was inhibited by heart rate reduction with ivabradine.31 Heart rate reduction of 10% led to a 40% decline in plaque load of the aortic sinus and a 70% decline in plaque load in the ascending aorta (Figure 5). Mechanistically, a reduction in NADPH (nicotinamide adenine dinucleotide phosphate) oxidase and superoxide production—and thus in oxidative stress—might be involved (Figure 6). In earlier stages of atherosclerosis, a reduction in endothelial dysfunction was observed with heart rate reduction by ivabradine.32 Presumably, therefore, mechanical load on the vessel wall caused by higher heart rates might lead to endothelial dysfunction, increased oxidative stress, and enhanced plaque formation, which can be reversed or prevented by the inhibition of I f channels and consecutive heart rate reduction with ivabradine.31,32



Figure 6. Panel A: nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity; Panel B: superoxide anion production; Panel C: lipid hydroperoxidase; and Panel D: dehydroetidium (DHE) fluorescent staining, in ApoE KO mice treated with vehicle or ivabradine.

Heart rate reduction with ivabradine leads to a marked

reduction in NADPH oxidase, superoxide production, lipid peroxidation, and free radicals according to fluorescence measurement with DHE.

Modified from reference 31: Custodis F, Baumhäkel M, Schlimmer N, et al. Circulation. 2008;117:2377-2387. Copyright © 2008, American Heart Association, Inc.

Coronary artery disease and myocardial infarction

Events in patients with stable CAD are correlated with resting heart rate.33 Diaz et al investigated 24 913 patients and demonstrated that total mortality rate, the mortality rate for cardiovascular diseases, as well as the rate of cardiovascular rehospitalization increases with increasing heart rate.34 Patients with a resting heart rate of more than 83 bpm had an increased relative risk of 1.23 and an elevated cardiovascular mortality risk of 1.31 compared with the control group. Kaplan et al demonstrated a reduced progression of atherosclerosis in monkeys fed with a cholesterol-rich diet, as a result of heart rate lowering with propranolol.35 A high heart rate could additionally impair the stability of coronary plaques through enhanced mechanical stress caused by repetitive pressure changes. Myocardial infarction develops when coronary plaques rupture and thrombosis occludes the vessel. The probability of plaque rupture depends on the stability of the fibrous cap covering the plaque shoulder, as well as the mechanical stress imposed on it. An increased mechanical load has been shown to provoke rupture of the plaque.36 Furthermore, Lee et al found that rupture of explanted human aortic plaques was augmented with increased heart rates.37 This effect was supported by the work of Heidland and Strauer, who studied 106 patients who underwent two coronary angiography procedures within 6 months.38 All patients had only smooth stenosis on initial observation. The group with higher heart rates (>80 bpm) developed significantly more plaque ruptures compared with the group with the lower heart rates. Regression analysis identified heart rate as an independent risk factor for development of plaque rupture.



Figure 7. Comparison of mortality in patients with myocardial infarction according to heart rate. Bpm, beats per minute.

Modified from reference 39: Hjalmarson A, Gilpin E, Kjekshus J, et al. Am J Cardiol. 1990;65:547-553. Copyright © 1990, Elsevier Inc.



Several trials have demonstrated the relevance of heart rate regarding the prognosis of patients after myocardial infarction. According to a study by Hjalmarson et al, the heart rate of patients with myocardial infarction was significantly higher than that of controls.39 Furthermore, higher heart rates in myocardial infarction patients at hospital discharge correlate with an increase in mortality rate after 1 year (Figure 7). Meta-analyses of the GISSI-2 and GISSI-3 trials (Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico), which included about 20 000 patients, demonstrated that in-hospital mortality rates of patients after myocardial infarction rise from 3.3% for patients with a heart rate <60 bpm on admission to 10.1% for patients with a heart rate >100 bpm.40

The GISSI trials showed that even myocardial infarction patients without heart failure who had an elevated heart rate had a worse long-term survival prognosis.40 The relevance of heart rate after myocardial infarction is supported by results from β-blocker trials. Heart rate reduction by â-blockers is associated with a decrease in total mortality and sudden cardiac death.41-44 Accordingly, heart rate–reducing verapamil- like calcium antagonists have beneficial effects in terms of prognosis of patients after myocardial infarction in the absence of heart failure.45 In contrast, dihydropyridinetype calcium antagonists have detrimental effects on survival because of reflex tachycardia.

Taken together, heart rate reduction is correlated with an improvement in the long-term survival of patients with myocardial infarction, which has been best demonstrated by β-blocker trials.

Effects of heart rate reduction on outcome

The role of I f channel inhibition on cardiovascular events in patients with CAD and reduced left ventricular function was studied in BEAUTIFUL (morBidity mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction).46,47 The BEAUTIFUL investigators studied patients with known CAD who also presented with left ventricular dysfunction. In the epidemiological part of the trial,47 it was shown that patients had an adverse prognosis if heart rate was above 70 bpm (Figure 8). This held true for hospitalizations for heart failure, coronary revascularization, and cardiovascular death. Treatment with ivabradine46 resulted in a reduction of ischemia-related end points like myocardial infarction and cardiovascular revascularization in patients with a heart rate above 70 bpm. The combined end point was not significantly affected by the treatment with ivabradine. It thus seems apparent that atherosclerosis, and in particular atherosclerotic events, are favorably influenced by a reduction in heart rate. This is not self-evident, because in a reduced heart rate, other mechanisms like higher daily levels of exercise, fewer comorbidities, and less obesity might be involved.48 Nevertheless, further trials will have to establish the role of I f channel inhibition, possibly in other conditions associated with high heart rates such as heart failure or renal damage in high-risk hypertensive individuals.49,50



Figure 8. Relation between heart rate and ischemia-related end points (upper Panel A) and cardiovascular end points (upper Panel B) as well as Kaplan-Meier curves (lower Panel A and B) in BEAUTIFUL (morBidity mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction).

HF, heart failure.

Modified from reference 47: Fox K, Ford I, Steg PG, et al. Lancet. 2008; 372:817-821. Copyright © 2008, Elsevier Ltd.

Future perspectives: heart failure

As with the conditions hypertension and CAD, heart failure, in particular in the decompensated state, is accompanied by high heart rates. This is brought about by activation of the sympathetic nervous system as one component of neuroendocrine activation. It is also known that in this condition, elevated heart rate is associated with a poor outcome. Heart rate reduction has been discussed as being one of the mechanisms by which β-blockers mediate an improvement of outcome in heart failure. Interestingly, there is discussion that in heart failure, there may be energy depletion, which is improved by heart rate reduction. Furthermore, in the failing heart, the positive force frequency relationship turns into a negative inverted relationship that results in a decline in the force of contraction when heart rate is increased (impaired Bowditch-effect). It is therefore tempting to speculate that heart rate reduction might also be beneficial to reduce heart failure–related events.

However, in BEAUTIFUL, heart failure hospitalizations were not significantly reduced. It is noteworthy that heart rate in BEAUTIFUL was rather low. It was therefore extremely important to carry out a trial specifically in patients with heart failure and neuroendocrine activation, and therefore higher heart rates. In Systolic Heart failure treatment with the I f inhibitor ivabradine Trial (SHIFT), patients with heart failure who are Haron standard medication are being investigated. These patients are receiving ivabradine as an add-on therapy. The average heart rate in SHIFT is higher than in BEAUTIFUL. Therefore, this trial will give a definite answer as to whether there is a reduction in heart failure outcome with heart rate reduction in this high-risk population. Furthermore, it will provide proof of the pathophysiological concept that along the cardiovascular continuum, events are dependent on heart rate and can be targeted by heart rate–lowering therapies (Figure 9). All patients are randomized in SHIFT and the results can be expected at the end of 2010.



Figure 9. Clinical and experimental evidence for the potential role of heart rate along the cardiovascular continuum. In patients with high heart rates, there is a high risk of the development of atherosclerosis. A high heart rate leads to ischemia and remodeling of the heart and vessels, and contributes to comorbidities in hypertension and chronic heart failure. Inhibition of the If channel might reduce heart rate, and therefore cardiovascular events, following treatment with ivabradine.

Modified from reference 48: Reil JC, Böhm M. Lancet. 2008; 372:779-780. Copyright © 2008, Elsevier Ltd.

Conclusion

Heart rate is an independent risk factor for patients with cardiovascular disease, in particular arterial hypertension, myocardial infarction, CAD, and heart failure. This relationship is supported by a large number of animal studies that have shown detrimental effects of increased heart rate on the function and structure of the cardiovascular system, in particular in atherosclerosis. Whether pharmacological heart rate reduction might be beneficial in other conditions, such as for prevention of atherosclerotic disease or heart failure, must be the subject of future clinical trials. _

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