Heart rate response to exercise: impact on myocardial ischemia and left ventricular function






Michael BÖHM, MD
Christian UKENA, MD
Universitätsklinikum des Saarlandes, Klinik für Innere
Medizin III, Kardiologie, Angiologie und Internistische
Intensivmedizin Homburg/Saar
GERMANY

Heart rate response to exercise: impact on myocardial ischemia and left ventricular function


by M. Böhm and C. Ukena, Germany



Elevated heart rate is associated with cardiovascular outcome in the general population and in patients with hypertension, ischemic heart disease, and heart failure. During exercise the autonomic nervous system increases heart rate in response to increasing peripheral demand. In non-diseased hearts, increased rate is associated with enhanced myocardial contractility (Bowditch effect). In coronary artery disease, on the other hand, increased rate shortens diastole, thereby decreasing myocardial perfusion, with the risk of severe ischemia and angina. In heart failure, in addition to these mechanisms, the Bowditch effect is impaired. The combination of a negative force-frequency relationship and myocardial ischemia during exercise increases ventricular filling pressures and respiratory work, causing hypoxia, dyspnea, and impaired exercise tolerance. Thus, in heart failure, the hemodynamically optimal upper heart rate may be below the maximum achieved heart rate. Since heart rate determines oxygen consumption and delivery, its modulation, as by the If channel inhibitor ivabradine, strongly influences exercise tolerance, in particular in coronary artery disease and heart failure.

Medicographia. 2012;34:395-399 (see French abstract on page 399)



Heart rate is a major determinant at rest and during exercise of the response to increased oxygen demand by working skeletal muscles and other vital organs. 1 Adaptation to increased physical activity is accomplished by an increase in cardiac output, which requires an increase in heart rate in addition to adaptation of stroke volume in response to exercise. In special conditions, heart rate can afford to be low at rest when stroke volume is high (as in athletes), or is obliged to be high when cardiac function is compromised (as in heart failure). Stimulation of the sympathetic nervous system and withdrawal of parasympathetic activity during exercise increases heart rate (positive chronotropy), shortens atrioventricular conduction (positive dromotropy), increases intraventricular conductivity (positive bathmotropy), and enhances the force of contraction (positive inotropy).2-4

The direct effects of heart rate on contractility were described in 1871 by the American physiologist Henry Pickering Bowditch (1840-1911), writing in German in the course of a 3-year stay in Europe.5 In non-diseased hearts, contractility increases with increases in rate. This positive Bowditch (or Treppe) effect is an important addition to sympathetic activation in adapting contractility and cardiac output to increased peripheral demand. When the heart rate response to exercise is subnormal, as in chronotropic incompetence,6-9 the increase in cardiac output remains inade- quate, due directly to the inadequate increase in heart rate, but also to the impaired adaptation of inotropy to exercise-related increases in heart rate, resulting in abnormally low exercise performance and aerobic capacity.6 The crucial role of heart rate is highlighted by the fact that maximal heart rate during exercise and heart rate recovery are the most commonly used parameters in cardiology for assessing the effects of rehabilitation10,11 and exercise training.12-14 Rate-adaptive cardiac pacing was developed to optimize exercise tolerance in patients with chronotropic incompetence.7,15 In summary, exercise tolerance can be impaired by chronotropic incompetence, structural heart disease, or by both acting in concert.

Myocardial ischemia

In coronary artery disease, increased heart rate is accompanied by overproportional shortening of diastole.16 Since myocardial perfusion takes place predominantly in diastole, a high heart rate is the primary denominator of myocardial ischemia in the presence of significant coronary artery stenosis.16 Furthermore, relaxation and contraction at high heart rates consume extensive energy, predisposing to ATP deficiency during exercise. In critical coronary artery disease, this can result in severe ischemia with angina as its typical clinical manifestation.16

During ischemia, in particular in the presence of high heart rate, ventricular muscle develops diastolic dysfunction.17 The resulting rise in filling pressure impairs exercise tolerance and increases pulmonary wedge pressure, causing shortness of breath.17 Compounding factors are an increase in pulmonary stiffness, responsible for an increase in ventilatory work,18,19 and an increase in diffusion distance, when interstitial pulmonary edema develops into alveolar fluid accumulation in advanced pulmonary edema. The result is intrapulmonary shunting, resulting in decreased oxygen saturation,20,21 aggravation of clinical congestion, and decreasing exercise tolerance.22 Heart rate reduction with β-blockers23 or the If channel inhibitor ivabradine,24,25 has been shown to reduce symptoms in myocardial ischemia by lengthening diastole, prolonging coronary perfusion, and reducing oxygen consumption. The example of ivabradine demonstrates that the effect of heart rate reduction is crucially and uniquely mechanistic: ivabradine is a pure If channel inhibitor with no other known cardiovascular effects.26

Left ventricular dysfunction

In the failing heart, the Bowditch effect is impaired, resulting in a negative force-frequency relationship in vitro27,28 and in vivo.29,30 Initial evidence to this effect came from isolated cardiac preparations from patients undergoing heart transplantation.27,28 Failing heart preparations also develop a relaxation deficit at higher heart rates.27 Although a high heart rate is a key clinical finding in severe heart failure, one must assume that adaptation of contractility in response to the elevated heart rate is also blunted.30 The situation is aggravated by the fact that the mechanisms described for coronary artery disease and ischemia are replicated in the failing heart, since this is an energy-depleted organ. Systolic dysfunction with left ventricular dilatation results in an increase in wall tension. This in turn increases extracoronary/coronary resistance, resulting in reduced oxygen delivery to the myocardium. These findings were obtained in patients with systolic dysfunction. The situation in patients with a preserved ejection fraction is largely unknown.

The optimal heart rate in elderly individuals31 or in exercising heart failure patients is still debated.30 Experimental data suggest that heart rate limits should differ from those in individuals with normal myocardial function because the inverse force-frequency relationship limits the ability of cardiac output to increase exercise tolerance.27-30 In addition, the deleterious effects of oxygen deficiency at high heart rates persist in coronary artery disease or impaired left ventricular function, prompting speculation that high heart rates compound deterioration in myocardial function. In particular, cardiac pacemakers could be set to different parameters in patients with heart failure and those with normal left ventricular function.30 Cardiac pacing at higher rates has been shown to produce progressive remodeling, in particular in patients with impaired left and/or right ventricular function.31,32

A study in patients requiring pacemaker therapy compared those with impaired and normal left ventricular function.30 In those with normal left ventricular function, pacing at rates from 70 to 160 bpm showed a close association with increases in cardiac output as determined by maximum oxygen uptake (VO2max). Up to maximal exercise tolerance, the increases in heart rate ran parallel to those in VO2max. However, in individuals with heart failure, pacing only produced a parallel increase in VO2max from 70 to 120 bpm, after which VO2 leveled off while heart rate continued to increase and patients continued to exercise. This finding indicates that in many patients with chronotropic incompetence the optimal upper rate is below the maximal upper rate limit. In patients with pacemakers for chronotropic incompetence, optimal heart rate was 86% of age-predicted values at ejection fraction >55%, but only 75% of age-predicted values at ejection fraction <45%. Figure 1 summarizes the mechanisms of impaired exercise tolerance at high heart rates.

When patients develop dyspnea, the adverse effects of elevated heart rate, such as shorter diastole and ischemia, may be partly responsible for reduced exercise tolerance. A similar situation has been described in patients with critical low output due to acute decompensated heart failure. The positive inotropic effect of the β-adrenoceptor agonist dobutamine is often used to increase cardiac output and lower left ventricular filling pressure in acute heart failure.33 However, as a β-adrenergic agonist, it also increases heart rate to a variable extent,33 which can have adverse effects on outcome in acute heart failure.34 Ivabradine, on the other hand—administered in an attempt to restore chronotropic-inotropic balance— lowered heart rate while leaving inotropy unaffected in a patient with severe heart failure on dobutamine: doses of 5 to 7.5 mg twice daily lowered heart rate from 110 to 72 bpm while increasing cardiac output, stroke volume, and oxygen saturation, and decreasing systemic vascular resistance.34 This case report provides proof of concept that heart rate reduction in severe heart failure is not necessarily associated with a reduction in cardiac output, but can actually increase cardiac output and myocardial efficiency, resulting in improved hemodynamics.


Figure 1
Figure 1. Mechanisms of dyspnea in heart failure.

Activation of the sympathetic nervous system during exercise increases phase 4 depolarization and increases
heart rate. During exercise in heart failure, the increased heart rate shortens diastole, leading
to an increase in right ventricular filling pressures, which in turn increases respiratory work, hypoxia, and
hypercapnia. These changes signal to the brain stem that diuresis is taking place thereby triggering
dyspnea. In chronic heart failure altered chemoreceptor sensing leads to dyspnea at lower hypoxia
thresholds. Thus, there are vicious cycles in the interaction between sympathetic activation, heart rate,
heart, lung, and central nervous system.



Elevated resting heart rate is a general marker of morbidity. It is associated with cardiovascular mortality in normal individuals,35,36 and in those with hypertension,37 coronary artery disease,38 and in particular heart failure, where an additional 5 bpm is associated with a 16% increase per year in the composite outcome of cardiovascular death and hospitalization for heart failure.39 Use of the exercise heart rate in risk prediction is more complicated. While the absolute increase in heart rate appears associated with a good prognosis,40,41 impaired recovery of heart rate after exercise has proved an important denominator of cardiovascular outcomes.42 Delayed decrease in heart rate after exercise is associated with an increase in cardiovascular death and sudden cardiac death in particular.42 Interestingly, a novel technique to treat resistant hypertension by renal sympathetic denervation produces not only a marked reduction in blood pressure,43,44 but also faster heart rate recovery after exercise, while leaving the absolute increase in heart rate intact.43 Denervation reduces excessive sympathetic drive without inducing chronotropic incompetence and appears to restore sympathetic-parasympathetic balance during rest.45 More studies are required to determine whether improved heart rate recovery after exercise is associated with better outcome in conditions such as severe hypertension, ischemic heart disease and, in particular, heart failure, where such data are completely lacking. We need to know whether outcome in such common and serious conditions can be enhanced by modulating the exercise heart rate, whether pharmacologically with β-blockers and ivabradine, chronic endurance training, or sympathetic denervation.

Conclusion

Heart rate patterns at rest and during exercise predict cardiovascular outcomes. Since heart rate determines oxygen consumption and delivery, its modulation by ivabradine strongly influences exercise tolerance, in particular during ischemia. This property makes the drug a valuable component in the armamentarium of coronary therapy. Chronic heart rate reduction reduces cardiovascular hospitalizations in heart failure patients in sinus rhythm at heart rates ≥70 bpm,46 and cardiovascular death and all cardiovascular hospitalizations at heart rates ≥75 bpm.47

Heart rate regulates cardiovascular function and, in particular, cardiac output during exercise and other output conditions. Regulation by the autonomic nervous system, along with activation of sympathetic outflow and reduction of parasympathetic activity, increases heart rate and cardiac output, but also determines training condition and cardiovascular comorbidities. Heart rate elevation is a determinant of cardiovascular outcome in the general population, and in patients with hypertension, ischemic heart disease, and heart failure. Delayed return of heart rate to resting levels after exercise is a risk factor for cardiovascular death, and in particular, sudden death. In heart failure the force-frequency relationship reverses from positive to negative. As a result, increases in heart rate reduce contractility, increase myocardial stiffness, impair exercise tolerance, and precipitate dyspnea and cardiac congestion.

Clinical studies have provided pathophysiological proof of the benefits of heart rate reduction in conditions such as impaired left ventricular function and heart failure. We need further studies using novel techniques such as sympathetic denervation if we want to fully elucidate the role of heart rate not only at rest, but during and after exercise. _

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Keywords: exercise; heart rate; heart rate reduction; ivabradine; left ventricular dysfunction; myocardial ischemia