Central and peripheral effects of p-blockers in heart failure
ympathetic stimulation can influence exercise capacity through both central and peripheral effects. Myocardial P-adrenoceptor downregulation is likely to be partially responsible for the reduced chronotropic and inotropic responses to peak exercise in mild-to-moderate symptomatic heart failure due to idiopathic dilated cardiomyopathy. Also, in chronic heart failure, cardiac sensitivity to sympathetic drive and, in particular, P-adrenoceptor density are positively and independently related to maximal exercise capacity.
By blunting the inotropic and chronotropic responses to exercise, P-blockers impair maximal exercise capacity in healthy subjects. However, this is not the case in heart failure: long-term P-blockade improves myocardial function in the failing heart, even if it does not actually improve maximal exercise capacity.
Peripheral sympathetic effects are partly responsible. Sympathetic activation may constrict skeletal muscle blood vessels and impair blood flow. This mechanism has often been considered a cause of impaired exercise capacity in heart failure. However, blockade of the vasoconstrictor effects of the sympathetic nervous system does not improve exercise performance, at least not in the acute situation. It takes time before improvement is observed in the vasodilator capacity of skeletal muscle blood vessels and in the aerobic capacity of the muscles themselves.
Sympathetic activation also causes metabolic changes in skeletal muscle, with a greater uptake of free fatty acids relative to glucose. Consequently, oxygen consumption at each workload is augmented by sympathetic stimulation, and acute inhibition of the sympathetic drive has been shown to decrease limb oxygen consumption in heart failure. Although this metabolic change actually increases skeletal muscle efficiency, with reduced oxygen consumption at each work rate, it may also decrease V02, mimicking impaired functional capacity.
Differences between p-blockers in their effects on exercise capacity
Selective fij-receptor blockers. Long-term metoprolol administration induces a highly significant improvement in stroke volume, stroke work, and cardiac indices with a slight reduction, or no change, in left ventricular filling pressures. It leaves coronary sinus blood flow and myocardial V02 unchanged, while increasing myocardial lactate extraction. These changes are consistent with a shift in myocardial metabolism, involving a greater uptake of glucose rather than free fatty acids and improved myocardial efficiency (myocardial work/V02 ratio), which may help to improve the cardiovascular response to exercise. The properties which enable metoprolol to increase maximal exercise capacity are probably its Pj selectivity and ability to induce Pt receptor upregulation; these properties preserve, at least partially, the chronotropic response to exercise which, concomitantly with an improvement in left ventricular function, may help to improve peak exercise capacity.
Nonselective (3-blockers. Carvedilol is a nonselective P-blocker with associated al antagonist, antioxidant, and antiproliferative activities. It downregulates
P-receptors in the experimental setting and does not change P-receptor density in heart failure. Moreover, carvedilol decreases cardiac norepinephrine spillover (metoprolol either increases transmyocardial norepinephrine levels or leaves them unchanged). Despite favorable effects on left ventricular function and the clinical course of heart failure, the effects of carvedilol on maximal exercise capacity are neutral. It significantly increases stroke volume and stroke work indices, and concomitantly decreases right atrial, pulmonary arterial, and pulmonary wedge pressures vs placebo at rest and during exercise. Given such significant improvement in left ventricular function, its inability to increase maximal exercise capacity may be due to its negative chronotropism: by slowing the heart rate, it may prevent peak exercise cardiac output from improving sufficiently to allow an increase in maximal functional capacity. Blunting of the maximal vasodilation response mediated by peripheral P2 antagonism may also account for the noneffect on maximal exercise.
These actions may also explain why carvedilol is more effective than metoprolol in attenuating the chronotropic response to exercise (an accurate measure of the cardiac response to sympathetic stimulation). The ability of carvedilol to provide more comprehensive protection against the deleterious actions of the sympathetic nervous system on the heart may account for its greater stimulation of left ventricular performance. Despite producing greater increases in the left ventricular ejection fraction and greater decreases in left ventricular chamber size, it produces lower increases in maximal exercise capacity than metoprolol.
The greater antiadrenergir activity of the third-gener-ation p-blockers causes a greater reduction in the heart rate response to exercise. This may prevent peak exercise cardiac output from increasing sufficiently to improve peak V02 despite the increase in stroke volume. This is probably the main reason why third-generation P-blockers fail to improve maximal exercise performance, in contrast to metoprolol, which has lower antiadrenergic activity.
Assessing the effects of P-blockade on exercise performance
Maximal exercise testing should not be used to assess the effects of P-blockers on functional capacity in heart failure as it is highly dependent on the chronotropic response to exercise. Peak V02 remains significantly correlated with peak exercise cardiac index when the values obtained at baseline, or after short- or long-term p-blockade, are used. A more appropriate method of assessing exercise capacity in heart failure is the level of effort required in a submaximal exercise test, which is less dependent on the heart rate response to exercise and more closely related to the improvement observed in left ventricular function following P-blockade. It may also better reflect everyday physical activity. The 6-min corridor walk test was recently validated as a predictor of prognosis in heart failure, especially in advanced heart failure where the exertional level may actually approach maximal exercise capacity. Macdonald et al showed that patients significantly improved their 6-min walk distance after carvedilol treatment for 3 months, with class
IV patients improving more than the less symptomatic group. Another study a randomized double-blind controlled trial of carvedilol vs metoprolol in heart failure showed significant improvement in exercise capacity (6-min walk test) with both drugs (the difference between the drugs was not significant). Unfortunately, however, submaximal testing is not well standardized and has suffered from considerable interobserver variability, particularly in multicenter studies which have failed to duplicate the improvement in submaximal exercise capacity and 6-min walk distance observed with carvedilol in single-center studies.
In summary, the main reason why p-blockers fail to increase maximal exercise capacity in heart failure, despite improving the symptoms and clinical course, is probably a combination of impaired chronotropic response to exercise and peripheral metabolic changes. Submaximal exercise tests may be preferable for assessing change in functional capacity on p-blockade but require further standardization before they can be validated for use in multicenter trials.