Effects of Exercise, Pharmacologic Stress, and Pacing on the Cardiovascular System

Hemodynamic Effects

The hemodynamic effects of treadmill or bicycle exercise include an increase in heart rate (chiefly caused by sympathetic activation and partly by parasympathetic withdrawal), increase in inotropic state, increase in systolic blood pressure, decrease in systemic vascular resistance (SVR), and increased venous return (caused by sympathetic vasoconstriction of the large-capacitance veins and the pumping effect of skeletal muscles), contributing via the Frank-Starling mechanism to an increase in stroke volume. Treadmill exercise permits the achievement of higher oxygen consumption than bicycle exercise. The increment of blood pressure with exertion is mainly caused by an increase in cardiac output, which outweighs the decline in peripheral resistance. The opposite changes in after- and preload are seen with isometric (handgrip) exercise, that is, SVR increases, and venous return decreases ( Table 49.1 ).

The major effects of dobutamine are mediated by β ₁ adrenergic receptors. At low doses, an enhancement in myocardial contractility without tachycardia is a predominant response. At doses above 20 mcg/kg/min, there is an increase in systolic blood pressure to about 170 mm Hg (i.e., by 30–40 mm Hg) and in heart rate to about 120 beats/min (i.e., by 40–50 beats/min). A decrease in blood pressure at higher doses is common, most commonly caused by the vasodilating effect of dobutamine reflecting the stimulation of β ₂ adrenergic receptors. Bradycardia is less common and reflects a reflex response to blood pressure elevation or the activation of mechanoreceptors caused by myocardial hypercontractility.

The most commonly used coronary vasodilators—dipyridamole, adenosine, and regadenoson—involve the same metabolic pathway, either increasing endogenous adenosine levels (dipyridamole) or directly acting on the vasculature (exogenous adenosine or regadenoson, an A2A adenosine receptor agonist). All these agents produce a small decrease in blood pressure and modest tachycardia with a minor increase in myocardial function.

Pacing represents an alternative method to increase cardiac work by the induction of tachycardia, usually of 160 beats/min. Atrial stimulation (either transvenously or by transesophageal approach) is a preferable technique because asynchronous regional contractility from ventricular pacing provides interpretive challenges. Tachycardia attained with pacing is accompanied by stable blood pressure and unchanged loading, and a major advantage of this modality is a better hemodynamic control than with other stressors. The disadvantage is that the lack of a suitable blood pressure response leads to only a modest increment of the rate-pressure product.

Ergonovine stress testing is thought to be the gold standard for diagnosis of coronary artery spasm. This drug exerts coronary vasoconstricting effects by agonizing β-adrenergic, dopaminergic, and serotonin receptors. The high sensitivity of this modality, even in patients with single-vessel spasm, can be explained by the transmural nature of vasospastic ischemia leading to severe wall motion abnormalities.

Mechanisms Of Ischemia

Exercise, dobutamine, and pacing can induce myocardial ischemia by an increase in cardiac work and oxygen demand exceeding the limited blood supply resulting from significant coronary stenosis. Additional mechanisms responsible for ischemia include coronary flow maldistribution with a reduction of subendocardial perfusion because of adenosine accumulation in the myocardial tissue during stress ^, and the “oxygen-wasting” effect evidenced for dobutamine.

The use of vasoactive stressors is based in part on the development of perfusion heterogeneity. The generation of maximal vasodilation causes flow heterogeneity because the hyperemic response is limited in the territory supplied by a coronary stenosis. More controversially, it has been thought to provoke ischemia through coronary steal, implying that overperfusion of myocardial regions supplied by normal coronary arteries is at the cost of the heart muscle fed by the stenotic vessel (the so-called “reverse Robin Hood effect”). ^, In “horizontal steal,” vasodilation of distal arteriolar beds of nonstenosed coronary artery causes a decrease in perfusion pressure in the collateral circulation to the stenosed territory. In “vertical steal,” the vasodilator-induced depressurization of the microcirculation in the territory of the stenotic artery produces a collapse of subendocardial vessels caused by higher extravascular pressure in this layer with a subsequent flow maldistribution favoring the subepicardium. Another contribution to the ischemic effect of vasodilators is increased oxygen demand from a reflex tachycardia in response to the decrease in blood pressure or administration of atropine.

Left Ventricular Response To Stress

The normal response elicited by inotropic stress includes an increase in endocardial systolic movement, systolic wall thickening, and velocity of contraction. The typical effect of dobutamine infusion is a reduction in end-diastolic and end-systolic volumes and a rise in cardiac output with a larger contribution to this from elevated heart rate than stroke volume. Increased inotropic state together with the substantial decrease in loading may cause left ventricular (LV) cavity obliteration, which is a potential reason of false-negative responses, caused by reduced transmural wall stress, as well as smaller areas where wall motion abnormalities can be identified.

The decrement of regional myocardial function, both systolic excursion and wall thickening, from the resting level or after an initial augmentation of contractility represents a key marker of ischemia. The phase of transient enhancement of function is particularly important for recognition of ischemia in akinetic or dyskinetic segments, which despite their poor functional status may still include some ischemic or viable tissue. A deterioration of performance without antecedent improvement may reflect increased loading rather than ischemia.

LV cavity dilation and a decrease in ejection fraction during stress strongly suggests multivessel or left main coronary artery disease. However, these findings are much less common with pharmacologic than exercise testing, possibly because of the reduction of loading. According to some observations, an abnormal end-diastolic volume response during dobutamine infusion implying severe coronary artery disease should be defined as a decrease less than 15%.

Myocardium that is dysfunctional at rest, which improves in response to low-dose dobutamine (<20 mcg/kg/min) or dipyridamole (0.28–0.56 mg/kg), is considered to be viable. With dobutamine stress, the mechanism is clearly associated with adrenergic effects on contractility. However, the mechanisms behind the contractile response to dipyridamole are less obvious and possibly include sympathetic activation or systemic vasodilation causing a “local Frank-Starling effect” whereby the expansion of myocardial blood volume leads to increased tension of the myofibrils.

In the presence of a patent infarct-related artery, the augmentation of function is sustained even if workload and oxygen demand increase. Generally, this is understood to signify the presence of stunned myocardium, although nontransmural infarction can also provide this “uniphasic” response. As a consequence, this is not specific for functional recovery. Initial improvement at low heart rates followed by a deterioration of regional function, as tachycardia becomes more evident and induces ischemia, is typical for viable tissue supplied by a stenosed infarct-related artery, representing hibernating myocardium. However, if the region is nourished by a critically narrowed artery, the stage of conspicuous improvement may not appear because of a very early advent of ischemia. The biphasic response is strongly predictive of functional recovery after revascularization, which is an argument for proceeding to maximal stress whenever possible ( Table 49.2 ). However, it should be emphasized that the presence of severe LV dysfunction and extensive coronary artery disease necessitates a more cautious approach and early termination of the test.

Comparisons Of Stressors

Dissimilarities in hemodynamic effects of inotropic stressors account for the greater workload and, consequently, more extensive ischemia imposed by exercise than dobutamine. The rate-pressure product is higher with exercise (>25,000) than with dobutamine (∼20,000) or pacing (<20,000). ^, The potency of exercise or dobutamine in inducing myocardial ischemia (and as a result, their diagnostic sensitivity) depends on the target heart rate, with maximal stress providing better reliability than submaximal testing. ^, β-Blockade may diminish the chronotropic response to dobutamine and decrease the double product to around 14,000, but this may be circumvented by the administration of atropine. The combined use of dobutamine and atropine also avoids the heart rate–depressant effect of vagal activation occurring in response to hypertensive reaction or cardiac mechanoreceptor stimulation. The addition of atropine to vasodilator stress increases heart rate and myocardial oxygen demand, thereby improving diagnostic sensitivity.