Clin. Cardiol. 15 (Suppl. II), II-18-11-21 (1992)

Future Uses of Ambulatory Blood Pressure Monitoring: Implications for Therapy THOMAS D.GILES, M.D.

Tulane University School of Medicine, New Orleans, Louisiana, USA

Summary: Ambulatory blood pressure monitoring can play a significantrole in evaluating the effects of treatment on the circadian cardiovascular pattern of patients with ischemic heart disease and/or congestive heart disease. In ischemic heart disease, drug therapy should be designed to reduce heart rate and blood pressure throughout the 24hour cycle, including the early morning surge. Beta-blocking agents appear to accomplish these reductions. In congestive heart failure, some patients maintain their circadian variation while others do not, leaving them without the normal period of cardiac rest during the nighttime hours. Therapy should be designed to reduce this cardiac overload, and vasodilating agents appear to accomplish this. Ambulatory monitoring is especially useful in monitoring the effectiveness of drug interventions throughout the 24hour cycle.

The increasing recognition of the 24-h variation in cardiovascular parameters and in the circadian pattern of cardiovascular events contributes to the potential utility of this modality. Early morning peaks or nadirs have been reported in a number of physiologic processes central to cardiac function,14 and morning increases in the incidence of acute cardiovascular events have been documented over the past five yearse5Awareness of circadian variations underline the importance of 24-h protection in patients taking antihypertensive, anti-ischemic, and other agents affecting hemodynamic and other factors that may determine cardiovascular outcomes. ABPM is a valuable tool for the assessment of such protection in ischemic heart disease and congestive heart failure.

Ischemic Heart Disease Key words: ambulatory monitoring, ischemic heart disease, congestive heart failure

Introduction Ambulatory blood pressure monitoring (ABPM) has value beyond its obvious utility in diagnosing and monitoring treatment in hypertension. In addition to blood pressure, ABPM records heart rate, a crucial parameter in two clinical settings, ischemic heart disease and congestive heart failure.

Address for reprints:

Thomas D. Giles, M.D. Tulane University School of Medicine New Orleans, LA 70112, USA

Ischemic heart disease, especially as a result of coronary artery obstruction or vasospasm, is produced when the myocardial blood supply is exceeded by myocardial demand. This myocardial ischemia has special clinical significance in that, even during transient episodes, it renders the heart vulnerable to arrhythmias which can end in sudden cardiac death. Increased myocardial demand results from an increased heart rate, an increase in myocardial contractility, and an increase in myocardial wall tension. The development of increased myocardial tension has as its major components heart rate and blood pressure. Heart rate and blood pressure, therefore, are extremely important factors in the determination of the myocardial supply/demand ratio. Beta-adrenergic-blockingdrugs is the only class of agents that have been shown in many clinical trials to reduce the incidence of sudden cardiac death or secondary myocardial infarction in survivors within 2 years of myocardial infarction.6 One of the largest and most extensively analyzed of these trials is the Beta Blocker Heart Attack Trial, conducted in 1983.7 Figure 1 analyzes the circadian variation in deaths occumng in this trial over a 24-h peri-

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T.D. Giles: ABPM’s future role

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FIG. 1 Circadian rhythmicity in the occurrence of sudden death in the Beta-Blocker Heart Attack Trial. Note, that the effects of ropranolol are greatest at a time when the heart rate is lowest. Placebo; 0, propranolol. (Reproduced with permission of Am J Cardiol, Ref. 6 . )

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od. As expected, the incidence of these events was highest in the early and mid-morning hours, between 8 a.m. and 11 a.m., and was lowest between 2 a.m. and 8 a.m., indicating that the effects of the drug were greatest at a time when the heart rate was at its lowest. Beta blockers lower both blood pressure and heart rate, and are effective throughout a 24-h period, suggesting that such drug therapy for patients with ischemic heart disease should produce a prolonged and sustained lowering of both parameters.

Congestive Heart Failure

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Congestive heart failure is another condition where treatment requires the ability to control both heart rate and blood pressure. The therapeutic goals in heart failure include the relief of symptoms and signs and the prolongation of life. Avoidance of future myocardial damage may be accomplished by controlling myocardial load or by interfering with the intrinsic disease process. Relief of edema and amelioration of dyspnea and exercise intolerance will improve the patient’s ability to engage in daily activities. The goal is to extend life, but since life has “width” as well as “length,” therapy should also aim to improve its quality. Treatment of heart failure, therefore, means decreasing systemic arterial blood pressure and heart rate, two important components of myocardial load. Demand for higher cardiac output and myocardial contractility should be decreased, while the ultimate goal is a decrease in heart size. It has become apparent that patients with heart failure fall into two categories from the point of view of circadian variation of blood pressure and heart rate. One type of patient, usually those with Class Il and III heart failure, is able to maintain the normal pattern, while the second, usually patients with severe congestive heart failure, is unable

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FIG.2 Hourly mean values of intra-arterial blood pressure and heart rate in (a) 22 normal subjects and (b) 20 heart failure patients. There is reduced circadian amplitude in heart failure. (Reproduced with permission of Am J Cardiol,Ref. 8 . )

to do so. Figure 2 demonstrates the normal circadian curves for heart rate and blood pressure, showing nocturnal declines in these, as well the curves in heart failure patients who have lost much of the ability to lower heart rate and blood pressures at night.* Thus, at a time when normal hearts enjoy a period of rest, these severe heart failure patients not only do not experience cardiac rest, but in many cases suffer increased cardiac load, particularly if measured by the product of heart rate and systolic blood pressure (i.e., the rate-pressure product). The heart rate plays a

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Clin. Cardiol. Vol. 15 (Suppl. 11), October 1992

creased myocardial load. The patient tries to adapt to a decrease in cardiac output or an increase in left ventricular filling pressure by an increase in heart rate. Therapy should be designed to reduce this overload. The mechanism by which heart rate and blood pressure are increased in advanced heart failure involves many components. A number of neurohumoral systems, including the sympathetic, the renin-angiotensin and the arginine vasopressin systems, are activated. The cumulative effect is to constrict blood flow, particularly blood flow to relatively nonpriority vascular beds supplying the skin and working skeletal muscle. To unload the heart, then, some way has to be found to reduce both blood pressure and heart rate. In the heart failure patient in whom normal circadian variation is blunted, it is advisable to unload the heart as much as possible during the entire 24-h period, avoiding time gaps in therapy. It follows that drug therapy for heart failure must consider the time course of the drug's effect on hemodynamic parameters, since different agents have different time-variable phannacologic actions. Nitrates, for example, produce effective and sustained declines in pulmonary artery, pulmonary capillary wedge, and right atrial pressures over a 24-h period. But this effect is not repeated at the second dose, and is even less apparent with succeedingdoses. This is an example of markedly different hemodynamic effects resulting from the early tolerance which develops with this class of agents. Another example of how drug time course may affect a patient with heart failure is seen in Figure 3, showing the effects on diastolic and systolic blood pressures of longand short-acting angiotensin-converting enzyme (ACE) inhibitor^.^ The short-acting agent, produces an abrupt decrease in blood pressure, but after from 4 to 5 hours this effect is attenuated. The longer-acting agent, produces a gradual decline in blood pressures, which continues for the 8 hours studied. These and other data suggest that this effect continues for 24 hours.

Circadian Pattern and Heart Failure The use of 24-h ABPM in heart failure has documented the normal circadian rhythm in patients with less severe heart failure, those in Class 11and III. At our center, we have monitored 30 such patients maintained on digitalis and a diuretic, but no vasodilating agent. Their mean heart rate and rate-pressure product demonstrated the typical diurnal pattern, with increases in the early morning hours upon rising, slightly lower values during daytime, and declining to the lowest levels at night. This pattern has considerable therapeutic relevance from a hypotheticalpoint of view. A number of recent landmark studies have assessed the effectivenessof adding vasodilator therapy to the conventional treatment of congestive heart failure. The recently completed Veterans Administration Cooperative Vasodilator-Heart Failure Trial (V-

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FIG.3 Mean change in sitting systolic and diastolic blood pressure (BP) after the first dose of the long-acting agent or the short-acting agent.(x = short-acting ACE, = long-acting ACE) (Reproduced with permission of J A m Coll Cardiol, Ref. 9.)

HeFT 11)compared the effectiveness of the ACE inhibitor enalapril with hydralazine-isosorbide dinitrate in patients with mild to moderate congestive heart failure maintained on digitalis and diuretics.lO After two years, mortality was significantly lower in those patients treated with the ACE inhibitor than in those treated with the hydralazine-isosorbide dinitrate combination. The lower mortality in the ACE inhibitor-treated group was attributed to a lower incidence of sudden death, as seen in Table I, while no significant difference was seen in mortality from pump failure. Forty-six percent of the cardiac deaths in the hydralazine-isosorbidedinitrate group were sudden, while only 37% of those in the ACE inhibitor group were sudden. This contrasts with the earlier CONSENSUSll study, in which only mortality from pump failure, and not that from sudden death, was reduced by the ACE inhibitor enalapril. In general, patients in the CONSENSUS group exhibited more symptoms than those in V-HeFT II. These results support the hypothesis that in patients with mild to moderate heart failure, in whom marked circadian variation in heart rate and blood pressure is maintained, there is an enhanced propensity for sudden death. In more serious heart failure, where the circadian surges are lacking and the heart is subject to constant stimulation, there is instead the inexorable progressive decline in cardiac function termed pump failure.

Conclusion Alterations in normal time-dependent variations in circulatory dynamics, and neurohumoral mechanisms, are important considerations in the pathophysiology of congestive heart failure. The amount of time during which myocardial unloading and relief from excessive neurohumoral mechanisms is achieved is an important factor in the

T.D. Giles: ABPM’s future role

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TABLE I Deaths occurring during the study, according to causea Hydralazineisosorbide dinitrate

Enalapril

Deaths All Cardiac Sudden, no warning Sudden, with warning Due to pump failure Other or unknown Noncardiac Cancer Other

Deaths no. (%) 132 112 41 16

(100) (85) (37) (14) 50 (45)

5 (5) 20 (15) 9 (45) 11 (55)

Cumulative mortality %

16 7 23 -

11 -

Deaths no. (%) 153 137 63 29 40

5 16 9 7

(100) (89) (46) (21) (29) (4) (11) (56) (44)

Cumulative mortality

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0.0 I5 0.032 0.44

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Values for cumulative mortality were obtained from the cause-specific analysis of survival, which was performed by censoring the data for survivors and patients who died of other causes.

selection of treatment. ABPM can play a role in determining and achieving that period of cardiac respite.

References 1. Panza JA, Epstein SE, Quyyumi AA: Circadian variation in vascular tone and its relation to alpha-sympathetic vasoconstrictor activity. N Engl JMed 325,986-990 (1991) 2. Rosing DR, Brakman P, Redwood DR, Goldstein R, Beiser G, Astrop P, Epstein S: Blood fibrinolytic activity in man: Diurnal variation and the response to varying degrees of exercise. Circ Res 27, 171-184 (1970) 3. Tofler GH, Brezinski DA, Schafer AI, Czeiler C, Rutherford J, Willich S, Gleason RE, Williams GH, Muller GH: Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl JMed 3 16, 1514-1518(1987) 4. Linsell CR, Lightman SL, Mullen PE, Brown MJ, Causon MC: Circadian rhythms of epinephrine and norepinephrine in man. J CIin Endocrinol Metub 60, I2 10-1215 ( 1985) 5. Muller JE, Tofler GH: Circadian variation and cardiovascular disease. N E n g l J Med 325, 1038-1039(1991)

6. Singh BN: Advantages of beta blockers versus antiarrhythmic agents and calcium antagonists in secondary prevention after myocardial infarction.Am J Cardiol66.9C-20C (1 990) 7. Beta Blocker Heart Attack Trial Research Group: A randomized trial of propranolol in patients with acute myocardial infarction. Morbidity results. JAm MedAssoc 250,2814-2819 (1983) 8. Caruana, M P Effects of chronic congestive heart failure secondary to coronary artery disease on the circadian rhythm of blood pressure and heart rate. Am J Curdiol62,755 (1988) 9. Giles T, Katz R, Sullivan JM, Wolfson P,Haugland M, Kirlin P, Powers E, Rich S, Hackshaw B, Chiaramida A, Rouleau JL, Fisher MB, Pigeon J, Rush JE: Short- and long-acting angiotens-convertingenzyme inhibitors: A randomized trial of lisinopril versus captopril in congestive heart failure. JAm Coll Cardiol 13, 1240-1247 (1989) 10. Cohn JH, Johnson G , Ziesche S, Cobb F, Francis G , Tristani F, Smith R, Dunkman B, Loeb H, Wong M, Bhat G , Goldman S, Fletcher R, Doherty J, Hughes CV, Carson P, Cintron G , Shabetai R, Haakenson C: A comparison of enalapril with hydralazine-isosorbidedinitrate in the treatment of chronic congestive heart failure. NEngl J Med 325,303-310 (1991) 11. The CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe congestive heart failure; results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl JMed 316, 1429-1435 (1987)

Future uses of ambulatory blood pressure monitoring: implications for therapy.

Ambulatory blood pressure monitoring can play a significant role in evaluating the effects of treatment on the circadian cardiovascular pattern of pat...
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