Commentary: Revisiting the Early Morning Blood Pressure Surge and Myocardial Ischemia

In this issue of the Journal, Uen and colleagues’ article entitled “Early Morning Surge and Dipping Status of Blood Pressure: Are These of Predictive Value for Silent Myocardial Ischemia?” ¹ revisits the entity of circadian rhythms and coronary ischemia. In their study, the group evaluated 76 patients of 344 who demonstrated ST depression on 24‐hour monitoring for ST‐segment characteristics and blood pressure (BP). They determined that the degree of overnight BP dipping and concomitant early morning BP surge did not correlate with the presence of ST‐segment depression indicative of myocardial ischemia. Notable within the data presented, but not specifically addressed by the authors in the discussion section, is the fact that in all of the time frames measured with the ambulatory BP monitoring system, the patients who did not demonstrate ST depression during the course of the day had statistically significantly lower mean systolic BP. Therefore, the most important fact to arise from these authors’ work is that overall BP control is more predictive of silent ischemia than either overnight BP dipping or early morning surges.

The presence of a morning peak for acute myocardial infarction (MI) has been noted for decades but was disregarded from the earliest papers as being a reporting bias from patients sleeping through their symptoms. The Multicenter Investigation of Limitation of Infarct Size (MILIS) ² study demonstrated an increase in cardiac events during the hours of 6 am to 12 noon, utilizing time to peak creatinine kinase–MB fraction to determine the time of onset for the MI. A second study, the Intravenous Streptokinase in Acute Myocardial Infarction (ISAM) trial³ corroborated these results in more than 1700 patients, demonstrating a 4‐fold greater likelihood of events between 8 am and 9 am compared with overnight hours. Similar patterns have emerged in patients presenting with sudden cardiac death (SCD) in several studies. ⁴ , ⁵ , ⁶

There are several physiologic events demonstrating circadian rhythms that could account for the morning peak in acute ischemic cardiac events. There is an increase in sympathetic activity that accompanies and readies the body for awakening in the morning. ⁷ Coincident with this is a rise in BP, pulse pressure, and heart rate, which may increase the hemodynamic stresses across the coronary arteries, most notably at the shoulder regions of the vulnerable plaques. Additionally, higher sympathetic tone may promote increased vascular tone and coronary vasoconstriction, while increasing metabolic demands on the myocardium. Furthermore, there is an early morning increase in platelet aggregability ⁸ and a reduction in the fibrinolytic activity, ⁹ which sways the coagulation balance in favor of thrombosis.

Several studies have demonstrated the presence of external triggers that increase the risk of ischemic cardiovascular events, including MI and sudden cardiac death. The Determinants of Onset of Myocardial Infarction Study (ONSET) ¹⁰ demonstrated an increase in risk of MI for heavy physical activity, defined as >6 metabolic equivalents of work. The relative risk (RR) increased from 2.4 for patients who exercised ≥4 times per week to 107 in patients who engaged in heavy exertion less than once per week. The Triggers and Mechanisms of Myocardial Infarction (TRIMM) study ¹¹ looked at a similar population and demonstrated a 1.3‐fold RR of heavy exertion in patients who exercise regularly and 6.9 RR in those who exercise infrequently. Anger was also shown to be a trigger for MI in ONSET, with a RR of 2.0 in the 2 hours after the episode of extreme anger. ¹² Additional external triggers that have been defined include sexual activity (RR 2.5), ¹³ earthquakes (RR 4), ¹⁴ and cocaine use (RR 23.7), ¹⁵ , ¹⁶ , ¹⁷ among others.

There have been reports in the literature to support a reduction in the early morning event rate in patients taking β‐blockers ³ , ¹⁸ and taking aspirin. ¹⁹ Based on these and other findings, Tofler and Muller ²⁰ have created a strategy for prevention of triggered coronary events they refer to as TARP (triggered acute risk prevention)—to be distinguished from the 2008 US government’s Toxic Asset Relief Program (TARP). First and foremost, aggressive preventive care for the traditional risk factors—diabetes mellitus, hypertension, hypercholesterolemia, and tobacco abuse—are warranted to reduce the development of the vulnerable plaque responsible for the ultimate event, the MI or ischemic‐mediated sudden cardiac death. Next, trigger‐specific lifestyle modification such as biofeedback training for stress reduction or regular cardiovascular exercise programs to reduce the hazard in the vaunted “weekend warriors” who exercise once a month at “the big game.”

Additionally, Tofler and Muller stress the realization that some triggers, such as sexual activity, have such a low absolute risk in most people that no specific remedy needs to be undertaken. In those individuals who demonstrate a high risk, avoidance of the trigger should be encouraged. As an example, the authors cite hiring a snow removal service rather that snow shoveling for the physically disinclined. As the authors note in their paper, there are very few data for any of the levels of prevention they propose, but they advocate for future research in the field.

Finally, the possibility exists to administer a medication to prevent the effects of the trigger from producing the event. As noted earlier, chronic β‐blocker ³ , ¹⁸ or aspirin ¹⁹ administration appears to blunt the effects of the morning peak in acute MI. Drug producers have attempted to utilize chronotherapy, or timing release of medications, to attempt to thwart the circadian changes in physiologic parameters. The first example of this is Covera‐HS (verapamil hydrochloride extended‐release tablets; Pfizer, New York, NY) a controlled‐onset extended‐release formulation of verapamil hydrochloride, meant to be taken at bedtime and approved by the Food and Drug Administration in 1996 for the treatment of hypertension and ischemic heart disease. ²¹ , ²² The timing of release allowed for the highest concentrations of the drug in the bloodstream between 6 am and 10 am, ²³ which have been demonstrated to be the peak hours of acute ischemic events. There is no evidence of a reduction in MI or ischemic SCD, but the drug has demonstrated efficacy in reducing circadian increases in heart rate, BP, and rate‐pressure product, ²⁴ as a surrogate of myocardial ischemia.

In summary, authors Uen and colleagues have provided us with a reminder of the impact of physiologic drives and circadian rhythms. While they are a necessary facet of human existence, they can also be counterproductive and even result in pathologic events. Ischemic cardiac events remain the major killer of Americans today. Aggressive prevention of the development of coronary artery disease through appropriate pharmacologic and nonpharmacologic risk factor management remains the bedrock of care for this disease process.