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Circadian Influence in Cardiovascular Disease (Part 1)

1990; Elsevier BV; Volume: 97; Issue: 6 Linguagem: Inglês

10.1378/chest.97.6.1453

1931-3543

Gabriel A. Valle, Louis Lemberg,

Nitric Oxide and Endothelin Effects

This department will offer stylized clinical presentations of current cardiovascular issues. Questions raised as a case history evolves highlight key elements that are elaborated upon in the discussions which follow. This department will offer stylized clinical presentations of current cardiovascular issues. Questions raised as a case history evolves highlight key elements that are elaborated upon in the discussions which follow. = endothelial-derived relaxing factor The circadian effects on major cardiovascular and cerebrovascular diseases result in an increased vulnerability to myocardial ischemia, cerebral ischemia, and myocardial dysfunction during the early hours of the morning after awakening and rising. A comprehensive approach to management in patients with cardiovascular disorders must take into consideration the chronobiology of the cardiovascular system and its relevance to the underlying disease process that affects the cardiovascular system. The interaction between endogenous and exogenous daily rhythms can moderate cardiovascular morbidity and mortality. The capacity to adapt to temporal changes in the environment may well be a factor in the survival of the species. Three cases were chosen to illustrate current views regarding the effects of circadian rhythms on cardiovascular disease. The first two of three cases are presented this month as part 1 of a two-part series. The third will appear in another issue as part 2 of “Circadian Influence in Cardiovascular Disease.” A 68-year-old retired salesperson experienced severe precordial oppression while backing the car out of his driveway in the morning. Associated symptoms included shortness of breath and apprehension. Four sublingual nitroglycerin 1/150 grain tablets over a 20-minute period were required to control the symptoms. A few hours later, on the advice of his primary physician, he was admitted to the coronary care unit. The patient had a strong family history of premature coronary artery disease and had undergone three-vessel coronary artery bypass graft surgery five years prior. He had remained essentially asymptomatic since his surgery, taking a daily low-dose aspirin and topical nitrates for 12 of 24 hours. Baseline electrocardiogram revealed nonspecific ST-T abnormalities and rare unifocal premature ventricular beats. Subsequent workup failed to reveal any acute myocardial damage. Telemetry monitoring showed a brief episode of nonsustained ventricular tachycardia detected shortly after hospital admission, with no further recurrence. Therapy with diltiazem 60 mg orally every eight hours was begun and he remained asymptomatic while fully ambulatory in the telemetry ward. He refused cardiac catheterization. A submaximal exercise stress test prior to hospital discharge was nondiagnostic due to deconditioning. One week later 24-hour Holter monitoring revealed frequent episodes of 2-mm ST depression lasting two to eight minutes clustered in the early morning hours, all asymptomatic. The diltiazem dosage was increased to 90 mg orally every six hours. Repeated ambulatory Holter monitoring on two occasions revealed a 60 to 80 percent decrease in the frequency and severity of the silent ischemic episodes. Metoprolol 25 mg orally twice a day was added to the therapeutic regimen and one week later ambulatory Holter monitoring was unremarkable. 1.Concerning the therapeutic implications of the circadian variability in cardiovascular integration and cardiovascular morbidity and mortality: Tabled 1a.tolerance to nitrate therapy exhibits a circadian variabilityT,Fb.antihypertensive agents may vary in their direct (anti-ischemic) cardioprotective effectsT,Fc.β-blocker therapy has been shown to be effective in patients with predominantly silent ischemia, as well as in patients with anginaT,Fd.platelet inhibition must be considered in most patients with coronary artery diseaseT,Fe.exercise therapy is better tolerated in the afternoon and evening hoursT,F Open table in a new tab A 51-year-old bartender en route to his workplace in the early evening lost control of his vehicle which came to a stop on a front lawn. He was pronounced dead on the scene. Autopsy revealed 95 percent occlusion of the left anterior descending artery and no evidence of intracoronary thrombus or myocardial necrosis. Death was ruled cardiogenic in origin related to a possible ischemia-induced arrhythmia. 2.Concerning the pathogenesis of acute myocardial infarction, transient myocardial ischemia, and sudden cardiac death, which one of the following statements is false? a.approximately one half of victims of sudden cardiac death are found to have thrombotic coronary occlusion on autopsyb.most Q-wave myocardial infarctions are caused by thrombotic coronary artery occlusionc.intracoronary thrombosis may lead to an unstable anginal patternd.both the magnitude and rapidity of blood pressure increase are the leading mechanisms postulated to explain the disruption and rupture of the atherosclerotic plaque which may promote coagulation in situ within the coronary treee.atherosclerotic damage of the coronary vessel wall and endothelium is associated with an abnormal coronary artery reactivity and predisposition to vasospasm.3.Which of the following variables have been implicated in determining the increased vulnerability to major morbid cardiovascular events in the morning? a.changes in coronary arterial toneb.hypercoagulabilityc.autonomic changesd.activation of the renin-angiotensin-aldosterone axise.blood pressure response associated with the arousal phenomenaf.increased oxygen demand. 1. a. F; b. T; c. T; d. T; e. T. Multiple physiologic mechanisms are operative in the early hours of the morning that could potentially contribute to create a state of cardiovascular vulnerability. From the cellular and tissue level to the level of organ response and system integration, this circadian functional variability can modulate the incidence of different (morbid) cardiovascular events. Nitrates are the cornerstone of antianginal therapy; their coronary vasodilating properties as well as their vasodilating effects in various vascular beds are secondary to a direct relaxing effect on smooth muscle.1Frishman WH Multifactorial actions of beta-adrenergic blocking drugs in ischemic heart disease: current concepts.Circulation. 1983; 67: 11PubMed Google Scholar Because tachyphylaxis to nitrate therapy may be responsible for therapeutic failures, a word of caution is warranted when prescribing nitrates. Short-term, repetitive use of nitrates induces intracellular depletion of glutathione, the compound that mediates the myorelaxing effects of nitrates. This drug “tolerance” is a function of frequency and duration of nitrate therapy and does not exhibit circadian variability. Since restoration of intracellular glutathione takes place within a few hours after discontinuances of nitrate therapy, smooth muscle responsiveness to such agents usually returns within six to eight hours of nitrate therapy withdrawal. It is therefore recommended that a ten to 12-hour drug-free interval be scheduled during long-term nitrate therapy. In light of the circadian variation in cardiac events, the nitrate-free interval would be better tolerated during the afternoon and evening hours. The addition of another class of antianginal agents can protect the anginal patient during this nitrate-free period. When appropriately used, all the antihypertensive agents (acting through different pathways) modulate cardiovascular function and result in improvement or normalization of the blood pressure. Despite this common end point, different hemodynamic profiles are present under steady-state conditions during therapy with various classes of agents. This, in turn, may determine different responses to additional cardiovascular stimuli. In general terms, however, antihypertensive agents tend to “normalize” the response of the patient to these stimuli, therefore mitigating or preventing abrupt or excessive fluctuations of blood pressure. In this sense the normalization of blood pressure in the hypertensive individual is imperative. Due to their intrinsic mechanism of action, antihypertensive agents vary in their ability to modulate blood pressure variations induced by adrenergic stimulation, as it occurs for instance, in normotensive and hypertensive individuals on awakening or under circumstances of mental or emotional stress. In the hypertensive individual with known coronary artery disease or with additional coronary risk factors, the use of β-blockers offers a definite therapeutic advantage.2Wikstrand J Warnold I Olsson G et al.Primary prevention with metoprolol in patients with hypertension: mortality results from the MAPHY study.JAMA. 1988; 259: 1976-1982Crossref PubMed Scopus (374) Google Scholar In addition to controlling chronic blood pressure elevation, β-adrenergic blockade blunts the increase in heart rate associated with awakening/rising and modulates the blood pressure surge that accompanies the transition from sleep to an aroused/active state. α2-agonist agents (clonidine, guanabenz, guanfacine) are attractive therapeutic alternatives. By virtue of their direct effect in the central nervous system, these agents prevent the peripheral release of cathecholamines. Many of the circadian cardiovascular changes could potentially be mitigated during treatment with such antihypertensives, thus affording additional cardiovascular protection. The availability of long-acting or sustained-release preparation of these drugs is important for the patient at risk of coronary artery disease. Since a maximal effect is needed in the early hours of the morning during awakening and arising, most once-a-day agents should be administered during the evening hours to obtain a plateau of protection the following morning. All calcium channel blockers are vasodilators that relax smooth muscle. Each of the various calcium blockers vary in their cardiovascular selectivity and their antihypertensive and antiarrhythmic properties. Most agents currently available have a selective action in the coronary bed in both intramural and epicardial vessels that improves myocardial perfusion and counteracts any increase in coronary tone and vasospasm. Other antihypertensive agents affect heart function or coronary physiology indirectly. β-blockers are drugs of proven efficacy in the treatment of patients with coronary artery disease.1Frishman WH Multifactorial actions of beta-adrenergic blocking drugs in ischemic heart disease: current concepts.Circulation. 1983; 67: 11PubMed Google Scholar Although classically prescribed for cases of effort-induced angina, the spectrum of their cardioprotective action transcends this single therapeutic indication. Several trials ofβ-blockers in acute myocardial infarction have shown that such agents caused parallel reduction in the incidence of sudden cardiac death and recurrent attacks of acute myocardial infarction.3The Norwegian MultiCenter Study GroupTimolol-induced reduction in mortality and re-infarction in patients surviving acute myocardial infarction.N Engl J Med. 1981; 304: 801-807Crossref PubMed Scopus (1524) Google Scholar, 4Beta Blocker Heart Attack Trial Research Group: A randomized trial of propranolol in patients with acute myocardial infarction, I: morality resultsJAMA. 1982; 247: 1707-1714Crossref PubMed Scopus (1584) Google Scholar More recently, various authors have reported favorable effects of β-blocker therapy in patients with silent ischemia.5Pepine CJ Hill JA Imferi GA Howell N Beta-adrenergic blockers in silent myocardial ischemia.Am J Cardiol. 1988; 61: 18B-21BAbstract Full Text PDF PubMed Scopus (19) Google Scholar, 6Imferi GA Beta adrenergic blockade: effect on occurrence, circadian variation, and heart rate relationships of silent myocardial ischemia.CVRR. 1988 (suppl June); : 14-18Google Scholar, 7Cohen PF Lawson WE Can beta-blockade abolish AM and PM peaks in silent myocardial ischemic activity?.Circulation. 1988; 78 ([abstract 0171])PubMed Google Scholar Despite observation that silent ischemia is frequently detected during nonexertional periods and therefore is considered to reflect enhanced coronary vasoreactivity (decreased supply rather than increased demand), therapy withβ-adrenergic blockade nevertheless resulted in marked reduction in the frequency and duration of silent ischemic events.5Pepine CJ Hill JA Imferi GA Howell N Beta-adrenergic blockers in silent myocardial ischemia.Am J Cardiol. 1988; 61: 18B-21BAbstract Full Text PDF PubMed Scopus (19) Google Scholar, 6Imferi GA Beta adrenergic blockade: effect on occurrence, circadian variation, and heart rate relationships of silent myocardial ischemia.CVRR. 1988 (suppl June); : 14-18Google Scholar The close linkage between transient myocardial ischemia, acute myocardial infarction, and sudden cardiac death is supported by their common risk factors, the extent of vascular abnormalities accompanying them, as well as the parallel reduction of acute myocardial infarction and sudden cardiac death following long-term administration of β-blockers. Moreover, an important observation stemmed from the circadian variation of acute myocardial infarction study: the circadian variation in the frequency of acute myocardial infarction was abolished in patients receiving β-blockers.8Muller JE Stone PH Turi ZG Poole WK Passamani E Roberts R et al.Circadian variation in the frequency of onset of acute myocardial infarction.N Engl J Med. 1985; 313: 1315-1322Crossref PubMed Scopus (1655) Google Scholar With the ever-growing number of β-blocking drugs, many long-acting agents are now available to formulate a rational antianginal program that derives from a better understanding of the pathophysiology of coronary artery disease. Nitrates, β-blockers, and calcium channel entry blockers need to be prescribed in the appropriate dosage and at the appropriate time to maximize their anti-ischemic and cardioprotective properties. Additionally, adjunctive therapy with antiplatelet agents is strongly recommended for most patients with coronary artery disease. The complex interaction between circulating platelets, coronary endothelium, atherosclerotic lesions, and coronary vessel reactivity underscores the importance of these cellular events triggering a chain reaction which, after further amplification, could lead to perfusion abnormalities and organ dysfunction. Both aspirin and dipyridamole are widely used as antiplatelet agents. Aspirin therapy has been shown to decrease the incidence of sudden death in patients with coronary artery disease.7Cohen PF Lawson WE Can beta-blockade abolish AM and PM peaks in silent myocardial ischemic activity?.Circulation. 1988; 78 ([abstract 0171])PubMed Google Scholar While the timing of aspirin administration is not crucial to its antiplatelet activity (platelet cyclooxygenase is acetylated irreversibly and the platelets are inactivated until they are destroyed several days later), the use of dipyridamole should fit an appropriate dosage schedule in order to provide effective “morning coverage” for hyperaggregability. Newer agents with promising therapeutic potential are currently being investigated. It has been recognized recently that dietary fish oil has several cardiovascular protective effects. An important mechanism that mediates this positive action is the direct effect on coronary endothelial function facilitating the formation and release of vasodilating products and restoring the normal responsiveness during platelet-endothelium interaction.9Maseri A Role of coronary artery spasm in symptomatic and silent myocardial ischemia.J Am Coll Cardiol. 1987; 9: 249-262Abstract Full Text PDF PubMed Scopus (102) Google Scholar Additionally, dietary intake of fish oil produces a reduction in platelet aggregability and by inducing changes in the physiochemical properties of the cell membrane, it may improve the nonthrombogenic properties of the endothelial cell surface. Therefore, by acting at a cellular level, the eicosapentanoic acid (the dominant fatty acid in cod fiver oil) improves endothelial integrity and promotes unified vessel wall function that could potentially improve or restore vasomotor tone and reactivity and prevent platelet aggregation and coagulation in situ. However, to our knowledge, a safe and effective long-term dose for fish oils has not been established. The increase in oxygen demand associated with exercise can act synergistically during the morning period of cardiovascular vulnerability and increase the number of morbid cardiovascular events. Various authors have studied different populations of patients with coronary artery disease and found that the anginal threshold in exercise stress testing was lower in the morning hours. Moreover, the dose of ergonovine required to induce coronary spasm was also lower in the morning reflecting an increased vulnerability to ischemia during the morning hours (circadian influence).10Vendsalu A Studies on adrenaline and norachenaline on human plasma.Acta Physiol Scand. 1960; 49: 7-114Google Scholar 2. a. F; b. T; c. T; d. T; e. T. Although the relationship between acute myocardial infarction, transient myocardial ischemia, and sudden cardiac death is not completely understood, a subgroup of patients who have had sudden cardiac death (approximately 30 percent) have been found to have an occlusive coronary thrombus at autopsy.11Muller JE Tofler GH Circadian variation in onset of cardiovascular disease.Heart Disease Update. 1987; : 13-24Google Scholar On the other hand, the anatomic basis for Q-wave infarctions has been clearly established: thrombosis of the coronary artery supplying the necrotic area can be found in up to 90 percent of patients subjected to early angiography.12DeWood MA Spores J Notske R Mouser LT Burroughs R Golden MS Lang HT Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction.N Engl J Med. 1980; 303: 897-902Crossref PubMed Scopus (2124) Google Scholar In situ coronary thrombosis is often found in connection with a ruptured atherosclerotic plaque. Therefore, the disruption of the atheromatous segment is regarded as an important triggering event for local thrombogenesis. The two leading theories advanced to explain this rupture invoke the establishment of a pressure gradient between the lumen and the vessel wall that leads to local hemorrhage either from the lumen into the plaque or within the plaque from the vasovasorum, which may extend into the lumen. Events leading to a rapid increase in blood pressure (as occurs on awakening) may precipitate this process. Of the many factors implicated in the genesis of unstable angina, in situ hypercoagulability has received increasing attention and is now recognized as a leading etiologic mechanism.13Tofler GH Brezinski DA Schafer AI Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death.N Engl J Med. 1987; 316: 1514-1520Crossref PubMed Google Scholar In patients with chronic stable angina or variant angina subjected to rapid atrial pacing, the coronary sinus levels of thromboxane B2, a stable metabolic product of thromboxane A2 produced by platelet activation, were significantly elevated.14Maseri A Role of coronary artery spasm in symptomatic and silent myocardial ischemia.J Am Coll Cardiol. 1987; 9: 249-262Abstract Full Text PDF PubMed Google Scholar The findings of a high prevalence of intracoronary thrombosis in patients with unstable angina in two recent studies by Vetrovec et al15Vetrovec GW Lemback RC Gold HK Cowley MJ Intracoronary thrombolysis in syndromes of unstable ischemia: angiographic and clinical results.Am Heart J. 1979; 104: 946-952Abstract Full Text PDF Scopus (107) Google Scholar and Cowley et al16Cowley MJ DiScrascis Rehr RB Vetrovec GW Angiographic observations and clinical relevance of coronary thrombus in unstable angina pectoris.Am J Cardiol. 1989; 63: 108E-113EAbstract Full Text PDF PubMed Scopus (43) Google Scholar and the beneficial effect of thrombolytic agents in selected patients provide further support for this pathophysiologic mechanism. In the presence of normal endothelium, in situ platelet activation and aggregation, and subsequent release of vasoactive mediators (adenosine triphosphate [ATP], vasopressin, (adenosine diphosphate [ADP], serotonin, platelet activating factor, and thromboplastin) stimulate the endothelial production of relaxing factors (endothelial-derived relaxing factor [EDRF]) that inhibit contractility of adjacent smooth muscle. Simultaneous activation of the prostaglandin cascade (cyclooxygenase pathway) leads to the formation of prostacyclin, a potent vasodilator and antiaggregatory substance, thereby providing synergistic protection against coronary vasospasm. In addition, an intact endothelial lining is an effective biologic barrier that prevents the diffusion of vasoactive agents into the vessel wall. The evidence that links endothelial injury to fixed obstructive ischemic heart disease is well established. In atherosclerotic coronary artery disease, the formation and progression of an atheromatous plaque causes both functional and morphologic disruption of the endothelial lining of the vessel causing critical alterations in mechanisms of cell-to-cell interactions. A number of recent studies have demonstrated that endothelial dysfunction may be present even at the early stages of atheromatous transformation of the vessel wall. Impaired formation of EDRF in response to acetylcholine has been postulated as the mechanism responsible for the paradoxic vasoconstrictive effect of this substance in patients with atherosclerosis. The impaired production of vascular prostacyclin in diabetic and atherosclerotic patients represents additional evidence of endothelial dysfunction in systemic disorders.17Vanhoutte PM The endothelium and control of coronary artery tone.Hosp Pract. 1988; 23: 67-84Crossref Scopus (7) Google Scholar Moreover, acute anoxia inhibits EDRF release and triggers the generation of endothelium-derived contracting factors that may enhance and perpetuate vasoconstriction. With more advanced atheromatous lesions, endothelial damage leads to cell death and denudation of the vessel lining, allowing the exposure of collagen, remnants of basement membrane, and myocytes to the circulation which in turn triggers platelet aggregation. The consequences of the unopposed action of platelet-derived vasoconstrictive agents and procoagulant substances superimposed on a fixed subocclusive coronary lesion are predictable, ie, local vasospasm and thrombosis. Further tissue anoxia perpetuates this vicious cycle. 3.a.changes in coronary arterial toneb.hypercoagulabilityc.autonomic changesd.activation of the renin-angiotensin-aldosterone axise.blood pressure response associated with the arousal phenomenaf.increased oxygen demand. Ischemia, the cardinal manifestation of coronary artery insufficiency, has different anatomic and physiologic substrates: both static and dynamic physical factors alike can be potentially responsible for inadequate myocardial perfusion.14Maseri A Role of coronary artery spasm in symptomatic and silent myocardial ischemia.J Am Coll Cardiol. 1987; 9: 249-262Abstract Full Text PDF PubMed Google Scholar Changes in coronary vessel wall structure and reactivity, changes in the blood properties or in myocardial oxygen, and nutrient requirements may lead to a critical supply-demand imbalance. Additionally, at a systemic level, time-related changes in cardiovascular integration may affect various vascular beds in different ways. In most cases, morbid cardiovascular events are the consequence of the complex interaction between several pathologic and physiologic mechanisms occurring simultaneously. As mentioned previously the circadian variability in the incidence of acute myocardial infarction, ischemia, sudden death, arrhythmias, and stroke, offers support to the concept of a period of greater cardiovascular vulnerability in the early hours of the morning, specifically, in association with the transition from sleep to an aroused and physically active state. Various pathophysiologic mechanisms have been postulated to explain the increased incidence of cardiovascular morbidity and mortality in the early hours of the morning. As previously mentioned, the autonomic system plays a paramount role in orchestrating the physiologic changes associated with awakening/rising: this period is characterized by the predominance of sympathetic stimulation.10Vendsalu A Studies on adrenaline and norachenaline on human plasma.Acta Physiol Scand. 1960; 49: 7-114Google Scholar The catecholamine release that takes place on awakening and arising is an important mediator of the increase in blood pressure, heart rate, and myocardial contractility that occurs in the morning, all of which cause alterations in pressure gradients across the vessel wall and increase myocardial oxygen consumption. Moreover, the vasoactive effects of such hormones could target the coronary arterial bed and modulate vessel tone. Yasue et al18Yasue H Pathophysiology and treatment of coronary arterial spasm.Chest. 1980; 78: 216-220Abstract Full Text Full Text PDF PubMed Google Scholar showed that the coronary artery tone in patients with Prinzmetal angina was increased in the morning and suggested a circadian variation in epicardial arterial tone. The greater incidence of anginal attacks in the morning8Muller JE Stone PH Turi ZG Poole WK Passamani E Roberts R et al.Circadian variation in the frequency of onset of acute myocardial infarction.N Engl J Med. 1985; 313: 1315-1322Crossref PubMed Scopus (1655) Google Scholar, 19Shea J Deanfield JE Wilson R Transient ischemia in angina pectoris: frequent silent events with everyday activities.AJCCC. 1985; 56: 34E-38EAbstract Full Text PDF Scopus (28) Google Scholar may be indirect evidence of increased coronary tone. Other hormonal systems are also activated on assuming an erect posture, notably the renin-angiotensin-aldosterone axis. The enhanced formation and circulation of an extremely potent vasoconstrictive peptide, angiotensin II, could produce both local and systemic hemodynamic changes leading to increased cardiac work and myocardial hypoperfusion. Other physiologic morning changes may act synergistically with active coronary atherosclerosis and arterial vessel reactivity and lead to cardiovascular morbidity. The presence of a hypercoagulable tendency in the morning has been recognized recently.11Muller JE Tofler GH Circadian variation in onset of cardiovascular disease.Heart Disease Update. 1987; : 13-24Google Scholar, 13Tofler GH Brezinski DA Schafer AI Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death.N Engl J Med. 1987; 316: 1514-1520Crossref PubMed Google Scholar, 20Tofler GH Stone PH Circadian variation of silent ischemia: mechanism and potential significance.CVR&R. 1988; 6: 19-22Google Scholar Current research indicates that there are several components to the circadian-related change in the properties of blood. The period from 6 am to 9 am was associated with a significant increase in platelet aggregability. Subsequent studies have further clarified the putative mechanisms for this platelet “hyperfunction”: the assumption of the upright posture was identified as the triggering event, possibly mediated by the increase in circulating catecholamines that occurs on rising.21Tofler GH Brezinsky D Schafer AI Geisler CA Rutherford JD Willich SN et al.Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death.N Engl J Med. 1987; 316: 1514-1517Crossref PubMed Scopus (995) Google Scholar In addition, the natural fibrinolytic activity of the body is decreased in early morning, possibly due to a concomitant increase in the circulating levels of tissue plasminogen inhibitor.13Tofler GH Brezinski DA Schafer AI Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death.N Engl J Med. 1987; 316: 1514-1520Crossref PubMed Google Scholar Enhanced heparin metabolism and the increase in hematocrit and blood viscosity, both of which peak in the morning, are also potential modulators of these hypercoagulable states. In most cases it is likely that a complex interaction of several factors takes place to produce an increased vulnerability to cardiovascular events in this period of the day.