**6. Myocardial infarction and circadian rhythm**

Many cardiovascular events and diseases have a circadian pattern of appearance. The normal circadian blood pressure shows the two highest values during the day, around 9 am and 7 pm, while there is a slight decrease around 3 pm. It is considered that circadian variations in the tone of coronary vessels and endothelial function play an essential role in the onset of myocardial infarction. As myocardial infarction is significant medical stress, it causes increased cortisol levels in plasma [3]. In the acute phase of myocardial infarction, the phase of the circadian clock in the ischemic part of the heart differs from the non-ischemic part of the heart. The arrhythmia may occur because of the difference in the phase of the rhythm, or different expressions of the circadian clock genes. The loss of synchronization of the circadian rhythm between organs or tissues occurs more often than we would expect [4]. Circadian regulation of physiological processes is regulated locally. Peripheral tissue clocks control tissue-specific expression [27].

Homeostatic changes, gene expression changes, and external triggers can cause a stressful environment and cause damage to the atherosclerotic plaque in the coronary arteries in the morning, when prothrombin is increased [57]. Many intrinsic vasoactive and cardioactive substances, such as angiotensin II, melatonin, plasminogen activator inhibitor 1 (PAI-1), glucocorticoids, epinephrine, norepinephrine, and nitrogen oxide, show a specific circadian pattern. The fibrinolytic system, which regulates PAI-1, shows a circadian pattern of occurrence in both healthy patients and those with ischemic heart disease. The concentration and activity of PAI-1 depend on the circadian rhythm and are the highest in the morning [28]. CLIF (Cycle-Like Factor) expression in endothelial cells creates heterodimers with CLOCK protein, and binds to the E-box of the *PAI-1* gene promoter and promotes its expression, while PER2 and CRY1 inhibit expression of *PAI-1* by blocking heterodimer CLOCK-CLIF. CLIF controls the circadian rhythm of PAI-1 in endothelial cells, which might explain the higher incidence of myocardial infarction in the morning [26, 58]. As a result of this, the fibrinolytic system in patients with MI might be a potential goal for chronotherapy, to treat acute cardiovascular events. The circadian clock regulates the endothelial response to vascular injury. The main factor that can be affected by potential chronotherapy is PAI-1 because it is a crucial fibrinolysis inhibitor [59]. Chronotherapy includes the accurate timing of drug taking and can improve the therapeutic efficacy of the drug, while limiting its toxicity [41]. That is why many studies support chronotherapy for cardiovascular disease by limiting pathogenesis and improving treatment after the occurrence of acute cardiovascular events [59].

It is known that melatonin levels decrease during the night in coronary heart disease and infarction. Melatonin is an antioxidant that can inhibit the action of reactive oxygen radicals during heart ischemia. It also plays a vital role in regulating blood pressure, depending on the circadian rhythm. Animal studies have shown that animals with the pineal gland removed develop hypertension. Clinical examinations have shown that in patients with hypertension melatonin drugs taken daily before bedtime reduced blood pressure [3].

The appearance of myocardial infarction has two peaks during the day. The highest incidence of myocardial infarction is during the morning, and the second peak occurs late at night [60]. The beta blockers prevent increased sympathetic activity, catecholamine concentration, heart rate, blood pressure and lack of oxygen in the heart, and these are the physiological reasons for the existence of two peaks of myocardial infarction [57, 61].

Ischemia occurs in the morning due to increased oxygen demand, whereas in the evening it is due to decreased coronary blood flow. The appearance of myocardial infarction depends on ethnic origin, and the British differ from Asians in the

frequency of the infarction [3]. In the Mediterranean, the highest incidence of myocardial infarction is between midday and midnight, while in the UK the highest incidence is between midnight and midday [62]. Numerous factors might affect the later occurrence of infarction in the Mediterranean, such as the number of sunlight hours, inequality in the prevalence of risk factors for cardiovascular disease, and the habit of afternoon rest or 'siesta' [63]. It has also been noted that the incidence of myocardial infarction is higher in the winter [3]. The specific circadian pattern of infarction symptoms has been observed, and the correlation of the circadian rhythm gene with the infarction investigated. The role of the molecular circadian clock in myocardial activity was initially investigated on animal models. It has been observed that the clock gene mutations of the circadian rhythm affect the heart rate, myocardial contractility, energy metabolism, which altogether leads to ischemia [64, 65]. In contrast, variants of the *Per2* gene in mice reduce the severity of the injury after myocardial infarction because it does not only reduce inflammatory response, but also reduces apoptosis, induces cardiovascular hypertrophy, and thus preserves cardiac function [65].

Different variations of circadian rhythm genes are associated with many risk factors for cardiovascular disease. Thus, CLOCK gene variations are associated with metabolic syndrome in humans, type 2 diabetes, and some with stroke [64, 66–68], while *CRY2* and *PER2* gene variations are associated with myocardial infarction [69]. Expression of *CRY1* and *PER2* genes in fatty tissue is associated with metabolic syndrome in humans [64, 70]. Metabolic syndrome is a significant risk factor for cardiovascular disease and contributes to the common pathophysiological processes leading to the development of diabetes and cardiovascular diseases [48]. Atherosclerotic changes in blood vessels in patients with diabetes are more severe than those with normal glucose concentration [71]. It has been shown that the risk of cardiovascular disease in diabetic patients is two to three times higher than in healthy subjects [72]. Patients with diabetes usually have a higher heart rate in sleep and lower heart rate variability over the day than people without diabetes, which causes unnecessary oxygen consumption in the myocardium, with reduced nutritional blood supply. Biological and epidemiological studies suggest a direct link between lifestyle and metabolic disorders [12], although the genetic and biochemical linkage of human circadian rhythm with metabolic disorders has not been fully explored. Accordingly, the importance of the circadian rhythm in maintaining 'energy' homeostasis and metabolism is evident.

## **6.1 Cardiomyocyte circadian clock**

A peripheral clock is also found in cardiomyocytes, and the internal molecular mechanism of cardiomyocytes, such as the circadian clock, might contribute to cardiovascular disease [73]. Similar to SCN, cardiomyocytes have a circadian expression of clock genes in response to serum shock or norepinephrine. Several genes are associated with intracellular metabolism or physiological activity that has a circadian expression in cardiomyocytes [74]. After development, cardiomyocytes do not replicate, although they possess a meager and permanent rate of renewal. Cardiomyocytes renew cellular structure with their new proteins and membrane lipids every few weeks [75]. The ischemic precondition is an adaptation of cardiomyocytes to hypoxia, and once the heart has suffered an ischemic insult, cardiomyocytes become more resistant to MI because of PER2 and hypoxia inducible factor (HIF)-1a [74]. Circadian genes regulate a group of genes encoding for cardiac metabolic enzymes, and it is considered that a significant role of circadian genes in the heart is to synchronize cardiomyocyte metabolic activity with the availability of nutrients in the blood (i.e., feeding time) [29]. It is known that *PER2* plays an essential role in carbohydrate metabolism during myocardial ischemia [76].

**29**

**Author details**

**7. Conclusions**

the circadian rhythm.

**Conflict of interest**

Croatia

provided the original work is properly cited.

Ivana Škrlec\*, Svjetlana Marić and Aleksandar Včev

Authors declare no conflict of interest.

\*Address all correspondence to: iskrlec@fdmz.hr

*Myocardial Infarction and Circadian Rhythm DOI: http://dx.doi.org/10.5772/intechopen.83393*

The cardiomyocyte circadian clock affects the daily variations in the heart. Studies show that the cardiomyocyte circadian clock affects myocardial contractions, the metabolism and gene expression. This clock is vital since impairment of the cardiomyocyte circadian clock might significantly alter cardiac function, cardiovascular disease pathogenesis, and treatment strategies for cardiovascular diseases (e.g., chronopharmacology) [77]. Desynchronization between different cell types (e.g., cardiomyocytes, vascular smooth muscle cells, endothelial cells) could occur within the organs (e.g. the heart) during certain physiological or pathological conditions [78]. The cardiomyocyte circadian clock allows the heart to predict circadian rhythm by extracellular stimuli, allowing rapid and temporally response [77]. The cardiomyocyte circadian clock has a crucial role in mediating the daily rhythm in myocardial metabolism and affects the cardiovascular function [79]. The cardiomyocyte circadian clock changes during illness, and this molecular

mechanism might affect the etiology of cardiovascular disease [78].

Circadian rhythm adjusts the physiological functions of an individual on a daily basis. Daily variations of physiological parameters in the cardiovascular system maintain cardiovascular function according to the needs of different activities during the day. This information suggests that we need to know not only how, but also when to treat heart disease, and also to treat pathological changes not only symptomatically but to treat non-symptomatic but potentially harmful changes in

Understanding the pathophysiological processes involved in the onset of myocardial infarction requires additional studies to assess the crucial elements of the circadian rhythm. In today's personalized medicine, knowledge of the circadian rhythm (i.e., the genetic background) of an individual can be significant for treat-

ment and should be included as an essential part of the diagnostic process.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek,

*Myocardial Infarction and Circadian Rhythm DOI: http://dx.doi.org/10.5772/intechopen.83393*

The cardiomyocyte circadian clock affects the daily variations in the heart. Studies show that the cardiomyocyte circadian clock affects myocardial contractions, the metabolism and gene expression. This clock is vital since impairment of the cardiomyocyte circadian clock might significantly alter cardiac function, cardiovascular disease pathogenesis, and treatment strategies for cardiovascular diseases (e.g., chronopharmacology) [77]. Desynchronization between different cell types (e.g., cardiomyocytes, vascular smooth muscle cells, endothelial cells) could occur within the organs (e.g. the heart) during certain physiological or pathological conditions [78]. The cardiomyocyte circadian clock allows the heart to predict circadian rhythm by extracellular stimuli, allowing rapid and temporally response [77]. The cardiomyocyte circadian clock has a crucial role in mediating the daily rhythm in myocardial metabolism and affects the cardiovascular function [79]. The cardiomyocyte circadian clock changes during illness, and this molecular mechanism might affect the etiology of cardiovascular disease [78].
