**7. Conclusions**

*Visions of Cardiomyocyte - Fundamental Concepts of Heart Life and Disease*

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

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].

'energy' homeostasis and metabolism is evident.

**6.1 Cardiomyocyte circadian clock**

**28**

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 the circadian rhythm.

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