In a randomized blinded trial, Redwine et al. (2016) found that circulating inflammatory markers were reduced in patients with asymptomatic heart failure (HF) after an 8-week gratitude intervention. Furthermore, a study by Mills et al. (2015) found that gratitude was associated with reduced inflammatory biomarker levels, including CRP, TNF-α, IL-6, IFN-γ, and ST2. Redwine et al. (2016) and Hartanto et al. (2019) found that decreases in personality gratitude were significantly associated with decreases in IL-6 in 1054 adults. For Moieni et al. (2019), while a direct effect on inflammatory markers was not observed, it was concluded that the effect of gratitude on inflammation is an extremely complex process. It is highly recommended that further large-scale experimental investigations into other biological indicators, including inflammatory indices, be performed before drawing conclusions.

The American Heart Association proposed 7 parameters regarding healthy lifestyle behaviors (smoking, diet, physical activity, body weight) and metabolic measures (plasma glucose, cholesterol, blood pressure) to reduce the risk of CVD and promote optimal cardiovascular health (Lloyd-Jones et al., 2010). Hypertension, hypercholesterolemia, and cigarette smoking are well-known and modifiable risk factors for various CVD largely influenced by behavioral routines. It is estimated that 80% of CVDs are considered preventable through engagement in healthy behaviors (Masters et al., 2020). Gratitude may facilitate the establishment of health-promoting behaviors in individuals, such as medication compliance (Cousin et al., 2020), appropriate glucose/lipid control, and healthy eating (Wolfe and Patterson, 2017; Fritz et al., 2019; Schache et al., 2020). A study by Redwine et al. (2016) found that gratitude interventions can increase medication adherence and delay the progression of heart failure by improving self-efficacy. In a randomized blinded trial, Redwine et al. (2016) and Fritz et al. (2019) found that gratitude interventions can improve eating behaviors. Furthermore, another randomized blinded trial by Redwine et al. (2016) and Wolfe and Patterson (2017) found that gratitude interventions were demonstrated to effectively reduce eating disorders and lower the risk of depressive symptoms. A randomized blinded trial by Redwine et al. (2016) and Schache et al. (2020) found that gratitude interventions can help improve glucose control in patients with type 1 diabetes. In a study involving 1775 adults, Krause et al. (2017) reported that increases in gratitude were correlated to improvements in hemoglobin A1c levels. Moreover, recent studies have revealed that gratitude interventions after acute coronary syndromes (ACS) are associated with elevated adherence to health behaviors that influence cardiometabolic health, including diet, physical activity, and medication adherence (Millstein et al., 2016). Additionally, several studies have suggested that gratitude may impact the occurrence and development of CVD by increasing a wide variety of health behaviors and positive health outcomes (Sacco et al., 2014; Huffman et al., 2016b; Sultan et al., 2018; Legler et al., 2019).

Furthermore, gratitude can reduce the risk of CVD by improving sleep quality. In a single-blind randomized controlled trial among young females, Jackowska et al. (2016) found that gratitude interventions improved the quality and duration of sleep and boosted energy recovery when compared with the control. In a randomized blinded trial among undergraduates, improvements in sleep quality and quantity and reductions in the level of pre-sleep arousal were observed after writing gratitude journals (Digdon and Koble, 2011). A study by Mills et al. (2015) and Redwine et al. (2016) found that gratitude was associated with improvements in depression and sleep quality among patients with stage B HF. It is critical to change pre-sleep cognitive processes, including anxiety, fear of sleep or nightmares, and rumination, that potentially interfere with the processes that initiate and maintain sleep. Wood et al. (2009) found that gratitude may help reduce sleep-onset latency and facilitate sleep efficiency by altering sleep-related cognitive processes. Although gratitude can, to some extent, boost subjective sleep quality, more research on its clinical efficacy and potential mechanisms are needed (Alkozei et al., 2019).

Gratitude can also relieve psychological stress by decreasing negative emotions and fostering positive thoughts, emotions, and behaviors, thus affecting the development of CVD (O’Connell and Killeen-Byrt, 2018). Thrombosis and abnormalities in hemostasis, including increased platelet aggregability, have been found in patients with chronic stress (Levine et al., 1985; Räikkönen et al., 1996). Studies have shown that gratitude has a significant negative correlation with subjective stress levels (Wood et al., 2007) and can improve subjective or objective indicators of stress across time (Fredrickson, 2004; Wood et al., 2008). An extensive volume of evidence supports the potential of gratitude interventions in decreasing negative feelings and reducing their adverse effects on health (O’Connell et al., 2017; Wolfe and Patterson, 2017; Yang et al., 2018; Salces-Cubero et al., 2019). Furthermore, the results of several studies have demonstrated that various interventions to improve gratitude were also effective in reducing depression levels (Ramírez et al., 2014; Cheng et al., 2015; Watkins et al., 2015; Jackowska et al., 2016; Disabato et al., 2017; O’Connell et al., 2017; Sirois and Wood, 2017; Southwell and Gould, 2017; Wolfe and Patterson, 2017; Salces-Cubero et al., 2019).

While gratitude can help patients with CVD, it can also be affected by CVD. As a positive psychological state, gratitude is influenced by many factors, such as physical health conditions, emotion regulation abilities, social support, subjective well-being (Salces-Cubero et al., 2019), psychological resilience, anxiety, and depression. Therefore, the severity of CVD can have crucial impact on gratitude. Poor physical condition is a risk factor for CVD and also affects gratitude levels, thus creating a vicious cycle in which poor health leads to increased CVD risk and lower gratitude levels, further increasing the risk of behaviors that induce poor health (Arnett et al., 2019). Studies have suggested that CVD, which can manifest as angina, myocardial infarction, HF, and coronary revascularization, can lower gratitude levels and cause both acute and chronic negative mental changes (Januzzi et al., 2000; Thombs et al., 2006; Lichtman et al., 2008; Smolderen et al., 2017). Hence, preventing and treating CVD can help improve gratitude levels to a large extent. Improvements in cardiovascular health can help promote positive mental states, which can build positive resources that foster well-being and enhance positive behaviors (Benjamin et al., 2019; Figure 2).

The levels of inflammatory factors, including interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP), soluble tumor necrosis factor receptor 1 (sTNFr1), interferon-gamma (IFN-γ), growth stimulation expressed gene 2 (ST2), and tumor necrosis factor-alpha (TNF-α) decreased among individuals with higher gratitude levels (Mills et al., 2015; Redwine et al., 2016; Huffman et al., 2016b; Hartanto et al., 2019). As part of the “neural alarm system,” the vCA1–amygdala pathway is crucial in the process of triggering inflammation (Irwin and Cole, 2011; Eisenberger and Cole, 2012). Gratitude may reduce inflammatory processes by increasing support giving and favoring decreased amygdala activity (Hazlett et al., 2021). Inflammation, a recognized risk factor for both atherosclerosis progression and plaque rupture, can directly accelerate atherosclerosis progression (Levine et al., 2021). Several studies have suggested that elevated hsCRP levels after ACS are independently associated with an increased risk of mortality (Zebrack et al., 2002; James et al., 2003; Ribeiro et al., 2014). In a prospective observational study of patients with ACS, Huffman et al. (2016a) reported a correlation between decreased levels of TNF-α and increased gratitude. Further, chronic pro-inflammatory factors can cause endothelial cell dysfunction by inducing chronic inflammatory processes. Some studies on vascular endothelial function have found that gratitude is associated with improvement in vascular endothelial function. For example, in a cohort study of patients with ACS, Celano et al. (2017) found that gratitude is associated with reduced markers of endothelial dysfunction, including endothelin-1 (ET-1) and soluble intercellular adhesion molecule-1 (sICAM-1).

Inflammation has also been implicated in the pathogenesis and prognosis of HF (Bouras et al., 2014). Pro-inflammatory factors are activated in asymptomatic HF, and their increase leads to worsening congestive HF (Bozkurt et al., 2010). In a randomized controlled trial among patients with asymptomatic HF, multiple inflammatory biomarkers, such as CRP, TNF-α, IL-6, and sTNFr1, were extracted from the patient’s blood before and after an 8-week gratitude diary intervention. At the end of the study, the biomarkers were checked again and were lower in the gratitude intervention group than in the usual treatment group (Redwine et al., 2016). Similar findings were reported in another HF study (Mills et al., 2015). In a study of 1,054 adults, Hartanto found that decreases in personal gratitude were significantly associated with decreases in IL-6 (Hartanto et al., 2019). This suggests that gratitude may suppress atherosclerosis and inhibit ventricular remodeling by reducing inflammation, which reduces the risk of major adverse cardiovascular events.

Gratitude may influence the occurrence and development of various CVD by increasing parasympathetic tone and decreasing heart rate and diastolic blood pressure. In a study of 32 healthy volunteers, the results showed that the average heart rate during a gratitude intervention was lower than during resentment intervention (Kyeong et al., 2017). A randomized blinded trial by Jackowska et al. (2016) and Redwine et al. (2016) found that gratitude interventions were associated with a decrease in diastolic blood pressure compared with no treatment controls. The limbic system in the human brain, especially the amygdala, is the neural basis of emotion processing. Increased amygdala activation can trigger strong emotional reactions including autonomic and endocrine responses. Gratitude levels are related to activity in the medial prefrontal cortex. Some evidence suggests that gratitude interventions may decrease sympathetic nervous system activity by reducing amygdala reactivity and activating the ventral striatum and diaphragm area (Hazlett et al., 2021). However, increased sympathetic tone, an important predictor of HF, is associated with higher mortality in patients with myocardial infarction (La Rovere et al., 1998; Machado et al., 2006; Shah et al., 2013). Increase in heart rate is associated with greater sympathetic than parasympathetic activity. Increased heart rate (>180 beats/min) was shown to shorten diastole duration (cardiac relaxation), further reducing coronary flow and cardiac output, increasing myocardial oxygen consumption, and aggravating myocardial ischemia and hypoxia.

Gratitude can inhibit the sympatho adrenomedullary (SAM) system and the renin–angiotensin–aldosterone system (RAAS), reducing cardiovascular responses to acute stress. Impaired baroreflex is regarded as a sensitive marker of autonomic cardiovascular regulation. Stress influences ischemic heart disease (Frasure-Smith and Prince, 1989; Frasure-Smith, 1991; Frasure-Smith et al., 1992, 1997) and has been demonstrated to cause myocardial ischemia in patients with coronary heart disease through several mechanisms (Krantz et al., 1991; Yeung et al., 1991; Manuck et al., 1992; Dakak et al., 1995). Studies have reported impaired vasomotor regulation of atherosclerotic epicardial coronary vasculature (Yeung et al., 1991) and coronary microcirculation (Dakak et al., 1995). The mu-opioid receptor, which is part of the opioid system, appears to be involved in stress relief and restoration of homeostasis. The experience of gratitude is accompanied by mu-opioid signaling, which explains the positive effects of gratitude on human physiological health. Self-reported levels of gratitude correlate with brain regions associated with emotional activities. Practicing gratitude can alleviate physiological stress and strain on the body and thus favorably influences health outcomes (Henning et al., 2017). In a study of patients with ACS, gratitude interventions reduced stress levels after ACS (Millstein et al., 2016). A double-blind randomized controlled trial included three groups: gratitude diary intervention group, bothered diary intervention group, and no intervention group. Individuals who received the gratitude diary intervention reported a decrease in self-reported depressive symptoms and stress (Cheng et al., 2015). In the study conducted by Rash et al., gratitude practices reduced stress and increased cardiac coherence, represented by a steady and ordered sinusoidal pattern in the heart rate variability waveform compared to baseline measurements. Subjecting participants to gratitude reflection in a dedicated laboratory can result in more ordered electrocardiogram waveforms and greater physiological coordination (Rash et al., 2011).

Gratitude can inhibit the hypothalamic–pituitary–adrenal (HPA) axis and lower cortisol levels. Cortisol, considered a critical mediator of mental states and health-related outcomes, is the hormonal end-product of the HPA axis and can modulate neuroendocrine stress responses (Matvienko-Sikar and Dockray, 2017). The relationship between cortisol and mental state has been intensively investigated for many years. Stress has been frequently linked to elevated concentrations of endogenous cortisol, a hormone involved in the stress response (Biondi and Picardi, 1999). Writing gratitude journals can relieve pressure experienced during pregnancy, for example, and cortisol release is decreased as the pressure is relieved. In a randomized controlled trial of 46 pregnant women, gratitude interventions were provided 4 times per week for 3 weeks. The gratitude intervention group showed lower cortisol and stress levels in both wakefulness and sleep during pregnancy than the control group that received conventional therapy (Matvienko-Sikar and Dockray, 2017). Furthermore, CD38 gene expression can influence oxytocin signaling, and the oxytocin system has been implicated in the quality and frequency of gratitude expression. Studies have indicated that higher gratitude expression is related to lower CD38 expression, and functional genetic variation in CD38 is related to the quality and quantity of gratitude behavior (Algoe and Way, 2014; Figure 3).