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This report is written by MaltSci based on the latest literature and research findings

What are the mechanisms of cardiovascular diseases? ​

Abstract ​

Cardiovascular diseases (CVDs) represent a significant global health challenge, accounting for approximately 31% of all deaths worldwide. The multifactorial nature of CVDs arises from complex interactions among genetic predispositions, environmental influences, and lifestyle choices. Understanding the underlying mechanisms of CVDs is crucial for developing effective preventive and therapeutic strategies. This review systematically explores the various mechanisms contributing to CVDs, beginning with an overview of their definitions, classifications, and epidemiology. It highlights the critical role of inflammation, oxidative stress, and endothelial dysfunction as pathophysiological mechanisms driving disease progression. Genetic factors, including hereditary influences and gene-environment interactions, are examined to elucidate their contributions to cardiovascular health. Additionally, lifestyle factors such as diet, physical activity, smoking, and alcohol consumption are assessed for their impact on CVD risk. Emerging risk factors, including psychosocial stress and alterations in gut microbiota, are also discussed in the context of cardiovascular health. The findings underscore the need for a comprehensive understanding of these mechanisms to identify novel therapeutic targets and intervention strategies. In conclusion, addressing the multifaceted nature of CVDs through integrated approaches is essential for improving cardiovascular health outcomes and reducing the global burden of these diseases.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Overview of Cardiovascular Diseases
    • 2.1 Definition and Classification
    • 2.2 Epidemiology and Burden of Disease
  • 3 Genetic Mechanisms
    • 3.1 Hereditary Factors
    • 3.2 Gene-Environment Interactions
  • 4 Environmental and Lifestyle Factors
    • 4.1 Diet and Nutrition
    • 4.2 Physical Activity and Sedentary Behavior
    • 4.3 Smoking and Alcohol Consumption
  • 5 Pathophysiological Mechanisms
    • 5.1 Inflammation and Immune Response
    • 5.2 Oxidative Stress
    • 5.3 Endothelial Dysfunction
    • 5.4 Metabolic Disturbances
  • 6 Emerging Risk Factors
    • 6.1 Psychosocial Stress
    • 6.2 Gut Microbiota and Cardiovascular Health
  • 7 Summary

1 Introduction ​

Cardiovascular diseases (CVDs) have emerged as one of the foremost global health challenges, contributing significantly to morbidity and mortality across diverse populations. According to the World Health Organization, CVDs account for approximately 31% of all global deaths, underscoring the urgent need for a comprehensive understanding of their underlying mechanisms[1]. The complexity of CVDs arises from a multitude of interacting factors, including genetic predispositions, environmental influences, and lifestyle choices, which collectively contribute to their pathogenesis. This multifactorial nature necessitates a detailed exploration of the biological, physiological, and environmental mechanisms that underlie these diseases.

Understanding the mechanisms of CVDs is critical not only for developing effective preventive strategies but also for advancing therapeutic interventions. Recent research has illuminated various pathways involved in CVD development, including inflammation, oxidative stress, endothelial dysfunction, and metabolic disturbances[2][3]. Moreover, emerging risk factors such as psychosocial stress and alterations in gut microbiota are increasingly recognized for their roles in cardiovascular health[4]. These insights pave the way for novel therapeutic targets and strategies that could mitigate the rising incidence of CVDs.

The current state of research indicates that while significant progress has been made in identifying genetic risk factors and their associations with CVDs[5][6], much remains to be elucidated regarding the intricate interplay between these factors and environmental influences. For instance, the role of chronic inflammation as a common pathway linking various cardiovascular conditions has garnered attention, suggesting that interventions aimed at modulating inflammatory responses may offer therapeutic benefits[3]. Additionally, the impact of lifestyle factors such as diet, physical activity, and smoking on cardiovascular health has been extensively documented, highlighting the importance of lifestyle modifications in CVD prevention[7][8].

In this review, we will systematically explore the multifaceted mechanisms contributing to cardiovascular diseases. The report is organized as follows:

  1. Overview of Cardiovascular Diseases: We will begin with definitions and classifications of CVDs, followed by an examination of their epidemiology and the burden they impose on healthcare systems.

  2. Genetic Mechanisms: This section will delve into hereditary factors and gene-environment interactions that influence cardiovascular health.

  3. Environmental and Lifestyle Factors: We will assess the roles of diet, physical activity, smoking, and alcohol consumption in the context of cardiovascular disease risk.

  4. Pathophysiological Mechanisms: A detailed discussion on the mechanisms of inflammation, oxidative stress, endothelial dysfunction, and metabolic disturbances will be presented.

  5. Emerging Risk Factors: This section will focus on the implications of psychosocial stress and gut microbiota on cardiovascular health.

  6. Summary: Finally, we will synthesize the findings and discuss potential therapeutic targets and strategies for intervention.

By synthesizing current research findings, this review aims to provide a comprehensive overview of the mechanisms involved in cardiovascular diseases, thereby serving as a valuable resource for healthcare professionals, researchers, and policymakers committed to combating the rising incidence of these debilitating conditions. Understanding these mechanisms is essential for developing targeted interventions that can effectively reduce the burden of cardiovascular diseases and improve patient outcomes.

2 Overview of Cardiovascular Diseases ​

2.1 Definition and Classification ​

Cardiovascular diseases (CVDs) encompass a range of disorders affecting the heart and blood vessels, significantly contributing to global morbidity and mortality. The underlying mechanisms of these diseases are multifaceted, involving genetic, environmental, and lifestyle factors that interact in complex ways.

One of the primary mechanisms contributing to CVD is the role of inflammation. Chronic inflammation is recognized as a significant factor in various cardiovascular conditions, including atherosclerosis, myocardial ischemia, and heart failure. Extracellular vesicles have been implicated in mediating inflammatory processes, linking innate and adaptive immune responses to cardiovascular pathology (Akhmerov & Parimon, 2022) [2]. Furthermore, inflammation resolution mechanisms are crucial in the context of arterial hypertension and ischemic heart disease, where failures in resolution can exacerbate chronic inflammatory states and disease progression (Gonzalez et al., 2024) [3].

Genetic factors also play a critical role in the development of cardiovascular diseases. Studies utilizing microarray technology have highlighted the importance of gene expression changes in various cardiovascular conditions, including coronary artery disease (CAD) and heart failure. These investigations have led to the identification of specific gene subsets associated with distinct disease processes, enhancing our understanding of the molecular mechanisms at play (Archacki & Wang, 2004) [1]. Moreover, genome-wide association studies (GWAS) have uncovered novel genetic variations linked to cardiovascular traits, revealing pathways previously unrecognized in atherosclerosis and other cardiovascular disorders (Lusis, 2012) [9].

The interplay between metabolic disorders and cardiovascular diseases is another critical area of concern. Diabetes and insulin resistance are known to accelerate atherosclerosis, increasing the risk of cardiovascular events. The molecular mechanisms underlying this relationship include hyperglycemia and hyperinsulinemia, which directly promote vascular dysfunction and thrombotic events (Reusch & Draznin, 2007) [10]. Additionally, oxidative stress and endothelial dysfunction are commonly observed in patients with chronic kidney disease, further complicating the landscape of cardiovascular health (Ravarotto et al., 2018) [11].

Psychological factors, such as stress, anxiety, and depression, have also been linked to cardiovascular disease. The neurocardiology perspective highlights the central nervous system's involvement in cardiovascular pathogenesis, suggesting that psychological stress can contribute to conditions like heart failure and arrhythmias (Pereira et al., 2013) [4].

Finally, lifestyle factors, including physical activity and smoking, have profound effects on cardiovascular health. Regular moderate-intensity exercise is associated with a reduced risk of cardiovascular diseases, while vigorous exercise can transiently increase this risk (Wang, 2006) [8]. Smoking exacerbates cardiovascular risk by altering lipoprotein metabolism, leading to increased cholesterol levels and inflammation (Campbell et al., 2008) [7].

In summary, the mechanisms underlying cardiovascular diseases are diverse and interrelated, encompassing inflammatory processes, genetic predispositions, metabolic disorders, psychological factors, and lifestyle choices. A comprehensive understanding of these mechanisms is essential for developing effective prevention and treatment strategies to combat the growing burden of cardiovascular diseases globally.

2.2 Epidemiology and Burden of Disease ​

Cardiovascular diseases (CVDs) are a major global health concern, representing the leading cause of morbidity and mortality. The underlying mechanisms of these diseases are complex and multifaceted, involving interactions between genetic, environmental, and lifestyle factors.

One of the primary mechanisms implicated in cardiovascular diseases is the role of inflammation. Chronic inflammation has been recognized as a significant contributor to various cardiovascular conditions, including atherosclerosis, myocardial ischemia, and heart failure. Extracellular vesicles have been identified as mediators in the inflammatory processes associated with cardiovascular diseases, facilitating communication between cells and modulating immune responses (Akhmerov & Parimon, 2022) [2]. The resolution of inflammation is also critical; failures in this process can exacerbate chronic inflammatory states, thereby promoting disease progression (Gonzalez et al., 2024) [3].

Genetic factors play a crucial role in the development of cardiovascular diseases. Genome-wide association studies (GWAS) have identified numerous genetic loci associated with various cardiovascular conditions, revealing previously unknown pathways and mechanisms (Lusis, 2012) [9]. These genetic variations can influence lipid metabolism, inflammatory responses, and vascular function, thereby contributing to the risk of developing cardiovascular diseases.

Additionally, metabolic factors such as diabetes and obesity are significant risk factors for cardiovascular diseases. Diabetes, particularly, is associated with increased thrombotic risk due to elevated platelet activity and endothelial dysfunction (Batten et al., 2023) [12]. The metabolic syndrome, characterized by insulin resistance, dyslipidemia, and hypertension, accelerates the development of atherosclerosis and increases cardiovascular morbidity and mortality (Reusch & Draznin, 2007) [10].

Moreover, lifestyle factors such as physical inactivity, smoking, and poor dietary habits contribute significantly to the burden of cardiovascular diseases. Smoking is particularly detrimental, as it adversely affects lipoprotein metabolism, increasing levels of low-density lipoprotein (LDL) and decreasing high-density lipoprotein (HDL), which is protective against cardiovascular disease (Campbell et al., 2008) [7].

The aging process also contributes to cardiovascular diseases through structural and functional changes in cardiomyocytes and vascular cells. Aging is associated with alterations in gene expression and cellular signaling pathways that can lead to heart failure and other cardiovascular syndromes (Sheydina et al., 2011) [13].

Lastly, psychosocial factors such as stress, anxiety, and depression have emerged as important contributors to cardiovascular diseases. The interplay between the nervous system and cardiovascular system can exacerbate disease conditions, highlighting the need for a holistic approach to cardiovascular health (Pereira et al., 2013) [4].

In summary, the mechanisms underlying cardiovascular diseases are intricate and involve a combination of genetic predispositions, inflammatory processes, metabolic dysregulation, lifestyle choices, and psychosocial factors. Understanding these mechanisms is crucial for developing effective prevention and treatment strategies to mitigate the burden of cardiovascular diseases globally.

3 Genetic Mechanisms ​

3.1 Hereditary Factors ​

Cardiovascular diseases (CVDs) are complex conditions that often exhibit a significant heritable component. The understanding of hereditary factors contributing to CVD has evolved significantly, particularly through the application of genome-wide association studies (GWAS). These studies have identified numerous genetic loci associated with various forms of cardiovascular disease, including coronary artery disease, aortic aneurysm, and atrial fibrillation, among others (Smith & Newton-Cheh, 2015) [14].

Hereditary factors in cardiovascular diseases can be classified into several categories based on their roles in disease mechanisms. First, specific gene defects can directly influence cardiovascular pathology. For instance, genetic variations affecting lipid metabolism, blood pressure regulation, and inflammatory responses have been linked to an increased risk of developing coronary artery disease (Varghese, 2024) [15]. Such variations can lead to metabolic disorders, which in turn heighten the risk of cardiovascular complications.

Furthermore, GWAS have highlighted that many genetic loci associated with coronary artery disease do not overlap with conventional risk factors, suggesting the presence of novel biological pathways influencing disease risk. For example, out of 46 genetic loci identified, only 16 were associated with traditional cardiovascular risk factors, while the remaining loci might reflect alternative pathways yet to be fully understood (Sivapalaratnam et al., 2011) [16]. This emphasizes the importance of continuing research to uncover the functional roles of these genetic variations.

Additionally, the heritable nature of cardiovascular diseases is also influenced by gene-gene and gene-environment interactions. Some cardiovascular conditions may arise from complex interactions between multiple genetic factors and external influences such as diet, lifestyle, and environmental exposures (Pang, 1998) [17]. The integration of genetic and epigenetic factors plays a crucial role in understanding the full scope of cardiovascular disease mechanisms.

Epigenetics, which involves changes in gene expression regulation without altering the DNA sequence, has also been implicated in cardiovascular diseases. Factors such as DNA methylation and histone modifications can significantly influence cardiovascular development and disease progression (Webster et al., 2013) [18]. This emerging field suggests that environmental factors can modify gene expression patterns, further complicating the hereditary landscape of cardiovascular diseases.

In summary, hereditary factors contributing to cardiovascular diseases are multifaceted, encompassing direct genetic defects, novel pathways identified through GWAS, and complex interactions between genes and environmental factors. Continued exploration of these genetic mechanisms is essential for developing targeted therapeutic strategies and improving preventive measures in cardiovascular health.

3.2 Gene-Environment Interactions ​

Cardiovascular diseases (CVDs) are complex conditions influenced by a myriad of factors, prominently including gene-environment interactions. The understanding of these interactions is critical in elucidating the mechanisms underlying CVDs, which are recognized as the leading cause of death globally.

Gene-environment interactions refer to the ways in which genetic predispositions can be modified by environmental factors, thereby influencing the risk and progression of cardiovascular diseases. Historically, the etiology of cardiovascular diseases was understood in terms of either genetic (nature) or environmental (nurture) factors. However, contemporary models acknowledge the interplay between these elements, emphasizing that the interaction between genetic and environmental risk factors often leads to disease manifestations that are more pronounced than the effects of either factor alone [19].

Research has identified several environmental and behavioral factors that can alter genetic risks associated with cardiovascular diseases. These include lifestyle choices such as diet, physical activity, smoking, and exposure to stress, which can all modulate the expression of genes related to cardiovascular health [20]. For instance, certain dietary patterns may interact with genetic predispositions to affect lipid metabolism and hypertension, leading to increased cardiovascular risk [18].

Epigenetic mechanisms are particularly relevant in the context of gene-environment interactions. Epigenetics involves modifications that regulate gene expression without altering the underlying DNA sequence, including DNA methylation and histone modifications. These changes can be influenced by environmental exposures, such as diet and toxins, and can subsequently impact cardiovascular disease pathways, including those associated with atherosclerosis and ischemia [21].

Moreover, advancements in systems genetics, which integrate omics technologies, have facilitated a more comprehensive understanding of how genetic variations interact with environmental factors to influence cardiovascular health. This approach allows for the identification of candidate genes and pathogenic pathways, thereby providing insights into gene-gene and gene-environment interactions that contribute to the development of cardiovascular diseases [22].

Despite these advancements, significant gaps remain in our understanding of the specific mechanisms through which gene-environment interactions influence cardiovascular diseases. For example, while some interactions have been consistently observed, many require further validation through additional studies [20]. Future research is essential to elucidate the complex interplay between genetic and environmental factors and to translate these findings into clinical applications for prevention and treatment of cardiovascular diseases [23].

In conclusion, the mechanisms of cardiovascular diseases, particularly in relation to gene-environment interactions, are multifaceted and require an integrative approach to fully understand their implications for public health and personalized medicine. Continued exploration of these interactions will be crucial in developing effective strategies for risk assessment, prevention, and therapeutic interventions in cardiovascular health.

4 Environmental and Lifestyle Factors ​

4.1 Diet and Nutrition ​

Cardiovascular diseases (CVD) are influenced by a multitude of factors, particularly environmental and lifestyle determinants, with diet and nutrition playing a pivotal role. The interplay between these factors contributes to the etiology and progression of cardiovascular conditions, and various mechanisms have been identified that elucidate how diet and nutrition affect cardiovascular health.

Dietary patterns significantly influence the risk of coronary heart disease (CHD), which is fundamentally linked to both genetic and environmental factors. Modifiable environmental factors, particularly diet and lifestyle, are major contributors to the increased risk of CHD at the population level. Research indicates that the types of fats and carbohydrates consumed are more critical than their total amounts in determining CHD risk. Diets rich in fruits, vegetables, whole grains, and nuts have been shown to reduce this risk, suggesting that dietary patterns are essential in the prevention of cardiovascular diseases (Hu 2009) [24].

Moreover, the role of nutrition extends to the early-life origins of cardiovascular diseases. Factors such as prenatal nutrition, maternal weight status, and infant feeding practices are crucial during the developmental stages and can lead to long-lasting cardiometabolic consequences. Evidence suggests that adverse nutritional environments in early life can trigger epigenetic changes that predispose individuals to cardiovascular diseases later in life. This epigenetic influence highlights the importance of early dietary interventions to prevent the transmission of risk factors across generations (Loche & Ozanne 2016) [25].

The Mediterranean diet, characterized by its high content of fruits, vegetables, whole grains, and healthy fats, has been associated with improved cardiovascular health. This dietary pattern not only helps in managing traditional risk factors like lipid profiles and glycemia but also appears to mitigate emergent risk factors associated with cardiovascular diseases. The cumulative effects of various foods and nutrients within this diet suggest a synergistic interaction that benefits cardiovascular health (Fitó & Konstantinidou 2016) [26].

In addition to dietary influences, lifestyle factors such as physical activity, smoking, and socioeconomic status further compound the risk of cardiovascular diseases. These factors are interrelated; for instance, socioeconomic status can affect access to healthy food options and opportunities for physical activity, thereby influencing dietary choices and overall cardiovascular health (Rios et al. 2023) [27].

Environmental pollutants and chemicals also play a significant role in cardiovascular health. Exposure to fine particulate matter in ambient air has been linked to increased cardiovascular mortality and various cardiovascular conditions, including ischemic heart disease and heart failure. Mechanistically, these environmental stressors may alter nitric oxide synthesis and increase the production of reactive oxygen species, contributing to vascular dysfunction and inflammation (Bhatnagar 2006) [28].

In summary, the mechanisms underlying cardiovascular diseases are multifaceted, involving complex interactions between dietary patterns, lifestyle choices, and environmental factors. Understanding these interactions is crucial for developing effective prevention strategies and interventions aimed at reducing the burden of cardiovascular diseases. Further research is essential to clarify these relationships and to identify specific dietary components and lifestyle modifications that can optimize cardiovascular health across different populations.

4.2 Physical Activity and Sedentary Behavior ​

Cardiovascular diseases (CVDs) are influenced by a complex interplay of environmental and lifestyle factors, particularly physical activity and sedentary behavior. Sedentary behavior has been recognized as a significant risk factor for CVD and is associated with various adverse health outcomes. Prolonged sedentary behavior is linked to an increased risk of chronic non-communicable diseases (NCDs) such as obesity, type 2 diabetes mellitus, and cardiovascular diseases, primarily due to its detrimental effects on cardiometabolic health [29].

One of the key mechanisms through which sedentary behavior impacts cardiovascular health involves modifications in hemodynamic, inflammatory, and metabolic processes. It is hypothesized that such behavior leads to impaired arterial health, which directly contributes to the development of cardiovascular diseases [30]. For instance, prolonged sitting can negatively affect lipid metabolism, insulin sensitivity, and overall vascular function, which are crucial for maintaining cardiovascular health [29].

Moreover, the relationship between sedentary behavior and cardiovascular risk is not solely dependent on the overall level of physical activity. Research indicates that even individuals who meet recommended physical activity levels can still be at risk if they engage in high amounts of sedentary behavior. This suggests that sedentary behavior represents a distinct cardiovascular risk factor independent of physical activity levels [31].

The mechanisms by which sedentary behavior contributes to cardiovascular disease include alterations in carbohydrate and lipid metabolism, increased oxidative stress, and heightened inflammatory responses. These factors can lead to atherosclerosis, a condition characterized by the buildup of plaques in the arteries, ultimately resulting in cardiovascular complications [29].

In addition to sedentary behavior, environmental factors such as pollution, socioeconomic status, and lifestyle choices also play a significant role in cardiovascular health. For example, exposure to air pollutants has been associated with increased cardiovascular mortality and morbidity, as these pollutants can induce oxidative stress and inflammation, exacerbating cardiovascular risk [28].

The importance of addressing both physical activity and sedentary behavior is underscored by the need for comprehensive strategies to improve cardiovascular health. Interventions aimed at reducing sedentary time, such as promoting regular physical activity and encouraging breaks from prolonged sitting, can lead to improved insulin sensitivity, better blood lipid profiles, and enhanced cardiovascular health [29].

In summary, the mechanisms linking cardiovascular diseases to environmental and lifestyle factors, particularly physical activity and sedentary behavior, are multifaceted. They encompass a range of biological processes including metabolic dysregulation, inflammation, and vascular impairment. Understanding these mechanisms is crucial for developing effective prevention and intervention strategies to mitigate the risk of cardiovascular diseases.

4.3 Smoking and Alcohol Consumption ​

Cardiovascular diseases (CVD) are influenced by a complex interplay of environmental and lifestyle factors, including smoking and alcohol consumption. These factors contribute to the pathophysiological mechanisms underlying CVD, affecting various biological processes that ultimately lead to adverse cardiovascular outcomes.

Cigarette smoking is a well-established risk factor for cardiovascular diseases, associated with increased incidence of myocardial infarction and coronary artery disease. The inhalation of tobacco smoke introduces numerous toxicants into the body, leading to oxidative stress, inflammation, and endothelial dysfunction. These changes contribute to atherogenesis—the formation of plaques in the arteries—by promoting lipid modification, inflammation, and vasomotor dysfunction, all of which are integral components of atherosclerosis development (Mallah et al. 2023) [32]. Furthermore, smoking is linked to changes in nitric oxide synthesis and reactivity, which can exacerbate vascular dysfunction and increase thrombosis risk (Bhatnagar 2006) [28].

Alcohol consumption presents a dual-edged effect on cardiovascular health. Moderate alcohol intake has been suggested to provide some protective benefits, such as slight improvements in lipid profiles. However, excessive alcohol consumption is associated with numerous adverse cardiovascular effects, including hypertension, cardiomyopathy, and arrhythmias. The detrimental impacts of heavy drinking can significantly outweigh any potential benefits, leading to increased mortality and morbidity from cardiovascular diseases (Georgescu et al. 2024) [33].

The mechanisms through which smoking and alcohol affect cardiovascular health involve alterations in key physiological processes. Smoking-induced oxidative stress can lead to endothelial injury, promoting atherosclerosis and increasing the risk of thrombotic events. Additionally, both smoking and excessive alcohol consumption are linked to hypertension, a primary risk factor for CVD, through mechanisms involving increased sympathetic nervous system activity and alterations in vascular reactivity (Cosselman et al. 2015) [34].

Furthermore, the interaction between genetic predisposition and environmental factors, such as smoking and alcohol consumption, plays a crucial role in modifying individual risk for cardiovascular diseases. Gene-environment interactions can influence how individuals respond to these lifestyle factors, potentially exacerbating or mitigating their effects on cardiovascular health (Talmud 2007) [35].

In summary, the mechanisms of cardiovascular diseases related to smoking and alcohol consumption are multifaceted, involving oxidative stress, inflammation, endothelial dysfunction, and interactions with genetic predispositions. These factors collectively contribute to the pathogenesis of CVD, highlighting the importance of lifestyle modifications in prevention and management strategies.

5 Pathophysiological Mechanisms ​

5.1 Inflammation and Immune Response ​

Cardiovascular diseases (CVDs) are complex conditions characterized by various pathophysiological mechanisms, among which inflammation and immune responses play pivotal roles. These mechanisms are intertwined with metabolic processes and the overall immune environment, contributing to the initiation and progression of cardiovascular conditions.

Autoimmune diseases (AIDs) have been found to significantly increase cardiovascular risk through various immunological mechanisms. A systematic review identified that 92.8% of cohort studies demonstrated a significant association between AIDs and heightened cardiovascular risk, with chronic inflammation, endothelial dysfunction, oxidative stress, and immune cell dysregulation being the primary contributors to this relationship. Key immune components, including T cells, B cells, and neutrophils, are implicated in the atherosclerotic process via cytokine secretion, expression of adhesion molecules, and thrombogenic activity, thereby exacerbating cardiovascular complications in affected patients [36].

Recent research emphasizes the role of immune cells in regulating cardiac pathophysiology through alterations in their metabolic processes, a concept termed "immune metabolism." Immune cells modulate cardiac functions by influencing both intracellular metabolism (glycolysis and oxidative phosphorylation) and the extracellular metabolic environment, which changes during cardiovascular diseases. This interaction can lead to an imbalance between anti-inflammatory and pro-inflammatory responses, affecting myocardial ischemia, cardiac fibrosis, and remodeling [37].

Inflammatory processes are also critical in microvascular endothelial dysfunction, particularly in the context of ischemic heart disease and other conditions like diabetes and hypercholesterolemia. These inflammatory alterations result in reduced bioactivity of nitric oxide (NO), leading to endothelial dysfunction, no-reflow phenomena, and increased vascular permeability [38]. The inflammatory response in cardiovascular disease is often mediated by various factors, including reactive oxygen species, neutrophils, and pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-alpha) [38].

Moreover, the interplay between inflammation and hypertension is noteworthy. Chronic inflammation in autoimmune diseases can disrupt blood pressure regulation, contributing to an increased risk of cardiovascular events. This relationship highlights the multifactorial nature of hypertension in these patients, wherein immune-mediated mechanisms and traditional cardiovascular risk factors interact [39].

The role of monocytes and macrophages in cardiovascular disease has gained attention, as these immune cells contribute to both acute myocardial injury and chronic inflammation in atherosclerosis. The heterogeneity of monocyte populations influences their function and impact on cardiovascular pathology [40]. Furthermore, the activation of innate immune responses during ischemia-reperfusion injury underscores the complex role of inflammation in cardiac conditions, with potential beneficial and maladaptive effects [41].

In summary, the pathophysiological mechanisms underlying cardiovascular diseases are deeply rooted in inflammatory and immune responses. These mechanisms include chronic inflammation, immune cell dysregulation, metabolic reprogramming, and the interactions between traditional risk factors and autoimmune processes. Understanding these pathways is crucial for developing targeted therapeutic strategies aimed at mitigating cardiovascular complications.

5.2 Oxidative Stress ​

Oxidative stress is a pivotal factor in the pathophysiology of various cardiovascular diseases (CVDs), characterized by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defense mechanisms. This imbalance leads to cellular damage and contributes significantly to the development and progression of CVDs.

Reactive oxygen species are chemically reactive molecules that play essential roles in cellular signaling and homeostasis. However, when their levels exceed the capacity of antioxidant defenses, oxidative stress occurs, resulting in damage to lipids, proteins, and nucleic acids. This oxidative damage can trigger inflammatory responses, alter cellular functions, and promote apoptosis, all of which are critical in the context of cardiovascular health[42].

The mechanisms by which oxidative stress contributes to cardiovascular diseases are diverse. For instance, in conditions such as atherosclerosis, stroke, and heart failure, increased oxidative stress is linked to endothelial dysfunction, which is characterized by impaired nitric oxide (NO) signaling and increased vascular permeability. Elevated ROS levels can activate NAD(P)H oxidases, which are key enzymes responsible for ROS production, further exacerbating oxidative stress and leading to vascular injury and remodeling[43][44].

In heart failure, oxidative stress is associated with mitochondrial dysfunction, which results in the excessive generation of ROS and the degradation of mitochondrial DNA. This mitochondrial impairment contributes to the progressive nature of heart diseases by promoting myocardial remodeling and cellular apoptosis[45]. Furthermore, oxidative stress can influence the expression of various genes and proteins involved in inflammation and fibrosis, thereby facilitating the pathological processes underlying heart failure and other cardiovascular conditions[46].

The relationship between oxidative stress and hypertension is also significant. Increased ROS production can lead to vascular dysfunction, renal impairment, and stimulation of the sympathetic nervous system, which collectively contribute to elevated blood pressure. Notably, NADPH oxidases are identified as major sources of ROS in the cardiovascular system, particularly in the context of hypertension[47][48].

Oxidative stress also plays a crucial role in the pathogenesis of ischemia-reperfusion injury, where the restoration of blood flow after a period of ischemia leads to a surge in ROS production, causing further tissue damage. This phenomenon underscores the importance of redox homeostasis in maintaining cardiovascular health[49].

Therapeutically, addressing oxidative stress has been a focus in cardiovascular research. Strategies such as antioxidant supplementation and lifestyle modifications (e.g., increased physical activity and dietary changes) have been explored to mitigate oxidative stress and improve cardiovascular outcomes. However, the efficacy of these interventions remains a subject of ongoing investigation, as results from clinical trials have shown mixed outcomes[50][51].

In summary, oxidative stress is a central mechanism in the pathophysiology of cardiovascular diseases, influencing various biological processes that lead to endothelial dysfunction, inflammation, and tissue damage. Understanding these mechanisms is crucial for developing targeted therapeutic strategies aimed at reducing oxidative stress and improving cardiovascular health.

5.3 Endothelial Dysfunction ​

Endothelial dysfunction is a critical factor in the pathogenesis of various cardiovascular diseases (CVDs), including atherosclerosis, hypertension, heart failure, stroke, and peripheral artery disease. It is characterized by a reduced bioavailability of nitric oxide (NO), increased oxidative stress, and chronic inflammation, which collectively lead to vascular damage, atherosclerotic plaque formation, and thrombosis [52]. The mechanisms underlying endothelial dysfunction are multifaceted and can be influenced by various risk factors, including metabolic conditions, oxidative stress, and inflammatory processes.

One of the key features of endothelial dysfunction is the impaired availability of nitric oxide, which is essential for maintaining vascular homeostasis. Nitric oxide acts as a vasodilator and plays a protective role against vascular inflammation and thrombosis. The disruption of NO production or signaling leads to vasoconstriction and promotes an atherogenic environment [53]. Additionally, oxidative stress, which results from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, exacerbates endothelial dysfunction. ROS can directly damage endothelial cells, leading to further impairment of NO bioavailability and promoting inflammatory pathways [54].

Chronic inflammation is another critical component of endothelial dysfunction. It is often associated with conditions such as obesity, diabetes, and chronic kidney disease, where inflammatory mediators can induce endothelial cell activation, leading to increased expression of adhesion molecules and the recruitment of inflammatory cells to the vascular wall [11]. This inflammatory state can perpetuate a cycle of endothelial injury and dysfunction, further contributing to the progression of cardiovascular diseases [55].

Furthermore, the endothelial-to-mesenchymal transition (EndMT) has been identified as a process that contributes to vascular remodeling and accelerates CVD progression. This transition involves endothelial cells acquiring mesenchymal-like properties, which can lead to increased fibrosis and structural changes in the vascular wall [52].

Emerging evidence also highlights the role of epigenetic mechanisms, such as DNA methylation and noncoding RNAs, in regulating endothelial function in response to shear stress and other stimuli. These mechanisms may play a crucial role in the development of endothelial dysfunction and subsequent cardiovascular complications [52].

In summary, endothelial dysfunction is a central mechanism in the pathophysiology of cardiovascular diseases, driven by a combination of impaired nitric oxide signaling, oxidative stress, chronic inflammation, and structural changes in the endothelium. Understanding these mechanisms is essential for developing targeted therapeutic strategies aimed at restoring endothelial function and mitigating the risk of cardiovascular diseases [11][52][54].

5.4 Metabolic Disturbances ​

Cardiovascular diseases (CVDs) are characterized by complex pathophysiological mechanisms, with metabolic disturbances playing a crucial role in their development and progression. The heart, being a high-energy-demand organ, relies on a dynamic equilibrium of substrates such as fatty acids (FAs) and glucose for adenosine triphosphate (ATP) production. Disruptions in this metabolic balance can lead to significant pathological consequences.

One primary mechanism underlying CVDs is the dysregulation of energy metabolism, particularly evident in conditions such as heart failure (HF), atherosclerosis, and myocardial infarction (MI). These metabolic disturbances are characterized by suppressed FA oxidation and aberrant activation of glycolysis, which contribute to an energy crisis within cardiac tissues. This energy deficit can trigger oxidative stress and inflammatory responses, further exacerbating cardiac dysfunction (Chen et al. 2025) [56].

In diabetic cardiomyopathy, a specific type of heart disease associated with diabetes mellitus, metabolic disorders such as hyperglycemia and insulin resistance lead to structural and functional alterations in the heart muscle. Key mechanisms include mitochondrial dysfunction, increased oxidative stress, and impaired calcium signaling, all of which culminate in heart failure. The accumulation of intramyocardial triglycerides and enhanced lipid oxidation are also significant contributors to the metabolic derangements observed in this condition (Avagimyan et al. 2024) [57]; (Palomer et al. 2013) [58].

Moreover, the role of ferroptosis, a form of regulated cell death distinct from apoptosis, has gained attention in the context of cardio-metabolic diseases. Ferroptosis is driven by iron metabolism dysregulation, mitochondrial malfunction, and the accumulation of lipid peroxides, which can disrupt cell membranes and contribute to the progression of cardiovascular pathologies (Zhang et al. 2023) [59].

Additionally, there is increasing recognition of the crosstalk between metabolic and immune pathways in cardiovascular disease. Altered immune responses, often linked to obesity and insulin resistance, can further exacerbate metabolic disturbances. The spleen has been identified as a critical hub for the interaction between the nervous and immune systems, influencing the progression of cardiovascular and metabolic diseases (Lori et al. 2017) [60].

In summary, the mechanisms of cardiovascular diseases related to metabolic disturbances are multifaceted, involving a complex interplay of energy metabolism dysregulation, oxidative stress, immune responses, and cellular death pathways. Understanding these mechanisms is vital for developing targeted therapeutic strategies aimed at mitigating the impact of metabolic disturbances on cardiovascular health.

6 Emerging Risk Factors ​

6.1 Psychosocial Stress ​

Psychosocial stress is increasingly recognized as a significant risk factor contributing to the pathogenesis of cardiovascular diseases (CVD). Various studies have elucidated the mechanisms through which psychosocial stress influences cardiovascular health, highlighting both behavioral and pathophysiological pathways.

Firstly, psychosocial stress is associated with systemic inflammation, which plays a crucial role in the initiation and progression of atherosclerosis. Chronic exposure to psychosocial stress can lead to neuroimmune interactions that promote vascular inflammation, thereby exacerbating cardiovascular conditions [61]. Epidemiological studies have consistently linked both chronic and acute psychosocial stress to increased incidence of cardiovascular diseases, suggesting that stress-induced inflammatory processes are fundamental to understanding this relationship [61].

The mechanisms can be divided into two broad categories: behavioral mechanisms and direct pathophysiological mechanisms. Behavioral mechanisms involve the promotion of adverse health behaviors, such as poor diet, physical inactivity, smoking, and non-adherence to medical advice, all of which increase cardiovascular risk [62]. For instance, individuals experiencing chronic stress may be more likely to engage in unhealthy lifestyle choices, which can further elevate their risk for coronary artery disease (CAD) [62].

Direct pathophysiological mechanisms include neuroendocrine responses that activate the sympathetic nervous system, leading to increased heart rate and blood pressure, as well as heightened platelet activation [62]. Stress has been shown to trigger endothelial dysfunction and can cause acute myocardial ischemia, arrhythmogenesis, and increased blood viscosity through hemoconcentration [62]. This sympathetic nervous system hyperresponsivity is particularly evident in individuals with pre-existing cardiovascular conditions, where acute stress can precipitate adverse cardiac events [62].

Moreover, specific psychosocial factors such as depression, anxiety, and hostility have been linked to the exacerbation of coronary artery disease. Studies indicate that these negative emotional states can lead to increased platelet activity and reactivity, thereby enhancing thrombotic risk [63]. Chronic stress can also result in dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, leading to elevated cortisol levels, which may contribute to vascular inflammation and endothelial dysfunction [64].

In summary, psychosocial stress influences cardiovascular disease through a multifaceted interplay of behavioral and physiological mechanisms. It promotes unhealthy behaviors, triggers inflammatory responses, and activates neuroendocrine pathways that collectively heighten cardiovascular risk. Understanding these mechanisms is critical for developing targeted interventions aimed at mitigating the adverse effects of psychosocial stress on cardiovascular health [61][62][64].

6.2 Gut Microbiota and Cardiovascular Health ​

Emerging evidence underscores the significant role of gut microbiota in the regulation of cardiovascular health and the pathogenesis of cardiovascular diseases (CVDs). The gut microbiota, a diverse community of microorganisms residing in the gastrointestinal tract, interacts with the host through various mechanisms, including the production of metabolites, immune modulation, and systemic signaling pathways, which collectively influence cardiovascular physiology.

Dysbiosis, or an imbalance in gut microbial composition, has been implicated in several cardiovascular diseases, such as hypertension, heart failure, and atherosclerosis. Key microbial metabolites, particularly short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), and lipopolysaccharides (LPS), play critical roles in mediating the effects of gut microbiota on cardiovascular health. For instance, SCFAs have been shown to possess anti-inflammatory properties and may improve endothelial function, whereas TMAO is associated with promoting atherosclerosis and cardiovascular risk through mechanisms involving endothelial dysfunction and systemic inflammation [65][66].

The interplay between gut microbiota and cardiovascular health is multifaceted. The gut microbiota acts as an endocrine organ, secreting bioactive metabolites that contribute to cardiovascular homeostasis. These metabolites can influence the development of CVD by affecting metabolic pathways and immune responses. For example, alterations in gut microbiota composition can lead to the production of pro-inflammatory metabolites that exacerbate conditions such as atherosclerosis and hypertension [67][67].

Furthermore, gut microbiota-host interactions have been shown to affect cardiovascular risk factors, including obesity, diabetes, and chronic kidney disease. Dysbiosis can lead to increased intestinal permeability, allowing bacterial products to enter the systemic circulation, thereby promoting inflammatory responses that contribute to cardiovascular pathologies [67][68].

In addition to these metabolic and inflammatory mechanisms, there is growing interest in the potential therapeutic strategies targeting the gut-heart axis. Interventions such as dietary modifications, prebiotics, and probiotics may offer novel avenues for managing cardiovascular health by restoring gut microbiota balance and mitigating the effects of dysbiosis on cardiovascular disease progression [65][66].

Overall, the emerging understanding of the gut microbiota's role in cardiovascular disease highlights its potential as a critical factor in the development and progression of these conditions, emphasizing the need for further research to elucidate the underlying mechanisms and explore therapeutic interventions aimed at modulating gut microbiota for improved cardiovascular outcomes.

7 Conclusion ​

The exploration of cardiovascular diseases (CVDs) reveals a complex interplay of various mechanisms that contribute to their pathogenesis. Key findings indicate that inflammation, oxidative stress, endothelial dysfunction, and metabolic disturbances are critical factors in the development of CVDs. Chronic inflammation is a common pathway linking various cardiovascular conditions, emphasizing the need for interventions targeting inflammatory responses. Genetic predispositions, influenced by environmental factors and lifestyle choices, further complicate the risk landscape. Notably, emerging risk factors such as psychosocial stress and gut microbiota are gaining recognition for their roles in cardiovascular health. As research continues to unveil the intricate mechanisms underlying CVDs, it is evident that a multifaceted approach is essential for effective prevention and treatment strategies. Future research should focus on elucidating the interactions between genetic and environmental factors, exploring novel therapeutic targets, and developing personalized interventions to mitigate the burden of cardiovascular diseases globally.

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