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Impact of Supplemental Oxygen on Cardiovascular Physiology

Submitted:

02 April 2026

Posted:

03 April 2026

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Abstract
Supplemental oxygen is a cornerstone intervention in modern clinical practice, widely used to correct hypoxemia in emergencies, perioperative, and critical care settings. While oxygen therapy is lifesaving, accumulating evidence indicates that excessive oxygen exposure can induce significant pathophysiological disturbances, particularly within the cardiovascular and pulmonary systems. Hyperoxia (PaO2 > 100 mm Hg) promotes the generation of reactive oxygen species (ROS), leading to oxidative stress, mitochondrial dysfunction, and activation of pro-fibrotic pathways. When combined with mechanical ventilation, these effects are further amplified through alterations in intrathoracic pressure, reduced venous return, and increased pulmonary vascular resistance, collectively imposing hemodynamic stress on the myocardium. These mechanical and biochemical perturbations converge to drive structural, functional, and electrical remodeling of the heart, including conduction abnormalities and arrhythmogenesis. Emerging clinical insights, particularly from critically ill and COVID-19 populations, underscore the importance of titrated oxygen strategies that balance adequate tissue oxygenation with minimization of hyperoxic injury. This review synthesizes current evidence on hyperoxia-induced oxidative stress, heart–lung interactions, and mechanisms underlying myocardial remodeling to provide a comprehensive framework for optimizing oxygen therapy.
Keywords: 
supplemental oxygen
;  
mechanical ventilation
;  
hyperoxia
;  
cardiac remodeling
;  
arrhythmias
;  
systolic dysfunction
Subject: 
Medicine and Pharmacology  -   Cardiac and Cardiovascular Systems

1. Introduction

Supplemental oxygen therapy remains one of the most frequently administered interventions in modern medicine and is considered an essential treatment for patients experiencing hypoxemia, respiratory failure, or critical illness [1,2]. By increasing arterial oxygen content, it preserves tissue oxygen delivery and prevents organ dysfunction. Consequently, approximately half of patients admitted to intensive care units receive oxygen therapy at some point during their clinical course [2] . However, oxygen is not biologically inert. Increasing evidence demonstrates that excessive oxygen exposure can disrupt cellular homeostasis and induce systemic toxicity [1,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22].
A central mechanism underlying oxygen toxicity is hyperoxia, defined as supraphysiological oxygen levels in blood and tissues. When the partial pressure of arterial oxygen (PaO2) levels is greater than 100 mmHg, it is considered as hyperoxia [23]. Hyperoxia occurs when oxygen levels in blood and tissues exceed physiological requirements, typically as a result of high fractions of inspired oxygen (FiO₂) during supplemental oxygen therapy or mechanical ventilation [9]. Under these conditions, molecular oxygen undergoes partial reduction, generating reactive oxygen species (ROS) such as superoxide, hydrogen peroxide, and hydroxyl radicals [24]. While low levels of ROS participate in normal cellular signaling, excessive ROS production overwhelms endogenous antioxidant defenses and induces oxidative damage to lipids, proteins, and nucleic acids. The resulting oxidative stress has been implicated in the development of pulmonary injury, vascular dysfunction, and myocardial damage.
In critically ill patients, the interaction between oxygen therapy and cardiopulmonary physiology is particularly complex. Mechanical ventilation and elevated oxygen concentrations can alter intrathoracic pressure, pulmonary vascular resistance, and ventricular loading conditions, thereby affecting cardiac output and myocardial stress [25]. In addition to hemodynamic changes, hyperoxia promotes inflammatory signaling and mitochondrial dysfunction that may contribute to myocardial remodeling and electrical instability [5]. These processes highlight the interconnected nature of the heart and lungs, where pulmonary injury can propagate systemic effects through inflammatory mediators and oxidative stress pathways.
Recent clinical and experimental studies have therefore shifted attention toward a more conservative and titrated approach to oxygen administration, aiming to maintain adequate oxygenation while minimizing hyperoxic injury [12]. Understanding the physiological consequences of supplemental oxygen on cardiovascular function is essential for optimizing oxygen therapy strategies in critically ill patients.
This review explores the impact of supplemental oxygen and hyperoxia on cardiovascular physiology, with particular emphasis on heart–lung interactions during mechanical ventilation, mechanisms of myocardial structural remodeling, functional hemodynamic alterations, and electrophysiological disturbances associated with excessive oxygen exposure.

Supplemental Oxygen

Supplemental oxygen is a cornerstone of emergency and intensive care medicine, primarily utilized to reverse hypoxemia in respiratory failure. While nearly half of all Intensive Care Unit (ICU) patients receive oxygen therapy, the clinical challenge lies in balancing therapeutic benefit against the risks of oxygen toxicity [1,2]. Supplemental oxygen provides a higher concentration than room air to improve gas exchange, with the current guidelines emphasizing a “titrated approach”, where delivery methods are chosen based on bedside respiratory assessment such as chest movement and breath sounds [2,26].

Clinical Delivery and Hemodynamic Impact

Supplemental oxygen delivery follows a stepwise manner starting from a noninvasive (NIV) delivery pattern leading to more invasive techniques depending on the severity of oxygenation needed. Noninvasive oxygen delivery includes nasal cannulas providing a fraction of inspired oxygen (FiO₂) of 24–40% at flow rates of 1–6 L/min and simple face masks providing an FiO₂ of 40–60% at flow rates of 5–10 L/min [26]. As flow rates and device support increase, FiO₂ can be titrated from just above ambient levels to nearly 100% with systems such as non-rebreather masks or high-flow oxygen devices [27]. NIV is used as first-line therapy in emergency departments and out-of-hospital settings for acute chronic obstructive pulmonary disease (COPD)/ asthma exacerbations with hypercapnic respiratory failure, pulmonary edema, and hypoxemic failure in immunocompromised patients including post-transplant and cancer, avoiding intubation when possible [28].
Recent clinical guidelines suggest the use of high-flow nasal cannula (HFNC) over conventional oxygen therapy in acute hypoxemic respiratory failure, as it provides physiological benefits like anatomical dead space reduction and heated humidification while improving patient comfort and tolerance. Furthermore, HFNC is recommended during breaks from non-invasive ventilation (NIV) to maintain oxygenation, though clinicians must ensure its use does not delay necessary intubation in deteriorating patients [29]. When oxygenation demands exceed the capabilities of high-flow systems, NIV is considered advantageous because it lowers inspiratory muscle workload, enhances alveolar recruitment, and maintains airway patency while avoiding the complications of mechanical ventilation (MV) [30].
Invasive ventilation on the other hand involves endotracheal intubation or tracheostomy with MV delivering FiO₂ up to 1.0 (100%), typically combined with positive end-expiratory pressure to support gas exchange in critically ill patients [26]. During MV, such high inspired oxygen fractions can lead to arterial hyperoxia and tissue hyperoxia. Experimental work in rats has shown that supplementing MV with 100% oxygen increases diaphragm vascular resistance and further reduces diaphragmatic blood flow and oxygen delivery compared with normoxic ventilation, providing a mechanistic basis for hyperoxia-related diaphragm injury. [8]
Moore et al. demonstrated that supplemental oxygen (50% O2) significantly enhanced exercise capacity and reduced exertional breathlessness in patients with chronic congestive heart failure. While these improvements suggested that supplemental oxygen concentrations can acutely alleviate ventilatory and hemodynamic constraints, it is not without cardiovascular cost [31]. Supplemental oxygen is often administered in patients with symptomatic heart failure; however, high concentrations have been shown to acutely reduce cardiac output and stroke volume while increasing pulmonary capillary wedge pressure. These findings suggest that oxygen therapy can impose significant hemodynamic strain, particularly in patients with precariously low baseline cardiac performance [32]. Conversely, inhalation of oxygen at concentrations exceeding 21% induces a vagus-mediated reduction in heart rate, resulting in a rate-dependent decrease in cardiac index. [33]

Hyperoxia

Hyperoxia is a condition in which oxygen levels in tissues and organs become abnormally elevated due to exposure to excessive FiO₂ or high partial pressure of arterial oxygen (PaO2≥ 100 mmHg). These highly inspired oxygen fractions produce toxic effects through the excess generation of reactive oxygen species (ROS), which disrupt redox balance and damage cellular lipids, proteins, and DNA. At high partial pressures, oxygen becomes toxic, with injury most prominently affecting the lung, central nervous system, and eye. The timing and severity of toxicity depends on both dose and duration of exposure [1]. This vulnerability is underscored by the ‘oxygen paradox,’ where the sudden reintroduction of molecular oxygen to oxygen-starved tissues triggers a unique injury response that paradoxically enhances tissue damage beyond the initial period of ischemia [24].

Types of Hyperoxia

Hyperoxia is distinguished between two types. Normobaric hyperoxia refers to exposure to elevated oxygen concentrations at normal atmospheric pressure, typically achieved by administering high FiO₂ oxygen mixtures through masks or ventilatory support in a standard pressure environment. Hyperbaric hyperoxia is produced during hyperbaric oxygen therapy, where patients breathe near-100% oxygen inside a pressurized chamber set above 1 atmosphere absolute pressure [9].
Normobaric hyperoxia is delivered via nasal cannula or facemask and is widely used as a standard intervention in conditions such as acute ischemic stroke. In stroke, normobaric hyperoxia raises brain tissue oxygen, increasing interstitial partial pressure of arterial oxygen (PaO₂) in the ischemic penumbra (but not in the infarct core), helping to preserve penumbral tissue without substantially increasing oxidative radical injury in experimental models [6].
While hyperbaric hyperoxia is used in wound healing measures, it makes oxygen toxicity develop faster than normobaric oxygen due to the increasing amount of oxygen dissolved in blood and tissues, which boosts harmful oxygen radicals and places stress on organs like the lungs and brain. In the lungs, it first causes irritation of the airways with cough and reduced mucus clearance which then leads to lung inflammation, fluid in the lungs, chest pain, and shortness of breath if exposure continues. It also has a clear nerve-related component, with brain and vagus-nerve pathways helping drive symptoms, showing that both direct oxygen damage and nervous-system signals are involved in how the body responds [12].

Systemic Toxicity and Organ Dysfunction

Hyperoxia exerts systemic effects that extend to multiple organs. In the kidney, excessive oxygen administration alters renal blood flow and oxygen homeostasis and has been implicated in the development of acute kidney injury. Interactions of the lung–heart–kidney organs further amplify these effects, so that injury in one organ can influence dysfunction in the other organs under sustained hyperoxia exposure. Beyond these systemic effects, hyperoxia is also a key driver of cardiac remodeling. MV together with prolonged hyperoxia can injure pulmonary epithelial cells [10]. A previous study reported that hyperoxia-induced lung injury in mice often led to mortality after approximately 72 to 96 hours of exposure evidenced by a 10-15% reduction in total body weight [34]. Hyperoxia was also known to cause elevated QTc and JT intervals, decrease in cardiac output and ejection fraction, bradycardia and cardiac arrhythmias in previous studies from our laboratory [5,13,14,15,16,17,18,19,20,21,22].
Despite these risks, hyperoxia also has beneficial effects like supporting postoperative wound healing by providing the high tissue oxygen tensions required for neutrophil-mediated ROS production, phagocytosis, and superoxide-driven bactericidal activity against wound pathogens [4]. Ultimately, supplemental oxygen therapy must be carefully administered to balance therapeutic necessity against the risk of systemic oxidative injury.

Impact of Supplemental Oxygen on Lung Physiology

Mechanical ventilation serves as a vital therapy for patients suffering from a multitude of different ailments. The primary goal of this intervention is to maintain adequate gas exchange, specifically by ensuring systemic oxygenation and the clearance of carbon dioxide. Central to this process is the titration of the fraction of inspired oxygen (FiO2). For decades, the clinical “safety net” leaned toward liberal oxygen administration to prevent the immediate risks of cellular hypoxia. However, an emerging body of evidence suggests that the lungs are exquisitely sensitive to oxygen concentrations, and that “too much” oxygen may be as detrimental as “too little” [35].
Furthermore, the physical presence of high-concentration oxygen within the alveoli alters the mechanical stability of the lung. The “washout” of inert nitrogen, which normally provides a structural scaffold for the air sacs, can lead to absorption atelectasis, effectively reducing the surface area available for gas exchange and creating a paradoxical need for even higher pressures or oxygen levels [36].
For a healthy lung, the biological standard for oxygen in inhaled air is 21%, which is equivalent to the amount of oxygen present in a regular environment. In ventilated patients, maintaining an FiO2 between 21% and 41% is generally considered the “safe zone,” provided it maintains adequate systemic oxygenation (between 92–96% for SaO2). At these levels, the risk of oxidative stress is minimal. Antioxidants such as glutathione and superoxide dismutase in the lung tissue can easily neutralize the standard production of reactive oxygen species (ROS). N2 makes up the bulk of the gas at these levels, acting as a “stent” that keeps the alveoli open at the end of expiration [36].
Within the 41% to 60% range for FiO2, the partial pressure of nitrogen within the alveoli decreases. Oxygen is rapidly sequestered by pulmonary capillary hemoglobin, and if the rate of oxygen uptake exceeds the rate of alveolar ventilation, the alveolar volume decreases, leading to alveolar collapse. The 41%–60% range has been shown to blunt the hypoxic pulmonary vasoconstriction (HPV) reflex. HPV is a homeostatic mechanism that diverts blood flow away from poorly ventilated lung units toward well-ventilated ones [37]. By increasing alveolar oxygen tension in poorly ventilated areas without necessarily improving their gas-exchange capacity, moderate FiO2 levels can cause vasodilation in these “shunt” areas. This redistribution of blood flow can lead to an increase in the venous admixture and a decrease in the efficiency of gas exchange. Animal research for low-to-moderate hyperoxia, defined as FiO2 between 21% to 60%, has shown an increase in lung lavage protein concentrations, suggesting early injury [11]. Studies also found that exposure to FiO2 of 50% to 60% for 7 days alone decreased survival time when animals were subsequently exposed to 100% oxygen, suggesting that moderate hyperoxia “primes” the lung for more severe toxicity [11]. In models involving an inflammatory challenge (infectious and noninfectious) low-to-moderate FiO2 consistently increased standardized mean differences in lung weights-- an indication for pulmonary edema and fluid accumulation [11].
Clinical literature frequently identifies a FiO2 of 0.60 as the pivotal threshold where the risk of pulmonary oxygen toxicity begins to outweigh the benefits of supplemental oxygenation. Sustained exposure to 60% FiO2 overwhelms the lung’s endogenous antioxidant defenses, leading to an accelerated production of reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. These ROS directly attack the lipids and proteins within the cell membranes of Alveolar Type I and Type II cells, a process termed lipid peroxidation [7]. This cellular damage specifically impairs the production of surfactants, which increases surface tension and reduces lung compliance, making the lungs “stiff” and harder to ventilate. Beyond chemical damage, high concentrations of oxygen exert a mechanical effect known as absorption atelectasis [36]. In a normal environment, nitrogen provides a structural scaffold that keeps the alveoli open because it is not easily absorbed into the blood. When FiO2 increases to 60% or higher, oxygen replaces this nitrogen; as the oxygen is rapidly absorbed into the bloodstream, the alveoli lose internal pressure and collapse. This nitrogen “washout” reduces the functional surface area for gas exchange and can lead to hyperoxic acute lung injury (HALI), a condition pathologically similar to acute respiratory distress syndrome (ARDS) characterized by non-cardiogenic edema and, eventually, pulmonary fibrosis [3].

Supplemental Oxygen Induced Cardiac Pathophysiology

I. Mechanical Ventilation as a Structural Stressor of the Myocardium

Mechanical ventilation (MV) must be understood as more than a respiratory support strategy because it directly alters the mechanical environment in which the heart functions [25]. This is because the heart and lungs share the same thoracic cavity, so any change in intrathoracic pressure or lung volume inevitably affects cardiac loading conditions [38]. Under normal spontaneous breathing, inspiration generates negative intrathoracic pressure. This negative pressure lowers right atrial pressure and increases the pressure gradient between the systemic venous system and the right atrium, thereby enhancing venous return and supporting physiological ventricular filling [39]. In contrast, positive-pressure ventilation delivers air by actively increasing airway and intrathoracic pressure during inspiration [40]. This is important because when intrathoracic pressure rises, right atrial pressure rises as well, and the pressure gradient that drives venous return correspondingly decreases. As a result, less blood returns to the heart during inspiration [41]. This reduction in venous return is often described simply as “decreased preload,” but the underlying mechanism is more precisely explained by changes in transmural pressure the difference between the pressure inside the cardiac chambers and the pressure surrounding the heart [42]. Myocardial wall tension depends on this transmural pressure rather than on intracavitary pressure alone [43]. Therefore, when intrathoracic pressure increases during mechanical ventilation, it reduces effective transmural pressure even if systemic arterial pressure remains stable [42]. This means that the actual mechanical load experienced by myocardial fibers changes with each ventilator’s breath. Over time, these repeated shifts in wall stress alter myocardial strain patterns and cyclic fiber stretch, which can activate intracellular signaling pathways involved in structural adaptation [44]. Thus, mechanical ventilation influences the heart not only by transiently modifying cardiac output but by fundamentally reshaping the pressure conditions that determine myocardial stress and long-term remodeling (Figure 1).
Mechanical ventilation does not merely alter pressures around the heart; it also exposes the myocardium to repeated mechanical strain, and the heart is biologically programmed to respond to such strain [45]. This is because cardiomyocytes are not passive contractile units. They contain stretch-sensitive ion channels and cytoskeletal structures that function as mechanosensors, meaning they detect changes in mechanical load and convert those forces into intracellular biochemical signals [46]. When ventricular wall stress increases, whether from elevated afterload or chamber dilation, these mechanosensors activate signaling pathways within the cell. Pathways such as MAP kinase, calcineurin–NFAT, and PI3K–Akt become engaged, leading to changes in gene transcription [47]. These transcriptional changes promote the synthesis of contractile proteins and expansion of sarcomeric units, increasing cardiomyocyte cross-sectional areas [48]. In this way, mechanical strain is translated into cellular growth. Therefore, repetitive mechanical stress during mechanical ventilation is not physiologically neutral; when sustained, it becomes encoded as a hypertrophic growth signal within the myocardium [49].
This mechanotransduction process is particularly significant in the right ventricle because of its unique structural design and functional role [50] as it causes the right ventricle to adapt to pump blood into a low-resistance pulmonary circulation. Under normal conditions, pulmonary vascular resistance (PVR) remains low, allowing the RV to function efficiently with relatively thin walls [51]. However, pulmonary vascular resistance is highly sensitive to changes in lung volume and alveolar pressure [52], so when positive end-expiratory pressure (PEEP) is elevated, or alveoli become overdistended, pulmonary capillaries are compressed, increasing resistance within the pulmonary circulation [53]. As PVR rises, the right ventricle must generate higher pressures to maintain forward flow. This increases right ventricular afterload, which translates directly into increased wall stress. According to Laplace’s law, wall stress increases in proportion to chamber pressure and radius [54]. In the early phase, the right ventricle compensates by increasing contractility and initiating hypertrophic remodeling to reduce wall tension per unit area. Thickening of the ventricular wall distributes stress across a greater muscle mass, temporarily restoring mechanical balance [55]. However, if elevated afterload persists, this adaptive response becomes maladaptive. When contractile reserve is exceeded, the right ventricle begins to dilate, which increases chamber radius, increasing wall stress, thus creating a self-perpetuating cycle of mechanical overload [56]. At this stage, structural remodeling is no longer compensatory but progressive.
The structural consequences of right ventricular remodeling extend beyond the right ventricle itself because of ventricular interdependence [57] as both ventricles share the interventricular septum, and the heart is constrained within the pericardial sac. As right ventricular pressure rises and dilation develops, the septum shifts toward the left ventricle [58], which alters the left ventricular geometry, reducing its diastolic compliance and changing the distribution of wall stress within the LV myocardium [59]. In particular, subendocardial regions may experience increased strain over time, as abnormal mechanical strain patterns activate hypertrophic and fibrotic signaling pathways within the left ventricle, even in the absence of primary LV pathology [60]. In this way, pulmonary vascular stress initiated by mechanical ventilation can secondarily induce structural remodeling of the left ventricle through mechanical coupling alone.
Mechanical strain is not the only factor driving this remodeling process, as neurohormonal activation significantly amplifies structure during mechanical ventilation [52]. Patients requiring ventilatory support often exhibit increased sympathetic activity and activation of the renin–angiotensin–aldosterone system (RAAS) [61]. Sustained catecholamine exposure increases intracellular calcium cycling and metabolic demand within cardiomyocytes, and over time, chronic adrenergic stimulation promotes hypertrophy and can induce apoptotic signaling pathways [62]. Angiotensin II further contributes to this process by binding to myocardial AT1 receptors and directly stimulating hypertrophic gene expression [63]. In addition, angiotensin II activates cardiac fibroblasts, promoting extracellular matrix production. Aldosterone enhances collagen synthesis within the myocardial interstitium [64].
The structural consequence of persistent neurohormonal signaling is expansion of the extracellular matrix and increased myocardial stiffness [65], as when collagen accumulates, ventricular compliance decreases. Reduced compliance impairs diastolic relaxation and elevates filling pressures, which in turn further alters wall stress distribution [66]. Thus, neurohormonal activation does not simply accompany mechanical strain; it transforms transient mechanical stress into durable architectural change. Over time, the combined effects of mechanotransduction and hormonal signaling reshape ventricular structure in a manner that predisposes to functional impairment and electrical instability [67].
Inflammatory spillovers from ventilator-induced lung injury represent a major pathway through which mechanical ventilation can influence myocardial structure [68]. For example, when alveoli are exposed to excessive mechanical stretch or high oxygen concentrations, epithelial and endothelial cells within the lung release pro-inflammatory mediators into the systemic circulation. This process, often referred to as biotrauma, pushes the consequences of lung injury beyond the pulmonary compartment [69]. Cytokines such as tumor necrosis factor–α and interleukin-6 do not remain localized; once in circulation, they interact with receptors expressed on cardiomyocytes and cardiac fibroblasts [70].
Binding these cytokines into myocardial receptors activates intracellular signaling pathways, including nuclear factor κB (NF-κB) and other transcriptional regulators [71]. These transcription factors alter gene expression patterns within cardiac tissue. Specifically, they upregulate genes involved in hypertrophy and extracellular matrix production while downregulating genes associated with normal contractile homeostasis [72]. Over time, this shift in gene expression stimulates fibroblast proliferation and enhances collagen synthesis within the interstitial space [73].
The development of interstitial fibrosis carries significant structural consequences as collagen deposition increases the density of extracellular matrix between cardiomyocytes, thus disrupting their normal alignment and mechanical coupling [74]. In a healthy myocardium, coordinated contraction depends on tightly organized myofiber organization and efficient force transmission. As the fibrotic tissue accumulates, compliance decreases, and passive stiffness increases [75]. Even modest increases in interstitial collagen alter ventricular relaxation properties, making the myocardium less capable of expanding during diastole [76] as reduced compliance elevates filling pressures and changes wall stress distribution, reinforcing remodeling pathways [58]. Thus, inflammatory signaling originating in the lung can progressively reshape myocardial architecture through sustained extracellular matrix expansion.
Oxidative stress further intensifies this structural remodeling process. Hyperoxia, which is frequently employed during mechanical ventilation to ensure adequate arterial oxygenation, increases the generation of reactive oxygen species (ROS) in both pulmonary and systemic tissues [77]. ROS are highly reactive molecules capable of modifying lipids, proteins, and nucleic acids. Within cardiomyocytes, oxidative stress damages mitochondrial membranes and impairs components of the electron transport chain [78]. As mitochondrial efficiency declines, oxidative phosphorylation becomes less effective, and ATP production decreases [79].
Energy availability is critical for myocardial function. Actin–myosin cross-bridge cycling during contraction requires ATP, as does calcium reuptake into the sarcoplasmic reticulum during relaxation [80]. When ATP production is impaired, relaxation becomes energetically inefficient, and diastolic function deteriorates [81]. Chronic energetic stress also activates compensatory signaling pathways that promote structural remodeling and hypertrophic adaptation [82]. In this way, oxidative injury links metabolic stress to architectural change.
Reactive oxygen species additionally influence extracellular matrix remodeling directly. Oxidative signaling activates pro-fibrotic transcription factors and promotes differentiation of fibroblasts into myofibroblasts, the cells responsible for collagen deposition [83]. Increased myofibroblast activity accelerates interstitial fibrosis and stiffening of the ventricular wall. Beyond the interstitium, oxidative stress affects the coronary microvasculature. ROS reduces nitric oxide bioavailability and impairs endothelial function [84]. Endothelial dysfunction compromises coronary microcirculation, limiting oxygen delivery at the tissue level. Subclinical microvascular ischemia may develop, which further stimulates inflammatory and fibrotic signaling cascades [85]. This creates a reinforcing cycle in which oxidative stress promotes fibrosis, and fibrosis impairs perfusion, leading to additional oxidative stress.
The duration of exposure plays a decisive role in determining whether these responses remain adaptive or progress toward maladaptive remodeling [86]. Short-term mechanical ventilation may induce transient changes in preload and afterload without lasting structural consequences. However, sustained pulmonary vascular stress, persistent inflammatory activation, chronic neurohormonal signaling, and ongoing oxidative injury establish a feed-forward cycle of remodeling [87]. As hypertrophy progresses and the extracellular matrix expands, chamber geometry gradually changes. Ventricular walls may thicken or dilate, compliance decreases, and diastolic filling becomes impaired [88]. Once interstitial fibrosis is established, reversal becomes increasingly limited because collagen deposition represents structural reorganization rather than temporary cellular adaptation [89]. For this reason, prolonged mechanical ventilation may leave a persistent structural imprint on the myocardium even after respiratory support is discontinued [90].
Taken together, mechanical ventilation influences cardiac structure through an integrated network of mechanical load redistribution, pulmonary vascular stress, ventricular interdependence, neurohormonal amplification, inflammatory signaling, and oxidative injury [52]. These mechanisms operate simultaneously at the molecular, cellular, tissue, and organ levels. Mechanical strain activates intracellular signaling; inflammation alters gene transcription; oxidative stress damages mitochondria and promotes fibrosis; and extracellular matrix expansion reshapes ventricular geometry [71]. The result is a gradual transformation of myocardial architecture characterized by increased stiffness, altered chamber configuration, and reduced mechanical efficiency. Structural remodeling therefore serves as the foundational substrate upon which later functional impairment and electrical instability may develop [74].

II. Functional Cardiac Consequences of Mechanical Ventilation

Mechanical ventilation changes cardiac function in ways that are not just academically interesting but clinically consequential, because cardiac output is the final common pathway for oxygen delivery to tissues [40]. Even if the lungs are oxygenating well, inadequate cardiac output can still result in poor organ perfusion and tissue hypoxia [91]. This is why MV cannot be evaluated only by oxygen saturation or lung mechanics; it must also be evaluated by its effects on circulation [92]. In critically ill patients, the margin for error is small: modest drops in preload or increases in right ventricular afterload can meaningfully reduce systemic perfusion, worsen shock physiology, and contribute to organ injury [92]. Functionally, MV acts like a repeated mechanical “load intervention” on the heart, changing filling and ejection conditions breath-by-breath [93]. Understanding these effects matters because ventilator settings can be adjusted, and those adjustments can either support or strain the heart depending on the physiological context [93].
Venous return is not simply “blood going back to the heart.” It is a pressure-driven flow governed by the gradient between the mean systemic filling pressure (the pressure stored in the systemic venous reservoir) and right atrial pressure [94]. This is why intrathoracic pressure matters so much: raising thoracic pressure raises right atrial pressure, and when right atrial pressure rises, the gradient for venous return falls [41]. In positive-pressure ventilation, the inspiratory phase increases intrathoracic pressure and effectively “pushes back” against venous return [95].
Functionally, this indicates that the heart can receive less blood per beat as stroke volume then falls through the Frank–Starling relationship, which links end-diastolic volume (preload) to contractile force [96]. The critical point is that this is not a subtle effect on many ICU patients, as in volume-depleted states, systemic filling pressure is already low; therefore, the same absolute rise in right atrial pressure produces a much larger proportional reduction in the venous return gradient [41]. This explains why patients with sepsis, dehydration, bleeding, or aggressive diuresis can become hypotensive or poorly perfused when PEEP or mean airway pressure is increased [97].
This is important as reduced venous return decreases the cardiac output, thus reducing cardiac output and oxygen delivery. If oxygen delivery drops below metabolic demand, organs begin to fail even if oxygenation in the lungs looks normal [98]. Thus, MV can create a mismatch where respiratory targets look improved while systemic perfusion worsens [99]. The practical implication is that ventilator changes must be interpreted in the context of hemodynamics, not only oxygenation [99].
Mechanical ventilation does not only reduce preload. It can also increase right ventricular (RV) afterload by increasing pulmonary vascular resistance [100]. Pulmonary circulation is extremely sensitive to lung volume and alveolar pressure. When alveoli are overdistended, capillaries are compressed; when areas of the lung are collapsed, hypoxic vasoconstriction and structural vessel changes raise resistance [101]. Ventilator settings like PEEP and tidal volume can shift lung regions into these high-resistance states [102]. This means that the RV must pump against a higher pressure; the RV is structurally designed for a low-resistance circuit so it can often handle volume changes, but it is far less tolerant of acute pressure overload [52]. When PVR rises, the RV may initially compensate by increasing contractility, but if afterload rises quickly or remains high, RV stroke volume drops [103]. RV dilation may follow, and once the RV dilates, wall tension rises further, increasing oxygen demand and reducing mechanical efficiency [104]. This is emphasized as RV failure during ventilation is not an isolated “right-sided” problem since the RV output is the LV’s preload. If RV forward flow decreases, LV filling decreases, and systemic output falls [105]. This is a central reason why cardiopulmonary management in ARDS focuses heavily on RV protection: the lung strategy can unintentionally create RV strain that drives systemic shock physiology [106]. In other words, MV can indirectly affect systemic perfusion by forcing the RV into an energetically unfavorable state [97].
A major concept that explains sudden cardiac output drops on MV is ventricular interdependence [58]. The ventricles share a septum and are constrained by the pericardium. When the RV dilates under pressure overload, it physically encroaches on LV space [58]. The septum shifts toward the LV cavity, and LV filling becomes mechanically restricted [58]. This means is that the LV can look “normal” in contractility but still fail to generate adequate output because it is underfilled and geometrically distorted [107]. This is a mechanical limitation, not necessarily a myocardial weakness problem. It is also why some ventilated patients show reduced systemic output despite preserved ejection fraction (EF): the LV is ejecting a high fraction of a small volume [107]. This means that ejection fraction can be misleading in MV as a patient can have a “normal EF” and still have a critically low stroke volume [108]. In a review, it’s valuable to explicitly point out that EF is a loading-dependent metric and can be falsely reassuring when intrathoracic pressure and afterload are changing [109]. The clinically meaningful variables are often stroke volume, LVOT VTI, and signs of RV strain, rather than EF alone [110].
Cardiac output is not just a number it is the main determinant of tissue oxygen delivery when combined with hemoglobin and arterial oxygen content [111]. Mechanical ventilation can lower cardiac output through preload reduction, RV afterload increase, and ventricular interdependence. In response, the body may attempt compensation through sympathetic activation, raising heart rate and vascular tone [112]. This means that a patient may maintain blood pressure through vasoconstriction while still having poor flow to organs [113]. Blood pressure alone is not a reliable marker of adequate perfusion. A ventilated patient may appear “stable” by MAP but still have low stroke volume and inadequate tissue oxygen delivery [114]. This is highly emphasized as prolonged low-flow states contribute to acute kidney injury, hepatic congestion or hypoperfusion, gut ischemia, delirium, and worsening lactic acidosis [115]. This is why the functional cardiovascular effects of MV have downstream relevance to outcomes far beyond the heart itself [115]. It becomes an organ-systems issue: ventilation settings influence hemodynamics, which influence organ perfusion, which influences morbidity and mortality [93].
Diastolic function is often the hidden limiter of cardiac performance during MV [116]. When intrathoracic pressure rises and preload drops, the heart is operating at lower filling volumes. In patients with stiff ventricles from hypertrophy, fibrosis, or inflammation, small reductions in filling can cause disproportionate drops in stroke volume [39]. Additionally, inflammation and oxidative stress affect calcium handling, delaying relaxation and raising diastolic filling pressures [117]. What this means is that MV can unmask or worsen diastolic dysfunction because it reduces filling reserve [116]. A stiff ventricle cannot “recruit” more volume when needed; it becomes output-limited quickly [118]. Why this matters is that diastolic dysfunction is common in older patients, hypertensive patients, and critically ill patients with systemic inflammation. It is also commonly under-recognized because systolic function may appear preserved [110]. In ventilated patients, diastolic failure can therefore be a major mechanism of low cardiac output that is missed if one focuses only on EF [39].
Echocardiography is essential in ventilated patients because it provides real-time insight into chamber size, RV strain, filling patterns, and flow surrogates [39]. However, its interpretation is complicated by the fact that MV changes loading conditions. What this means is that many echo parameters are dependent on context. EF is load-dependent and may appear “improved” simply because LV afterload decreases when intrathoracic pressure rises, lowering transmural LV systolic pressure [25]. A seemingly normal EF can coexist with low stroke volume if LV filling is restricted [25]. Reports from our previous research also indicated hyperdynamic left ventricular ejection fraction (HDLVEF) in hyperoxia treated mice hearts in both ages and sexes despite significant reduction of cardiac output and stroke volume [13,17,21]. Hyperdynamic left ventricular ejection fraction (HDLVEF) is a phenomenon with ejection fraction >70% which is commonly observed in patients admitted to ICU [119]. Similarly, diastolic indices can shift due to changes in intrathoracic pressure and venous return rather than intrinsic relaxation changes alone [120]. Why this matters is that echocardiography must be used strategically: looking for RV dilation, septal flattening, reduced TAPSE or RV fractional area change, respiratory variation in LVOT VTI, and signs of elevated filling pressures provides a clearer picture of MV-induced functional compromise than focusing on a single metric [39].
In the context of a review, stating this explicitly signals to the reader that the relationship between MV and “pump strength” is not simple and that echo is valuable precisely because it helps disentangle these interacting mechanisms.
Mechanical ventilation affects cardiac function because it changes the pressure environment of the thorax and the resistance the right ventricle pumps against [25]. These changes alter venous return, RV afterload, ventricular interaction, and ultimately cardiac output [41]. The reason this matters is that cardiac output determines organ perfusion and oxygen delivery, and reductions in output can worsen shock physiology and contribute to multi-organ dysfunction even when oxygenation improves [121]. Therefore, the functional cardiac impact of MV should be treated as a core component of ventilator management rather than a side effect, particularly in patients with ARDS, sepsis, low preload reserve, or limited RV function [97].

III. Electrical Remodeling During Mechanical Ventilation

The electrical activity in the myocardium depends on the coordinated activation and inactivation of ion channels embedded within the cardiomyocyte membrane [122]. The initiation of each heartbeat begins with a rapid depolarization phase, followed by a precisely timed repolarization process that restores membrane stability before the next excitation cycle [122]. The integrity of this sequence depends on both the density of available ion channels and the kinetics governing their gating behavior [123]. Mechanical ventilation does not directly impose electrical stimulation on the heart; however, it alters the physiologic environment in which ion channels function [124]. The combination of systemic inflammation, oxidative stress, mechanical strain, and temperature shifts progressively modifies ion channel expression and conductance [125]. Thus, mechanical ventilation indirectly reshapes the electrophysiologic landscape of the myocardium [124].
The rapid upstroke of the ventricular action potential is mediated by the fast inward sodium current (INa), conducted primarily through Nav1.5 channels encoded by SCN5A [126]. The magnitude of this sodium current determines the slope of phase for depolarization and therefore establishes conduction velocity across myocardial tissue [127]. Efficient propagation requires a sufficient density of functional sodium channels at the sarcolemmal membrane and rapid channel activation kinetics [128]. During prolonged mechanical ventilation, systemic inflammatory mediators such as TNF-α and IL-6 become elevated [128,129]. The binding of these cytokines to myocardial receptors activates intracellular signaling pathways that regulate ion channel gene transcription [130]. Sustained inflammatory signaling has been shown to reduce sodium channel expression and impair channel trafficking to the membrane [131]. Due to this reduction in channel availability, peak sodium current declines [132].
The decrease in sodium current slows the rate of membrane depolarization and reduces conduction velocity [133]. The slowing of impulse propagation produces spatial heterogeneity in electrical conduction across the ventricular myocardium [127]. Thus, wavefronts may encounter regions of partially recovered excitability, allowing reentrant circuits to form [134]. Reentry represents one of the principal mechanisms underlying sustained ventricular tachyarrhythmias [135]. Therefore, even moderate sodium channel downregulation during mechanical ventilation can create a conduction substrate vulnerable to arrhythmia [136].
The repolarization phase of the action potential is governed primarily by outward potassium currents, including IKr, IKs, IK1, and Ito [137]. The duration of repolarization determines the refractory period and coordinates recovery of excitability across myocardial tissue [138]. Uniform repolarization ensures synchronized ventricular relaxation and prevents premature re-excitation [139]. Inflammatory mediators and reactive oxygen species directly influence potassium channel expression and conductance [140]. The oxidative modification of channel proteins alters their gating properties, while cytokine-driven transcriptional changes may reduce potassium channel subunit synthesis [141]. Thus, outward repolarizing current density declines [142].
The reduction in potassium current prolongs action potential duration and extends the refractory period [143]. On surface electrocardiography, this manifests as QT interval prolongation [144]. However, the more critical effect occurs at the tissue level. Repolarization does not prolong uniformly; instead, regional differences in recovery time develop [145]. This dispersion of refractoriness creates voltage gradients that facilitate abnormal impulse propagation [146]. Due to prolonged repolarization, early afterdepolarization may arise during phase 2 or phase 3 of the action potential [147]. Our laboratory being pioneer in hyperoxia-induced cardiac electrical and structural remodeling reported significant increase in QTc intervals along with brady-arrythmias in both ages and sexes [13,14,15,17,20,21]. In mechanically ventilated patients receiving QT-prolonging medications, this effect may be amplified [148]. Figure 2 illustrates impact of supplemental oxygen/hyperoxia on cardiac electrophysiology and thereby arrhythmias.
The stability of myocardial excitation also depends on tightly regulated intracellular calcium cycling [149]. The entry of calcium during the action potential triggers further calcium release from the sarcoplasmic reticulum, initiating contraction [150]. The reuptake of calcium into the sarcoplasmic reticulum during diastole requires ATP-dependent pumps, primarily SERCA [151]. Oxidative stress impairs SERCA function and increases ryanodine receptor leakiness [152]. Due to impaired reuptake and increased spontaneous release, intracellular calcium homeostasis becomes unstable [153].
The spontaneous release of calcium during diastole activates the sodium–calcium exchanger, generating inward depolarizing current [154]. This inward current produces delayed afterdepolarizations [154]. Delayed afterdepolarizations serve as electrical triggers capable of initiating premature ventricular contractions [155]. The presence of heightened sympathetic activity during critical illness further increases intracellular calcium load [156]. Thus, the probability of triggered depolarizations rises in mechanically ventilated patients [157]. When such triggers occur in myocardium characterized by slowed conduction and repolarization dispersion, sustained arrhythmias may develop [158].
Mechanical stretching introduces an additional mechanism of electrical instability. The increase in right ventricular afterload during mechanical ventilation elevates ventricular wall tension [101]. The stretch of cardiomyocyte membranes activates mechanosensitive ion channels [157]. The activation of these channels generates depolarizing currents that lower the excitation threshold [159]. Thus, mechanical stress can directly provoke electrical activity independent of inflammatory or oxidative influences [159]. This phenomenon, termed mechano-electric feedback, demonstrates the integration between structural load and membrane excitability [160].
Temperature further modulates ion channel kinetics. The opening and closing of sodium and potassium channels involve conformational protein transitions that are temperature-dependent [161]. The elevation of body temperature accelerates channel activation and inactivation rates [162]. Fever, common in critically ill ventilated patients, alters action potential morphology [163]. Due to regional differences in channel expression and metabolic stress, temperature shifts may increase repolarization heterogeneity. Thus, fever does not merely increase heart rate; it modifies the balance between depolarizing and repolarizing currents at the molecular level [145].
Arrhythmogenesis requires both a trigger and a vulnerable substrate [164]. The triggers during mechanical ventilation include delayed afterdepolarizations arising from calcium dysregulation and stretch-induced depolarizations [159]. The substrate consists of slowed conduction from sodium channel dysfunction and repolarization dispersion from potassium channel remodeling [165]. Structural fibrosis, when present, further disrupts electrical continuity [166]. Thus, mechanical ventilation creates an environment in which mechanical strain, inflammatory signaling, oxidative injury, metabolic stress, and temperature modulation converge upon ion channel systems [167]. This convergence produces cumulative electrophysiologic instability rather than a single isolated disturbance [167].

IV Supplemental Oxygen Exacerbates Cardiac Injury in COVID-19 Patients

While mechanical ventilation has been integral in the treatment of COVID-19 since its beginnings, longitudinal clinical data demonstrates invasive mechanical ventilation exacerbates and accelerates cardiac remodeling. Extensive data from the CARDIO COVID 20-21 registry [168] indicates that COVID-19 patients with myocardial infarction (MI) during their hospitalization were significantly more likely to have received invasive mechanical ventilation (p<0.001). These patients also had greater odds of cardiopulmonary hospitalizations after they recovered from the initial COVID-19 illness, even when adjusting for other factors. In addition, Latin American cohort studies reported high mortality in patients with myocardial injury who received mechanical ventilation. In fact, except for being more than 80 years old, invasive mechanical ventilation was the single biggest risk factor for in-hospital mortality among these cohorts of COVID-19 patients, even among other risk factors such as chronic kidney disease [169]. Another piece of compelling evidence for cardiac injury during COVID-19 infection being exacerbated by mechanical ventilation is the timeline of de novo (new onset) cardiac injury that only occurred after intubation. In one study where echocardiograms were conducted during serial visits of critically ill COVID-19 patients, it was found that 31% of patients with no pre-existing right ventricular injury developed de novo RV dysfunction after being intubated and placed on mechanical ventilation [170]. These studies collectively evidence worse cardiac outcomes for COVID-19 patients receiving mechanical ventilation.
One potential mechanism to explain this pattern is continuous high positive end expiratory pressure (PEEP) from invasive mechanical ventilation artificially raising pressure in the thorax, compressing alveolar capillaries, and increasing pulmonary vascular resistance [171]. This, in turn, increases the stress on the thin-walled right ventricle, causing progressive decline. As time passes on the ventilator, COVID-19 patients show structural damage, such as progressive RV dilation and uncoupling initially absent during intubation [172]. The longer the lungs are compromised by high pressure, the greater the effect on the heart.
Ultimately, the combination of mechanical ventilation and COVID-19 infection produces a potent synergy that exacerbates cardiac remodeling and injury. The right ventricle is mechanically overloaded by the pressure from the ventilator, causing mechanical strain, while reactive oxygen species activate biosignaling pathways that cause cellular harm. Mechanical ventilation should therefore be administered more conservatively, especially in the case of treating COVID-19 patients. Several studies echo this warning, suggesting that tightly controlled, lower physiological PaO2 levels can mitigate both cardiac injury and lower mortality rates. [173]

Conclusions

In summary, supplemental oxygen remains an indispensable therapeutic intervention in modern medicine; however, its administration is not without significant cardiovascular consequences when delivered in excess. This review highlights that hyperoxia is a critical driver of cardiopulmonary dysfunction through interconnected mechanisms involving oxidative stress, inflammation, and mechanical perturbations introduced by mechanical ventilation. Elevated reactive oxygen species disrupt mitochondrial function, impair calcium handling, and activate pro-fibrotic and hypertrophic signaling pathways, collectively promoting structural remodeling of the myocardium. Simultaneously, alterations in intrathoracic pressure and pulmonary vascular resistance impose hemodynamic strain, particularly on the right ventricle, ultimately compromising cardiac output and systemic perfusion. These structural and functional changes are further compounded by electrophysiological remodeling, creating a substrate for arrhythmogenesis (Table 1). Importantly, emerging clinical evidence underscores that these effects are dose- and duration-dependent, reinforcing the need for precision in oxygen delivery. A paradigm shift toward conservative, titrated oxygen therapy is therefore essential to balance adequate tissue oxygenation with the minimization of hyperoxic injury. Future research should focus on defining optimal oxygenation thresholds, elucidating patient-specific susceptibilities, and developing targeted interventions to mitigate oxidative and inflammatory damage, thereby improving cardiovascular outcomes in critically ill populations.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. This is a review article based on published research.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

The following abbreviations are used in this manuscript:
Abbreviation Full Term
AKI Acute kidney injury
ARDS Acute respiratory distress syndrome
AT1 Angiotensin II type 1 receptor
ATP Adenosine triphosphate
COPD Chronic obstructive pulmonary disease
COVID-19 Coronavirus disease 2019
ECM Extracellular matrix
EF Ejection fraction
FiO₂ Fraction of inspired oxygen
HALI Hyperoxic acute lung injury
HDLVEF Hyperdynamic left ventricular ejection fraction
HFNC High-flow nasal cannula
HPV Hypoxic pulmonary vasoconstriction
ICU Intensive Care Unit
IL-6 Interleukin-6
I_K1 Inward rectifier potassium current
I_Kr Rapid delayed rectifier potassium current
I_Ks Slow delayed rectifier potassium current
I_Na Fast inward sodium current
I_to Transient outward potassium current
LV Left ventricle/left ventricular
LVOT VTI Left ventricular outflow tract velocity-time integral
MAP Mean arterial pressure
MI Myocardial infarction
mRNA Messenger RNA
MV Mechanical ventilation
Nav1.5 Voltage-gated sodium channel isoform 1.5
NF-κB Nuclear factor kappa B
NFAT Nuclear factor of activated T-cells
NIV Non-invasive ventilation
PaO₂ Partial pressure of arterial oxygen
PEEP Positive end-expiratory pressure
PI3K–Akt Phosphoinositide 3-kinase – protein kinase B pathway
PVR Pulmonary vascular resistance
RAAS Renin–angiotensin–aldosterone system
ROS Reactive oxygen species
RV Right ventricle/right ventricular
RyR Ryanodine receptor
SaO₂ Arterial oxygen saturation
SCN5A Gene encoding Nav1.5 sodium channel
SERCA Sarco/endoplasmic reticulum calcium ATPase
SpO₂ Peripheral oxygen saturation
T1DM Type 1 diabetes mellitus
TAPSE Tricuspid annular plane systolic excursion
TNF-α Tumor necrosis factor alpha
VILI Ventilator-induced lung injury
V/Q Ventilation-perfusion

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Figure 1. Heart–lung–ROS axis in hyperoxia-induced cardiovascular remodeling: Excessive oxygen administration during mechanical ventilation elevates reactive oxygen species (ROS) production within the lung, leading to epithelial injury, nitrogen washout, and absorption atelectasis. This pulmonary insult triggers systemic dissemination of inflammatory mediators such as TNF-α and IL-6. Circulating oxidative and inflammatory signals converge on the myocardium, promoting structural remodeling (fibrosis and hypertrophy), functional impairment (reduced cardiac output and increased right ventricular afterload), and electrophysiological disturbances (ion channel dysfunction and arrhythmogenesis). These processes collectively contribute to adverse clinical outcomes, including ventricular arrhythmias, right ventricular failure, and multi-organ dysfunction.
Figure 1. Heart–lung–ROS axis in hyperoxia-induced cardiovascular remodeling: Excessive oxygen administration during mechanical ventilation elevates reactive oxygen species (ROS) production within the lung, leading to epithelial injury, nitrogen washout, and absorption atelectasis. This pulmonary insult triggers systemic dissemination of inflammatory mediators such as TNF-α and IL-6. Circulating oxidative and inflammatory signals converge on the myocardium, promoting structural remodeling (fibrosis and hypertrophy), functional impairment (reduced cardiac output and increased right ventricular afterload), and electrophysiological disturbances (ion channel dysfunction and arrhythmogenesis). These processes collectively contribute to adverse clinical outcomes, including ventricular arrhythmias, right ventricular failure, and multi-organ dysfunction.
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Figure 2. Electrophysiological remodeling under hyperoxic and inflammatory stress: Inflammation and oxidative stress alter cardiomyocyte ion channel expression and function. Downregulation of sodium channels (Nav1.5) slows conduction velocity, while reduced potassium currents prolong repolarization, manifesting as QT interval prolongation. Concurrent calcium handling abnormalities promote delayed and early afterdepolarizations. Together, these changes create a substrate for reentrant circuits and triggered activity, increasing susceptibility to malignant arrhythmias.
Figure 2. Electrophysiological remodeling under hyperoxic and inflammatory stress: Inflammation and oxidative stress alter cardiomyocyte ion channel expression and function. Downregulation of sodium channels (Nav1.5) slows conduction velocity, while reduced potassium currents prolong repolarization, manifesting as QT interval prolongation. Concurrent calcium handling abnormalities promote delayed and early afterdepolarizations. Together, these changes create a substrate for reentrant circuits and triggered activity, increasing susceptibility to malignant arrhythmias.
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Table 1. Comparative Pathophysiology of Respiratory Support and Oxygen Concentrations.
Table 1. Comparative Pathophysiology of Respiratory Support and Oxygen Concentrations.
Category Driver Lung Status ROS/Stress Cardiac effect Long-term risk
Normoxia (baseline) 21% O2/ATM pressure Stable Alveoli (N₂ scaffold intact) Balanced /antioxidants sufficient (glutathione, superoxide dismutase) Normal hemodynamics Physiological baseline
Supplemental 02 (controlled) FiO2 21-60% Blunted HPV reflex → V/Q mismatch
↑ Lung lavage protein (early injury)
↓ N₂ → early alveolar instability ≥7 days at 50–60%: lung “primed” for toxicity
↑ Lung weights in inflammatory models (pulmonary edema)		 Antioxidants sufficient at low FiO₂, increasingly stressed approaching 60% Vagus-mediated
↓ HR → ↓ cardiac index,
↓ Stroke volume,
↑ Pulmonary capillary wedge pressure,
Hemodynamic strain in heart failure patients		 O₂ toxicity, V/Q mismatch, hemodynamic compromise
Mechanical Ventilation (Pressure) Positive pressure/PEEP N₂ washout → absorption atelectasis,
Alveolar overdistension → capillary compression,
VILI → biotrauma (TNF-α, IL-6 released systemically)		 Mechanical strain,
Neurohormonal activation: sympathetic ↑, RAAS (angiotensin II, aldosterone),
Catecholamine-driven ↑ Ca²⁺ cycling		 ↓ Venous return / preload,
↑ RV afterload (↑ PVR),
Septal shift → ↓ LV filling, Diastolic dysfunction (stiff ventricle → output-limited),
EF preserved but stroke volume low — EF misleading in MV,
Angiotensin II → hypertrophic gene expression,
Aldosterone → collagen synthesis		 RV dilation, Interstitial fibrosis (ECM expansion, reversal limited once established), Electrical instability, Progressive structural remodeling
Hyperoxia (Pathological) FiO2 > 90% Lipid peroxidation → Type I & II alveolar cell destruction,
Surfactant dysfunction → ↑ surface tension, ↓ compliance, HALI → ARDS-like injury → pulmonary fibrosis, Mortality in animal models at 72–96 hrs 		Massive ROS,
↓ Nitric oxide → endothelial dysfunction,
NF-κB → myofibroblast differentiation, Mitochondrial dysfunction → ↓ ATP, SERCA↓ + RyR leak → Ca²⁺ dysregulation		 ↓ Cardiac output & ejection fraction, Bradycardia,
↑ QTc & JT intervals, Nav1.5↓ → slowed conduction → reentry, K⁺ channel remodeling → repolarization dispersion, Ca²⁺ dysregulation → delayed afterdepolarizations, Septal shift / RV failure, ROS → myofibroblast activation		 Interstitial fibrosis, Arrhythmogenesis,
Reversal increasingly limited once fibrosis established, AKI / multi-organ dysfunction (lung–heart–kidney axis), COVID-19: 31% de novo RV dysfunction post-intubation,
MV = largest independent mortality risk factor (beyond age >80)
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Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
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