Oxidative stress has been associated with diverse pathophysiological events, including cancer, renal disease, and neurodegeneration. More recently, it has become apparent that reactive oxygen species (ROS) also play a role in the development of vasculopathies, including those that define atherosclerosis, hypertension, and restenosis after angioplasty. The “response to injury” hypothesis developed by Russell Ross in the late 1970s suggested that atherosclerosis, at least, resulted from an initial injury to endothelial cells, leading to impaired endothelial function and subsequent macrophage infiltration and smooth muscle dysfunction. Many investigators then focused on oxidation of LDL and its interaction with the endothelium as the initial injury leading to the formation of fatty streaks and ultimately atherogenesis. It is now clear not only that diverse ROS are produced in the vessel wall, but that they individually and in combination contribute to many of the abnormalities associated with vascular disease.

There are many ROS that play central roles in vascular physiology (Figure 1) and pathophysiology, the most important of which are nitric oxide (NO·), superoxide (O2·−), hydrogen peroxide (H2O2) and peroxynitrite (ONOO·−). NO· is normally produced by endothelial nitric oxide synthase (eNOS) in the vasculature, but in inflammatory states, inducible NOS can be expressed in macrophages and smooth muscle cells and contributes to NO·production. NO·is a crucial mediator of endothelium-dependent vasodilation and may also play a role in platelet aggregation and in maintaining the balance between smooth muscle cell growth and differentiation. Superoxide results from one electron reduction of oxygen by a variety of oxidases (Figure 2). When O2·− is produced in concert with NO·, they rapidly react to form the highly reactive molecule ONOO·−. ONOO·− is an important mediator of lipid peroxidation and protein nitration, including oxidation of LDL, which has dramatic proatherogenic effects. …

Oxidative Stress and Cardiovascular Injury Part I: Basic Mechanisms and In Vivo Monitoring of ROS

This review so far has considered the role of vascular cells in the generation of reactive oxygen species (ROS) and novel approaches to their detection in integrated systems such as animal models of vascular disease and humans. We now turn attention to evidence consistent with a role for ROS in models of human disease and in discrete patient populations. We also briefly comment on the outcomes of clinical trials of antioxidants. Mainly, these have been disappointing. However, it is premature to conclude that the oxidation hypothesis of disease causality has been adequately tested.

Animal studies, for the most part, support a fundamental role for ROS in cardiovascular disease. Any controversy could in part reflect the use of ineffective antioxidants and the selection of models in which ROS generation is of marginal relevance to the measured outcome. Both of these issues require a quantitatively accurate measurement of drug effect (ie, antioxidant capacity) before hypotheses relating to the role of oxidant stress can be addressed rationally. These issues pertain to clinical trials also, as we will discuss. However, animal studies permit administration of much more powerful antioxidants (eg, rate constant for interaction of superoxide dismutase (SOD) with O2·− ≈1.6×109 · mol/L−1 · s−1) than is possible in humans (eg, rate constant for vitamin E ≈0.59 mol/L−1 · s−1) or, like in the case of vitamin E, doses of the antioxidant in excess of those usually applied in clinical research.

### Atherosclerosis

Animal models of atherosclerosis have documented that all the constituents of the plaque produce and use ROS. Lesion formation is associated with the accumulation of lipid peroxidation products1,2 and induction of inflammatory genes,3 inactivation of NO·resulting in endothelial dysfunction, 4,5 activation of matrix metalloproteinases,6 and increased smooth muscle cell growth.7 …

Oxidative Stress and Cardiovascular Injury: Part II: Animal and Human Studies

Free radical oxidative stress has been implicated in the pathogenesis of a variety of human diseases. Natural antioxidant defences have been found to be defective in many of the same diseases. This has led to suggestions that oxidative damage and therefore disease progression may be retarded by supplementing natural antioxidant defences. Potential antioxidant therapy includes natural antioxidant enzymes and vitamins or synthetic agents with antioxidant activity. Diseases where antioxidant therapy may be beneficial include diabetes mellitus, reperfusion injury, inflammatory diseases and the prevention of chronic processes such as atherosclerosis and carcinogenesis. Further well controlled prospective clinical trials of antioxidants are required to establish the efficacy and tolerability of antioxidant therapy in the treatment of human diseases.

Prospects for the use of antioxidant therapies.

https://www.internationaljournalofcardiology.com/article/S0167-5273(96)02854-9/pdf

Reperfusion injury: a review of the pathophysiology, clinical manifestations and therapeutic options

In this review the process of lipid peroxidation and the atherogenicity of peroxidied lipids are discussed. Recent findings with regard to the effect of selected dietary factors on susceptibility of lipids to oxidative stress and on antioxidant defences are analysed with particular reference to their potential use in the prevention and treatment of atherogenesis and, by extension, coronary heart disease. Laboratory methods of assessing antioxidant defences, lipid peroxidation and the effects of lipid peroxidation are also reviewed and discussed with particular reference to their ability to assess in vivo oxidative stress and lipid peroxidation status. A range of oxidative stress indices are presented and their limitations discussed, but the main focus is on the most commonly used laboratory test for lipid peroxidation, the thiobarbituric acid reacting substances (TBARS) test. Finally, the influence of selected dietary factors on measured peroxidation status is discussed, with particular reference to the antioxidant vitamins C (ascorbic acid) and E (alpha tocopherol) and the type of fatty acids (mono- and poly-unsaturated) in the diet.

Lipid peroxidation: A review of causes, consequences, measurement and dietary influences

Patients undergoing percutaneous transluminal coronary angioplasty (PTCA) were investigated for the production of free radicals and cholesterol hydroperoxides during reperfusion. Fifteen patients were studied. Ischaemia during balloon inflation was assessed by serial coronary sinus lactate analysis (mean maximal increase in anterior descending artery dilation was 130%), and by the demonstration of reperfusion hyperaemia (mean increase of coronary sinus oxygen saturation 74%). Free radicals were detected by electron spin resonance (ESR) spin trapping using the spin trap PBN (N-t-Butyl-alpha-phenylnitrone). Radical adducts were detected in up to 50% of samples taken during reperfusion after anterior descending lesion angioplasty. No radicals were detected in control samples or during the ischaemic phase. Radical detection was positively correlated with the change in coronary sinus lactate (p less than 0.025). Coronary sinus cholesterol hydroperoxide analysis did not show a significant increase over control during reperfusion, due in part to unexpectedly high pre angioplasty levels. This study provides clear evidence for the production of a burst of free radicals and evidence for lipid peroxidation in the minutes following myocardial reperfusion during angioplasty. A relationship between the severity of the ischaemic insult and the detection of radical adducts has also been found.

Detection of free radicals and cholesterol hydroperoxides in blood taken from the coronary sinus of man during percutaneous transluminal coronary angioplasty

OBJECTIVE--To evaluate a clinic set up specifically to assess patients with recent onset chest pain, particularly those presenting with a normal resting electrocardiogram. DESIGN--Retrospective review of case notes. SETTING--Cardiac department of a tertiary referral cardiothoracic centre. PATIENTS--250 consecutive patients with recent onset chest pain seen within 24 hours of general practitioner referral. OUTCOME MEASURES--Clinical diagnosis and management. RESULTS--40% of patients were seen within seven days of the onset of symptoms. Twenty seven per cent had non-cardiac symptoms and could be discharged while 60% were considered to have cardiac pain. Sixty six patients (26%) were admitted directly from the clinic and 48 of these underwent coronary angiography within three weeks. Seventy patients (28%) have so far undergone intervention (angioplasty or coronary artery surgery), 22 within one month of presentation. One hundred and nine patients (44%) presented with a normal resting electrocardiogram, 21 of whom were considered to have unstable angina. Forty one of these patients were investigated of whom 37 were found to have significant coronary disease and 26 have undergone intervention. CONCLUSIONS--This experience highlights the inadequacy of a routine electrocardiogram reporting service in patients with recent onset of chest pain. An alternative facility offering immediate and complete cardiac assessment produced patient benefit with early diagnosis and intervention. Investigation of these patients, however, accounted for 5% of cardiac catheterisation laboratory throughput; this was a significant additional and unscheduled workload.

https://heart.bmj.com/content/heartjnl/67/1/53.full.pdf

Limited value of the resting electrocardiogram in assessing patients with recent onset chest pain: lessons from a chest pain clinic.

OBJECTIVE--This study investigated the changes in regional myocardial ultrasonic backscatter, measured as myocardial echo amplitude, that occur during reversible myocardial ischaemia in humans. DESIGN--Left anterior descending coronary angioplasty was used to produce reversible myocardial ischaemia in human subjects. Regional myocardial echo amplitude was studied in the interventricular septum and left ventricular posterior free wall before, during, and after coronary occlusion with the angioplasty balloon. Wall motion analysis of the left ventricle was performed from simultaneous cross sectional echocardiographic imaging. Patients were studied prospectively. PATIENTS--Six patients (mean age 56 (SD 11), range 46 to 69 years) with single vessel, left anterior descending coronary artery stenoses, were investigated during elective coronary angioplasty. A total of 11 balloon inflations were studied. SETTING--All patient studies were performed at Harefield Hospital. Echo amplitude analysis was performed at the Royal Brompton Hospital. INTERVENTIONS--Angioplasty was performed by the usual procedure at Harefield Hospital for elective coronary angioplasty. All routine medication including beta blockers and calcium antagonists were continued. Inflation pressures were up to 12 atm (1212 kPa) and mean inflation time ranged from 30 to 120 (86 (31)) s. In four studies the first inflation was examined, in three the second, in two the third, and in one each the fourth and fifth inflations. Echo amplitude and cross sectional echo-cardiographic studies were recorded with a 3.5 MHz Advanced Technology Laboratories (ATL) (720A/8736 series) mechanical sector scanner and an ATL Mark III (860-1 series) echocardiograph system with 45 dB logarithmic grey scale compression. MAIN OUTCOME MEASURES--Regional echo amplitude was examined in four regions of the left ventricle--namely, the basal and mid-septum, and basal and mid-posterior wall. Consecutive end diastolic and end systolic frames were analysed and cyclic variation was determined as the difference between the level of echo amplitude at end diastole and at end systole. Measurements were made before balloon inflation, at peak inflation, and after balloon deflation. Regional wall motion and systolic wall thickening were analysed qualitatively. RESULTS--Before balloon inflation, cyclic variation in echo amplitude was noted in all regions (basal septum, 2.4 (SD 1.1) dB; mid-septum, 2.5 (1.1) dB; basal posterior wall, 3.3 (2.1) dB; mid-posterior wall, 3.9 (1.6) dB). During balloon inflation there was a significant fall in cyclic variation to 0.4 (0.9) dB (p < 0.0002) in the mid-septum. This was predominantly owing to an increase in end systolic echo amplitude from 5.4 (2.0) dB to 9.3 (1.9) dB (p < or = 0.01). This was associated with the development of severe hypokinesis or akinesis in the mid-septum. No significant changes in echo amplitude occurred in the three other regions examined. Changes were completely reversed after balloon deflation. CONCLUSIONS--These results suggest a causal relation between occlusion of the supplying coronary artery and blunting of myocardial echo amplitude cyclic variation. It is suggested that balloon occlusion produced myocardial ischaemia. The resultant impairment of myocardial contraction then caused a blunting of cyclic variation in echo amplitude. The results of this study provide further data about the ability of quantitative studies of ultrasonic backscatter to identify alterations in the myocardium during injury.

https://heart.bmj.com/content/heartjnl/67/5/368.full.pdf

Changes in myocardial echo amplitude during reversible ischaemia in humans.

Oral treatment with enoximone in patients referred for cardiac transplantation

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Detection of free radicals and cholesterol hydroperoxides in blood taken from the coronary sinus of man during percutaneous transluminal coronary angioplasty

Limited value of the resting electrocardiogram in assessing patients with recent onset chest pain: lessons from a chest pain clinic.

Changes in myocardial echo amplitude during reversible ischaemia in humans.

Oral treatment with enoximone in patients referred for cardiac transplantation