Triggering Of Acute Coronary Syndromes Research Articles

Epicardial and Pericoronary Adipose Tissue, Coronary Inflammation, and Acute Coronary Syndromes

Vascular inflammation is recognized as the primary trigger of acute coronary syndrome (ACS). However, current noninvasive methods are not capable of accurately detecting coronary inflammation. Epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT), in addition to their role as an energy reserve system, have been found to contribute to the development and progression of coronary artery calcification, inflammation, and plaque vulnerability. They also participate in the vascular response during ischemia, sympathetic stimuli, and arrhythmia. As a result, the evaluation of EAT and PCAT using imaging techniques such as computed tomography (CT), cardiac magnetic resonance (CMR), and nuclear imaging has gained significant attention. PCAT-CT attenuation, which measures the average CT attenuation in Hounsfield units (HU) of the adipose tissue, reflects adipocyte differentiation/size and leukocyte infiltration. It is emerging as a marker of tissue inflammation and has shown prognostic value in coronary artery disease (CAD), being associated with plaque development, vulnerability, and rupture. In patients with acute myocardial infarction (AMI), an inflammatory pericoronary microenvironment promoted by dysfunctional EAT/PCAT has been demonstrated, and more recently, it has been associated with plaque rupture in non-ST-segment elevation myocardial infarction (NSTEMI). Endothelial dysfunction, known for its detrimental effects on coronary vessels and its association with plaque progression, is bidirectionally linked to PCAT. PCAT modulates the secretory profile of endothelial cells in response to inflammation and also plays a crucial role in regulating vascular tone in the coronary district. Consequently, dysregulated PCAT has been hypothesized to contribute to type 2 myocardial infarction with non-obstructive coronary arteries (MINOCA) and coronary vasculitis. Recently, quantitative measures of EAT derived from coronary CT angiography (CCTA) have been included in artificial intelligence (AI) models for cardiovascular risk stratification. These models have shown incremental utility in predicting major adverse cardiovascular events (MACEs) compared to plaque characteristics alone. Therefore, the analysis of PCAT and EAT, particularly through PCAT-CT attenuation, appears to be a safe, valuable, and sufficiently specific noninvasive method for accurately identifying coronary inflammation and subsequent high-risk plaque. These findings are supported by biopsy and in vivo evidence. Although speculative, these pieces of evidence open the door for a fascinating new strategy in cardiovascular risk stratification. The incorporation of PCAT and EAT analysis, mainly through PCAT-CT attenuation, could potentially lead to improved risk stratification and guide early targeted primary prevention and intensive secondary prevention in patients at higher risk of cardiac events.

Short-term effects of air pollution on coronary events. Importance of seasonal variations

Air pollution contributes to an enhanced cardiovascular morbidity burden including the trigger of acute coronary syndromes. The aim of this study, is to investigate the effects of a short-term exposure to air pollutants, as assessed by Nitrogen dioxide (NO 2 ), Particulate Matter (PM) 2.5 and 10 concentrations, on coronary event onsets in Strasbourg, France. An observational, retrospective, epidemiological study was conducted in Strasbourg between 2012 and 2014. The cases comprised coronary events in inhabitants of Strasbourg as identified by the MONICA Project. The data on daily air pollution provided a measurement of the 24-hour average concentration of NO 2 , PM 10 and PM 2.5. A total of 1265 coronary events were recorded within 1096 days (on average 1.154/day). The NO 2 concentration was higher than 30 μg/m 3 for 677 days (61.8%). Higher daily coronary events rates were evidenced when NO 2 concentrations were measured above 30 μg/m 3 1.208 [95% CI 1.128–1.289 vs. 1.067 (95% CI 0.961–1,172) P = 0.009]. No impact of PM on daily coronary events could be demonstrated. A marked seasonality of NO 2 , PM 2.5 and PM 10 concentrations characterized by an increase during winter, and a decrease during the summer could be established. The seasonality of coronary events was evidenced simultaneously. After adjustments were made to account, for the time and the month, no independent impact of NO 2 , PM 2.5, or PM 10 on daily coronary events could be demonstrated. Higher daily coronary events were recorded when NO 2 concentrations peaked above > 30 ug/m 3 . An important seasonality of air pollution, which was concurrent with a coronary event burden could be demonstrated. After the time adjustment, no independent impact of the air pollution on coronary events could be determined. The specific impact of cold weather conditions, of a concurrent respiratory infection, or of the decrease in the number of hours of sunshine deserves further investigation.

Abstract 29: Chronic Stress Predisposes to Thrombosis by Abnormal Megakaryopiesis: Protective Effect of Apocynin

Introduction: Psychological stress (e.g. anxiety and depression) has been identified as an important trigger of acute coronary syndromes (ACS), as a consequence of enhanced coagulation and of hyper-reactive platelets. Changes in redox balance, alteration of genes regulating antioxidant systems, including NADPH oxidase, and increased production of reactive oxygen species (ROS) have been measured in both chronic stress and ACS. However, the mechanisms by which chronic stress affects platelet activation and predisposes to thrombosis are not well known. Hypothesis: We hypothesized that Apocynin, an inhibitor of NADPH oxidase influences the alteration of megakaryopoiesis and activation of platelets induced by chronic stress in mice. Methods and Results: We show the NADPH/NADP + ratio in bone marrow (BM) of mice exposed to forced swimming for 4 days (5 min twice/day) is markedly reduced compared to control mice, and that Apocynin treatment (2.4 mg/ml in drinking water for 4 days) prevents this alteration. Chronic stress leads to an abnormal megakaryopoiesis increasing the number of BM megakaryocytes (MKs) and affecting circulating platelets. MKs of stressed mice show an advanced maturation state (e.g. nuclear/cytoplasmic ratios and expression of CD42d), and an enhanced ability to produce ROS. Interestingly, a higher number of large and reticulated platelets with marked functional activation (e.g. integrin α IIb β3 and P-selectin expression, and platelet/leukocyte aggregates) is detected after chronic stress. In addition, Apocynin prevents ROS MKs generation and decreases the total number of MKs without affecting the percentage of CD42d + cells. Finally, the inhibitor of NADPH oxidase activity reduces the hyper-activation of platelets and the enhanced susceptibility to FeCl3-induced arterial thrombosis in stressed mice. Conclusion: Apocynin treatment, reducing ROS generation in MKs, restores the physiological bone marrow megakaryopoiesis and platelet behaviour, and it prevents the detrimental effect of chronic stress on atherothrombosis. These data suggest a potential use of NADPH oxidase inhibitors in the occurrence of thrombosis associated with chronic stress. Studies in human will verify the clinical impact of these findings.

Apocynin Prevents Abnormal Megakaryopoiesis and Platelet Activation Induced by Chronic Stress.

Environmental chronic stress (ECS) has been identified as a trigger of acute coronary syndromes (ACS). Changes in redox balance, enhanced reactive oxygen species (ROS) production, and platelet hyperreactivity were detected in both ECS and ACS. However, the mechanisms by which ECS predisposes to thrombosis are not fully understood. Here, we investigated the impact of ECS on platelet activation and megakaryopoiesis in mice and the effect of Apocynin in this experimental setting. ECS induced by 4 days of forced swimming stress (FSS) treatment predisposed to arterial thrombosis and increased oxidative stress (e.g., plasma malondialdehyde levels). Interestingly, Apocynin treatment prevented these alterations. In addition, FSS induced abnormal megakaryopoiesis increasing the number and the maturation state of bone marrow megakaryocytes (MKs) and affecting circulating platelets. In particular, a higher number of large and reticulated platelets with marked functional activation were detected after FSS. Apocynin decreased the total MK number and prevented their ability to generate ROS without affecting the percentage of CD42d+ cells, and it reduced the platelet hyperactivation in stressed mice. In conclusion, Apocynin restores the physiological megakaryopoiesis and platelet behavior, preventing the detrimental effect of chronic stress on thrombosis, suggesting its potential use in the occurrence of thrombosis associated with ECS.

Coronary atherosclerosis is already ongoing in pre-diabetic status: Insight from intravascular imaging modalities.

Diabetes mellitus is a powerful risk factor of coronary artery disease (CAD), leading to death and disability. In recent years, given the accumulating evidence that prediabetes is also related to increasing risk of CAD including cardiovascular events, a new guideline has been proposed for the treatment of blood cholesterol for primary prevention of cardiovascular events. This guideline recommends aggressive lipid-lowering statin therapy for primary prevention in diabetes and other patients. The ultimate goal of patient management is to inhibit progression of systemic atherosclerosis and prevent fatal cardiovascular events such as acute coronary syndrome (ACS). Because disruption of atherosclerotic coronary plaques is a trigger of ACS, the high-risk atheroma is called a vulnerable plaque. Several types of novel diagnostic imaging technologies have been developed for identifying the characteristics of coronary atherosclerosis before the onset of ACS, especially vulnerable plaques. According to coronary angioscopic evaluation, atherosclerosis severity and plaque vulnerability were more advanced in prediabetic than in nondiabetic patients and comparable to that in diabetic patients. In addition, pharmacological intervention by statin therapy changed plaque color and complexity, and the dynamic changes in plaque features are considered plaque stabilization. In this article, we review the findings of atherosclerosis in prediabetes, detected by intravascular imaging modalities, and the therapeutic implications.

Association between anger and mental stress–induced myocardial ischemia

Mental stress-induced myocardial ischemia is associated with adverse prognosis in coronary artery disease patients. Anger is thought to be a trigger of acute coronary syndromes and is associated with increased cardiovascular risk; however, little direct evidence exists for a link between anger and myocardial ischemia. [(99m)Tc]-sestamibi single-photon emission tomography was performed at rest, after mental stress (a social stressor with a speech task) and after exercise/pharmacologic stress. Summed scores of perfusion abnormalities were obtained by observer-independent software. A summed-difference score, the difference between stress and rest scores, was used to quantify myocardial ischemia under both stress conditions. The Spielberger's State-Trait Anger Expression Inventory was used to assess different anger dimensions. The mean age was 50 years, 50% were female, and 60% were non-white. After adjusting for demographic factors, smoking, coronary artery disease severity, depressive, and anxiety symptoms, each IQR increment in state-anger score was associated with 0.36 U-adjusted increase in ischemia as measured by the summed-difference score (95% CI 0.14-0.59); the corresponding association for trait anger was 0.95 (95% CI 0.21-1.69). Anger expression scales were not associated with ischemia. None of the anger dimensions was related to ischemia during exercise/pharmacologic stress. Anger, both as an emotional state and as a personality trait, is significantly associated with propensity to develop myocardial ischemia during mental stress but not during exercise/pharmacologic stress. Patients with this psychologic profile may be at increased risk for silent ischemia induced by emotional stress, and this may translate into worse prognosis.

Abstract MP86: Depressive Symptoms are Associated with Mental Stress-Induced Myocardial Ischemia After Acute Myocardial Infarction

Objectives: Previous studies indicated that depressed mood may act as a trigger of acute coronary syndromes, although the mechanisms are not clear. We aimed to examine the association between depression and mental stress-induced myocardial ischemia in young survivors of a myocardial infarction (MI), and the possible differential association of somatic and cognitive depressive symptom dimensions. Hypothesis: Higher levels of depressive symptoms are associated with a higher propensity to develop myocardial ischemia with mental stress. Methods: We studied 98 patients (49 women and 49 men) age 38-59 years who were hospitalized for acute MI in the previous 6 months. Patients underwent myocardial perfusion imaging with [99mTc]sestamibi single-proton emission computed tomography at rest, after mental stress (speech task), and after exercise treadmill stress. If unable to exercise (N=16), patients underwent pharmacological stress test with regadenoson. Myocardial perfusion defect scores were obtained with observer-independent software. A summed difference score, the difference between stress and rest perfusion defect scores, was used to quantify myocardial perfusion defects due to ischemia under both stress conditions. The Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms. Two separate scores of somatic and cognitive depressive symptoms were calculated. Multivariate linear regression models were used in the analysis. Results: There was a significant and graded positive association between depressive symptoms and summed difference score with mental stress. After adjustment for demographical and lifestyle factors, severity of coronary heart disease and medications, each incremental depressive symptom was associated with 0.14 higher ischemia perfusion defect score [β=0.14, 95% CI: (0.03, 0.24), p=0.01]. When somatic and cognitive depressive symptoms were examined separately, both somatic symptoms [β=0.17, 95% CI: (0.04, 0.30), p=0.01] and cognitive symptoms [β=0.31, 95% CI: (0.07, 0.56), p=0.01] showed a significant association with mental stress-induced ischemia. Depressive symptoms were not associated with ischemia induced by exercise or pharmacological stress. Conclusion: Among young post-MI patients, higher levels of both cognitive and somatic depressive symptoms are associated with a higher propensity to develop myocardial ischemia with mental stress, but not with exercise/pharmacological stress. Future studies should explore whether mental stress-induced ischemia explains the poorer prognosis associated with depressive symptoms in post-MI patients.

Triggers of acute myocardial infarction

The existence of specific risk factors for the development of coronary heart disease, both chronic and acute, has been extensively investigated and is well understood by cardiology professionals. Diabetes, hypertension, hypercholesterolemia, psychological patterns and smoking are assumed to interact in a complex way with individual heritable predisposition, thus determining the long-term probability of coronary disease. However, the possibility that defined circumstances and activities may act as immediate triggers of acute coronary syndromes, particularly acute myocardial infarction, has not been given comparable attention in clinical research. For example, the recently issued 2012 European guidelines on cardiovascular disease prevention completely overlook the topic of triggers and their possible prevention. This review presents a picture of the most reliable evidence regarding the triggering of myocardial infarction and contributes to further investigation in the field.

Acute coronary syndrome after levamisole-adultered cocaine abuse

Cocaine is a well known trigger of acute coronary syndromes. Over the last 10 years levamisole, a veterinary anthelminthic drug has been increasingly used as an adulterant of cocaine. Levamisole was used to treat pediatric nephritic syndrome and rheumatoid arthritis before being withdrawn from the market due to its significant toxicity, i.e. hematological complications and vasculitis. The major complications of levamisole-adultered cocaine reported up to now are hematological and dermatological.The case reported here is of a 25 year old man with a history of cocaine abuse who died at home after complaining of retrosternal pain. Postmortem CT-angiography, autopsy, and chemical and toxicological analyses were performed. An eroded coronary artery plaque was found at the proximal segment of the left anterior descending coronary artery. Two myocardial infarct scars were present in the left ventricle. Microscopic examination of the coronary artery revealed infiltration of eosinophils into the adventitia and intima. Toxicological examination confirmed the presence of cocaine and its metabolites in the peripheral blood, and of levamisole in the urine and pericardial fluid.Eosinophilic inflammatory coronary artery pathologies have been clinically linked to coronary dissection, hypersensitivity coronary syndrome and vasospastic allergic angina. The coronary pathology in the presented case could be a complication of levamisole-adultered cocaine use, in which an allergic or immune-mediated mechanism might play a role. The rise in cocaine addiction worldwide and the increase of levamisole adulterated cocaine highlights the importance of updating our knowledge of the effects of adultered cocaine abuse.

Stress, psychische Erkrankungen und koronare Herzkrankheit

There are numerous associations between stress, mental disorders and coronary heart disease (CHD). Exposure to an acute stressor leads to activation of the hypothalamus-pituitary-adrenal and sympathoadrenal systems and chronic stressors are associated with sustained functional changes of these systems. Experiencing acute and chronic stress is paralleled by an increased incidence of mental disorders with the most consistent evidence on the triggering of major depressive episodes. Various mental disorders, including depression, anxiety and schizophrenia, are associated with an increased risk of CHD. Furthermore, acute and chronic stressors have been identified as risk factors or triggers of acute coronary syndromes. Thus therapeutic strategies aim at reducing subjective stress experience, therapy of mental disorders and treatment of cardiac risk factors known to be more prevalent in increased stress states and mental disorders.

Continuing Professional Development: Cocaine toxicity: assessment and cardiac risk

Overview The UK has the highest prevalence of drug use within Europe, with a 13% increase in cocaine and ecstasy related deaths between 2004–2005. This is significant to emergency medical personnel as cocaine toxicity may present clinically as acute coronary syndrome (ACS) minus typical associated risk factors. Cocaine use has an immediate effect on the body within seconds to minutes of administration. The resultant effect is manifold and can be divided into the two broad categories of central nervous system (CNS) and cardiovascular. Cocaine has a strong association as a trigger of ACS, acute myocardial infarction (MI) and sudden death in a population of patients largely free of classic cardiovascular risk factors. This module will assist in understanding the effects of acute cocaine toxicity, recognizing electrocardiogram (ECG) changes and implementing an appropriate treatment plan. Learning Outcomes After completing this module you will be able to: ▪ Refresh your understanding of the anatomy and physiology of cardio-vasculature and the central nervous system (CNS) ▪ Have an understanding of the effect of cocaine on the body, and how this may present in the clinical setting ▪ Further develop ECG recognition in the symptomatic patient, and understand the consequences of significant cardiac changes. ▪ Explore the concept of critical thinking within clinical decision-making ▪ Be able to better anticipate and implement a treatment plan in accordance to JRCALC guidelines.

Acute cocaine toxicity: assessment and cardiac risk

The UK has the highest prevalence of drug use within Europe, with a 13% increase in cocaine and ecstasy related deaths reported between 2004 and 2005. This is significant to emergency medical personnel because cocaine toxicity can present clinically as acute coronary syndrome (ACS) minus typical associated risk factors. Cocaine use has an immediate effect on the body, having an onset of action seconds to minutes after administration. The resultant effect is manyfold, but can be divided into the two broad categories of central nervous system and cardiovascular effects. Cocaine misuse is a trigger of ACS, acute myocardial infarction and sudden death in a population of patients largely free of classic cardiovascular risk factors. Emergency medical staff are in a position to provide early and effective management through history-taking and assessment tools in conjunction with therapeutic intervention. The aim of this article is to highlight the presentation and consequence of acute cocaine toxicity in relation to its assessment, management and cardiac emergencies within the prehospital setting.

3: A new target for prevention: Influenza as a trigger of acute coronary syndromes

3: A new target for prevention: Influenza as a trigger of acute coronary syndromes

The long-term effects of acute triggers of acute coronary syndromes on adaptation and quality of life

Background A proportion of acute coronary syndromes (ACS) are thought to be triggered acutely by physical exertion, emotional stress and other stimuli. We assessed the consequences of triggering for long-term adaptation following ACS. Methods We assessed mental and physical health status in 150 male and 44 female ACS survivors 12 and 36 months after cardiac events using standardised questionnaire measures. Triggers were assessed by interview an average of 2.56 days after hospital admission. Emotional triggers were defined as moderate or intense anger, stress or sadness/depressed mood in the 2 h before symptom onset, while vigorous physical exertion was defined as activity ≥ 6 metabolic equivalents in the hour before symptom onset. Clinical characteristics, psychiatric history, health behaviours and the Global Registry of Acute Coronary Events (Grace) risk algorithm were also assessed. Results Emotional triggers predicted elevated anxiety and poor mental health status at 12 months independently of age, gender, socioeconomic status, ACS presentation, Grace risk scores, pre-admission medication, anxiety in hospital, depression history and symptom recurrence ( p < 0.001). Effects persisted at 36 months. Emotional triggers were not related to physical health status at follow up. By contrast, impaired physical health status was predicted by vigorous exertion during the trigger period independently of covariates ( p = 0.019). Conclusions ACS triggering has a long-term impact on adaptation and quality of life, with differential effects of physical and emotional triggers.

Effect of oral melatonin on the procoagulant response to acute psychosocial stress in healthy men: a randomized placebo‐controlled study

Acute mental stress is a potent trigger of acute coronary syndromes. Catecholamine-induced hypercoagulability with acute stress contributes to thrombus growth after coronary plaque rupture. Melatonin may diminish catecholamine activity. We hypothesized that melatonin mitigates the acute procoagulant stress response and that this effect is accompanied by a decrease in the stress-induced catecholamine surge. Forty-five healthy young men received a single oral dose of either 3 mg melatonin (n = 24) or placebo medication (n = 21). One hour thereafter, they underwent a standardized short-term psychosocial stressor. Plasma levels of clotting factor VII activity (FVII:C), FVIII:C, fibrinogen, D-dimer, and catecholamines were measured at rest, immediately after stress, and 20 min and 60 min post-stress. The integrated change in D-dimer levels from rest to 60 min post-stress differed between medication groups controlling for demographic and metabolic factors (P = 0.047, eta(p)(2) = 0.195). Compared with the melatonin group, the placebo group showed a greater increase in absolute D-dimer levels from rest to immediately post-stress (P = 0.13; eta(p)(2) = 0.060) and significant recovery of D-dimer levels from immediately post-stress to 60 min thereafter (P = 0.007; eta(p)(2) = 0.174). Stress-induced changes in FVII:C, FVIII:C, fibrinogen, and catecholamines did not significantly differ between groups. Oral melatonin attenuated the stress-induced elevation in the sensitive coagulation activation marker D-dimer without affecting catecholamine activity. The finding provides preliminary support for a protective effect of melatonin in reducing the atherothrombotic risk with acute mental stress.

Emotional Triggers of Acute Coronary Syndromes: Strength of Evidence, Biological Processes, and Clinical Implications

Emotional triggers of acute coronary syndromes include population-level events such as earthquakes and terrorist attacks, and individual experiences of acute anger, stress and depression. The methodology of studying emotional triggers has developed markedly over recent years, though limitations remain. The biological processes underlying triggering include acute autonomic dysregulation, neuroendocrine activation, hemostatic and inflammatory responses which, when associated with plaque disruption, promote myocardial ischemia, cardiac dysrhythmia and thrombosis formation. Prevention and management strategies for ameliorating emotional triggering remain to be effectively developed.

When a Myocardial Infarction Comes Out of the Not-So-Blue Air

Acute coronary syndromes such as unstable angina or myocardial infarction often develop unexpectedly and severely interrupt a patient’s life. Two main pathological processes, atherosclerosis and thrombosis, lead to acute coronary syndromes such as unstable angina and myocardial infarction.1,2 The typical atherosclerotic lesion is a fibrolipid plaque composed of a pool of lipids covered with a connective tissue cap. Although the plaque narrows the coronary arteries, acute coronary syndromes only occur when a plaque erodes, fissures, or ruptures and a thrombus is formed that partially or totally occludes the arteries and impedes blood flow. The sudden onset of the disease has led to research examining triggers of acute coronary syndromes. Among the factors that contribute to acute coronary syndromes in vulnerable patients1,2 are physical exertion, extreme anger, sexual activity, and drug abuse.3 These factors alter the shear stress at the arterial walls and increase the risk of thrombosis. Triggering of myocardial infarction caused by these stressors occurs within 1 or 2 hours of exposure, and the risk subsides rapidly after this time window. This further emphasizes the transient nature of the risks associated with triggers and distinguishes these factors from those risk factors promoting the gradual development of atherosclerosis over decades. Article p 2443 Recent research on ambient fine particles has …

Acute Depressed Mood as a Trigger of Acute Coronary Syndromes

Some cases of acute coronary syndrome (ACS) may be triggered by emotional states such as anger, but it is not known if acute depressed mood can act as a trigger. 295 men and women with a verified ACS were studied. Depressed mood in the two hours before ACS symptom onset was compared with the same period 24 hours earlier (pair-matched analysis), and with usual levels of depressed mood, using case-crossover methods. 46 (18.2%) patients experienced depressed mood in the two hours before ACS onset. The odds of ACS following depressed mood were 2.50 (95% confidence intervals 1.05 to 6.56) in the pair-matched analysis, while the relative risk of ACS onset following depressed mood was 4.33 (95% confidence intervals 3.39 to 6.11) compared with usual levels of depressed mood. Depressed mood preceding ACS onset was more common in lower income patients (p = .032), and was associated with recent life stress, but was not related to psychiatric status. Acute depressed mood may elicit biological responses that contribute to ACS, including vascular endothelial dysfunction, inflammatory cytokine release and platelet activation. Acute depressed mood may trigger potentially life-threatening cardiac events.

Behavioral and Emotional Triggers of Acute Coronary Syndromes: A Systematic Review and Critique

The objective of this study was to review the evidence that behavioral and emotional factors are triggers of acute coronary syndromes. Systematic review of the published literature from 1970 to 2004 of trigger events, defined as stimuli or activities occurring within 24 hours of the onset of acute coronary syndromes. There is consistent evidence that physical exertion (particularly by people who are not normally active), emotional stress, anger, and extreme excitement can trigger acute myocardial infarction and sudden cardiac death in susceptible individuals. Many triggers operate within 1 to 2 hours of symptom onset. There are methodologic limitations to the current literature, including sampling, retrospective reporting, and presentation biases, the role of memory decay and salience, and reverse causation because of silent prodromal events. Behavioral and emotional factors are probable triggers of acute coronary syndromes in vulnerable individuals, and the pathophysiological processes elicited by these stimuli are being increasingly understood. The benefits to patients of knowledge to these processes have yet to accrue.

Genetically determined resistance to collagenase action augments interstitial collagen accumulation in atherosclerotic plaques.

We hypothesized that collagenolytic activity produced by activated macrophages contributes to collagen loss and the subsequent instability of atheromatous lesions, a common trigger of acute coronary syndromes. However, no direct in vivo evidence links collagenases with the regulation of collagen content in atherosclerotic plaques. To test the hypothesis that collagenases influence the structure of atheromata, we examined collagen accumulation in atherosclerotic lesions of apolipoprotein E-deficient mice (apoE-/-) that express collagenase-resistant collagen-I (ColR/R/apoE-/-, n=12) or wild-type collagen-expressing mice (Col+/+/apoE-/-, n=12). Aortic atheromata of both groups had similar sizes and numbers of macrophages, a major source of collagenases. However, aortic intimas from ColR/R/apoE-/- mice contained fewer smooth muscle cells, a source of collagen, probably because of decreased migration or proliferation or increased cell death. Despite reduced numbers of smooth muscle cells, atheromata of ColR/R/apoE-/- mice contained significantly more intimal collagen than did those of Col+/+/apoE-/- mice. These results establish that collagenase action regulates plaque collagen turnover and smooth muscle cell accumulation.