Pathophysiology of acute coronary syndromes

The natural history of coronary artery disease is punctuated by clinical manifestations of unstable angina, acute myocardial infarction, and ischemic sudden death. These acute coronary syndromes share common pathophysiologic mechanisms that include fissuring of a plaque followed by varying degrees of dynamic coronary obstruction, which is due to vasoconstriction and coronary thrombosis. The response to plaque fissure is likely to be modulated by local and/or systemic procoagulant and anticoagulant-fibrinolytic activities. The key role of coronary thrombosis in acute coronary syndromes has substantial implications for prevention and treatment of complications of coronary atherosclerosis.     

Triggers of acute coronary syndromes

Despite recent progress in prevention of coronary heart disease, approximately 50% of the deaths from coronary artery disease continue to occur out of hospital, and many major cardiac events occur in individuals not previously known to be at risk. These facts create the need to identify the acute causes of myocardial infarction (MI) and sudden death, which has led to a rapid growth in interest over the last 15 years in the field of triggering research. Since initial observations that the incidence of MI onset was time and activity dependent with circadian, circaseptan, and circannual variation, triggering of MI by heavy exertion, sexual activity, anger, mental stress, cocaine and marijuana use, and exposure to air pollution has been demonstrated. Study of the pathophysiological changes produced by these triggers may provide novel therapeutic and preventive targets by a more thorough understanding of vulnerable plaque disruption and coronary thrombosis.     

Physiopathology of acute coronary syndromes

Coronary atherosclerosis and its thrombotic complications represent one of the leading causes of lesions usually consists of successive acute episodes, either silent or in the form of an acute coronary syndrome such as unstable angina, non-Q-wave myocardial infarctions, transmural myocardial infarctions or sudden death. This mode of progression does not exclude phases of regression, or more frequently stabilization of plaques, which, depending on their haemodynamic repercussions, are then responsible for chronic myocardial ischaemia. Acute coronary syndrome (ACS) correspond to the same pathophysiological process: rupture of an atheromatous plaque initiating harmful thrombotic, inflammatory and vasomotor phenomena. This is not a new concept, but progress over recent years suggests that the composition and biology of the plaque are factors involved more in the initiation of ACS than the size of the plaque. "Soft" lesions, rich in lipids, are clearly not only the most unstable lesions, but also the most thrombogenic because of their large tissue factor content. After describing the structure of vulnerable plaques, the authors discuss the causes of their rupture and the resulting cascade or events, responsible for life-threatening clinical situations.     

Perspectives on acute coronary syndromes

The occurrence of an acute coronary syndrome (ACS) represents a dramatic stage in the otherwise relatively slow and progressive course of coronary artery disease, bringing into perspective its life-threatening implications. The modern era of aggressive management of these syndromes was first introduced by the establishment of the coronary care unit, and later by the development of reperfusion therapies, which led, within two decades, to a reduction in death rates of ST segment elevation myocardial infarction from 30% or more to less than 10%. The insights gained into the pathophysiology of ACSs, combined with increasingly efficient risk stratification schemes in screening patients with non-ST segment ACS, have given a boost to the development of antithrombotic therapies. Acetylsalicylic acid, as well as the combination of acetylsalicylic acid and heparin with the addition of an intravenous glycoprotein IIb/IIIa antagonist and/or the addition of an ADP P2Y12 receptor blocker, when combined with an invasive strategy targeting revascularization of the culprit coronary lesion (when appropriate), have successfully reduced the rates of adverse clinical outcomes in non-ST segment elevation ACS from 25% to 10%. These rates, however, did not improve further during the past few years, while the number of such patients is increasing to now account for the majority of admissions to coronary care units. A new research focus in cardiology is emerging, following the discovery that culprit lesions may be multiple and multifocal in association with a more diffuse inflammatory state. New therapeutic frontiers are thus being suggested to control the most fundamental mechanisms involved in ACSs and related to inflammation and autoimmunity.     

Inflammation and acute coronary syndromes

The presence of inflammatory infiltrates in unstable coronary plaques suggests that inflammatory processes may contribute to the pathogenesis of these syndromes. In patients with unstable angina, coronary atherosclerotic plaques are characterized by the presence of macrophages, and to a lesser extent, T-lymphocytes, at the immediate site of either plaque rupture or superficial erosion; moreover, the rupture-related inflammatory cells are activated, indicating ongoing inflammation at the site of plaque disruption. These observations are confirmed by clinical studies demonstrating activated circulating neutrophils, lymphocytes and monocytes, and increased concentrations of pro-inflammatory cytokines, such as interleukin (IL) 1 and 6, and of acute phase reactants in patients with unstable angina and myocardial infarction. In particular elevated levels of C-reactive protein are associated with an increased risk of in-hospital and 1 to 2 years new coronary events in patients with unstable angina, but are also associated with an increased long-term risk of death and myocardial infarction in apparently normal subjects. Thus, accumulating evidence suggests that inflammation may cause local endothelial activation and, possibly, plaque fissure, leading to unstable angina and infarction. Although no information is yet available on the causes of inflammation and on its localization, these novel lines of research may open the way to a different approach to the patient with acute coronary syndromes.     

Statins in acute coronary syndromes

Statins are the main resource available to reduce LDL-cholesterol levels. Their continuous use decreases cardiovascular morbidity and mortality due to atherosclerosis. The administration of these medications demonstrated to be effective in primary and secondary prevention clinical trials in low and high risk patients. Specialists believe that a possible benefit of hypolipidemic therapy in preventing complications of atherosclerotic diseases is in the reduction of deposition of atherogenic lipoproteins in vulnerable areas of the vasculature. Experimental studies with statins have shown an enormous variety of other effects that could extend the clinical benefit beyond the lipid profile modification itself. Statin-based therapies benefit other important components of the atherothrombotic process: inflammation, oxidation, coagulation, fibrinolysis, endothelial function, vasoreactivity and platelet function. The demonstration of the effects that do not depend on cholesterol lowering or the pleiotropic effects of statins provides the theoretical basis for their potential role as adjunctive therapy in acute coronary syndromes. Retrospective analyses of a variety of studies indicate the potential benefit of statins during acute coronary events. Recent clinical studies have addressed this important issue in prospective controlled trials showing strong evidence for the administration of statins as adjunctive therapy in acute coronary syndromes.     

Troponins in acute coronary syndromes

Cardiac troponins have replaced creatine kinase-MB as the preferred biomarker for establishing the diagnosis of myocardial infarction (MI). Expert recommendations set the diagnostic decision-limit for each assay at the 99th percentile of troponin levels in an apparently healthy reference population, which due to a lack of standardization, will vary depending upon the manufacturer. Among patients presenting with an acute coronary syndrome (ACS), even low-level elevations of cardiac troponin T or I correlate with higher risk of death and recurrent ischemic events compared to patients with levels of troponin below the decision limit. Renal failure does not appear to diminish the prognostic value of troponins among patients with a high clinical probability of ACS. Moreover, patients with elevated levels of troponin derive the most benefit from more intense medical therapy with antithrombin and antiplatelet medications, as well as an early invasive management strategy. Whereas cardiac troponins are extremely specific for myocardial necrosis, they do not discriminate between ischemic and non-ischemic etiologies of myocardial injury. Clinicians must, therefore, determine whether a patient's presenting symptoms are consistent with ACS. Combining troponin with other cardiac biomarkers may offer complimentary information on the underlying pathobiology and prognosis in an individual patient. Future generations of troponin assays may detect specific posttranslational modifications of troponins that may increase the analytic sensitivity for myocardial damage and offer insight into the timing and mechanism of myocardial injury.     

Echocardiography in acute coronary syndromes

Echocardiography including 2 Dimensional, Color Doppler, Tissue Doppler Imaging, Myocardial Contrast Echocardiography, Strain and Strain rate, etc are the most powerful modalities for the assessment of myocardial performance in patients with established orsuspected acute coronary syndrome and acute myocardial infarction with a high accuracy, sensitivity and specificity. Dobutamine Stress Echocardiography has tremendous potential of evaluating microcirculation impairment especially in diagnosing the extent of myocardial damage, reversibility component at rest and at the peak levels of stress with appropriate drugs, mechanical (percutaneous coronary intervention) or surgical intervention. Echocardiography and its newer modalities are therefore, promising and valuable tools for assessment of myocardial perfusion in the setting of myocardial infarction. This article provides an overview of clinical evidence supporting the efficacy of echocardiography and its newer modalities in assessment of myocardial function and performance. Timely effective evaluation of acute coronary syndrome and myocardial infarction by echocardiography and its newer modalities may help in early diagnosis,prognositification and warrant specific therapeutic intervention, thereby help in reducing morbidity and mortality.     

Troponins in acute coronary syndromes

Delivering superior clinical specificity and sensitivity for myocardial necrosis, cardiac troponin has replaced creatine kinase-MB as the preferred biomarker for establishing the diagnosis of myocardial infarction. On the basis of expert recommendations, present convention sets the diagnostic decision-limit for each assay at the 99th percentile of troponin levels in an apparently healthy reference population. Owing to a lack of standardization between different assays, this level, corresponding to the 99th percentile, will vary depending upon the manufacturer. Among patients presenting with an acute coronary syndrome (ACS), even low-level elevations of cardiac troponin T or I are associated with higher risk of death and recurrent ischemic events compared with patients with a troponin level below the appropriate decision limit. Renal failure does not appear to diminish the prognostic value of troponins among patients with a high clinical probability of ACS. In addition, patients with elevated levels of troponin appear to gain the most benefit from more aggressive medical therapy with antithrombin and antiplatelet medications as well as an early invasive management strategy. Cardiac troponins offer extremely high tissue specificity but do not discriminate between ischemic and nonischemic mechanisms of myocardial injury; thus, presently the clinician must assess whether a patient's presenting symptoms are consistent with ACS. It is possible that future generations of troponin assays will detect specific post-translational modifications of troponins that may increase the analytic sensitivity for myocardial damage and offer insight into the timing and mechanism of myocardial injury.     

Inflammation in acute coronary syndromes

Extensive evidence supports a pathogenic role for both local and systemic inflammation in acute coronary syndromes. However, several important questions remain unanswered. Is the observed inflammatory process a precursor or a consequence of coronary plaque rupture? Is the inflammatory component of unstable coronary disease a potential therapeutic target? Finally, do infectious agents have a pathogenic role in coronary atherosclerosis and acute coronary syndromes?     

Inflammation and acute coronary syndromes

A great variety of stimuli, such as free radicals, oxidized LDL or some bacteria or virus infections, can act upon the vascular surface and lead to the development of an acute inflammatory reaction. There is more and more evidence supporting the hypothesis that the mechanism responsible for the transformation of a non-complicated atherosclerotic lesion into an hemorrhagic and ulcerated lesion, with the subsequent acute and unstable clinical status, is due to the onset of an inflammatory reaction. Many studies have tried to investigate the presence of any systemic marker able to predict the prognosis of patients at risk from developing acute events, and to distinguish them from those in stable status. The increase of the levels of C-reactive-protein has been related to the development of acute coronary syndromes, though often the results obtained in the different studies have had a quite poor prognostic value when applied to the general population. The lack of direct association between the increase of the levels of C-reactive-protein and Troponin I seems to rule out the possibility that the inflammatory stimulus might be the consequence of an irreversible injury, even though there is no doubt that severe ischemia is likely to play an active role in this sense.     

Lipids and acute coronary syndromes

Eccentric atherogenic plaques which cause only insignificant narrowing of the diameter of coronary arteries are the cause of 60-80% of all acute coronary syndromes. The plaque becomes unstable (vulnerable) due to cytokines released by macrophages in the lipid rich core. Weakening of the fibrous capsule of the core then leads to rupture of the plaque and subsequently to intracoronary thrombosis with a wide spectrum of ischaemia or even necrosis of the myocardium. Secondary preventive studies (4S, LIPID, CARE), morphological non-mortality studies (e.g. AVERT, REGRESS, LCAS) and primary preventive studies (WOSCOPS, AFCAPS/TexCAPS) revealed that statins reduce significantly, as compared with placebo, total and LDL-cholesterol by 20-35% and lead in subsequent years to a significant decline of the relative risk of the general and coronary mortality and morbidiy by 20-40%. They prevent progression and may lead to regression of coronary sclerosis. They do not act by mere reduction of the cholesterol level but also by their extralipid effects which stabilize the plaque. 80% of patients with coronary syndrome have cholesterol levels between 6.0 and 7.5 mmol/l, similarly as ca 40% of healthy middle aged persons. The difference is in the risk caused either by the presence of ischaemic heart disease or in healthy subjects by the cumulation of several coronary risk factors. A special risk group are the remaining 20% patients. They include subjects with a cholesterol level above 8 mmol/l who must be treated more aggressively, similarly as patients after a venous aortocoronary bypass. Subjects with slightly elevated LDL-cholesterol values but high triacylglycerol levels and lower HDL-cholesterol levels have also an atherogenic risk. This applies not only to postmenopausal women, elderly people, obese and diabetic subjects, hypertensive subjects with insulin resistance but also to young subjects. In the latter reduction of triacylglycerols is indicated. In coronary patients a combination of statins and fibrates may be used. Basic hypolipidaemic treatment for reduction of the atherothrombotic risk are statins. Despite statin treatment the prospective mortality and morbidity of coronary patients is still high and it is necessary to make an effort to achieve target lipid levels. Recent studies provide new findings, further progress and stricter therapy are foreseen.