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Abbreviations
ACE: angiotensin-converting enzyme
ACEI: angiotensin-converting enzyme inhibitor
ACS: acute coronary syndrome
ALDH2: mitochondrial aldehyde dehydrogenase
ARB: angiotensin receptor blocker
AV: atrioventricular
CABG: coronary artery bypass grafting
CAD: coronary artery disease
COX-1: cyclooxygenase isoform 1
CYP: cytochrome P450
EC50: half-maximal effective concentration
EMA: European Medicines Agency
eNOS: endothelial NOS
FDA: U.S. Food and Drug Administration
FFA: free fatty acid
GI: gastrointestinal
GTN: glyceryl trinitrate (nitroglycerin)
HCM: hypertrophic cardiomyopathy
HCN: hyperpolarization-activated cyclic nucleotide–gated
HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A
iNOS: inducible NOS
IP3: inositol 1,4,5-trisphosphate
ISDN: isosorbide dinitrate
ISMN: isosorbide-5-mononitrate
MI: myocardial infarction
nNOS: neuronal NOS
NO: nitric oxide
NOS: nitric oxide synthase
NSTEMI: non–ST-elevation myocardial infarction
PDE: cyclic nucleotide phosphodiesterase
Pgp: P-glycoprotein
PLC: phospholipase C
rTPA: recombinant tissue plasminogen activator
SA: sinoatrial
SNS: sympathetic nervous system
STEMI: ST-segment elevation myocardial infarction
Tn: troponin
TxA2: thromboxane A2
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PATHOPHYSIOLOGY OF ISCHEMIC HEART DISEASE
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The pathophysiological understanding of ischemic heart disease has seen major changes over the past two decades—from a concept of localized calcification causing progressive constrictions of coronary arteries, ischemia, and exercise-induced angina pectoris to a systemic inflammatory disease of the arteries, including the coronaries (therefore the CAD name). A key finding in this change of paradigm was that most infarct-causing occlusions occur at small-to-medium plaques (“active plaques”) by thrombosis rather than at hemodynamically relevant stenoses by progressive narrowing. Thus, in addition to the mere size of an obstructing plaque, the inflammatory activity of the atherosclerotic process, the stability of the plaque, and platelet reactivity appear to determine the prognosis (Libby et al., 2002).
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Atherosclerosis encompasses increased lipid deposition in the subendothelial space (early plaque), endothelial dysfunction with decreased production of NO, less vasodilation and increased risk of platelet adhesion, influx of lipid scavenger cells (mainly macrophages), necrosis, sterile inflammation, proliferation of smooth muscle cells, and calcification and narrowing of the blood vessel by increasing plaque formation. If the endothelium covering of the plaque or the cell layer enclosing the necrotic core of the plaque disrupt, thrombogenic materials such as collagen are presented to the bloodstream, causing platelet adhesion, fibrin deposition, thrombus formation, and closure of the blood vessel.
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Triggering factors can be not only acute inflammation (e.g., influenza), but also blood pressure peaks during physical exercise or emotional stress (e.g., demonstrated during a life-threatening emergency and in avid fans during football games). Importantly, the process is dynamic, and the net thrombus formation is the result of the balance between thrombosis and thrombolysis by the fibrinolytic system (plasminogen). The degree and the duration of coronary obstruction and thereby of the ischemia of downstream myocardium (and its size) determine the degree of necrosis of muscle tissue, that is, infarct size.
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Taken together, important factors that determine the progress of CAD are the concentration of lipids in the blood, endothelial function, blood pressure (as a mechanical factor predisposing to plaque ...