Myocardial infarction and Ischemic heart disease Flashcards
How does ischemia occur in the heart?
When myocardial oxygen supply fails to meet myocardial demand myocardial, ischemia results. Myocardial ischemia is an imbalance between myocardial oxygen supply and demand.
Myocardial Ischemia is the result of an imbalance between myocardial oxygen supply and myocardial oxygen demand. Explain the factors that lead to oxygen supply and demand?
Blockage of coronary artery?
Blockage or occlusion of a coronary artery reduces coronary blood flow. A reduction in coronary blood flow reduces myocardial oxygen supply. In this case, oxygen supply may not meet oxygen demand (requirements), resulting in hypoxia. Hypoxia produces electrophysiological and mechanical changes in the heart and ultimately lead to cellular death and total loss of electrical activity.
Hypoxic conditions do what to ATP concentrations? what are the effects of this?
Hypoxic conditions reduce intracellular concentrations of ATP. Reduced ATP decreases the activity of ATP-dependent transport systems, including the Na+/K+-ATPase pump. This pump transports K+ into the cell and Na+ out of the cell. The Na+/K+-ATPase pump is electrogenic, meaning it normally produces hyperpolarizing currents. Decreased activity therefore, causes membrane depolarization because of the loss of hyperpolarizing currents.
Moreover, loss of the Na+/K+-ATPase pump prevents K+ from being pumped back into the cell so that its extracellular concentration increases as its intracellular concentration falls. This causes membrane depolarization.
Reduced concentrations of ATP also affect the movement of K+ through KATP channels which open when there is reduced ATP. Thus, hypoxia and reduced ATP lead to an outward movement of K+, which initially can lead to hyperpolarization; however, excessive outward movement of K+ leads to an increase in extracelluar K+ and membrane depolarization.
explain how Reduced concentrations of ATP affect contractility and relaxation?
Hypoxia and reduced ATP also negatively impacts movement (“ratcheting”) between the myosin heads and the actin (see below) and calcium sequestration by the sarcoplasmic reticulum by an ATP-dependent calcium pump (SERCA, sarcoendoplasmic reticulum calcium-ATPase)
Hypoxia also results in anaerobic metabolism with the production of hydrogen ions. Intracellular H+ accumulates and activates the Na/H exchanger resulting in the exchange of Na (into the cell) for H (out of the cell). Depolarization inactivates fast Na++ channels and, as a result, decreases action potential upstroke velocity by inhibiting fast Na+ channels. Inhibiting fast sodium channels causes a decreased conduction velocity. Cellular depolarization and decreased conduction velocity contribute to arrhythmias. The reduction in ATP along with these events alter myocardial excitationcontraction coupling.
explain excitation contraction in the heart?
An action potential causes a myocyte to depolarize and calcium ions enter the cell during phase 2 of the action potential through L-type calcium channels located on the sarcolemma. This calcium triggers the release of calcium from the sarcoplasmic reticulum (SR) through calcium-release channels (“ryanodine receptors”). Calcium released by the SR increases the intracellular calcium concentration. The free calcium binds to troponin-C (TN-C) This induces a conformational change in the regulatory complex such that troponin I (TN-I) exposes a site on the actin molecule that is able to bind to the myosin ATPase located on the myosin head. This binding results in ATP hydrolysis and movement (“ratcheting”) between the myosin heads and the actin.
Ratcheting cycles occur as long as the cytosolic calcium remains elevated. At the end of phase 2, calcium entry into the cell slows and calcium is sequestered by the SR by an ATP-dependent calcium pump (SERCA, sarco-endoplasmic reticulum calciumATPase), thus lowering the cytosolic calcium concentration and removing calcium from the TN-C. Calcium is also transported out of the cell by the sodium-calcium-exchange pump and the Ca ATPase. The reduced intracellular calcium induces a conformational change in the troponin complex leading, once again, to TN-I inhibition of the actin binding site.
Explain myocardial ischemia effects on the sympathetic system?
Myocardial Ischemia also activates the sympathetic Nervous System. The sympathetic system increases inotropy (contractility) and lusitropy (relaxation).
The ischemia myocardium does what to diastolic function?
By inhibiting the Na+/K+-ATPase, hypoxia cause intracellular sodium concentration to increase. This then leads to an accumulation of intracellular calcium via the Na+-Ca++ exchange system. Hypoxia and reduced ATP also reduces activity of sarcoplasmic reticulum (SR) and plasma membrane (PM) calcium pumps. This also increases diastolic calcium levels making more calcium available to bind to troponin-C, which reduces relaxation.
An accumulation of intracellular sodium causes the sodium / calcium exchanger to work in the “reverse” mode bring more calcium into the cell.
High intracellular calcium prevents TN-I inhibition of the actin binding site.
The ischemia myocardium effects on systolic function?
The reduced ATP reduces cross bridge cycling. In addition, since less calcium is sequestered by the SR, less calcium is released. Pi and hydrogen limit Calcium binding to troponin C.
Ischemic myocardium effects on arrhythmia’s?
Decreased activity of the calcium pumps increases diastolic calcium. The increased calcium is exchanged for sodium triggering depolarization or triggered after depolarizations.
Reduced activity of the sodium potassium pump also raises membrane potential leading to conduction block and re-entry.
Norepinephrine binds to beta receptors increasing cAMP and PKA. PKA opens potassium and calcium channels leading to altered membrane excitability and arrhythmias.
explain the fick principle?
The Fick principle (Adolph Fick, 1870) can be written:
Myocardial oxygen consumption = Coronary Blood Flow X Coronary Arterial – Coronary Venous Oxygen Content (arterio-venous oxygen difference).
- About 75% of the oxygen in arterial blood is extracted as blood passes through the resting myocardium
- This means that any substantial increase in oxygen consumption must be accompanied by increased Coronary Blood Flow
increased coronary blood flow primarily results from? Caused by?
- Increased coronary blood flow primarily results from dilatation of coronary arterioles.
- Dilatation of arterioles is caused by the accumulation of metabolites including adenosine, potassium ion, CO2, and H+ as well as some paracrines including prostaglandins.
- Large distributing arteries also dilate because the increased flow brought about by dilatation of arterioles causes the endothelium of large arteries to release nitric oxide. Nitric Oxide diffuses from endothelium to smooth muscle and causes dilatation.
Explain the paracrine and endothelial factors that lead to vasoconstriction and vasodilation?
Extravascular compression during systole does what to coronary flow? with tachycardia?
Extravascular compression during systole reduces coronary flow. Most of the coronary blood flow to the left ventricle occurs during diastole because during systole the contracting myocardium compresses coronary vessels.
Because of extravascular compression, the endocardium is more susceptible to ischemia.
This is of greater importance at lower perfusion pressures.
Importantly, with tachycardia there is relatively less time available for coronary flow during diastole to occur.
what is coronary autoregulation?
Autoregulation is the intrinsic ability of an organ to maintain a constant blood flow despite changes in perfusion pressure. The autoregulatory range is the range of pressure over which there is little if any change in blood flow.
Vascular smooth muscle depolarizes when stretched. Depolarization increases calcium entry and promotes smooth muscle contraction.
Increased sympathetic nervous system activity does what?
Increased sympathetic nervous system activity increases afterload, preload, contractility and Heart Rate
What is the primary factor determining myocardial oxygen consumption? What are things increase MVO2?
Myocyte contraction is the primary factor determining myocardial oxygen consumption (MVO2). Accordingly, factors that enhance tension development by the cardiac muscle cells, the rate of tension development, or the number of tension generating cycles per unit time will increase MVO2.
For example, doubling Heart Rate approximately doubles MVO2 because ventricular myocyte generates twice the number of tension cycles per minute.
Increasing inotropy increases MVO2 because the rate of tension development is increased as well as the magnitude of tension, both of which result in increased ATP hydrolysis and oxygen consumption.
Increasing afterload (arterial pressure), because it increases tension development, also increases MVO2.
Increasing preload (e.g., ventricular end-diastolic volume) also increases MVO2; however, the increase is much less than what might be expected because of the LaPlace relationship.
Explain wall tension? increasing Ventricular volume increases wall tension how? Increasing intraventricular pressure by 100% does what to wall tension?
The LaPlace relationship says that wall tension (T) is proportional to the product of intraventricular pressure (P) and ventricular radius (r).
Wall tension is the tension generated by myocytes that results in a given intraventricular pressure at a particular ventricular radius. Therefore, when the ventricle needs to generate greater pressure, for example with increased afterload or inotropic stimulation, the wall tension is increased. In addition, a dilated ventricle (as occurs in dilated cardiomyopathy) must generate increased wall tension to produce the same intraventricular pressure.
Ventricular preload volume does not affect MVO2 to the same extent as changes in afterload. This is because preload is usually expressed as the ventricular end-diastolic volume. Because the ventricle is a sphere with many radii, the radius does not proportionally effect MVO2.
Thus a 100% increase in ventricular volume (V) increases wall tension (T) by only
26%.
In contrast, increasing intraventricular pressure (P) by 100% increases wall tension (T) by 100%.
Increasing heart rate, aortic pressure, inotropy, does what to MVO2? With myocardial hypertrophy force development is? this does what?
In summary, increasing heart rate, aortic pressure, inotropy, increase MVO2 about 4-times more than an equivalent percent change in stroke volume.
With myocardial hypertrophy, force development is spread over more sarcomeres, reducing the load on any one sarcomere. This reduces the oxygen requirements of any one sarcomere. However: with hypertrophy, growth of blood vessels does not keep pace with growth of cardiac cells and the demand for oxygen increases out of proportion with capacity to supply oxygen.
What is ischemic heart disease?
IHD comprises a series of clinical syndromes whose evolution is due to chronic ischemia. IHD is the leading cause of death in the US, and so prevention, screening, and therapeutics are of course actively engaged across the medical system.
At its core, IHD is an imbalance between myocardial demand and actual myocardial perfusion, resulting over time in myocardial (myocyte) cell injury, potential cell death, tissue repair, and states of new cardiac functioning/homeostasis.
What are the etiologies of the perfusion imbalance in ischemic heart disease?
The etiologies of the perfusion imbalance:
- Atherosclerosis: 90%+ of IHD is due to atherosclerotic narrowing of the (medium-sized) coronary arteries, so much so that another name for IHD is coronary artery disease (CAD). Atherosclerosis involves the coronary arteries most prominently at their takeoffs and extends for a certain distance. As in the schematic, when present enough to cause symptoms of IHD, often all three arteries will be affected to a reasonable degree, and quantifying their relative occlusion will help guide therapies, stratify immediate risk, etc.
- Vasospasm: recall that vessels can undergo uncoordinated contraction sequences in response to unknown factors, resulting in generally less blood flow at somewhat unpredictable times. One of the known factors that can induce vasospasm is the presence of atherosclerosis.
- Vasculitis: inflammation affecting the coronary arteries will impact their function.
- Emboli: physical occlusion of coronary arteries by emboli of any type is problematic
what are the clinical symptoms of myocardial ischemia?
- angina, which can further evolve into myocardial infarction
- sudden cardiac death (may or may not be related to some degree of infarction)
- chronic ischemic heart disease
Stable angina happens with what?
This most common form occurs when over (roughly) 75% atherosclerotic occlusion is present (see image) and the patient is asymptomatic at rest, but then increased demand becomes necessary and it’s unable to be met.
Unstable or cresendo angina happens when what pathology happens?
Chest pain at rest can evolve when the atherosclerotic plaque becomes so severe that demand outstrips perfusion when no activity is occurring and/or plaque complexity/plaque rupture/vessel vasospasm causes severe occlusion. In the right panel below, plaque rupture has caused thrombus formation, which is causing near total occlusion (arrow). The chest pain of unstable angina may change in quality, location, or duration (vs. stable angina). These patients are at high risk for further evolution towards infarction.
Prinzmetal angina is usually due to?
Prinzmetal (variant) angina – this uncommon form of chest pain is unrelated to physical activity, can even occur when sleeping, is usually due to vasospasm, and is readily relieved by vasodilator therapy.
Truism in biology… vasospasm leads to clinical symptoms in affected vessels, and named diseases, such as migraine headaches, Raynaud phenomena, variant angina, etc.
Classic symptoms of MI?
These days, patients with chest pain are evaluated in a systematic manner to rule in/out an MI: history, physical exam, ECG findings, and serologic evidence of myocyte death. Classic symptomatology starts the evaluation:
- chest pain of longer duration (often >30 minutes)
- chest pain of a different quality (stabbing, sharp, crushing)
- rapid and/or weak pulse
- sweating (sometimes profuse)
- nausea and/or vomiting
- dyspnea as backflow congestion into pulmonary vessels occurs
- asymptomatic (such as in diabetes)
Treatment strategy of MI?
Of course, prompt reperfusion is desired in order to limit damage and/or salvage as many myocytes as possible.
Truism… Injury to cells the duration or severity pushes past tipping point leads to irreversible cell injury/cell death
Hour 1.5 to 4 of ischemia in the heart will show what gross findings? histopathology? Clinical correlations?
4-12 hours of myocardial ischemia will show what gross findings? Histopathology? Clinial findings?
12- 24 hours after myocardial ischemia what are the gross, histopathological, and clinical correlations?
1-3 days after myocardial infarction shows what histopathological findings and clinical correlates?
what does this image show?
This micro image is an infarct at 48 hours duration, and at this point, the predominant findings are coagulative necrosis (notice there are no myocyte nuclei visible, just myocyte ghost cells) and a neutrophilic infiltrate.
At 3-7 days what are the gross, histopathological, and clinical features of myocardial ischemia?
what are the histopathological findings seen at 7-10 days post myocardial ischemia?
10-14 days post myocardial ischemia we see what histopathological and clinical correlates?
At about 10 days (although beginning much earlier), well-developed granulation tissue and angiogenesis can be seen. Marginal myocytes that were destined to live now are appearing more normal, and can be seen at the edge of the irreversibly injured myocytes
2-8 weeks after myocardial ischemia what is gross, histopathologic, and clinical correlates we see?
After a few to several weeks, the infarcted region becomes collagenized during the wound healing process of scar. In the micro image stained with trichrome, new but incomplete collagen is being laid down and will fill in the space left by the intensive macrophage phagocytosis. Eventually the collagen will mature, contract, and fill in the space completely. It will also interdigitate at its edges with viable myocytes. After several weeks (such as gross image above), the lesion takes on the appearance of what is called a ‘remote’ infarct – cell death that happened in the past, and the further in the past it becomes, the less one can tell when it originally occurred.
